XROMI is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.

{ "type": "p", "children": [], "text": "XROMI is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises." }

The recommended XROMI dosage in pediatric patients aged 6 months and older is described in Table 1.

<div class="scrollingtable"><table border="none"> <caption> <span>Table 1. Dosing Recommendation Based on Blood Count</span> </caption> <colgroup> <col align="left" class="Rrule" width="400"/> <col align="center" class="Rrule" width="400"/> <col align="center" class="Rrule" width="400"/> <col align="center" width="400"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dosing Regimen</span> </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose</span> </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose modification criteria</span> </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Monitoring parameters</span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Initial Recommended dosing </p> </td><td align="left" class="Botrule Rrule" valign="top"> <p class="First">15 mg/kg/day (rounded to nearest 10 mg) orally as a single dose once daily based on the patient’s actual body weight.</p> </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule" valign="top">Monitor the patient’s complete blood count (CBC) with differential and reticulocyte count every 2 weeks while adjusting dosage <span class="Italics">[see<a href="#S5.1"> Warnings and Precautions (5.1)</a>]</span>.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Dosing Adjustment Based on Blood Counts in the acceptable range </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First"> Increase dose 5 mg/kg/day every 8 to 12 weeks.<br/> Maximal dose: 35 mg/kg/day.*<br/> <br/> *Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks. </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First">Increase dose only if blood counts are in an acceptable range.<br/> <br/> Do not increase if myelosuppression occurs. </p> </td><td align="left" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Target Blood Counts</span> <br/> Absolute neutrophil count (ANC) 1 to 3 x 10<span class="Sup">9</span>/L and platelets at least 80 x 10<span class="Sup">9</span>/L </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dosing Adjustment Based on Blood Counts below acceptable range</p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First">Do not increase dose.</p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First">If blood counts are considered toxic, discontinue XROMI until hematologic recovery.</p> </td><td align="left" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Blood Counts Toxic Range</span> </p> <ul class="Unordered"> <li>ANC less than 1 x 10<span class="Sup">9</span>/L</li> <li>Platelets less than 80 x 10<span class="Sup">9</span>/L</li> <li>Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL</li> <li>Reticulocytes less than 80 x10<span class="Sup">9</span>/L if the hemoglobin concentration is less than 9 g/dL.</li> </ul> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dosing after Hematologic Recovery</p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First">If hematologic toxicity resolved within 1 week, restart at the same XROMI dose.<br/> If hematologic toxicity persisted for more than 1 week or occurred twice in a 3 month period, reduce dose by 5 mg/kg/day. </p> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> <p class="First"></p> </td><td align="left" class="Botrule Rrule Toprule"> <p class="First">Once a stable dose is established, monitor CBC with differential and reticulocyte count every 4 weeks for 2 months and then as clinically indicated.</p> </td> </tr> </tbody> </table></div>

Caregivers must be able to follow directions regarding drug administration and their monitoring and care.

If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

The patient should not take two doses to make up for a missed dose.

Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value.

XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

XROMI is for oral use. See Instructions for Use for details on preparation and administration of XROMI for oral solution. Do not shake. Two oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 mL) are provided for accurate measurement of the prescribed dose of the oral solution. It is recommended that the healthcare professional advises the caregiver which oral dosing syringe to use to ensure that the correct volume is administered. The smaller 3 mL oral dosing syringe, marked from 0.5 mL to 3 mL, is for measuring doses of less than or equal to 3 mL. This oral dosing syringe should be recommended for doses less than or equal to 3 mL (each graduation of 0.1 mL contains 10 mg of hydroxyurea). The larger 10 mL oral dosing syringe, marked 1 mL to 10 mL, is for measuring doses of more than 3 mL. This oral dosing syringe should be recommended for doses greater than 3 mL (each graduation of 0.25 mL contains 25 mg of hydroxyurea). XROMI may be taken with or after meals at any time of the day but caregivers should standardize the method of administration and time of day. XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see Reference (15)].

Reduce the dose of XROMI by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Creatinine clearance were obtained using 24-hour urine collection.

<div class="scrollingtable"><table frame="border"> <caption> <span>Table 2. Creatinine Clearance</span> </caption> <colgroup> <col width="600"/> <col width="400"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule"><span class="Bold">Creatinine Clearance (mL/min)</span></td><td align="center" class="Lrule"><span class="Bold">Recommended XROMI Initial Dose</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> Greater than or equal to 60 </td><td align="center" class="Botrule Lrule Toprule">15 mg/kg once daily </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> Less than 60 or ESRD* </td><td align="center" class="Botrule Rrule"> 7.5 mg/kg once daily </td> </tr> <tr class="Last"> <td>* On dialysis days, administer XROMI to patients with ESRD following hemodialysis</td><td></td> </tr> </tbody> </table></div>

Monitor the hematologic parameters closely in these patients.

Oral solution: 100 mg/mL clear colorless to pale yellow liquid in a multiple-dose amber bottle.

{ "type": "p", "children": [], "text": "Oral solution: 100 mg/mL clear colorless to pale yellow liquid in a multiple-dose amber bottle." }

XROMI is contraindicated in patients:

{ "type": "p", "children": [], "text": "XROMI is contraindicated in patients:" }

{ "type": "ul", "children": [ " who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. [see Adverse Reactions (6)]." ], "text": "" }

Hydroxyurea causes severe myelosuppression. Do not initiate treatment with XROMI in patients if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia.

Some patients, treated at the recommended initial dose of 15 mg/kg/day, have experienced severe or life-threatening myelosuppression.

Evaluate hematologic status (CBC, reticulocyte count) prior to and every 2 weeks during dose-escalation period of XROMI treatment. Once a stable dose of XROMI is achieved, monitor every 4 weeks. Provide supportive care and modify dose or discontinue XROMI as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted. [see Dosage and Administration (2.1)].

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)]. Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia and in the absence of other causes, discontinue XROMI.

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which XROMI is not approved), secondary leukemia has been reported.

Secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell anemia. Leukemia has also been reported in patients with sickle cell anemia and no prior history of treatment with hydroxyurea.

All patients using XROMI should be followed up on a long-term basis with regular blood counts to detect development of leukemia.

Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

Based on the mechanism of action and findings in animals, XROMI can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis.

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue XROMI.

Avoid use of live vaccines in patients taking XROMI. Concomitant use of XROMI with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by XROMI. Vaccination with live vaccines in a patient receiving XROMI may result in severe infection [see Drug Interactions (7.2)]. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)].

XROMI may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Safety and effectiveness have not been established for the use of XROMI in the treatment of myeloproliferative neoplasms and the use is not approved by the FDA. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue XROMI and manage with corticosteroids [see Adverse Reactions (6.1)].

Interference with uric acid, urea, or lactic acid assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.2)].

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods [see Drug Interactions (7.2)].

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

The safety of XROMI was evaluated in 32 pediatric patients aged 10 months -16 years with sickle cell anemia in a single-arm, open-label, prospective, multi-center, pharmacokinetic, safety and efficacy study (HUPK study). Only adverse reactions associated with the use of XROMI in pediatric patients aged 10 months to less than 2 years are presented.

The most frequently reported adverse reactions in HUPK study (<33%) were neutropenia, and thrombocytopenia [see Table 3].

<div class="scrollingtable"><table border="none"> <caption> <span>Table 3. Adverse Reactions Reported in Pediatric Patients Aged 10 Months and Older Enrolled in HUPK</span> </caption> <colgroup> <col width="300"/> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule"><span class="Bold">10 Months–&lt;2 Years</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">2 –&lt;6 Years</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">6 –&lt;18 Years</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">Overall</span></td> </tr> <tr> <td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"><span class="Bold">Body System Adverse Reactions</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">(n=6)%</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">(n=16)%</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">(n=10)%</span></td><td align="center" class="Botrule Lrule Rrule"><span class="Bold">(n=32)%</span></td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Neutropenia</span></td><td align="center" class="Botrule Rrule">3 (50)</td><td align="center" class="Botrule Rrule">1 (6)</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">4 (13)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Thrombocytopenia</span></td><td align="center" class="Botrule Rrule">2 (33)</td><td align="center" class="Botrule Rrule">1 (6)</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3 (9)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Diarrhea</span></td><td align="center" class="Botrule Rrule">1 (17)</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">GGT Increased</span></td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1(10)</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Absolute Reticulocyte Count Decreased</span></td><td align="center" class="Botrule Rrule">1 (17)</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Alopecia</span></td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (6)</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Nail Discolouration </span></td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (10)</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Italics">Rash </span></td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (10)</td><td align="center" class="Botrule Rrule">1 (3)</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule"><span class="Italics">Rash Popular </span></td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1 (6)</td><td align="center" class="Botrule Rrule">1 (10)</td><td align="center" class="Botrule Rrule">2 (6)</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of hydroxyurea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal cases of pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

Interference with Continuous Glucose Monitoring Systems Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Risk Summary XROMI can cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no data with XROMI use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis (see Data). Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with XROMI. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability.

Risk Summary It is not known whether XROMI is excreted in human milk, the effects of XROMI on the breastfed child, or the effects of XROMI on milk production. Because of the potential for serious adverse reactions in a breastfed child from XROMI, including carcinogenicity, advise patients not to breastfeed during treatment with XROMI.

Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating XROMI therapy. Contraception Females XROMI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and after treatment with XROMI for at least 6 months after therapy. Advise females to immediately report pregnancy. Males XROMI may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with XROMI for at least 1 year after therapy [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in animals and humans, male fertility may be compromised by treatment with XROMI. Azoospermia or oligospermia, sometimes reversible, has been observed in men. Inform male patients about the possibility of sperm conservation before the start of therapy [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of XROMI have been established in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate to severe painful crises. Use of XROMI in these age groups is supported by evidence from a pharmacokinetic, efficacy and safety study, in which 32 pediatric patients ages 6 months to <18 years were enrolled. Among the 32 pediatric patients treated with XROMI, 6 were infants (6 months – 2 years), 16 children (2-6 years) and 10 were adolescents (6-18 years) [see Clinical Studies (14)]. Continuous follow-up of the growth of treated children is recommended.

The exposure to XROMI is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when XROMI is to be administered to these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.

Acute mucocutaneous toxicity and neutropenia has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed.

{ "type": "p", "children": [], "text": "Acute mucocutaneous toxicity and neutropenia has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. \n\t\t\t Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed.\n\t\t\t " }

XROMI (hydroxyurea) is available for oral use as oral solution containing 100 mg/mL hydroxyurea. Inactive ingredients include methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan gum. Hydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH4N2O2 and it has a molecular weight of 76.05. Its structural formula is:

{ "type": "p", "children": [], "text": "XROMI (hydroxyurea) is available for oral use as oral solution containing 100 mg/mL hydroxyurea. Inactive ingredients include methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan gum.\n\n\t\t\t\t\tHydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH4N2O2 and it has a molecular weight of 76.05. Its structural formula is:" }

The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which XROMI produces its beneficial effects in patients with sickle cell anemia are uncertain. Known pharmacologic effects of XROMI that may contribute to its beneficial effects include increasing HbF levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

In pediatric patients treated with hydroxyurea for up to 15 months, the ratio of fetal hemoglobin to total hemoglobin was 25%, 23.6% and 11.2% at the end of the study, representing a change from baseline increase of 9%, 148% and 167% in patients aged 6 months to <2 years, 2 to <6 years and 6 to <18 years, respectively.

Absorption Following oral administration of XROMI, hydroxyurea reaches peak plasma concentrations in 0 to 2 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.

Effect of Food There are no data on the effect of food on the absorption of hydroxyurea.

Distribution Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. Hydroxyurea concentrates in leukocytes and erythrocytes.

Elimination Metabolism Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.

Excretion In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

Specific Populations Renal Impairment The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl =30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Creatinine clearance values were obtained using 24-hour urine collections. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Pediatric Patients The model estimated steady state exposures (AUC) in pediatric patients receiving a daily dose of 15 mg/kg is lower in patients aged 6 months to <2 years and 2 to <6 years by 40% and 28% compared to adults receiving the same dose while the exposures in 6 to <18 year old patients are similar to adult exposures (XROMI is not approved for use in adults).

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype [see Warnings and Precautions (5.3 , 5.4)]. Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see Use in Specific Populations (8.3)].

The effectiveness of XROMI has been established for the indication, “to reduce the frequency of painful crises and to reduce the need for blood transfusions in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate to severe painful crises” based on an adequate and well-controlled study of hydroxyurea capsules in adult patients with sickle cell anemia with recurrent moderate to severe pain crises and additional pharmacokinetic data from a single-arm, open-label study of XROMI in pediatric patients aged 10 months to less than 18 years with sickle cell anemia, who were treatment naïve or had not received hydroxyurea in the 6 months prior to enrollment: HUPK study [see Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "The effectiveness of XROMI has been established for the indication, “to reduce the frequency of painful crises and to reduce the need for blood transfusions in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate to severe painful crises” based on an adequate and well-controlled study of hydroxyurea capsules in adult patients with sickle cell anemia with recurrent moderate to severe pain crises and additional pharmacokinetic data from a single-arm, open-label study of XROMI in pediatric patients aged 10 months to less than 18 years with sickle cell anemia, who were treatment naïve or had not received hydroxyurea in the 6 months prior to enrollment: HUPK study [see Adverse Reactions (6.1)].\n" }

OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html" }

XROMI (hydroxyurea) 100 mg/mL is a colorless to pale yellow liquid supplied in an Amber type III glass bottle with tamper evident child-resistant closure (HDPE with expanded polyethylene liner) containing 148 mL of oral solution. Each carton NDC 62484-0015-5 contains 1 bottle XROMI NDC 62484-0015-4, an LDPE bottle adaptor and 2 oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 mL).

Store XROMI between 2°C to 8°C (35°F to 46°F) excursions permitted to 25°C (77°F) for up to 72 hours. Keep the bottle tightly closed to protect the integrity of the product and minimize the risk of accidental spillage. Do not freeze. Use within 12 weeks after initially opening the bottle. Discard unused XROMI remaining after 12 weeks of first opening the bottle.

XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see References (15)]. Anyone handling XROMI should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and caregivers should wear disposable gloves when handling XROMI. To minimize air bubbles, the bottle should not be shaken prior to dosing. XROMI contact with skin or mucous membrane must be avoided. If XROMI comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The spill areas should be cleaned three times using a detergent solution followed by clean water. If contact with XROMI occurs in the eye(s), flush the eye(s) thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. Parents / care givers should be advised to keep hydroxyurea out of the sight and reach of children. Accidental ingestion can be lethal for children. Oral dosing syringes should be rinsed and washed with cold or warm water and dried completely before the next use. Store oral dosing syringes in a hygienic place with the medicine.

Advise the caregiver to read the FDA-approved patient labeling (Instructions for Use and Medication Guide).

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

{ "type": "ul", "children": [ "There is a risk of myelosuppression. Emphasize the importance of monitoring blood counts every two weeks throughout the duration of therapy to caregivers of patients taking XROMI [see Warnings and Precautions (5.1)]. Advise caregivers to report signs and symptoms of infection or bleeding in patients immediately.", "Advise caregivers of the risk of hemolytic anemia. Advise caregivers that the patient will have blood tests to evaluate for this if they develop persistent anemia. [see Warnings and Precautions (5.2)].", "Advise caregivers that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia. Advise use of sun protection [see Warnings and Precautions (5.3,5.5)].", "Advise caregivers to inform the patient's healthcare provider if they have received or are planning to receive vaccinations while taking XROMI as this may result in a severe infection [see Warnings and Precautions (5.6)].", "Advise females of reproductive potential of the potential risk to a fetus should they become pregnant while taking XROMI. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with XROMI [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1,8.3)].", "Advise females to discontinue breastfeeding during treatment with XROMI [see Use in Specific Populations (8.2)].", "Advise male patients of potential risk to fertility.", "Advise caregivers of patients with HIV infection to contact their healthcare provider for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings and Precautions (5.7)].", "Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking XROMI [see Warnings and Precautions (5.9)].", "Advise caregivers of the symptoms of potential pulmonary toxicity and instruct them to seek prompt medical attention for the patient in the event of pyrexia, cough, dyspnea, or other respiratory symptoms [see Warnings and Precautions (5.9)]." ], "text": "" }

Because XROMI package includes two oral dosing syringes, advise patients on which oral dosing syringe they should use.

{ "type": "p", "children": [], "text": "Because XROMI package includes two oral dosing syringes, advise patients on which oral dosing syringe they should use." }

Manufactured by: Nova Laboratories Ltd. Leicester LE18 4YL United Kingdom

{ "type": "p", "children": [], "text": "Manufactured by:\n\t\t\t\t\tNova Laboratories Ltd.\n\t\t\t\t\tLeicester \n\t\t\t\t\tLE18 4YL \n\t\t\t\t\tUnited Kingdom" }

Manufactured for: Rare Disease Therapeutics, Inc. 2550 Meridian Blvd., Suite 150 Franklin, Tennessee 37067 www.raretx.com

{ "type": "p", "children": [], "text": "Manufactured for:\n\t\t\t\t\tRare Disease Therapeutics, Inc.\n\t\t\t\t\t2550 Meridian Blvd., Suite 150\n\t\t\t\t\tFranklin, Tennessee 37067\n\t\t\t\t\twww.raretx.com\n" }

Part Number: D001427/1

{ "type": "p", "children": [], "text": "Part Number: D001427/1" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="48%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="20%"/> <tfoot> <tr class="First"> <td align="left" colspan="3">This Medication Guide has been approved by the U.S. Food and Drug Administration. </td><td align="right" colspan="1">Issued: DEC 2024    </td> </tr> <tr class="Last"> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="4"><span class="Bold">MEDICATION GUIDE</span> <br/>XROMI<span class="Sup">®</span> (ex-ro-mee)<br/>(hydroxyurea)<br/>oral solution</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">What is the most important information I should know about XROMI?</span> </p> <p> <span class="Bold">XROMI can cause serious side effects including:</span> </p> <ul class="Disc"> <li> <span class="Bold">Low blood cell counts are common with XROMI, including low red blood cells, white blood cells, and platelets, and can be severe and life-threatening. If your child's white blood cell count becomes very low, your child is at increased risk for infection.</span> Your child's healthcare provider will check your child's blood cell counts before and during treatment with XROMI. Your child's healthcare provider may change your child's dose or tell your child to stop taking XROMI if your child has low blood cell counts. Tell your child's healthcare provider right away if your child gets any of the following symptoms:</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Disk"> <li>fever or chills</li> <li>body aches</li> <li>feeling very tired</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disk"> <li>shortness of breath</li> <li>bleeding or unexplained bruising</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <ul class="Disc"> <li> <span class="Bold">Hemolytic Anemia,</span> the fast breakdown of red blood cells, has happened in people who take XROMI. Tell your child’s healthcare provider if your child develops yellowing of their skin (jaundice) or blood in their urine. Your child’s healthcare provider may do blood tests if your child has persistent or worsening anemia not related to sickle cell anemia.</li> <li> <span class="Bold">Cancer.</span> Some people have developed cancer, such as leukemia and skin cancer, after taking XROMI for a long time. Your child's healthcare provider will check your child for cancer. You should protect your child's skin from the sun using sunblock, hats, and sun-protective clothing.</li> <li> <span class="Bold">XROMI can harm an unborn baby.<br/>Females taking XROMI who can become pregnant should:</span> <br/> • avoid becoming pregnant during treatment with XROMI.<br/> • talk with your healthcare provider about the risks of XROMI to your unborn baby.<br/> • use effective birth control during treatment with XROMI and for at least 6 months after treatment.<br/> • expect that their healthcare provider will perform a pregnancy test before they start treatment with XROMI.<br/> • tell their healthcare provider right away if you become pregnant or think you may be pregnant.<br/> <span class="Bold">For males taking XROMI:</span> <br/> If your child has a female sexual partner who can become pregnant, your child should use effective birth control during treatment with XROMI and for at least 6 months after treatment.</li> </ul> <p class="First"> <span class="Bold">XROMI may cause fertility problems in males. Talk to your child’s healthcare provider if this is a concern for you.</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What is XROMI?</span> <br/>XROMI is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in children aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.<br/>XROMI is not for use in adults.<br/> It is not known if XROMI is safe and effective in children less than 6 months old. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Your child should not take XROMI if your child is allergic to hydroxyurea or any of the ingredients in XROMI</span>. See the end of this Medication Guide for a list of the ingredients in XROMI.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">Before taking XROMI, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <ul class="Disc"> <li>have kidney problems or is receiving hemodialysis.</li> <li>have liver problems</li> <li>have human immunodeficiency virus (HIV) or take HIV medicines. <span class="Bold">Taking XROMI with certain HIV medicines can cause serious reactions and may lead to death. Tell your child's healthcare provider if your child takes an HIV medicine.</span> </li> <li>have increased levels of uric acid in their blood (hyperuricemia).</li> <li>have a history of receiving interferon therapy or is currently receiving interferon therapy.</li> <li>have leg wounds or ulcers.</li> <li>plan to receive any vaccinations. You should not receive "live vaccines" during treatment with XROMI.</li> <li>are pregnant or plan to become pregnant. See <span class="Bold">“What is the most important information I should know about XROMI?”</span> </li> <li>are breastfeeding or plan to breastfeed. It is not known if XROMI can pass into your breast milk. Do not breastfeed during treatment with XROMI.</li> <li>are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it is safe to use while you are taking XROMI.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">Tell your healthcare provider about all the medicines your child takes</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">How should your child take XROMI?</span> </p> <p> <span class="Bold">Read the Instructions for Use that comes with XROMI for information about the right way to measure and give a dose of XROMI. If you have any questions, talk to your child's healthcare provider or pharmacist.</span> </p> <ul class="Disc"> <li>Administer XROMI exactly as your child's healthcare provider tells you to administer it. XROMI is taken 1 time a day at the same time each day.</li> <li>Administer XROMI with or after meals. Administer XROMI the same way each day.</li> <li>Drink some water after each dose of XROMI.</li> <li>If your child takes too much XROMI, call your child's healthcare provider or go to the nearest hospital emergency room.</li> <li>If you miss a dose of XROMI, call your healthcare provider for advice.</li> <li> <span class="Bold">XROMI oral solution should be handled with care. To decrease the risk of exposure, caregivers should do the following when handling XROMI:</span> </li> <li>Wear disposable gloves when handling oral dosing syringes or bottles containing XROMI.</li> <li>Wash your hands with soap and water before and after handling oral dosing syringes or bottles containing XROMI.</li> <li>Avoid contact with the oral solution. If contact with the oral solution happens on the skin, wash the skin area right away and thoroughly with soap and water. If contact with the oral solution happens in the eyes, flush the eyes thoroughly with water and isotonic eyewash used for that purpose for at least 15 minutes.</li> <li>If the oral solution is spilled, wipe it up right away with a damp disposable towel. Throw the damp disposable towel away in a closed container such as a plastic bag. The spill area should then be cleaned up using a detergent solution followed by clean water.</li> <li>During treatment with XROMI, your child's healthcare provider will do blood tests regularly to check your child's blood cell counts and liver function. Your healthcare provider may change your child's dose if your child has side effects.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">What are the possible side effects of XROMI?<br/>XROMI may cause serious side effects, including:</span> <br/> See <span class="Bold">What is the most important information I should know about XROMI?"</span> </p> <ul class="Disc"> <li> <span class="Bold">Skin ulcers and death of tissue (gangrene)</span> have happened in people who take XROMI. This has happened most often in people who receive interferon therapy or have a history of interferon therapy. Your child's healthcare provider will decrease your dose or stop treatment with XROMI if your child develops any skin ulcers.</li> <li> <span class="Bold">Enlarged red blood cells (macrocytosis)</span>. Macrocytosis is common in people who take XROMI and can make it difficult to detect a decrease of folic acid. Your child's healthcare provider may prescribe a folic acid supplement for your child. </li> <li>Respiratory (breathing) problems. Some people have developed life-threatening respiratory conditions called interstitial lung disease. Your child’s healthcare provider may tell your child to stop taking XROMI if your child develops respiratory problems. Tell your child’s healthcare provider right away if your child gets any of the following symptoms:<br/> • fever<br/> • cough <br/> • shortness of breath </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">The most common side effects of XROMI include:</span> <ul> <li>low blood levels of a type of white blood cell (neutropenia)</li> <li>low blood levels of platelets (thrombocytopenia)</li> <li>raised bumps on the skin (papular rash)</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4">These are not all the possible side effects of XROMI.<br/> Call your child's doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">How should I store XROMI?</span> <ul class="Disc"> <li>XROMI comes in a bottle with a child-resistant cap.</li> <li>Refrigerate XROMI between 35°F to 46°F (2°C to 8°C). <span class="Bold">Do not freeze.</span> </li> <li>Store the XROMI bottle and oral dosing syringe in a clean place.</li> <li>XROMI oral solution should be used within 12 weeks after opening the bottle. Dispose of (throw away) any unused medicine and the dosing syringes after 12 weeks.</li> <li>Do not use after the expiration date on the carton and bottle.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Keep XROMI and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">General information about the safe and effective use of XROMI</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XROMI for a condition for which it was not prescribed. Do not give XROMI to other people, even if they have the same symptoms your child has. It may harm them. You can ask your child's healthcare provider or pharmacist for information about XROMI that is written for health professionals.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the ingredients of XROMI?</span> <br/> <span class="Bold">Active ingredient:</span> hydroxyurea<br/> <span class="Bold">Inactive ingredients:</span> methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan gum.<br/> <br/> <p class="First">Manufactured by: Nova Laboratories Ltd., Leicester, LE18 4YL, United Kingdom<br/> Manufactured for: Rare Disease Therapeutics, Inc., 2550 Meridian Blvd., Suite 150, Franklin, TN 37067<br/> For more information, go to www.xromi-us.com.<br/> Part Number: D001230/1</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"48%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"3\">This Medication Guide has been approved by the U.S. Food and Drug Administration. </td><td align=\"right\" colspan=\"1\">Issued: DEC 2024    </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>XROMI<span class=\"Sup\">®</span> (ex-ro-mee)<br/>(hydroxyurea)<br/>oral solution</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about XROMI?</span>\n</p>\n<p>\n<span class=\"Bold\">XROMI can cause serious side effects including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Low blood cell counts are common with XROMI, including low red blood cells, white blood cells, and platelets, and can be severe and life-threatening. If your child's white blood cell count becomes very low, your child is at increased risk for infection.</span> Your child's healthcare provider will check your child's blood cell counts before and during treatment with XROMI. Your child's healthcare provider may change your child's dose or tell your child to stop taking XROMI if your child has low blood cell counts. Tell your child's healthcare provider right away if your child gets any of the following symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Disk\">\n<li>fever or chills</li>\n<li>body aches</li>\n<li>feeling very tired</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disk\">\n<li>shortness of breath</li>\n<li>bleeding or unexplained bruising</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Hemolytic Anemia,</span> the fast breakdown of red blood cells, has happened in people who take XROMI. Tell your child’s healthcare provider if your child develops yellowing of their skin (jaundice) or blood in their urine. Your child’s healthcare provider may do blood tests if your child has persistent or worsening anemia not related to sickle cell anemia.</li>\n<li>\n<span class=\"Bold\">Cancer.</span> Some people have developed cancer, such as leukemia and skin cancer, after taking XROMI for a long time. Your child's healthcare provider will check your child for cancer. You should protect your child's skin from the sun using sunblock, hats, and sun-protective clothing.</li>\n<li>\n<span class=\"Bold\">XROMI can harm an unborn baby.<br/>Females taking XROMI who can become pregnant should:</span>\n<br/>\n\t\t\t\t\t\t\t\t\t•\tavoid becoming pregnant during treatment with XROMI.<br/>\n\t\t\t\t\t\t\t\t\t•\ttalk with your healthcare provider about the risks of XROMI to your unborn baby.<br/>\n\t\t\t\t\t\t\t\t\t•\tuse effective birth control during treatment with XROMI and for at least 6 months after treatment.<br/>\n\t\t\t\t\t\t\t\t\t•\texpect that their healthcare provider will perform a pregnancy test before they start treatment with XROMI.<br/> \n\t\t\t\t\t\t\t\t\t•\ttell their healthcare provider right away if you become pregnant or think you may be pregnant.<br/>\n<span class=\"Bold\">For males taking XROMI:</span>\n<br/>\n\t\t\t\t\t\t\t\t\tIf your child has a female sexual partner who can become pregnant, your child should use effective birth control during treatment with XROMI and for at least 6 months after treatment.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">XROMI may cause fertility problems in males. Talk to your child’s healthcare provider if this is a concern for you.</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What is XROMI?</span>\n<br/>XROMI is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in children aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.<br/>XROMI is not for use in adults.<br/>\n\t\t\t\t\t\t\t\t\tIt is not known if XROMI is safe and effective in children less than 6 months old.\n\n\t\t\t\t\t\t\t </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Your child should not take XROMI if your child is allergic to hydroxyurea or any of the ingredients in XROMI</span>. See the end of this Medication Guide for a list of the ingredients in XROMI.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking XROMI, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have kidney problems or is receiving hemodialysis.</li>\n<li>have liver problems</li>\n<li>have human immunodeficiency virus (HIV) or take HIV medicines. <span class=\"Bold\">Taking XROMI with certain HIV medicines can cause serious reactions and may lead to death. Tell your child's healthcare provider if your child takes an HIV medicine.</span>\n</li>\n<li>have increased levels of uric acid in their blood (hyperuricemia).</li>\n<li>have a history of receiving interferon therapy or is currently receiving interferon therapy.</li>\n<li>have leg wounds or ulcers.</li>\n<li>plan to receive any vaccinations. You should not receive \"live vaccines\" during treatment with XROMI.</li>\n<li>are pregnant or plan to become pregnant. See <span class=\"Bold\">“What is the most important information I should know about XROMI?”</span>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if XROMI can pass into your breast milk. Do not breastfeed during treatment with XROMI.</li>\n<li>are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it is safe to use while you are taking XROMI.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">Tell your healthcare provider about all the medicines your child takes</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">How should your child take XROMI?</span>\n</p>\n<p>\n<span class=\"Bold\">Read the Instructions for Use that comes with XROMI for information about the right way to measure and give a dose of XROMI. If you have any questions, talk to your child's healthcare provider or pharmacist.</span>\n</p>\n<ul class=\"Disc\">\n<li>Administer XROMI exactly as your child's healthcare provider tells you to administer it. XROMI is taken 1 time a day at the same time each day.</li>\n<li>Administer XROMI with or after meals. Administer XROMI the same way each day.</li>\n<li>Drink some water after each dose of XROMI.</li>\n<li>If your child takes too much XROMI, call your child's healthcare provider or go to the nearest hospital emergency room.</li>\n<li>If you miss a dose of XROMI, call your healthcare provider for advice.</li>\n<li>\n<span class=\"Bold\">XROMI oral solution should be handled with care. To decrease the risk of exposure, caregivers should do the following when handling XROMI:</span>\n</li>\n<li>Wear disposable gloves when handling oral dosing syringes or bottles containing XROMI.</li>\n<li>Wash your hands with soap and water before and after handling oral dosing syringes or bottles containing XROMI.</li>\n<li>Avoid contact with the oral solution. If contact with the oral solution happens on the skin, wash the skin area right away and thoroughly with soap and water. If contact with the oral solution happens in the eyes, flush the eyes thoroughly with water and isotonic eyewash used for that purpose for at least 15 minutes.</li>\n<li>If the oral solution is spilled, wipe it up right away with a damp disposable towel. Throw the damp disposable towel away in a closed container such as a plastic bag. The spill area should then be cleaned up using a detergent solution followed by clean water.</li>\n<li>During treatment with XROMI, your child's healthcare provider will do blood tests regularly to check your child's blood cell counts and liver function. Your healthcare provider may change your child's dose if your child has side effects.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of XROMI?<br/>XROMI may cause serious side effects, including:</span>\n<br/>\n\t\t\t\t\t\t\t\t See <span class=\"Bold\">What is the most important information I should know about XROMI?\"</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Skin ulcers and death of tissue (gangrene)</span> have happened in people who take XROMI. This has happened most often in people who receive interferon therapy or have a history of interferon therapy. Your child's healthcare provider will decrease your dose or stop treatment with XROMI if your child develops any skin ulcers.</li>\n<li>\n<span class=\"Bold\">Enlarged red blood cells (macrocytosis)</span>. Macrocytosis is common in people who take XROMI and can make it difficult to detect a decrease of folic acid. Your child's healthcare provider may prescribe a folic acid supplement for your child.\n\t\t\t\t\t\t\t\t\t</li>\n<li>Respiratory (breathing) problems. Some people have developed life-threatening respiratory conditions called interstitial lung disease. Your child’s healthcare provider may tell your child to stop taking XROMI if your child develops respiratory problems. Tell your child’s healthcare provider right away if your child gets any of the following symptoms:<br/>\n\t\t\t\t\t\t\t\t\t•\tfever<br/>\n\t\t\t\t\t\t\t\t\t•\tcough\t<br/>\n\t\t\t\t\t\t\t\t\t•\tshortness of breath\n\t\t\t\t\t\t \n\t\t\t\t\t\t\t </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">The most common side effects of XROMI include:</span>\n<ul>\n<li>low blood levels of a type of white blood cell (neutropenia)</li>\n<li>low blood levels of platelets (thrombocytopenia)</li>\n<li>raised bumps on the skin (papular rash)</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">These are not all the possible side effects of XROMI.<br/> Call your child's doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">How should I store XROMI?</span>\n<ul class=\"Disc\">\n<li>XROMI comes in a bottle with a child-resistant cap.</li>\n<li>Refrigerate XROMI between 35°F to 46°F (2°C to 8°C). <span class=\"Bold\">Do not freeze.</span>\n</li>\n<li>Store the XROMI bottle and oral dosing syringe in a clean place.</li>\n<li>XROMI oral solution should be used within 12 weeks after opening the bottle. Dispose of (throw away) any unused medicine and the dosing syringes after 12 weeks.</li>\n<li>Do not use after the expiration date on the carton and bottle.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Keep XROMI and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">General information about the safe and effective use of XROMI</span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XROMI for a condition for which it was not prescribed. Do not give XROMI to other people, even if they have the same symptoms your child has. It may harm them. You can ask your child's healthcare provider or pharmacist for information about XROMI that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the ingredients of XROMI?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> hydroxyurea<br/>\n<span class=\"Bold\">Inactive ingredients:</span> methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan gum.<br/>\n<br/>\n<p class=\"First\">Manufactured by: Nova Laboratories Ltd., Leicester, LE18 4YL, United Kingdom<br/>\n\t\t\t\t\t\t\tManufactured for: Rare Disease Therapeutics, Inc., 2550 Meridian Blvd., Suite 150, Franklin, TN 37067<br/>\n\t\t\t\t\t\t\tFor more information, go to www.xromi-us.com.<br/> \n\t\t\t\t\t\t\tPart Number: D001230/1</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" width="50%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">INSTRUCTIONS FOR USE<br/>XROMI<span class="Sup">®</span>(ex-ro-mee)<br/>hydroxyurea)<br/>oral solution</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"center\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\"><span class=\"Bold\">INSTRUCTIONS FOR USE<br/>XROMI<span class=\"Sup\">®</span>(ex-ro-mee)<br/>hydroxyurea)<br/>oral solution</span></td>\n</tr>\n</tbody>\n</table></div>" }

Read these Instructions for Use before your child starts taking XROMI, and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your child's healthcare provider about your child's medical condition or treatment.

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

Important information:

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

{ "type": "ul", "children": [ "\nAlways use the oral dosing syringe provided with your child's XROMI oral solution to measure your child's prescribed dose.\n Ask your child’s healthcare provider or pharmacist to show you which oral dosing syringe to use and how to measure your child’s prescribed dose if you are not sure.", "Wash your hands with soap and water before and after handling XROMI oral solution and oral dosing syringes.", "Wear disposable gloves when handling XROMI oral solution and oral dosing syringes.", "Avoid contact with the oral solution. If contact with the oral solution happens on the skin, nose, or mouth, wash the area right away and thoroughly with soap and water. If contact with the oral solution happens in the eyes, flush the eyes thoroughly with water and isotonic eyewash used for that purpose for at least 15 minutes.", "If the oral solution is spilled, wipe it up right away with a damp disposable towel. Throw the damp disposable towel away in a closed container such as a plastic bag. The spill area should then be cleaned up using a detergent solution followed by clean water.", "Do not shake the bottle.\n\nEach carton of XROMI oral solution contains:\n    •\t 1 bottle of XROMI oral solution    •\t1 bottle adapter    •\tOne 3 mL oral dosing syringe (for doses of 3 mL or less)    •\tOne 10 mL oral dosing syringe (for doses more than 3 mL)" ], "text": "" }

If your carton does not contain two oral dosing syringes, contact your pharmacist. You will also need disposable gloves.

{ "type": "p", "children": [], "text": "\nIf your carton does not contain two oral dosing syringes, contact your pharmacist.\nYou will also need disposable gloves.\n" }

<div class="scrollingtable"><table frame="border" width="80%"> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="5%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left"><span class="Bold">Before giving XROMI:</span></td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 1.</span> Wash your hands well with soap and water.</td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 2.</span> Put on disposable gloves.</td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 3.</span> Place the items from the carton on a clean flat surface.</td><td align="center"></td> </tr> <tr class="Botrule"> <td align="justify" class="Rrule"><span class="Bold">Step 4.</span> Open the bottle by pushing down firmly on the child-resistant cap and turning it counter-clockwise (See <a href="#figA">Figure A</a>).<br/> <br/> <br/> <span class="Bold">Do not throw away the child-resistant cap.</span></td><td align="center" valign="top"><img alt="Figure A" src="/dailymed/image.cfm?name=xromi-03.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure A</span> <br/> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 5.</span> First time use only: Insert the bottle adapter.<br/> <br/>Push the ribbed end of the bottle adapter into the neck of the bottle until it is firmly in place. The bottom edge of the adapter should fully contact the top rim of the bottle (See <a href="#figB">Figure B</a>). <br/> <br/> <span class="Bold">Do not remove the adapter from the bottle after it is inserted.</span></td><td align="center"><img alt="Figure B" src="/dailymed/image.cfm?name=xromi-04.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure B</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left"><span class="Bold">Measuring your child's prescribed dose of XROMI:</span></td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 6.</span> Choose the oral dosing syringe you need to measure your child's prescribed dose. (See <a href="#figC">Figure C</a>).<br/> <br/> Check the dose in mL as prescribed by your child’s healthcare provider. Choose the right oral dosing syringe for your child’s dose. <ul> <li> <span class="Bold">Use the 3 mL oral dosing syringe for doses of 3 mL or less.</span> </li> <li> <span class="Bold">Use the 10 mL oral dosing syringe for doses more than 3 mL.</span> </li> </ul> <p class="First">Find the marking for your child’s prescribed dose on the right oral dosing syringe.</p> </td><td align="center"><img alt="Figure C" src="/dailymed/image.cfm?name=xromi-05.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure C</span> <br/> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 7.</span> Push the plunger of the oral dosing syringe all the way down to remove any air in the oral dosing syringe (See <a href="#figD">Figure D</a>).</td><td align="center"><img alt="Figure D" src="/dailymed/image.cfm?name=xromi-06.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure D</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 8.</span> Hold the bottle upright. Insert the tip of the oral dosing syringe into the opening of the bottle adapter until it is firmly in place (See <a href="#figE">Figure E</a>). </td><td align="center"><img alt="Figure E" src="/dailymed/image.cfm?name=xromi-07.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure E</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 9.</span> Turn the bottle upside down with the oral dosing syringe in place. Pull back slowly on the plunger of the oral dosing syringe until the top of the plunger is even with the mL mark on the oral dosing syringe that corresponds to your child’s prescribed dose. <br/> <br/>See <a href="#figF">Figure F</a> for an <span class="Bold">example</span> of a dose of 6 mL. Your dose may be different than the example shown.</td><td align="center"><img alt="Figure F" src="/dailymed/image.cfm?name=xromi-08.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure F</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 10.</span> Leave the oral dosing syringe in the bottle adapter and turn the bottle upright. Place the bottle onto a flat surface. Hold the oral dosing syringe by the barrel and carefully remove it from the adapter. <span class="Bold">Do not</span> hold the oral dosing syringe by the plunger (See <a href="#figG">Figure G</a>).</td><td align="center"><img alt="Figure G" src="/dailymed/image.cfm?name=xromi-09.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure G</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 11.</span> Hold the oral dosing syringe with the oral dosing syringe tip pointing up. Check that the correct dose was drawn up into the oral dosing syringe (See <a href="#figH">Figure H</a>). <br/> <br/>If there are large air bubbles in the oral dosing syringe (See <a href="#figI">Figure I</a>) or if you have drawn up the wrong dose, re-insert the oral dosing syringe tip firmly into the bottle adapter while the bottle is in an upright position. Fully push in the plunger so the oral solution flows back into the bottle. Repeat Steps 8 and 9.</td><td align="center"><img alt="Figure H" src="/dailymed/image.cfm?name=xromi-10.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure H</span> <br/> <img alt="Figure I" src="/dailymed/image.cfm?name=xromi-11.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure I</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left"><span class="Bold">Giving the prescribed dose of XROMI:</span></td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 12.</span> Place the tip of the oral dosing syringe in your child’s mouth and place the tip against the inside of your child’s cheek.<br/> <br/> Gently push the plunger all the way down to give all the medicine in the oral dosing syringe and then remove the oral dosing syringe from your child’s mouth (See <a href="#figJ">Figure J</a>).<br/> <br/>Make sure the child has time to swallow the medicine.<br/> <br/>If your child’s prescribed dose is more than 10 mL, you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to divide the dose and repeat Steps 6 through 12. </td><td align="center"><img alt="Figure J" src="/dailymed/image.cfm?name=xromi-12.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b"/><span class="Bold">Figure J</span> <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 13.</span> Have your child drink some water to make sure no medicine is left in your child’s mouth.</td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule"><span class="Bold">Step 14.</span> Close the bottle tightly by turning the child-resistant cap clockwise, leaving the bottle adapter in place.</td><td align="center"></td> </tr> <tr class="Botrule Last"> <td align="left" class="Rrule"><span class="Bold">Step 15.</span> Wash your hands well with soap and water. <br/> <br/>Rinse and wash the oral dosing syringes with cold or warm water and dry completely before next use. Hold the oral dosing syringe under water and move the plunger up and down several times to make sure the inside of the oral dosing syringe is clean. Let the oral dosing syringe dry completely before you use it again. <span class="Bold">Do not throw away the oral dosing syringe after use.</span></td><td align="center"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table frame=\"border\" width=\"80%\">\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"center\" valign=\"top\" width=\"5%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\"><span class=\"Bold\">Before giving XROMI:</span></td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 1.</span> Wash your hands well with soap and water.</td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 2.</span> Put on disposable gloves.</td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 3.</span> Place the items from the carton on a clean flat surface.</td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Rrule\"><span class=\"Bold\">Step 4.</span> Open the bottle by pushing down firmly on the child-resistant cap and turning it counter-clockwise (See <a href=\"#figA\">Figure A</a>).<br/>\n<br/>\n<br/>\n<span class=\"Bold\">Do not throw away the child-resistant cap.</span></td><td align=\"center\" valign=\"top\"><img alt=\"Figure A\" src=\"/dailymed/image.cfm?name=xromi-03.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure A</span>\n<br/>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 5.</span> First time use only: Insert the bottle adapter.<br/>\n<br/>Push the ribbed end of the bottle adapter into the neck of the bottle until it is firmly in place. The bottom edge of the adapter should fully contact the top rim of the bottle (See <a href=\"#figB\">Figure B</a>). <br/>\n<br/>\n<span class=\"Bold\">Do not remove the adapter from the bottle after it is inserted.</span></td><td align=\"center\"><img alt=\"Figure B\" src=\"/dailymed/image.cfm?name=xromi-04.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure B</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\"><span class=\"Bold\">Measuring your child's prescribed dose of XROMI:</span></td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 6.</span> Choose the oral dosing syringe you need to measure your child's prescribed dose. (See <a href=\"#figC\">Figure C</a>).<br/>\n<br/>\n\t\t\t\t\t\t\t\t\tCheck the dose in mL as prescribed by your child’s healthcare provider. Choose the right oral dosing syringe for your child’s dose.\n\t\t\t\t\t\t\t\t\t<ul>\n<li>\n<span class=\"Bold\">Use the 3 mL oral dosing syringe for doses of 3 mL or less.</span>\n</li>\n<li>\n<span class=\"Bold\">Use the 10 mL oral dosing syringe for doses more than 3 mL.</span>\n</li>\n</ul>\n<p class=\"First\">Find the marking for your child’s prescribed dose on the right oral dosing syringe.</p>\n</td><td align=\"center\"><img alt=\"Figure C\" src=\"/dailymed/image.cfm?name=xromi-05.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure C</span>\n<br/>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 7.</span> Push the plunger of the oral dosing syringe all the way down to remove any air in the oral dosing syringe (See <a href=\"#figD\">Figure D</a>).</td><td align=\"center\"><img alt=\"Figure D\" src=\"/dailymed/image.cfm?name=xromi-06.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure D</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 8.</span> Hold the bottle upright. Insert the tip of the oral dosing syringe into the opening of the bottle adapter until it is firmly in place (See <a href=\"#figE\">Figure E</a>).\n\t\t\t\t\t\t\t\t\t</td><td align=\"center\"><img alt=\"Figure E\" src=\"/dailymed/image.cfm?name=xromi-07.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure E</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 9.</span> Turn the bottle upside down with the oral dosing syringe in place. Pull back slowly on the plunger of the oral dosing syringe until the top of the plunger is even with the mL mark on the oral dosing syringe that corresponds to your child’s prescribed dose. <br/>\n<br/>See <a href=\"#figF\">Figure F</a> for an <span class=\"Bold\">example</span> of a dose of 6 mL. Your dose may be different than the example shown.</td><td align=\"center\"><img alt=\"Figure F\" src=\"/dailymed/image.cfm?name=xromi-08.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure F</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 10.</span> Leave the oral dosing syringe in the bottle adapter and turn the bottle upright. Place the bottle onto a flat surface. Hold the oral dosing syringe by the barrel and carefully remove it from the adapter. <span class=\"Bold\">Do not</span> hold the oral dosing syringe by the plunger (See <a href=\"#figG\">Figure G</a>).</td><td align=\"center\"><img alt=\"Figure G\" src=\"/dailymed/image.cfm?name=xromi-09.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure G</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 11.</span> Hold the oral dosing syringe with the oral dosing syringe tip pointing up. Check that the correct dose was drawn up into the oral dosing syringe (See <a href=\"#figH\">Figure H</a>). <br/>\n<br/>If there are large air bubbles in the oral dosing syringe (See <a href=\"#figI\">Figure I</a>) or if you have drawn up the wrong dose, re-insert the oral dosing syringe tip firmly into the bottle adapter while the bottle is in an upright position. Fully push in the plunger so the oral solution flows back into the bottle. Repeat Steps 8 and 9.</td><td align=\"center\"><img alt=\"Figure H\" src=\"/dailymed/image.cfm?name=xromi-10.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure H</span>\n<br/>\n<img alt=\"Figure I\" src=\"/dailymed/image.cfm?name=xromi-11.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure I</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\"><span class=\"Bold\">Giving the prescribed dose of XROMI:</span></td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 12.</span> Place the tip of the oral dosing syringe in your child’s mouth and place the tip against the inside of your child’s cheek.<br/>\n<br/>\n\t\t\t\t\t\t\t\t\tGently push the plunger all the way down to give all the medicine in the oral dosing syringe and then remove the oral dosing syringe from your child’s mouth (See <a href=\"#figJ\">Figure J</a>).<br/>\n<br/>Make sure the child has time to swallow the medicine.<br/>\n<br/>If your child’s prescribed dose is more than 10 mL, you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to divide the dose and repeat Steps 6 through 12.\n\t\t\t\t\t\t\t\t\t</td><td align=\"center\"><img alt=\"Figure J\" src=\"/dailymed/image.cfm?name=xromi-12.jpg&amp;setid=4b37d336-86da-4363-aef1-34a7d3ba973b\"/><span class=\"Bold\">Figure J</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 13.</span> Have your child drink some water to make sure no medicine is left in your child’s mouth.</td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 14.</span> Close the bottle tightly by turning the child-resistant cap clockwise, leaving the bottle adapter in place.</td><td align=\"center\"></td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Step 15.</span> Wash your hands well with soap and water. <br/>\n<br/>Rinse and wash the oral dosing syringes with cold or warm water and dry completely before next use. Hold the oral dosing syringe under water and move the plunger up and down several times to make sure the inside of the oral dosing syringe is clean. \n\t\t\t\t\t\tLet the oral dosing syringe dry completely before you use it again. <span class=\"Bold\">Do not throw away the oral dosing syringe after use.</span></td><td align=\"center\"></td>\n</tr>\n</tbody>\n</table></div>" }

Storing XROMI

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

{ "type": "ul", "children": [ "Store XROMI in a refrigerator between 35°F to 46°F (2°C to 8°C). Do not freeze.\n", "XROMI comes in a bottle with a child-resistant cap. Keep the bottle tightly closed. ", "Store the XROMI bottle and oral dosing syringe in a clean place.", "XROMI oral solution should be used within 12 weeks after opening the bottle. Dispose of (throw away) any unused medicine and the dosing syringes after 12 weeks.", "Do not use after the expiration date on the carton and the bottle.", "\nKeep XROMI and all medicines out of the reach of children.\n" ], "text": "" }

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

{ "type": "ul", "children": [ "Ask your pharmacist for instructions on how to throw away (dispose of) XROMI that is expired or no longer needed." ], "text": "" }

Manufactured by: Nova Laboratories Ltd., Leicester, LE18 4YL, United Kingdom Manufactured for: Rare Disease Therapeutics, Inc., 2550 Meridian Blvd., Suite 150, Franklin, TN 37067 Part Number: D001426/1 This “Instructions for Use” has been approved by the U.S. Food and Drug Administration     Revised: 12/2024

{ "type": "p", "children": [], "text": "Manufactured by: Nova Laboratories Ltd., Leicester, LE18 4YL, United Kingdom\n Manufactured for: Rare Disease Therapeutics, Inc., 2550 Meridian Blvd., Suite 150, Franklin, TN 37067\n \n Part Number: D001426/1\nThis “Instructions for Use” has been approved by the U.S. Food and Drug Administration     Revised: 12/2024" }

PACKAGE LABEL

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

XROMI Carton Label

{ "type": "p", "children": [], "text": "\nXROMI Carton Label\n" }

XROMI Bottle label

{ "type": "p", "children": [], "text": "\nXROMI Bottle label\n" }

Hydroxyurea capsules are indicated for the treatment of:

{ "type": "p", "children": [], "text": "Hydroxyurea capsules are indicated for the treatment of:" }

{ "type": "ul", "children": [ "Resistant chronic myeloid leukemia.", "Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation." ], "text": "" }

Hydroxyurea is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.

Base all dosage on the patient’s actual or ideal weight, whichever is less.

Hydroxyurea is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

Swallow hydroxyurea capsules whole. Do NOT open, break, or chew capsules because hydroxyurea is a cytotoxic drug.

Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.8)] .

Monitor blood counts at least once a week during hydroxyurea therapy. Severe anemia must be corrected before initiating therapy with hydroxyurea.

Monitor for the following and reduce the dose or discontinue hydroxyurea accordingly:

Consider dose modifications for other toxicities.

Reduce the dose of hydroxyurea capsules by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [ see Use in Specific Populations( 8.6) and Clinical Pharmacology( 12.3) ].

<div class="scrollingtable"><table width="80%"> <col width="46%"/> <col width="47%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Creatinine Clearance</span> </p> <span class="Bold">(mL/min)</span></td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Recommended Hydroxyurea Capsules Initial </span><span class="Bold">Dose </span><span class="Bold">(mg/kg once daily)</span> </p> </td> </tr> <tr> <td align="center" valign="top"> <p class="First">≥60</p> </td><td align="center" valign="top"> <p class="First">15</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"> <p class="First">&lt;60 or ESRD*</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">7.5</p> </td> </tr> </tbody> </table></div>

* On dialysis days, administer hydroxyurea capsules to patients following hemodialysis.

Close monitoring of hematologic parameters is advised in these patients.

Capsules: 500 mg opaque pink body and opaque powder blue cap, imprinted with “83” on the body in black ink.

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Hydroxyurea capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation.

{ "type": "p", "children": [], "text": "Hydroxyurea capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation." }

Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients.

Evaluate hematologic status prior to and during treatment with hydroxyurea capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)]. Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia and in the absence of other causes, discontinue hydroxyurea.   

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

Based on the mechanism of action and findings in animals, hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2basis. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations( 8.1)] . Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 1 year after therapy [see Use in Specific Populations( 8.1,8.3)] .

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules.

Avoid use of live vaccine in patients taking hydroxyurea capsules. Concomitant use of hydroxyurea capsules with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by hydroxyurea capsules. Vaccination with live vaccines in a patient receiving hydroxyurea capsules may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)] .

Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.

Hydroxyurea capsules may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B 12or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue hydroxyurea and manage with corticosteroids [see Adverse Reactions (6.1)] .

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions( 7.2)] .

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods [see Drug Interactions (7.2)].

The following adverse reactions have been identified during post-approval use of hydroxyurea capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm 3) has occurred in the presence of marked leukopenia. Hydroxyurea capsules may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Hydroxyurea capsules can cause fetal harm based on findings from animal studies and the drug’s mechanism of action [seeClinical Pharmacology (12.1)]. There are no data with hydroxyurea capsules use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2basis (see Data) . Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with hydroxyurea capsules.

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

Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2basis) to rats caused growth retardation and impaired learning ability.

Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed infant from hydroxyurea, including carcinogenicity, discontinue breastfeeding during treatment with hydroxyurea capsules.

Verify the pregnancy status of females of reproductive potential prior to initiating hydroxyurea therapy.

Hydroxyurea capsules can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 6 months after therapy. Advise females to immediately report pregnancy.

Hydroxyurea may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with hydroxyurea capsules for at least 1 year after therapy [see Nonclinical Toxicology (13.1)] .

Based on findings in animals and humans, male fertility may be compromised by treatment with hydroxyurea capsules. Azoospermia or oligospermia, sometimes reversible, has been observed in men. Inform male patients about the possibility of sperm conservation before the start of therapy [see Adverse Reactions (6)and Nonclinical Toxicology (13.1)] .

Safety and effectiveness in pediatric patients have not been established.

Elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.3)] .

The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce dosage and closely monitor the hematologic parameters when hydroxyurea capsule is to be administered to these patients [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)] .

There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed.

{ "type": "p", "children": [], "text": "Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed." }

Hydroxyurea capsules, USP are an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea, USP. Inactive ingredients include colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 3, gelatin, magnesium stearate, titanium dioxide and black ink. The black ink contains black iron oxide, dewaxed shellac and potassium hydroxide.

{ "type": "p", "children": [], "text": "Hydroxyurea capsules, USP are an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea, USP. Inactive ingredients include colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 3, gelatin, magnesium stearate, titanium dioxide and black ink. The black ink contains black iron oxide, dewaxed shellac and potassium hydroxide." }

Hydroxyurea is a white to off-white crystalline powder. It is non-hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH ​4N 2O 2and it has a molecular weight of 76.05. Its structural formula is:

{ "type": "p", "children": [], "text": "Hydroxyurea is a white to off-white crystalline powder. It is non-hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH\n \n ​4N\n \n 2O\n \n 2and it has a molecular weight of 76.05. Its structural formula is:\n\n " }

Meets USP dissolution test 2.

{ "type": "p", "children": [], "text": "Meets USP dissolution test 2." }

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.

Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitrostudies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitrostudies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.

Following oral administration of hydroxyurea capsules, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.

There are no data on the effect of food on the absorption of hydroxyurea.

Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water.

Hydroxyurea concentrates in leukocytes and erythrocytes.

Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.

In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell disease and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50‑80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). Reduce the dose of hydroxyurea capsules when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [seeDosage and Administration (2.3)and Use in Specific Populations (8.6)] .

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m 2basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitroto bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro(hamster cells, human lymphoblasts) and in vivo(SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.

Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

{ "type": "p", "children": [], "text": "OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html." }

Hydroxyurea capsules, USP are supplied as 500 mg capsules. The cap is opaque powder blue and the body is opaque pink. The capsules are imprinted with “83” on the body in black ink

{ "type": "p", "children": [], "text": "Hydroxyurea capsules, USP are supplied as 500 mg capsules. The cap is opaque powder blue and the body is opaque pink. The capsules are imprinted with “83” on the body in black ink" }

NDC: 70518-4302-00

{ "type": "p", "children": [], "text": "NDC: 70518-4302-00" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

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

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

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

{ "type": "ul", "children": [ "There is a risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking hydroxyurea capsules. Advise patients to report signs and symptoms of infection or bleeding immediately\n \n [see\n \n Warnings and Precautions (5.1)]\n \n .\n \n ", " Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia\n \n [see\n \n Warnings and Precautions (5.2)]\n \n .\n \n ", "Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia and skin cancers\n \n [see\n \n Warnings and Precautions (5.3,\n \n 5.5)]\n \n .\n \n ", "Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with hydroxyurea capsules \n \n [seeWarnings and Precautions (5.4)and\n \n Use in Specific Populations (8.1,\n \n 8.3)].\n \n ", "Advise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking hydroxyurea capsules as this may result in a severe infection\n \n [see\n \n Warnings and Precautions (5.6)]\n \n .\n \n ", "Advise females to discontinue breastfeeding during treatment with hydroxyurea capsules \n \n [seeUse in Specific Populations (8.2)].\n \n ", "Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy\n \n [seeWarnings and Precautions (5.7)].\n \n ", "Post-irradiation erythema can occur in patients who have received previous irradiation therapy\n \n [seeWarnings and Precautions (5.8)].\n \n ", "Advise patients of the symptoms of potential pulmonary toxicity and instruct them to seek prompt medical attention in the event of pyrexia, cough, dyspnea, or other respiratory symptoms\n \n [see\n \n Warnings and Precautions (5.10)]\n \n .\n \n ", "Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking hydroxyurea capsules\n \n [see\n \n Warnings and Precautions (5.11)].\n \n \n" ], "text": "" }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "\nRepackaged and Distributed By:\n" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "\nRemedy Repack, Inc.\n" }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "\n625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762\n" }

DRUG: HYDROXYUREA

{ "type": "p", "children": [], "text": "DRUG: HYDROXYUREA" }

GENERIC: HYDROXYUREA

{ "type": "p", "children": [], "text": "GENERIC: HYDROXYUREA" }

DOSAGE: CAPSULE

{ "type": "p", "children": [], "text": "DOSAGE: CAPSULE" }

ADMINSTRATION: ORAL

{ "type": "p", "children": [], "text": "ADMINSTRATION: ORAL" }

NDC: 70518-4302-0

{ "type": "p", "children": [], "text": "NDC: 70518-4302-0" }

COLOR: pink

{ "type": "p", "children": [], "text": "COLOR: pink" }

SHAPE: CAPSULE

{ "type": "p", "children": [], "text": "SHAPE: CAPSULE" }

SCORE: No score

{ "type": "p", "children": [], "text": "SCORE: No score" }

SIZE: 22 mm

{ "type": "p", "children": [], "text": "SIZE: 22 mm" }

IMPRINT: 83

{ "type": "p", "children": [], "text": "IMPRINT: 83" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

ACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "ACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "Hydroxyurea 500mg in 1" ], "text": "" }

INACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "INACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "Silicon Dioxide", "Magnesium Stearate", "Gelatin", "Titanium Dioxide", "FD&C Red No. 3", "FD&C Blue No. 1", "SHELLAC", "FERROSOFERRIC OXIDE", "POTASSIUM HYDROXIDE" ], "text": "" }

SIKLOS ®is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises

{ "type": "p", "children": [], "text": "\nSIKLOS\n \n ®is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises\n\n \n" }

The recommended SIKLOS dosing is described in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Dosing Recommendation Based on Blood Count</span> </caption> <col align="left" valign="top" width="23%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="27%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Dosing Regimen</th><th align="left" class="Rrule">Dose</th><th align="left" class="Rrule">Dose Modification Criteria</th><th align="left" class="Rrule">Monitoring Parameters</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Initial Recommended Dosing</span></td><td align="left" class="Rrule">Adults: 15 mg/kg <br/> Pediatrics: 20 mg/kg <br/> once daily based on patient's actual or ideal weight, whichever is less. </td><td align="left" class="Rrule"></td><td align="left" class="Rrule">Monitor the patient's blood count every 2 weeks <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>] </span>. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span><span class="Bold">Dosing Adjustment Based on Blood Counts</span>in an acceptable range </span></td><td align="left" class="Rrule">Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. <br/> Give until mild myelosuppression (absolute neutrophil count 2,000/uL to 4,000/uL) is achieved, up to a maximum of 35 mg/kg/day. </td><td align="left" class="Rrule">Increase dosing only if blood counts are in an acceptable range. <br/> Increase dosing if a painful crisis occurs. <br/> Do not increase if myelosuppression occurs. </td><td align="left" class="Rrule"><span class="Bold">Blood Counts Acceptable Range:</span> <br/> - neutrophils greater than or equal to 2,000 cells/mm <span class="Sup">3</span> <br/> - platelets greater than or equal to 80,000/mm <span class="Sup">3</span> <br/> - hemoglobin greater than 5.3 g/dL <br/> - reticulocytes greater than or equal to 80,000/mm <span class="Sup">3</span>if the hemoglobin concentration less than 9 g/dL </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span><span class="Bold">Dosing Adjustment Based on Blood Counts</span>in a toxic range </span></td><td align="left" class="Rrule">Discontinue treatment.</td><td align="left" class="Rrule">If blood counts are considered toxic, discontinue SIKLOS until hematologic recovery.</td><td align="left" class="Rrule"><span class="Bold">Blood Counts Toxic Range: <br/> - </span>neutrophils less than 2,000 cells/mm <span class="Sup">3</span> <br/> younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm <span class="Sup">3</span>. <br/> - platelets less than 80,000/mm <span class="Sup">3</span> <br/> - hemoglobin less than 4.5 g/dL <br/> - reticulocytes less than 80,000/mm <span class="Sup">3</span>if the hemoglobin concentration less than 9 g/dL </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span><span class="Bold">Dosing After Hematologic Recovery</span></span></td><td align="left" class="Rrule">Reduce dose by 5 mg/kg/day.</td><td align="left" class="Rrule">Reduce the dose from the dose associated with hematologic toxicity. <br/> May titrate up or down every 8 weeks in 5 mg/kg/day increments. <br/> The patient should be at a stable dose with no hematologic toxicity for 24 weeks. <br/> Discontinue the treatment permanently if a patient develops hematologic toxicity twice. </td><td align="left" class="Rrule"></td> </tr> </tbody> </table></div>

Siklos is available in 100 mg and 1,000 mg tablets. The 100 mg tablets have 1 score line and can be split into 2 parts (each 50 mg). The 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg). Therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, 50 mg and combinations thereof. Calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment.

Patients must be able to follow directions regarding drug administration and their monitoring and care.

Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of SIKLOS in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value.

Administration:

The tablets should be taken once daily, at the same time each day, with a glass of water. For patients who are not able to swallow the tablets, these can be dispersed immediately before usein a small quantity of water in a teaspoon.

SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

Reduce the dose of SIKLOS by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)] . Obtain the creatinine clearance using a 24-hour urine collection.

<div class="scrollingtable"><table width="75%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule">Creatinine Clearance <br/> (mL/min) </th><th align="left" class="Rrule" colspan="2">Recommended SIKLOS Initial Dose <br/> (mg/kg daily) </th> </tr> <tr class="Botrule Last"> <th align="left" class="Lrule Rrule"></th><th align="left" class="Rrule">Pediatrics</th><th align="left" class="Rrule">Adults</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>On dialysis days, administer SIKLOS to patients with ESRD following hemodialysis</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Greater than or equal to 60</td><td align="left" class="Rrule">20</td><td align="left" class="Rrule">15</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Less than 60 or ESRD <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">10</td><td align="left" class="Rrule">7.5</td> </tr> </tbody> </table></div>

Monitor the hematologic parameters closely in these patients.

Tablets:

SIKLOS is contraindicated in:

{ "type": "p", "children": [], "text": "SIKLOS is contraindicated in:" }

{ "type": "ul", "children": [ "Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation\n \n [see\n \n Adverse Reactions (6)].\n \n \n" ], "text": "" }

Hydroxyurea causes severe myelosuppression. Do not initiate treatment with hydroxyurea in patients if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia.

Some patients, treated at the recommended initial dose of 15 mg/kg/day in adults or 20 mg/kg/day in children, have experienced severe or life-threatening myelosuppression. Due to the change in body weight requiring modification of daily dose, pediatric patients have an increased risk of myelosuppression at the time of dose adjustment.

Evaluate hematologic status prior to and every two weeks during treatment with SIKLOS. Provide supportive care and modify dose or discontinue SIKLOS as needed. Recovery from myelosuppression is usually observed within 15 days when therapy is interrupted. Resume therapy after interruption at a lower dose [see Dosage and Administration (2.1)] .

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which Siklos is not approved), secondary leukemia has been reported.

Leukemia secondary to long-term hydroxyurea has also been reported in patients with sickle cell disease. Leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea.

Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

Based on the mechanism of action and findings in animals, SIKLOS can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)] .

Advise females of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy [see Use in Specific Populations (8.1, 8.3)] .

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease (a condition for which SIKLOS is not approved), treatment with SIKLOS should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis.

Avoid use of SIKLOS in patients with wounds on the legs (leg ulcers).

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)] .

Avoid use of live virus vaccine in patients taking SIKLOS. Concomitant use of hydroxyurea with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus and result in severe infections [see Drug Interactions (7.2)]. Patient's antibody response to vaccines may be decreased. Consider consultation with a specialist.

SIKLOS may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.3)].

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)] . Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia not related to the disease and in the absence of other causes, discontinue SIKLOS.

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

The safety of SIKLOS has been assessed in 405 pediatric patients with sickle cell disease from 2-18 years of age and 1077 adults in the European Sickle Cell Disease prospective Cohort study ESCORT-HU.

The most frequently reported adverse reactions in ESCORT-HU were infections and myelosuppression, with mild to moderate neutropenia as the most common manifestation.

Other adverse reactions include skin and subcutaneous disorders (skin depigmentation/melanonychia, skin rash, alopecia), gastrointestinal disorders, vitamin D deficiency and headache.

At least one serious adverse reaction was reported in 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="7%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2">Global Safety Set (N=405)</th><th align="center" class="Rrule" colspan="2" rowspan="2">Total</th><th align="center" class="Rrule" colspan="6">Severity</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule" colspan="2">Mild</th><th align="center" class="Rrule" colspan="2">Moderate</th><th align="center" class="Rrule" colspan="2">Severe</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="9">n: number of patients with an adverse reaction</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">At least one adverse reaction</td><td align="center" class="Rrule">261</td><td align="center" class="Rrule">64</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Infections</span></td><td align="center" class="Rrule">161</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">120</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">88</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">4.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Infections</td><td align="center" class="Rrule">92</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">66</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">32</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bacterial</td><td align="center" class="Rrule">65</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">2.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Viral</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">3.5</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Parvovirus B19</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Blood and lymphatic system disorders</span></td><td align="center" class="Rrule">85</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">3.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Neutropenia</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">26</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">31</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Thrombocytopenia</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anemia</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">4.2</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Rrule">53</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">29</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Gastrointestinal Disorders</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">3.2</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">2.5</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">2.5</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Metabolic and nutrition disorders</span></td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Deficiency of vitamin D</td><td align="center" class="Rrule">25</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Metabolic and nutrition disorders</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Weight gain</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Rrule">45</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Nervous system disorders</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">2.7</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">General disorders</span></td><td align="center" class="Rrule">41</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">4.2</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fever</td><td align="center" class="Rrule">31</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">4.9</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Skin and subcutaneous tissue disorders</span></td><td align="center" class="Rrule">38</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">29</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">3.5</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Skin reactions</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Skin and subcutaneous tissue disorders</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">3.2</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Other Not SCD-related reactions</span></td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other Not SCD-related reactions</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Respiratory thoracic and mediastinal disorders</span></td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">1.5</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.7</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Renal and urinary disorders</span></td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.5</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="8%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="7%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2">Global adult safety set (N=1077)</th><th align="center" class="Rrule" colspan="2" rowspan="2">Total</th><th align="center" class="Rrule" colspan="6">Severity</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule" colspan="2">Mild</th><th align="center" class="Rrule" colspan="2">Moderate</th><th align="center" class="Rrule" colspan="2">Severe</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th><th align="center" class="Rrule">n</th><th align="center" class="Rrule">%</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">At least one adverse reaction</span></td><td align="center" class="Rrule">897</td><td align="center" class="Rrule">84</td><td align="center" class="Rrule">586</td><td align="center" class="Rrule">54</td><td align="center" class="Rrule">617</td><td align="center" class="Rrule">57</td><td align="center" class="Rrule">345</td><td align="center" class="Rrule">32</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Infections</span></td><td align="center" class="Rrule"><span class="Bold">465</span></td><td align="center" class="Rrule"><span class="Bold">43</span></td><td align="center" class="Rrule"><span class="Bold">171</span></td><td align="center" class="Rrule"><span class="Bold">16</span></td><td align="center" class="Rrule"><span class="Bold">240</span></td><td align="center" class="Rrule"><span class="Bold">22</span></td><td align="center" class="Rrule"><span class="Bold">101</span></td><td align="center" class="Rrule"><span class="Bold">9</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Viral infection</td><td align="center" class="Rrule">47</td><td align="center" class="Rrule">4.4</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">1.6</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bacterial infection</td><td align="center" class="Rrule">45</td><td align="center" class="Rrule">4.2</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">0.8</td><td align="center" class="Rrule">27</td><td align="center" class="Rrule">2.5</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bronchitis</td><td align="center" class="Rrule">41</td><td align="center" class="Rrule">3.8</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">0.9</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Influenza</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">0.7</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Urinary tract infection</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nasopharyngitis</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Rrule"><span class="Bold">313</span></td><td align="center" class="Rrule"><span class="Bold">29</span></td><td align="center" class="Rrule"><span class="Bold">131</span></td><td align="center" class="Rrule"><span class="Bold">12</span></td><td align="center" class="Rrule"><span class="Bold">125</span></td><td align="center" class="Rrule"><span class="Bold">12</span></td><td align="center" class="Rrule"><span class="Bold">54</span></td><td align="center" class="Rrule"><span class="Bold">5</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">211</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">84</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">74</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">27</td><td align="center" class="Rrule">2.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">100</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">43</td><td align="center" class="Rrule">4.0</td><td align="center" class="Rrule">32</td><td align="center" class="Rrule">3.0</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">0.8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">General disorders and administration site conditions</span></td><td align="center" class="Rrule"><span class="Bold">300</span></td><td align="center" class="Rrule"><span class="Bold">28</span></td><td align="center" class="Rrule"><span class="Bold">111</span></td><td align="center" class="Rrule"><span class="Bold">10</span></td><td align="center" class="Rrule"><span class="Bold">113</span></td><td align="center" class="Rrule"><span class="Bold">10</span></td><td align="center" class="Rrule"><span class="Bold">24</span></td><td align="center" class="Rrule"><span class="Bold">2.2</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Asthenia</td><td align="center" class="Rrule">100</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">2.8</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">0.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pyrexia</td><td align="center" class="Rrule">91</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">27</td><td align="center" class="Rrule">2.5</td><td align="center" class="Rrule">39</td><td align="center" class="Rrule">3.6</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">0.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fatigue</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">2.0</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">1.6</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Edema peripheral</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">3.1</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">0.8</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Skin and subcutaneous tissue disorders</span></td><td align="center" class="Rrule"><span class="Bold">297</span></td><td align="center" class="Rrule"><span class="Bold">28</span></td><td align="center" class="Rrule"><span class="Bold">160</span></td><td align="center" class="Rrule"><span class="Bold">15</span></td><td align="center" class="Rrule"><span class="Bold">123</span></td><td align="center" class="Rrule"><span class="Bold">11</span></td><td align="center" class="Rrule"><span class="Bold">23</span></td><td align="center" class="Rrule"><span class="Bold">2.1</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dry skin</td><td align="center" class="Rrule">128</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">67</td><td align="center" class="Rrule">6.2</td><td align="center" class="Rrule">36</td><td align="center" class="Rrule">3.3</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Skin ulcer</td><td align="center" class="Rrule">80</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">4.1</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">1.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Alopecia</td><td align="center" class="Rrule">49</td><td align="center" class="Rrule">4.5</td><td align="center" class="Rrule">31</td><td align="center" class="Rrule">2.9</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Rrule"><span class="Bold">267</span></td><td align="center" class="Rrule"><span class="Bold">25</span></td><td align="center" class="Rrule"><span class="Bold">116</span></td><td align="center" class="Rrule"><span class="Bold">11</span></td><td align="center" class="Rrule"><span class="Bold">110</span></td><td align="center" class="Rrule"><span class="Bold">10</span></td><td align="center" class="Rrule"><span class="Bold">25</span></td><td align="center" class="Rrule"><span class="Bold">2.3</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">28</td><td align="center" class="Rrule">2.6</td><td align="center" class="Rrule">26</td><td align="center" class="Rrule">2.4</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abdominal pain upper</td><td align="center" class="Rrule">52</td><td align="center" class="Rrule">4.8</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">2.0</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Diarrhea</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">3.4</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">0.9</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1.2</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Respiratory, thoracic and mediastinal disorders</span></td><td align="center" class="Rrule"><span class="Bold">256</span></td><td align="center" class="Rrule"><span class="Bold">24</span></td><td align="center" class="Rrule"><span class="Bold">70</span></td><td align="center" class="Rrule"><span class="Bold">7</span></td><td align="center" class="Rrule"><span class="Bold">103</span></td><td align="center" class="Rrule"><span class="Bold">10</span></td><td align="center" class="Rrule"><span class="Bold">48</span></td><td align="center" class="Rrule"><span class="Bold">4.5</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Cough</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">5.5</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">2.1</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Lung disorder</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">0.4</td><td align="center" class="Rrule">28</td><td align="center" class="Rrule">2.6</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspnea</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">4.1</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">1.1</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">1.3</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">0.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Blood and lymphatic system disorders</span></td><td align="center" class="Rrule"><span class="Bold">250</span></td><td align="center" class="Rrule"><span class="Bold">23</span></td><td align="center" class="Rrule"><span class="Bold">74</span></td><td align="center" class="Rrule"><span class="Bold">7</span></td><td align="center" class="Rrule"><span class="Bold">121</span></td><td align="center" class="Rrule"><span class="Bold">11.2</span></td><td align="center" class="Rrule"><span class="Bold">61</span></td><td align="center" class="Rrule"><span class="Bold">6</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anemia</td><td align="center" class="Rrule">103</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">4.7</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">3.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Thrombocytopenia</td><td align="center" class="Rrule">70</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">29</td><td align="center" class="Rrule">2.7</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">2.8</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Neutropenia</td><td align="center" class="Rrule">50</td><td align="center" class="Rrule">4.6</td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">2.2</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">0.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td><td align="center" class="Rrule"><span class="Bold">247</span></td><td align="center" class="Rrule"><span class="Bold">23</span></td><td align="center" class="Rrule"><span class="Bold">93</span></td><td align="center" class="Rrule"><span class="Bold">9</span></td><td align="center" class="Rrule"><span class="Bold">101</span></td><td align="center" class="Rrule"><span class="Bold">9</span></td><td align="center" class="Rrule"><span class="Bold">25</span></td><td align="center" class="Rrule"><span class="Bold">2.3</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Arthralgia</td><td align="center" class="Rrule">95</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">26</td><td align="center" class="Rrule">2.4</td><td align="center" class="Rrule">31</td><td align="center" class="Rrule">2.9</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">0.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Back pain</td><td align="center" class="Rrule">48</td><td align="center" class="Rrule">4.5</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">0.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pain in extremity</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">3.1</td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">1.3</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">0.9</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Investigations</span></td><td align="center" class="Rrule"><span class="Bold">198</span></td><td align="center" class="Rrule"><span class="Bold">18</span></td><td align="center" class="Rrule"><span class="Bold">40</span></td><td align="center" class="Rrule"><span class="Bold">3.7</span></td><td align="center" class="Rrule"><span class="Bold">47</span></td><td align="center" class="Rrule"><span class="Bold">4.4</span></td><td align="center" class="Rrule"><span class="Bold">10</span></td><td align="center" class="Rrule"><span class="Bold">0.9</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Weight increased</td><td align="center" class="Rrule">43</td><td align="center" class="Rrule">4.0</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">2.0</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">0.4</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of SIKLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pancreatitis

Pancreatitis (including fatal cases) have occurred in patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, monitor closely for signs and symptoms of pancreatitis. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity

Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy

Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

Concomitant use of SIKLOS with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus, because normal defense mechanisms may be suppressed by SIKLOS therapy. Vaccination with a live vaccine in a patient taking SIKLOS may result in severe infections. Generally, the patient's antibody response to vaccines may be decreased. Treatment with SIKLOS and concomitant immunization with live virus vaccines should only be performed if benefits clearly outweigh potential risks. Consider consultation with a specialist.

Interference with Uric Acid, Urea, or Lactic Acid Assays

Studies have shown that there is an analytical interference of SIKLOS with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with SIKLOS.

Interference with Continuous Glucose Monitoring Systems

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Risk Summary

SIKLOS can cause fetal harm based on findings from animal studies and the drug's mechanism of action [see Clinical Pharmacology (12.1)] . There are no studies with the use of SIKLOS in pregnant women, and limited available data on SIKLOS use during pregnancy are insufficient to inform drug-associated risks. Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2basis. In rats and rabbits, fetal malformations were observed with partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays (see Data) . Advise pregnant women of the potential risk to a fetus (see Clinical Considerations).

Background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Although the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the fetus/newborn, patients on SIKLOS should be made aware of the potential risks to the fetus.

Based on the limited amount of available information, in case of an exposure to SIKLOS of pregnant female patients or pregnant partners of male patients, treated by SIKLOS, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered.

Data

Human Data

According to a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, twenty-three pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men not using barrier contraception treated with hydroxyurea. Most (61%) had no adverse developmental outcomes. In the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice.

In retrospective cohorts of 352 children and adolescents with sickle cell disease older than 2 years treated with hydroxyurea for a period of up to 12 years, 3 pregnancies under hydroxyurea were reported with no adverse developmental outcomes.

From post-marketing data of SIKLOS, 3 pregnancies have been reported while the father was treated with SIKLOS and 16 pregnancies have been reported in 15 females treated with SIKLOS. Among the 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated.

Animal Data

Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2basis) to rats caused growth retardation and impaired learning ability.

Risk Summary

It is not known whether SIKLOS is excreted in human milk, the effects of SIKLOS on the breastfed child, or the effects of SIKLOS on milk production. Because of the potential for serious adverse reactions in a breastfed child from SIKLOS, including carcinogenicity, advise patients not to breastfeed during treatment with SIKLOS.

Pregnancy Testing

SIKLOS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] .

Verify the pregnancy status of females of reproductive potential prior to initiating SIKLOS therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy. Advise females to immediately report pregnancy.

Males

SIKLOS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy [see Nonclinical Toxicology (13.1)] .

Infertility

Males

Based on findings in animals and humans, male fertility may be compromised by treatment with SIKLOS. Azoospermia or oligospermia, sometimes reversible, has been observed in men. Before the start of therapy, inform male patients about the possibility of sperm conservation [see Adverse Reactions (6)and Nonclinical Toxicology (13.1)] .

The safety and effectiveness of SIKLOS have been established in pediatric patients aged 2-18 years with sickle cell anemia with recurrent moderate to severe painful crises. Use of SIKLOS in these age groups is supported by evidence from a non-interventional cohort study, the European Sickle Cell Disease prospective Cohort study, ESCORT-HU, in which 405 pediatric patients ages 2 to <18 were enrolled. Among the 405 pediatric patients treated with SIKLOS, 274 were children (2-11) and 108 were adolescents (12-16) [see Clinical Studies (14)] .

Continuous follow-up of the growth of treated children is recommended.

Pediatric patients aged 2-16 years had a higher risk of neutropenia than patients more than 16 years old.

The safety and effectiveness of SIKLOS have not been established in pediatric patients less than 2 years of age.

The exposure to SIKLOS is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when SIKLOS is to be administered to these patients [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)] .

Monitor hematologic parameters more frequently in patients with hepatic impairment receiving SIKLOS.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery. Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function.

{ "type": "p", "children": [], "text": "Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery. Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function." }

SIKLOS (hydroxyurea) is an antimetabolite that is available for oral use as functionally scored 100 mg film-coated tablet and functionally triple-scored 1,000 mg film-coated tablet containing 100 and 1,000 mg of hydroxyurea, respectively. Inactive ingredients include silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer.

{ "type": "p", "children": [], "text": "SIKLOS (hydroxyurea) is an antimetabolite that is available for oral use as functionally scored 100 mg film-coated tablet and functionally triple-scored 1,000 mg film-coated tablet containing 100 and 1,000 mg of hydroxyurea, respectively. Inactive ingredients include silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer." }

Hydroxyurea is a white crystalline powder. It has a molecular weight of 76.05. Its structural formula is:

{ "type": "p", "children": [], "text": "Hydroxyurea is a white crystalline powder. It has a molecular weight of 76.05. Its structural formula is:" }

The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.

The mechanisms by which SIKLOS produces its beneficial effects in patients with sickle cell Anemia (SCA) are uncertain. Known pharmacologic effects of SIKLOS that may contribute to its beneficial effects include increasing hemoglobin F levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known.

Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose. There is no drug accumulation upon once daily dosing of hydroxyurea.

Absorption

Following oral administration, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. The oral bioavailability of hydroxyurea was reported to be 85 -100%.

Effect of Food

There are no data on the effect of food on the absorption of hydroxyurea.

Distribution

Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. Hydroxyurea concentrates in leukocytes and erythrocytes.

Elimination

Half-life of hydroxyurea is about 2-4 hours.

Metabolism

Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.

Excretion

The percentage of the dose excreted in urine was approximately 40% in pediatric patients with sickle cell anemia.

Specific Populations

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl =30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Creatinine clearance values were obtained using 24-hour urine collections. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). Reduce the dose of SIKLOS when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.2)and Use in Specific Populations (8.6)].

Patients with Hepatic impairment

There are no data that support specific guidance for dose adjustment in patients with hepatic impairment.

Pediatric Patients

The pharmacokinetics of hydroxyurea is similar between children (4 to 17 years) and adults.

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, hydroxyurea is presumed to be a transspecies carcinogen. Intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m 2basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitroto bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro(hamster cells, human lymphoblasts) and in vivo(SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype [see Warnings and Precautions (5.2, 5.3)].

Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m 2basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see Use in Specific Populations (8.3)].

Pediatric Patients with Sickle Cell Disease

The efficacy of SIKLOS was assessed in the European Sickle Cell Disease Cohort study (ESCORT HU) [NCT02516579]. This is an open-label single-arm study of 405 pediatric patients with sickle cell disease from 2-18 years of age, of which 141 had not been previously treated with hydroxyurea prior to enrollment. Evaluable patients had at least 12 months follow-up (median [range] 23 months [12,80]). Median (range) hemoglobin F percentages were 5.6% (1.3, 15.0) at baseline and 12.8% (2.1, 37.2) at least 6 months (the value closest to 6 months collected between 5 and 14 months) after initiation of SIKLOS treatment, with median (range) change of 5.9% (-2.2, 34.7) in 47 patients. Median (range) hemoglobin levels were 8.2 g/dL (3.7, 14.2) at baseline, 8.8 g/dL (0.7, 13.1) at 6 months (the value closest to 6 months collected between 5 and 7 months), and 8.9 g/dL (5.5, 13.2) at 12 months (the value closest to 12 months collected between 10 and 14 months) after initiation of SIKLOS treatment. The median (range) change was 0.5 g/dL (-4.6, 6.1) in 63 patients at 6 months (the post-baseline value closest to 6 months collected between 5 and 7 months) and 0.7 g/dL (-6.4, 6.0) in 83 patients at 12 months (the post-baseline value closest to 12 months collected between 10 and 14 months) after initiation of SIKLOS treatment.

Among pediatric patients not previously treated with hydroxyurea prior to enrollment and analyzable for efficacy (N=141), the percentage of patients with at least one vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD or one blood transfusion decreased after 12 months of SIKLOS treatment (Table 4).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Comparison of SCD Events in the First Year of Treatment with SIKLOS with SCD Events in the 12 Months Prior to Enrollment – ESCORT HU Trial (N=141) in Pediatric Patients</span> </caption> <col align="center" valign="top" width="27%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="23%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" rowspan="2" valign="middle">SCD events</th><th align="center" class="Rrule" colspan="3">Patients under 18 years old previously not treated with hydroxyurea with at least 12 months follow-up data available for clinical efficacy (N=141)</th> </tr> <tr class="Last"> <th align="center" class="Rrule">In the 12 months prior to enrolment</th><th align="center" class="Rrule">After 12 months of Siklos <span class="Sup">®</span>treatment </th><th align="center" class="Rrule">Change</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one vaso-occlusive episode (in 120 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">37 (31%)</td><td align="center" class="Rrule">69 (57.5%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">83 (69%)</td><td align="center" class="Rrule">51 (42.5%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of vasoocclusive episodes over 12 months (in 113 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">2 (0, 1)</td><td align="center" class="Rrule">0 (0.0, 7.0)</td><td align="center" class="Rrule">-1 (-10.0, 5.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one episode of acute chest syndrome (in 123 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">94 (76%)</td><td align="center" class="Rrule">116 (94%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">29 (24%)</td><td align="center" class="Rrule">7 (6%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of episodes of acute chest syndrome over 12 months (in 123 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">0 (0.0, 2.0)</td><td align="center" class="Rrule">0 (0.0, 1.0)</td><td align="center" class="Rrule">0 (-2.0, 1.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one hospitalization related to SCD (in 110 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">27 (25%)</td><td align="center" class="Rrule">64 (58%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">83 (75%)</td><td align="center" class="Rrule">46 (42%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of hospitalizations related to SCD over 12 months (in 106 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">2 (0.0, 6.0)</td><td align="center" class="Rrule">0 (0.0, 7.0)</td><td align="center" class="Rrule">-1 (-6.0, 6.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of days of hospitalizations related to SCD over 12 months (in 100 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">8 (0.0, 58.0)</td><td align="center" class="Rrule">0 (0.0, 100.0)</td><td align="center" class="Rrule">-3 (-58.0, 86.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one blood transfusion (in 122 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">66 (54%)</td><td align="center" class="Rrule">94 (77%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">56 (46%)</td><td align="center" class="Rrule">28 (23%)</td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

Adult Patients with Sickle Cell Disease

In ESCORT-HU 1077 adult patients were included of which 436 patients were naïve to HU treatment. There were 370 evaluable patients who had at least 12 months follow-up (Median [range] 41 months [29, 54].

Median (range) hemoglobin F percentages were 5.2% (0.2, 30.9) at baseline and 14.2% (0.5, 41.5) at least 6 months (the value closest to 6 months collected between 5 and 14 months) after initiation of SIKLOS treatment, with a median (range) change of 8% (-8.0, 33.3) in 181 patients. Among adult patients previously not treated with hydroxyurea prior to enrollment and analyzable for efficacy (N=370), the incidence and number of vaso-occlusive events, hospitalizations, acute chest syndrome and blood transfusions in the 12 month period before treatment and after initiation of treatment decreased after 12 months of SIKLOS treatment. Table 5 provides the efficacy results for ESCORT-HU.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Comparison of SCD Events in the First Year of Treatment with SIKLOS with SCD Events in the 12 Months Prior to Enrollment – ESCORT HU Trial (N=370) in Adult Patients</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" rowspan="2" valign="middle">SCD events</th><th align="center" class="Rrule" colspan="3">Adult Patients previously not treated with hydroxyurea with at least 12 months follow-up data available for clinical efficacy (N=369)</th> </tr> <tr class="Last"> <th align="center" class="Rrule">In the 12 months prior to enrolment</th><th align="center" class="Rrule">After 12 months of Siklos <span class="Sup">®</span>treatment </th><th align="center" class="Rrule">Change</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one vaso-occlusive episode (in 367 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">133 (36.2%)</td><td align="center" class="Rrule">226 (61.6%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">234 (63.8%)</td><td align="center" class="Rrule">141 (38.4%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of vasoocclusive episodes over 12 months (in 343 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">1.0 (0.0, 20.0)</td><td align="center" class="Rrule">0.0 (0.0, 30.0)</td><td align="center" class="Rrule">0.0 (-20.0, 24.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one episode of acute chest syndrome (in 365 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">273 (74.8%)</td><td align="center" class="Rrule">338 (92.6%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">92 (25.2%)</td><td align="center" class="Rrule">27 (7.4%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of episodes of acute chest syndrome over 12 months (in 364 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">1.0 (0.0, 5.0)</td><td align="center" class="Rrule">0.0 (0.0, 3.0)</td><td align="center" class="Rrule">0.0 (-5.0 ; 2.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one hospitalization related to SCD (in 366 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">152 (41.5%)</td><td align="center" class="Rrule">252 (68.9%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">214 (58.5%)</td><td align="center" class="Rrule">114 (31.1%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of hospitalizations related to SCD over 12 months (in 360 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">1 (0.0, 15.0)</td><td align="center" class="Rrule">0 (0.0, 10.0)</td><td align="center" class="Rrule">0 (-15.0, 8.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of days of hospitalizations related to SCD over 12 months (in 313 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Median (range)</td><td align="center" class="Rrule">2 (0.0, 90.0)</td><td align="center" class="Rrule">0 (0.0, 77.0)</td><td align="center" class="Rrule">0 (-90.0, 57.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Number of patients with at least one blood transfusion (in 365 evaluable patients)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">No</td><td align="center" class="Rrule">207 (56.7%)</td><td align="center" class="Rrule">296 (81.1%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Yes</td><td align="center" class="Rrule">158 (43.3%)</td><td align="center" class="Rrule">69 (18.9%)</td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

OSHA Hazardous Drugs. OSHA.http://www.osha.gov/SLTC/hazardousdrugs/index.html.

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SIKLOS (hydroxyurea) film-coated tablet is supplied in high density polyethylene (HDPE) bottle with polypropylene child-resistant cap with a desiccant unit containing 30 (SIKLOS 1,000 mg) or 60 (SIKLOS 100 mg) film coated tablets. Each bottle containing SIKLOS 100 mg tablets or SIKLOS 1000 mg tablets is supplied in a carton.

SIKLOS is supplied in the following strengths:

<div class="scrollingtable"><table width="75%"> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Bottles of 30</th><th align="center" class="Rrule">Bottles of 60</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">100 mg</td><td align="left" class="Rrule">N/A</td><td align="left" class="Rrule">NDC 71770-105-60</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">1,000 mg</td><td align="left" class="Rrule">NDC 71770-120-30</td><td align="left" class="Rrule">N/A</td> </tr> </tbody> </table></div>

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]. Keep tightly closed.

Broken tablets must be stored in the bottle and must be used within three months.

SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)] .

To decrease the risk of contact, advise caregivers to wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash hands with soap and water before and after contact with the bottle or tablets when handling SIKLOS. Avoid exposure to crushed tablets. If contact with crushed tablets occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed tablets occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes.

Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use and Medication Guide).

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{ "type": "ul", "children": [ "There is a risk of myelosuppression. Emphasize the importance of monitoring blood counts every two weeks throughout the duration of therapy to patients taking SIKLOS\n \n [see\n \n Warnings and Precautions (5.1)]\n \n . Advise patients to report signs and symptoms of infection or bleeding immediately.\n \n ", "Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia. Advise use of sun protection\n \n [see\n \n Warnings and Precautions (5.1)]\n \n .\n \n ", "Advise females of reproductive potential of the potential risk to a fetus should they become pregnant while taking SIKLOS. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with SIKLOS\n \n [see\n \n Warnings and Precautions (5.3)and\n \n Use in Specific Populations (8.1,\n \n 8.3)]\n \n .\n \n ", "Advise females to discontinue breastfeeding during treatment with SIKLOS\n \n [see\n \n Use in Specific Populations (8.2)]\n \n .\n \n ", "Advise male patients of potential risk to fertility\n \n [see\n \n Use in Specific Populations (8.3)]\n \n .\n \n ", "Advise patients with HIV infection to contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy\n \n [see\n \n Warnings and Precautions (5.5)]\n \n .\n \n ", "Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking SIKLOS\n \n [see\n \n Warnings and Precautions (5.8)].\n \n \n", "Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia not related to sickle cell anemia\n \n [see\n \n Warnings and Precautions (5.9)]\n \n .\n \n ", "Because SIKLOS tablets are scored, advise patients on how to take SIKLOS properly." ], "text": "" }

Distributed by: Medunik USA, 2 Research Way, suite 1B, Princeton, NJ 08540. Manufactured for. Theravia: 16 rue Montrosier 92200 Neuilly-sur-Seine France Manufactured by: Delpharm Lille, 22 rue de Toufflers 59452 Lys Lez Lannoy France

{ "type": "p", "children": [], "text": "Distributed by: \n Medunik USA, 2 Research Way, suite 1B, Princeton, NJ 08540. \n Manufactured for. Theravia: 16 rue Montrosier 92200 Neuilly-sur-Seine France \n Manufactured by: Delpharm Lille, 22 rue de Toufflers 59452 Lys Lez Lannoy France\n " }

SIKLOS is a trademark of Theravia.

{ "type": "p", "children": [], "text": "\nSIKLOS is a trademark of Theravia.\n" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="48%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="20%"/> <tfoot> <tr class="First"> <td align="left" colspan="3">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="1">Revised: 11/2023</td> </tr> <tr class="Last"> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="4"><span class="Bold">MEDICATION GUIDE</span> <br/> SIKLOS (See – k – los) <br/> (hydroxyurea) <br/> tablets </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <a name="IMPORTANT"></a><span class="Bold">What is the most important information I should know about SIKLOS?</span> </p> <p> <span class="Bold">SIKLOS can cause serious side effects including:</span> </p> <ul class="Disc"> <li> <span class="Bold">Low blood cell counts are common with SIKLOS, including low red blood cells, white blood cells, and platelets, and can be severe and life-threatening. If your white blood cell count becomes very low, you are at increased risk for infection.</span>Your healthcare provider will check your blood cell counts before and every 2 weeks during treatment with SIKLOS. Your healthcare provider may change your dose or tell you to stop taking SIKLOS if you have low blood cell counts. Tell your healthcare provider right away if you get any of the following symptoms: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Circle"> <li>fever or chills</li> <li>body aches</li> <li>feeling very tired</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Circle"> <li>shortness of breath</li> <li>unusual headache</li> <li>bleeding or unexplained bruising</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <ul class="Disc"> <li> <span class="Bold">Cancer.</span>Some people have developed cancer, such as leukemia and skin cancer, after taking SIKLOS for a long time. Your healthcare provider will check you for cancer. You should protect your skin from the sun using sunblock, hats, and sun-protective clothing. </li> <li> <span class="Bold">SIKLOS can harm your unborn baby. <br/> For females taking SIKLOS who can become pregnant: </span> <ul class="Circle"> <li>You should talk with your healthcare provider about the risks of SIKLOS to your unborn baby.</li> <li>You should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment with SIKLOS.</li> <li>Your healthcare provider will perform a pregnancy test before you start treatment with SIKLOS. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.</li> </ul> <p class="First"> <span class="Bold">For males taking SIKLOS:</span>SIKLOS can affect your sperm. If you have a female sexual partner who can become pregnant, you should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment. </p> <p> <span class="Bold">SIKLOS may cause fertility problems in males. Talk to your healthcare provider if this is a concern for you.</span> </p> </li> </ul> <p class="First">See " <span class="Bold"><a href="#EFFECTS">What are the possible side effects of SIKLOS?</a></span>" for more information about side effects. </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What is SIKLOS?</span> <br/> SIKLOS is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in adults and children, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. <br/> It is not known if SIKLOS is safe and effective in children less than 2 years of age. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Do not take SIKLOS if you are allergic to hydroxyurea or any of the ingredients in SIKLOS</span>. See the end of this Medication Guide for a list of the ingredients in SIKLOS. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">Before taking SIKLOS, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <ul class="Disc"> <li>have kidney problems or are receiving hemodialysis</li> <li>have liver problems</li> <li>have human immunodeficiency virus (HIV) or take HIV medicines. <span class="Bold">Taking SIKLOS with certain HIV medicines can cause serious reactions and may lead to death.</span> </li> <li>have increased levels of uric acid in your blood (hyperuricemia)</li> <li>have a history of receiving interferon therapy or are currently receiving interferon therapy</li> <li>have leg wounds or ulcers</li> <li>plan to receive any vaccinations. You should not receive "live vaccines" during treatment with SIKLOS.</li> <li>are pregnant or plan to become pregnant. See <span class="Bold">" <a href="#IMPORTANT">What is the most important information I should know about SIKLOS?</a></span>" </li> <li>are breastfeeding or plan to breastfeed. It is not known if SIKLOS can pass into your breast milk. Do not breastfeed during treatment with SIKLOS.</li> <li>are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it is safe to use while you are taking SIKLOS.</li> </ul> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <span class="Bold">How should I take SIKLOS?</span> </p> <p> <span class="Bold">Read the Instructions for Use at the end of this Medication Guide for step-by-step instructions on how to prepare a dose of SIKLOS. If you have any questions, talk to your healthcare provider or pharmacist.</span> </p> <ul class="Disc"> <li>Take SIKLOS exactly as your healthcare provider tells you to take it.</li> <li>Take SIKLOS 1 time a day at the same time each day.</li> <li>Swallow the tablet(s) with a glass of water. If you are not able to swallow SIKLOS tablets, you can dissolve your prescribed dose in a small amount of water in a teaspoon and swallow right away.</li> <li>SIKLOS is supplied as 100 mg tablets and 1,000 mg tablets. The SIKLOS tablets have separation lines (score lines) and can be broken at these score lines to provide smaller doses. <ul class="Circle"> <li>Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).</li> <li>Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).</li> </ul> </li> <li>Your healthcare provider will tell you how many tablets or parts of a tablet you should take.</li> <li>SIKLOS tablets must be handled with care. To decrease the risk of exposure, you or your caregivers should do the following when handling SIKLOS: <ul class="Circle"> <li>Wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash your hands with soap and water before and after handling SIKLOS tablets or bottles containing SIKLOS.</li> <li>Avoid contact with crushed tablets. If contact with crushed tablets happens on the skin, wash the skin area right away and thoroughly with soap and water. If contact with crushed tablets happens in the eyes, flush the eyes thoroughly with water or isotonic eyewash used for that purpose for at least 15 minutes.</li> <li>Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.</li> </ul> </li> <li>If you take too much SIKLOS, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"> <p class="First"> <a name="EFFECTS"></a><span class="Bold">What are the possible side effects of SIKLOS? <br/> SIKLOS may cause serious side effects, including: <br/> See " <a href="#IMPORTANT">What is the most important information I should know about SIKLOS?</a>" </span> </p> <ul class="Disc"> <li> <span class="Bold">Skin ulcers, including leg ulcers, and death of skin tissue (gangrene)</span>have happened in people who take SIKLOS. This has happened most often in people who receive interferon therapy or have a history of interferon therapy. Your healthcare provider will decrease your dose or stop treatment with SIKLOS if you develop any skin ulcers. </li> <li> <span class="Bold">Enlarged red blood cells (macrocytosis)</span>. Macrocytosis is common in people who take SIKLOS and can make it difficult to detect a decrease of folic acid. Your healthcare provider may prescribe a folic acid supplement for you. </li> <li> <span class="Bold">Hemolytic Anemia,</span>the fast breakdown of red blood cells, has happened in people who take SIKLOS. Tell your healthcare provider if you develop yellowing of your skin (jaundice) or blood in your urine. Your healthcare provider may do blood tests if you have persistent or worsening anemia. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">The most common side effects of SIKLOS in children include:</span> <ul> <li>infections</li> <li>low white blood cells</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">The most common side effects of SIKLOS in adults include:</span> <ul> <li>infections</li> <li>headache</li> <li>dry skin</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4">These are not all the possible side effects of SIKLOS. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">How should I store SIKLOS?</span> <ul class="Disc"> <li>Store SIKLOS at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep the SIKLOS bottle tightly closed.</li> <li>Broken SIKLOS tablets must be stored in the bottle and must be used within three months.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Keep SIKLOS and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">General information about the safe and effective use of SIKLOS.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SIKLOS for a condition for which it was not prescribed. Do not give SIKLOS to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SIKLOS that is written for health professionals. </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the ingredients of SIKLOS?</span> <br/> <span class="Bold">Active ingredient:</span>hydroxyurea <br/> <span class="Bold">Inactive ingredients:</span>silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer. <br/> Distributed by: Medunik USA, 2 Research Way, suite 1B, Princeton, NJ 08540. <br/> Manufactured for:. Theravia : 16 rue Montrosier 92200 Neuilly-sur-Seine, France <br/> Manufactured by: Delpharm Lille, 22 rue de Toufflers 59452 Lys Lez Lannoy France. <br/> <span class="Bold">SIKLOS is a trademark of Theravia.</span>For more information, call 1-844-884-5520. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"48%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"3\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"1\">Revised: 11/2023</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/> SIKLOS (See – k – los) \n <br/> (hydroxyurea) \n <br/> tablets\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<a name=\"IMPORTANT\"></a><span class=\"Bold\">What is the most important information I should know about SIKLOS?</span>\n</p>\n<p>\n<span class=\"Bold\">SIKLOS can cause serious side effects including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Low blood cell counts are common with SIKLOS, including low red blood cells, white blood cells, and platelets, and can be severe and life-threatening. If your white blood cell count becomes very low, you are at increased risk for infection.</span>Your healthcare provider will check your blood cell counts before and every 2 weeks during treatment with SIKLOS. Your healthcare provider may change your dose or tell you to stop taking SIKLOS if you have low blood cell counts. Tell your healthcare provider right away if you get any of the following symptoms:\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Circle\">\n<li>fever or chills</li>\n<li>body aches</li>\n<li>feeling very tired</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>shortness of breath</li>\n<li>unusual headache</li>\n<li>bleeding or unexplained bruising</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Cancer.</span>Some people have developed cancer, such as leukemia and skin cancer, after taking SIKLOS for a long time. Your healthcare provider will check you for cancer. You should protect your skin from the sun using sunblock, hats, and sun-protective clothing.\n \n </li>\n<li>\n<span class=\"Bold\">SIKLOS can harm your unborn baby. \n <br/> For females taking SIKLOS who can become pregnant:\n </span>\n<ul class=\"Circle\">\n<li>You should talk with your healthcare provider about the risks of SIKLOS to your unborn baby.</li>\n<li>You should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment with SIKLOS.</li>\n<li>Your healthcare provider will perform a pregnancy test before you start treatment with SIKLOS. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">For males taking SIKLOS:</span>SIKLOS can affect your sperm. If you have a female sexual partner who can become pregnant, you should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment.\n \n </p>\n<p>\n<span class=\"Bold\">SIKLOS may cause fertility problems in males. Talk to your healthcare provider if this is a concern for you.</span>\n</p>\n</li>\n</ul>\n<p class=\"First\">See \"\n \n <span class=\"Bold\"><a href=\"#EFFECTS\">What are the possible side effects of SIKLOS?</a></span>\" for more information about side effects.\n \n </p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What is SIKLOS?</span>\n<br/> SIKLOS is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in adults and children, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. \n <br/> It is not known if SIKLOS is safe and effective in children less than 2 years of age.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Do not take SIKLOS if you are allergic to hydroxyurea or any of the ingredients in SIKLOS</span>. See the end of this Medication Guide for a list of the ingredients in SIKLOS.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking SIKLOS, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have kidney problems or are receiving hemodialysis</li>\n<li>have liver problems</li>\n<li>have human immunodeficiency virus (HIV) or take HIV medicines.\n \n <span class=\"Bold\">Taking SIKLOS with certain HIV medicines can cause serious reactions and may lead to death.</span>\n</li>\n<li>have increased levels of uric acid in your blood (hyperuricemia)</li>\n<li>have a history of receiving interferon therapy or are currently receiving interferon therapy</li>\n<li>have leg wounds or ulcers</li>\n<li>plan to receive any vaccinations. You should not receive \"live vaccines\" during treatment with SIKLOS.</li>\n<li>are pregnant or plan to become pregnant. See\n \n <span class=\"Bold\">\"\n \n <a href=\"#IMPORTANT\">What is the most important information I should know about SIKLOS?</a></span>\"\n \n </li>\n<li>are breastfeeding or plan to breastfeed. It is not known if SIKLOS can pass into your breast milk. Do not breastfeed during treatment with SIKLOS.</li>\n<li>are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it is safe to use while you are taking SIKLOS.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n \n </p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take SIKLOS?</span>\n</p>\n<p>\n<span class=\"Bold\">Read the Instructions for Use at the end of this Medication Guide for step-by-step instructions on how to prepare a dose of SIKLOS. If you have any questions, talk to your healthcare provider or pharmacist.</span>\n</p>\n<ul class=\"Disc\">\n<li>Take SIKLOS exactly as your healthcare provider tells you to take it.</li>\n<li>Take SIKLOS 1 time a day at the same time each day.</li>\n<li>Swallow the tablet(s) with a glass of water. If you are not able to swallow SIKLOS tablets, you can dissolve your prescribed dose in a small amount of water in a teaspoon and swallow right away.</li>\n<li>SIKLOS is supplied as 100 mg tablets and 1,000 mg tablets. The SIKLOS tablets have separation lines (score lines) and can be broken at these score lines to provide smaller doses.\n \n <ul class=\"Circle\">\n<li>Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).</li>\n<li>Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).</li>\n</ul>\n</li>\n<li>Your healthcare provider will tell you how many tablets or parts of a tablet you should take.</li>\n<li>SIKLOS tablets must be handled with care. To decrease the risk of exposure, you or your caregivers should do the following when handling SIKLOS:\n \n <ul class=\"Circle\">\n<li>Wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash your hands with soap and water before and after handling SIKLOS tablets or bottles containing SIKLOS.</li>\n<li>Avoid contact with crushed tablets. If contact with crushed tablets happens on the skin, wash the skin area right away and thoroughly with soap and water. If contact with crushed tablets happens in the eyes, flush the eyes thoroughly with water or isotonic eyewash used for that purpose for at least 15 minutes.</li>\n<li>Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.</li>\n</ul>\n</li>\n<li>If you take too much SIKLOS, call your healthcare provider or go to the nearest hospital emergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">\n<a name=\"EFFECTS\"></a><span class=\"Bold\">What are the possible side effects of SIKLOS? \n <br/> SIKLOS may cause serious side effects, including: \n <br/> See \"\n \n <a href=\"#IMPORTANT\">What is the most important information I should know about SIKLOS?</a>\"\n \n </span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Skin ulcers, including leg ulcers, and death of skin tissue (gangrene)</span>have happened in people who take SIKLOS. This has happened most often in people who receive interferon therapy or have a history of interferon therapy. Your healthcare provider will decrease your dose or stop treatment with SIKLOS if you develop any skin ulcers.\n \n </li>\n<li>\n<span class=\"Bold\">Enlarged red blood cells (macrocytosis)</span>. Macrocytosis is common in people who take SIKLOS and can make it difficult to detect a decrease of folic acid. Your healthcare provider may prescribe a folic acid supplement for you.\n \n </li>\n<li>\n<span class=\"Bold\">Hemolytic Anemia,</span>the fast breakdown of red blood cells, has happened in people who take SIKLOS. Tell your healthcare provider if you develop yellowing of your skin (jaundice) or blood in your urine. Your healthcare provider may do blood tests if you have persistent or worsening anemia.\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">The most common side effects of SIKLOS in children include:</span>\n<ul>\n<li>infections</li>\n<li>low white blood cells</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">The most common side effects of SIKLOS in adults include:</span>\n<ul>\n<li>infections</li>\n<li>headache</li>\n<li>dry skin</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">These are not all the possible side effects of SIKLOS. \n <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">How should I store SIKLOS?</span>\n<ul class=\"Disc\">\n<li>Store SIKLOS at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Keep the SIKLOS bottle tightly closed.</li>\n<li>Broken SIKLOS tablets must be stored in the bottle and must be used within three months.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Keep SIKLOS and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">General information about the safe and effective use of SIKLOS.</span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SIKLOS for a condition for which it was not prescribed. Do not give SIKLOS to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SIKLOS that is written for health professionals.\n \n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the ingredients of SIKLOS?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span>hydroxyurea \n <br/>\n<span class=\"Bold\">Inactive ingredients:</span>silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer. \n <br/> Distributed by: Medunik USA, 2 Research Way, suite 1B, Princeton, NJ 08540. \n <br/> Manufactured for:. Theravia : 16 rue Montrosier 92200 Neuilly-sur-Seine, France \n <br/> Manufactured by: Delpharm Lille, 22 rue de Toufflers 59452 Lys Lez Lannoy France. \n <br/>\n<span class=\"Bold\">SIKLOS is a trademark of Theravia.</span>For more information, call 1-844-884-5520.\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

SIKLOS (See – k – los) (hydroxyurea) tablets

{ "type": "p", "children": [], "text": "SIKLOS (See – k – los) \n (hydroxyurea) \n tablets\n " }

Read this Instructions for Use before you start taking SIKLOS and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about SIKLOS when you start taking it and at regular checkups.

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

Important Information:

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

{ "type": "ul", "children": [ "Wash your hands with soap and water before and after handling SIKLOS tablets or bottles containing SIKLOS.", "Wear disposable gloves when handling SIKLOS tablets or bottles containing SIKLOS.", "Take SIKLOS 1 time a day at the same time each day.", "Powder spilled from a broken tablet should be wiped up right away with a damp disposable paper towel and thrown away in a closed container, such as a plastic bag to avoid harm to other people. The spill area should then be cleaned using a detergent solution followed by clean water.", "When the tablet is broken, avoid touching the broken surfaces.", "If contact with crushed tablets happens on the skin, wash the skin area right away and thoroughly with soap and water.", "If contact with crushed tablets happens in the eyes, flush the eyes thoroughly with water or isotonic eyewash used for that purpose for at least 15 minutes." ], "text": "" }

SIKLOS is supplied in 2 different strengths:

{ "type": "p", "children": [], "text": "\nSIKLOS is supplied in 2 different strengths:\n" }

SIKLOS 100 mg tablethas one separation line (score line) and can be broken at this score line to provide smaller doses. Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).

{ "type": "p", "children": [], "text": "\nSIKLOS 100 mg tablethas one separation line (score line) and can be broken at this score line to provide smaller doses. Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).\n\n " }

SIKLOS 1,000 mg tablethas three separation lines (score lines) and can be broken at these score lines to provide smaller doses. Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).

{ "type": "p", "children": [], "text": "\nSIKLOS 1,000 mg tablethas three separation lines (score lines) and can be broken at these score lines to provide smaller doses. Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).\n\n " }

SIKLOS tablet breaking instructions

{ "type": "p", "children": [], "text": "\nSIKLOS tablet breaking instructions\n" }

You will need the following supplies to break a SIKLOS tablet:

{ "type": "p", "children": [], "text": "You will need the following supplies to break a SIKLOS tablet:" }

{ "type": "ul", "children": [ "SIKLOS tablets", "A damp disposable paper towel", "A tablet cutter", "Disposable gloves" ], "text": "" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 1:</span>Place a damp disposable paper towel on a flat surface where the tablets will be broken. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 2:</span>Wash and dry your hands before handling SIKLOS tablets or bottles containing the tablets. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-04.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 3:</span>Check your prescribed dose. You may need more than 1 tablet to get your prescribed dose. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 4:</span>Put on disposable gloves. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-05.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 5:</span>Remove the SIKLOS tablet out of the bottle needed to get your dose. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-06.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 6:</span>Use your index fingers and thumbs to hold each end of the SIKLOS tablet. </td> </tr> <tr> <td align="left" class="Lrule"><span class="Bold">SIKLOS 100 mg</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-07.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" valign="bottom">side view</td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=siklos-08.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" class="Rrule" valign="bottom">side view between fingers and thumbs</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">SIKLOS 1,000 mg</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-09.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" valign="bottom">side view</td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=siklos-10.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" class="Rrule" valign="bottom">side view between fingers and thumbs</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 7:</span>While holding the ends of the SIKLOS tablet, push down on the tablet to break the tablet on the score line to get your prescribed dose. <br/> <span class="Bold">SIKLOS 100 mg tablets can be broken as:</span></td> </tr> <tr> <td align="center" class="Lrule" colspan="2">Whole tablet</td><td align="left"></td><td align="left" class="Rrule"></td> </tr> <tr> <td align="center" class="Lrule">top view <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-11.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="center">side view <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-12.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" class="Rrule" colspan="2"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-13.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">1/2 of a tablet for a dose of 50 mg of SIKLOS:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-14.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">a whole tablet for a dose of 100 mg of SIKLOS <span class="Bold">(no breaking needed)</span>:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-15.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">SIKLOS 1,000 mg tablets can be broken as:</span></td> </tr> <tr> <td align="center" class="Lrule" colspan="2">Whole tablet</td><td align="left"></td><td align="left" class="Rrule"></td> </tr> <tr> <td align="center" class="Lrule">Top view <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-16.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="center">side view <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-17.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td><td align="left" class="Rrule" colspan="2"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-18.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">1/4 of a tablet for a dose of 250 mg of SIKLOS:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-19.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">1/2 of a tablet for a dose of 500 mg of SIKLOS:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-20.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">3/4 of a tablet for a dose of 750 mg of SIKLOS:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-21.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li> <p class="First">a whole tablet for a dose of 1,000 mg of SIKLOS <span class="Bold">(no breaking needed)</span>:   <img alt="Image" src="/dailymed/image.cfm?name=siklos-22.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Note: You may need to use a tablet cutter.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 8:</span>Take your prescribed dose by swallowing it with a glass of water. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-23.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/><br/> <span class="Bold">Important:</span>If you have difficulty swallowing SIKLOS tablets, please stop here and follow the instructions below, "For people who cannot swallow SIKLOS tablets". </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 9:</span>Throw away the damp disposable paper towel in the trash. Pull off disposable gloves and throw away in the trash. </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="right"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-24.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td><td align="left" class="Rrule" colspan="2"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-25.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="right"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-26.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td><td align="left" class="Rrule" colspan="2"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-27.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4">Wash and dry your hands. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-28.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Step 10:</span>Store any unused broken tablets in the bottle and put the bottle back in the box. <span class="Bold">Broken tablets must be used within three months.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 1:</span>Place a damp disposable paper towel on a flat surface where the tablets will be broken.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 2:</span>Wash and dry your hands before handling SIKLOS tablets or bottles containing the tablets. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-04.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 3:</span>Check your prescribed dose. You may need more than 1 tablet to get your prescribed dose.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 4:</span>Put on disposable gloves. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-05.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 5:</span>Remove the SIKLOS tablet out of the bottle needed to get your dose. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-06.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 6:</span>Use your index fingers and thumbs to hold each end of the SIKLOS tablet.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"><span class=\"Bold\">SIKLOS 100 mg</span>\n<br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-07.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" valign=\"bottom\">side view</td><td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-08.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" class=\"Rrule\" valign=\"bottom\">side view between fingers and thumbs</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\"><span class=\"Bold\">SIKLOS 1,000 mg</span>\n<br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-09.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" valign=\"bottom\">side view</td><td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-10.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" class=\"Rrule\" valign=\"bottom\">side view between fingers and thumbs</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 7:</span>While holding the ends of the SIKLOS tablet, push down on the tablet to break the tablet on the score line to get your prescribed dose. \n <br/>\n<span class=\"Bold\">SIKLOS 100 mg tablets can be broken as:</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule\" colspan=\"2\">Whole tablet</td><td align=\"left\"></td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule\">top view \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-11.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"center\">side view \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-12.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-13.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">1/2 of a tablet for a dose of 50 mg of SIKLOS:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-14.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">a whole tablet for a dose of 100 mg of SIKLOS\n \n <span class=\"Bold\">(no breaking needed)</span>:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-15.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">SIKLOS 1,000 mg tablets can be broken as:</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule\" colspan=\"2\">Whole tablet</td><td align=\"left\"></td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule\">Top view \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-16.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"center\">side view \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-17.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-18.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">1/4 of a tablet for a dose of 250 mg of SIKLOS:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-19.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">1/2 of a tablet for a dose of 500 mg of SIKLOS:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-20.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">3/4 of a tablet for a dose of 750 mg of SIKLOS:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-21.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<p class=\"First\">a whole tablet for a dose of 1,000 mg of SIKLOS\n \n <span class=\"Bold\">(no breaking needed)</span>:  \n \n <img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-22.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Note: You may need to use a tablet cutter.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 8:</span>Take your prescribed dose by swallowing it with a glass of water. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-23.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/><br/>\n<span class=\"Bold\">Important:</span>If you have difficulty swallowing SIKLOS tablets, please stop here and follow the instructions below, \"For people who cannot swallow SIKLOS tablets\".\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 9:</span>Throw away the damp disposable paper towel in the trash. Pull off disposable gloves and throw away in the trash.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"right\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-24.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-25.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"right\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-26.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-27.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">Wash and dry your hands. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-28.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Step 10:</span>Store any unused broken tablets in the bottle and put the bottle back in the box.\n \n <span class=\"Bold\">Broken tablets must be used within three months.</span></td>\n</tr>\n</tbody>\n</table></div>" }

For people who cannot swallow SIKLOS tablets

{ "type": "p", "children": [], "text": "\nFor people who cannot swallow SIKLOS tablets\n" }

You will need the following supplies to prepare and take your dose by dissolving the tablet:

{ "type": "p", "children": [], "text": "\nYou will need the following supplies to prepare and take your dose by dissolving the tablet:\n" }

{ "type": "ul", "children": [ "Your bottle of SIKLOS tablets\n \n \n\nNote:If you need to break your tablets, use the\n \n SIKLOS Tablet Breaking Instructions aboveto get your prescribed dose\n \n beforeyou begin the steps below.\n \n \n\n", "A teaspoon", "Water to dissolve tablets" ], "text": "" }

<div class="scrollingtable"><table width="60%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 1:</span>Get your prescribed dose of SIKLOS tablets. Put your prescribed dose of SIKLOS tablets onto the teaspoon. </td> </tr> <tr> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-29.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td><td align="left" class="Rrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-30.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule"><span class="Bold">SIKLOS 100 mg tablet  </span></td><td align="left" class="Rrule"><span class="Bold">SIKLOS 1,000 mg tablet (broken)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 2:</span>Add a small amount of water to the teaspoon. The tablet dissolves within about 1 minute. </td> </tr> <tr> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-31.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td><td align="left" class="Rrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-32.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" colspan="2"><span class="Bold">SIKLOS 100 mg tablet</span></td> </tr> <tr> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-33.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td><td align="left" class="Rrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=siklos-34.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></p> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2"><span class="Bold">SIKLOS 1,000 mg tablet (broken)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 3:</span>Swallow the mixture right away. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-35.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 4:</span>After you take your prescribed dose of SIKLOS tablets, drink a glass of water. When you are finished drinking a glass of water, continue to Step 9 and Step 10 above. <br/> <img alt="Image" src="/dailymed/image.cfm?name=siklos-36.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule" colspan="2"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"60%\">\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 1:</span>Get your prescribed dose of SIKLOS tablets. Put your prescribed dose of SIKLOS tablets onto the teaspoon.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Lrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-29.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td><td align=\"left\" class=\"Rrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-30.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule\"><span class=\"Bold\">SIKLOS 100 mg tablet  </span></td><td align=\"left\" class=\"Rrule\"><span class=\"Bold\">SIKLOS 1,000 mg tablet (broken)</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 2:</span>Add a small amount of water to the teaspoon. The tablet dissolves within about 1 minute.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Lrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-31.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td><td align=\"left\" class=\"Rrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-32.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">SIKLOS 100 mg tablet</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Lrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-33.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td><td align=\"left\" class=\"Rrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-34.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">SIKLOS 1,000 mg tablet (broken)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 3:</span>Swallow the mixture right away. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-35.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 4:</span>After you take your prescribed dose of SIKLOS tablets, drink a glass of water. When you are finished drinking a glass of water, continue to Step 9 and Step 10 above. \n <br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=siklos-36.jpg&amp;setid=76957c0d-0f98-4376-bb06-eee651adc09d\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"></td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"></td>\n</tr>\n</tbody>\n</table></div>" }

Storing your SIKLOS tablets:

{ "type": "p", "children": [], "text": "\nStoring your SIKLOS tablets:\n" }

{ "type": "ul", "children": [ "Store SIKLOS at room temperature between 68°F to 77°F (20°C to 25°C).", "Keep the SIKLOS bottle tightly closed." ], "text": "" }

Keep SIKLOS and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep SIKLOS 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. Revised 11/2023

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. \n Revised 11/2023\n " }

NDC 71770-120-30

{ "type": "p", "children": [], "text": "NDC 71770-120-30" }

Siklos ®1,000 mg (hydroxyurea) tablets

{ "type": "p", "children": [], "text": "\nSiklos\n \n ®1,000 mg\n \n \n (hydroxyurea) tablets\n\n " }

1,000 mg per tablet

{ "type": "p", "children": [], "text": "\n1,000 mg per tablet\n" }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide

{ "type": "p", "children": [], "text": "\nATTENTION PHARMACIST: \n Each patient is required \n to receive the enclosed \n Medication Guide\n \n" }

30 tablets

{ "type": "p", "children": [], "text": "\n30 tablets\n" }

RX Only.

{ "type": "p", "children": [], "text": "\nRX Only.\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)

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

WARNING: MYELOSUPPRESSION AND MALIGNANCIES

{ "type": "p", "children": [], "text": "\nWARNING: MYELOSUPPRESSION AND \n MALIGNANCIES\n \n" }

Handle tablets with care. Do not use or dispense before reading directions and warnings in accompanying product information.

{ "type": "p", "children": [], "text": "Handle tablets with care. \n Do not use or dispense before reading directions \n and warnings in accompanying product \n information.\n " }

Wear disposable gloves when handling Siklos ®or bottles containing Siklos ®

{ "type": "p", "children": [], "text": "Wear disposable gloves when handling Siklos\n \n ®or \n bottles containing Siklos\n \n ®\n" }

Dosage and Use:See prescribing information.

{ "type": "p", "children": [], "text": "\nDosage and Use:See prescribing information.\n\n " }

Distributed by Medunik USA Princeton, NJ, USA 08540

{ "type": "p", "children": [], "text": "Distributed by Medunik USA \n Princeton, NJ, USA 08540\n " }

theravia

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

NDC 71770-120-30

{ "type": "p", "children": [], "text": "NDC 71770-120-30" }

Siklos ®1,000 mg (hydroxyurea) tablets

{ "type": "p", "children": [], "text": "\nSiklos\n \n ®1,000 mg\n \n \n (hydroxyurea) \n tablets\n\n " }

1,000 mg per tablet

{ "type": "p", "children": [], "text": "\n1,000 mg per tablet\n" }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide

{ "type": "p", "children": [], "text": "\nATTENTION \n PHARMACIST: \n Each patient is \n required to receive \n the enclosed \n Medication Guide\n \n" }

30 tablets

{ "type": "p", "children": [], "text": "30 tablets" }

theravia

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

Siklos ® 100 mg (hydroxyurea) 100 mg per tablet 60 tablets

{ "type": "p", "children": [], "text": "\nSiklos\n \n ®\n 100 mg\n \n \n (hydroxyurea) \n \n100 mg per tablet\n 60 tablets\n\n " }

NDC 71770-105-60 Store at 20°C to 25°C (68°F to 77°F) Wear disposable gloves when handling Siklos ®or bottles containing Siklos ® ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide

{ "type": "p", "children": [], "text": "NDC 71770-105-60 \n Store at 20°C to 25°C (68°F to 77°F) \n Wear disposable gloves when handling Siklos\n \n ®or bottles containing Siklos\n \n ®\n\nATTENTION PHARMACIST: \n Each patient is required to \n receive the enclosed \n Medication Guide\n \n" }

RX Only. theravia

{ "type": "p", "children": [], "text": "\nRX Only.\n\ntheravia\n" }

NDC 71770-105-60 Siklos ®100 mg (hydroxyurea) tablets 100 mg per tablet

{ "type": "p", "children": [], "text": "\nNDC 71770-105-60 \n Siklos\n \n ®100 mg\n \n \n (hydroxyurea) \n tablets \n \n100 mg per tablet\n" }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide

{ "type": "p", "children": [], "text": "\nATTENTION \n PHARMACIST: \n Each patient is \n required to receive \n the enclosed \n Medication Guide\n \n" }

60 tablets

{ "type": "p", "children": [], "text": "60 tablets" }

theravia

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