AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.

AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.

AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

Limitations of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].

AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.

AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

AFINITOR and AFINITOR DISPERZ® are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

The recommended starting dosage of AFINITOR/AFINITOR DISPERZ is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

The recommended starting dosage of AFINITOR DISPERZ is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

New dose* = current dose x (target concentration divided by current concentration)

*The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration.

<div class="scrollingtable"><table> <caption> <span>Table 1: Recommended Timing of Therapeutic Drug Monitoring</span> </caption> <col width="450"/> <col width="300"/> <tfoot> <tr class="First Last"> <td colspan="2">Abbreviation: P-gp, P-glycoprotein.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Toprule"><span class="Bold">Event</span></td><td align="center" class="Toprule"><span class="Bold">When to Assess Trough<br/> Concentrations After Event</span></td> </tr> <tr> <td class="Toprule"> Initiation of AFINITOR/AFINITOR DISPERZ</td><td align="center" class="Toprule">1 to 2 weeks</td> </tr> <tr> <td> Modification of AFINITOR/AFINITOR DISPERZ dose</td><td align="center">1 to 2 weeks</td> </tr> <tr> <td> Switch between AFINITOR and AFINITOR DISPERZ</td><td align="center">1 to 2 weeks</td> </tr> <tr> <td> Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor</td><td align="center">2 weeks</td> </tr> <tr> <td> Initiation or discontinuation of P-gp and strong CYP3A4 inducer</td><td align="center">2 weeks</td> </tr> <tr> <td> Change in hepatic function</td><td align="center">2 weeks</td> </tr> <tr> <td> Stable dose with changing body surface area (BSA)</td><td align="center">Every 3 to 6 months</td> </tr> <tr class="Last"> <td> Stable dose with stable BSA</td><td align="center">Every 6 to 12 months</td> </tr> </tbody> </table></div>

Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions.

<div class="scrollingtable"><table> <caption> <span>Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ for Adverse Reactions</span> </caption> <col width="300"/> <col width="300"/> <col width="450"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Toprule"><span class="Bold">Adverse Reaction</span></td><td align="left" class="Toprule"><span class="Bold">Severity</span></td><td align="left" class="Toprule"><span class="Bold">Dosage Modification </span></td> </tr> <tr> <td class="Toprule" valign="top"> Non-infectious<br/> pneumonitis<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.1)]</span></td><td align="left" class="Toprule" valign="top">Grade 2</td><td align="left" class="Toprule">Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/> Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.<br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 3</td><td align="left">Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/>If toxicity recurs at Grade 3, permanently discontinue.<br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Permanently discontinue.</td> </tr> <tr> <td class="Toprule" valign="top"> Stomatitis<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.5)]</span></td><td align="left" class="Toprule" valign="top">Grade 2</td><td align="left" class="Toprule">Withhold until improvement to Grade 0 or 1. Resume at same dose.<br/> If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. <br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 3</td><td align="left">Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Permanently discontinue.</td> </tr> <tr> <td class="Toprule" valign="top"> Metabolic events<br/> (e.g., hyperglycemia,<br/> dyslipidemia)<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.9)]</span></td><td align="left" class="Toprule" valign="top">Grade 3</td><td align="left" class="Toprule" valign="top">Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Permanently discontinue.</td> </tr> <tr> <td class="Toprule" valign="top"> Other non-hematologic<br/> toxicities<br/> </td><td align="left" class="Toprule" valign="top">Grade 2</td><td align="left" class="Toprule">If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose.<br/> If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 3</td><td align="left">Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/>If recurs at Grade 3, permanently discontinue.<br/> <br/> </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Permanently discontinue.</td> </tr> <tr> <td class="Toprule" valign="top"> Thrombocytopenia<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.10)]</span></td><td align="left" class="Toprule" valign="top">Grade 2</td><td align="left" class="Toprule" valign="top">Withhold until improvement to Grade 0 or 1. Resume at same dose. </td> </tr> <tr> <td></td><td align="left">Grade 3<br/>   <span class="Bold">OR</span> <br/> Grade 4</td><td align="left">Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.</td> </tr> <tr> <td class="Toprule" valign="top"> Neutropenia<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.10)]</span></td><td align="left" class="Toprule" valign="top">Grade 3</td><td align="left" class="Toprule" valign="top">Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. </td> </tr> <tr> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.</td> </tr> <tr> <td class="Toprule" valign="top"> Febrile neutropenia<br/> <span class="Italics">[see Warnings and<br/> Precautions (5.10)]</span></td><td align="left" class="Toprule" valign="top">Grade 3</td><td align="left" class="Toprule">Withhold until improvement to Grade 0, 1, or 2, and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.<br/> <br/> </td> </tr> <tr class="Last"> <td></td><td align="left" valign="top">Grade 4</td><td align="left">Permanently discontinue.</td> </tr> </tbody> </table></div>

The recommended dosages of AFINITOR/AFINITOR DISPERZ for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]:

<div class="scrollingtable"><table> <caption> <span>Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment</span> </caption> <col width="450"/> <col width="450"/> <tfoot> <tr class="First Last"> <td colspan="3">Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Indication</span></td><td align="center" class="Toprule"><span class="Bold">Dose Modification for AFINITOR/AFINITOR DISPERZ</span></td> </tr> <tr> <td class="Toprule" valign="top"> Breast Cancer, NET, RCC, and<br/> TSC-Associated Renal<br/> Angiomyolipoma </td><td class="Toprule"> <ul> <li>Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated.</li> <li>Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated.</li> <li>Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. </li> </ul> </td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> TSC-Associated SEGA and TSC-<br/>Associated Partial-Onset Seizures </td><td class="Toprule" valign="top"> <ul> <li>Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m<span class="Sup">2</span> orally once daily.</li> <li>Adjust dose based on everolimus trough concentrations as recommended <span class="Italics">[see Dosage and Administration (2.8)]</span>.</li> </ul> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table> <caption> <span>Table 4: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ With a P-gp and Moderate CYP3A4 Inhibitor</span> </caption> <col width="450"/> <col width="450"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Indication</span></td><td align="center" class="Toprule"><span class="Bold">Dose Modification for AFINITOR/AFINITOR DISPERZ</span></td> </tr> <tr> <td class="Toprule" valign="top"> Breast Cancer, NET, RCC, and<br/> TSC-Associated Renal<br/> Angiomyolipoma </td><td class="Toprule"> <ul> <li>Reduce dose to 2.5 mg once daily.</li> <li>May increase dose to 5 mg once daily if tolerated.</li> <li>Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.</li> </ul> </td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> TSC-Associated SEGA and TSC-<br/>Associated Partial-Onset Seizures </td><td class="Toprule"> <ul> <li>Reduce the daily dose by 50%.</li> <li>Change to every other day dosing if the reduced dose is lower than the lowest available strength.</li> <li>Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.</li> <li>Assess trough concentrations when initiating and discontinuing the inhibitor <span class="Italics">[see Dosage and Administration (2.8)]</span>.</li> </ul> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table> <caption> <span>Table 5: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ With P-gp and Strong CYP3A4 Inducers</span> </caption> <col width="450"/> <col width="450"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Indication</span></td><td align="center" class="Toprule"><span class="Bold">Dose Modification for AFINITOR/AFINITOR DISPERZ</span></td> </tr> <tr> <td class="Toprule" valign="top"> Breast Cancer, NET, RCC, and<br/> TSC-Associated Renal<br/> Angiomyolipoma </td><td class="Toprule"> <ul> <li>Avoid coadministration where alternatives exist.</li> <li>If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. </li> <li>Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.</li> </ul> </td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> TSC-Associated SEGA and TSC-<br/>Associated Partial-Onset Seizures </td><td class="Toprule"> <ul> <li>Double the daily dose using increments of 5 mg or less. Multiple increments may be required.</li> <li>Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification.</li> <li>Assess trough concentrations when initiating and discontinuing the inducer <span class="Italics">[see Dosage and Administration (2.8)]</span>.</li> <li>Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. </li> </ul> </td> </tr> </tbody> </table></div>

AFINITOR

AFINITOR DISPERZ

Using an Oral Syringe to Prepare Oral Suspension:

Using a Small Drinking Glass to Prepare Oral Suspension:

AFINITOR

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Tablets, white to slightly yellow and elongated with a bevelled edge:

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AFINITOR DISPERZ

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Tablets for oral suspension, white to slightly yellowish, round, and flat with a bevelled edge:

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AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3)].

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Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections, such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms.

Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis.

For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)]. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.

AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4)].

Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection [see Dosage and Administration (2.9)].

Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4)]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking AFINITOR with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1)]. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)]. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed.

Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ [see Adverse Reactions (6.1)]. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ have the potential to adversely affect wound healing.

Withhold AFINITOR/AFINITOR DISPERZ for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.

In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.9), Use in Specific Populations (8.5)].

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1)]. In non-diabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For Grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1)]. Monitor complete blood count (CBC) prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment [see Adverse Reactions (6.2)].

Monitor patients closely when AFINITOR/AFINITOR DISPERZ is administered during or sequentially with radiation treatment.

Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Hormone Receptor-Positive, HER2-Negative Breast Cancer

The safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were white. The median follow-up was approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks.

<div class="scrollingtable"><table> <caption> <span>Table 6: Adverse Reactions Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2</span> </caption> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration.<br/> <span class="Sup">b</span>Includes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.<br/> <span class="Sup">c</span>Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. <br/> <span class="Sup">d</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR with Exemestane</span> <br/> <span class="Bold">N = 482</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo with Exemestane </span> <br/> <span class="Bold">N = 238</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">67</td><td align="center">8<span class="Sup">d</span></td><td align="center">11</td><td align="center">0.8</td> </tr> <tr> <td>       Diarrhea</td><td align="center">33</td><td align="center">2</td><td align="center">18</td><td align="center">0.8</td> </tr> <tr> <td>       Nausea</td><td align="center">29</td><td align="center">0.4</td><td align="center">28</td><td align="center">1</td> </tr> <tr> <td>       Vomiting</td><td align="center">17</td><td align="center">1</td><td align="center">12</td><td align="center">0.8</td> </tr> <tr> <td>       Constipation</td><td align="center">14</td><td align="center">0.4<span class="Sup">d</span></td><td align="center">13</td><td align="center">0.4</td> </tr> <tr> <td>       Dry mouth</td><td align="center">11</td><td align="center">0</td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Fatigue</td><td align="center">36</td><td align="center">4</td><td align="center">27</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Edema peripheral</td><td align="center">19</td><td align="center">1<span class="Sup">d</span></td><td align="center">6</td><td align="center">0.4<span class="Sup">d</span></td> </tr> <tr> <td>       Pyrexia</td><td align="center">15</td><td align="center">0.2<span class="Sup">d</span></td><td align="center">7</td><td align="center">0.4<span class="Sup">d</span></td> </tr> <tr> <td>       Asthenia</td><td align="center">13</td><td align="center">2</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Infections<span class="Sup">b</span></td><td align="center">50</td><td align="center">6</td><td align="center">25</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Investigations</span></td> </tr> <tr> <td>       Weight loss</td><td align="center">25</td><td align="center">1<span class="Sup">d</span></td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Metabolism and nutrition</span></td> </tr> <tr> <td>       Decreased appetite</td><td align="center">30</td><td align="center">1<span class="Sup">d</span></td><td align="center">12</td><td align="center">0.4<span class="Sup">d</span></td> </tr> <tr> <td>       Hyperglycemia</td><td align="center">14</td><td align="center">5</td><td align="center">2</td><td align="center">0.4<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Musculoskeletal and connective tissue</span></td> </tr> <tr> <td>       Arthralgia</td><td align="center">20</td><td align="center">0.8<span class="Sup">d</span></td><td align="center">17</td><td align="center">0</td> </tr> <tr> <td>       Back pain</td><td align="center">14</td><td align="center">0.2<span class="Sup">d</span></td><td align="center">10</td><td align="center">0.8<span class="Sup">d</span></td> </tr> <tr> <td>       Pain in extremity</td><td align="center">9</td><td align="center">0.4<span class="Sup">d</span></td><td align="center">11</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Nervous system</span></td> </tr> <tr> <td>       Dysgeusia</td><td align="center">22</td><td align="center">0.2<span class="Sup">d</span></td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td>       Headache</td><td align="center">21</td><td align="center">0.4<span class="Sup">d</span></td><td align="center">14</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Psychiatric</span></td> </tr> <tr> <td>       Insomnia</td><td align="center">13</td><td align="center">0.2<span class="Sup">d</span></td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough</td><td align="center">24</td><td align="center">0.6<span class="Sup">d</span></td><td align="center">12</td><td align="center">0</td> </tr> <tr> <td>       Dyspnea</td><td align="center">21</td><td align="center">4</td><td align="center">11</td><td align="center">1</td> </tr> <tr> <td>       Epistaxis</td><td align="center">17</td><td align="center">0</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td>       Pneumonitis<span class="Sup">c</span></td><td align="center">19</td><td align="center">4</td><td align="center">0.4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous tissue</span></td> </tr> <tr> <td>       Rash</td><td align="center">39</td><td align="center">1<span class="Sup">d</span></td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td>       Pruritus</td><td align="center">13</td><td align="center">0.2<span class="Sup">d</span></td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Alopecia</td><td align="center">10</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Vascular</span></td> </tr> <tr class="Last"> <td>       Hot flush</td><td align="center">6</td><td align="center">0</td><td align="center">14</td><td align="center">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table> <caption> <span>Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2</span> </caption> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.<br/> <span class="Sup">b</span>No Grade 4 laboratory abnormalities were reported.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Laboratory Parameter</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR with Exemestane</span> <br/> <span class="Bold">N = 482</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo with Exemestane </span> <br/> <span class="Bold">N = 238</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology<span class="Sup">a</span></span></td> </tr> <tr> <td>       Anemia</td><td align="center">68</td><td align="center">6</td><td align="center">40</td><td align="center">1</td> </tr> <tr> <td>       Leukopenia</td><td align="center">58</td><td align="center">2<span class="Sup">b</span></td><td align="center">28</td><td align="center">6</td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">54</td><td align="center">3</td><td align="center">5</td><td align="center">0.4</td> </tr> <tr> <td>       Lymphopenia</td><td align="center">54</td><td align="center">12</td><td align="center">37</td><td align="center">6</td> </tr> <tr> <td>       Neutropenia</td><td align="center">31</td><td align="center">2<span class="Sup">b</span></td><td align="center">11</td><td align="center">2</td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">70</td><td align="center">1</td><td align="center">38</td><td align="center">2</td> </tr> <tr> <td>       Hyperglycemia</td><td align="center">69</td><td align="center">9</td><td align="center">44</td><td align="center">1</td> </tr> <tr> <td>       Increased AST</td><td align="center">69</td><td align="center">4</td><td align="center">45</td><td align="center">3</td> </tr> <tr> <td>       Increased ALT</td><td align="center">51</td><td align="center">4</td><td align="center">29</td><td align="center">5<span class="Sup">b</span></td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">50</td><td align="center">0.8<span class="Sup">b</span></td><td align="center">26</td><td align="center">0</td> </tr> <tr> <td>       Hypoalbuminemia</td><td align="center">33</td><td align="center">0.8<span class="Sup">b</span></td><td align="center">16</td><td align="center">0.8<span class="Sup">b</span></td> </tr> <tr> <td>       Hypokalemia</td><td align="center">29</td><td align="center">4</td><td align="center">7</td><td align="center">1<span class="Sup">b</span></td> </tr> <tr class="Last"> <td>       Increased creatinine </td><td align="center">24</td><td align="center">2</td><td align="center">13</td><td align="center">0</td> </tr> </tbody> </table></div>

Topical Prophylaxis for Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5 mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with AFINITOR and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.

Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Pancreatic Neuroendocrine Tumors (PNET)

In a randomized, controlled trial (RADIANT-3) of AFINITOR (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were white, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia.

Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks.

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females.

<div class="scrollingtable"><table> <caption> <span>Table 8: Adverse Reactions Reported in ≥ 10% of Patients With PNET in RADIANT-3</span> </caption> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.<br/> <span class="Sup">b</span>Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.<br/> <span class="Sup">c</span>Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease.<br/> <span class="Sup">d</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 204</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 203</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">70</td><td align="center">7<span class="Sup">d</span></td><td align="center">20</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea<span class="Sup">b</span></td><td align="center">50</td><td align="center">6</td><td align="center">25</td><td align="center">3<span class="Sup">d</span></td> </tr> <tr> <td>       Abdominal pain</td><td align="center">36</td><td align="center">4<span class="Sup">d</span></td><td align="center">32</td><td align="center">7</td> </tr> <tr> <td>       Nausea</td><td align="center">32</td><td align="center">2<span class="Sup">d</span></td><td align="center">33</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td>       Vomiting</td><td align="center">29</td><td align="center">1<span class="Sup">d</span></td><td align="center">21</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td>       Constipation</td><td align="center">14</td><td align="center">0</td><td align="center">13</td><td align="center">0.5<span class="Sup">d</span></td> </tr> <tr> <td>       Dry mouth</td><td align="center">11</td><td align="center">0</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Fatigue/malaise</td><td align="center">45</td><td align="center">4</td><td align="center">27</td><td align="center">3</td> </tr> <tr> <td>       Edema (general and peripheral)</td><td align="center">39</td><td align="center">2</td><td align="center">12</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Fever </td><td align="center">31</td><td align="center">1</td><td align="center">13</td><td align="center">0.5<span class="Sup">d</span></td> </tr> <tr> <td>       Asthenia</td><td align="center">19</td><td align="center">3<span class="Sup">d</span></td><td align="center">20</td><td align="center">3<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Nasopharyngitis/rhinitis/URI</td><td align="center">25</td><td align="center">0</td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td>       Urinary tract infection</td><td align="center">16</td><td align="center">0</td><td align="center">6</td><td align="center">0.5<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Investigations</span></td> </tr> <tr> <td>       Weight loss</td><td align="center">28</td><td align="center">0.5<span class="Sup">d</span></td><td align="center">11</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Metabolism and nutrition</span></td> </tr> <tr> <td>       Decreased appetite</td><td align="center">30</td><td align="center">1<span class="Sup">d</span></td><td align="center">18</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Diabetes mellitus</td><td align="center">10</td><td align="center">2<span class="Sup">d</span></td><td align="center">0.5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Musculoskeletal and connective tissue</span></td> </tr> <tr> <td>       Arthralgia</td><td align="center">15</td><td align="center">1</td><td align="center">7</td><td align="center">0.5<span class="Sup">d</span></td> </tr> <tr> <td>       Back pain</td><td align="center">15</td><td align="center">1<span class="Sup">d</span></td><td align="center">11</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Pain in extremity</td><td align="center">14</td><td align="center">0.5<span class="Sup">d</span></td><td align="center">6</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Muscle spasms</td><td align="center">10</td><td align="center">0</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Nervous system</span></td> </tr> <tr> <td>       Headache/migraine</td><td align="center">30</td><td align="center">0.5<span class="Sup">d</span></td><td align="center">15</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Dysgeusia</td><td align="center">19</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Dizziness</td><td align="center">12</td><td align="center">0.5<span class="Sup">d</span></td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Psychiatric</span></td> </tr> <tr> <td>       Insomnia</td><td align="center">14</td><td align="center">0</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough/productive cough</td><td align="center">25</td><td align="center">0.5<span class="Sup">d</span></td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td>       Epistaxis</td><td align="center">22</td><td align="center">0</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td>       Dyspnea/dyspnea exertional</td><td align="center">20</td><td align="center">3</td><td align="center">7</td><td align="center">0.5<span class="Sup">d</span></td> </tr> <tr> <td>       Pneumonitis<span class="Sup">c</span></td><td align="center">17</td><td align="center">4</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td>       Oropharyngeal pain</td><td align="center">11</td><td align="center">0</td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous</span></td> </tr> <tr> <td>       Rash</td><td align="center">59</td><td align="center">0.5</td><td align="center">19</td><td align="center">0</td> </tr> <tr> <td>       Nail disorders</td><td align="center">22</td><td align="center">0.5</td><td align="center">2</td><td align="center">0</td> </tr> <tr> <td>       Pruritus/pruritus generalized</td><td align="center">21</td><td align="center">0</td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td>       Dry skin/xeroderma</td><td align="center">13</td><td align="center">0</td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Vascular</span></td> </tr> <tr class="Last"> <td>       Hypertension</td><td align="center">13</td><td align="center">1</td><td align="center">6</td><td align="center">1<span class="Sup">d</span></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table> <caption> <span>Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With PNET in RADIANT-3</span> </caption> <col width="384"/> <col width="140"/> <col width="133"/> <col width="128"/> <col width="124"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Laboratory parameter</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 204</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 203</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology</span></td> </tr> <tr> <td>       Anemia</td><td align="center">86</td><td align="center">15</td><td align="center">63</td><td align="center">1</td> </tr> <tr> <td>       Lymphopenia</td><td align="center">45</td><td align="center">16</td><td align="center">22</td><td align="center">4</td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">45</td><td align="center">3</td><td align="center">11</td><td align="center">0</td> </tr> <tr> <td>       Leukopenia</td><td align="center">43</td><td align="center">2</td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td>       Neutropenia</td><td align="center">30</td><td align="center">4</td><td align="center">17</td><td align="center">2</td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hyperglycemia (fasting)</td><td align="center">75</td><td align="center">17</td><td align="center">53</td><td align="center">6</td> </tr> <tr> <td>       Increased alkaline phosphatase</td><td align="center">74</td><td align="center">8</td><td align="center">66</td><td align="center">8</td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">66</td><td align="center">0.5</td><td align="center">22</td><td align="center">0</td> </tr> <tr> <td>       Bicarbonate decreased</td><td align="center">56</td><td align="center">0</td><td align="center">40</td><td align="center">0</td> </tr> <tr> <td>       Increased AST</td><td align="center">56</td><td align="center">4</td><td align="center">41</td><td align="center">4</td> </tr> <tr> <td>       Increased ALT</td><td align="center">48</td><td align="center">2</td><td align="center">35</td><td align="center">2</td> </tr> <tr> <td>       Hypophosphatemia</td><td align="center">40</td><td align="center">10</td><td align="center">14</td><td align="center">3</td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">39</td><td align="center">0</td><td align="center">10</td><td align="center">0</td> </tr> <tr> <td>       Hypocalcemia</td><td align="center">37</td><td align="center">0.5</td><td align="center">12</td><td align="center">0</td> </tr> <tr> <td>       Hypokalemia</td><td align="center">23</td><td align="center">4</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Increased creatinine </td><td align="center">19</td><td align="center">2</td><td align="center">14</td><td align="center">0</td> </tr> <tr> <td>       Hyponatremia</td><td align="center">16</td><td align="center">1</td><td align="center">16</td><td align="center">1</td> </tr> <tr> <td>       Hypoalbuminemia</td><td align="center">13</td><td align="center">1</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Hyperbilirubinemia</td><td align="center">10</td><td align="center">1</td><td align="center">14</td><td align="center">2</td> </tr> <tr class="Last"> <td>       Hyperkalemia</td><td align="center">7</td><td align="center">0</td><td align="center">10</td><td align="center">0.5</td> </tr> </tbody> </table></div>

Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin

In a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were white, and 53% were female. The median duration of exposure to AFINITOR was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients.

Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at ≥ 5% absolute incidence over placebo (all Grades) or ≥ 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11.

<div class="scrollingtable"><table> <caption> <span>Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4</span> </caption> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 4.03.<br/> <span class="Sup">a</span>Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation.<br/> <span class="Sup">b</span>Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.<br/> <span class="Sup">c</span>Includes pneumonitis and interstitial lung disease.<br/> <span class="Sup">d</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 202</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 98</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">63</td><td align="center">9<span class="Sup">d</span></td><td align="center">22</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea</td><td align="center">41</td><td align="center">9</td><td align="center">31</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td>       Nausea</td><td align="center">26</td><td align="center">3</td><td align="center">17</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Vomiting</td><td align="center">15</td><td align="center">4<span class="Sup">d</span></td><td align="center">12</td><td align="center">2<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Peripheral edema</td><td align="center">39</td><td align="center">3<span class="Sup">d</span></td><td align="center">6</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Fatigue</td><td align="center">37</td><td align="center">5</td><td align="center">36</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td>       Asthenia</td><td align="center">23</td><td align="center">3</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Pyrexia</td><td align="center">23</td><td align="center">2</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Infections<span class="Sup">b</span></td><td align="center">58</td><td align="center">11</td><td align="center">29</td><td align="center">2</td> </tr> <tr> <td colspan="5"><span class="Bold">Investigations</span></td> </tr> <tr> <td>       Weight loss</td><td align="center">22</td><td align="center">2<span class="Sup">d</span></td><td align="center">11</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Metabolism and nutrition</span></td> </tr> <tr> <td>       Decreased appetite</td><td align="center">22</td><td align="center">1<span class="Sup">d</span></td><td align="center">17</td><td align="center">1<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Nervous system</span></td> </tr> <tr> <td>       Dysgeusia</td><td align="center">18</td><td align="center">1<span class="Sup">d</span></td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough</td><td align="center">27</td><td align="center">0</td><td align="center">20</td><td align="center">0</td> </tr> <tr> <td>       Dyspnea</td><td align="center">20</td><td align="center">3<span class="Sup">d</span></td><td align="center">11</td><td align="center">2</td> </tr> <tr> <td>       Pneumonitis<span class="Sup">c</span></td><td align="center">16</td><td align="center">2<span class="Sup">d</span></td><td align="center">2</td><td align="center">0</td> </tr> <tr> <td>       Epistaxis</td><td align="center">13</td><td align="center">1<span class="Sup">d</span></td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous</span></td> </tr> <tr> <td>       Rash</td><td align="center">30</td><td align="center">1<span class="Sup">d</span></td><td align="center">9</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Pruritus</td><td align="center">17</td><td align="center">1<span class="Sup">d</span></td><td align="center">9</td><td align="center">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table> <caption> <span>Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4</span> </caption> <col width="384"/> <col width="140"/> <col width="133"/> <col width="128"/> <col width="124"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 4.03.<br/> <span class="Sup">a</span>No Grade 4 laboratory abnormalities were reported.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 202</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 98</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology</span></td> </tr> <tr> <td>       Anemia</td><td align="center">81</td><td align="center">5<span class="Sup">a</span></td><td align="center">41</td><td align="center">2<span class="Sup">a</span></td> </tr> <tr> <td>       Lymphopenia</td><td align="center">66</td><td align="center">16</td><td align="center">32</td><td align="center">2<span class="Sup">a</span></td> </tr> <tr> <td>       Leukopenia</td><td align="center">49</td><td align="center">2<span class="Sup">a</span></td><td align="center">17</td><td align="center">0</td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">33</td><td align="center">2</td><td align="center">11</td><td align="center">0</td> </tr> <tr> <td>       Neutropenia</td><td align="center">32</td><td align="center">2<span class="Sup">a</span></td><td align="center">15</td><td align="center">3<span class="Sup">a</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">71</td><td align="center">0</td><td align="center">37</td><td align="center">0</td> </tr> <tr> <td>       Increased AST</td><td align="center">57</td><td align="center">2</td><td align="center">34</td><td align="center">2<span class="Sup">a</span></td> </tr> <tr> <td>       Hyperglycemia (fasting)</td><td align="center">55</td><td align="center">6<span class="Sup">a</span></td><td align="center">36</td><td align="center">1<span class="Sup">a</span></td> </tr> <tr> <td>       Increased ALT</td><td align="center">46</td><td align="center">5</td><td align="center">39</td><td align="center">1<span class="Sup">a</span></td> </tr> <tr> <td>       Hypophosphatemia</td><td align="center">43</td><td align="center">4<span class="Sup">a</span></td><td align="center">15</td><td align="center">2<span class="Sup">a</span></td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">30</td><td align="center">3</td><td align="center">8</td><td align="center">1<span class="Sup">a</span></td> </tr> <tr> <td>       Hypokalemia</td><td align="center">27</td><td align="center">6</td><td align="center">12</td><td align="center">3<span class="Sup">a</span></td> </tr> <tr class="Last"> <td>       Hypoalbuminemia</td><td align="center">18</td><td align="center">0</td><td align="center">8</td><td align="center">0</td> </tr> </tbody> </table></div>

Renal Cell Carcinoma (RCC)

The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were white, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia.

Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13.

<div class="scrollingtable"><table> <caption> <span>Table 12: Adverse Reactions Reported in ≥ 10% of Patients With RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm in RECORD-1</span> </caption> <col width="150"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.<br/> <span class="Sup">b</span>Includes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.<br/> <span class="Sup">c</span>Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.<br/> <span class="Sup">d</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 274</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 137</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">44</td><td align="center">4</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea</td><td align="center">30</td><td align="center">2<span class="Sup">d</span></td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td>       Nausea</td><td align="center">26</td><td align="center">2<span class="Sup">d</span></td><td align="center">19</td><td align="center">0</td> </tr> <tr> <td>       Vomiting</td><td align="center">20</td><td align="center">2<span class="Sup">d</span></td><td align="center">12</td><td align="center">0</td> </tr> <tr> <td><span class="Bold">Infections<span class="Sup">b</span></span></td><td align="center">37</td><td align="center">10</td><td align="center">18</td><td align="center">2</td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Asthenia</td><td align="center">33</td><td align="center">4</td><td align="center">23</td><td align="center">4</td> </tr> <tr> <td>       Fatigue</td><td align="center">31</td><td align="center">6<span class="Sup">d</span></td><td align="center">27</td><td align="center">4</td> </tr> <tr> <td>       Edema peripheral</td><td align="center">25</td><td align="center">&lt; 1<span class="Sup">d</span></td><td align="center">8</td><td align="center">&lt; 1<span class="Sup">d</span></td> </tr> <tr> <td>       Pyrexia</td><td align="center">20</td><td align="center">&lt; 1<span class="Sup">d</span></td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td>       Mucosal inflammation</td><td align="center">19</td><td align="center">2<span class="Sup">d</span></td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough</td><td align="center">30</td><td align="center">&lt; 1<span class="Sup">d</span></td><td align="center">16</td><td align="center">0</td> </tr> <tr> <td>       Dyspnea</td><td align="center">24</td><td align="center">8</td><td align="center">15</td><td align="center">3<span class="Sup">d</span></td> </tr> <tr> <td>       Epistaxis</td><td align="center">18</td><td align="center">0</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td>       Pneumonitis<span class="Sup">c</span></td><td align="center">14</td><td align="center">4<span class="Sup">d</span></td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous tissue </span></td> </tr> <tr> <td>       Rash</td><td align="center">29</td><td align="center">1<span class="Sup">d</span></td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td>       Pruritus</td><td align="center">14</td><td align="center">&lt; 1<span class="Sup">d</span></td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td>       Dry skin</td><td align="center">13</td><td align="center">&lt; 1<span class="Sup">d</span></td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Metabolism and nutrition</span></td> </tr> <tr> <td>       Anorexia</td><td align="center">25</td><td align="center">2<span class="Sup">d</span></td><td align="center">14</td><td align="center">&lt; 1<span class="Sup">d</span></td> </tr> <tr> <td colspan="5"><span class="Bold">Nervous system</span></td> </tr> <tr> <td>       Headache</td><td align="center">19</td><td align="center">1</td><td align="center">9</td><td align="center">&lt; 1<span class="Sup">d</span></td> </tr> <tr> <td>       Dysgeusia</td><td align="center">10</td><td align="center">0</td><td align="center">2</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Musculoskeletal and connective tissue</span></td> </tr> <tr class="Last"> <td>       Pain in extremity</td><td align="center">10</td><td align="center">1<span class="Sup">d</span></td><td align="center">7</td><td align="center">0</td> </tr> </tbody> </table></div>

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:

      Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

      General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)

      Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

      Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%)

      Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)

      Psychiatric: Insomnia (9%)

      Nervous system: Dizziness (7%), paresthesia (5%)

      Ocular: Eyelid edema (4%), conjunctivitis (2%)

      Vascular: Hypertension (4%), deep vein thrombosis (< 1%)

      Renal and urinary: Renal failure (3%)

      Cardiac: Tachycardia (3%), congestive cardiac failure (1%)

      Musculoskeletal and connective tissue: Jaw pain (3%)

      Hematologic: Hemorrhage (3%)

<div class="scrollingtable"><table> <caption> <span>Table 13: Selected Laboratory Abnormalities Reported in Patients With RCC at a Higher Rate in the AFINITOR Arm Than the Placebo Arm in RECORD-1</span> </caption> <col width="384"/> <col width="140"/> <col width="133"/> <col width="128"/> <col width="124"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.<br/> <span class="Sup">b</span>No Grade 4 laboratory abnormalities were reported.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Laboratory parameter</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 274</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 137</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology<span class="Sup">a</span></span></td> </tr> <tr> <td>       Anemia</td><td align="center">92</td><td align="center">13</td><td align="center">79</td><td align="center">6</td> </tr> <tr> <td>       Lymphopenia</td><td align="center">51</td><td align="center">18</td><td align="center">28</td><td align="center">5<span class="Sup">b</span></td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">23</td><td align="center">1<span class="Sup">b</span></td><td align="center">2</td><td align="center">&lt; 1</td> </tr> <tr> <td>       Neutropenia</td><td align="center">14</td><td align="center">&lt; 1</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">77</td><td align="center">4<span class="Sup">b</span></td><td align="center">35</td><td align="center">0</td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">73</td><td align="center">&lt; 1<span class="Sup">b</span></td><td align="center">34</td><td align="center">0</td> </tr> <tr> <td>       Hyperglycemia</td><td align="center">57</td><td align="center">16</td><td align="center">25</td><td align="center">2<span class="Sup">b</span></td> </tr> <tr> <td>       Increased creatinine</td><td align="center">50</td><td align="center">2<span class="Sup">b</span></td><td align="center">34</td><td align="center">0</td> </tr> <tr> <td>       Hypophosphatemia</td><td align="center">37</td><td align="center">6<span class="Sup">b</span></td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Increased AST</td><td align="center">25</td><td align="center">1</td><td align="center">7</td><td align="center">0</td> </tr> <tr> <td>       Increased ALT</td><td align="center">21</td><td align="center">1<span class="Sup">b</span></td><td align="center">4</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Hyperbilirubinemia</td><td align="center">3</td><td align="center">1</td><td align="center">2</td><td align="center">0</td> </tr> </tbody> </table></div>

Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were white, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR.

The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15.

<div class="scrollingtable"><table> <caption> <span>Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2</span> </caption> <col width="300"/> <col width="300"/> <col width="300"/> <col width="300"/> <col width="300"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.<br/> <span class="Sup">b</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 79</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 39</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">78</td><td align="center">6<span class="Sup">b</span></td><td align="center">23</td><td align="center">0</td> </tr> <tr> <td>       Vomiting</td><td align="center">15</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea</td><td align="center">14</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Peripheral edema</td><td align="center">13</td><td align="center">0</td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Upper respiratory tract infection</td><td align="center">11</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Musculoskeletal and connective tissue</span></td> </tr> <tr> <td>       Arthralgia</td><td align="center">13</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough</td><td align="center">20</td><td align="center">0</td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous tissue</span></td> </tr> <tr class="Last"> <td>       Acne</td><td align="center">22</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> </tbody> </table></div>

Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%).

<div class="scrollingtable"><table> <caption> <span>Table 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2</span> </caption> <col width="384"/> <col width="140"/> <col width="133"/> <col width="128"/> <col width="124"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>No Grade 4 laboratory abnormalities were reported.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 79</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 39</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology</span></td> </tr> <tr> <td>       Anemia</td><td align="center">61</td><td align="center">0</td><td align="center">49</td><td align="center">0</td> </tr> <tr> <td>       Leukopenia</td><td align="center">37</td><td align="center">0</td><td align="center">21</td><td align="center">0</td> </tr> <tr> <td>       Neutropenia</td><td align="center">25</td><td align="center">1</td><td align="center">26</td><td align="center">0</td> </tr> <tr> <td>       Lymphopenia</td><td align="center">20</td><td align="center">1<span class="Sup">a</span></td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">19</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">85</td><td align="center">1<span class="Sup">a</span></td><td align="center">46</td><td align="center">0</td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">52</td><td align="center">0</td><td align="center">10</td><td align="center">0</td> </tr> <tr> <td>       Hypophosphatemia</td><td align="center">49</td><td align="center">5<span class="Sup">a</span></td><td align="center">15</td><td align="center">0</td> </tr> <tr> <td>       Increased alkaline phosphatase</td><td align="center">32</td><td align="center">1<span class="Sup">a</span></td><td align="center">10</td><td align="center">0</td> </tr> <tr> <td>       Increased AST</td><td align="center">23</td><td align="center">1<span class="Sup">a</span></td><td align="center">8</td><td align="center">0</td> </tr> <tr> <td>       Increased ALT</td><td align="center">20</td><td align="center">1<span class="Sup">a</span></td><td align="center">15</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Hyperglycemia (fasting)</td><td align="center">14</td><td align="center">0</td><td align="center">8</td><td align="center">0</td> </tr> </tbody> </table></div>

Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).

TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were white, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR.

The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia.

There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17.

<div class="scrollingtable"><table> <caption> <span>Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1</span> </caption> <col width="400"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>Includes mouth ulceration, stomatitis, and lip ulceration.<br/> <span class="Sup">b</span>Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral.<br/> <span class="Sup">c</span>Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection.<br/> <span class="Sup">d</span>Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.<br/> <span class="Sup">e</span>Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria.<br/> <span class="Sup">f</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 78</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 39</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">62</td><td align="center">9<span class="Sup">f</span></td><td align="center">26</td><td align="center">3<span class="Sup">f</span></td> </tr> <tr> <td>       Vomiting</td><td align="center">22</td><td align="center">1<span class="Sup">f</span></td><td align="center">13</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea</td><td align="center">17</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Constipation</td><td align="center">10</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Respiratory tract infection<span class="Sup">b</span></td><td align="center">31</td><td align="center">3</td><td align="center">23</td><td align="center">0</td> </tr> <tr> <td>       Gastroenteritis<span class="Sup">c</span></td><td align="center">10</td><td align="center">5</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td>       Pharyngitis streptococcal</td><td align="center">10</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">General</span></td> </tr> <tr> <td>       Pyrexia</td><td align="center">23</td><td align="center">6<span class="Sup">f</span></td><td align="center">18</td><td align="center">3<span class="Sup">f</span></td> </tr> <tr> <td>       Fatigue</td><td align="center">14</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Psychiatric</span></td> </tr> <tr> <td>       Anxiety, aggression or other behavioral disturbance<span class="Sup">d</span></td><td align="center">21</td><td align="center">5<span class="Sup">f</span></td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Skin and subcutaneous tissue</span></td> </tr> <tr> <td>       Rash<span class="Sup">e</span></td><td align="center">21</td><td align="center">0</td><td align="center">8</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Acne</td><td align="center">10</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> </tbody> </table></div>

Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%).

<div class="scrollingtable"><table> <caption> <span>Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1</span> </caption> <col width="384"/> <col width="140"/> <col width="133"/> <col width="128"/> <col width="124"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5">Grading according to NCI CTCAE Version 3.0.<br/> <span class="Sup">a</span>No Grade 4 laboratory abnormalities were reported.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule" colspan="2"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 78</span></td><td align="center" class="Toprule" colspan="2"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 39</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td><td align="center"><span class="Bold">All Grades</span></td><td align="center"><span class="Bold">Grade 3-4</span></td> </tr> <tr> <td align="center"></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td><td align="center"><span class="Bold">%</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Hematology</span></td> </tr> <tr> <td>       Elevated partial thromboplastin time</td><td align="center">72</td><td align="center">3<span class="Sup">a</span></td><td align="center">44</td><td align="center">5<span class="Sup">a</span></td> </tr> <tr> <td>       Neutropenia</td><td align="center">46</td><td align="center">9<span class="Sup">a</span></td><td align="center">41</td><td align="center">3<span class="Sup">a</span></td> </tr> <tr> <td>       Anemia</td><td align="center">41</td><td align="center">0</td><td align="center">21</td><td align="center">0</td> </tr> <tr> <td colspan="5"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia</td><td align="center">81</td><td align="center">0</td><td align="center">39</td><td align="center">0</td> </tr> <tr> <td>       Elevated AST</td><td align="center">33</td><td align="center">0</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td>       Hypertriglyceridemia</td><td align="center">27</td><td align="center">0</td><td align="center">15</td><td align="center">0</td> </tr> <tr> <td>       Elevated ALT</td><td align="center">18</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Hypophosphatemia</td><td align="center">9</td><td align="center">1<span class="Sup">a</span></td><td align="center">3</td><td align="center">0</td> </tr> </tbody> </table></div>

Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%).

TSC-Associated Partial-Onset Seizures

The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were white, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.

The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia.

Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19.

<div class="scrollingtable"><table> <caption> <span>Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients With TSC-Associated Partial-Onset Seizures in EXIST-3</span> </caption> <col width="200"/> <col width="75"/> <col width="75"/> <col width="75"/> <col width="75"/> <col width="75"/> <col width="75"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="7">Grading according to NCI CTCAE Version 4.03.<br/> <span class="Sup">a</span>Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain.<br/> <span class="Sup">b</span>No Grade 4 adverse reactions were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="bottom"></td><td align="center" class="Toprule" colspan="4" valign="bottom"><span class="Bold">AFINITOR DISPERZ</span></td><td align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="center" valign="bottom"></td><td align="center" class="Toprule" colspan="2" valign="bottom"><span class="Bold">Target of<br/>3-7 ng/mL<br/>N = 117</span></td><td align="center" class="Toprule" colspan="2" valign="bottom"><span class="Bold"> <br/>Target of<br/>9-15 ng/mL<br/>N = 130</span></td><td align="center" colspan="2" valign="top"><span class="Bold"> <br/> <br/> <br/>N = 119</span></td> </tr> <tr> <td align="center" valign="bottom"></td><td align="center" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td><td align="center" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td><td align="center" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td> </tr> <tr> <td class="Toprule" colspan="7"><span class="Bold">Gastrointestinal</span></td> </tr> <tr> <td>       Stomatitis<span class="Sup">a</span></td><td align="center">55</td><td align="center">3<span class="Sup">b</span></td><td align="center">64</td><td align="center">4<span class="Sup">b</span></td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td>       Diarrhea</td><td align="center">17</td><td align="center">0</td><td align="center">22</td><td align="center">0</td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td>       Vomiting</td><td align="center">12</td><td align="center">0</td><td align="center">10</td><td align="center">2<span class="Sup">b</span></td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td colspan="7"><span class="Bold">Infections</span></td> </tr> <tr> <td>       Nasopharyngitis </td><td align="center">14</td><td align="center">0</td><td align="center">16</td><td align="center">0</td><td align="center">16</td><td align="center">0</td> </tr> <tr> <td>       Upper respiratory tract infection </td><td align="center">13</td><td align="center">0</td><td align="center">15</td><td align="center">0</td><td align="center">13</td><td align="center">0.8<span class="Sup">b</span></td> </tr> <tr> <td colspan="7"><span class="Bold">General</span></td> </tr> <tr> <td>       Pyrexia</td><td align="center">20</td><td align="center">0</td><td align="center">14</td><td align="center">0.8<span class="Sup">b</span></td><td align="center">5</td><td align="center">0</td> </tr> <tr> <td colspan="7"><span class="Bold">Respiratory, thoracic and mediastinal</span></td> </tr> <tr> <td>       Cough </td><td align="center">11</td><td align="center">0</td><td align="center">10</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td colspan="7"><span class="Bold">Skin and subcutaneous tissue</span></td> </tr> <tr class="Last"> <td>       Rash </td><td align="center">6</td><td align="center">0</td><td align="center">10</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> </tbody> </table></div>

The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR DISPERZ LT, % AFINITOR DISPERZ HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%).

<div class="scrollingtable"><table> <caption> <span>Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients With TSC-Associated Partial-Onset Seizures</span> </caption> <col width="250"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="7">Grading according to NCI CTCAE version 4.03.<br/> <span class="Sup">a</span>No Grade 4 laboratory abnormalities were reported. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="bottom"></td><td align="center" class="Toprule" colspan="4" valign="bottom"><span class="Bold">AFINITOR DISPERZ</span></td><td align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="center" valign="bottom"></td><td align="center" class="Toprule" colspan="2" valign="bottom"><span class="Bold">Target of<br/>3-7 ng/mL<br/>N = 117</span></td><td align="center" class="Toprule" colspan="2" valign="bottom"><span class="Bold"> <br/>Target of<br/>9-15 ng/mL<br/>N = 130</span></td><td align="center" colspan="2" valign="top"><span class="Bold"> <br/> <br/> <br/>N = 119</span></td> </tr> <tr> <td align="center" class="Botrule" valign="bottom"></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">All Grades</span><span class="Bold"> <br/>%</span></td><td align="center" class="Botrule" valign="bottom"><span class="Bold">Grade 3-4</span><span class="Bold"> <br/>%</span></td> </tr> <tr> <td colspan="7"><span class="Bold">Hematology</span></td> </tr> <tr> <td>       Neutropenia </td><td align="center">25</td><td align="center">4<span class="Sup">a</span></td><td align="center">37</td><td align="center">6</td><td align="center">23</td><td align="center">7<span class="Sup">a</span></td> </tr> <tr> <td>       Anemia</td><td align="center">27</td><td align="center">0.9<span class="Sup">a</span></td><td align="center">30</td><td align="center">0</td><td align="center">21</td><td align="center">0.8<span class="Sup">a</span></td> </tr> <tr> <td>       Thrombocytopenia</td><td align="center">12</td><td align="center">0</td><td align="center">15</td><td align="center">0</td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td colspan="7"><span class="Bold">Chemistry</span></td> </tr> <tr> <td>       Hypercholesterolemia </td><td align="center">86</td><td align="center">0</td><td align="center">85</td><td align="center">0.8<span class="Sup">a</span></td><td align="center">58</td><td align="center">0</td> </tr> <tr> <td>       Hypertriglyceridemia </td><td align="center">43</td><td align="center">2<span class="Sup">a</span></td><td align="center">39</td><td align="center">2</td><td align="center">22</td><td align="center">0</td> </tr> <tr> <td>       Increased ALT </td><td align="center">17</td><td align="center">0</td><td align="center">22</td><td align="center">0</td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td>       Increased AST </td><td align="center">13</td><td align="center">0</td><td align="center">19</td><td align="center">0</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td>       Hyperglycemia </td><td align="center">19</td><td align="center">0</td><td align="center">18</td><td align="center">0</td><td align="center">17</td><td align="center">0</td> </tr> <tr> <td>       Increased alkaline phosphatase </td><td align="center">24</td><td align="center">0</td><td align="center">16</td><td align="center">0</td><td align="center">29</td><td align="center">0</td> </tr> <tr class="Last"> <td>       Hypophosphatemia </td><td align="center">9</td><td align="center">0.9<span class="Sup">a</span></td><td align="center">16</td><td align="center">2</td><td align="center">3</td><td align="center">0</td> </tr> </tbody> </table></div>

Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

The following adverse reactions have been identified during postapproval use of AFINITOR/AFINITOR DISPERZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure:

Inhibitors

Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Inducers

Increase the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12), Clinical Pharmacology (12.3)].

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ [see Warnings and Precautions (5.4)].

Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data). Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data

Animal Data

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on BSA. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Risk Summary

There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to starting AFINITOR/AFINITOR DISPERZ [see Use in Specific Populations (8.1)].

Contraception

AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Females: Advise female patients of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose.

Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.

Infertility

Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR/AFINITOR DISPERZ. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in female patients [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)].

Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in male patients [see Nonclinical Toxicology (13.1)].

TSC-Associated SEGA

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of AFINITOR/AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.5)]. The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA.

In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years.

Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years.

TSC-Associated Partial-Onset Seizures

The safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)]. The safety and effectiveness of AFINITOR DISPERZ and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures.

The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 AFINITOR DISPERZ-treated patients < 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years. Sixteen percent of 70 AFINITOR DISPERZ-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients.

Other Indications

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in:

In BOLERO-2, 40% of patients with breast cancer treated with AFINITOR were ≥ 65 years of age, while 15% were ≥ 75 years of age. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age.

In RECORD-1, 41% of patients with renal cell carcinoma treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

AFINITOR/AFINITOR DISPERZ exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the AFINITOR dose as recommended [see Dosage and Administration (2.10)].

For patients with TSC-associated SEGA and TSC-associated partial-onset seizures who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR/AFINITOR DISPERZ as recommended and adjust the dose based on everolimus trough concentrations [see Dosage and Administration (2.8, 2.10)].

AFINITOR (everolimus) and AFINITOR DISPERZ (everolimus tablets for oral suspension) are kinase inhibitors.

{ "type": "p", "children": [], "text": "AFINITOR (everolimus) and AFINITOR DISPERZ (everolimus tablets for oral suspension) are kinase inhibitors." }

The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C53H83NO14 and the molecular weight is 958.2 g/mol. The structural formula is:

{ "type": "p", "children": [], "text": "The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C53H83NO14 and the molecular weight is 958.2 g/mol. The structural formula is:" }

AFINITOR for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.

{ "type": "p", "children": [], "text": "AFINITOR for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate." }

AFINITOR DISPERZ for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.

{ "type": "p", "children": [], "text": "AFINITOR DISPERZ for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose." }

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner.

Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

Exposure-Response Relationship

In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration.

In patients with TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration.

Cardiac Electrophysiology

In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

Absorption

After administration of AFINITOR in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.

In patients with TSC-associated SEGA, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

Effect of Food: In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to AFINITOR 10 mg (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and Cmax by 42%.

In healthy subjects who received 9 mg of AFINITOR DISPERZ, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%.

Relative Bioavailability: The AUCinf of everolimus was equivalent between AFINITOR DISPERZ and AFINITOR; the Cmax of everolimus in the AFINITOR DISPERZ dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

Elimination

The mean elimination half-life of everolimus is approximately 30 hours.

Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.

Specific Populations

No relationship was apparent between oral clearance and age or sex in patients with cancer.

Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.

Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10), Use in Specific Populations (8.6)].

Pediatric Patients: In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean Cmin values normalized to mg/m2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to BSA was higher in pediatric patients as compared to adults.

Race or Ethnicity: Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in black patients than in white patients.

Drug Interaction Studies

Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when AFINITOR was coadministered with:

Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of AFINITOR with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and Cmax by 58% compared to AFINITOR alone [see Dosage and Administration (2.12)].

Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).

The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with AFINITOR resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC0-inf.

The coadministration of AFINITOR with exemestane increased exemestane Cmin by 45% and C2h by 64%; however, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

The coadministration of AFINITOR with long-acting octreotide increased octreotide Cmin by approximately 50%.

Effect of Everolimus on Antiepileptic Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam’s metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily.

Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m2/day, approximately 255-fold the recommended dose of AFINITOR 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA and TSC-associated partial-onset seizures, based on the BSA), administered as 2 doses, 24 hours apart.

Based on non-clinical findings, AFINITOR/AFINITOR DISPERZ may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%.

Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of AFINITOR in combination with exemestane vs. placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR).

Patients were randomized 2:1 to AFINITOR 10 mg orally once daily in combination with exemestane 25 mg once daily (n = 485) or to placebo in combination with exemestane 25 mg orally once daily (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to AFINITOR at the time of disease progression.

The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 20 and Figure 1). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.

ORR was higher in the AFINITOR in combination with exemestane arm vs. the placebo in combination with exemestane arm (Table 20). There were 3 complete responses (0.6%) and 58 partial responses (12%) in the AFINITOR arm. There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm.

After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)].

<div class="scrollingtable"><table> <caption> <span>Table 20: Efficacy Results in Hormone-Receptor Positive, HER-2 Negative Breast Cancer in BOLERO-2</span> </caption> <col width="282"/> <col width="233"/> <col width="209"/> <col width="209"/> <col width="217"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="6"><span class="Sup">a</span>Hazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasis.<br/> <span class="Sup">b</span>p-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis.<br/> <span class="Sup">c</span>Objective response rate = proportion of patients with CR or PR.<br/> <span class="Sup">d</span>Not applicable.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"><span class="Bold">Analysis</span></td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">with Exemestane </span> <br/> <span class="Bold">N = 485</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span> <br/> <span class="Bold">with Exemestane </span> <br/> <span class="Bold">N = 239</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">Hazard Ratio</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">p-value</span></td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Median progression-free survival (months, 95% CI)</span></td> </tr> <tr> <td class="Toprule" valign="top">Investigator radiological review</td><td align="center" class="Toprule" valign="top">7.8<br/>(6.9, 8.5)</td><td align="center" class="Toprule" valign="top">3.2<br/>(2.8, 4.1)</td><td align="center" class="Toprule" valign="top">0.45<span class="Sup">a</span> <br/>(0.38, 0.54)</td><td align="center" class="Toprule" valign="top">&lt; 0.0001<span class="Sup">b</span></td> </tr> <tr> <td valign="top">Independent radiological review</td><td align="center" valign="top">11.0<br/>(9.7, 15.0)</td><td align="center" valign="top">4.1<br/>(2.9, 5.6)</td><td align="center" valign="top">0.38<span class="Sup">a</span> <br/>(0.3, 0.5)</td><td align="center" valign="top">&lt; 0.0001<span class="Sup">b</span> <br/> </td> </tr> <tr> <td class="Toprule" colspan="5"><span class="Bold">Best overall response (%, 95% CI)</span></td> </tr> <tr class="Last"> <td class="Toprule" valign="top">Objective response rate (ORR)<span class="Sup">c</span></td><td align="center" class="Toprule" valign="top">12.6%<br/>(9.8, 15.9)</td><td align="center" class="Toprule" valign="top">1.7%<br/>(0.5, 4.2)</td><td align="center" class="Toprule" valign="top">n/a<span class="Sup">d</span></td><td class="Toprule"></td> </tr> </tbody> </table></div>

Figure 1: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in Hormone Receptor-Positive, HER-2 Negative Breast Cancer in BOLERO-2

Pancreatic Neuroendocrine Tumors (PNET)

A randomized, double-blind, multicenter trial (RADIANT-3, NCT00510068) of AFINITOR in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes vs. no) and WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The major efficacy outcome was PFS evaluated by RECIST. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included ORR, response duration, and OS.

Patients were randomized 1:1 to receive either AFINITOR 10 mg once daily (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58 years, 55% male, 79% white). Of the 203 patients randomized to BSC, 172 patients (85%) received AFINITOR following documented radiologic progression.

The trial demonstrated a statistically significant improvement in PFS (Table 21 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 21.

<div class="scrollingtable"><table> <caption> <span>Table 21: Progression-Free Survival Results in PNET in RADIANT-3</span> </caption> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> <col width="150"/> <col width="100"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="6"><span class="Sup">a</span>Includes adjudication for discrepant assessments between investigator radiological review and central radiological review.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Analysis</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">N</span> <br/> </td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 207</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 203</span></td><td align="center" class="Toprule"><span class="Bold">Hazard Ratio <br/>(95% CI)</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">p-value</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold">410</span></td><td align="center" colspan="2"><span class="Bold">Median progression-free survival (months) (95% CI)</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td class="Toprule">Investigator radiological review</td><td align="center" class="Toprule"></td><td align="center" class="Toprule">11.0<br/>(8.4, 13.9)</td><td align="center" class="Toprule">4.6<br/>(3.1, 5.4)</td><td align="center" class="Toprule">0.35<br/>(0.27, 0.45)</td><td align="center" class="Toprule">&lt; 0.001</td> </tr> <tr> <td>Central radiological review</td><td align="center"></td><td align="center">13.7<br/>(11.2, 18.8)</td><td align="center">5.7<br/>(5.4, 8.3)</td><td align="center">0.38<br/>(0.28, 0.51)</td><td align="center">&lt; 0.001<br/> </td> </tr> <tr class="Last"> <td>Adjudicated radiological review<span class="Sup">a</span></td><td align="center"></td><td align="center">11.4<br/>(10.8, 14.8)</td><td align="center">5.4<br/>(4.3, 5.6)</td><td align="center">0.34<br/>(0.26, 0.44)</td><td align="center">&lt; 0.001</td> </tr> </tbody> </table></div>

Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3

Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses. Overall Survival (OS) was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30].

NET of Gastrointestinal (GI) or Lung Origin

A randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of AFINITOR in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin. The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. Patients were randomized 2:1 to receive either AFINITOR 10 mg once daily or placebo, and stratified by prior somatostatin analog use (yes vs. no), tumor origin and WHO performance status (0 vs. 1). The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST. Additional efficacy outcome measures were OS and ORR.

A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm. The median age was 63 years (22 to 86 years); 47% were male; 76% were white; 74% had WHO performance status of 0 and 26% had WHO performance status of 1. The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).

The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 22 and Figure 3). The final OS analysis did not show a statistically significant difference between those patients who received AFINITOR or placebo (HR = 0.90 [95% CI: 0.66, 1.24]).

<div class="scrollingtable"><table> <caption> <span>Table 22: Progression-Free Survival in Neuroendocrine Tumors of Gastrointestinal or Lung Origin in RADIANT-4</span> </caption> <col width="250"/> <col width="150"/> <col width="150"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="3"><span class="Sup">a</span>Hazard ratio is obtained from the stratified Cox model.<br/> <span class="Sup">b</span>p-value is obtained from the stratified log-rank test.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span> <br/> <span class="Bold">N = 205</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 97</span></td> </tr> <tr> <td align="left" class="Toprule" colspan="3"><span class="Bold">Progression-Free Survival</span></td> </tr> <tr> <td class="Toprule">Number of Events</td><td align="center" class="Toprule">113 (55%)</td><td align="center" class="Toprule">65 (67%)</td> </tr> <tr> <td>Progressive Disease</td><td align="center">104 (51%)</td><td align="center">60 (62%)</td> </tr> <tr> <td>Death</td><td align="center">9 (4%)</td><td align="center">5 (5%)</td> </tr> <tr> <td>Median PFS in months (95% CI)</td><td align="center">11.0 (9.2, 13.3)</td><td align="center">3.9 (3.6, 7.4)</td> </tr> <tr> <td>Hazard Ratio (95% CI)<span class="Sup">a</span></td><td align="center" colspan="2">0.48 (0.35, 0.67)</td> </tr> <tr> <td>p-value<span class="Sup">b</span></td><td align="center" colspan="2">&lt; 0.001</td> </tr> <tr class="Last"> <td class="Toprule"><span class="Bold">Overall Response Rate</span></td><td align="center" class="Toprule">2%</td><td align="center" class="Toprule">1%</td> </tr> </tbody> </table></div>

Figure 3: Kaplan-Meier Curves for Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4

Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors

The safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multicenter trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, AFINITOR in combination with long-acting octreotide (Sandostatin LAR®) was compared to placebo in combination with long-acting octreotide. After documented radiological progression, patients on the placebo arm could receive AFINITOR; of those randomized to placebo, 67% received open-label AFINITOR in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm.

An international, multicenter, randomized, double-blind trial (RECORD-1, NCT00410124) comparing AFINITOR 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included OS.

In total, 416 patients were randomized 2:1 to receive AFINITOR (n = 277) or placebo (n = 139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% white, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).

AFINITOR was superior to placebo for PFS (Table 23 and Figure 4). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label AFINITOR occurred in 80% of the 139 patients and may have confounded the OS benefit.

<div class="scrollingtable"><table> <caption> <span>Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1</span> </caption> <col width="233"/> <col width="111"/> <col width="111"/> <col width="111"/> <col width="111"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="5"><span class="Sup">a</span>Log-rank test stratified by prognostic score.<br/> <span class="Sup">b</span>Not applicable.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span><span class="Bold"> <br/>N = 277</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 139</span></td><td align="center" class="Toprule"><span class="Bold">Hazard </span><span class="Bold">R</span><span class="Bold">atio</span><span class="Bold"> <br/>(95%</span><span class="Bold"> </span><span class="Bold">CI)</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">p-value<span class="Sup">a</span></span></td> </tr> <tr> <td class="Toprule"><span class="Bold">Median P</span><span class="Bold">rogression-</span><span class="Bold">free S</span><span class="Bold">urvival</span><span class="Bold"> <br/>(95% CI)</span></td><td align="center" class="Toprule">4.9 months<br/>(4.0, 5.5)</td><td align="center" class="Toprule">1.9 months<br/>(1.8, 1.9)</td><td align="center" class="Toprule">0.33<br/>(0.25, 0.43)</td><td align="center" class="Toprule">&lt; 0.0001</td> </tr> <tr class="Last"> <td><span class="Bold">Objective </span><span class="Bold">R</span><span class="Bold">esponse </span><span class="Bold">R</span><span class="Bold">ate</span></td><td align="center">2%</td><td align="center">0%</td><td align="center">n/a<span class="Sup">b</span></td><td align="center">n/a<span class="Sup">b</span></td> </tr> </tbody> </table></div>

Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received AFINITOR 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).

Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were white. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (9 to 1612 cm3) and 120 cm3 (3 to 4520 cm3) in the AFINITOR and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis.

The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients (Table 24). The median response duration was 5.3+ months (2.3+ to 19.6+ months).

There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001).

<div class="scrollingtable"><table> <caption> <span>Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2</span> </caption> <col width="341"/> <col width="90"/> <col width="90"/> <col width="103"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="4"><span class="Sup">a</span>Per independent central radiology review.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span></td><td align="center" class="Toprule"><span class="Bold">p-value</span></td> </tr> <tr> <td valign="bottom"></td><td align="center" valign="bottom"><span class="Bold">N = 79</span></td><td align="center" valign="bottom"><span class="Bold">N = 39</span></td><td align="center" valign="bottom"></td> </tr> <tr> <td class="Toprule" colspan="4"><span class="Bold">Primary analysis</span></td> </tr> <tr> <td><span class="Bold">       Angiomyolipoma response rate<span class="Sup">a</span> - (%)</span></td><td align="center"><span class="Bold">41.8</span></td><td align="center"><span class="Bold">0</span></td><td align="center"><span class="Bold">&lt; 0.0001</span></td> </tr> <tr class="Last"> <td>       95% CI</td><td align="center">(30.8, 53.4)</td><td align="center">(0.0, 9.0)</td><td align="center"></td> </tr> </tbody> </table></div>

Skin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the AFINITOR arm (26% vs. 0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition).

Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR. The median duration of AFINITOR treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period. No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.

EXIST-1

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter.

The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).

Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were white. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm3 (0.18 to 25.15 cm3) and 1.30 cm3 (0.32 to 9.75 cm3) in the AFINITOR and placebo arms, respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis.

The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 25). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months).

With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention.

<div class="scrollingtable"><table> <caption> <span>Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1</span> </caption> <col width="341"/> <col width="90"/> <col width="90"/> <col width="103"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="4"><span class="Sup">a</span>Per independent central radiology review.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">AFINITOR</span></td><td align="center" class="Toprule"><span class="Bold">Placebo</span></td><td align="center" class="Toprule"><span class="Bold">p-value</span></td> </tr> <tr> <td valign="bottom"></td><td align="center" valign="bottom"><span class="Bold">N = 78</span></td><td align="center" valign="bottom"><span class="Bold">N = 39</span></td><td align="center" valign="bottom"></td> </tr> <tr> <td class="Toprule" colspan="4"><span class="Bold">Primary analysis</span></td> </tr> <tr> <td><span class="Bold">       SEGA response rate<span class="Sup">a</span> - (%)</span></td><td align="center"><span class="Bold">35</span></td><td align="center"><span class="Bold">0</span></td><td align="center"><span class="Bold">&lt; 0.0001</span></td> </tr> <tr class="Last"> <td>       95% CI</td><td align="center">24, 46</td><td align="center">0, 9</td><td align="center"></td> </tr> </tbody> </table></div>

Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR treatment and follow-up was 3.9 years (0.2 to 4.9 years).

By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study.

Study 2485

Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m2/orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study.

A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% white.

At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years).

By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on AFINITOR. Nine additional patients were identified as having a ≥ 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR, including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.

The efficacy of AFINITOR DISPERZ as an adjunctive anti-epileptic drug (AED) was evaluated in a randomized, double-blind, multicenter, placebo-controlled study conducted in patients with TSC-associated partial-onset seizures (EXIST-3, NCT01713946). Patients with a history of inadequate control of partial-onset seizures despite treatment with ≥ 2 sequential AED regimens were randomized to receive placebo or AFINITOR DISPERZ once daily at a dose to achieve a low trough (LT) level (3-7 ng/mL) or a high trough (HT) level (9-15 ng/mL). Randomization was stratified by age group (1 to < 6, 6 to < 12, 12 to < 18, ≥ 18 years). The study consisted of 3 phases: an 8-week Baseline observation phase; an 18-week double-blind, placebo-controlled Core phase (6-week titration period and a 12-week maintenance period), and an Extension phase of ≥ 48 weeks. Patients were required to have a diagnosis of TSC per the modified Gomez criteria, and ≥ 16 partial-onset seizures during the Baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs. The starting doses for AFINITOR DISPERZ in the Core phase ranged from 3 to 6 mg/m2 orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m2 orally once daily, depending on age, in patients receiving concomitant CYP3A4/P-gp inducers. During the 6-week titration period, everolimus trough levels were assessed every 2 weeks and up to 3 dose adjustments were allowed to attempt to reach the targeted everolimus trough concentration range.

The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the Core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the Baseline phase during the maintenance period of the Core phase, and seizure freedom rate during the maintenance period of the Core phase.

A total of 366 patients were randomized to AFINITOR DISPERZ LT (n = 117), AFINITOR DISPERZ HT (n = 130) or placebo (n = 119). Median age was 10.1 years (2.2 to 56 years); 28% of patients were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years). The majority were white (65%) and male (52%). The most common major features of TSC were cortical tubers (92%), hypomelanotic macules (84%), and subependymal nodules (83%). While 17% of the patients had SEGA, 42% had renal angiomyolipoma, and 9% had both SEGA and renal angiomyolipoma; no patients were receiving treatment with AFINITOR or AFINITOR DISPERZ for these manifestations of TSC. During the Baseline phase, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures. The median seizure frequency per week during the Baseline phase was 9.4 for all patients and 47% of patients were receiving 3 AEDs during the Baseline phase. The efficacy results are summarized in Table 26.

<div class="scrollingtable"><table> <caption> <span>Table 26: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3</span> </caption> <col width="500"/> <col width="200"/> <col width="200"/> <col width="200"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="4"><span class="Sup">a</span>If patient discontinued before starting the Maintenance period, then the Titration period is used.<br/> <span class="Sup">b</span>95% CI of the median based on bootstrap percentiles.<br/> <span class="Sup">c</span>p-values were for superiority vs. placebo, and obtained from rank ANCOVA with Baseline seizure frequency as covariate, stratified by age subgroup.<br/> <span class="Sup">d</span>Exact 95% CI obtained using Clopper-Pearson method. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" valign="bottom"></td><td align="center" colspan="2" valign="bottom"><span class="Bold">AFINITOR DISPERZ</span></td><td align="center" valign="top"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"><span class="Bold">Target of<br/>3-7 ng/mL<br/>N = 117</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Target of<br/>9-15 ng/mL<br/>N = 130</span></td><td align="center" class="Botrule" valign="top"><span class="Bold"> <br/> <br/>N = 119</span></td> </tr> <tr> <td colspan="4"><span class="Bold">Seizures per week</span></td> </tr> <tr> <td>       Median at Baseline (Min, Max) </td><td align="center">8.6 (1.4, 192.9)</td><td align="center">9.5 (0.3, 218.4)</td><td align="center">10.5 (1.3, 231.7)</td> </tr> <tr> <td>       Median at Core phase<span class="Sup">a</span> (Min, Max)</td><td align="center">6.8 (0.0, 193.5)</td><td align="center">4.9 (0.0, 133.7)</td><td align="center">8.5 (0.0, 217.7)</td> </tr> <tr> <td colspan="4"><span class="Bold">Percentage reduction from Baseline to Core phase (Maintenance<span class="Sup">a</span>)</span></td> </tr> <tr> <td>       Median </td><td align="center">29.3</td><td align="center">39.6</td><td align="center">14.9</td> </tr> <tr> <td>       95% CI<span class="Sup">b</span></td><td align="center">18.8, 41.9</td><td align="center">35.0, 48.7</td><td align="center">0.1, 21.7</td> </tr> <tr> <td>       p-value<span class="Sup">c</span></td><td align="center">0.003</td><td align="center">&lt; 0.001</td><td align="center"> </td> </tr> <tr> <td colspan="4"><span class="Bold">Response rate</span></td> </tr> <tr> <td>       Responders, n (%) </td><td align="center">28.2</td><td align="center">40</td><td align="center">15.1</td> </tr> <tr class="Last"> <td>       95% CI<span class="Sup">d</span></td><td align="center">20.3, 37.3</td><td align="center">31.5, 49.0</td><td align="center">9.2, 22.8</td> </tr> </tbody> </table></div>

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AFINITOR

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2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other; available in:" }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0594-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0594-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in:" }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0566-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0566-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in:" }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0620-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0620-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in:" }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0567-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0567-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

AFINITOR DISPERZ

{ "type": "p", "children": [], "text": "\nAFINITOR DISPERZ\n" }

2 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D2” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "2 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D2” on one side and “NVR” on the other; available in: " }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0626-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0626-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in: " }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0627-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0627-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in:

{ "type": "p", "children": [], "text": "5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in: " }

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0628-51

{ "type": "p", "children": [], "text": "Blisters of 28 tablets………………………………………………………………………………NDC 0078-0628-51" }

Each carton contains 4 blister cards of 7 tablets each

{ "type": "p", "children": [], "text": "Each carton contains 4 blister cards of 7 tablets each" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature.

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature." }

Store in the original container, protect from light and moisture.

{ "type": "p", "children": [], "text": "Store in the original container, protect from light and moisture.\n\t\t\t\t\t\t" }

Follow special handling and disposal procedures for anti-cancer pharmaceuticals.1

{ "type": "p", "children": [], "text": "Follow special handling and disposal procedures for anti-cancer pharmaceuticals.1\n" }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)." }

Non-infectious Pneumonitis

{ "type": "p", "children": [], "text": "\nNon-infectious Pneumonitis\n" }

Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1)]." }

Infections

{ "type": "p", "children": [], "text": "\nInfections\n" }

Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2)]." }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction, including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction, including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.3)]." }

Angioedema with Concomitant Use of ACE Inhibitors

{ "type": "p", "children": [], "text": "\nAngioedema with Concomitant Use of ACE Inhibitors\n" }

Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4)]." }

Stomatitis

{ "type": "p", "children": [], "text": "\nStomatitis\n" }

Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5)]." }

Renal Impairment

{ "type": "p", "children": [], "text": "\nRenal Impairment\n" }

Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6)]." }

Risk of Impaired Wound Healing

{ "type": "p", "children": [], "text": "\nRisk of Impaired Wound Healing\n" }

Advise patients that AFINITOR/AFINITOR DISPERZ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients that AFINITOR/AFINITOR DISPERZ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7)]." }

Geriatric Patients

{ "type": "p", "children": [], "text": "\nGeriatric Patients\n" }

Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions (5.8), Use in Specific Populations (8.5)].

{ "type": "p", "children": [], "text": "Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions (5.8), Use in Specific Populations (8.5)]." }

Metabolic Disorders

{ "type": "p", "children": [], "text": "\nMetabolic Disorders\n" }

Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9)]." }

Myelosuppression

{ "type": "p", "children": [], "text": "\nMyelosuppression\n" }

Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions (5.10)]." }

Risk of Infection or Reduced Immune Response with Vaccination

{ "type": "p", "children": [], "text": "\nRisk of Infection or Reduced Immune Response with Vaccination\n" }

Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11)]." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.13), Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.13), Use in Specific Populations (8.1, 8.3)]." }

Radiation Sensitization and Radiation Recall

{ "type": "p", "children": [], "text": "\nRadiation Sensitization and Radiation Recall \n" }

Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]." }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].\n\t\t\t\t\t\t" }

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

{ "type": "p", "children": [], "text": "Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936" }

T2022-07

{ "type": "p", "children": [], "text": "T2022-07" }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First Last"> <td>This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: January 2025</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">PATIENT INFORMATION</span></td> </tr> <tr> <td align="center" class="Lrule" valign="top"><span class="Bold">AFINITOR<span class="Sup">®</span> (a-fin-it-or)<br/>(everolimus)<br/>tablets</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">AFINITOR DISPERZ<span class="Sup">®</span> (a-fin-it-or dis-perz)<br/>(everolimus tablets for oral suspension)</span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">Read this Patient Information leaflet that comes with AFINITOR or AFINITOR DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What is the most important information I should know about AFINITOR and AFINITOR DISPERZ?<br/>AFINITOR and AFINITOR DISPERZ can cause serious side effects, including:</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">1. You may develop lung or breathing problems. </span>In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms:</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>New or worsening cough</li> <li>Shortness of breath</li> <li>Chest pain</li> <li>Difficulty breathing or wheezing</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">2. You may be more likely to develop an infection,</span> such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include active hepatitis B in people who have had hepatitis B in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible. <br/>Tell your healthcare provider right away if you have a temperature of 100.5˚F or above, chills, or do not feel well. <br/>Symptoms of hepatitis B or infection may include the following:</td> </tr> <tr> <td class="Lrule"> <ul> <li>Fever</li> <li>Chills</li> <li>Skin rash</li> <li>Joint pain and swelling</li> <li>Tiredness</li> </ul> </td><td class="Rrule"> <ul> <li>Loss of appetite</li> <li>Nausea</li> <li>Pale stools or dark urine</li> <li>Yellowing of the skin</li> <li>Pain in the upper right side of the stomach</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">3. Severe allergic reactions.</span> Call your healthcare provider or get medical help right away if you get signs and symptoms of a severe allergic reaction, including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">4. Possible increased risk for a type of allergic reaction called angioedema, </span>in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with AFINITOR or AFINITOR DISPERZ. Talk with your healthcare provider before taking AFINITOR or AFINITOR DISPERZ if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with AFINITOR or AFINITOR DISPERZ.</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">5. Mouth ulcers and sores.</span> Mouth ulcers and sores are common during treatment with AFINITOR or AFINITOR DISPERZ but can also be severe. When you start treatment with AFINITOR or AFINITOR DISPERZ, your healthcare provider may tell you to also start a prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare provider’s instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to restart this mouthwash or to use a special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">6. You may develop kidney failure.</span> In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with AFINITOR or AFINITOR DISPERZ.</td> </tr> <tr> <td class="Lrule Rrule" colspan="2">If you have any of the serious side effects listed above, you may need to stop taking AFINITOR or AFINITOR DISPERZ for a while or use a lower dose. Follow your healthcare provider’s instructions.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What is AFINITOR?</span> <br/>AFINITOR is a prescription medicine used to treat:</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>advanced hormone receptor-positive, HER2-negative breast cancer, along with the medicine exemestane, in postmenopausal women who have already received certain other medicines for their cancer.</li> <li>adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (PNET), that has progressed and cannot be treated with surgery.</li> <li>adults with a type of cancer known as neuroendocrine tumor (NET) of the stomach and intestine (gastrointestinal), or lung that has progressed and cannot be treated with surgery.<br/>AFINITOR is not for use in people with carcinoid tumors that actively produce hormones.</li> <li>adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked.</li> <li>people with the following types of tumors that are seen with a genetic condition called tuberous sclerosis complex (TSC): <ul> <li>adults with a kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.</li> <li>adults and children 1 year of age and older with a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.</li> </ul> </li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">What is AFINITOR DISPERZ?</span> <br/>AFINITOR DISPERZ is a prescription medicine used to treat:</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>adults and children 1 year of age and older with a genetic condition called tuberous sclerosis complex (TSC) who have a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.</li> <li>adults and children 2 years of age and older with a genetic condition called tuberous sclerosis complex (TSC) who have certain types of seizures (epilepsy), as an added treatment to other antiepileptic medicines.</li> </ul> <p class="First">It is not known if AFINITOR and AFINITOR DISPERZ are safe and effective in children to treat:</p> <ul> <li>hormone receptor-positive, HER-2 negative breast cancer</li> <li>a type of cancer called neuroendocrine tumors (NET)</li> <li>kidney cancer (renal cell carcinoma)</li> <li>a kidney tumor called angiomyolipoma, that can happen in children with a genetic condition called tuberous sclerosis complex (TSC).</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Do not take AFINITOR or AFINITOR DISPERZ</span> if you have had a severe allergic reaction to everolimus.<br/>Talk to your healthcare provider before taking this medicine if you are allergic to: <ul> <li>a medicine that contains sirolimus</li> <li>a medicine that contains temsirolimus</li> </ul> Ask your healthcare provider if you do not know.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Before taking AFINITOR or AFINITOR DISPERZ, tell your healthcare provider about all of your medical conditions, including if you:</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>Have or have had kidney problems</li> <li>Have or have had liver problems</li> <li>Have diabetes or high blood sugar</li> <li>Have high blood cholesterol levels</li> <li>Have any infections</li> <li>Previously had hepatitis B</li> <li>Are scheduled to receive any vaccinations. You should not receive a “live vaccine” or be around people who have recently received a “live vaccine” during your treatment with AFINITOR or AFINITOR DISPERZ. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. For children with TSC and SEGA or certain types of seizures, work with your healthcare provider to complete the recommended childhood series of vaccines before your child starts treatment with AFINITOR or AFINITOR DISPERZ.</li> <li>Are pregnant, can become pregnant, or have a partner who can become pregnant. AFINITOR or AFINITOR DISPERZ can cause harm to your unborn baby.<br/> <span class="Bold">Females who are able to become pregnant:</span> <br/>◦ Your healthcare provider will give you a pregnancy test before you start treatment with AFINITOR or AFINITOR DISPERZ.<br/>◦ You should use effective birth control during treatment and for 8 weeks after your last dose of AFINITOR or AFINITOR DISPERZ.<br/> <span class="Bold">Males</span> with a female partner, you should use effective birth control during treatment and for 4 weeks after your last dose of AFINITOR or AFINITOR DISPERZ.<br/>Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away.</li> <li>Are breastfeeding or plan to breastfeed. It is not known if AFINITOR or AFINITOR DISPERZ passes into your breast milk. Do not breastfeed during treatment and for 2 weeks after your last dose of AFINITOR or AFINITOR DISPERZ. </li> <li>Are planning to have surgery or if you have had a recent surgery. You should stop taking AFINITOR or AFINITOR DISPERZ at least 1 week before planned surgery. See <span class="Bold">“What are the possible side effects of AFINITOR and AFINITOR DISPERZ?”</span> </li> <li>Have received radiation therapy or are planning to receive radiation therapy in the future. See <span class="Bold">“What are the possible side effects of AFINITOR and AFINITOR DISPERZ?”</span> </li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">Tell your healthcare provider about all of the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.<br/>AFINITOR or AFINITOR DISPERZ may affect the way other medicines work, and other medicines can affect how AFINITOR or AFINITOR DISPERZ work. Taking AFINITOR or AFINITOR DISPERZ with other medicines can cause serious side effects.<br/>Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Especially tell your healthcare provider if you take:</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>St. John’s Wort <span class="Italics">(Hypericum perforatum)</span> </li> <li>Medicine for: <ul> <li>Fungal infections</li> <li>Bacterial infections</li> <li>Tuberculosis</li> <li>Seizures</li> <li>HIV-AIDS</li> <li>Heart conditions or high blood pressure</li> </ul> </li> <li>Medicines that weaken your immune system (your body’s ability to fight infections and other problems)</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2">Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe a different medicine or your dose of AFINITOR or AFINITOR DISPERZ may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">How should I take AFINITOR or AFINITOR DISPERZ?</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>Your healthcare provider will prescribe the dose of AFINITOR or AFINITOR DISPERZ that is right for you.</li> <li>Take AFINITOR or AFINITOR DISPERZ exactly as your healthcare provider tells you to.</li> <li>Your healthcare provider may change your dose of AFINITOR or AFINITOR DISPERZ or tell you to temporarily interrupt dosing, if needed.</li> <li> <span class="Bold">Take only AFINITOR or AFINITOR DISPERZ. Do not mix AFINITOR and AFINITOR DISPERZ together.</span> </li> <li>Use scissors to open the blister pack.</li> <li>Take AFINITOR or AFINITOR DISPERZ 1 time each day at about the same time.</li> <li>Take AFINITOR or AFINITOR DISPERZ the same way each time, either with food or without food.</li> <li>If you take too much AFINITOR or AFINITOR DISPERZ, contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of AFINITOR or AFINITOR DISPERZ with you.</li> <li>If you miss a dose of AFINITOR or AFINITOR DISPERZ, you may take it if it is <span class="Bold">less than 6 hours</span> after the time you normally take it. If it is <span class="Bold">more than 6 hours</span> after you normally take your AFINITOR or AFINITOR DISPERZ, skip the dose for that day. The next day, take AFINITOR or AFINITOR DISPERZ at your usual time. Do not take 2 doses to make up for a missed dose. If you are not sure about what to do, call your healthcare provider.</li> <li>You should have blood tests before you start AFINITOR or AFINITOR DISPERZ and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels.</li> <li>If you take AFINITOR or AFINITOR DISPERZ to treat SEGA or AFINITOR DISPERZ to treat certain types of seizures with TSC, you will also need to have blood tests regularly to measure how much medicine is in your blood. This will help your healthcare provider decide how much AFINITOR or AFINITOR DISPERZ you need to take.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">AFINITOR:</span> <ul> <li>Swallow AFINITOR tablets whole with a glass of water. Do not take any tablet that is broken or crushed.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">AFINITOR DISPERZ:</span> <ul> <li>If your healthcare provider prescribes AFINITOR DISPERZ for you, see the “Instructions for Use” that comes with your medicine for instructions on how to prepare and take your dose.</li> <li>Each dose of AFINITOR DISPERZ must be prepared as a suspension before it is given.</li> <li>AFINITOR DISPERZ can cause harm to an unborn baby. When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.</li> <li>Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What should I avoid while taking AFINITOR or AFINITOR DISPERZ? </span> <br/>You should not drink grapefruit juice or eat grapefruit during your treatment with AFINITOR or AFINITOR DISPERZ. It may make the amount of AFINITOR or AFINITOR DISPERZ in your blood increase to a harmful level.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What are the possible side effects of AFINITOR or AFINITOR DISPERZ?</span> <br/> <span class="Bold">AFINITOR and AFINITOR DISPERZ can cause serious side effects, including:</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li> <span class="Bold">See “What is the most important information I should know about AFINITOR and AFINITOR DISPERZ?” for more information.</span> </li> <li> <span class="Bold">Risk of wound healing problems.</span> Wounds may not heal properly during AFINITOR and AFINITOR DISPERZ treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with AFINITOR and AFINITOR DISPERZ. <ul class="Circle"> <li>You should stop taking AFINITOR and AFINITOR DISPERZ at least 1 week before planned surgery.</li> <li>Your healthcare provider should tell you when you may start taking AFINITOR and AFINITOR DISPERZ again after surgery.</li> </ul> </li> <li> <span class="Bold">Increased blood sugar and fat (cholesterol and triglyceride) levels in the blood.</span> Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with AFINITOR or AFINITOR DISPERZ.</li> <li> <span class="Bold">Decreased blood cell counts.</span> AFINITOR and AFINITOR DISPERZ can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with AFINITOR or AFINITOR DISPERZ.</li> <li> <span class="Bold">Worsening side effects from radiation treatment, </span> that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">The most common side effects of AFINITOR in people with advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of the pancreas, stomach and intestine (gastrointestinal) or lung, and advanced kidney cancer include:</span></td> </tr> <tr> <td class="Lrule" valign="top"> <ul> <li>Infections</li> <li>Rash</li> <li>Feeling weak or tired</li> <li>Diarrhea</li> <li>Swelling of arms, hands, feet, ankles, face, or other parts of the body</li> </ul> </td><td class="Rrule" valign="top"> <ul> <li>Stomach-area (abdominal) pain</li> <li>Nausea</li> <li>Fever</li> <li>Cough</li> <li>Headache</li> <li>Decreased appetite</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">The most common side effects of AFINITOR and AFINITOR DISPERZ in people who have SEGA, renal angiomyolipoma, or certain types of seizures with TSC include</span> respiratory tract infections. </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">Other side effects that may occur with AFINITOR and AFINITOR DISPERZ:</span> <ul> <li>Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens.</li> <li>AFINITOR and AFINITOR DISPERZ may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</li> <li>AFINITOR and AFINITOR DISPERZ may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.</li> </ul> <p class="First">Tell your healthcare provider if you have any side effect that bothers you or does not go away.</p> <p>These are not all the possible side effects of AFINITOR and AFINITOR DISPERZ. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">How should I store AFINITOR or AFINITOR DISPERZ?</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul> <li>Store AFINITOR or AFINITOR DISPERZ at room temperature, between 68°F to 77°F (20°C to 25°C). </li> <li>Keep AFINITOR or AFINITOR DISPERZ in the pack it comes in.</li> <li>Open the blister pack just before taking AFINITOR or AFINITOR DISPERZ.</li> <li>Keep AFINITOR or AFINITOR DISPERZ dry and away from light.</li> <li>Do not use AFINITOR or AFINITOR DISPERZ that is out of date or no longer needed. <br/> <span class="Bold">Keep AFINITOR or AFINITOR DISPERZ and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">General information about the safe and effective use of AFINITOR and AFINITOR DISPERZ.</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AFINITOR or AFINITOR DISPERZ for a condition for which it was not prescribed. Do not give AFINITOR or AFINITOR DISPERZ to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about AFINITOR and AFINITOR DISPERZ. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals. </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What are the ingredients in AFINITOR?</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2">Active ingredient: everolimus.<br/>Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.</td> </tr> <tr> <td class="Lrule Rrule" colspan="2"><span class="Bold">What are the ingredients in AFINITOR DISPERZ?</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2">Active ingredient: everolimus.<br/>Inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.<br/> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="2">Distributed by:<br/>Novartis Pharmaceuticals Corporation<br/>East Hanover, New Jersey 07936<br/> <br/>The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis.<br/> <br/>© Novartis<br/> <br/>For more information call 1-888-669-6682 or go to www.AFINITOR.com. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td>This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: January 2025</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">PATIENT INFORMATION</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule\" valign=\"top\"><span class=\"Bold\">AFINITOR<span class=\"Sup\">®</span> (a-fin-it-or)<br/>(everolimus)<br/>tablets</span></td><td align=\"center\" class=\"Rrule\" valign=\"top\"><span class=\"Bold\">AFINITOR DISPERZ<span class=\"Sup\">®</span> (a-fin-it-or dis-perz)<br/>(everolimus tablets for oral suspension)</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\">Read this Patient Information leaflet that comes with AFINITOR or AFINITOR DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What is the most important information I should know about AFINITOR and AFINITOR DISPERZ?<br/>AFINITOR and AFINITOR DISPERZ can cause serious side effects, including:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">1. You may develop lung or breathing problems. </span>In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms:</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>New or worsening cough</li>\n<li>Shortness of breath</li>\n<li>Chest pain</li>\n<li>Difficulty breathing or wheezing</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">2. You may be more likely to develop an infection,</span> such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include active hepatitis B in people who have had hepatitis B in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible.\n\t\t\t\t\t\t\t\t\t\t<br/>Tell your healthcare provider right away if you have a temperature of 100.5˚F or above, chills, or do not feel well.\n\t\t\t\t\t\t\t\t\t\t<br/>Symptoms of hepatitis B or infection may include the following:</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul>\n<li>Fever</li>\n<li>Chills</li>\n<li>Skin rash</li>\n<li>Joint pain and swelling</li>\n<li>Tiredness</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul>\n<li>Loss of appetite</li>\n<li>Nausea</li>\n<li>Pale stools or dark urine</li>\n<li>Yellowing of the skin</li>\n<li>Pain in the upper right side of the stomach</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">3.\tSevere allergic reactions.</span> Call your healthcare provider or get medical help right away if you get signs and symptoms of a severe allergic reaction, including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">4.\tPossible increased risk for a type of allergic reaction called angioedema, </span>in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with AFINITOR or AFINITOR DISPERZ. Talk with your healthcare provider before taking AFINITOR or AFINITOR DISPERZ if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with AFINITOR or AFINITOR DISPERZ.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">5.\tMouth ulcers and sores.</span> Mouth ulcers and sores are common during treatment with AFINITOR or AFINITOR DISPERZ but can also be severe. When you start treatment with AFINITOR or AFINITOR DISPERZ, your healthcare provider may tell you to also start a prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare provider’s instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to restart this mouthwash or to use a special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">6.\tYou may develop kidney failure.</span> In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with AFINITOR or AFINITOR DISPERZ.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">If you have any of the serious side effects listed above, you may need to stop taking AFINITOR or AFINITOR DISPERZ for a while or use a lower dose. Follow your healthcare provider’s instructions.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What is AFINITOR?</span>\n<br/>AFINITOR is a prescription medicine used to treat:</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>advanced hormone receptor-positive, HER2-negative breast cancer, along with the medicine exemestane, in postmenopausal women who have already received certain other medicines for their cancer.</li>\n<li>adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (PNET), that has progressed and cannot be treated with surgery.</li>\n<li>adults with a type of cancer known as neuroendocrine tumor (NET) of the stomach and intestine (gastrointestinal), or lung that has progressed and cannot be treated with surgery.<br/>AFINITOR is not for use in people with carcinoid tumors that actively produce hormones.</li>\n<li>adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked.</li>\n<li>people with the following types of tumors that are seen with a genetic condition called tuberous sclerosis complex (TSC):\n\t\t\t\t\t\t\t\t\t\t\t\t<ul>\n<li>adults with a kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.</li>\n<li>adults and children 1 year of age and older with a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is AFINITOR DISPERZ?</span>\n<br/>AFINITOR DISPERZ is a prescription medicine used to treat:</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>adults and children 1 year of age and older with a genetic condition called tuberous sclerosis complex (TSC) who have a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.</li>\n<li>adults and children 2 years of age and older with a genetic condition called tuberous sclerosis complex (TSC) who have certain types of seizures (epilepsy), as an added treatment to other antiepileptic medicines.</li>\n</ul>\n<p class=\"First\">It is not known if AFINITOR and AFINITOR DISPERZ are safe and effective in children to treat:</p>\n<ul>\n<li>hormone receptor-positive, HER-2 negative breast cancer</li>\n<li>a type of cancer called neuroendocrine tumors (NET)</li>\n<li>kidney cancer (renal cell carcinoma)</li>\n<li>a kidney tumor called angiomyolipoma, that can happen in children with a genetic condition called tuberous sclerosis complex (TSC).</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Do not take AFINITOR or AFINITOR DISPERZ</span> if you have had a severe allergic reaction to everolimus.<br/>Talk to your healthcare provider before taking this medicine if you are allergic to:\n\t\t\t\t\t\t\t\t\t\t<ul>\n<li>a medicine that contains sirolimus</li>\n<li>a medicine that contains temsirolimus</li>\n</ul>\n\t\t\t\t\t\t\t\t\t\tAsk your healthcare provider if you do not know.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Before taking AFINITOR or AFINITOR DISPERZ, tell your healthcare provider about all of your medical conditions, including if you:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>Have or have had kidney problems</li>\n<li>Have or have had liver problems</li>\n<li>Have diabetes or high blood sugar</li>\n<li>Have high blood cholesterol levels</li>\n<li>Have any infections</li>\n<li>Previously had hepatitis B</li>\n<li>Are scheduled to receive any vaccinations. You should not receive a “live vaccine” or be around people who have recently received a “live vaccine” during your treatment with AFINITOR or AFINITOR DISPERZ. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. For children with TSC and SEGA or certain types of seizures, work with your healthcare provider to complete the recommended childhood series of vaccines before your child starts treatment with AFINITOR or AFINITOR DISPERZ.</li>\n<li>Are pregnant, can become pregnant, or have a partner who can become pregnant. AFINITOR or AFINITOR DISPERZ can cause harm to your unborn baby.<br/>\n<span class=\"Bold\">Females who are able to become pregnant:</span>\n<br/>◦ Your healthcare provider will give you a pregnancy test before you start treatment with AFINITOR or AFINITOR DISPERZ.<br/>◦ You should use effective birth control during treatment and for 8 weeks after your last dose of AFINITOR or AFINITOR DISPERZ.<br/>\n<span class=\"Bold\">Males</span> with a female partner, you should use effective birth control during treatment and for 4 weeks after your last dose of AFINITOR or AFINITOR DISPERZ.<br/>Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away.</li>\n<li>Are breastfeeding or plan to breastfeed. It is not known if AFINITOR or AFINITOR DISPERZ passes into your breast milk. Do not breastfeed during treatment and for 2 weeks after your last dose of AFINITOR or AFINITOR DISPERZ. </li>\n<li>Are planning to have surgery or if you have had a recent surgery. You should stop taking AFINITOR or AFINITOR DISPERZ at least 1 week before planned surgery. See <span class=\"Bold\">“What are the possible side effects of AFINITOR and AFINITOR DISPERZ?”</span>\n</li>\n<li>Have received radiation therapy or are planning to receive radiation therapy in the future. See <span class=\"Bold\">“What are the possible side effects of AFINITOR and AFINITOR DISPERZ?”</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Tell your healthcare provider about all of the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.<br/>AFINITOR or AFINITOR DISPERZ may affect the way other medicines work, and other medicines can affect how AFINITOR or AFINITOR DISPERZ work. Taking AFINITOR or AFINITOR DISPERZ with other medicines can cause serious side effects.<br/>Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Especially tell your healthcare provider if you take:</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>St. John’s Wort <span class=\"Italics\">(Hypericum perforatum)</span>\n</li>\n<li>Medicine for: \n\t\t\t\t\t\t\t\t\t\t\t\t<ul>\n<li>Fungal infections</li>\n<li>Bacterial infections</li>\n<li>Tuberculosis</li>\n<li>Seizures</li>\n<li>HIV-AIDS</li>\n<li>Heart conditions or high blood pressure</li>\n</ul>\n</li>\n<li>Medicines that weaken your immune system (your body’s ability to fight infections and other problems)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe a different medicine or your dose of AFINITOR or AFINITOR DISPERZ may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">How should I take AFINITOR or AFINITOR DISPERZ?</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>Your healthcare provider will prescribe the dose of AFINITOR or AFINITOR DISPERZ that is right for you.</li>\n<li>Take AFINITOR or AFINITOR DISPERZ exactly as your healthcare provider tells you to.</li>\n<li>Your healthcare provider may change your dose of AFINITOR or AFINITOR DISPERZ or tell you to temporarily interrupt dosing, if needed.</li>\n<li>\n<span class=\"Bold\">Take only AFINITOR or AFINITOR DISPERZ. Do not mix AFINITOR and AFINITOR DISPERZ together.</span>\n</li>\n<li>Use scissors to open the blister pack.</li>\n<li>Take AFINITOR or AFINITOR DISPERZ 1 time each day at about the same time.</li>\n<li>Take AFINITOR or AFINITOR DISPERZ the same way each time, either with food or without food.</li>\n<li>If you take too much AFINITOR or AFINITOR DISPERZ, contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of AFINITOR or AFINITOR DISPERZ with you.</li>\n<li>If you miss a dose of AFINITOR or AFINITOR DISPERZ, you may take it if it is <span class=\"Bold\">less than 6 hours</span> after the time you normally take it. If it is <span class=\"Bold\">more than 6 hours</span> after you normally take your AFINITOR or AFINITOR DISPERZ, skip the dose for that day. The next day, take AFINITOR or AFINITOR DISPERZ at your usual time. Do not take 2 doses to make up for a missed dose. If you are not sure about what to do, call your healthcare provider.</li>\n<li>You should have blood tests before you start AFINITOR or AFINITOR DISPERZ and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels.</li>\n<li>If you take AFINITOR or AFINITOR DISPERZ to treat SEGA or AFINITOR DISPERZ to treat certain types of seizures with TSC, you will also need to have blood tests regularly to measure how much medicine is in your blood. This will help your healthcare provider decide how much AFINITOR or AFINITOR DISPERZ you need to take.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">AFINITOR:</span>\n<ul>\n<li>Swallow AFINITOR tablets whole with a glass of water. Do not take any tablet that is broken or crushed.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">AFINITOR DISPERZ:</span>\n<ul>\n<li>If your healthcare provider prescribes AFINITOR DISPERZ for you, see the “Instructions for Use” that comes with your medicine for instructions on how to prepare and take your dose.</li>\n<li>Each dose of AFINITOR DISPERZ must be prepared as a suspension before it is given.</li>\n<li>AFINITOR DISPERZ can cause harm to an unborn baby. When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.</li>\n<li>Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What should I avoid while taking AFINITOR or AFINITOR DISPERZ? </span>\n<br/>You should not drink grapefruit juice or eat grapefruit during your treatment with AFINITOR or AFINITOR DISPERZ. It may make the amount of AFINITOR or AFINITOR DISPERZ in your blood increase to a harmful level.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of AFINITOR or AFINITOR DISPERZ?</span>\n<br/>\n<span class=\"Bold\">AFINITOR and AFINITOR DISPERZ can cause serious side effects, including:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>\n<span class=\"Bold\">See “What is the most important information I should know about AFINITOR and AFINITOR DISPERZ?” for more information.</span>\n</li>\n<li>\n<span class=\"Bold\">Risk of wound healing problems.</span> Wounds may not heal properly during AFINITOR and AFINITOR DISPERZ treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with AFINITOR and AFINITOR DISPERZ.\n\t\t\t\t\t\t\t\t\t\t\t\t<ul class=\"Circle\">\n<li>You should stop taking AFINITOR and AFINITOR DISPERZ at least 1 week before planned surgery.</li>\n<li>Your healthcare provider should tell you when you may start taking AFINITOR and AFINITOR DISPERZ again after surgery.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Increased blood sugar and fat (cholesterol and triglyceride) levels in the blood.</span> Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with AFINITOR or AFINITOR DISPERZ.</li>\n<li>\n<span class=\"Bold\">Decreased blood cell counts.</span> AFINITOR and AFINITOR DISPERZ can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with AFINITOR or AFINITOR DISPERZ.</li>\n<li>\n<span class=\"Bold\">Worsening side effects from radiation treatment, </span> that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">The most common side effects of AFINITOR in people with advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of the pancreas, stomach and intestine (gastrointestinal) or lung, and advanced kidney cancer include:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul>\n<li>Infections</li>\n<li>Rash</li>\n<li>Feeling weak or tired</li>\n<li>Diarrhea</li>\n<li>Swelling of arms, hands, feet, ankles, face, or other parts of the body</li>\n</ul>\n</td><td class=\"Rrule\" valign=\"top\">\n<ul>\n<li>Stomach-area (abdominal) pain</li>\n<li>Nausea</li>\n<li>Fever</li>\n<li>Cough</li>\n<li>Headache</li>\n<li>Decreased appetite</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">The most common side effects of AFINITOR and AFINITOR DISPERZ in people who have SEGA, renal angiomyolipoma, or certain types of seizures with TSC include</span> respiratory tract infections.\n\t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Other side effects that may occur with AFINITOR and AFINITOR DISPERZ:</span>\n<ul>\n<li>Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens.</li>\n<li>AFINITOR and AFINITOR DISPERZ may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</li>\n<li>AFINITOR and AFINITOR DISPERZ may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.</li>\n</ul>\n<p class=\"First\">Tell your healthcare provider if you have any side effect that bothers you or does not go away.</p>\n<p>These are not all the possible side effects of AFINITOR and AFINITOR DISPERZ. For more information, ask your healthcare provider or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">How should I store AFINITOR or AFINITOR DISPERZ?</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul>\n<li>Store AFINITOR or AFINITOR DISPERZ at room temperature, between 68°F to 77°F (20°C to 25°C). </li>\n<li>Keep AFINITOR or AFINITOR DISPERZ in the pack it comes in.</li>\n<li>Open the blister pack just before taking AFINITOR or AFINITOR DISPERZ.</li>\n<li>Keep AFINITOR or AFINITOR DISPERZ dry and away from light.</li>\n<li>Do not use AFINITOR or AFINITOR DISPERZ that is out of date or no longer needed.\n\t\t\t\t\t\t\t\t\t\t\t\t<br/>\n<span class=\"Bold\">Keep AFINITOR or AFINITOR DISPERZ and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">General information about the safe and effective use of AFINITOR and AFINITOR DISPERZ.</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AFINITOR or AFINITOR DISPERZ for a condition for which it was not prescribed. Do not give AFINITOR or AFINITOR DISPERZ to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about AFINITOR and AFINITOR DISPERZ. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals.\n\t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in AFINITOR?</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">Active ingredient: everolimus.<br/>Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in AFINITOR DISPERZ?</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">Active ingredient: everolimus.<br/>Inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.<br/>\n<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule\" colspan=\"2\">Distributed by:<br/>Novartis Pharmaceuticals Corporation<br/>East Hanover, New Jersey 07936<br/>\n<br/>The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis.<br/>\n<br/>© Novartis<br/>\n<br/>For more information call 1-888-669-6682 or go to www.AFINITOR.com.\n\t\t\t\t\t\t\t\t\t</td>\n</tr>\n</tbody>\n</table></div>" }

T2025-02

{ "type": "p", "children": [], "text": "T2025-02" }

Instructions For Use AFINITOR (a-fin-it-or) DISPERZ® (dis-perz) (everolimus tablets for oral suspension)

{ "type": "p", "children": [], "text": "\nInstructions For Use\n\nAFINITOR (a-fin-it-or) DISPERZ® (dis-perz)\n\n(everolimus tablets for oral suspension)\n" }

Read these Instructions for Use for AFINITOR DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read these Instructions for Use for AFINITOR DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment." }

Important Information:

{ "type": "p", "children": [], "text": "\nImportant Information:\n" }

{ "type": "ul", "children": [ "\nTake AFINITOR DISPERZ as a suspension only. AFINITOR DISPERZ is prepared as a suspension of undissolved medicine that is mixed with water, and then it is taken by mouth. Do not chew, crush, or swallow AFINITOR DISPERZ whole.", "\nAFINITOR DISPERZ can cause harm to an unborn baby. When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.", "Keep AFINITOR DISPERZ and the prepared suspension out of the reach of children.", "Anyone who prepares suspensions of AFINITOR DISPERZ for another person should wear gloves to avoid possible contact with the drug.", "Only use water with AFINITOR DISPERZ to prepare the suspension. Do not prepare the suspension with juice or any other liquids.", "The suspension must be given right away. If you do not give the dose within 60 minutes after it has been prepared, throw away the dose and prepare a new dose of AFINITOR DISPERZ.", "Before starting to prepare the suspension, collect all of the supplies that you will need to prepare and take the suspension. Do not use any of these supplies for purposes other than preparing and taking the AFINITOR DISPERZ suspension." ], "text": "" }

Supplies needed to prepare the suspension in an oral syringe:

{ "type": "p", "children": [], "text": "\nSupplies needed to prepare the suspension in an oral syringe:\n" }

{ "type": "ul", "children": [ "Blister card with AFINITOR DISPERZ", "Scissors to open the blister card", "Disposable gloves (for one time use)", "2 clean drinking glasses", "Approximately 30 mL of water", "10 mL oral syringe (for one time use) (see Figure A)", "Paper towels" ], "text": "" }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

Supplies needed to prepare the suspension in a small drinking glass:

{ "type": "p", "children": [], "text": "\nSupplies needed to prepare the suspension in a small drinking glass: \n" }

{ "type": "ul", "children": [ "Blister card with AFINITOR DISPERZ", "Scissors to open the blister card", "Disposable gloves (for one time use)", "30 mL dose cup for measuring water (you can ask your pharmacist for this)", "1 clean drinking glass (maximum size 100 mL)", "Water to prepare the suspension", "Spoon for stirring", "Paper towels" ], "text": "" }

Preparing a dose of AFINITOR DISPERZ suspension using an oral syringe:

{ "type": "p", "children": [], "text": "\nPreparing a dose of AFINITOR DISPERZ suspension using an oral syringe:\n" }

Step 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

{ "type": "p", "children": [], "text": "\nStep 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel." }

Step 2: Wash and dry your hands well before preparing the medicine (see Figure B).

{ "type": "p", "children": [], "text": "\nStep 2: Wash and dry your hands well before preparing the medicine (see Figure B)." }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

Step 3: If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure C).

{ "type": "p", "children": [], "text": "\nStep 3: If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure C)." }

Figure C

{ "type": "p", "children": [], "text": "\nFigure C\n" }

Step 4: Take a 10 mL oral syringe and pull back on the plunger. Remove the plunger from the barrel of the syringe (see Figure D).

{ "type": "p", "children": [], "text": "\nStep 4: Take a 10 mL oral syringe and pull back on the plunger. Remove the plunger from the barrel of the syringe (see Figure D)." }

Figure D

{ "type": "p", "children": [], "text": "\nFigure D\n" }

Step 5: Use scissors to open the blister card along the dotted line (see Figure E) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card. Place them into the barrel of the oral syringe (see Figure F).

{ "type": "p", "children": [], "text": "\nStep 5: Use scissors to open the blister card along the dotted line (see Figure E) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card. Place them into the barrel of the oral syringe (see Figure F)." }

Figure E

{ "type": "p", "children": [], "text": "\nFigure E\n" }

Figure F

{ "type": "p", "children": [], "text": "\nFigure F\n" }

{ "type": "ul", "children": [ "Doses of up to 10 mg can be prepared with the oral syringe. If your total prescribed dose is more than 10 mg, you will need to split the dose. Follow steps 4 through 17 for the first half of the dose. Then repeat steps 4 through 17 for the second half of the dose. Do not prepare a dose of more than 10 mg in one syringe. Ask your pharmacist or healthcare provider if you are not sure what to do." ], "text": "" }

Step 6: Re-insert the plunger into the barrel of the oral syringe (see Figure G) and push the plunger in until it comes into contact with the AFINITOR DISPERZ tablets for oral suspension (see Figure H).

{ "type": "p", "children": [], "text": "\nStep 6: Re-insert the plunger into the barrel of the oral syringe (see Figure G) and push the plunger in until it comes into contact with the AFINITOR DISPERZ tablets for oral suspension (see Figure H)." }

Figure G

{ "type": "p", "children": [], "text": "\nFigure G\n" }

Figure H

{ "type": "p", "children": [], "text": "\nFigure H\n" }

Step 7: Fill a small drinking glass with about 30 mL of water. Insert the tip of the oral syringe into the water. Then slowly pull back on the plunger until the syringe is about half full of water and all the tablets are covered by water (see Figure I).

{ "type": "p", "children": [], "text": "\nStep 7: Fill a small drinking glass with about 30 mL of water. Insert the tip of the oral syringe into the water. Then slowly pull back on the plunger until the syringe is about half full of water and all the tablets are covered by water (see Figure I)." }

Figure I

{ "type": "p", "children": [], "text": "\nFigure I\n" }

Step 8: Hold the oral syringe with the tip pointing up. Pull back on the plunger to draw back about 4 mL of air (see Figure J).

{ "type": "p", "children": [], "text": "\nStep 8: Hold the oral syringe with the tip pointing up. Pull back on the plunger to draw back about 4 mL of air (see Figure J). " }

Figure J

{ "type": "p", "children": [], "text": "\nFigure J\n" }

Step 9: Place the filled oral syringe in the clean, empty glass with the tip pointing up. Wait 3 minutes to allow AFINITOR DISPERZ to break apart (see Figure K).

{ "type": "p", "children": [], "text": "\nStep 9: Place the filled oral syringe in the clean, empty glass with the tip pointing up. Wait 3 minutes to allow AFINITOR DISPERZ to break apart (see Figure K)." }

Figure K

{ "type": "p", "children": [], "text": "\nFigure K\n" }

Step 10: Slowly turn the oral syringe up and down five times just before giving the dose (see Figure L). Do not shake the syringe.

{ "type": "p", "children": [], "text": "\nStep 10: Slowly turn the oral syringe up and down five times just before giving the dose (see Figure L). Do not shake the syringe." }

Figure L

{ "type": "p", "children": [], "text": "\nFigure L\n" }

Step 11: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure M).

{ "type": "p", "children": [], "text": "\nStep 11: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure M)." }

Figure M

{ "type": "p", "children": [], "text": "\nFigure M\n" }

Step 12: Give the full contents of the oral syringe slowly and gently into the mouth right away, within 60 minutes of preparing it (see Figure N). Carefully remove the syringe from the mouth. Continue with steps 13 through 17 to make sure that the entire dose of medicine is given.

{ "type": "p", "children": [], "text": "\nStep 12: Give the full contents of the oral syringe slowly and gently into the mouth right away, within 60 minutes of preparing it (see Figure N). Carefully remove the syringe from the mouth. Continue with steps 13 through 17 to make sure that the entire dose of medicine is given." }

Figure N

{ "type": "p", "children": [], "text": "\nFigure N\n" }

Step 13: Insert the tip of the oral syringe into the drinking glass that is filled with water, and pull up about 5 mL of water by slowly pulling back on the plunger (see Figure O).

{ "type": "p", "children": [], "text": "\nStep 13: Insert the tip of the oral syringe into the drinking glass that is filled with water, and pull up about 5 mL of water by slowly pulling back on the plunger (see Figure O)." }

Figure O

{ "type": "p", "children": [], "text": "\nFigure O\n" }

Step 14: Hold the oral syringe with the tip pointing up and use the plunger to draw back about 4 mL of air (see Figure P).

{ "type": "p", "children": [], "text": "\nStep 14: Hold the oral syringe with the tip pointing up and use the plunger to draw back about 4 mL of air (see Figure P)." }

Figure P

{ "type": "p", "children": [], "text": "\nFigure P\n" }

Step 15: With the tip of the syringe still pointing up, swirl the contents by gently rotating the syringe in a circular motion (see Figure Q).

{ "type": "p", "children": [], "text": "\nStep 15: With the tip of the syringe still pointing up, swirl the contents by gently rotating the syringe in a circular motion (see Figure Q)." }

Figure Q

{ "type": "p", "children": [], "text": "\nFigure Q\n" }

Step 16: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure R).

{ "type": "p", "children": [], "text": "\nStep 16: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure R)." }

Figure R

{ "type": "p", "children": [], "text": "\nFigure R\n" }

Step 17: Give the full contents of the oral syringe slowly and gently into the mouth by pushing on the plunger (see Figure S). Carefully remove the syringe from the mouth.

{ "type": "p", "children": [], "text": "\nStep 17: Give the full contents of the oral syringe slowly and gently into the mouth by pushing on the plunger (see Figure S). Carefully remove the syringe from the mouth." }

Figure S

{ "type": "p", "children": [], "text": "\nFigure S\n" }

If the total prescribed dose is more than 10 mg, repeat steps 4 through 17 to finish giving the dose.

{ "type": "p", "children": [], "text": "\nIf the total prescribed dose is more than 10 mg, repeat steps 4 through 17 to finish giving the dose.\n" }

Step 18: Throw away the oral syringe, paper towel, and used gloves in your household trash.

{ "type": "p", "children": [], "text": "\nStep 18: Throw away the oral syringe, paper towel, and used gloves in your household trash." }

Step 19: Wash your hands.

{ "type": "p", "children": [], "text": "\nStep 19: Wash your hands." }

Preparing a dose of AFINITOR DISPERZ suspension using a small drinking glass:

{ "type": "p", "children": [], "text": "\nPreparing a dose of AFINITOR DISPERZ suspension using a small drinking glass:\n" }

Step 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

{ "type": "p", "children": [], "text": "\nStep 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel." }

Step 2: Wash and dry your hands before preparing the medicine (see Figure T).

{ "type": "p", "children": [], "text": "\nStep 2: Wash and dry your hands before preparing the medicine (see Figure T)." }

Figure T

{ "type": "p", "children": [], "text": "\nFigure T\n" }

Step 3: If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure U).

{ "type": "p", "children": [], "text": "\nStep 3: If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure U)." }

Figure U

{ "type": "p", "children": [], "text": "\nFigure U\n" }

Step 4: Add about 25 mL of water to the 30 mL dose cup. The amount of water added does not need to be exact (see Figure V).

{ "type": "p", "children": [], "text": "\nStep 4: Add about 25 mL of water to the 30 mL dose cup. The amount of water added does not need to be exact (see Figure V)." }

Figure V

{ "type": "p", "children": [], "text": "\nFigure V\n" }

Step 5: Pour the water from the dose cup into a small drinking glass (maximum size 100 mL) (see Figure W).

{ "type": "p", "children": [], "text": "\nStep 5: Pour the water from the dose cup into a small drinking glass (maximum size 100 mL) (see Figure W)." }

Figure W

{ "type": "p", "children": [], "text": "\nFigure W\n" }

{ "type": "ul", "children": [ "Doses up to 10 mg can be prepared in the small drinking glass. If your total prescribed dose is more than 10 mg, you will need to split the dose. Follow steps 4 through 10 for the first half of the dose. Then repeat steps 4 through 10 for the second half of the dose. Ask your pharmacist or healthcare provider if you are not sure what to do." ], "text": "" }

Step 6: Use scissors to open the blister card along the dotted line (see Figure X) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card.

{ "type": "p", "children": [], "text": "\nStep 6: Use scissors to open the blister card along the dotted line (see Figure X) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card." }

Figure X

{ "type": "p", "children": [], "text": "\nFigure X\n" }

Step 7: Add the prescribed number of AFINITOR DISPERZ tablets for oral suspension into the water (see Figure Y).

{ "type": "p", "children": [], "text": "\nStep 7: Add the prescribed number of AFINITOR DISPERZ tablets for oral suspension into the water (see Figure Y)." }

Figure Y

{ "type": "p", "children": [], "text": "\nFigure Y\n" }

Step 8: Wait 3 minutes to allow AFINITOR DISPERZ tablets for oral suspension to break apart (see Figure Z).

{ "type": "p", "children": [], "text": "\nStep 8: Wait 3 minutes to allow AFINITOR DISPERZ tablets for oral suspension to break apart (see Figure Z)." }

Figure Z

{ "type": "p", "children": [], "text": "\nFigure Z\n" }

Step 9: Gently stir the contents of the glass with a spoon and place the spoon back on the paper towel (see Figure AA). Drink the full amount of the suspension right away, within 60 minutes of preparing it (see Figure BB).

{ "type": "p", "children": [], "text": "\nStep 9: Gently stir the contents of the glass with a spoon and place the spoon back on the paper towel (see Figure AA). Drink the full amount of the suspension right away, within 60 minutes of preparing it (see Figure BB)." }

Figure AA

{ "type": "p", "children": [], "text": "\nFigure AA\n" }

Figure BB

{ "type": "p", "children": [], "text": "\nFigure BB\n" }

Step 10: Refill the glass with the same amount of water (about 25 mL). Stir the contents with the same spoon and place the spoon back on the paper towel (see Figure CC). Drink the full amount right away so that you take any remaining medicine (see Figure DD).

{ "type": "p", "children": [], "text": "\nStep 10: Refill the glass with the same amount of water (about 25 mL). Stir the contents with the same spoon and place the spoon back on the paper towel (see Figure CC). Drink the full amount right away so that you take any remaining medicine (see Figure DD)." }

Figure CC

{ "type": "p", "children": [], "text": "\nFigure CC\n" }

Figure DD

{ "type": "p", "children": [], "text": "\nFigure DD\n" }

If your total prescribed dose is more than 10 mg, repeat steps 4 through 10 to finish taking your dose.

{ "type": "p", "children": [], "text": "\nIf your total prescribed dose is more than 10 mg, repeat steps 4 through 10 to finish taking your dose.\n" }

Step 11: Wash the glass and the spoon thoroughly with water. Wipe the glass and spoon with a clean paper towel and store them in a dry and clean place until your next dose of AFINITOR DISPERZ (see Figure EE).

{ "type": "p", "children": [], "text": "\nStep 11: Wash the glass and the spoon thoroughly with water. Wipe the glass and spoon with a clean paper towel and store them in a dry and clean place until your next dose of AFINITOR DISPERZ (see Figure EE)." }

Figure EE

{ "type": "p", "children": [], "text": "\nFigure EE\n" }

Step 12: Throw away the used paper towel and gloves in your household trash.

{ "type": "p", "children": [], "text": "\nStep 12: Throw away the used paper towel and gloves in your household trash. " }

Step 13: Wash your hands.

{ "type": "p", "children": [], "text": "\nStep 13: Wash your hands." }

How should I store AFINITOR DISPERZ?

{ "type": "p", "children": [], "text": "\nHow should I store AFINITOR DISPERZ?\n" }

{ "type": "ul", "children": [ "Store AFINITOR DISPERZ at room temperature, between 68°F to 77°F (20°C to 25°C).", "Keep AFINITOR DISPERZ in the pack it comes in.", "Open the blister pack just before taking AFINITOR DISPERZ.", "Keep AFINITOR DISPERZ dry and away from light.", "Do not use AFINITOR DISPERZ that is out of date or no longer needed." ], "text": "" }

Keep AFINITOR DISPERZ and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep AFINITOR DISPERZ and all medicines out of the reach of children.\n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

{ "type": "p", "children": [], "text": "\n\t\t\t\t\t\tDistributed by:\n\t\t\t\t\t\tNovartis Pharmaceuticals Corporation\n\t\t\t\t\t\tEast Hanover, New Jersey 07936" }

T2018-82June 2018

{ "type": "p", "children": [], "text": "T2018-82June 2018" }

NDC 0078-0594-51

{ "type": "p", "children": [], "text": "NDC 0078-0594-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets

{ "type": "p", "children": [], "text": "28 Tablets" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR® (everolimus) tablets

{ "type": "p", "children": [], "text": "AFINITOR®\n(everolimus) tablets" }

Each tablet contains

{ "type": "p", "children": [], "text": "Each tablet contains" }

2.5 mg

{ "type": "p", "children": [], "text": "2.5 mg" }

everolimus

{ "type": "p", "children": [], "text": "everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0566-51

{ "type": "p", "children": [], "text": "NDC 0078-0566-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets

{ "type": "p", "children": [], "text": "28 Tablets" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR® (everolimus) tablets

{ "type": "p", "children": [], "text": "AFINITOR®\n(everolimus) tablets" }

Each tablet contains

{ "type": "p", "children": [], "text": "Each tablet contains" }

5 mg

{ "type": "p", "children": [], "text": "5 mg" }

everolimus

{ "type": "p", "children": [], "text": "everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0620-51

{ "type": "p", "children": [], "text": "NDC 0078-0620-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets

{ "type": "p", "children": [], "text": "28 Tablets" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR® (everolimus) tablets

{ "type": "p", "children": [], "text": "AFINITOR®\n(everolimus) tablets" }

Each tablet contains

{ "type": "p", "children": [], "text": "Each tablet contains" }

7.5 mg

{ "type": "p", "children": [], "text": "7.5 mg" }

everolimus

{ "type": "p", "children": [], "text": "everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0567-51

{ "type": "p", "children": [], "text": "NDC 0078-0567-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets

{ "type": "p", "children": [], "text": "28 Tablets" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR® (everolimus) tablets

{ "type": "p", "children": [], "text": "AFINITOR®\n(everolimus) tablets" }

Each tablet contains

{ "type": "p", "children": [], "text": "Each tablet contains" }

10 mg

{ "type": "p", "children": [], "text": "10 mg" }

everolimus

{ "type": "p", "children": [], "text": "everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0626-51

{ "type": "p", "children": [], "text": "NDC 0078-0626-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets for Oral Suspension

{ "type": "p", "children": [], "text": "28 Tablets for Oral Suspension" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR DISPERZ® (everolimus tablets for oral suspension)

{ "type": "p", "children": [], "text": "AFINITOR DISPERZ®\n(everolimus tablets for oral suspension)" }

2 mg

{ "type": "p", "children": [], "text": "2 mg" }

TABLETS MUST BE DISPERSED IN WATER.

{ "type": "p", "children": [], "text": "TABLETS MUST BE DISPERSED IN WATER." }

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

{ "type": "p", "children": [], "text": "TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED." }

Each tablet contains 2 mg everolimus

{ "type": "p", "children": [], "text": "Each tablet contains 2 mg everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0627-51

{ "type": "p", "children": [], "text": "NDC 0078-0627-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets for Oral Suspension

{ "type": "p", "children": [], "text": "28 Tablets for Oral Suspension" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR DISPERZ® (everolimus tablets for oral suspension)

{ "type": "p", "children": [], "text": "AFINITOR DISPERZ®\n(everolimus tablets for oral suspension)" }

3 mg

{ "type": "p", "children": [], "text": "3 mg" }

TABLETS MUST BE DISPERSED IN WATER.

{ "type": "p", "children": [], "text": "TABLETS MUST BE DISPERSED IN WATER." }

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

{ "type": "p", "children": [], "text": "TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED." }

Each tablet contains 3 mg everolimus

{ "type": "p", "children": [], "text": "Each tablet contains 3 mg everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

NDC 0078-0628-51

{ "type": "p", "children": [], "text": "NDC 0078-0628-51" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

28 Tablets for Oral Suspension

{ "type": "p", "children": [], "text": "28 Tablets for Oral Suspension" }

Carton contains 4 individual blister cards of 7 tablets.

{ "type": "p", "children": [], "text": "Carton contains 4 individual blister cards of 7 tablets." }

AFINITOR DISPERZ® (everolimus tablets for oral suspension)

{ "type": "p", "children": [], "text": "AFINITOR DISPERZ®\n(everolimus tablets for oral suspension)" }

5 mg

{ "type": "p", "children": [], "text": "5 mg" }

TABLETS MUST BE DISPERSED IN WATER.

{ "type": "p", "children": [], "text": "TABLETS MUST BE DISPERSED IN WATER." }

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

{ "type": "p", "children": [], "text": "TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED." }

Each tablet contains 5 mg everolimus

{ "type": "p", "children": [], "text": "Each tablet contains 5 mg everolimus" }

NOVARTIS

{ "type": "p", "children": [], "text": "NOVARTIS" }

Everolimus tablets are indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunologic risk receiving a kidney transplant [see Clinical Studies (14.1)]. Everolimus tablets are to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus and cyclosporine is recommended for all patients receiving these products [see Dosage and Administration (2.2, 2.3)].

Everolimus tablets are indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus tablets are to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [see Warnings and Precautions (5.5), Clinical Studies (14.2)]. TDM of everolimus and tacrolimus is recommended for all patients receiving these products [see Dosage and Administration (2.3, 2.5)].

The safety and efficacy of everolimus tablets has not been established in the following populations:

An initial everolimus tablets dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine, administered as soon as possible after transplantation [see Dosage and Administration (2.3, 2.4), Clinical Studies (14.1)]. 

Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.

Start everolimus tablets at least 30 days posttransplant. An initial dose of 1 mg orally twice daily (2 mg per day) is recommended for adult liver transplant patients in combination with reduced-dose tacrolimus [see Dosage and Administration (2.3, 2.5), Clinical Studies (14.2)].

Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.

Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended everolimus therapeutic range is 3 to 8 ng/mL [see Clinical Pharmacology(12.7)]. Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors or cannabidiol, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations [see Drug Interactions (7),Clinical Pharmacology (12.7, 12.8)].

There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced [see Drug Interactions (7.2)].

The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay.

Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the risk of nephrotoxicity [see Warnings and Precautions (5.6), Drug Interactions (7.2), Clinical Pharmacology (12.8)].

The recommended cyclosporine therapeutic ranges when administered with everolimus tablets are 100 to 200 ng/mL through Month 1 posttransplant, 75 to 150 ng/mL at Months 2 and 3 posttransplant, 50 to 100 ng/mL at Month 4 posttransplant, and 25 to 50 ng/mL from Month 6 through Month 12 posttransplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 posttransplant and between 111 to 140 ng/mL at Months 2 and 3 posttransplant. The median trough concentration was 99 ng/mL at Month 4 posttransplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 posttransplant [see Clinical Pharmacology (12.8), Clinical Studies (14.1)]. 

Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible, and no later than 48 hours after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards.

If impairment of renal function is progressive, the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations [see Clinical Pharmacology (12.8)].

In renal transplantation, there are limited data regarding dosing everolimus tablets with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Everolimus tablets have not been evaluated in clinical trials with other formulations of cyclosporine. Prior to dose reduction of cyclosporine, it should be ascertained that steady-state everolimus whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced [see Drug Interactions (7.2)].

Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the potential risk of nephrotoxicity [see Warnings and Precautions (5.6), Clinical Pharmacology (12.9)].

The recommended tacrolimus therapeutic range when administered with everolimus tablets are whole blood trough (C-0h) concentrations of 3 to 5 ng/mL by three weeks after the first dose of everolimus tablets (approximately Month 2) and through Month 12 posttransplant.

The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 posttransplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 posttransplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 posttransplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 posttransplant [see Clinical Pharmacology (12.9), Clinical Studies (14.2)].

Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided.

In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations [see Clinical Pharmacology (12.9)].

In liver transplantation, there are limited data regarding dosing everolimus tablets with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus, it should be ascertained that the steady-state everolimus whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do not decrease if the tacrolimus exposure is reduced.

Everolimus tablets should be swallowed whole with a glass of water and not crushed before use.

Administer everolimus tablets consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus [see Clinical Pharmacology (12.3)].

Whole blood trough concentrations of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [see Clinical Pharmacology (12.6)]. 

Everolimus tablets are available as 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg tablets.

{ "type": "p", "children": [], "text": "\nEverolimus tablets are available as 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg tablets.\n" }

Table 1. Description of everolimus tablets

{ "type": "p", "children": [], "text": "\nTable 1. Description of everolimus tablets \n" }

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">Dosage strength</span></td><td><span class="Bold">0.25 mg</span></td><td><span class="Bold">0.5 mg</span></td><td><span class="Bold">0.75 mg</span></td><td><span class="Bold">1 mg</span></td> </tr> <tr> <td><span class="Bold">Appearance</span></td><td align="center" colspan="4">White to off white, round shaped, flat faced bevelled edge tablets</td> </tr> <tr class="Last"> <td><span class="Bold">Imprint</span></td><td>Debossed B1 on one side and plain on other side.</td><td>Debossed B2 on one side and plain on other side.</td><td>Debossed B3 on one side and plain on other side.</td><td>Debossed B4 on one side and plain on other side.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<col/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td><span class=\"Bold\">Dosage strength</span></td><td><span class=\"Bold\">0.25 mg</span></td><td><span class=\"Bold\">0.5 mg</span></td><td><span class=\"Bold\">0.75 mg</span></td><td><span class=\"Bold\">1 mg</span></td>\n</tr>\n<tr>\n<td><span class=\"Bold\">Appearance</span></td><td align=\"center\" colspan=\"4\">White to off white, round shaped, flat faced bevelled edge tablets</td>\n</tr>\n<tr class=\"Last\">\n<td><span class=\"Bold\">Imprint</span></td><td>Debossed B1 on one side and plain on other side.</td><td>Debossed B2 on one side and plain on other side.</td><td>Debossed B3 on one side and plain on other side.</td><td>Debossed B4 on one side and plain on other side.</td>\n</tr>\n</tbody>\n</table></div>" }

Everolimus tablets are contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product. 

Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe everolimus tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. In limited data with the complete elimination of calcineurin inhibition (CNI), there was an increased risk of acute rejection.

Patients receiving immunosuppressants, including everolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Patients receiving immunosuppressants, including everolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.13), Adverse Reactions (6.1, 6.2)]. These infections may lead to serious, including fatal, outcomes. Because of the danger of over-immunosuppression, which can cause increased susceptibility to infection, combination immunosuppressant therapy should be used with caution.

Antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients.

An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days posttransplantation [see Boxed Warning].

Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT). Reported cases mostly have occurred within the first 30 days posttransplant and most also lead to graft loss or death. Therefore, everolimus tablets should not be administered earlier than 30 days after liver transplant.

In kidney transplant recipients, everolimus with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combination with everolimus in order to reduce renal dysfunction [see Boxed Warning, Indications and Usage (1.1), Clinical Pharmacology (12.8)]. 

In liver transplant recipients, everolimus has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with everolimus in order to minimize the potential risk of nephrotoxicity [see Indications and Usage (1.2), Clinical Pharmacology (12.9)]. 

Renal function should be monitored during the administration of everolimus. Consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related. Caution should be exercised when using other drugs which are known to impair renal function.

In a clinical trial of de novo heart transplant patients, everolimus in an immunosuppressive regimen, with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months posttransplantation compared to the control regimen. Use of everolimus in heart transplantation is not recommended.

Everolimus has been associated with the development of angioedema. The concomitant use of everolimus with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.

Everolimus increases the risk of delayed wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele and seroma. These wound-related complications may require more surgical intervention. Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported.

A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations. Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension [including pulmonary arterial hypertension (PAH)] as a secondary event, have occurred in patients receiving rapamycins and their derivatives, including everolimus. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.

Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of everolimus and the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations [see Adverse Reactions (6.2)]. Use of anti-lipid therapy may not normalize lipid levels in patients receiving everolimus tablets. 

Any patient who is administered everolimus tablets should be monitored for hyperlipidemia. If detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing everolimus. Similarly, the risk/benefit of continued everolimus tablets therapy should be reevaluated in patients with severe refractory hyperlipidemia. Everolimus has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL.

Due to an interaction with cyclosporine, clinical trials of everolimus and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During everolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents [see Drug Interactions (7.7)].

The use of everolimus in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving everolimus tablets should be monitored for proteinuria [see Adverse Reactions (6.2)].

Patients receiving immunosuppressants, including everolimus, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving immunosuppressants, including everolimus. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.2)]. Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. 

Coadministration of everolimus with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) or strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations [see Drug Interactions (7)].

The concomitant use of everolimus with cyclosporine may increase the risk of thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Monitor hematologic parameters [see Adverse Reactions (6.2)].

Everolimus has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients using everolimus.

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], everolimus may cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception while using everolimus tablets and for 8 weeks after ending treatment [see Use in Specific Populations (8.1, 8.3)].

Azoospermia or oligospermia may be observed [see Adverse Reactions (6.2), Nonclinical Toxicology (13.1)]. Everolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

The use of live vaccines should be avoided during treatment with everolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus and cyclosporine or tacrolimus.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take everolimus as this may result in diarrhea and malabsorption.

When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol [see Dosage and Administration (2.3), Drug Interactions (7.13)].

The following adverse reactions are discussed in greater detail in other sections of the label.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Kidney Transplantation

The data described below reflect exposure to everolimus in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled everolimus at an initial everolimus starting dose of 1.5 mg per day [target trough concentrations 3 to 8 ng/mL with reduced exposure cyclosporine (N = 274) compared to mycophenolic acid (N = 273) with standard exposure cyclosporine]. All patients received basiliximab induction therapy and corticosteroids. The population was between 18 and 70 years, more than 43% were 50 years of age or older (mean age was 46 years in the everolimus group, 47 years control group); a majority of recipients were male (64% in the everolimus group, 69% control group); and a majority of patients were Caucasian (70% in the everolimus group, 69% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups and included hypertension/nephrosclerosis, glomerulonephritis/glomerular disease and diabetes mellitus. Significantly more patients discontinued everolimus 1.5 mg per day treatment (83/277, 30%) than discontinued the control regimen (60/277, 22%). Of those patients who prematurely discontinued treatment, most discontinuations were due to adverse reactions: 18% in the everolimus group compared to 9% in the control group (p-value = 0.004). This difference was more prominent between treatment groups among female patients. In those patients discontinuing study medication, adverse reactions were collected up to 7 days after study medication discontinuation and serious adverse reactions up to 30 days after study medication discontinuation.

Discontinuation of everolimus at a higher dose (3 mg per day) was 95/279, 34%, including 20% due to adverse reactions, and this regimen is not recommended (see below).

The overall incidences of serious adverse reactions were 57% (159/278) in the everolimus group and 52% (141/273) in the mycophenolic acid group. Infections and infestations reported as serious adverse reactions had the highest incidence in both groups [20% (54/274) in the everolimus group and 25% (69/273) in the control group]. The difference was mainly due to the higher incidence of viral infections in the mycophenolic acid group, mainly CMV and BK virus infections. Injury, poisoning and procedural complications reported as serious adverse reactions had the second highest incidence in both groups [14% (39/274) in the everolimus group and 12% (32/273) in the control group] followed by renal and urinary disorders [10% (28/274) in the everolimus group and 13% (36/273) in the control group] and vascular disorders [10% (26/274) in the everolimus group and 7% (20/273) in the control group].

A total of 13 patients died during the first 12 months of study; 7 (3%) in the everolimus group and 6 (2%) in the control group. The most common causes of death across the study groups were related to cardiac conditions and infections.

There were 12 (4%) graft losses in the everolimus group and 8 (3%) in the control group over the 12-month study period. Of the graft losses, 4 were due to renal artery and two due to renal vein thrombosis in the everolimus group (2%) compared to two renal artery thromboses in the control group (1%) [see Boxed Warning, Warnings and Precautions (5.4)].

The most common (greater than or equal to 20%) adverse reactions observed in the everolimus group were: peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia.

Infections

The overall incidence of bacterial, fungal and viral infections reported as adverse reactions was higher in the control group (68%) compared to the everolimus group (64%) and was primarily due to an increased number of viral infections (21% in the control group and 10% in the everolimus group). The incidence of CMV infections reported as adverse reactions was 8% in the control group compared to 1% in the everolimus group; and 3% of the serious CMV infections in the control group versus 0% in the everolimus group were considered serious [see Warnings and Precautions (5.3)].

BK Virus

BK virus infections were lower in incidence in the everolimus group (2 patients, 1%) compared to the control group (11 patients, 4%). One of the two BK virus infections in the everolimus group, and two of the 11 BK virus infections in the control group were also reported as serious adverse reactions. BK virus infections did not result in graft loss in any of the groups in the clinical trial.

Wound Healing and Fluid Collections

Wound healing-related reactions were identified through a retrospective search and request for additional data. The overall incidence of wound-related reactions, including lymphocele, seroma, hematoma, dehiscence, incisional hernia, and infections was 35% in the everolimus group compared to 26% in the control group. More patients required intraoperative repair debridement or drainage of incisional wound complications and more required drainage of lymphoceles and seromas in the everolimus group compared to control.

Adverse reactions due to major fluid collections such as edema and other types of fluid collections was 45% in the everolimus group and 40% in the control group [see Warnings and Precautions (5.9)].

Neoplasms

Adverse reactions due to malignant and benign neoplasms were reported in 3% of patients in the everolimus group and 6% in the control group. The most frequently reported neoplasms in the control group were basal cell carcinoma, squamous cell carcinoma, skin papilloma and seborrheic keratosis. One patient in the everolimus group who underwent a melanoma excision prior to transplantation died due to metastatic melanoma [see Boxed Warning, Warnings and Precautions (5.2)]. 

New Onset Diabetes Mellitus (NODM)

NODM reported based on adverse reactions and random serum glucose values, was 9% in the everolimus group compared to 7% in the control group.

Endocrine Effects in Males

In the everolimus group, serum testosterone levels significantly decreased while the FSH levels significantly increased without significant changes being observed in the control group. In both the everolimus and the control groups mean testosterone and FSH levels remained within the normal range with the mean FSH level in the everolimus group being at the upper limit of the normal range (11.1 U/L). More patients were reported with erectile dysfunction in the everolimus treatment group compared to the control group (5% compared to 2%, respectively).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving everolimus with reduced dose cyclosporine or mycophenolic acid with standard dose cyclosporine. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

<div class="scrollingtable"><table> <caption> <span>Table 2. Incidence Rates of Frequent (Greater Than or Equal to 10% in Any Treatment Group) Adverse Reactions (Safety Population*)</span> </caption> <col width="375"/> <col width="250"/> <col width="250"/> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">*</span>The safety analysis population defined as all randomized kidney transplant patients who received at least one dose of treatment and had at least one post-baseline safety assessment.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" valign="top"><span class="Bold">Adverse reactions</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus </span> <br/> <span class="Bold">1.5 mg</span> <br/> <span class="Bold">with reduced exposure cyclosporine</span> <br/> <span class="Bold">N = 274 </span> <br/> <span class="Bold">n (%)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Mycophenolic acid</span> <br/> <span class="Bold">1.44 g</span> <br/> <span class="Bold">with standard exposure cyclosporine</span> <br/> <span class="Bold">N = 273 </span> <br/> <span class="Bold">n (%)</span></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Any adverse</span><span class="Bold"> </span><span class="Bold">reactions</span><span class="Bold">*</span><span class="Bold"> </span></td><td align="center" class="Lrule Rrule Toprule">271 (99)</td><td align="center" class="Lrule Rrule Toprule">270 (99)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Blood lymphatic system disorders</span></td><td align="center" class="Lrule Rrule Toprule">93 (34)</td><td align="center" class="Lrule Rrule Toprule">111 (41)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Anemia </td><td align="center" class="Lrule Rrule Toprule">70 (26)</td><td align="center" class="Lrule Rrule Toprule">68 (25)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Leukopenia </td><td align="center" class="Lrule Rrule Toprule">8 (3)</td><td align="center" class="Lrule Rrule Toprule">33 (12)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Lrule Rrule Toprule">196 (72)</td><td align="center" class="Lrule Rrule Toprule">207 (76)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Constipation </td><td align="center" class="Lrule Rrule Toprule">105 (38)</td><td align="center" class="Lrule Rrule Toprule">117 (43)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Nausea </td><td align="center" class="Lrule Rrule Toprule">79 (29)</td><td align="center" class="Lrule Rrule Toprule">85 (31)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Diarrhea </td><td align="center" class="Lrule Rrule Toprule">51 (19)</td><td align="center" class="Lrule Rrule Toprule">54 (20)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Vomiting </td><td align="center" class="Lrule Rrule Toprule">40 (15)</td><td align="center" class="Lrule Rrule Toprule">60 (22)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Abdominal pain </td><td align="center" class="Lrule Rrule Toprule">36 (13)</td><td align="center" class="Lrule Rrule Toprule">42 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Dyspepsia </td><td align="center" class="Lrule Rrule Toprule">12 (4)</td><td align="center" class="Lrule Rrule Toprule">31 (11)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Abdominal pain upper </td><td align="center" class="Lrule Rrule Toprule">9 (3)</td><td align="center" class="Lrule Rrule Toprule">30 (11)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">General disorders and administrative-site conditions</span></td><td align="center" class="Lrule Rrule Toprule">181 (66)</td><td align="center" class="Lrule Rrule Toprule">160 (59)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Edema peripheral</td><td align="center" class="Lrule Rrule Toprule">123 (45)</td><td align="center" class="Lrule Rrule Toprule">108 (40)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Pyrexia </td><td align="center" class="Lrule Rrule Toprule">51 (19)</td><td align="center" class="Lrule Rrule Toprule">40 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Fatigue </td><td align="center" class="Lrule Rrule Toprule">25 (9)</td><td align="center" class="Lrule Rrule Toprule">28 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Infections and infestations</span></td><td align="center" class="Lrule Rrule Toprule">169 (62)</td><td align="center" class="Lrule Rrule Toprule">185 (68)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Urinary tract infection</td><td align="center" class="Lrule Rrule Toprule"> 60 (22)</td><td align="center" class="Lrule Rrule Toprule">63 (23)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Upper respiratory tract infection</td><td align="center" class="Lrule Rrule Toprule">44 (16)</td><td align="center" class="Lrule Rrule Toprule">49 (18)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Injury, poisoning and procedural complications</span></td><td align="center" class="Lrule Rrule Toprule">163 (60)</td><td align="center" class="Lrule Rrule Toprule">163 (60)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Incision-site pain </td><td align="center" class="Lrule Rrule Toprule">45 (16)</td><td align="center" class="Lrule Rrule Toprule">47 (17)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Procedural pain </td><td align="center" class="Lrule Rrule Toprule">40 (15)</td><td align="center" class="Lrule Rrule Toprule">37 (14)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Investigations</span></td><td align="center" class="Lrule Rrule Toprule">137 (50)</td><td align="center" class="Lrule Rrule Toprule">133 (49)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Blood creatinine increased</td><td align="center" class="Lrule Rrule Toprule">48 (18)</td><td align="center" class="Lrule Rrule Toprule">59 (22)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Metabolism and nutrition disorders</span></td><td align="center" class="Lrule Rrule Toprule">222 (81)</td><td align="center" class="Lrule Rrule Toprule">199 (73)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hyperlipidemia </td><td align="center" class="Lrule Rrule Toprule">57 (21)</td><td align="center" class="Lrule Rrule Toprule">43 (16)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hyperkalemia </td><td align="center" class="Lrule Rrule Toprule">49 (18)</td><td align="center" class="Lrule Rrule Toprule">48 (18)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hypercholesterolemia </td><td align="center" class="Lrule Rrule Toprule">47 (17)</td><td align="center" class="Lrule Rrule Toprule">34 (13)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Dyslipidemia </td><td align="center" class="Lrule Rrule Toprule">41 (15)</td><td align="center" class="Lrule Rrule Toprule">24 (9)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hypomagnesemia </td><td align="center" class="Lrule Rrule Toprule">37 (14)</td><td align="center" class="Lrule Rrule Toprule">40 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hypophosphatemia </td><td align="center" class="Lrule Rrule Toprule">35 (13)</td><td align="center" class="Lrule Rrule Toprule">35 (13)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hyperglycemia </td><td align="center" class="Lrule Rrule Toprule">34 (12)</td><td align="center" class="Lrule Rrule Toprule">38 (14)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hypokalemia </td><td align="center" class="Lrule Rrule Toprule">32 (12)</td><td align="center" class="Lrule Rrule Toprule">32 (12)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td><td align="center" class="Lrule Rrule Toprule">112 (41)</td><td align="center" class="Lrule Rrule Toprule">105 (39)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Pain in extremity</td><td align="center" class="Lrule Rrule Toprule">32 (12)</td><td align="center" class="Lrule Rrule Toprule">29 (11)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Back pain </td><td align="center" class="Lrule Rrule Toprule">30 (11)</td><td align="center" class="Lrule Rrule Toprule">28 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Lrule Rrule Toprule">92 (34)</td><td align="center" class="Lrule Rrule Toprule">109 (40)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Headache </td><td align="center" class="Lrule Rrule Toprule">49 (18)</td><td align="center" class="Lrule Rrule Toprule">40 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Tremor </td><td align="center" class="Lrule Rrule Toprule">23 (8)</td><td align="center" class="Lrule Rrule Toprule">38 (14)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Psychiatric disorders</span></td><td align="center" class="Lrule Rrule Toprule">90 (33)</td><td align="center" class="Lrule Rrule Toprule">72 (26)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Insomnia </td><td align="center" class="Lrule Rrule Toprule">47 (17)</td><td align="center" class="Lrule Rrule Toprule">43 (16)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Renal and urinary disorders</span></td><td align="center" class="Lrule Rrule Toprule">112 (41)</td><td align="center" class="Lrule Rrule Toprule">124 (45)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Hematuria </td><td align="center" class="Lrule Rrule Toprule">33 (12) </td><td align="center" class="Lrule Rrule Toprule">33 (12)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Dysuria </td><td align="center" class="Lrule Rrule Toprule">29 (11)</td><td align="center" class="Lrule Rrule Toprule">28 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Respiratory, thoracic and mediastinal disorders</span></td><td align="center" class="Lrule Rrule Toprule">86 (31)</td><td align="center" class="Lrule Rrule Toprule">93 (34)</td> </tr> <tr> <td class="Lrule Rrule Toprule">       Cough </td><td align="center" class="Lrule Rrule Toprule">20 (7)</td><td align="center" class="Lrule Rrule Toprule">30 (11)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Vascular disorders</span></td><td align="center" class="Lrule Rrule Toprule">122 (45)</td><td align="center" class="Lrule Rrule Toprule">124 (45)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">       Hypertension </td><td align="center" class="Lrule Rrule Toprule">81 (30)</td><td align="center" class="Lrule Rrule Toprule">82 (30)</td> </tr> </tbody> </table></div>

Adverse reaction that occurred with at least a 5% higher frequency in the everolimus 1.5 mg group compared to the control group were: peripheral edema (45% compared to 40%), hyperlipidemia (21% compared to 16%), dyslipidemia (15% compared to 9%), and stomatitis/mouth ulceration (8% compared to 3%).

A third treatment group of everolimus 3 mg per day (1.5 mg twice daily; target trough concentrations 6 to 12 ng/mL) with reduced exposure cyclosporine was included in the study described above. Although as effective as the lower dose everolimus group, the overall safety was worse and consequently higher doses of everolimus cannot be recommended. Out of 279 patients, 95 (34%) discontinued the study medication with 57 (20%) doing so because of adverse reactions. The most frequent adverse reactions leading to discontinuation of everolimus when used at this higher dose were injury, poisoning and procedural complications (everolimus 1.5 mg: 5%, everolimus 3 mg: 7%, and control: 2%), infections (2%, 6%, and 3%, respectively), renal and urinary disorders (4%, 7%, and 4%, respectively), and gastrointestinal disorders (1%, 3%, and 2%).

The combination of fixed-dose everolimus and standard doses of cyclosporine in previous kidney clinical trials resulted in frequent elevations of serum creatinine with higher mean and median serum creatinine values observed than in the current study with reduced exposure cyclosporine. These results indicate that everolimus increases the cyclosporine-induced nephrotoxicity, and, therefore, should only be used in a concentration-controlled regimen with reduced exposure cyclosporine [see Boxed Warning, Indications and Usage (1.1), Warnings and Precautions (5.6)].

Liver Transplantation

The data described below reflect exposure to everolimus starting 30 days after transplantation in an open-label, randomized trial of liver transplant patients. Seven hundred and nineteen (719) patients who fulfilled the inclusion/exclusion criteria [see Clinical Studies (14.2)] were randomized into one of the three treatment groups of the study. During the first 30 days prior to randomization, patients received tacrolimus and corticosteroids, with or without mycophenolate mofetil (about 70% to 80% received MMF). No induction antibody was administered. At randomization, MMF was discontinued and patients were randomized to everolimus initial dose of 1 mg twice per day (2 mg daily) and adjusted to protocol specified target trough concentrations of 3 to 8 ng/mL with reduced exposure tacrolimus [protocol-specified target troughs 3 to 5 ng/mL] (N = 245) [see Clinical Pharmacology (12.7, 12.9)] or to a control group of standard exposure tacrolimus [protocol specified target troughs 8 to 12 ng/mL up to Month 4 posttransplant, then 6 to 10 ng/mL Month 4 through Month 12 posttransplant] (N = 241). A third randomized group was discontinued prematurely [see Clinical Studies (14.2)] and is not described in this section.

The population was between 18 and 70 years, more than 50% were 50 years of age (mean age was 54 years in the everolimus group, 55 years in the tacrolimus control group); 74% were male in both everolimus and control groups, respectively, and a majority were Caucasian (86% everolimus group, 80% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups. The most frequent causes of end-stage liver disease (ESLD) were alcoholic cirrhosis, hepatitis C, and hepatocellular carcinoma and were balanced between groups.

Twenty-seven percent (27%) discontinued study drug in the everolimus group compared with 22% for the tacrolimus control group during the first 12 months of study. The most common reason for discontinuation of study medication was due to adverse reactions (19% and 11%, respectively), including proteinuria, recurrent hepatitis C, and pancytopenia in the everolimus group. At 24 months, the rate of discontinuation of study medication in liver transplant patients was greater for the everolimus group (42%) compared to tacrolimus control group (33%). 

The overall incidences of serious adverse reactions were 50% (122/245) in the everolimus group and 43% (104/241) in the control group at 12 months and similar at 24 months (56% and 54%, respectively). Infections and infestations were reported as serious adverse reactions with the highest incidence followed by gastrointestinal disorders and hepatobiliary disorders. 

During the first 12 months of study, 13 deaths were reported in the everolimus group (one patient never took everolimus). In the same 12-month period, 7 deaths were reported in the tacrolimus control group. Deaths occurred in both groups for a variety of reasons and were mostly associated with liver-related issues, infections and sepsis. In the following 12 months of study, four additional deaths were reported in each treatment group.

The most common adverse reactions (reported for greater or equal to 10% patients in any group) in the everolimus group were: diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia (see Table 3).

Infections

The overall incidence of infections reported as adverse reactions was 50% for everolimus and 44% in the control group and similar at 24 months (56% and 52%, respectively). The types of infections were reported as follows: bacterial 16% vs 12%, viral 17% vs 13%; and fungal infections 2% vs 5% for everolimus and control, respectively [see Warnings and Precautions (5.3)]. 

Wound Healing and Fluid Collections

Wound healing complications were reported as adverse reactions for 11% of patients in the everolimus group compared to 8% of patients in the control group up to 24 months. Pleural effusions were reported in 5% in both groups, and ascites in 4% of patients in the everolimus group and 3% in the control arm.

Neoplasms

Malignant and benign neoplasms were reported as adverse reactions in 4% of patients in the everolimus group and 7% in the control group at 12 months. In the everolimus group, 3 malignant tumors were reported compared to 9 cases in the control group. For the everolimus group this included lymphoma, lymphoproliferative disorder and a hepatocellular carcinoma, and for the control group included Kaposi’s sarcoma (2), metastatic colorectal cancer, glioblastoma, malignant hepatic neoplasm, pancreatic neuroendocrine tumor, hemophagocytic histiocytosis, and squamous cell carcinomas. At 24 months, the rates of malignancies were similar (10% and 11%, respectively) [see Boxed Warning, Warnings and Precautions (5.2)]. 

Lipid Abnormalities

Hyperlipidemia adverse reactions (including the preferred terms: hyperlipidemia, hypercholesterolemia, blood cholesterol increased, blood triglycerides increased, hypertriglyceridemia lipids increased, total cholesterol/HDL ratio increased, and dyslipidemia) were reported for 24% everolimus patients, and 10% control patients at 12 months. Results were similar at 24 months (28% and 12%, respectively). 

New Onset of Diabetes after Transplant (NODAT)

Of the patients without diabetes mellitus at randomization, NODAT was reported in 32% in the everolimus group compared to 29% in the control group at 12 months and similar at 24 months.

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving everolimus with reduced exposure tacrolimus or standard dose tacrolimus from randomization to 24 months. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

<div class="scrollingtable"><table> <caption> <span>Table 3. Incidence Rates of Most Frequent (Greater Than or Equal to 10% in Any Treatment Group) Adverse Reactions at 12 Months and 24 Months After Liver Transplantation (Safety population*)</span> </caption> <col width="166"/> <col width="127"/> <col width="142"/> <col width="151"/> <col width="132"/> <tfoot> <tr class="First Last"> <td colspan="5"> <p class="First"> <span class="Sup">*</span>The safety analysis population is defined as all randomized liver transplant patients who received at least one dose of treatment and had at least one post-baseline safety assessment. Primary system organ classes are presented alphabetically.</p> <p>**No <span class="Italics">de novo</span> hepatitis C cases were reported.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" rowspan="2"><span class="Bold">Adverse reactions</span></td><td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">12 months</span></td><td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">24</span><span class="Bold"> </span><span class="Bold">months</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus </span> <br/> <span class="Bold">with reduced exposure tacrolimus</span> <br/> <span class="Bold">N = 245</span> <br/> <span class="Bold">n (%)</span></td><td align="center" class="Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Tacrolimus</span> <br/> <span class="Bold">standard exposure</span> <br/> </p> <p> <span class="Bold">N = 241</span> <br/> <span class="Bold">n (%)</span> </p> </td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus </span> <br/> <span class="Bold">with reduced exposure tacrolimus</span> <br/> <span class="Bold">N = 245</span> <br/> <span class="Bold">n (%)</span></td><td align="center" class="Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Tacrolimus</span> <br/> <span class="Bold">standard exposure</span> <br/> </p> <p> <span class="Bold">N = 242</span> <br/> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Any adverse reaction/infection</span></td><td align="center" class="Lrule Rrule Toprule">232 (95)</td><td align="center" class="Lrule Rrule Toprule">229 (95)</td><td align="center" class="Lrule Rrule Toprule">236 (96)</td><td align="center" class="Lrule Rrule Toprule">237 (98)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Blood &amp; lymphatic system disorders</span></td><td align="center" class="Lrule Rrule Toprule">66 (27)</td><td align="center" class="Lrule Rrule Toprule">47 (20)</td><td align="center" class="Lrule Rrule Toprule">79 (32)</td><td align="center" class="Lrule Rrule Toprule">58 (24)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Leukopenia</td><td align="center" class="Lrule Rrule Toprule">29 (12)</td><td align="center" class="Lrule Rrule Toprule">12 (5)</td><td align="center" class="Lrule Rrule Toprule">31 (13)</td><td align="center" class="Lrule Rrule Toprule">12 (5)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">G</span><span class="Bold">as</span><span class="Bold">t</span><span class="Bold">r</span><span class="Bold">o</span><span class="Bold">i</span><span class="Bold">n</span><span class="Bold">t</span><span class="Bold">e</span><span class="Bold">s</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">nal</span><span class="Bold"> </span><span class="Bold">d</span><span class="Bold">i</span><span class="Bold">s</span><span class="Bold">ord</span><span class="Bold">e</span><span class="Bold">rs</span></td><td align="center" class="Lrule Rrule Toprule">136 (56)</td><td align="center" class="Lrule Rrule Toprule">121 (50)</td><td align="center" class="Lrule Rrule Toprule">148 (60)</td><td align="center" class="Lrule Rrule Toprule">138 (57)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Diarrhea</td><td align="center" class="Lrule Rrule Toprule">47 (19)</td><td align="center" class="Lrule Rrule Toprule">50 (21)</td><td align="center" class="Lrule Rrule Toprule">59 (24)</td><td align="center" class="Lrule Rrule Toprule">61 (25)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Nausea</td><td align="center" class="Lrule Rrule Toprule">33 (14)</td><td align="center" class="Lrule Rrule Toprule">28 (12)</td><td align="center" class="Lrule Rrule Toprule">36 (15)</td><td align="center" class="Lrule Rrule Toprule">33 (14)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Abdominal pain</td><td align="center" class="Lrule Rrule Toprule">32 (13)</td><td align="center" class="Lrule Rrule Toprule">22 (9)</td><td align="center" class="Lrule Rrule Toprule">37 (15)</td><td align="center" class="Lrule Rrule Toprule">31 (13)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">G</span><span class="Bold">eneral</span><span class="Bold"> </span><span class="Bold">d</span><span class="Bold">i</span><span class="Bold">s</span><span class="Bold">o</span><span class="Bold">rde</span><span class="Bold">r</span><span class="Bold">s</span><span class="Bold"> </span><span class="Bold">and a</span><span class="Bold">d</span><span class="Bold">mi</span><span class="Bold">n</span><span class="Bold">i</span><span class="Bold">s</span><span class="Bold">t</span><span class="Bold">ra</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">on</span><span class="Bold"> </span><span class="Bold">s</span><span class="Bold">i</span><span class="Bold">t</span><span class="Bold">e</span><span class="Bold"> </span><span class="Bold">con</span><span class="Bold">d</span><span class="Bold">i</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">o</span><span class="Bold">ns</span></td><td align="center" class="Lrule Rrule Toprule">94 (38)</td><td align="center" class="Lrule Rrule Toprule">85 (35)</td><td align="center" class="Lrule Rrule Toprule">113 (46)</td><td align="center" class="Lrule Rrule Toprule">98 (41)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Peripheral edema</td><td align="center" class="Lrule Rrule Toprule">43 (18)</td><td align="center" class="Lrule Rrule Toprule">26 (11)</td><td align="center" class="Lrule Rrule Toprule">49 (20)</td><td align="center" class="Lrule Rrule Toprule">31 (13)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Pyrexia</td><td align="center" class="Lrule Rrule Toprule">32 (13)</td><td align="center" class="Lrule Rrule Toprule">25 (10)</td><td align="center" class="Lrule Rrule Toprule">43 (18)</td><td align="center" class="Lrule Rrule Toprule">28 (12)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Fatigue</td><td align="center" class="Lrule Rrule Toprule">22 (9)</td><td align="center" class="Lrule Rrule Toprule">26 (11)</td><td align="center" class="Lrule Rrule Toprule">27 (11)</td><td align="center" class="Lrule Rrule Toprule">28 (12)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">I</span><span class="Bold">n</span><span class="Bold">f</span><span class="Bold">e</span><span class="Bold">c</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">ons</span><span class="Bold"> </span><span class="Bold">and</span><span class="Bold"> </span><span class="Bold">i</span><span class="Bold">n</span><span class="Bold">f</span><span class="Bold">es</span><span class="Bold">t</span><span class="Bold">a</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">o</span><span class="Bold">n</span><span class="Bold">s</span></td><td align="center" class="Lrule Rrule Toprule">123 (50)</td><td align="center" class="Lrule Rrule Toprule">105 (44)</td><td align="center" class="Lrule Rrule Toprule">135 (56)</td><td align="center" class="Lrule Rrule Toprule">125 (52)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Hepatitis C**</td><td align="center" class="Lrule Rrule Toprule">28 (11)</td><td align="center" class="Lrule Rrule Toprule">19 (8)</td><td align="center" class="Lrule Rrule Toprule">33 (14)</td><td align="center" class="Lrule Rrule Toprule">24 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Inve</span><span class="Bold">s</span><span class="Bold">ti</span><span class="Bold">g</span><span class="Bold">a</span><span class="Bold">t</span><span class="Bold">i</span><span class="Bold">ons</span></td><td align="center" class="Lrule Rrule Toprule">81 (33)</td><td align="center" class="Lrule Rrule Toprule">78 (32)</td><td align="center" class="Lrule Rrule Toprule">92 (38)</td><td align="center" class="Lrule Rrule Toprule">98 (41)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Liver function test abnormal</td><td align="center" class="Lrule Rrule Toprule">16 (7)</td><td align="center" class="Lrule Rrule Toprule">24 (10)</td><td align="center" class="Lrule Rrule Toprule">19 (8)</td><td align="center" class="Lrule Rrule Toprule">25 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Metabolism and nutrition disorders</span></td><td align="center" class="Lrule Rrule Toprule">111 (45)</td><td align="center" class="Lrule Rrule Toprule">92 (38)</td><td align="center" class="Lrule Rrule Toprule">134 (55)</td><td align="center" class="Lrule Rrule Toprule">106 (44)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Hypercholesterolemia</td><td align="center" class="Lrule Rrule Toprule">23 (9)</td><td align="center" class="Lrule Rrule Toprule">6 (3)</td><td align="center" class="Lrule Rrule Toprule">27 (11)</td><td align="center" class="Lrule Rrule Toprule">9 (4)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">N</span><span class="Bold">ervous</span><span class="Bold"> </span><span class="Bold">s</span><span class="Bold">ys</span><span class="Bold">t</span><span class="Bold">em</span><span class="Bold"> </span><span class="Bold">d</span><span class="Bold">i</span><span class="Bold">s</span><span class="Bold">orde</span><span class="Bold">r</span><span class="Bold">s</span></td><td align="center" class="Lrule Rrule Toprule">89 (36)</td><td align="center" class="Lrule Rrule Toprule">85 (35)</td><td align="center" class="Lrule Rrule Toprule">99 (40)</td><td align="center" class="Lrule Rrule Toprule">101 (42)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Headache</td><td align="center" class="Lrule Rrule Toprule">47 (19)</td><td align="center" class="Lrule Rrule Toprule">46 (19)</td><td align="center" class="Lrule Rrule Toprule">53 (22)</td><td align="center" class="Lrule Rrule Toprule">54 (22)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Tremor</td><td align="center" class="Lrule Rrule Toprule">23 (9)</td><td align="center" class="Lrule Rrule Toprule">29 (12)</td><td align="center" class="Lrule Rrule Toprule">25 (10)</td><td align="center" class="Lrule Rrule Toprule">37 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Insomnia</td><td align="center" class="Lrule Rrule Toprule">14 (6)</td><td align="center" class="Lrule Rrule Toprule">19 (8)</td><td align="center" class="Lrule Rrule Toprule">17 (7)</td><td align="center" class="Lrule Rrule Toprule">24 (10)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Renal and urinary disorders</span></td><td align="center" class="Lrule Rrule Toprule">49 (20)</td><td align="center" class="Lrule Rrule Toprule">53 (22)</td><td align="center" class="Lrule Rrule Toprule">67 (27)</td><td align="center" class="Lrule Rrule Toprule">73 (30)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     -Renal failure</td><td align="center" class="Lrule Rrule Toprule">13 (5)</td><td align="center" class="Lrule Rrule Toprule">17 (7)</td><td align="center" class="Lrule Rrule Toprule">24 (10)</td><td align="center" class="Lrule Rrule Toprule">37 (15)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">V</span><span class="Bold">ascu</span><span class="Bold">l</span><span class="Bold">a</span><span class="Bold">r</span><span class="Bold"> </span><span class="Bold">d</span><span class="Bold">i</span><span class="Bold">sord</span><span class="Bold">e</span><span class="Bold">rs</span></td><td align="center" class="Lrule Rrule Toprule">56 (23)</td><td align="center" class="Lrule Rrule Toprule">57 (24)</td><td align="center" class="Lrule Rrule Toprule">72 (29)</td><td align="center" class="Lrule Rrule Toprule">68 (28)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">     -Hypertension</td><td align="center" class="Lrule Rrule Toprule">42 (17)</td><td align="center" class="Lrule Rrule Toprule">38 (16)</td><td align="center" class="Lrule Rrule Toprule">52 (21)</td><td align="center" class="Lrule Rrule Toprule">44 (18)</td> </tr> </tbody> </table></div>

Less Common Adverse Reactions

Less common adverse reactions, occurring overall in greater than or equal to 1% to less than 10% of either kidney or liver transplant patients treated with everolimus include:

Blood and Lymphatic System Disorders: anemia, leukocytosis, lymphadenopathy, neutropenia, pancytopenia, thrombocythemia, thrombocytopenia

Cardiac and Vascular Disorders: angina pectoris, atrial fibrillation, cardiac failure congestive, palpitations, tachycardia, hypertension, including hypertensive crisis, hypotension, deep-vein thrombosis

Endocrine Disorders: Cushingoid, hyperparathyroidism, hypothyroidism

Eye Disorders: cataract, conjunctivitis, vision blurred

Gastrointestinal Disorders: abdominal distention, abdominal hernia, ascites, constipation, dyspepsia, dysphagia, epigastric discomfort, flatulence, gastritis, gastroesophageal reflux disease, gingival hypertrophy, hematemesis, hemorrhoids, ileus, mouth ulceration, peritonitis, stomatitis

General Disorders and Administrative Site Conditions: chest discomfort, chest pain, chills, fatigue, incisional hernia, inguinal hernia, malaise, edema, including generalized edema, pain

Hepatobiliary Disorders: hepatic enzyme increased, bile duct stenosis, bilirubin increased, cholangitis, cholestasis, hepatitis (non-infectious)

Infections and Infestations: BK virus infection [see Warnings and Precautions (5.13)], bacteremia, bronchitis, candidiasis, cellulitis, CMV, folliculitis, gastroenteritis, herpes infections, influenza, lower respiratory tract, nasopharyngitis, onychomycosis, oral candidiasis, oral herpes, osteomyelitis, pneumonia, pyelonephritis, sepsis, sinusitis, tinea pedis, upper respiratory tract infection, urethritis, urinary tract infection, wound infection [see Boxed Warning, Warnings and Precautions (5.3)]

Injury Poisoning and Procedural Complications: incision site complications, including infections, perinephric collection, seroma, wound dehiscence, incisional hernia, perinephric hematoma, localized intra-abdominal fluid collection, impaired healing, lymophocele, lymphorrhea

Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood glucose increased, hemoglobin decreased, white blood cell count decreased, transaminases increased

Metabolism and Nutrition Disorders: blood urea increased, acidosis, anorexia, dehydration, diabetes mellitus [see Warnings and Precautions (5.16)], decreased appetite, fluid retention, gout, hypercalcemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypokalemia, hypoglycemia, hypomagnesemia, hyponatremia, iron deficiency, new onset diabetes mellitus, vitamin B12 deficiency

Musculoskeletal and Connective Tissues Disorders: arthralgia, joint swelling, muscle spasms, muscular weakness, musculoskeletal pain, myalgia, osteoarthritis, osteonecrosis, osteopenia, osteoporosis, spondylitis

Nervous System Disorders: dizziness, hemiparesis, hypoesthesia, lethargy, migraine, neuralgia, paresthesia, somnolence, syncope, tremor

Psychiatric Disorders: agitation, anxiety, depression, hallucination

Renal and Urinary Disorders: bladder spasm, hydronephrosis, micturation urgency, nephritis interstitial, nocturia, pollakiuria, polyuria, proteinuria [see Warnings and Precautions (5.12)], pyuria, renal artery thrombosis [see Boxed Warning, Warnings and Precautions (5.4)], acute renal failure, renal impairment [see Warnings and Precautions (5.6)], renal tubular necrosis, urinary retention

Reproductive System and Breast Disorders: amenorrhea, benign prostatic hyperplasia, erectile dysfunction, ovarian cyst, scrotal edema

Respiratory, Thoracic, Mediastinal Disorders: atelectasis, bronchitis, dyspnea, cough, epistaxis, lower respiratory tract infection, nasal congestion, oropharyngeal pain, pleural effusions, pulmonary edema, rhinorrhea, sinus congestion, wheezing

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis acneiform, ecchymosis, hirsutism, hyperhidrosis, hypertrichosis, night sweats, pruritus, rash

Vascular Disorders: venous thromboembolism (including deep vein thrombosis), phlebitis, pulmonary embolism

Less common, serious adverse reactions occurring overall in less than 1% of either kidney or liver transplant patients treated with everolimus include: 

Adverse reactions identified from the postmarketing use of the combination regimen of everolimus and cyclosporine that are not specific to any one transplant indication include angioedema [see Warnings and Precautions (5.8)], erythroderma, leukocytoclastic vasculitis, pancreatitis,  pulmonary alveolar proteinosis, and pulmonary embolism. There have also been reports of male infertility with mTOR inhibitors, including everolimus [see Warnings and Precautions (5.18)]. 

Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-gp. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-gp (e.g., digoxin, cyclosporine) may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when coadministering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index [see Dosage and Administration (2.3)]. 

All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between everolimus and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

The steady-state Cmax and area under the curve (AUC) estimates of everolimus were significantly increased by coadministration of single dose cyclosporine [see Clinical Pharmacology (12.5)]. Dose adjustment of everolimus might be needed if the cyclosporine dose is altered [see Dosage and Administration (2.3)]. Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral).

Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus [see Warnings and Precautions (5.14), Clinical Pharmacology (12.5)]. 

Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Clinical Pharmacology (12.5)].

Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax and AUC. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Clinical Pharmacology (12.5)].

Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse reactions as described in the respective labeling for these products. 

Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin [see Warnings and Precautions (5.11)].

Pretreatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus Cmax and AUC estimates. Combination with rifampin is not recommended [see Warnings and Precautions (5.14), Clinical Pharmacology (12.5)].

Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates [see Clinical Pharmacology (12.5)]. 

Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood concentrations (e.g., St. John’s Wort [Hypericum perforatum]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine).

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and consequently, dose adjustment of everolimus is not necessary when everolimus is coadministered with tacrolimus.

The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol [see Dosage and Administration (2.3), Warnings and Precautions (5.22)].

Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus use in pregnant women; however, these reports are insufficient to inform a drug-associated risk of adverse developmental outcomes. Reproductive studies in animals have demonstrated that everolimus was maternally toxic in rabbits and caused embryo-fetal toxicities in rats and rabbits, at exposures near or below those achieved in human transplant patients. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

Everolimus crossed the placenta and was toxic to the conceptus.

Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg (approximately one tenth the exposure in humans administered the lowest starting dose of 0.75 mg twice daily), from before mating through organogenesis, resulted in increased preimplantation loss and embryonic resorptions. These effects occurred in the absence of maternal toxicities.

Everolimus administered daily by oral gavage to pregnant rabbits during organogenesis resulted in abortions, maternal toxicity and lethality, and increased fetal resorptions. At these doses, exposure to everolimus (AUC) was approximately one-tenth-, one-half-, and one- and one-half-fold the exposures in humans administered the starting clinical dose, respectively.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At a dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction) and in survival of offspring (~5%). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Risk Summary

There is no data regarding the presence of everolimus in human milk, the effects on breastfed infants, or the effects on milk production. Everolimus and/or its metabolites are readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal rat serum. In pre-post-natal and juvenile studies in rats, exposure to everolimus during the postnatal period caused developmental toxicity [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.2)]. Advise lactating women not to breastfeed because of the potential for serious adverse reactions in infants exposed to everolimus.

Contraception

Females should not be pregnant or become pregnant while receiving everolimus. Advise females of reproductive potential that animal studies have been performed showing everolimus to be harmful to the mother and developing fetus [see Use in Specific Populations (8.1)]. Females of reproductive potential are recommended to use highly effective contraception methods while receiving everolimus and up to 8 weeks after treatment has been stopped.

Infertility

Females

Amenorrhea occurred in female patients taking everolimus [see Adverse Reactions (6.2)]. Everolimus may cause pre-implantation loss in females based on animal data [see Nonclinical Toxicology (13.1)].

Female fertility may be compromised by treatment with everolimus.

Males

Everolimus treatment may impair fertility in males based on human [see Warnings and Precautions (5.18), Adverse Reactions (6.2, 6.3)] and animal findings [see Nonclinical Toxicology (13.1)].

The safe and effective use of everolimus in kidney or liver transplant patients younger than 18 years of age has not been established.

There is limited clinical experience on the use of everolimus in patients of age 65 years or older. There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients [see Clinical Pharmacology (12.5)].

Everolimus whole blood trough concentrations should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), the initial daily dose should be reduced to approximately half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [see Clinical Pharmacology (12.6)].

No dose adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.6)].

Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. General supportive measures should be followed in all cases of overdose. Everolimus is not considered dialyzable to any relevant degree (less than 10% of everolimus removed within 6 hours of hemodialysis). In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats.

{ "type": "p", "children": [], "text": "Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. General supportive measures should be followed in all cases of overdose. Everolimus is not considered dialyzable to any relevant degree (less than 10% of everolimus removed within 6 hours of hemodialysis). In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats." }

Everolimus tablets are a macrolide immunosuppressant.

{ "type": "p", "children": [], "text": "Everolimus tablets are a macrolide immunosuppressant." }

The chemical name of everolimus USP is

{ "type": "p", "children": [], "text": "The chemical name of everolimus USP is" }

(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1- [(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30 dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.

{ "type": "p", "children": [], "text": "(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1- [(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30 dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone." }

The molecular formula is C53H83NO14 and the molecular weight is 958.24 g/mol. The structural formula is:

{ "type": "p", "children": [], "text": "The molecular formula is C53H83NO14 and the molecular weight is 958.24 g/mol. The structural formula is:" }

Everolimus tablets are supplied for oral administration containing 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg of everolimus USP together with butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188 as inactive ingredients.

{ "type": "p", "children": [], "text": "Everolimus tablets are supplied for oral administration containing 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg of everolimus USP together with butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188 as inactive ingredients." }

Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).

{ "type": "p", "children": [], "text": "Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye)." }

Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.

In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian target of rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity.

In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.

Everolimus pharmacokinetics have been characterized after oral administration of single and multiple doses to adult kidney transplant patients, hepatically-impaired patients, and healthy subjects.

Absorption

After oral dosing, peak everolimus concentrations occur 1 to 2 hours post dose. Over the dose range of 0.5 mg to 2 mg twice daily, everolimus Cmax and AUC are dose proportional in transplant patients at steady-state.

Food Effect

In 24 healthy subjects, a high-fat breakfast (44.5 g fat) reduced everolimus Cmax by 60%, delayed Tmax by a median 1.3 hours, and reduced AUC by 16% compared with a fasting administration. To minimize variability, everolimus should be taken consistently with or without food [see Dosage and Administration (2.6)].

Distribution

The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range: 128 to 589 L).

Elimination

Metabolism

Everolimus is a substrate of CYP3A4 and P-gp. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including 3 monohydroxylated metabolites, 2 hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies and showed approximately 100 times less activity than everolimus itself.

Excretion

After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and feces.

Pharmacokinetics in Kidney Transplant Patients

Steady-state is reached by Day 4 with an accumulation in blood concentrations of 2- to 3-fold compared with the exposure after the first dose. Table 4 below provides a summary of the steady-state pharmacokinetic parameters.

<div class="scrollingtable"><table> <caption> <span>Table 4. Steady-State Pharmacokinetic Parameters (mean +/- SD) Following the Administration of 0.75 mg Twice Daily</span> </caption> <col width="122"/> <col width="122"/> <col width="122"/> <col width="122"/> <col width="122"/> <col width="122"/> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">1</span>population pharmacokinetic analysis.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">C</span><span class="Bold"><span class="Sub">max</span></span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">T</span><span class="Bold"><span class="Sub">max</span></span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">AUC</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">CL/F</span><span class="Bold"><span class="Sup">1</span></span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Vc/F</span><span class="Bold"><span class="Sup">1</span></span></td><td class="Lrule Rrule Toprule"><span class="Bold">Half-life (T</span><span class="Bold"><span class="Sub">1/2</span></span><span class="Bold">)</span></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule Toprule">11.1 <span class="Underline">+</span> 4.6 ng/mL</td><td align="center" class="Lrule Rrule Toprule">1-2 h</td><td align="center" class="Lrule Rrule Toprule">75 + 31 ng•h/mL</td><td align="center" class="Lrule Rrule Toprule">8.8 L/h</td><td align="center" class="Lrule Rrule Toprule">110 L</td><td align="center" class="Lrule Rrule Toprule">30 ± 11h</td> </tr> </tbody> </table></div>

The half-life estimates from 12 maintenance renal transplant patients who received single doses of everolimus capsules at 0.75 mg or 2.5 mg with their maintenance cyclosporine regimen indicate that the pharmacokinetics of everolimus are linear over the clinically-relevant dose range. Results indicate the half-life of everolimus in maintenance renal transplant patients receiving single doses of 0.75 mg or 2.5 mg everolimus during steady-state cyclosporine treatment was 30 ± 11 hours (range: 19 to 53 hours).

Everolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between everolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below [see Warnings and Precautions (5.14), Drug Interactions (7)].

Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate): Everolimus should be taken concomitantly with cyclosporine in kidney transplant patients. Everolimus concentrations may decrease when doses of cyclosporine are reduced, unless the everolimus dose is increased [see Dosage and Administration (2.1), Drug Interactions (7.2)]. 

In a single-dose study in healthy subjects, cyclosporine (Neoral) administered at a dose of 175 mg increased everolimus AUC by 168% (range: 46% to 365%) and Cmax by 82% (range: 25% to 158%) when administered with 2 mg everolimus compared with administration of everolimus alone [see Drug Interactions (7.2)].

Ketoconazole and Other Strong CYP3A4 Inhibitors: Multiple-dose administration of 200 mg ketoconazole twice daily for 5 days to 12 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 3.9-fold, 15-fold, and 89%, respectively, when coadministered with 2 mg everolimus. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus [see Warnings and Precautions (5.14), Drug Interactions (7.3)]. 

Erythromycin (Moderate CYP3A4 Inhibitor): Multiple-dose administration of 500 mg erythromycin 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 2-fold, 4.4-fold, and 39%, respectively, when coadministered with 2 mg everolimus. If erythromycin is co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Drug Interactions (7.4)].

Verapamil (CYP3A4 Inhibitor and P-gp Substrate): Multiple-dose administration of 80 mg verapamil 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax and AUC by 2.3-fold and 3.5-fold, respectively, when coadministered with 2 mg everolimus. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Drug Interactions (7.5)].

Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate): Following administration of a single dose of 2 mg everolimus to 12 healthy subjects, the concomitant administration of a single oral dose administration of atorvastatin 20 mg or pravastatin 20 mg only slightly decreased everolimus Cmax and AUC by 9% and 10%, respectively. There was no apparent change in the mean T1/2 or median Tmax. In the same study, the concomitant everolimus dose slightly increased the mean Cmax of atorvastatin by 11% and slightly decreased the AUC by 7%. The concomitant everolimus dose decreased the mean Cmax and AUC of pravastatin by 10% and 5%, respectively. No dosage adjustments are needed for concomitant administration of everolimus and atorvastatin and pravastatin [see Drug Interactions (7.6)].

Midazolam (CYP3A4/5 Substrate): In 25 healthy male subjects, coadministration of a single dose of midazolam 4 mg oral solution with steady-state everolimus (10 mg daily dose for 5 days) resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC; whereas the terminal half-life of midazolam and the metabolic AUC-ratio (1-hydroxymidazolam/midazolam) were not affected [see Drug Interactions (7.9)].

Rifampin (Strong CYP3A4 and P-gp Inducer): Pretreatment of 12 healthy subjects with multiple-dose rifampin (600 mg once-daily for 8 days) followed by a single dose of 4 mg everolimus increased everolimus clearance nearly 3-fold, and decreased Cmax by 58% and AUC by 63%. Combination with rifampin is not recommended [see Drug Interactions (7.8)].

Hepatic Impairment

Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher following administration of a 10 mg single dose. In 2 independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1-fold and 3.3-fold higher following administration of a 2 mg or a 10 mg single dose, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6-fold higher following administration of a 10 mg single dose. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [see Dosage and Administration (2.7)].

Renal Impairment

No pharmacokinetic studies in patients with renal impairment were conducted. Posttransplant renal function (creatinine clearance range: 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus; therefore, no dosage adjustments are needed in patients with renal impairment.

Geriatrics

A limited reduction in everolimus oral CL/F of 0.33% per year was estimated in adults (age range studied was 16 to 70 years). There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients.

Race

Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in black transplant patients.

Everolimus in Kidney Transplantation

Based on exposure-efficacy and exposure-safety analyses of clinical trials and using an LC/MS/MS assay method, kidney transplant patients achieving everolimus whole blood trough concentrations greater than or equal to 3 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3 ng/mL. Patients who attained everolimus trough concentrations within the range of 6 to 12 ng/mL had similar efficacy and more adverse reactions than patients who attained lower trough concentrations between 3 to 8 ng/mL [see Dosage and Administration (2.3)]. 

In the kidney clinical trial [see Clinical Studies (14.1)], everolimus whole blood trough concentrations were measured at Days 3, 7, and 14 and Months 1, 2, 3, 4, 6, 7, 9, and 12. The proportion of patients receiving 0.75 mg twice daily everolimus treatment regimen who had everolimus whole blood trough concentrations within the protocol specified target range of 3 to 8 ng/mL at Days 3, 7, and 14 were 55%, 71% and 69%, respectively. Approximately 80% of patients had everolimus whole blood trough concentrations within the 3 to 8 ng/mL target range by Month 1 and remained stable within range through Month 12 posttransplant. The median everolimus trough concentration for the 0.75 mg twice daily treatment group was between 3 and 8 ng/mL throughout the study duration.  

Everolimus in Liver Transplantation

In the liver clinical trial [see Clinical Studies (14.2)],  everolimus dosing was initiated after 30 days following transplantation. Whole blood trough everolimus concentrations were measured within 5 days after first dose, followed by weekly intervals for 3 to 4 weeks, and then monthly thereafter. Approximately 49%, 37%, and 18% of patients, respectively, were below 3 ng/mL at 1, 2, and 4 weeks after initiation of everolimus dosing. The majority of patients (approximately 70% to 80%) had everolimus trough blood concentrations within the target range of 3 to 8 ng/mL from Month 2 through Month 24 posttransplant.

In the kidney transplant clinical trial [see Clinical Studies (14.1)], the target cyclosporine whole blood trough concentration for the everolimus treatment arm of 0.75 mg twice daily were 100 to 200 ng/mL through Month 1 posttransplant, 75 to 150 ng/mL at Months 2 and 3 posttransplant, 50 to 100 ng/mL at Month 4 posttransplant, and 25 to 50 ng/mL from Month 6 through Month 12 posttransplant. Table 5 below provides a summary of the observed cyclosporine whole blood trough concentrations during the study.

<div class="scrollingtable"><table> <caption> <span>Table 5. Cyclosporine Trough Concentrations Over 12 Months Posttransplant – Kidney Study Median Values (ng/mL) With 10<span class="Sup">th</span> and 90<span class="Sup">th</span> Percentiles</span> </caption> <col width="155"/> <col width="80"/> <col width="69"/> <col width="92"/> <col width="94"/> <col width="94"/> <col width="94"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"><span class="Bold">Treatment Group</span></td><td class="Lrule Rrule Toprule"><span class="Bold">Visit </span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">N</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Target </span><span class="Bold"> <br/>(ng/mL)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Median</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">10<span class="Sup">th</span> percentile</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">90<span class="Sup">th</span> percentile</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Everolimus tablets <br/>0.75 mg twice daily</td><td class="Lrule Rrule Toprule">Day 3</td><td align="center" class="Lrule Rrule Toprule">242</td><td align="center" class="Lrule Rrule Toprule">100-200</td><td align="center" class="Lrule Rrule Toprule">172</td><td align="center" class="Lrule Rrule Toprule">46</td><td align="center" class="Lrule Rrule Toprule">388</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Day 7</td><td align="center" class="Lrule Rrule Toprule">265</td><td align="center" class="Lrule Rrule Toprule">100-200</td><td align="center" class="Lrule Rrule Toprule">185</td><td align="center" class="Lrule Rrule Toprule">75</td><td align="center" class="Lrule Rrule Toprule">337</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Day 14</td><td align="center" class="Lrule Rrule Toprule">243</td><td align="center" class="Lrule Rrule Toprule">100-200</td><td align="center" class="Lrule Rrule Toprule">182</td><td align="center" class="Lrule Rrule Toprule">97</td><td align="center" class="Lrule Rrule Toprule">309</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 1</td><td align="center" class="Lrule Rrule Toprule">245</td><td align="center" class="Lrule Rrule Toprule">100-200</td><td align="center" class="Lrule Rrule Toprule">161</td><td align="center" class="Lrule Rrule Toprule">85</td><td align="center" class="Lrule Rrule Toprule">274</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 2</td><td align="center" class="Lrule Rrule Toprule">232</td><td align="center" class="Lrule Rrule Toprule">75-150</td><td align="center" class="Lrule Rrule Toprule">140</td><td align="center" class="Lrule Rrule Toprule">84</td><td align="center" class="Lrule Rrule Toprule">213</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 3</td><td align="center" class="Lrule Rrule Toprule">220</td><td align="center" class="Lrule Rrule Toprule">75-150</td><td align="center" class="Lrule Rrule Toprule">111</td><td align="center" class="Lrule Rrule Toprule">68</td><td align="center" class="Lrule Rrule Toprule">187</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 4</td><td align="center" class="Lrule Rrule Toprule">208</td><td align="center" class="Lrule Rrule Toprule">50-100</td><td align="center" class="Lrule Rrule Toprule">99</td><td align="center" class="Lrule Rrule Toprule">56</td><td align="center" class="Lrule Rrule Toprule">156</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 6</td><td align="center" class="Lrule Rrule Toprule">200</td><td align="center" class="Lrule Rrule Toprule">25-50</td><td align="center" class="Lrule Rrule Toprule">75</td><td align="center" class="Lrule Rrule Toprule">43</td><td align="center" class="Lrule Rrule Toprule">142</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 7</td><td align="center" class="Lrule Rrule Toprule">199</td><td align="center" class="Lrule Rrule Toprule">25-50</td><td align="center" class="Lrule Rrule Toprule">59</td><td align="center" class="Lrule Rrule Toprule">36</td><td align="center" class="Lrule Rrule Toprule">117</td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 9</td><td align="center" class="Lrule Rrule Toprule">194</td><td align="center" class="Lrule Rrule Toprule">25-50</td><td align="center" class="Lrule Rrule Toprule">49</td><td align="center" class="Lrule Rrule Toprule">28</td><td align="center" class="Lrule Rrule Toprule">91</td> </tr> <tr class="Last"> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule">Month 12</td><td align="center" class="Lrule Rrule Toprule">186</td><td align="center" class="Lrule Rrule Toprule">25-50</td><td align="center" class="Lrule Rrule Toprule">46</td><td align="center" class="Lrule Rrule Toprule">25</td><td align="center" class="Lrule Rrule Toprule">100</td> </tr> </tbody> </table></div>

In the liver transplant clinical trial [see Clinical Studies (14.2)], the target tacrolimus whole blood trough concentrations were greater than or equal to 8 ng/mL in the first 30 days posttransplant. The protocol required that patients had a tacrolimus trough concentration of at least 8 ng/mL in the week prior to initiation of everolimus. Everolimus was initiated after 30 days posttransplant. At that time, the target tacrolimus trough concentrations were reduced to 3 to 5 ng/mL. Table 6 below provides a summary of the tacrolimus whole blood trough concentrations observed during the study through Month 24 posttransplant.

<div class="scrollingtable"><table> <caption> <span>Table 6. Tacrolimus Trough Concentrations Over 24 Months Posttransplant – Liver Study Median Values (ng/mL) With 10<span class="Sup">th</span> and 90<span class="Sup">th</span> Percentiles</span> </caption> <col width="157"/> <col width="90"/> <col width="78"/> <col width="94"/> <col width="105"/> <col width="105"/> <col width="105"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"> <span class="Bold">Treatment Group</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Visit</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">N</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Target (ng/mL)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Median</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">10</span><span class="Bold"><span class="Sup">th</span></span> <br/> <span class="Bold">percentile</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">90</span><span class="Bold"><span class="Sup">th</span></span> <br/> <span class="Bold">percentile</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Pre-dose group<br/> <br/>Everolimus tablets<br/>1 mg twice daily (initiated at Month 1)</td><td align="center" class="Lrule Rrule Toprule">Week 4</td><td align="center" class="Lrule Rrule Toprule">234</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">9.5</td><td align="center" class="Lrule Rrule Toprule">5.8</td><td align="center" class="Lrule Rrule Toprule">14.6</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Week 5</td><td align="center" class="Lrule Rrule Toprule">219</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">8.1</td><td align="center" class="Lrule Rrule Toprule">4.5</td><td align="center" class="Lrule Rrule Toprule">13.8</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Week 6</td><td align="center" class="Lrule Rrule Toprule">233</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">7.0</td><td align="center" class="Lrule Rrule Toprule">4.1</td><td align="center" class="Lrule Rrule Toprule">12.0</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 2</td><td align="center" class="Lrule Rrule Toprule">219</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">5.6</td><td align="center" class="Lrule Rrule Toprule">3.4</td><td align="center" class="Lrule Rrule Toprule">10.3</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 3</td><td align="center" class="Lrule Rrule Toprule">218</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">5.2</td><td align="center" class="Lrule Rrule Toprule">3.1</td><td align="center" class="Lrule Rrule Toprule">9.7</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 4</td><td align="center" class="Lrule Rrule Toprule">196</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">4.9</td><td align="center" class="Lrule Rrule Toprule">2.9</td><td align="center" class="Lrule Rrule Toprule">7.7</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 5</td><td align="center" class="Lrule Rrule Toprule">195</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">4.8</td><td align="center" class="Lrule Rrule Toprule">2.7</td><td align="center" class="Lrule Rrule Toprule">7.3</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 6</td><td align="center" class="Lrule Rrule Toprule">200</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">4.6</td><td align="center" class="Lrule Rrule Toprule">3.0</td><td align="center" class="Lrule Rrule Toprule">7.5</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 9</td><td align="center" class="Lrule Rrule Toprule">186</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">4.4</td><td align="center" class="Lrule Rrule Toprule">2.9</td><td align="center" class="Lrule Rrule Toprule">8.0</td> </tr> <tr> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 12</td><td align="center" class="Lrule Rrule Toprule">175</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">4.3</td><td align="center" class="Lrule Rrule Toprule">2.6</td><td align="center" class="Lrule Rrule Toprule">7.3</td> </tr> <tr class="Last"> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">Month 24</td><td align="center" class="Lrule Rrule Toprule">109</td><td align="center" class="Lrule Rrule Toprule">3 to 5</td><td align="center" class="Lrule Rrule Toprule">3.8</td><td align="center" class="Lrule Rrule Toprule">2.3</td><td align="center" class="Lrule Rrule Toprule">5.5</td> </tr> </tbody> </table></div>

Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses up to 0.9 mg/kg, the highest dose tested. In these studies, AUCs in mice were higher (at least 20 times) than those in humans receiving 0.75 mg twice daily, and AUCs in rats were in the same range as those in humans receiving 0.75 mg twice daily.

Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.

In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily.

Oral doses of everolimus in female rats greater or equal to 0.1 mg/kg (approximately 0.13-fold the estimated AUC 0-24h in patients receiving the starting dose 0.75 mg twice daily) resulted in increased incidence of pre-implantation loss.

In an oral neonatal and juvenile development study in rats, oral administration of everolimus from postnatal Day 7 to 70 produced dose-related delayed attainment of developmental landmarks, including delayed eye-opening, delayed reproductive development in males and females, and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day. Exposures in the rat at these doses were equal to or less than those obtained in adult human transplant patients.

A 24-month, multi-national, open-label, randomized (1:1:1) trial was conducted comparing two concentration-controlled everolimus regimens of 1.5 mg per day starting dose (targeting 3 to 8 ng/mL using an LC/MS/MS assay method and 3 mg per day starting dose (targeting 6 to 12 ng/mL using an LC/MS/MS assay method) with reduced exposure cyclosporine and corticosteroids, to 1.44 g per day of mycophenolic acid with standard exposure cyclosporine and corticosteroids. The mean cyclosporine starting dose was 5.2, 5 and 5.7 mg/kg body weight/day in the everolimus 1.5 mg, 3 mg and in mycophenolic acid groups, respectively. The cyclosporine dose in the everolimus group was then adjusted to the blood trough concentration ranges indicated in Table 5, whereas in the mycophenolic acid group the target ranges were 200 to 300 ng/mL starting Day 5: 200 to 300 ng/mL, and 100 to 250 ng/mL from Month 2 to Month 12.

All patients received basiliximab induction therapy. The study population consisted of 18- to 70-year old male and female low-to-moderate risk renal transplant recipients undergoing their first transplant. Low to moderate immunologic risk was defined in the study as an ABO blood type compatible first organ or tissue transplant recipient with anti-human leukocyte antigen (HLA) Class I panel reactive antibody (PRA) less than 20% by a complement dependent cytotoxicity-based assay, or less than 50% by a flow cytometry or ELISA-based assay, and with a negative T-cell cross match. Eight hundred thirty-three (833) patients were randomized after transplantation; 277 randomized to the everolimus 1.5 mg per day group, 279 to the everolimus 3 mg per day group and 277 to the mycophenolic acid 1.44 g per day group. The study was conducted at 79 renal transplant centers across Europe, South Africa, North and South America, and Asia-Pacific. There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. The majority of transplant recipients in all groups (70% to 76%) had three or more HLA mismatches; mean percentage of panel reactive antibodies ranged from 1% to 2%. The rate of premature treatment discontinuation at 12 months was 30% and 22% in the everolimus 1.5 mg and control groups, respectively, (p = 0.03, Fisher’s exact test) and was more prominent between groups among female patients. Results at 12 months indicated that everolimus 1.5 mg per day is comparable to control with respect to efficacy failure, defined as treated biopsy-proven acute rejection*, graft loss, death, or loss to follow-up. The percentage of patients experiencing this endpoint and each individual variable in the everolimus and control groups is shown in Table 7.

<div class="scrollingtable"><table> <caption> <span>Table 7. Efficacy Failure by Treatment Group (ITT Population) at 12 Months After Kidney Transplantation</span> </caption> <col width="44"/> <col width="254"/> <col width="222"/> <col width="208"/> <tfoot> <tr class="First Last"> <td colspan="4"> <p class="First">Abbreviation: CsA, cyclosporine</p> <p> <span class="Sup">*</span>Treated biopsy-proven acute rejection (tBPAR) was defined as a histologically confirmed acute rejection with a biopsy graded as IA, IB, IIA, IIB, or III according to 1997 Banff criteria that were treated with anti-rejection medication.<br/> <span class="Sup">1</span>The difference in rates (everolimus–mycophenolic acid) with 95% confidence interval (CI) for primary efficacy failure endpoint is 1.1% (-6.1%, 8.3%); and for the graft loss, death or loss to follow-up endpoint is 2.2% (-2.9%, 7.3%).<br/> <span class="Sup">2</span>Includes treated BPAR, graft loss, death or loss to follow-up by Month 12 where loss to follow-up represents patient who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12-month visit.<br/> <span class="Sup">3</span>Loss to follow-up (for Graft Loss, Death, or Loss to Follow-up) represents patient who did not experience death or graft loss and whose last contact date is prior to 12-month visit.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" colspan="2"></td><td align="center" class="Lrule Rrule Toprule" valign="bottom"><span class="Bold">Everolimus </span> <br/> <span class="Bold">1.5 mg per day</span> <br/> <span class="Bold">with reduced exposure CsA<br/>N = 277<br/>n (%)</span></td><td align="center" class="Lrule Rrule Toprule" valign="bottom"><span class="Bold">Mycophenolic acid </span> <br/> <span class="Bold">1.44 g per day</span> <br/> <span class="Bold">with standard exposure CsA<br/>N = 277<br/>n (%)</span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"><span class="Bold">Efficacy endpoints</span><span class="Sup">1</span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">Efficacy failure endpoint<span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">70 (25.3)</td><td align="center" class="Lrule Rrule Toprule">67 (24.2)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">       Treated biopsy proven acute rejection</td><td align="center" class="Lrule Rrule Toprule">45 (16.2)</td><td align="center" class="Lrule Rrule Toprule">47 (17.0)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">       Death</td><td align="center" class="Lrule Rrule Toprule">7 (2.5)</td><td align="center" class="Lrule Rrule Toprule">6 (2.2)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">       Graft loss</td><td align="center" class="Lrule Rrule Toprule">12 (4.3)</td><td align="center" class="Lrule Rrule Toprule">9 (3.2)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">       Loss to follow-up</td><td align="center" class="Lrule Rrule Toprule">12 (4.3)</td><td align="center" class="Lrule Rrule Toprule">9 (3.2)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">Graft loss or death or loss to follow-up<span class="Sup">3</span></td><td align="center" class="Lrule Rrule Toprule">32 (11.6)</td><td align="center" class="Lrule Rrule Toprule">26 (9.4)</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">       Graft loss or death</td><td align="center" class="Lrule Rrule Toprule">18 (6.5)</td><td align="center" class="Lrule Rrule Toprule">15 (5.4)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule" colspan="2">       Loss to follow-up<span class="Sup">3</span></td><td align="center" class="Lrule Rrule Toprule">14 (5.1)</td><td align="center" class="Lrule Rrule Toprule">11 (4.0)</td> </tr> </tbody> </table></div>

The estimated mean glomerular filtration rate [using the Modification of Diet in Renal Disease (MDRD) equation] for everolimus 1.5 mg (target trough concentrations 3 to 8 ng/mL) and mycophenolic acid groups were comparable at Month 12 in the intent-to-treat (ITT) population (Table 8).

<div class="scrollingtable"><table> <caption> <span>Table 8. Estimated Glomerular Filtration Rates (mL/min/1.73 m<span class="Sup">2</span>) by MDRD at 12 Months After Kidney Transplantation*</span> </caption> <col width="245"/> <col width="245"/> <col width="245"/> <tfoot> <tr class="First Last"> <td colspan="3"> <p class="First">Abbreviations: CsA, cyclosporine; MDRD, modification of diet in renal disease; SD, standard deviation.</p> <p> <span class="Sup">*</span>Analysis based on using a subject’s last observation carried forward for missing data at 12 months due to death or lost to follow-up data, a value of zero is used for subjects who experienced a graft loss.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"><span class="Bold">Month 12 GFR (MDRD)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus </span> <br/> <span class="Bold">1.5 mg</span><span class="Bold"> per </span><span class="Bold">day</span> <br/> <span class="Bold">with reduced </span><span class="Bold">exposure </span><span class="Bold">CsA</span> <br/> <span class="Bold">N</span><span class="Bold"> = 27</span><span class="Bold">6</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Mycophenolic acid</span> <br/> <span class="Bold">1.44 g</span><span class="Bold"> per </span><span class="Bold">day</span> <br/> <span class="Bold">with </span><span class="Bold">standard</span><span class="Bold">exposure </span><span class="Bold">CsA</span> <br/> <span class="Bold">N</span><span class="Bold"> = 277</span></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Mean (SD)</span>**</td><td align="center" class="Lrule Rrule Toprule">54.6 (21.7)</td><td align="center" class="Lrule Rrule Toprule">52.3 (26.5)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule"><span class="Bold">Median (range)</span></td><td align="center" class="Lrule Rrule Toprule">55.0 (0-140.9)</td><td align="center" class="Lrule Rrule Toprule">50.1 (0.0-366.4)</td> </tr> </tbody> </table></div>

Two earlier studies compared fixed doses of everolimus 1.5 mg per day and 3 mg per day, without TDM, combined with standard exposure cyclosporine and corticosteroids to mycophenolate mofetil 2 g per day and corticosteroids. Antilymphocyte antibody induction was prohibited in both studies. Both were multicenter, double-blind (for first 12 months), randomized trials (1:1:1) of 588 and 583 de novo renal transplant patients, respectively. The 12-month analysis of GFR showed increased rates of renal impairment in both the everolimus groups compared to the mycophenolate mofetil group in both studies. Therefore, reduced exposure cyclosporine should be used in combination with everolimus in order to avoid renal dysfunction and everolimus trough concentrations should be adjusted using TDM to maintain trough concentrations between 3 to 8 ng/mL [see Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.6)].

A 24 month, multinational, open-label, randomized (1:1:1) trial was conducted in liver transplant patients starting 30 days posttransplant. During the first 30 days, after transplant and prior to randomization, patients received tacrolimus and corticosteroids, with or without mycophenolate mofetil. No induction antibody was administered. Approximately 70% to 80% of patients received at least one dose of mycophenolate mofetil at a median total daily dose of 1.5 g during the first 30 days. For eligibility, patients had to have a tacrolimus trough concentration of at least 8 ng/mL in the week prior to randomization.

At randomization, mycophenolate mofetil was discontinued and patients were randomized to one of two everolimus treatment groups [initial dose of 1 mg twice per day (2 mg daily) and adjusted to target trough concentrations using an LC/MS/MS assay of 3 to 8 ng/mL] either with reduced exposure of tacrolimus (target trough whole blood concentrations of 3 to 5 ng/mL) or tacrolimus elimination. In the tacrolimus elimination group, at Month 4 posttransplant, once the everolimus trough concentrations were within the target range of 6 to 10 ng/mL, reduced exposure tacrolimus was eliminated. The everolimus with tacrolimus elimination group was discontinued early due to higher incidence of acute rejection. In the control group, patients received standard exposure tacrolimus (target trough whole blood concentrations of 8 to 12 ng/mL tapered to 6 to 10 ng/mL by Month 4 posttransplant). All patients received corticosteroids during the trial.

The study population consisted of 18- to 70-year-old male and female liver transplant recipients undergoing their first transplant, mean age was approximately 54 years, more than 70% of patients were male, and the majority of patients were Caucasian, with approximately 89% of patients per treatment group completing the study. Key stratification parameters of HCV status (31% to 32% HCV positive across groups) and renal function (mean baseline eGFR range 79 to 83 mL/min/1.73 m2) were also balanced between groups.

A total of 1147 patients were enrolled into the run-in period of this trial. At 30 days posttransplant, a total 719 patients, who were eligible according to study inclusion/exclusion criteria, were randomized into 1 of 3 treatment groups:everolimus with reduced exposure tacrolimus; N = 245,everolimus with tacrolimus elimination (tacrolimus elimination group); N = 231, or standard dose/exposure tacrolimus (tacrolimus control); N = 243. The study was conducted at 89 liver transplant centers across Europe, including the United Kingdom and Ireland, North and South America, and Australia.

Key inclusion criteria were recipients 18 to 70 years of age, eGFR greater or equal to 30 mL/min/1.73 m2, tacrolimus trough level of greater or equal to 8 ng/mL in the week prior to randomization, and the ability to take oral medication.

Key exclusion criteria were recipients of multiple solid organ transplants, history of malignancy (except hepatocellular carcinoma within Milan criteria), human immunodeficiency virus, and any surgical or medical condition which significantly alter the absorption, distribution, metabolism and excretion of study drug.

There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. Mean MELD scores at time of transplantation, cold ischemia times (CIT), and ABO matching were similar across groups. Overall, the treatment groups were comparable with respect to the key determinants of liver transplantation.

The tacrolimus elimination group was stopped prematurely due to a higher incidence of acute rejection and adverse reactions leading to treatment discontinuation reported during the elimination phase of tacrolimus. Therefore, a treatment regimen of everolimus with tacrolimus elimination is not recommended.

Results up to 24 months are presented indicating that everolimus with reduced exposure tacrolimus is comparable to standard exposure tacrolimus with respect to efficacy failure, defined as treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up throughout 12 to 24 months of treatment. The percentage of patients experiencing this endpoint and each individual variable in the everolimus and control group for each time interval is shown in Table 9.

<div class="scrollingtable"><table> <caption> <span>Table 9. Efficacy Failure by Treatment Group (ITT Population) at 12 and 24 Months After Liver Transplantation</span> </caption> <col width="301"/> <col width="228"/> <col width="205"/> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">*</span>Treated biopsy-proven acute rejection (tBPAR) was defined as histologically confirmed acute rejection with a rejection activity index (RAI) greater than or equal to RAI score 3 that received anti-rejection treatment. <br/> <span class="Sup">1</span>The difference in rates (Everolimus – control) at 12 months with 97.5% CI for efficacy failure endpoint based on normal approximation with Yates continuity correction is -4.6% (-11.4%, 2.2%); and for the graft loss, death or loss to follow-up endpoint is -0.1% (-5.4%, 5.3%).<br/> <span class="Sup">2</span>Loss to follow-up (for treated BPAR, graft loss, death or loss to follow-up) represents patients who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12- or 24-month visit.<br/> <span class="Sup">3</span>Loss to follow-up (for graft loss, death, or loss to follow-up) represents patients who did not experience death or graft loss and whose last contact date is prior to 12- or 24-month visit.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus </span> <br/> <span class="Bold">with reduced exposure tacrolimus</span> <br/> <span class="Bold">N = 245 </span> <br/> <span class="Bold">n (%)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Tacrolimus </span> <br/> <span class="Bold">standard exposure</span> <br/> <span class="Bold">N = 243 </span> <br/> <span class="Bold">n (%)</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Efficacy endpoints<span class="Sup">1</span> at 12 months</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Composite efficacy failure endpoint<span class="Sup">1,</span><span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">22 (9.0) </td><td align="center" class="Lrule Rrule Toprule">33 (13.6) </td> </tr> <tr> <td class="Lrule Rrule Toprule">     Treated biopsy proven acute rejection*</td><td align="center" class="Lrule Rrule Toprule">7 (2.9)</td><td align="center" class="Lrule Rrule Toprule">17 (7.0)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Death</td><td align="center" class="Lrule Rrule Toprule">13 (5.3)</td><td align="center" class="Lrule Rrule Toprule">7 (2.9)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Graft Loss</td><td align="center" class="Lrule Rrule Toprule">6 (2.4)</td><td align="center" class="Lrule Rrule Toprule">3 (1.2)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Loss to follow-up<span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">4 (1.6)</td><td align="center" class="Lrule Rrule Toprule">9 (3.7)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Graft loss or death or loss to follow-up</td><td align="center" class="Lrule Rrule Toprule">18 (7.3)</td><td align="center" class="Lrule Rrule Toprule">18 (7.4)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Graft loss or death</td><td align="center" class="Lrule Rrule Toprule">14 (5.7)</td><td align="center" class="Lrule Rrule Toprule">8 (3.3)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Loss to follow-up</td><td align="center" class="Lrule Rrule Toprule">4 (1.6)</td><td align="center" class="Lrule Rrule Toprule">10 (4.1)</td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Efficacy endpoints at 24 months</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Composite efficacy failure endpoint<span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">45 (18.4)</td><td align="center" class="Lrule Rrule Toprule">53 (21.8)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Treated biopsy proven acute rejection</td><td align="center" class="Lrule Rrule Toprule">11 (4.5)</td><td align="center" class="Lrule Rrule Toprule">18 (7.4)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Death</td><td align="center" class="Lrule Rrule Toprule">17 (6.9)</td><td align="center" class="Lrule Rrule Toprule">11 (4.5)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Graft loss</td><td align="center" class="Lrule Rrule Toprule">9 (3.7)</td><td align="center" class="Lrule Rrule Toprule">7 (2.9)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Loss to follow-up<span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">18 (7.3)</td><td align="center" class="Lrule Rrule Toprule">23 (9.5)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Graft loss or death or loss to follow-up<span class="Sup">3</span></td><td align="center" class="Lrule Rrule Toprule">38 (15.5)</td><td align="center" class="Lrule Rrule Toprule">39 (16.0)</td> </tr> <tr> <td class="Lrule Rrule Toprule">     Graft loss or death</td><td align="center" class="Lrule Rrule Toprule">20 (8.2)</td><td align="center" class="Lrule Rrule Toprule">15 (6.2)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">     Loss to follow-up<span class="Sup">3</span></td><td align="center" class="Lrule Rrule Toprule">18 (7.3)</td><td align="center" class="Lrule Rrule Toprule">24 (9.9)</td> </tr> </tbody> </table></div>

At Month 12, the estimated mean glomerular filtration rate (eGFR) using the MDRD equation for the everolimus group was 80.9 mL/min/1.73 m2 and the tacrolimus control was 70.3 mL/min/1.73 m2 in the ITT population. At Month 24, the eGFR using the MDRD equation for the everolimus group was 74.7 mL/min/1.73 m2 and for the tacrolimus control the eGFR was 67.8 mL/min/1.73 m2 (Table 10).

<div class="scrollingtable"><table> <caption> <span>Table 10. Estimated Glomerular Filtration Rates (mL/min/1.73 m<span class="Sup">2</span>) by MDRD at 12 and 24 Months After Liver Transplantation</span> </caption> <col width="241"/> <col width="257"/> <col width="236"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"><span class="Bold">e</span><span class="Bold">GFR (MDRD)</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Everolimus with reduced exposure tacrolimus</span> <br/> </td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Tacrolimus standard exposure</span> <br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Month 12</span></td><td align="center" class="Lrule Rrule Toprule">N = 215</td><td align="center" class="Lrule Rrule Toprule">N = 209</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">           </span><span class="Bold">Mean (S</span><span class="Bold">D</span><span class="Bold">)</span></td><td align="center" class="Lrule Rrule Toprule">80.9 (27.3)</td><td align="center" class="Lrule Rrule Toprule">70.3 (23.1)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">           </span><span class="Bold">Median (range)</span></td><td align="center" class="Lrule Rrule Toprule">78.3 (28.4-153.1)</td><td align="center" class="Lrule Rrule Toprule">66.4 (27.9-155.8)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Month 24</span></td><td align="center" class="Lrule Rrule Toprule">N = 184</td><td align="center" class="Lrule Rrule Toprule">N = 186</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">           </span><span class="Bold">Mean (SD)</span></td><td align="center" class="Lrule Rrule Toprule">74.7 (26.1)</td><td align="center" class="Lrule Rrule Toprule">67.8 (21.0)</td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">           </span><span class="Bold">Median (range)</span></td><td align="center" class="Lrule Rrule Toprule">72.9 (20.3-151.6)</td><td align="center" class="Lrule Rrule Toprule">65.2 (27.0-148.9)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule" colspan="3">Abbreviations: eGFR, Estimated Glomerular Filtration Rates; MDRD, Modification Of Diet In Renal Disease; SD, standard deviation.</td> </tr> </tbody> </table></div>

Figure 1.  Mean and 95% CI of eGFR (MDRD 4) [mL/min/1.73 m2] by Visit Window and Treatment After Liver Transplantation (ITT population - 24-Month Analysis)*

*Everolimus dosing was initiated 30 days after transplantation.

Although the initial protocol was designed for 24 months, the study was subsequently extended to 36 months. One hundred six (106) patients (43%) in the everolimus group and 125 patients (51%) in the control group participated in the extension study from Month 24 to Month 36 after transplantation. The results for the everolimus group at 36 months were consistent with the results at 24 months in terms of tBPAR, graft loss, death, and eGFR.

Everolimus tablets are packed in child-resistant blisters and bottles with a child resistant closure.

{ "type": "p", "children": [], "text": "Everolimus tablets are packed in child-resistant blisters and bottles with a child resistant closure." }

Table 11. Description of Everolimus Tablets

{ "type": "p", "children": [], "text": "\nTable 11. Description of Everolimus Tablets \n" }

<div class="scrollingtable"><table> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">Dosage strength</span></td><td><span class="Bold">0.25 mg</span></td><td><span class="Bold">0.5 mg</span></td><td><span class="Bold">0.75 mg</span></td><td><span class="Bold">1 mg</span></td> </tr> <tr> <td><span class="Bold">Appearance</span></td><td colspan="4">White to off-white, round shaped, flat faced bevelled edge tablets</td> </tr> <tr> <td><span class="Bold">Imprint</span></td><td>Debossed B1 on one side and plain on other side.</td><td>Debossed B2 on one side and plain on other side.</td><td>Debossed B3 on one side and plain on other side.</td><td>Debossed B4 on one side and plain on other side.</td> </tr> <tr> <td><span class="Bold">NDC number for bottles of 60</span></td><td>70377-069-11</td><td>70377-070-11</td><td>70377-071-11</td><td>70377-112-11</td> </tr> <tr class="Last"> <td><span class="Bold">NDC number Blister</span></td><td>70377-069-21</td><td>70377-070-21</td><td>70377-071-21</td><td>70377-112-21</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td><span class=\"Bold\">Dosage strength</span></td><td><span class=\"Bold\">0.25 mg</span></td><td><span class=\"Bold\">0.5 mg</span></td><td><span class=\"Bold\">0.75 mg</span></td><td><span class=\"Bold\">1 mg</span></td>\n</tr>\n<tr>\n<td><span class=\"Bold\">Appearance</span></td><td colspan=\"4\">White to off-white, round shaped, flat faced bevelled edge tablets</td>\n</tr>\n<tr>\n<td><span class=\"Bold\">Imprint</span></td><td>Debossed B1 on one side and plain on other side.</td><td>Debossed B2 on one side and plain on other side.</td><td>Debossed B3 on one side and plain on other side.</td><td>Debossed B4 on one side and plain on other side.</td>\n</tr>\n<tr>\n<td><span class=\"Bold\">NDC number for bottles of 60</span></td><td>70377-069-11</td><td>70377-070-11</td><td>70377-071-11</td><td>70377-112-11</td>\n</tr>\n<tr class=\"Last\">\n<td><span class=\"Bold\">NDC number Blister</span></td><td>70377-069-21</td><td>70377-070-21</td><td>70377-071-21</td><td>70377-112-21</td>\n</tr>\n</tbody>\n</table></div>" }

Each strength is available in boxes of 60 tablets (6 blister cards of 10 tablets each) and in bottles of 60’s count.

{ "type": "p", "children": [], "text": "Each strength is available in boxes of 60 tablets (6 blister cards of 10 tablets each) and in bottles of 60’s count." }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]." }

Protect from light and moisture.

{ "type": "p", "children": [], "text": "Protect from light and moisture." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "\nAdvise the patient to read the FDA-approved patient labeling (Medication Guide).\n" }

Administration

{ "type": "p", "children": [], "text": "\nAdministration\n" }

Inform patients that everolimus tablets should be taken orally twice a day approximately 12 hours apart consistently either with or without food.

{ "type": "p", "children": [], "text": "Inform patients that everolimus tablets should be taken orally twice a day approximately 12 hours apart consistently either with or without food." }

Inform patients to avoid grapefruit and grapefruit juice, which increase blood drug concentrations of everolimus tablets [see Warnings and Precautions (5.20)].

{ "type": "p", "children": [], "text": "Inform patients to avoid grapefruit and grapefruit juice, which increase blood drug concentrations of everolimus tablets [see Warnings and Precautions (5.20)]." }

Advise patients that everolimus tablets should be used concurrently with reduced doses of cyclosporine and that any change in doses of these medications should be made under physician supervision. A change in the cyclosporine dose may also require a change in the dosage of everolimus tablets. 

{ "type": "p", "children": [], "text": "Advise patients that everolimus tablets should be used concurrently with reduced doses of cyclosporine and that any change in doses of these medications should be made under physician supervision. A change in the cyclosporine dose may also require a change in the dosage of everolimus tablets. " }

Inform patients of the necessity of repeated laboratory tests according to physician recommendations while they are taking everolimus tablets.

{ "type": "p", "children": [], "text": "Inform patients of the necessity of repeated laboratory tests according to physician recommendations while they are taking everolimus tablets." }

Development of Lymphomas and Other Malignancies

{ "type": "p", "children": [], "text": "\nDevelopment of Lymphomas and Other Malignancies\n" }

Inform patients they are at risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a sunscreen with a high protection factor [see Warnings and Precautions (5.2)]. 

{ "type": "p", "children": [], "text": "Inform patients they are at risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a sunscreen with a high protection factor [see Warnings and Precautions (5.2)]. \n" }

Increased Risk of Infection 

{ "type": "p", "children": [], "text": "\nIncreased Risk of Infection \n" }

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression. Advise patients to contact their physician if they develop any symptoms of infection [see Warnings and Precautions (5.3, 5.13)]. 

{ "type": "p", "children": [], "text": "Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression. Advise patients to contact their physician if they develop any symptoms of infection [see Warnings and Precautions (5.3, 5.13)]. \n" }

Kidney Graft Thrombosis

{ "type": "p", "children": [], "text": "\nKidney Graft Thrombosis\n" }

Inform patients that everolimus tablets has been associated with an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually within the first 30 days posttransplantation [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that everolimus tablets has been associated with an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually within the first 30 days posttransplantation [see Warnings and Precautions (5.4)].\n" }

Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity

{ "type": "p", "children": [], "text": "\nEverolimus and Calcineurin Inhibitor-Induced Nephrotoxicity\n" }

Advise patients of the risks of impaired kidney function with the combination of everolimus and cyclosporine as well as the need for routine blood concentration monitoring for both drugs. Advise patients of the importance of serum creatinine monitoring [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Advise patients of the risks of impaired kidney function with the combination of everolimus and cyclosporine as well as the need for routine blood concentration monitoring for both drugs. Advise patients of the importance of serum creatinine monitoring [see Warnings and Precautions (5.6)].\n" }

Angioedema

{ "type": "p", "children": [], "text": "\nAngioedema\n" }

Inform patients of the risk of angioedema and that concomitant use of ACE inhibitors may increase this risk. Advise patients to seek prompt medical attention if symptoms occur [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Inform patients of the risk of angioedema and that concomitant use of ACE inhibitors may increase this risk. Advise patients to seek prompt medical attention if symptoms occur [see Warnings and Precautions (5.8)].\n" }

Wound Healing Complications and Fluid Accumulation

{ "type": "p", "children": [], "text": "\nWound Healing Complications and Fluid Accumulation\n" }

Inform patients that the use of everolimus tablets has been associated with impaired or delayed wound healing, fluid accumulation and the need for careful observation of their incision site [see Warnings and Precautions (5.9)]. 

{ "type": "p", "children": [], "text": "Inform patients that the use of everolimus tablets has been associated with impaired or delayed wound healing, fluid accumulation and the need for careful observation of their incision site [see Warnings and Precautions (5.9)]. " }

Interstitial Lung Disease (ILD)/Non-Infectious Pneumonitis

{ "type": "p", "children": [], "text": "\nInterstitial Lung Disease (ILD)/Non-Infectious Pneumonitis\n" }

Inform patients that the use of everolimus tablets may increase the risk of non-infectious pneumonitis. Advise patients to seek medical attention if they develop clinical symptoms consistent with pneumonia [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Inform patients that the use of everolimus tablets may increase the risk of non-infectious pneumonitis. Advise patients to seek medical attention if they develop clinical symptoms consistent with pneumonia [see Warnings and Precautions (5.10)].\n" }

Hyperlipidemia

{ "type": "p", "children": [], "text": "\nHyperlipidemia\n" }

Inform patients that the use of everolimus tablets has been associated with increased serum cholesterol and triglycerides that may require treatment and the need for monitoring of blood lipid concentrations [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Inform patients that the use of everolimus tablets has been associated with increased serum cholesterol and triglycerides that may require treatment and the need for monitoring of blood lipid concentrations [see Warnings and Precautions (5.11)].\n" }

Proteinuria

{ "type": "p", "children": [], "text": "\nProteinuria\n" }

Inform patients that the use of everolimus tablets has been associated with an increased risk of proteinuria [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Inform patients that the use of everolimus tablets has been associated with an increased risk of proteinuria [see Warnings and Precautions (5.12)].\n" }

Pregnancy and Lactation

{ "type": "p", "children": [], "text": "\nPregnancy and Lactation\n" }

Advise women of childbearing age to avoid becoming pregnant throughout treatment and for 8 weeks after everolimus therapy has stopped. Everolimus tablets can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. Also advise not to breastfeed while taking everolimus tablets [see Use in Specific Populations (8.1, 8.2)].

{ "type": "p", "children": [], "text": "Advise women of childbearing age to avoid becoming pregnant throughout treatment and for 8 weeks after everolimus therapy has stopped. Everolimus tablets can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. Also advise not to breastfeed while taking everolimus tablets [see Use in Specific Populations (8.1, 8.2)]." }

Male and Female Fertility

{ "type": "p", "children": [], "text": "\nMale and Female Fertility\n" }

Inform male and female patients that everolimus tablets may impair fertility [see Warnings and Precautions (5.18), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Inform male and female patients that everolimus tablets may impair fertility [see Warnings and Precautions (5.18), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]." }

Medications That Interfere With Everolimus

{ "type": "p", "children": [], "text": "\nMedications That Interfere With Everolimus\n" }

Some medications can increase or decrease blood concentrations of everolimus. Advise patients to inform their physician if they are taking any of the following: antifungals, antibiotics, antivirals, anti-epileptic medicines including carbamazepine, phenytoin and barbiturates, herbal/dietary supplements (St. John’s Wort), cannabidiol, and/or rifampin [see Warnings and Precautions (5.14, 5.22)].

{ "type": "p", "children": [], "text": "Some medications can increase or decrease blood concentrations of everolimus. Advise patients to inform their physician if they are taking any of the following: antifungals, antibiotics, antivirals, anti-epileptic medicines including carbamazepine, phenytoin and barbiturates, herbal/dietary supplements (St. John’s Wort), cannabidiol, and/or rifampin [see Warnings and Precautions (5.14, 5.22)].\n" }

New Onset Diabetes

{ "type": "p", "children": [], "text": "\nNew Onset Diabetes\n" }

Inform patients that the use of everolimus tablets may increase the risk of diabetes mellitus and to contact their physician if they develop symptoms [see Warnings and Precautions (5.16)].

{ "type": "p", "children": [], "text": "Inform patients that the use of everolimus tablets may increase the risk of diabetes mellitus and to contact their physician if they develop symptoms [see Warnings and Precautions (5.16)].\n" }

Immunizations

{ "type": "p", "children": [], "text": "\nImmunizations\n" }

Inform patients that vaccinations may be less effective while they are being treated with everolimus tablets. Advise patients that live vaccines should be avoided [see Warnings and Precautions (5.19)].

{ "type": "p", "children": [], "text": "Inform patients that vaccinations may be less effective while they are being treated with everolimus tablets. Advise patients that live vaccines should be avoided [see Warnings and Precautions (5.19)].\n" }

Patient With Hereditary Disorders

{ "type": "p", "children": [], "text": "\nPatient With Hereditary Disorders\n" }

Advise patients to inform their physicians that if they have hereditary disorders of galactose intolerance (Lapp-lactase deficiency or glucose-galactose malabsorption) not to take everolimus tablets [see Warnings and Precautions (5.21)].

{ "type": "p", "children": [], "text": "Advise patients to inform their physicians that if they have hereditary disorders of galactose intolerance (Lapp-lactase deficiency or glucose-galactose malabsorption) not to take everolimus tablets [see Warnings and Precautions (5.21)].\n" }

Manufactured by:

{ "type": "p", "children": [], "text": "\nManufactured by:\n" }

Biocon Pharma Limited

{ "type": "p", "children": [], "text": "Biocon Pharma Limited" }

Bengaluru, India - 560099

{ "type": "p", "children": [], "text": "Bengaluru, India - 560099" }

Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:\n" }

Biocon Pharma Inc.,

{ "type": "p", "children": [], "text": "Biocon Pharma Inc.," }

Iselin, New Jersey, 08830-3009

{ "type": "p", "children": [], "text": "Iselin, New Jersey, 08830-3009 " }

United States of America

{ "type": "p", "children": [], "text": "United States of America" }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First Last"> <td align="left"></td><td align="right">Revised:March 2024</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> <br/> <br/> <span>(e” ver oh’ li mus)</span> </p> <p>Everolimus Tablets, for oral use</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What is the most important information I should know about everolimus tablets?</span> <br/> <br/> </p> <p> <span class="Bold">Everolimus tablets can cause serious side effects, including:</span> </p> <ul class="Disc"> <li> <span class="Bold">Increased risk of getting certain cancers. </span>People who take everolimus tablets have a higher chance of getting lymphoma and other cancers, especially skin cancer. Talk to your doctor about your risk for cancer.<br/> </li> <li> <span class="Bold">Increased risk of serious infections. </span>Everolimus tablets weakens the body’s immune system and affects your ability to fight infections. Serious infections can happen with everolimus tablets that may lead to death. People taking everolimus tablets have a higher chance of getting infections caused by viruses, bacteria, and fungi (yeast).<ul class="Circle"> <li>Call your doctor if you have symptoms of infection, including fever or chills.</li> </ul> </li> </ul> <ul class="Disc"> <li> <span class="Bold">Blood clot in the blood vessels of your transplanted kidney. </span>If this happens, it usually occurs within the first 30 days after your kidney transplant. Tell your doctor right away if you:<ul class="Circle"> <li>have pain in your groin, lower back, side or stomach (abdomen)<br/> </li> <li>make less urine or you do not pass any urine<br/> </li> <li>have blood in your urine or dark colored urine (tea-colored)<br/> </li> <li>have fever, nausea, or vomiting</li> </ul> <br/> </li> <li> <span class="Bold">Serious problems with your transplanted kidney (nephrotoxicity)</span>. You will need to start with a lower dose of cyclosporine when you take it with everolimus tablets. Your doctor should do regular blood tests to check your levels of both everolimus tablets and cyclosporine. </li> <li> <span class="Bold">Increased risk of death that can be related to infection, in people who have had a heart transplant</span>.<br/>You should not take everolimus tablets without talking to your doctor if you have had a heart transplant. </li> </ul> <span class="Bold">See the section “What are the possible side effects of everolimus tablets?” for information about other serious side effects.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are everolimus tablets?</span> </p> <p> <br/>Everolimus tablets are a prescription medicine used to prevent transplant rejection (antirejection medicine) in people who have received a kidney transplant or liver transplant. Transplant rejection happens when the body’s immune system perceives the new transplanted kidney or liver as “foreign” and attacks it.</p> <p> <br/>Everolimus tablets is used with other medicines called cyclosporine, corticosteroids and certain other transplant medicines to prevent rejection of your transplanted kidney. Everolimus tablets is used with other medicines called tacrolimus and corticosteroids to prevent rejection of your transplanted liver.</p> <p> <br/>It is not known if everolimus tablets is safe and effective in transplanted organs other than the kidney and liver.</p> <p> <br/>It is not known if everolimus tablets is safe and effective in children under 18 years of age.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Do not take everolimus tablets if you are allergic to:<br/> </span> </p> <ul class="Disc"> <li>Everolimus (ZORTRESS/AFINITOR<span class="Sup">®</span>) or any of the ingredients in everolimus tablets. See the end of this Medication Guide for a complete list of ingredients in everolimus tablets.<br/> </li> <li>sirolimus (Rapamune<span class="Sup">®</span>)</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Before taking everolimus tablets, tell your doctor about all of your medical conditions, including if you:<br/> </span> </p> <ul class="Disc"> <li>have liver problems</li> <li>have skin cancer or it runs in your family</li> <li>have high cholesterol or triglycerides (fat in your blood)</li> <li>have Lapp lactase deficiency or glucose-galactose malabsorption. You should not take everolimus tablets if you have this disorder.</li> <li>are pregnant or could become pregnant. Everolimus tablets may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment and for 8 weeks after your last dose of everolimus tablets. Talk to your doctor about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away. You should not become pregnant during treatment with everolimus tablets.</li> <li>are breastfeeding or plan to breastfeed. It is not known if everolimus passes into your breast milk.</li> </ul> <p> <span class="Bold">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p> <p>Especially tell your doctor if you take:</p> <ul class="Disc"> <li>antifungal medicine</li> <li>antibiotic medicine</li> <li>heart medicine</li> <li>high blood pressure medicine</li> <li>a medicine to lower cholesterol or triglycerides</li> <li> <p class="First">cyclosporine (Sandimmune<span class="Sup">®</span>, Gengraf<span class="Sup">®</span>, Neoral<span class="Sup">®</span>)</p> </li> <li>tuberculosis (TB) medicine</li> <li>HIV medicine</li> <li>St. John’s Wort</li> <li>seizure (anticonvulsant) medicine</li> <li> <p class="First">cannabidiol (Epidiolex<span class="Sup">®</span>)</p> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">How should I take everolimus tablets?</span> <br/> <ul> <li>Take everolimus tablets exactly as your doctor tells you to.<br/> </li> <li> <span class="Bold">Do not</span> stop taking everolimus tablets or change your dose unless your doctor tells you to.<br/> </li> <li> <p class="First">Take everolimus tablets at the same time as your dose of cyclosporine or tacrolimus medicine.</p> </li> </ul> <ul> <li> <span class="Bold">Do not</span> stop taking or change your dose of cyclosporine or tacrolimus medicine unless your doctor tells you to.<br/> </li> <li>If your doctor changes your dose of cyclosporine or tacrolimus, your dose of everolimus tablets may change.<br/> </li> <li>Take everolimus tablets 2 times a day about 12 hours apart.<br/> </li> <li>Swallow everolimus tablets whole with a glass of water. Do not crush or chew everolimus tablets.<br/> </li> <li>Take everolimus tablets with or without food. If you take everolimus tablets <span class="Bold">with food</span>, always take everolimus tablets with food. If you take everolimus tablets without food, always take everolimus tablets without food.<br/> </li> <li>Your doctor will do regular blood tests to check your kidney or liver function while you take everolimus tablets. It is important that you get these tests done when your doctor tells you to. Blood tests will monitor how your kidneys or liver are working and make sure you are getting the right dose of everolimus tablets and other transplant medications you may be on (cyclosporine or tacrolimus). <br/> </li> <li>If you take too much everolimus tablets, call your doctor or go to the nearest hospital emergency room right away.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What should I avoid while taking everolimus tablets?</span> </p> <ul class="Disc"> <li>Avoid receiving any live vaccines while taking everolimus tablets. Some vaccines may not work as well while you are taking everolimus tablets.<br/> </li> <li>Do not eat grapefruit or drink grapefruit juice while you are taking everolimus tablets. Grapefruit may increase your blood level of everolimus tablets.<br/> </li> <li>Limit the amount of time you spend in the sunlight. Avoid using tanning beds or sunlamps. People who take everolimus tablets have a higher risk of getting skin cancer. See the section <span class="Bold">“What is the most important information I should know about everolimus tablets?”</span> Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if you have fair skin or if you have a family history of skin cancer.<br/> </li> <li>Avoid becoming pregnant. See the section <span class="Bold">“What should I tell my doctor before taking everolimus tablets?”</span> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the possible side effects of everolimus tablets?</span> </p> <p> <span class="Bold">Everolimus tablets may cause serious side effects, including:</span> </p> <ul class="Disc"> <li>See <span class="Bold">“What is the most important information I should know about everolimus tablets?”</span> <br/> </li> <li> <p class="First"> <span class="Bold">swelling under your skin especially around your mouth, eyes and in your throat (angioedema)</span>. Your chance of having swelling under your skin is higher if you take everolimus tablets along with certain other medicines. Tell your doctor right away or go to the nearest emergency room if you have any of these symptoms of angioedema: </p> <ul class="Disc"> <li> <p class="First">sudden swelling of your face, mouth, throat, tongue or hands</p> </li> <li> <p class="First">hives or welts<br/> </p> </li> <li>itchy or painful swollen skin<br/> </li> <li>trouble breathing</li> </ul> </li> <li> <span class="Bold">delayed wound healing.</span> Everolimus tablets can cause your incision to heal slowly or not heal well. Call your doctor right away if you have any of the following symptoms:<ul class="Disc"> <li>your incision is red, warm or painful<br/> </li> <li>blood, fluid, or pus in your incision<br/> </li> <li>your incision opens up<br/> </li> <li>swelling of your incision</li> </ul> </li> <li> <span class="Bold">lung or breathing problems</span>. Tell your doctor right away if you have new or worsening cough, shortness of breath, difficulty breathing or wheezing. In some patients, lung or breathing problems have been severe and can even lead to death. Your doctor may need to stop everolimus tablets or lower your dose.</li> <li> <span class="Bold">increased cholesterol and triglycerides (fat in your blood).</span> If your cholesterol and triglyceride levels are high, your doctor may want to lower them with diet, exercise and certain medicines.</li> <li> <span class="Bold">protein in your urine (proteinuria).</span> </li> <li> <span class="Bold">change in kidney function.</span> Everolimus tablets may cause kidney problems when taken along with a standard dose of cyclosporine medicine instead of a lower dose.</li> </ul> <span class="Bold">Your doctor should do blood and urine tests to monitor your cholesterol, triglycerides and kidney function.</span> <ul class="Disc"> <li> <span class="Bold">viral infections. </span>Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with everolimus tablets include BK virus-associated nephropathy. BK virus can affect how your kidney works and cause your transplanted kidney to fail.<br/> </li> <li> <p class="First"> <span class="Bold">blood clotting problems.</span> Talk to your doctor if this is a concern for you.</p> </li> </ul> <ul class="Disc"> <li> <span class="Bold">diabetes.</span> Tell your doctor if you have frequent urination, increased thirst or hunger.<br/> </li> <li> <span class="Bold">infertility, male.</span> Everolimus tablets can affect fertility in males and may affect your ability to father a child. Talk with your doctor if this is a concern for you. </li> <li> <span class="Bold">infertility, female.</span> Everolimus tablets can affect fertility in females and may affect your ability to become pregnant. Talk to your doctor if this is a concern for you. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">The most common side effects of everolimus tablets</span> <span class="Bold">in people who have had a kidney or liver transplant</span><span class="Bold"> include:</span> </p> <p>These common side effects have been reported in both kidney and liver transplant patients:</p> <ul class="Disc"> <li>nausea<br/> </li> <li>swelling of the lower legs, ankles and feet<br/> </li> <li>high blood pressure</li> </ul> <p> <span class="Bold">The most common side effects of everolimus tablets in people who have had a kidney transplant include:</span> </p> <ul class="Disc"> <li>constipation<br/> </li> <li>low red blood cell count (anemia)<br/> </li> <li>urinary tract infection<br/> </li> <li>increased fat in the blood (cholesterol and triglycerides)</li> </ul> <p> <span class="Bold">The most common side effects of everolimus tablets in people who have had a liver transplant include:</span> </p> <ul class="Disc"> <li>diarrhea<br/> </li> <li>headache<br/> </li> <li>fever<br/> </li> <li>abdominal pain<br/> </li> <li>low white blood cells</li> </ul> <p>These are not all of the possible side effects of everolimus tablets. </p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">How should I store everolimus tablets?</span> <ul class="Disc"> <li> <p class="First">Store everolimus tablets between 59°F and 86°F (15°C and 30°C).</p> </li> </ul> <ul class="Disc"> <li>Everolimus tablets are packed in child-resistant blisters and bottles with a child resistant closure.<br/> </li> <li>Keep everolimus tablets out of the light.<br/> </li> <li>Keep everolimus tablets dry.<br/> </li> </ul> <span class="Bold">Keep everolimus tablets and all medicines out of the reach of children.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">General information about the safe and effective use of everolimus tablets.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use everolimus tablets for a condition for which it was not prescribed. Do not give everolimus tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about everolimus tablets that is written for healthcare professionals. </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the ingredients in everolimus tablets?</span> </p> <p> <span class="Bold">Active ingredient:</span> everolimus</p> <p> <span class="Bold">Inactive ingredients: </span>butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188.<br/>Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).<br/> <br/> <br/> </p> <p> <span class="Bold">Manufactured by:</span> </p> <p>Biocon Pharma Limited</p> <p>Bengaluru, India – 560099</p> <p> <span class="Bold">Manufactured for:</span> </p> <p>Biocon Pharma Inc.,</p> <p>Iselin, New Jersey, 08830-3009,</p> <p>United States of America</p> <p> <br/>The trademarks depicted in this piece are owned by their respective companies.<br/>This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\"></td><td align=\"right\">Revised:March 2024</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<br/>\n<span>(e” ver oh’ li mus)</span>\n</p>\n<p>Everolimus Tablets, for oral use</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about everolimus tablets?</span>\n<br/>\n<br/>\n</p>\n<p>\n<span class=\"Bold\">Everolimus tablets can cause serious side effects, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of getting certain cancers. </span>People who take everolimus tablets have a higher chance of getting lymphoma and other cancers, especially skin cancer. Talk to your doctor about your risk for cancer.<br/>\n</li>\n<li>\n<span class=\"Bold\">Increased risk of serious infections. </span>Everolimus tablets weakens the body’s immune system and affects your ability to fight infections. Serious infections can happen with everolimus tablets that may lead to death. People taking everolimus tablets have a higher chance of getting infections caused by viruses, bacteria, and fungi (yeast).<ul class=\"Circle\">\n<li>Call your doctor if you have symptoms of infection, including fever or chills.</li>\n</ul>\n</li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Blood clot in the blood vessels of your transplanted kidney. </span>If this happens, it usually occurs within the first 30 days after your kidney transplant. Tell your doctor right away if you:<ul class=\"Circle\">\n<li>have pain in your groin, lower back, side or stomach (abdomen)<br/>\n</li>\n<li>make less urine or you do not pass any urine<br/>\n</li>\n<li>have blood in your urine or dark colored urine (tea-colored)<br/>\n</li>\n<li>have fever, nausea, or vomiting</li>\n</ul>\n<br/>\n</li>\n<li>\n<span class=\"Bold\">Serious problems with your transplanted kidney (nephrotoxicity)</span>. You will need to start with a lower dose of cyclosporine when you take it with everolimus tablets. Your doctor should do regular blood tests to check your levels of both everolimus tablets and cyclosporine. </li>\n<li>\n<span class=\"Bold\">Increased risk of death that can be related to infection, in people who have had a heart transplant</span>.<br/>You should not take everolimus tablets without talking to your doctor if you have had a heart transplant. </li>\n</ul>\n<span class=\"Bold\">See the section “What are the possible side effects of everolimus tablets?” for information about other serious side effects.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are everolimus tablets?</span>\n</p>\n<p>\n<br/>Everolimus tablets are a prescription medicine used to prevent transplant rejection (antirejection medicine) in people who have received a kidney transplant or liver transplant. Transplant rejection happens when the body’s immune system perceives the new transplanted kidney or liver as “foreign” and attacks it.</p>\n<p>\n<br/>Everolimus tablets is used with other medicines called cyclosporine, corticosteroids and certain other transplant medicines to prevent rejection of your transplanted kidney. Everolimus tablets is used with other medicines called tacrolimus and corticosteroids to prevent rejection of your transplanted liver.</p>\n<p>\n<br/>It is not known if everolimus tablets is safe and effective in transplanted organs other than the kidney and liver.</p>\n<p>\n<br/>It is not known if everolimus tablets is safe and effective in children under 18 years of age.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take everolimus tablets if you are allergic to:<br/>\n</span>\n</p>\n<ul class=\"Disc\">\n<li>Everolimus (ZORTRESS/AFINITOR<span class=\"Sup\">®</span>) or any of the ingredients in everolimus tablets. See the end of this Medication Guide for a complete list of ingredients in everolimus tablets.<br/>\n</li>\n<li>sirolimus (Rapamune<span class=\"Sup\">®</span>)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking everolimus tablets, tell your doctor about all of your medical conditions, including if you:<br/>\n</span>\n</p>\n<ul class=\"Disc\">\n<li>have liver problems</li>\n<li>have skin cancer or it runs in your family</li>\n<li>have high cholesterol or triglycerides (fat in your blood)</li>\n<li>have Lapp lactase deficiency or glucose-galactose malabsorption. You should not take everolimus tablets if you have this disorder.</li>\n<li>are pregnant or could become pregnant. Everolimus tablets may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment and for 8 weeks after your last dose of everolimus tablets. Talk to your doctor about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away. You should not become pregnant during treatment with everolimus tablets.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if everolimus passes into your breast milk.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p>\n<p>Especially tell your doctor if you take:</p>\n<ul class=\"Disc\">\n<li>antifungal medicine</li>\n<li>antibiotic medicine</li>\n<li>heart medicine</li>\n<li>high blood pressure medicine</li>\n<li>a medicine to lower cholesterol or triglycerides</li>\n<li>\n<p class=\"First\">cyclosporine (Sandimmune<span class=\"Sup\">®</span>, Gengraf<span class=\"Sup\">®</span>, Neoral<span class=\"Sup\">®</span>)</p>\n</li>\n<li>tuberculosis (TB) medicine</li>\n<li>HIV medicine</li>\n<li>St. John’s Wort</li>\n<li>seizure (anticonvulsant) medicine</li>\n<li>\n<p class=\"First\">cannabidiol (Epidiolex<span class=\"Sup\">®</span>)</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I take everolimus tablets?</span>\n<br/>\n<ul>\n<li>Take everolimus tablets exactly as your doctor tells you to.<br/>\n</li>\n<li>\n<span class=\"Bold\">Do not</span> stop taking everolimus tablets or change your dose unless your doctor tells you to.<br/>\n</li>\n<li>\n<p class=\"First\">Take everolimus tablets at the same time as your dose of cyclosporine or tacrolimus medicine.</p>\n</li>\n</ul>\n<ul>\n<li>\n<span class=\"Bold\">Do not</span> stop taking or change your dose of cyclosporine or tacrolimus medicine unless your doctor tells you to.<br/>\n</li>\n<li>If your doctor changes your dose of cyclosporine or tacrolimus, your dose of everolimus tablets may change.<br/>\n</li>\n<li>Take everolimus tablets 2 times a day about 12 hours apart.<br/>\n</li>\n<li>Swallow everolimus tablets whole with a glass of water. Do not crush or chew everolimus tablets.<br/>\n</li>\n<li>Take everolimus tablets with or without food. If you take everolimus tablets <span class=\"Bold\">with food</span>, always take everolimus tablets with food. If you take everolimus tablets without food, always take everolimus tablets without food.<br/>\n</li>\n<li>Your doctor will do regular blood tests to check your kidney or liver function while you take everolimus tablets. It is important that you get these tests done when your doctor tells you to. Blood tests will monitor how your kidneys or liver are working and make sure you are getting the right dose of everolimus tablets and other transplant medications you may be on (cyclosporine or tacrolimus). <br/>\n</li>\n<li>If you take too much everolimus tablets, call your doctor or go to the nearest hospital emergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking everolimus tablets?</span>\n</p>\n<ul class=\"Disc\">\n<li>Avoid receiving any live vaccines while taking everolimus tablets. Some vaccines may not work as well while you are taking everolimus tablets.<br/>\n</li>\n<li>Do not eat grapefruit or drink grapefruit juice while you are taking everolimus tablets. Grapefruit may increase your blood level of everolimus tablets.<br/>\n</li>\n<li>Limit the amount of time you spend in the sunlight. Avoid using tanning beds or sunlamps. People who take everolimus tablets have a higher risk of getting skin cancer. See the section <span class=\"Bold\">“What is the most important information I should know about everolimus tablets?”</span> Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if you have fair skin or if you have a family history of skin cancer.<br/>\n</li>\n<li>Avoid becoming pregnant. See the section <span class=\"Bold\">“What should I tell my doctor before taking everolimus tablets?”</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of everolimus tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Everolimus tablets may cause serious side effects, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>See <span class=\"Bold\">“What is the most important information I should know about everolimus tablets?”</span>\n<br/>\n</li>\n<li>\n<p class=\"First\">\n<span class=\"Bold\">swelling under your skin especially around your mouth, eyes and in your throat (angioedema)</span>. Your chance of having swelling under your skin is higher if you take everolimus tablets along with certain other medicines. Tell your doctor right away or go to the nearest emergency room if you have any of these symptoms of angioedema: </p>\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">sudden swelling of your face, mouth, throat, tongue or hands</p>\n</li>\n<li>\n<p class=\"First\">hives or welts<br/>\n</p>\n</li>\n<li>itchy or painful swollen skin<br/>\n</li>\n<li>trouble breathing</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">delayed wound healing.</span> Everolimus tablets can cause your incision to heal slowly or not heal well. Call your doctor right away if you have any of the following symptoms:<ul class=\"Disc\">\n<li>your incision is red, warm or painful<br/>\n</li>\n<li>blood, fluid, or pus in your incision<br/>\n</li>\n<li>your incision opens up<br/>\n</li>\n<li>swelling of your incision</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">lung or breathing problems</span>. Tell your doctor right away if you have new or worsening cough, shortness of breath, difficulty breathing or wheezing. In some patients, lung or breathing problems have been severe and can even lead to death. Your doctor may need to stop everolimus tablets or lower your dose.</li>\n<li>\n<span class=\"Bold\">increased cholesterol and triglycerides (fat in your blood).</span> If your cholesterol and triglyceride levels are high, your doctor may want to lower them with diet, exercise and certain medicines.</li>\n<li>\n<span class=\"Bold\">protein in your urine (proteinuria).</span>\n</li>\n<li>\n<span class=\"Bold\">change in kidney function.</span> Everolimus tablets may cause kidney problems when taken along with a standard dose of cyclosporine medicine instead of a lower dose.</li>\n</ul>\n<span class=\"Bold\">Your doctor should do blood and urine tests to monitor your cholesterol, triglycerides and kidney function.</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">viral infections. </span>Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with everolimus tablets include BK virus-associated nephropathy. BK virus can affect how your kidney works and cause your transplanted kidney to fail.<br/>\n</li>\n<li>\n<p class=\"First\">\n<span class=\"Bold\">blood clotting problems.</span> Talk to your doctor if this is a concern for you.</p>\n</li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">diabetes.</span> Tell your doctor if you have frequent urination, increased thirst or hunger.<br/>\n</li>\n<li>\n<span class=\"Bold\">infertility, male.</span> Everolimus tablets can affect fertility in males and may affect your ability to father a child. Talk with your doctor if this is a concern for you. </li>\n<li>\n<span class=\"Bold\">infertility, female.</span> Everolimus tablets can affect fertility in females and may affect your ability to become pregnant. Talk to your doctor if this is a concern for you. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of everolimus tablets</span> <span class=\"Bold\">in people who have had a kidney or liver transplant</span><span class=\"Bold\"> include:</span>\n</p>\n<p>These common side effects have been reported in both kidney and liver transplant patients:</p>\n<ul class=\"Disc\">\n<li>nausea<br/>\n</li>\n<li>swelling of the lower legs, ankles and feet<br/>\n</li>\n<li>high blood pressure</li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of everolimus tablets in people who have had a kidney transplant include:</span>\n</p>\n<ul class=\"Disc\">\n<li>constipation<br/>\n</li>\n<li>low red blood cell count (anemia)<br/>\n</li>\n<li>urinary tract infection<br/>\n</li>\n<li>increased fat in the blood (cholesterol and triglycerides)</li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of everolimus tablets in people who have had a liver transplant include:</span>\n</p>\n<ul class=\"Disc\">\n<li>diarrhea<br/>\n</li>\n<li>headache<br/>\n</li>\n<li>fever<br/>\n</li>\n<li>abdominal pain<br/>\n</li>\n<li>low white blood cells</li>\n</ul>\n<p>These are not all of the possible side effects of everolimus tablets. </p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I store everolimus tablets?</span>\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">Store everolimus tablets between 59°F and 86°F (15°C and 30°C).</p>\n</li>\n</ul>\n<ul class=\"Disc\">\n<li>Everolimus tablets are packed in child-resistant blisters and bottles with a child resistant closure.<br/>\n</li>\n<li>Keep everolimus tablets out of the light.<br/>\n</li>\n<li>Keep everolimus tablets dry.<br/>\n</li>\n</ul>\n<span class=\"Bold\">Keep everolimus tablets and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of everolimus tablets.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use everolimus tablets for a condition for which it was not prescribed. Do not give everolimus tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about everolimus tablets that is written for healthcare professionals. </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in everolimus tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> everolimus</p>\n<p>\n<span class=\"Bold\">Inactive ingredients: </span>butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188.<br/>Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).<br/>\n<br/>\n<br/>\n</p>\n<p>\n<span class=\"Bold\">Manufactured by:</span>\n</p>\n<p>Biocon Pharma Limited</p>\n<p>Bengaluru, India – 560099</p>\n<p>\n<span class=\"Bold\">Manufactured for:</span>\n</p>\n<p>Biocon Pharma Inc.,</p>\n<p>Iselin, New Jersey, 08830-3009,</p>\n<p>United States of America</p>\n<p>\n<br/>The trademarks depicted in this piece are owned by their respective companies.<br/>This Medication Guide has been approved by the U.S. Food and Drug Administration.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Blister Label 0.25 mg

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Blister Label 0.5mg

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Blister Label 0.75mg

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Blister Label 1mg

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Carton Label 0.25mg

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Carton Label 0.5mg

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Carton Label 0.75mg

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Carton Label 1 mg

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Bottle Label 0.25 mg

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Bottle Label 0.5 mg

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Bottle Label 0.75 mg

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Bottle Label 1 mg

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