SIGNIFOR is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

The recommended dosage range of SIGNIFOR is 0.3 mg to 0.9 mg by subcutaneous injection twice a day. The recommended initial dose is either 0.6 mg or 0.9 mg twice a day. Titrate dose based on response and tolerability.

Patients should be evaluated for a treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease] and should continue receiving therapy with SIGNIFOR as long as benefit is derived [see Clinical Studies  (14)]. Maximum UFC reduction is typically seen by two months of treatment  [see Clinical Studies (14)]. For patients who are started on 0.6 mg twice a day, a dosage increase to 0.9 mg twice a day may be considered based on the response to the treatment, as long as the 0.6 mg dosage is well tolerated by the patient.

Management of suspected adverse reactions may require temporary dose reduction of SIGNIFOR. Dose reduction by 0.3 mg decrements per injection is suggested.

Prior to the start of SIGNIFOR, patients should have baseline levels of the following:

Patients should also have a baseline electrocardiogram (ECG) and gallbladder ultrasound [see Warnings and Precautions (5.3, 5.5)].

Treatment of patients with poorly controlled diabetes mellitus should be intensively optimized with anti-diabetic therapy prior to starting SIGNIFOR [see Warnings and Precautions (5.2)].

For patients with moderate hepatic impairment (Child-Pugh B), the recommended initial dosage is 0.3 mg twice a day and the maximum dosage is 0.6 mg twice a day. Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)].

Instruct patients to:

Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose, 1 mL colorless glass ampule.

{ "type": "p", "children": [], "text": "Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose, 1 mL colorless glass ampule." }

None.

{ "type": "p", "children": [], "text": "None." }

Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism.

Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g., weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, or hypoglycemia). If hypocortisolism occurs, consider temporary dose reduction or interruption of treatment with SIGNIFOR, as well as temporary, exogenous glucocorticoid replacement therapy.

Blood glucose elevations have been seen in healthy volunteers and patients treated with SIGNIFOR. In the clinical study [see Clinical Studies (14)], patients developed pre-diabetes and diabetes. Nearly all patients in the study, including those with normal glucose status at baseline, pre-diabetes, and diabetes, developed worsening glycemia in the first two weeks of treatment. Cushing's disease patients with poor glycemic control (HbA1c > 8%) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g., ketoacidosis.

Assess the patient's glycemic status prior to starting treatment with SIGNIFOR. In patients with uncontrolled diabetes mellitus, optimize anti-diabetic therapy prior to SIGNIFOR initiation. Glycemic monitoring should be done every week for the first two to three months and periodically thereafter, as well as over the first two to four weeks after any dose increase. If hyperglycemia develops, initiate or adjust anti-diabetic treatment per standard of care. If uncontrolled hyperglycemia persists despite appropriate treatment, reduce the dose or discontinue SIGNIFOR and perform glycemic monitoring according to clinical practice. Patients who were initiated on anti-diabetic treatment as a result of SIGNIFOR require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia.

Bradycardia

Bradycardia has been reported with the use of SIGNIFOR  [see Adverse Reactions (6)]. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be carefully monitored. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary.

QT Prolongation

SIGNIFOR is associated with QT prolongation. In two thorough QT studies with SIGNIFOR, QT prolongation occurred at therapeutic and supra-therapeutic doses. SIGNIFOR should be used with caution in patients who are at significant risk of developing prolongation of QTc, such as those:

A baseline ECG is recommended prior to initiating therapy with SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy.

In the Phase III trial, 5% of patients had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 3 times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were 4 cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and 3 healthy volunteers [see Adverse Reactions (6)]. In these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation.

Monitoring of liver tests should be done after 1- to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If ALT is normal at baseline and elevations of ALT of 3-5 times the ULN are observed on treatment, repeat the test within a week or within 48 hours if exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3 to 5 times the baseline values are observed on treatment, repeat the test within a week or sooner if exceeding 5 times ULN. Tests should be done in a laboratory that can provide same-day results. If the values are confirmed or rising, interrupt SIGNIFOR treatment and investigate for probable cause of the findings, which may or may not be SIGNIFOR-related. Serial measures of ALT, AST, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times the baseline value in case of abnormal baselines, or 5 times the ULN in case of normal baselines. If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found.

Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR  [see Adverse Reactions (6)]. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR. Ultrasonic examination of the gallbladder before, and periodically during SIGNIFOR therapy is recommended. If complications of cholelithiasis are suspected, discontinue SIGNIFOR and treat appropriately.

As the pharmacological activity of SIGNIFOR mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function [e.g., thyroid-stimulating harmone (TSH)/free T 4, GH/IGF-1] should occur prior to initiation of therapy with SIGNIFOR and periodically during treatment should be considered as clinically appropriate. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones.

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

A total of 162 Cushing's disease patients were exposed to SIGNIFOR in the Phase III study  [see Clinical Studies (14)]. At study entry, patients were randomized to receive twice a day doses of either 0.6 mg or 0.9 mg of SIGNIFOR given subcutaneously. The mean age of patients was approximately 40 years old with a predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushing's disease (83%) and few patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment was 10.4 months (0.03-37.8) with 68% of patients having at least 6-months exposure.

In the Phase III trial, adverse reactions were reported in 98% of patients. The most common adverse reactions (frequency ≥ 20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. There were no deaths during the study. Serious adverse events were reported in 25% of patients. Adverse events leading to study discontinuation were reported in 17% of patients.

Adverse reactions with an overall frequency higher than 5% are presented in Table 1 by randomized dose group and overall. Adverse reactions are ranked by frequency, with the most frequent reactions listed first.

<div class="scrollingtable"><table> <caption> <span>Table 1 - Adverse Reactions [n (%)] With an Overall Frequency of More Than 5% in the Combined Dose Group in the Phase III Study in Cushing's Disease Patients</span> </caption> <col width="300"/> <col width="147"/> <col width="150"/> <col width="111"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="bottom"></td><td align="center" class="Toprule" valign="top">SIGNIFOR <br/> 0.6 mg twice a day <br/> N = 82 </td><td align="center" class="Toprule" valign="top">SIGNIFOR <br/> 0.9 mg twice a day <br/> N = 80 </td><td align="center" class="Toprule" valign="top">Overall <br/> <br/> N = 162 </td> </tr> <tr> <td class="Toprule">Diarrhea</td><td align="center" class="Toprule">48 (59)</td><td align="center" class="Toprule">46 (58)</td><td align="center" class="Toprule">94 (58)</td> </tr> <tr> <td>Nausea</td><td align="center">38 (46)</td><td align="center">46 (58)</td><td align="center">84 (52)</td> </tr> <tr> <td>Hyperglycemia</td><td align="center">31 (38)</td><td align="center">34 (43)</td><td align="center">65 (40)</td> </tr> <tr> <td>Cholelithiasis</td><td align="center">25 (30)</td><td align="center">24 (30)</td><td align="center">49 (30)</td> </tr> <tr> <td>Headache</td><td align="center">23 (28)</td><td align="center">23 (29)</td><td align="center">46 (28)</td> </tr> <tr> <td>Abdominal pain</td><td align="center">19 (23)</td><td align="center">20 (25)</td><td align="center">39 (24)</td> </tr> <tr> <td>Fatigue</td><td align="center">12 (15)</td><td align="center">19(24)</td><td align="center">31 (19)</td> </tr> <tr> <td>Diabetes mellitus</td><td align="center">13 (16)</td><td align="center">16 (20)</td><td align="center">29 (18)</td> </tr> <tr> <td>Injection-site reactions</td><td align="center">14 (17)</td><td align="center">14 (18)</td><td align="center">28 (17)</td> </tr> <tr> <td>Nasopharyngitis</td><td align="center">10 (12)</td><td align="center">11 (14)</td><td align="center">21 (13)</td> </tr> <tr> <td>Alopecia</td><td align="center">10 (12)</td><td align="center">10 (13)</td><td align="center">20 (12)</td> </tr> <tr> <td>Asthenia</td><td align="center">13 (16)</td><td align="center">5 (6)</td><td align="center">18 (11)</td> </tr> <tr> <td>Glycosylated hemoglobin increased</td><td align="center">10 (12)</td><td align="center">8 (10)</td><td align="center">18 (11)</td> </tr> <tr> <td>Alanine aminotransferase increased</td><td align="center">11 (13)</td><td align="center">6 (8)</td><td align="center">17 (10)</td> </tr> <tr> <td>Gamma-glutamyl transferase increased</td><td align="center">10 (12)</td><td align="center">7 (9)</td><td align="center">17 (10)</td> </tr> <tr> <td>Edema peripheral</td><td align="center">9 (11)</td><td align="center">8 (10)</td><td align="center">17 (10)</td> </tr> <tr> <td>Abdominal pain upper</td><td align="center">10 (12)</td><td align="center">6 (8)</td><td align="center">16 (10)</td> </tr> <tr> <td>Decreased appetite</td><td align="center">7 (9)</td><td align="center">9 (11)</td><td align="center">16 (10)</td> </tr> <tr> <td>Hypercholesterolemia</td><td align="center">7 (9)</td><td align="center">9 (11)</td><td align="center">16 (10)</td> </tr> <tr> <td>Hypertension</td><td align="center">8 (10)</td><td align="center">8 (10)</td><td align="center">16 (10)</td> </tr> <tr> <td>Dizziness</td><td align="center">8 (10)</td><td align="center">7 (9)</td><td align="center">15 (9)</td> </tr> <tr> <td>Hypoglycemia</td><td align="center">12 (15)</td><td align="center">3 (4)</td><td align="center">15 (9)</td> </tr> <tr> <td>Type 2 diabetes mellitus</td><td align="center">10 (12)</td><td align="center">5 (6)</td><td align="center">15 (9)</td> </tr> <tr> <td>Anxiety</td><td align="center">5 (6)</td><td align="center">9 (11)</td><td align="center">14 (9)</td> </tr> <tr> <td>Influenza</td><td align="center">9 (11)</td><td align="center">5 (6)</td><td align="center">14 (9)</td> </tr> <tr> <td>Insomnia</td><td align="center">3 (4)</td><td align="center">11 (14)</td><td align="center">14 (9)</td> </tr> <tr> <td>Myalgia</td><td align="center">10 (12)</td><td align="center">4 (5)</td><td align="center">14 (9)</td> </tr> <tr> <td>Arthralgia</td><td align="center">5 (6)</td><td align="center">8 (10)</td><td align="center">13 (8)</td> </tr> <tr> <td>Pruritus</td><td align="center">6 (7)</td><td align="center">7 (9)</td><td align="center">13 (8)</td> </tr> <tr> <td>Lipase increased</td><td align="center">7 (9)</td><td align="center">5 (6)</td><td align="center">12 (7)</td> </tr> <tr> <td>Constipation</td><td align="center">7 (9)</td><td align="center">4 (5)</td><td align="center">11 (7)</td> </tr> <tr> <td>Hypotension</td><td align="center">5 (6)</td><td align="center">6 (8)</td><td align="center">11 (7)</td> </tr> <tr> <td>Vomiting</td><td align="center">3 (4)</td><td align="center">8 (10)</td><td align="center">11 (7)</td> </tr> <tr> <td>Back pain</td><td align="center">4 (5)</td><td align="center">6 (8)</td><td align="center">10 (6)</td> </tr> <tr> <td>Dry skin</td><td align="center">5 (6)</td><td align="center">5 (6)</td><td align="center">10 (6)</td> </tr> <tr> <td>Electrocardiogram QT prolonged</td><td align="center">5 (6)</td><td align="center">5 (6)</td><td align="center">10 (6)</td> </tr> <tr> <td>Hypokalemia</td><td align="center">6 (7)</td><td align="center">4 (5)</td><td align="center">10 (6)</td> </tr> <tr> <td>Pain in extremity</td><td align="center">6 (7)</td><td align="center">4 (5)</td><td align="center">10 (6)</td> </tr> <tr> <td>Sinus bradycardia</td><td align="center">8 (10)</td><td align="center">2 (3)</td><td align="center">10 (6)</td> </tr> <tr> <td>Vertigo</td><td align="center">4 (5)</td><td align="center">6 (8)</td><td align="center">10 (6)</td> </tr> <tr> <td>Abdominal distension</td><td align="center">4 (5)</td><td align="center">5 (6)</td><td align="center">9 (6)</td> </tr> <tr> <td>Adrenal insufficiency</td><td align="center">4 (5)</td><td align="center">5 (6)</td><td align="center">9 (6)</td> </tr> <tr> <td>Aspartate aminotransferase increased</td><td align="center">6 (7)</td><td align="center">3 (4)</td><td align="center">9 (6)</td> </tr> <tr class="Last"> <td>Blood glucose increased</td><td align="center">6 (7)</td><td align="center">3 (4)</td><td align="center">9 (6)</td> </tr> </tbody> </table></div>

Other notable adverse reactions which occurred with a frequency less than 5% were: anemia (4%), blood amylase increased (2%), and prothrombin time prolonged (2%).

Gastrointestinal Disorders

Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain, and vomiting were reported frequently in the Phase III trial (see Table 1). These events began to develop primarily during the first month of treatment with SIGNIFOR and required no intervention.

Hyperglycemia and Diabetes

Hyperglycemia-related terms were reported frequently in the Phase III trial. For all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), type 2 diabetes mellitus (9%). In general, increases in FPG and HbA1c were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean FPG levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting FPG levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6. In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month 6 [see Warnings and Precautions (5.2)].

At one-month follow-up visits, following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available.

Elevated Liver Tests

In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR. Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease.

In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and 3 healthy volunteers [see Warnings and Precautions (5.4)]. In all 4 cases, the elevations were noted within the first 10 days of treatment. In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing's disease developed jaundice. All 4 cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR.

Hypocortisolism

Cases of hypocortisolism were reported in the Phase III study in Cushing's disease patients [see Adverse Reactions (6), Clinical Studies (14)]. The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy [see Warnings and Precautions (5.1)].

Injection-Site Reactions

Injection-site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing's disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention.

Thyroid Function

Hypothyroidism, with the use of SIGNIFOR, was reported for seven patients participating in the Phase III study in Cushing's disease. All seven patients presented with a TSH close to or below the lower limit at study entry, which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR.

Other Abnormal Laboratory Findings

Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the association between cholelithiasis and acute pancreatitis.

For hemoglobin levels, mean decreases that remained within normal range were observed. Also, post-baseline elevations in prothrombin time (PT) and partial thromboplastin time (PTT) were noted in 33% and 47% of patients, respectively. The PT and PTT elevations were minimal.

These laboratory findings are of unclear clinical significance.

Additional adverse reactions have been identified during postapproval use of SIGNIFOR. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drugs That Prolong QT

Coadministration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when coadministering SIGNIFOR with drugs that may prolong the QT interval [see Warnings and Precautions (5.3)].

Cyclosporine

Concomitant administration of cyclosporine with pasireotide may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary.

Bromocriptine

Coadministration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

Risk Summary

The limited data with SIGNIFOR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryo-fetal development studies in rabbits, findings indicating developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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

In embryo-fetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 4 times higher than that at the maximum therapeutic dose based on area under the curve (AUC) comparisons across species. An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 144 times the exposure in humans at the highest recommended dose of 900 mcg SIGNIFOR administered as a subcutaneous injection twice a day.

In embryo-fetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 7 times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose.

In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses, including the lowest dose (12 times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay.

Risk Summary

There is no information available on the presence of SIGNIFOR in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that pasireotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SIGNIFOR and any potential adverse effects on the breastfed child from SIGNIFOR or from the underlying maternal condition.

Data

Available data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg [ 14C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity was 0.28, based on AUC 0-∞values.

Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing's disease treated with pasireotide may lead to improved fertility.

Safety and effectiveness of SIGNIFOR have not been established in pediatric patients.

Clinical studies of SIGNIFOR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy  [see Clinical Pharmacology (12.3)].

Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C).

No dosage adjustment of SIGNIFOR in patients with impaired renal function is required [see Clinical Pharmacology (12.3)].

No cases of overdosage have been reported in patients with Cushing's disease receiving SIGNIFOR subcutaneously. Doses up to 2.1 mg twice a day have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency.

{ "type": "p", "children": [], "text": "No cases of overdosage have been reported in patients with Cushing's disease receiving SIGNIFOR subcutaneously. Doses up to 2.1 mg twice a day have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency." }

In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.

{ "type": "p", "children": [], "text": "In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms." }

Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. Contact Poison Control (1-800-222-1222) for latest recommendations.

{ "type": "p", "children": [], "text": "Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. Contact Poison Control (1-800-222-1222) for latest recommendations." }

SIGNIFOR (pasireotide) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin.

{ "type": "p", "children": [], "text": "SIGNIFOR (pasireotide) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin." }

The molecular formula of pasireotide diaspartate is C 58H 66N 10O 9• 2 C 4H 7NO 4and the molecular weight is 1313.41 g/mol. The structural formula is:

{ "type": "p", "children": [], "text": "The molecular formula of pasireotide diaspartate is C\n \n 58H\n \n 66N\n \n 10O\n \n 9• 2 C\n \n 4H\n \n 7NO\n \n 4and the molecular weight is 1313.41 g/mol. The structural formula is:\n\n " }

SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection.

{ "type": "p", "children": [], "text": "SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection." }

Each glass ampule contains:

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

<div class="scrollingtable"><table> <col width="161"/> <col width="96"/> <col width="96"/> <col width="96"/> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">*</span>corresponds to 0.3/0.6/0.9 mg pasireotide base. <br/> Note: Each ampule contains an overfill of 0.1 mL to allow accurate administration of 1 mL from the ampule. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td class="Toprule">0.3 mg</td><td class="Toprule">0.6 mg</td><td class="Toprule">0.9 mg</td> </tr> <tr> <td class="Toprule">Pasireotide diaspartate</td><td class="Toprule">0.3762 <span class="Sup">*</span></td><td class="Toprule">0.7524 <span class="Sup">*</span></td><td class="Toprule">1.1286 <span class="Sup">*</span></td> </tr> <tr> <td>Mannitol</td><td>49.50</td><td>49.50</td><td>49.50</td> </tr> <tr> <td>Tartaric acid</td><td>1.501</td><td>1.501</td><td>1.501</td> </tr> <tr> <td>Sodium hydroxide</td><td>ad pH 4.2</td><td>ad pH 4.2</td><td>ad pH 4.2</td> </tr> <tr class="Last"> <td>Water for injection</td><td>ad 1 mL</td><td>ad 1 mL</td><td>ad 1 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"161\"/>\n<col width=\"96\"/>\n<col width=\"96\"/>\n<col width=\"96\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td colspan=\"4\"><span class=\"Sup\">*</span>corresponds to 0.3/0.6/0.9 mg pasireotide base. \n <br/> Note: Each ampule contains an overfill of 0.1 mL to allow accurate administration of 1 mL from the ampule.\n \n </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\"></td><td class=\"Toprule\">0.3 mg</td><td class=\"Toprule\">0.6 mg</td><td class=\"Toprule\">0.9 mg</td>\n</tr>\n<tr>\n<td class=\"Toprule\">Pasireotide diaspartate</td><td class=\"Toprule\">0.3762\n \n <span class=\"Sup\">*</span></td><td class=\"Toprule\">0.7524\n \n <span class=\"Sup\">*</span></td><td class=\"Toprule\">1.1286\n \n <span class=\"Sup\">*</span></td>\n</tr>\n<tr>\n<td>Mannitol</td><td>49.50</td><td>49.50</td><td>49.50</td>\n</tr>\n<tr>\n<td>Tartaric acid</td><td>1.501</td><td>1.501</td><td>1.501</td>\n</tr>\n<tr>\n<td>Sodium hydroxide</td><td>ad pH 4.2</td><td>ad pH 4.2</td><td>ad pH 4.2</td>\n</tr>\n<tr class=\"Last\">\n<td>Water for injection</td><td>ad 1 mL</td><td>ad 1 mL</td><td>ad 1 mL</td>\n</tr>\n</tbody>\n</table></div>" }

SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Five human somatostatin receptor subtypes are known: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing's disease patients frequently over-express SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2.

<div class="scrollingtable"><table> <caption> <span>Table 2 - Binding Affinities of Somatostatin (SRIF-14) and Pasireotide to the Five Human Somatostatin Receptor Subtypes (SSTR1-5)</span> </caption> <col width="175"/> <col width="108"/> <col width="96"/> <col width="96"/> <col width="96"/> <col width="102"/> <tfoot> <tr class="First Last"> <td colspan="6">Results are the mean ± SEM of IC50 values expressed as nmol/L.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Compound</span></td><td align="center" class="Toprule"><span class="Bold">SSTR1</span></td><td align="center" class="Toprule"><span class="Bold">SSTR2</span></td><td align="center" class="Toprule"><span class="Bold">SSTR3</span></td><td align="center" class="Toprule"><span class="Bold">SSTR4</span></td><td align="center" class="Toprule"><span class="Bold">SSTR5</span></td> </tr> <tr> <td class="Toprule">Somatostatin (SRIF-14)</td><td align="center" class="Toprule">0.93 ± 0.12</td><td align="center" class="Toprule">0.15 ± 0.02</td><td align="center" class="Toprule">0.56 ± 0.17</td><td align="center" class="Toprule">1.5 ± 0.4</td><td align="center" class="Toprule">0.29 ± 0.04</td> </tr> <tr class="Last"> <td>Pasireotide</td><td align="center">9.3 ± 0.1</td><td align="center">1.0 ± 0.1</td><td align="center">1.5 ± 0.3</td><td align="center">&gt; 100</td><td align="center">0.16 ± 0.01</td> </tr> </tbody> </table></div>

Glucose Metabolism

In a randomized, double-blind mechanism study conducted in healthy volunteers, the development of hyperglycemia with pasireotide at doses of 0.6 mg twice a day and 0.9 mg twice a day was related to significant decreases in insulin secretion as well as incretin hormones (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

Cardiac Electrophysiology

QTcI interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide doses of 0.6 mg twice a day and 1.95 mg twice a day. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg twice a day, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg twice a day. The supra-therapeutic dose (1.95 mg twice a day) produced mean steady-state C maxvalues 3.3-fold the mean C maxfor the 0.6 mg twice a day dose in the study.

In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a dose range from 0.0025 to 1.5 mg. In Cushing's disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3 mg to 1.2 mg.

Absorption and Distribution

In healthy volunteers, pasireotide peak plasma concentration is reached within T max 0.25-0.5 hour. C maxand AUC are dose-proportional following administration of single and multiple doses.

No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via a parenteral route.

In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (V z/F > 100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.

Pasireotide has low passive permeability and is likely to be a substrate of P-glycoprotein (P-gp), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition (e.g., verapamil) did not affect the rate or extent of pasireotide availability. Pasireotide is not a substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1.

Metabolism and Excretion

Pasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine, and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs, including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine.

The clearance (CL/F) of pasireotide in healthy volunteers and Cushing's disease patients is ~7.6 L/h and ~3.8 L/h, respectively.

Steady-State Pharmacokinetics

Following multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t 1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once a day doses).

Specific Populations

Population PK analyses of SIGNIFOR indicate that race, body weight, age, and gender do not have a clinically relevant influence on PK parameters. No dose adjustment is required for demographics.

Hepatic Impairment

In a clinical study with a single subcutaneous dose of 600 mcg pasireotide in subjects with impaired hepatic function (Child-Pugh A, B, and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUC infwas increased by 12%, 56%, and 42%; and C maxincreased by 3%, 46%, and 33%, respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations (8.6), Dosage and Administration (2.3)].

Pediatric Patients

No studies have been performed in pediatric patients [see Use in Specific Populations (8.4)].

Geriatric Patients

No clinical pharmacology studies have been performed in geriatric patients.

Renal Impairment

Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical study with a single subcutaneous dose of 900 mcg pasireotide, in subjects with impaired renal function, renal impairment of mild, moderate, or severe degree or end stage renal failure, did not have a significant impact on the pharmacokinetics of pasireotide [see Use in Specific Populations (8.7)].

Drug Interaction Studies

There was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide.

Carcinogenesis

A life-time carcinogenicity study was conducted in rats and transgenic mice. Rats were given daily subcutaneous doses of pasireotide at 0.01, 0.05, 0.3 mg/kg/day for 104 weeks. There were no drug-related tumors in rats at exposures up to 7-fold higher than the maximum recommended clinical exposure at the 1.8 mg/day dose. Mice were given subcutaneous doses of pasireotide at 0.5, 1.0, 2.5 mg/kg/day for 26 weeks and did not identify any carcinogenic potential.

Mutagenesis

Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonellaand Escherichia coliand mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivorat bone marrow nucleus test.

Impairment of Fertility

Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in rats at exposures less than the human clinical exposure based on body surface area comparisons across species resulted in statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species).

A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or de novopatients for whom surgery was not indicated or who had refused surgery.

{ "type": "p", "children": [], "text": "A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or\n \n de novopatients for whom surgery was not indicated or who had refused surgery.\n\n " }

Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x ULN were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous twice a day or 0.9 mg subcutaneous twice a day. After 3 months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice a day. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg twice a day at any time during the study for intolerability.

{ "type": "p", "children": [], "text": "Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x ULN were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous twice a day or 0.9 mg subcutaneous twice a day. After 3 months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice a day. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg twice a day at any time during the study for intolerability." }

A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed 6 months of treatment.

{ "type": "p", "children": [], "text": "A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed 6 months of treatment." }

The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after 6 months of treatment and did not dose increase during this period.

{ "type": "p", "children": [], "text": "The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after 6 months of treatment and did not dose increase during this period." }

24-Hour Urinary Free Cortisol Results

{ "type": "p", "children": [], "text": "\n24-Hour Urinary Free Cortisol Results\n" }

At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg twice a day and 0.9 mg twice a day groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg twice a day and 41% in the 0.9 mg twice a day groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3.

{ "type": "p", "children": [], "text": "At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg twice a day and 0.9 mg twice a day groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg twice a day and 41% in the 0.9 mg twice a day groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3." }

<div class="scrollingtable"><table> <caption> <span>Table 3 – 24-Hour Urinary Free Cortisol Study Results at Month 6 in Patients With Cushing's Disease</span> </caption> <col width="192"/> <col width="210"/> <col width="204"/> <tbody class="Headless"> <tr class="First"> <td></td><td align="center"><span class="Bold">SIGNIFOR</span> <br/> <span class="Bold">0.6 mg twice a day</span> <br/> <span class="Bold">N = 82</span></td><td align="center"><span class="Bold">SIGNIFOR</span> <br/> <span class="Bold">0.9 mg twice a day</span> <br/> <span class="Bold">N = 80</span></td> </tr> <tr> <td class="Toprule"><span class="Bold">UFC Responders</span> <br/> <span class="Bold">     n/N</span> <br/> <span class="Bold">     % (95% CI)</span></td><td align="center" class="Toprule">12/82 <br/> 15% (7%, 22%) </td><td align="center" class="Toprule">21/80 <br/> 26% (17%, 36%) </td> </tr> <tr> <td class="Toprule"><span class="Bold">UFC Levels</span>(nmol/24 hr) <span class="Bold"> </span> <br/> <span class="Bold">  Baseline</span> <br/> <span class="Bold">     Mean (SD)</span> <br/> <span class="Bold">     Median</span></td><td align="center" class="Toprule">N = 78 <br/> <br/> 868 (764) <br/> 704 </td><td align="center" class="Toprule">N = 72 <br/> <br/> 750 (930) <br/> 470 </td> </tr> <tr class="Last"> <td class="Toprule"><span class="Bold">  % Change from baseline</span> <br/> <span class="Bold">     Mean (95% CI)</span> <br/> <span class="Bold">     Median</span></td><td align="center" class="Toprule"> <br/> -22% (-44%, +1%) <br/> -47% </td><td align="center" class="Toprule"> <br/> -42% (-50%, -33%) <br/> -46% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<caption>\n<span>Table 3 – 24-Hour Urinary Free Cortisol Study Results at Month 6 in Patients With Cushing's Disease</span>\n</caption>\n<col width=\"192\"/>\n<col width=\"210\"/>\n<col width=\"204\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td></td><td align=\"center\"><span class=\"Bold\">SIGNIFOR</span>\n<br/>\n<span class=\"Bold\">0.6 mg twice a day</span>\n<br/>\n<span class=\"Bold\">N = 82</span></td><td align=\"center\"><span class=\"Bold\">SIGNIFOR</span>\n<br/>\n<span class=\"Bold\">0.9 mg twice a day</span>\n<br/>\n<span class=\"Bold\">N = 80</span></td>\n</tr>\n<tr>\n<td class=\"Toprule\"><span class=\"Bold\">UFC Responders</span>\n<br/>\n<span class=\"Bold\">     n/N</span>\n<br/>\n<span class=\"Bold\">     % (95% CI)</span></td><td align=\"center\" class=\"Toprule\">12/82 \n <br/> 15% (7%, 22%)\n </td><td align=\"center\" class=\"Toprule\">21/80 \n <br/> 26% (17%, 36%)\n </td>\n</tr>\n<tr>\n<td class=\"Toprule\"><span class=\"Bold\">UFC Levels</span>(nmol/24 hr)\n \n <span class=\"Bold\"> </span>\n<br/>\n<span class=\"Bold\">  Baseline</span>\n<br/>\n<span class=\"Bold\">     Mean (SD)</span>\n<br/>\n<span class=\"Bold\">     Median</span></td><td align=\"center\" class=\"Toprule\">N = 78 \n <br/>\n<br/> 868 (764) \n <br/> 704\n </td><td align=\"center\" class=\"Toprule\">N = 72 \n <br/>\n<br/> 750 (930) \n <br/> 470\n </td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Toprule\"><span class=\"Bold\">  % Change from baseline</span>\n<br/>\n<span class=\"Bold\">     Mean (95% CI)</span>\n<br/>\n<span class=\"Bold\">     Median</span></td><td align=\"center\" class=\"Toprule\">\n<br/> -22% (-44%, +1%) \n <br/> -47%\n </td><td align=\"center\" class=\"Toprule\">\n<br/> -42% (-50%, -33%) \n <br/> -46%\n </td>\n</tr>\n</tbody>\n</table></div>" }

SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n = 78) who stayed in the trial, similar UFC lowering was observed at Month 12.

{ "type": "p", "children": [], "text": "SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n = 78) who stayed in the trial, similar UFC lowering was observed at Month 12." }

Note: Only patients who completed 6 months of treatment are included in this analysis (n = 110). The reference line is the ULN for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed.

{ "type": "p", "children": [], "text": "Note: Only patients who completed 6 months of treatment are included in this analysis (n = 110). The reference line is the ULN for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed." }

Other Endpoints

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

Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any anti-hypertensive medication. However, due to the fact that the study allowed initiation of anti-hypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of anti-hypertensive medication adjustments cannot be clearly established.

{ "type": "p", "children": [], "text": "Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any anti-hypertensive medication. However, due to the fact that the study allowed initiation of anti-hypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of anti-hypertensive medication adjustments cannot be clearly established." }

The mean decreases from baseline at Month 6 for weight, body mass index, and waist circumference were 4.4 kg, 1.6 kg/m 2and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations, but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.

{ "type": "p", "children": [], "text": "The mean decreases from baseline at Month 6 for weight, body mass index, and waist circumference were 4.4 kg, 1.6 kg/m\n \n 2and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations, but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.\n\n " }

SIGNIFOR is supplied as a single dose, colorless glass ampule packaged in a box of 60 ampules, arranged in 10 packs of 6 ampules each. The following packaging configurations are available.

{ "type": "p", "children": [], "text": "SIGNIFOR is supplied as a single dose, colorless glass ampule packaged in a box of 60 ampules, arranged in 10 packs of 6 ampules each. The following packaging configurations are available." }

0.3 mg/1 mL pasireotide (as diaspartate)

{ "type": "p", "children": [], "text": "\n0.3 mg/1 mL pasireotide (as diaspartate)\n" }

Box of 60 ampules NDC# 55292-131-60

{ "type": "p", "children": [], "text": "Box of 60 ampules NDC# 55292-131-60" }

0.6 mg/1 mL pasireotide (as diaspartate)

{ "type": "p", "children": [], "text": "\n0.6 mg/1 mL pasireotide (as diaspartate)\n" }

Box of 60 ampules NDC# 55292-132-60

{ "type": "p", "children": [], "text": "Box of 60 ampules NDC# 55292-132-60" }

0.9 mg/1 mL pasireotide (as diaspartate)

{ "type": "p", "children": [], "text": "\n0.9 mg/1 mL pasireotide (as diaspartate)\n" }

Box of 60 ampules NDC# 55292-133-60

{ "type": "p", "children": [], "text": "Box of 60 ampules NDC# 55292-133-60" }

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F), protect from light.

{ "type": "p", "children": [], "text": "Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F), protect from light." }

See FDA approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "See FDA approved patient labeling (Medication Guide and Instructions for Use)." }

Counsel patients on the following possible significant adverse reactions:

{ "type": "p", "children": [], "text": "Counsel patients on the following possible significant adverse reactions:" }

{ "type": "ul", "children": [ "Hypocortisolism\n \n [see Warnings and Precautions (5.1)]\n", "Hyperglycemia and Diabetes\n \n [see Warnings and Precautions (5.2)]\n", "Bradycardia and QT Prolongation\n \n [see Warnings and Precautions (5.3)]\n", "Liver Test elevations\n \n [see Warnings and Precautions (5.4)]\n", "Cholelithiasis and Complications of Cholelithiasis: Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis or cholangitis)\n \n [see Warnings and Precautions (5.5)]\n", "Pituitary Hormone Deficiency\n \n [see Warnings and Precautions (5.6)]\n", "Pregnancy: Inform female patients that treatment with SIGNIFOR may result in unintended pregnancy\n \n [see Use in Specific Populations (8.3)]\n" ], "text": "" }

Instruct the patientson the proper use of SIGNIFOR, including instructions to:

{ "type": "p", "children": [], "text": "\nInstruct the patientson the proper use of SIGNIFOR, including instructions to:\n\n " }

{ "type": "ul", "children": [ "Carefully review the Medication Guide.", "Do not reuse unused portions of SIGNIFOR ampules and properly dispose of the ampules after use.", "Avoid multiple injections at or near the same site within short periods of time." ], "text": "" }

For instructions on the use of SIGNIFOR glass ampules, refer to the Medication Guide that follows.

{ "type": "p", "children": [], "text": "For instructions on the use of SIGNIFOR glass ampules, refer to the Medication Guide that follows." }

Distributed by: Recordati Rare Diseases Inc., Lebanon, NJ 08833 U.S.A

{ "type": "p", "children": [], "text": "Distributed by: \n Recordati Rare Diseases Inc., Lebanon, NJ 08833 U.S.A\n " }

RRD-LIAM-D2020-00

{ "type": "p", "children": [], "text": "\n RRD-LIAM-D2020-00\n " }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First Last"> <td>This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: March 2020</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Medication Guide</span> <br/> <br/> <span class="Bold">SIGNIFOR</span><span class="Bold"><span class="Sup">®</span></span><span class="Bold">[sig-na-for]</span> <br/> <br/> <span class="Bold">(pasireotide)</span> <br/> <br/> <span class="Bold">Injection</span></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First">Read this Medication Guide before you start using SIGNIFOR and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What is the most important information I should know about SIGNIFOR?</span> </p> <p> <span class="Bold">SIGNIFOR can cause serious side effects, including:</span> </p> <ul> <li> <span class="Bold">Low cortisol levels in your blood (hypocortisolism)</span>. Tell your doctor right away if you have any signs and symptoms of hypocortisolism. Signs and symptoms of hypocortisolism may include: <ul> <li>weakness <br/> </li> <li>fatigue <br/> </li> <li>loss of appetite <br/> </li> <li>nausea <br/> </li> <li>vomiting <br/> </li> <li>low blood pressure <br/> </li> <li>low level of sodium in your blood <br/> </li> <li>low blood sugar</li> </ul> <br/> <br/> If you get hypocortisolism while taking SIGNIFOR, your doctor may change your dose or ask you to stop taking it. </li> </ul> <ul class="Disc"> <li> <span class="Bold">High blood sugar (hyperglycemia)</span>. Your doctor should check your blood sugar level before you start taking SIGNIFOR and while you take it. Signs and symptoms of hyperglycemia may include: <ul> <li>excessive thirst <br/> </li> <li>high urine output <br/> </li> <li>increased appetite with weight loss <br/> </li> <li>tiredness</li> </ul> <br/> <br/> If you get hyperglycemia while taking SIGNIFOR, your doctor may give you another medicine to take to lower your blood sugar. Your doctor may also change your dose of SIGNIFOR or ask you to stop taking it. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What is SIGNIFOR?</span> </p> <p>SIGNIFOR is a prescription medicine used to treat Cushing's disease in adults who cannot have surgery or have failed surgery.</p> <p>It is not known if SIGNIFOR is safe and effective in children.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What should I tell my doctor before using SIGNIFOR?</span> </p> <p> <span class="Bold">Before you take SIGNIFOR, tell your doctor if you:</span> </p> <ul class="Disc"> <li>have or have had high blood sugar (hyperglycemia) <br/> </li> <li>have diabetes <br/> </li> <li>have or have had heart problems <br/> </li> <li>have a history of low levels of potassium or magnesium in your blood <br/> </li> <li>have or have had liver problems <br/> </li> <li>have or have had gallstones <br/> </li> <li>have any other medical conditions <br/> </li> <li>are pregnant or plan to become pregnant. SIGNIFOR may harm your unborn baby. <br/> </li> <li>are breastfeeding or plan to breastfeed. It is not known if SIGNIFOR passes into your breast milk. You and your doctor should decide if you will take SIGNIFOR or breastfeed. You should not do both.</li> </ul> <p> <span class="Bold">Tell your doctor about all the medicines you take</span>, including prescription and non-prescription medicines, vitamins, and herbal supplements. </p> <p>Taking SIGNIFOR with certain other medicines can affect each other and cause side effects. Especially tell your doctor if you take:</p> <ul class="Disc"> <li>medicines to control your heart beat (anti-arrhythmics) <br/> </li> <li>medicines that can affect the electrical system of your heart (QT prolongation) <br/> </li> <li>medicines to control your blood pressure (such as beta-blockers or calcium channel blockers) <br/> </li> <li>medicines to control the electrolyte (such as potassium or magnesium) levels in your blood <br/> </li> <li>cyclosporine (Gengraf <span class="Sup">®</span>, Neoral <span class="Sup">®</span>, Restasis <span class="Sup">®</span>, Sandimmune <span class="Sup">®</span>) <br/> </li> <li>bromocriptine (Cycloset <span class="Sup">®</span>, Parlodel <span class="Sup">®</span>) </li> </ul> <p>Ask your doctor for a list of these medicines, if you are not sure.</p> <p>Know the medicines you take. Keep a list of them to show to your doctor and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">How should I use SIGNIFOR?</span> </p> <ul class="Disc"> <li>Read the <span class="Bold">"Instructions for Use"</span>at the end of this Medication Guide for information about the right way to use SIGNIFOR. <br/> </li> <li>Use SIGNIFOR exactly as your doctor tells you to. <br/> </li> <li>Your doctor may change your dose if needed. <br/> </li> <li>Before you use SIGNIFOR for the first time, your doctor should do a blood test to check your blood sugar levels and your liver tests. <br/> </li> <li>Before you use SIGNIFOR for the first time, your doctor should do a test to check your heart (electrocardiogram) and your gallbladder (ultrasound). <br/> </li> <li>SIGNIFOR should be clear and colorless. Before you inject your dose, check to make sure that SIGNIFOR is clear and colorless, and does not have any clumps or particles in it. <br/> </li> <li>SIGNIFOR is given as an injection into the fat just under your skin (subcutaneous injection). <br/> </li> <li> <span class="Bold">Do not</span>inject SIGNIFOR into skin that is red or irritated. <br/> </li> <li>The recommended injection sites for SIGNIFOR are the top of your thigh or stomach area (abdomen). <br/> </li> <li>Change (rotate) your injection site with each dose. <span class="Bold">Do not</span>inject SIGNIFOR into the exact same spot for each injection. <br/> </li> <li>Your doctor should show you how to prepare and give your dose of SIGNIFOR before you use it for the first time. <br/> </li> <li>You should not inject SIGNIFOR until your doctor has shown you how to use it the right way.</li> </ul> <p>If you take too much SIGNIFOR, tell your doctor right away.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the possible side effects of SIGNIFOR?</span> </p> <p> <span class="Bold">SIGNIFOR may cause serious side effects, including:</span> </p> <ul class="Disc"> <li> <span class="Bold">See "What is the most important information I should know about SIGNIFOR?"</span> <ul> <li> <span class="Bold">slow heart rate (bradycardia)</span>. SIGNIFOR can cause your heart to beat slower, which may cause you to feel weak, dizzy or even faint. People who have, or have had, heart problems are at higher risk for bradycardia. <br/> </li> <li> <span class="Bold">problems with the electrical system of your heart (QT interval prolongation), which can put you at risk for abnormal heart beats, dizziness, and fainting spells that can be very serious. Call your doctor right away if you experience such spells.</span> <br/> </li> <li> <span class="Bold">elevation of your liver tests</span>. Your doctor should do blood tests to monitor your liver tests while you use SIGNIFOR. <span class="Bold"></span> <br/> </li> <li> <span class="Bold">gallstones (cholelithiasis) and complications that can happen if you have gallstones</span>. Gallstones are a serious but common side effect of SIGNIFOR. Possible complications of gallstones include inflammation and infection of the gallbladder. Your doctor should do a test (ultrasound) to check for gallstones before you start using SIGNIFOR and while you use it. <br/> <br/> Tell your healthcare provider if you get any of these symptoms. <ul> <li>sudden pain in your upper right stomach area (abdomen)</li> <li>yellowing of your skin and whites of your eyes</li> <li>nausea</li> <li>sudden pain in your right shoulder or between your shoulder blades</li> <li>fever with chills</li> </ul> </li> </ul> </li> </ul> <p> <span class="Bold">The most common side effects of SIGNIFOR include:</span> </p> <ul class="Disc"> <li>diarrhea <br/> </li> <li>nausea <br/> </li> <li>high blood sugar <br/> </li> <li>headache <br/> </li> <li>abdominal pain <br/> </li> <li>fatigue <br/> </li> <li>diabetes mellitus <br/> </li> <li>injection-site reactions <br/> </li> <li>common cold <br/> </li> <li>hair loss <br/> </li> <li>weakness <br/> </li> <li>fluid retention</li> <li>Abnormal blood test result for glycosylated hemoglobin (the level of glycosylated hemoglobin indicates the average blood sugar level over the previous months)</li> </ul> <p>Tell your doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of SIGNIFOR. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">How should I store SIGNIFOR?</span> </p> <ul class="Disc"> <li>Store SIGNIFOR at 68°F to 77°F (20°C to 25°C). <br/> </li> <li>Keep SIGNIFOR out of the light.</li> </ul> <p> <span class="Bold">Keep SIGNIFOR and all medicines out of the reach of children.</span> </p> <p> <span class="Bold">General information about the safe and effective use of SIGNIFOR.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SIGNIFOR for a condition for which it was not prescribed. Do not give SIGNIFOR to other people, even if they have the same symptoms that you have. It may harm them.</p> <p>This Medication Guide summarizes the most important information about SIGNIFOR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about SIGNIFOR that is written for health professionals.</p> <p>For more information go to www.SIGNIFOR.com or call 1-888-575-8344.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the ingredients in SIGNIFOR?</span> </p> <p> <span class="Bold">Active ingredient:</span>Pasireotide </p> <p> <span class="Bold">Inactive ingredients:</span>Mannitol, sodium hydroxide, tartaric acid, and water for injection. </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td>This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: March 2020</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Medication Guide</span>\n<br/>\n<br/>\n<span class=\"Bold\">SIGNIFOR</span><span class=\"Bold\"><span class=\"Sup\">®</span></span><span class=\"Bold\">[sig-na-for]</span>\n<br/>\n<br/>\n<span class=\"Bold\">(pasireotide)</span>\n<br/>\n<br/>\n<span class=\"Bold\">Injection</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">Read this Medication Guide before you start using SIGNIFOR and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about SIGNIFOR?</span>\n</p>\n<p>\n<span class=\"Bold\">SIGNIFOR can cause serious side effects, including:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Low cortisol levels in your blood (hypocortisolism)</span>. Tell your doctor right away if you have any signs and symptoms of hypocortisolism. Signs and symptoms of hypocortisolism may include:\n \n <ul>\n<li>weakness \n <br/>\n</li>\n<li>fatigue \n <br/>\n</li>\n<li>loss of appetite \n <br/>\n</li>\n<li>nausea \n <br/>\n</li>\n<li>vomiting \n <br/>\n</li>\n<li>low blood pressure \n <br/>\n</li>\n<li>low level of sodium in your blood \n <br/>\n</li>\n<li>low blood sugar</li>\n</ul>\n<br/>\n<br/> If you get hypocortisolism while taking SIGNIFOR, your doctor may change your dose or ask you to stop taking it.\n \n </li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">High blood sugar (hyperglycemia)</span>. Your doctor should check your blood sugar level before you start taking SIGNIFOR and while you take it. Signs and symptoms of hyperglycemia may include:\n \n <ul>\n<li>excessive thirst \n <br/>\n</li>\n<li>high urine output \n <br/>\n</li>\n<li>increased appetite with weight loss \n <br/>\n</li>\n<li>tiredness</li>\n</ul>\n<br/>\n<br/> If you get hyperglycemia while taking SIGNIFOR, your doctor may give you another medicine to take to lower your blood sugar. Your doctor may also change your dose of SIGNIFOR or ask you to stop taking it.\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What is SIGNIFOR?</span>\n</p>\n<p>SIGNIFOR is a prescription medicine used to treat Cushing's disease in adults who cannot have surgery or have failed surgery.</p>\n<p>It is not known if SIGNIFOR is safe and effective in children.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my doctor before using SIGNIFOR?</span>\n</p>\n<p>\n<span class=\"Bold\">Before you take SIGNIFOR, tell your doctor if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have or have had high blood sugar (hyperglycemia) \n <br/>\n</li>\n<li>have diabetes \n <br/>\n</li>\n<li>have or have had heart problems \n <br/>\n</li>\n<li>have a history of low levels of potassium or magnesium in your blood \n <br/>\n</li>\n<li>have or have had liver problems \n <br/>\n</li>\n<li>have or have had gallstones \n <br/>\n</li>\n<li>have any other medical conditions \n <br/>\n</li>\n<li>are pregnant or plan to become pregnant. SIGNIFOR may harm your unborn baby. \n <br/>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if SIGNIFOR passes into your breast milk. You and your doctor should decide if you will take SIGNIFOR or breastfeed. You should not do both.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take</span>, including prescription and non-prescription medicines, vitamins, and herbal supplements.\n \n </p>\n<p>Taking SIGNIFOR with certain other medicines can affect each other and cause side effects. Especially tell your doctor if you take:</p>\n<ul class=\"Disc\">\n<li>medicines to control your heart beat (anti-arrhythmics) \n <br/>\n</li>\n<li>medicines that can affect the electrical system of your heart (QT prolongation) \n <br/>\n</li>\n<li>medicines to control your blood pressure (such as beta-blockers or calcium channel blockers) \n <br/>\n</li>\n<li>medicines to control the electrolyte (such as potassium or magnesium) levels in your blood \n <br/>\n</li>\n<li>cyclosporine (Gengraf\n \n <span class=\"Sup\">®</span>, Neoral\n \n <span class=\"Sup\">®</span>, Restasis\n \n <span class=\"Sup\">®</span>, Sandimmune\n \n <span class=\"Sup\">®</span>) \n <br/>\n</li>\n<li>bromocriptine (Cycloset\n \n <span class=\"Sup\">®</span>, Parlodel\n \n <span class=\"Sup\">®</span>)\n \n </li>\n</ul>\n<p>Ask your doctor for a list of these medicines, if you are not sure.</p>\n<p>Know the medicines you take. Keep a list of them to show to your doctor and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use SIGNIFOR?</span>\n</p>\n<ul class=\"Disc\">\n<li>Read the\n \n <span class=\"Bold\">\"Instructions for Use\"</span>at the end of this Medication Guide for information about the right way to use SIGNIFOR. \n <br/>\n</li>\n<li>Use SIGNIFOR exactly as your doctor tells you to. \n <br/>\n</li>\n<li>Your doctor may change your dose if needed. \n <br/>\n</li>\n<li>Before you use SIGNIFOR for the first time, your doctor should do a blood test to check your blood sugar levels and your liver tests. \n <br/>\n</li>\n<li>Before you use SIGNIFOR for the first time, your doctor should do a test to check your heart (electrocardiogram) and your gallbladder (ultrasound). \n <br/>\n</li>\n<li>SIGNIFOR should be clear and colorless. Before you inject your dose, check to make sure that SIGNIFOR is clear and colorless, and does not have any clumps or particles in it. \n <br/>\n</li>\n<li>SIGNIFOR is given as an injection into the fat just under your skin (subcutaneous injection). \n <br/>\n</li>\n<li>\n<span class=\"Bold\">Do not</span>inject SIGNIFOR into skin that is red or irritated. \n <br/>\n</li>\n<li>The recommended injection sites for SIGNIFOR are the top of your thigh or stomach area (abdomen). \n <br/>\n</li>\n<li>Change (rotate) your injection site with each dose.\n \n <span class=\"Bold\">Do not</span>inject SIGNIFOR into the exact same spot for each injection. \n <br/>\n</li>\n<li>Your doctor should show you how to prepare and give your dose of SIGNIFOR before you use it for the first time. \n <br/>\n</li>\n<li>You should not inject SIGNIFOR until your doctor has shown you how to use it the right way.</li>\n</ul>\n<p>If you take too much SIGNIFOR, tell your doctor right away.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of SIGNIFOR?</span>\n</p>\n<p>\n<span class=\"Bold\">SIGNIFOR may cause serious side effects, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">See \"What is the most important information I should know about SIGNIFOR?\"</span>\n<ul>\n<li>\n<span class=\"Bold\">slow heart rate (bradycardia)</span>. SIGNIFOR can cause your heart to beat slower, which may cause you to feel weak, dizzy or even faint. People who have, or have had, heart problems are at higher risk for bradycardia. \n <br/>\n</li>\n<li>\n<span class=\"Bold\">problems with the electrical system of your heart (QT interval prolongation), which can put you at risk for abnormal heart beats, dizziness, and fainting spells that can be very serious. Call your doctor right away if you experience such spells.</span>\n<br/>\n</li>\n<li>\n<span class=\"Bold\">elevation of your liver tests</span>. Your doctor should do blood tests to monitor your liver tests while you use SIGNIFOR.\n \n <span class=\"Bold\"></span>\n<br/>\n</li>\n<li>\n<span class=\"Bold\">gallstones (cholelithiasis) and complications that can happen if you have gallstones</span>. Gallstones are a serious but common side effect of SIGNIFOR. Possible complications of gallstones include inflammation and infection of the gallbladder. Your doctor should do a test (ultrasound) to check for gallstones before you start using SIGNIFOR and while you use it. \n <br/>\n<br/> Tell your healthcare provider if you get any of these symptoms.\n \n <ul>\n<li>sudden pain in your upper right stomach area (abdomen)</li>\n<li>yellowing of your skin and whites of your eyes</li>\n<li>nausea</li>\n<li>sudden pain in your right shoulder or between your shoulder blades</li>\n<li>fever with chills</li>\n</ul>\n</li>\n</ul>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of SIGNIFOR include:</span>\n</p>\n<ul class=\"Disc\">\n<li>diarrhea \n <br/>\n</li>\n<li>nausea \n <br/>\n</li>\n<li>high blood sugar \n <br/>\n</li>\n<li>headache \n <br/>\n</li>\n<li>abdominal pain \n <br/>\n</li>\n<li>fatigue \n <br/>\n</li>\n<li>diabetes mellitus \n <br/>\n</li>\n<li>injection-site reactions \n <br/>\n</li>\n<li>common cold \n <br/>\n</li>\n<li>hair loss \n <br/>\n</li>\n<li>weakness \n <br/>\n</li>\n<li>fluid retention</li>\n<li>Abnormal blood test result for glycosylated hemoglobin (the level of glycosylated hemoglobin indicates the average blood sugar level over the previous months)</li>\n</ul>\n<p>Tell your doctor if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all the possible side effects of SIGNIFOR. For more information, ask your doctor or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store SIGNIFOR?</span>\n</p>\n<ul class=\"Disc\">\n<li>Store SIGNIFOR at 68°F to 77°F (20°C to 25°C). \n <br/>\n</li>\n<li>Keep SIGNIFOR out of the light.</li>\n</ul>\n<p>\n<span class=\"Bold\">Keep SIGNIFOR and all medicines out of the reach of children.</span>\n</p>\n<p>\n<span class=\"Bold\">General information about the safe and effective use of SIGNIFOR.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SIGNIFOR for a condition for which it was not prescribed. Do not give SIGNIFOR to other people, even if they have the same symptoms that you have. It may harm them.</p>\n<p>This Medication Guide summarizes the most important information about SIGNIFOR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about SIGNIFOR that is written for health professionals.</p>\n<p>For more information go to www.SIGNIFOR.com or call 1-888-575-8344.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in SIGNIFOR?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span>Pasireotide\n \n </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span>Mannitol, sodium hydroxide, tartaric acid, and water for injection.\n \n </p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

RRD-LIAM-D2020-00

{ "type": "p", "children": [], "text": "RRD-LIAM-D2020-00" }

Instructions for Use

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

SIGNIFOR®[sig-na-for]

{ "type": "p", "children": [], "text": "\nSIGNIFOR®[sig-na-for]\n" }

(pasireotide)

{ "type": "p", "children": [], "text": "\n(pasireotide)\n" }

Injection

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

Supplies you will need to give your SIGNIFOR injection:

{ "type": "p", "children": [], "text": "\nSupplies you will need to give your SIGNIFOR injection:\n" }

{ "type": "ul", "children": [ "1 SIGNIFOR ampule (See Figure A)", "1 sterile syringe (See Figure B)", "1 long sterile needle (See Figure B)\n \n \nThis needle is used to draw up your SIGNIFOR from the ampule. You should only use this needle if your doctor or nurse tells you to.\n\n", "1 short sterile needle (See Figure B)", "Alcohol wipes", "1 cotton ball or gauze", "A sharps disposal container or other closeable, puncture resistant disposal container" ], "text": "" }

Getting started:

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

Step 1:Wash your hands well with soap and water and dry them.

{ "type": "p", "children": [], "text": "\nStep 1:Wash your hands well with soap and water and dry them.\n\n " }

Step 2:Take 1 SIGNIFOR ampule out of the box.

{ "type": "p", "children": [], "text": "\nStep 2:Take 1 SIGNIFOR ampule out of the box.\n\n " }

Step 3:Look at the SIGNIFOR ampule. Check that the ampule is not cracked or broken and that the liquid medicine in the ampule is clear and colorless.

{ "type": "p", "children": [], "text": "\nStep 3:Look at the SIGNIFOR ampule. Check that the ampule is not cracked or broken and that the liquid medicine in the ampule is clear and colorless.\n\n " }

Do notuse SIGNIFOR if the ampule is cracked or broken or if the liquid looks cloudy or contains particles. Take the whole box back to the pharmacy and get a new one.

{ "type": "p", "children": [], "text": "\nDo notuse SIGNIFOR if the ampule is cracked or broken or if the liquid looks cloudy or contains particles. Take the whole box back to the pharmacy and get a new one.\n\n " }

Ampules should be opened just prior to administration and any unused portion discarded.

{ "type": "p", "children": [], "text": "Ampules should be opened just prior to administration and any unused portion discarded." }

Step 4:Check the dose and expiration date printed on the ampule (See Figure C).

{ "type": "p", "children": [], "text": "\nStep 4:Check the dose and expiration date printed on the ampule (See Figure C).\n\n " }

Preparing your SIGNIFOR dose:

{ "type": "p", "children": [], "text": "\nPreparing your SIGNIFOR dose:\n" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 5:</span>Hold the SIGNIFOR ampule at the bottom with 1 hand. With your other hand, tap the top of the SIGNIFOR ampule with your finger to make sure there is no liquid in the top of the ampule when you open it (See Figure D). </td><td align="center" class="Rrule Toprule" valign="bottom"><img alt="Figure D" src="/dailymed/image.cfm?name=signifor-05.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure D </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 5:</span>Hold the SIGNIFOR ampule at the bottom with 1 hand. With your other hand, tap the top of the SIGNIFOR ampule with your finger to make sure there is no liquid in the top of the ampule when you open it (See Figure D).\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\"><img alt=\"Figure D\" src=\"/dailymed/image.cfm?name=signifor-05.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure D\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 6:</span>Hold the ampule with 1 hand. With your other hand, hold the top of the ampule and <span class="Bold"></span>pull it sideways until the top snaps off at the line marked on the ampule neck (See Figure E). <ul class="Disc"> <li>Put the ampule upright on a clean and flat surface.</li> </ul> </td><td align="center" class="Rrule Toprule" valign="bottom"><img alt="Figure E" src="/dailymed/image.cfm?name=signifor-06.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure E </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 6:</span>Hold the ampule with 1 hand. With your other hand, hold the top of the ampule and\n \n <span class=\"Bold\"></span>pull it sideways until the top snaps off at the line marked on the ampule neck (See Figure E).\n \n <ul class=\"Disc\">\n<li>Put the ampule upright on a clean and flat surface.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\"><img alt=\"Figure E\" src=\"/dailymed/image.cfm?name=signifor-06.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure E\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 7:</span>Open the sterile needle package. Place the needle on the top of the syringe. Push down on the needle and twist it clockwise until it is tight (See Figure F). <ul class="Disc"> <li>If you have been told to use 1 long and 1 short needle, you should use the long needle for this step.</li> </ul> </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <img alt="Figure F" src="/dailymed/image.cfm?name=signifor-07.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure F </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 7:</span>Open the sterile needle package. Place the needle on the top of the syringe. Push down on the needle and twist it clockwise until it is tight (See Figure F).\n \n <ul class=\"Disc\">\n<li>If you have been told to use 1 long and 1 short needle, you should use the long needle for this step.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<img alt=\"Figure F\" src=\"/dailymed/image.cfm?name=signifor-07.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure F\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 8:</span>Pull the needle cover straight off the sterile needle (See Figure G). </td><td align="center" class="Rrule Toprule" valign="bottom"><img alt="Figure G" src="/dailymed/image.cfm?name=signifor-08.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure G </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 8:</span>Pull the needle cover straight off the sterile needle (See Figure G).\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\"><img alt=\"Figure G\" src=\"/dailymed/image.cfm?name=signifor-08.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure G\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 9:</span>Put the needle into the ampule making sure you do not touch the outside of the ampule and pull up on the plunger to draw up all of the SIGNIFOR liquid into the syringe (See Figure H). <ul class="Disc"> <li>If you have been told to use 1 long and 1 short needle, you should now take the long needle off of the syringe and put on the short one.</li> </ul> </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <br/> <br/> <img alt="Figure H" src="/dailymed/image.cfm?name=signifor-09.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure H </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 9:</span>Put the needle into the ampule making sure you do not touch the outside of the ampule and pull up on the plunger to draw up all of the SIGNIFOR liquid into the syringe (See Figure H).\n \n <ul class=\"Disc\">\n<li>If you have been told to use 1 long and 1 short needle, you should now take the long needle off of the syringe and put on the short one.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<br/>\n<br/>\n<img alt=\"Figure H\" src=\"/dailymed/image.cfm?name=signifor-09.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure H\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 10:</span>Hold the syringe upright in 1 hand between 2 fingers with your thumb at the bottom of the plunger. With your other hand, tap the syringe with your finger to get rid of air bubbles (See Figure I). </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <img alt="Figure I" src="/dailymed/image.cfm?name=signifor-0A.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure I </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 10:</span>Hold the syringe upright in 1 hand between 2 fingers with your thumb at the bottom of the plunger. With your other hand, tap the syringe with your finger to get rid of air bubbles (See Figure I).\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<img alt=\"Figure I\" src=\"/dailymed/image.cfm?name=signifor-0A.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure I\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 11:</span>Push up on the plunger until you see a drop of liquid on the tip of the needle (See Figure J). <ul class="Disc"> <li>Do not let the needle touch anything. You are now ready to inject your dose of SIGNIFOR.</li> </ul> </td><td align="center" class="Rrule Toprule" valign="bottom"><img alt="Figure J" src="/dailymed/image.cfm?name=signifor-0B.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure J </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 11:</span>Push up on the plunger until you see a drop of liquid on the tip of the needle (See Figure J).\n \n <ul class=\"Disc\">\n<li>Do not let the needle touch anything. You are now ready to inject your dose of SIGNIFOR.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\"><img alt=\"Figure J\" src=\"/dailymed/image.cfm?name=signifor-0B.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure J\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

Injecting your SIGNIFOR dose:

{ "type": "p", "children": [], "text": "\nInjecting your SIGNIFOR dose:\n" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 12:</span>Choose your injection site and wipe the site with an alcohol wipe (See Figure K). Let the site dry. </td><td align="center" class="Rrule Toprule" valign="bottom"><img alt="Figure K" src="/dailymed/image.cfm?name=signifor-0C.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure K </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 12:</span>Choose your injection site and wipe the site with an alcohol wipe (See Figure K). Let the site dry.\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\"><img alt=\"Figure K\" src=\"/dailymed/image.cfm?name=signifor-0C.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure K\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 13:</span>With 1 hand, gently pinch the skin at the injection site you have chosen and wiped with an alcohol wipe. With your other hand, pick up the syringe and hold it like a pencil. Insert the needle into the pinched skin at a 45 degree angle using a quick dart like motion (See Figure L). <ul class="Disc"> <li> <span class="Bold">Do not</span>let go of the skin. </li> </ul> </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <img alt="Figure L" src="/dailymed/image.cfm?name=signifor-0D.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure L </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 13:</span>With 1 hand, gently pinch the skin at the injection site you have chosen and wiped with an alcohol wipe. With your other hand, pick up the syringe and hold it like a pencil. Insert the needle into the pinched skin at a 45 degree angle using a quick dart like motion (See Figure L).\n \n <ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span>let go of the skin.\n \n </li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<img alt=\"Figure L\" src=\"/dailymed/image.cfm?name=signifor-0D.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure L\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 14:</span>Gently press the plunger all the way down, until the syringe is empty (See Figure M). </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <br/> <br/> <img alt="Figure M" src="/dailymed/image.cfm?name=signifor-0E.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure M </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 14:</span>Gently press the plunger all the way down, until the syringe is empty (See Figure M).\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<br/>\n<br/>\n<img alt=\"Figure M\" src=\"/dailymed/image.cfm?name=signifor-0E.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure M\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 15:</span>When the syringe is empty, <span class="Bold"></span>slowly let go of the skin and gently pull the needle out of the skin (See Figure N). </td><td align="center" class="Rrule Toprule" valign="bottom"> <br/> <br/> <img alt="Figure N" src="/dailymed/image.cfm?name=signifor-0F.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74"/><br/> <br/> Figure N </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 15:</span>When the syringe is empty,\n \n <span class=\"Bold\"></span>slowly let go of the skin and gently pull the needle out of the skin (See Figure N).\n \n </td><td align=\"center\" class=\"Rrule Toprule\" valign=\"bottom\">\n<br/>\n<br/>\n<img alt=\"Figure N\" src=\"/dailymed/image.cfm?name=signifor-0F.jpg&amp;setid=a09a25fc-a5a3-0c82-e053-2995a90a5d74\"/><br/>\n<br/> Figure N\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table> <col width="360"/> <col width="336"/> <tbody class="Headless"> <tr class="First Last"> <td class="Lrule Toprule"><span class="Bold">Step 16:</span>Place a cotton ball or gauze over the injection site and press for about 5 seconds. <span class="Bold">Do not</span>massage the injection site. <ul class="Disc"> <li>If there is bleeding, cover it with a bandage.</li> </ul> </td><td align="center" class="Rrule Toprule"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"360\"/>\n<col width=\"336\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Lrule Toprule\"><span class=\"Bold\">Step 16:</span>Place a cotton ball or gauze over the injection site and press for about 5 seconds.\n \n <span class=\"Bold\">Do not</span>massage the injection site.\n \n <ul class=\"Disc\">\n<li>If there is bleeding, cover it with a bandage.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule Toprule\"></td>\n</tr>\n</tbody>\n</table></div>" }

After injecting your SIGNIFOR dose:

{ "type": "p", "children": [], "text": "\nAfter injecting your SIGNIFOR dose:\n" }

{ "type": "ul", "children": [ "Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.\n \n \nIf you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n \n \nmade of a heavy-duty plastic,\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\nupright and stable during use,\nleak-resistant, and\nproperly labeled to warn of hazardous waste inside the container.\n\n\nWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at:\n \n http://www.fda.gov/safesharpsdisposal.\n \n \n\nDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.\n\n" ], "text": "" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: March 2020

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: March 2020" }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

Recordati Rare Diseases Inc., Lebanon, NJ 08833 U.S.A

{ "type": "p", "children": [], "text": "Recordati Rare Diseases Inc., Lebanon, NJ 08833 U.S.A" }

RRD-LIAM-D2020-00

{ "type": "p", "children": [], "text": "RRD-LIAM-D2020-00" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Package Label –0.3 mg/mL

{ "type": "p", "children": [], "text": "\nPackage Label –0.3 mg/mL\n" }

Rx Only NDC 55292-131-60 Signifor® (pasireotide) Injection 0.3 mg/mL For subcutaneous use only Dispense with enclosed Medication Guide. 60 ampules (10 packs of 6 ampules)

{ "type": "p", "children": [], "text": "Rx Only NDC 55292-131-60 \n \n Signifor® \n \n (pasireotide) Injection \n \n 0.3 mg/mL \n \n For subcutaneous use only \n \n Dispense with enclosed Medication Guide. \n \n 60 ampules (10 packs of 6 ampules)\n " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Package Label –0.6 mg/mL

{ "type": "p", "children": [], "text": "\nPackage Label –0.6 mg/mL\n" }

Rx Only NDC 55292-132-60 Signifor® (pasireotide) Injection 0.6 mg/mL For subcutaneous use only Dispense with enclosed Medication Guide. 60 ampules (10 packs of 6 ampules)

{ "type": "p", "children": [], "text": "Rx Only NDC 55292-132-60 \n \n Signifor® \n \n (pasireotide) Injection \n \n 0.6 mg/mL \n \n For subcutaneous use only \n \n Dispense with enclosed Medication Guide. \n \n 60 ampules (10 packs of 6 ampules)\n " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Package Label –0.9 mg/mL

{ "type": "p", "children": [], "text": "\nPackage Label –0.9 mg/mL\n" }

Rx Only NDC 55292-133-60 Signifor® (pasireotide) Injection 0.9 mg/mL For subcutaneous use only Dispense with enclosed Medication Guide. 60 ampules (10 packs of 6 ampules)

{ "type": "p", "children": [], "text": "Rx Only NDC 55292-133-60 \n \n Signifor® \n \n (pasireotide) Injection \n \n 0.9 mg/mL \n \n For subcutaneous use only \n \n Dispense with enclosed Medication Guide. \n \n 60 ampules (10 packs of 6 ampules)\n " }

SIGNIFOR LAR is indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

SIGNIFOR LAR is indicated for the treatment of patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

Prior to the initiation of SIGNIFOR LAR, it is recommended that patients have the following baseline evaluations:

Patients with poorly controlled diabetes mellitus, who have inadequate glucose control, should have anti-diabetic therapy optimized prior to starting SIGNIFOR LAR [see Warnings and Precautions (5.1)].

SIGNIFOR LAR must be reconstituted by a trained healthcare professional immediately before use. Illustrations on reconstitution are found in Instructions for Use [see Dosage and Administration (2.6)].

SIGNIFOR LAR must be inspected visually before use. The suspension should appear free of foreign particulates and should be homogeneous after mixing.

SIGNIFOR LAR must be administered by a trained healthcare professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR LAR must never be administered intravenously.

Acromegaly

The recommended initial dose of SIGNIFOR LAR for the treatment of acromegaly is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6)].

Cushing's Disease

The recommended initial dose of SIGNIFOR LAR for the treatment of Cushing's disease is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6)].

Acromegaly

The dose may be increased to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age and sex adjusted insulin-like growth factor-1 (IGF-1) levels after 3 months of treatment with SIGNIFOR LAR at 40 mg and who tolerate this dose.

Management of SIGNIFOR LAR-related adverse reactions or over-response to treatment (age and sex adjusted IGF-1 less than the lower limit of normal) may require dose reduction. The dose may be decreased, either temporarily or permanently, by 20 mg decrements [see Warnings and Precautions (5)].

Cushing's Disease

Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hour urinary free cortisol (UFC) and who tolerate this dose, up to a maximum dose of 40 mg once every 28 days.

Management of suspected adverse reactions or over-response to treatment (e.g., cortisol levels less than the lower limit of the normal range or in the low part of the normal range in patients with symptoms suggestive of adrenal insufficiency) may require dose reduction to the previous tolerated dose, dose interruption, or drug discontinuation of SIGNIFOR LAR. For patients treated with 10 mg once every 28 days, the dose may be either interrupted or discontinued [see Warnings and Precautions (5)].

For patients with moderately impaired hepatic function (Child-Pugh B) [see Use in Specific Populations (8.6)]:

Avoid use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)].

After reconstitution of the SIGNIFOR LAR vial with the provided 2 mL diluent, the intramuscular injectable suspension will have a final concentration of:

<div class="scrollingtable"><table> <colgroup> <col width="200"/> <col width="300"/> <col width="200"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"><span class="Bold">Strength per Vial</span></td><td align="center" class="Toprule"><span class="Bold">Final Concentration When Reconstituted<br/> <br/> (total product strength per total volume) </span></td><td align="center" class="Toprule"><span class="Bold">Final Concentration When<br/> <br/> Reconstituted (per mL) </span></td> </tr> <tr> <td align="center" class="Toprule">10 mg</td><td align="center" class="Toprule">10 mg/2 mL</td><td align="center" class="Toprule">5 mg/mL</td> </tr> <tr> <td align="center">20 mg</td><td align="center">20 mg/2 mL</td><td align="center">10 mg/mL</td> </tr> <tr> <td align="center">30 mg</td><td align="center">30 mg/2 mL</td><td align="center">15 mg/mL</td> </tr> <tr> <td align="center">40 mg</td><td align="center">40 mg/2 mL</td><td align="center">20 mg/mL</td> </tr> <tr class="Last"> <td align="center">60 mg</td><td align="center">60 mg/2 mL</td><td align="center">30 mg/mL</td> </tr> </tbody> </table></div>

The entire contents of the reconstituted solution should be administered immediately.

<div class="scrollingtable"><table> <colgroup> <col width="1000"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center"><span class="Bold">PAY PARTICULAR ATTENTION:</span></td> </tr> <tr> <td>There are 2 critical steps in the reconstitution of SIGNIFOR LAR. <span class="Bold"><span class="Underline">Not following these 2 steps could result in failure to deliver the drug appropriately</span>.</span> <br/> </td> </tr> <tr> <td><span class="Bold">1) </span><span class="Bold"><span class="Underline">The injection kit must reach room temperature (see <a href="#step1">Step 1</a> in Instructions for Use)</span>.</span> Remove the SIGNIFOR LAR injection kit from refrigerated storage and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours.<br/> </td> </tr> <tr class="Last"> <td><span class="Bold">2) </span>After adding the diluent solution, <span class="Bold"><span class="Underline">shake the vial moderately</span></span> in a horizontal direction for a minimum of 30 seconds <span class="Bold"><span class="Underline">until uniform suspension is formed (see Step 4 in Instructions for Use)</span></span>.<br/> </td> </tr> </tbody> </table></div>

The following items are included in the injection kit:

a) One vial containing SIGNIFOR LAR powder

b) One prefilled syringe containing the diluent solution for reconstitution

c) One vial adapter for drug product reconstitution

d) One safety injection needle (20G x 1.5")

Figure 1. Items Included in Injection Kit

SIGNIFOR LAR suspension must only be reconstituted immediately before administration.

Follow the directions in the Instructions for Use to ensure proper reconstitution of SIGNIFOR LAR before intramuscular injection.

SIGNIFOR LAR should only be administered by a trained healthcare professional.

<div class="scrollingtable"><table> <colgroup> <col width="500"/> <col width="300"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" colspan="2"><span class="Bold">Instructions for Use</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold"><a name="step1"></a>Step 1</span> <br/> <br/> <br/> <br/> Remove the SIGNIFOR LAR for injectable suspension kit from refrigerated storage.<br/> <br/> <br/> <br/> <span class="Bold">PAY PARTICULAR ATTENTION: It is essential to start the reconstitution process only after the injection kit has reached room temperature. Let the kit stand at room temperature for at least 30 minutes before starting reconstitution, but not more than 24 hours.</span> <br/> <br/> <br/> <br/> Note: The kit can be re-refrigerated if needed.</td><td class="Botrule Lrule Rrule Toprule"><img alt="Step 1" src="/dailymed/image.cfm?name=signiforLAR-04.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 2</span> <br/> <br/> <br/> <br/> Remove the plastic cap from the vial and clean the rubber stopper with an alcohol wipe.</td><td class="Lrule Rrule Toprule"><img alt="Step 2" src="/dailymed/image.cfm?name=signiforLAR-05.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule">Remove the lid film of the vial adapter packaging, <span class="Bold">but do NOT</span> remove the vial adapter from its packaging.<br/> <br/> <br/> <br/> Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place. You will hear an audible "click" when the vial adapter snaps in place.</td><td class="Lrule Rrule"><img alt="Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging." src="/dailymed/image.cfm?name=signiforLAR-06.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule">Lift the packaging off the vial adapter with a vertical movement.</td><td class="Lrule Rrule"><img alt="Lift the packaging off the vial adapter with a vertical movement. " src="/dailymed/image.cfm?name=signiforLAR-07.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 3</span> <br/> <br/> <br/> <br/> Remove the cap from the syringe prefilled with diluent solution and <span class="Bold">screw</span> the syringe onto the vial adapter.</td><td class="Lrule Rrule Toprule"><img alt="Step 3" src="/dailymed/image.cfm?name=signiforLAR-08.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule">Slowly push the plunger all the way down to transfer all the diluent solution in the vial.</td><td class="Lrule Rrule"><img alt="Slowly push the plunger all the way down to transfer all the diluent solution in the vial." src="/dailymed/image.cfm?name=signiforLAR-09.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 4</span> <br/> <br/> <br/> <br/> <span class="Bold">ATTENTION:</span> Keep the plunger pressed and shake the vial <span class="Bold">moderately</span> in a <span class="Underline">horizontal</span> direction <span class="Bold">for a minimum of 30 seconds</span> so that the powder is <span class="Underline">completely suspended</span>. <span class="Bold">Repeat moderate shaking for another 30 seconds if the powder is not completely suspended</span>.</td><td class="Lrule Rrule Toprule"><img alt="Step 4" src="/dailymed/image.cfm?name=signiforLAR-10.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 5</span> <br/> <br/> <br/> <br/> Turn the syringe and vial upside down, <span class="Bold">slowly</span> pull the plunger back and draw the entire content from the vial into the syringe.</td><td class="Lrule Rrule Toprule"><img alt="Step 5" src="/dailymed/image.cfm?name=signiforLAR-11.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule">Unscrew the syringe from the vial adapter.</td><td class="Lrule Rrule"><img alt="Unscrew the syringe from the vial adapter." src="/dailymed/image.cfm?name=signiforLAR-12.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 6</span> <br/> <br/> <br/> <br/> Screw the safety injection needle onto the syringe.</td><td class="Lrule Rrule Toprule"><img alt="Step 6" src="/dailymed/image.cfm?name=signiforLAR-13.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule">Pull the protective cover straight off the needle.<br/> <br/> <br/> <br/> To avoid sedimentation and maintain a uniform suspension, you may gently shake the syringe.<br/> <br/> <br/> <br/> Gently tap the syringe to remove any visible bubbles and expel them from the syringe.<br/> <br/> <br/> <br/> The reconstituted SIGNIFOR LAR is now ready for <span class="Bold">immediate</span> administration.</td><td class="Lrule Rrule"><img alt="Pull the protective cover straight off the needle." src="/dailymed/image.cfm?name=signiforLAR-14.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Step 7</span> <br/> <br/> <br/> <br/> SIGNIFOR LAR must only be given by intramuscular injection and <span class="Bold">NEVER</span> intravenously.<br/> <br/> <br/> <br/> Prepare the injection site by wiping with an alcohol wipe.<br/> <br/> <br/> <br/> Insert the needle fully into the left or right gluteus at a 90° angle to the skin.<br/> <br/> <br/> <br/> Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated).<br/> <br/> <br/> <br/> Slowly depress the plunger until the syringe is empty. Withdraw the needle from the injection site and activate the safety guard (as shown in Step 8).</td><td class="Lrule Rrule Toprule"><img alt="Step 7" src="/dailymed/image.cfm?name=signiforLAR-15.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule"><span class="Bold">Step 8</span> <br/> <br/> <br/> <br/> Activate the safety guard over the needle using 1 of the 2 methods shown:<br/> <br/> <br/> <br/> • either press the hinged section of the safety guard down onto a hard surface (Figure A),<br/> <br/> <br/> <br/> • or push the hinge forward with your finger (Figure B).<br/> <br/> <br/> <br/> An audible "click" will confirm proper activation of the safety guard.<br/> <br/> <br/> <br/> Dispose of syringe immediately in a sharps container.<br/> <br/> Any unused product or waste material should be disposed of in accordance with local requirements.</td><td class="Lrule Rrule Toprule"><img alt="Step 8" src="/dailymed/image.cfm?name=signiforLAR-16.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> </tbody> </table></div>

If a dose is missed and the patient returns prior to the next scheduled dose, a dose may be given up to but no later than 14 days prior to the next dose.

SIGNIFOR LAR for injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, or 60 mg of slightly yellow to yellow powder in a vial and 2 mL diluent.

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None.

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SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes.

In the acromegalic patient study, 5 patients naïve to drug therapy treated with SIGNIFOR LAR (2 of whom were normoglycemic at baseline) and none in the active comparator group were hospitalized for hyperglycemia (blood glucose range 359-506 mg/dL). Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial, were hospitalized for elevated glucose levels while on SIGNIFOR LAR; one of those patients developed diabetic ketoacidosis. In the Cushing's disease study, 2 patients were hospitalized for elevated blood glucose.

In clinical studies for acromegaly and Cushing's disease, SIGNIFOR LAR caused an increase in the incidence of diabetes and prediabetes. A majority of patients, including those with normal glucose tolerance, prediabetes and diabetes, experienced increased glucose levels within the first 3 months of treatment [see Adverse Reactions (6.1)]. In the drug-naïve acromegaly study, the prevalence of diabetes increased from 30% at baseline to 60% at Month 12. In the study evaluating acromegaly patients previously treated with somatostatin analogs, the prevalence of diabetes increased from 71% at baseline to 87% at Month 6 in patients treated with SIGNIFOR LAR 40 mg, and from 60% to 84% in patients treated with SIGNIFOR LAR 60 mg. In the Cushing's disease study, the prevalence of diabetes increased from 40% at baseline to 56% at Month 12.

Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess FPG and HbA1c prior to starting treatment with SIGNIFOR LAR [see Dosage and Administration (2.1)]. In patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before SIGNIFOR LAR initiation. Monitor blood glucose weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4- to 6 weeks after dose increases. Continue monitoring thereafter, as clinically appropriate.

Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose of SIGNIFOR LAR or discontinue SIGNIFOR LAR. Assess FPG and HbA1c after SIGNIFOR LAR discontinuation, if indicated. Patients receiving anti-diabetic treatment may require more frequent blood glucose monitoring and dose adjustment to their anti-diabetic drug therapy to mitigate the risk of hypoglycemia after discontinuing SIGNIFOR LAR.

Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. In some reported post-marketing cases of ketoacidosis in patients taking SIGNIFOR LAR, factors predisposing to ketoacidosis such as acute illness, infection, pancreatic disorders (e.g., pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

Bradycardia

Bradycardia has been reported with the use of SIGNIFOR LAR [see Adverse Reactions (6.1)]. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment.

QT Prolongation

In cardiac electrophysiology studies (i.e., thorough QT studies) with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses [see Clinical Pharmacology (12.2)].

In the clinical studies, a corrected QT interval (i.e., QTcF) of greater than 480 ms was reported in 6 patients and an increase in the QTcF from baseline of greater than 60 ms was reported for seven patients on SIGNIFOR LAR. No patient on SIGNIFOR LAR had a QTcF value of greater than 500 ms [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

SIGNIFOR LAR should be used with caution in patients who are at significant risk of developing prolongation of the QT interval, such as those listed below:

A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR. Monitoring for an effect on the QT interval at the time of maximum drug concentration (21 days after injection) should be obtained in patients at risk. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.

Increases in liver enzymes have been observed with SIGNIFOR LAR. In all Phase 3 acromegaly studies and across all doses, alanine aminostransferase (ALT) or aspartate aminotransferase (AST) elevations greater than 3 times the upper limit of normal (ULN) were observed in 4% of acromegaly patients and ALT or AST elevations greater than 5 times the ULN were observed in 1% of acromegaly patients treated with SIGNIFOR LAR.

In the Phase 3 Cushing's disease study and across all doses, ALT or AST elevations greater than 3 times the ULN were observed in 14% of Cushing's disease patients and ALT or AST elevations greater than 5 times the ULN were observed in 5% of Cushing's disease patients treated with SIGNIFOR LAR.

Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR , and after the first 2- to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels, should be monitored until values return to pre-treatment levels. Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop. Following discontinuation of treatment with SIGNIFOR LAR, patients should be monitored until resolution. Treatment should not be restarted, if the liver function abnormalities are suspected to be related to SIGNIFOR LAR.

Cholelithiasis was reported in 33% of drug-naïve and 10% of inadequately controlled (40 mg dose) acromegaly patients treated with SIGNIFOR LAR in clinical trials [see Adverse Reactions (6)]. Cholelithiasis was reported in 33% of Cushing's disease patients treated with SIGNIFOR LAR. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue SIGNIFOR LAR and treat appropriately.

Suppression of anterior pituitary hormones may occur on SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected, it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses.

New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including pasireotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving SIGNIFOR LAR, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.

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

Drug-Naïve Patients With Acromegaly

The data described in Table 1 are derived from an active-controlled trial in patients with acromegaly naïve to previous drug therapy [see Clinical Studies (14.1)]. The data reflect exposure of 178 patients with acromegaly to SIGNIFOR LAR for a mean duration of 43 weeks. In the overall study population, 52% were female and the average age of patients was 45 years.

Table 1 presents common adverse reactions associated with SIGNIFOR LAR in this study. These adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR.

<div class="scrollingtable"><table> <caption> <span>Table 1 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Naïve to Drug Therapy</span> </caption> <colgroup> <col width="300"/> <col width="250"/> <col width="250"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">a</span>Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus.<br/> <br/> <span class="Sup">b</span>Sinus bradycardia includes the following PTs: bradycardia and sinus bradycardia.<br/> <br/> <span class="Sup">c</span>Injection-site reaction related AEs includes the following PTs: injection-site pain, injection-site reaction, injection-site haematoma, injection-site pruritus, injection-site swelling, injection-site erythema.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Rrule Toprule"><span class="Bold">Adverse Reaction Type</span></td><td align="center" class="Rrule Toprule"><span class="Bold">SIGNIFOR LAR<br/> <br/> (40-60 mg)<br/> <br/> %<br/> <br/> N = 178 </span></td><td align="center" class="Toprule"><span class="Bold">Active Comparator<br/> <br/> %<br/> <br/> N = 180 </span></td> </tr> <tr> <td align="left" class="Toprule" colspan="3"><span class="Bold">Hyperglycemia Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Hyperglycemia</td><td align="center" class="Rrule Toprule">29</td><td align="center" class="Toprule">8</td> </tr> <tr> <td align="left" class="Rrule Toprule">Diabetes mellitus<span class="Sup">a</span></td><td align="center" class="Rrule Toprule">26</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Rrule Toprule">Blood glucose increased</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">2</td> </tr> <tr> <td align="left" class="Rrule Toprule">Glycosylated hemoglobin increased</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Toprule">2</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypoglycemia</td><td align="center" class="Rrule Toprule">5</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Toprule" colspan="3"><span class="Bold">Gastrointestinal Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Diarrhea</td><td align="center" class="Rrule Toprule">39</td><td align="center" class="Toprule">45</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal pain</td><td align="center" class="Rrule Toprule">18</td><td align="center" class="Toprule">22</td> </tr> <tr> <td align="left" class="Rrule Toprule">Nausea</td><td align="center" class="Rrule Toprule">14</td><td align="center" class="Toprule">22</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal distension</td><td align="center" class="Rrule Toprule">12</td><td align="center" class="Toprule">12</td> </tr> <tr> <td align="left" class="Rrule Toprule">Vomiting</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal pain upper</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Toprule">8</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Hepatobiliary Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Cholelithiasis</td><td align="center" class="Rrule Toprule">26</td><td align="center" class="Toprule">36</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Cardiac Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Sinus bradycardia<span class="Sup">b</span></td><td align="center" class="Rrule Toprule">10</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypertension</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Nervous System Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Headache</td><td align="center" class="Rrule Toprule">19</td><td align="center" class="Toprule">26</td> </tr> <tr> <td align="left" class="Rrule Toprule">Dizziness</td><td align="center" class="Rrule Toprule">10</td><td align="center" class="Toprule">11</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Skin Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Alopecia</td><td align="center" class="Rrule Toprule">18</td><td align="center" class="Toprule">19</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Infections Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Nasopharyngitis</td><td align="center" class="Rrule Toprule">16</td><td align="center" class="Toprule">16</td> </tr> <tr> <td align="left" class="Rrule Toprule">Influenza</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Rrule Toprule">Upper respiratory tract infection</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">3</td> </tr> <tr> <td align="left" class="Rrule Toprule">Cough</td><td align="center" class="Rrule Toprule">5</td><td align="center" class="Toprule">8</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Laboratory Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Blood creatine phosphokinase increased</td><td align="center" class="Rrule Toprule">13</td><td align="center" class="Toprule">12</td> </tr> <tr> <td align="left" class="Rrule Toprule">Alanine aminotransferase increased</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Rrule Toprule">Aspartate aminotransferase increased</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Rrule Toprule">Lipase increased</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Weight decreased</td><td align="center" class="Rrule Toprule">5</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">General and Injection-Site Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Fatigue</td><td align="center" class="Rrule Toprule">10</td><td align="center" class="Toprule">10</td> </tr> <tr> <td align="left" class="Rrule Toprule">Injection-site reaction<span class="Sup">c</span></td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Musculoskeletal and Connective Tissue Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Arthralgia</td><td align="center" class="Rrule Toprule">10</td><td align="center" class="Toprule">12</td> </tr> <tr> <td align="left" class="Rrule Toprule">Back pain</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">11</td> </tr> <tr> <td align="left" class="Rrule Toprule">Pain in extremity</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">4</td> </tr> <tr> <td align="left" class="Toprule" colspan="6"><span class="Bold">Blood Related Adverse Reactions</span></td> </tr> <tr class="Last"> <td align="left" class="Rrule Toprule">Anemia</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Toprule">6</td> </tr> </tbody> </table></div>

Other notable adverse reactions which occurred with a frequency of 5% or less for SIGNIFOR LAR were: adrenal insufficiency (3%); glucose tolerance impaired (1%); QT-prolongation (4%); blood amylase increased (2%).

Patients With Acromegaly Inadequately Controlled on Other Somatostatin Analogs at Baseline

The data described in Table 2 are derived from an active-controlled study in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs [see Clinical Studies (14.2)]. These data reflect exposure of 63 and 62 patients to SIGNIFOR LAR 40 mg and 60 mg, respectively, for a mean duration of 24 weeks. In the overall study population, 56% were female and the average age of patients was 45 years.

Table 2 presents common adverse reactions associated with SIGNIFOR LAR in this study. These common adverse reactions were not present at baseline, or if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR.

<div class="scrollingtable"><table> <caption> <span>Table 2 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Previously Treated With Other Somatostatin Analogs</span> </caption> <colgroup> <col width="300"/> <col width="250"/> <col width="250"/> <col width="250"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">a</span>Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Rrule Toprule"><span class="Bold">Adverse Drug Reactions</span></td><td align="center" class="Rrule Toprule"><span class="Bold">SIGNIFOR LAR 40 mg<br/> <br/> %<br/> <br/> N = 63 </span></td><td align="center" class="Rrule Toprule"><span class="Bold">SIGNIFOR LAR 60 mg<br/> <br/> %<br/> <br/> N = 62 </span></td><td align="center" class="Toprule"><span class="Bold">Active Comparators<br/> <br/> %<br/> <br/> N = 66 </span></td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Hyperglycemia Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Hyperglycemia</td><td align="center" class="Rrule Toprule">33</td><td align="center" class="Rrule Toprule">30</td><td align="center" class="Toprule">14</td> </tr> <tr> <td align="left" class="Rrule Toprule">Diabetes mellitus<span class="Sup">a</span></td><td align="center" class="Rrule Toprule">21</td><td align="center" class="Rrule Toprule">31</td><td align="center" class="Toprule">9</td> </tr> <tr> <td align="left" class="Rrule Toprule">Blood glucose increased</td><td align="center" class="Rrule Toprule">5</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">0</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypoglycemia</td><td align="center" class="Rrule Toprule">3</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">0</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Gastrointestinal Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Diarrhea</td><td align="center" class="Rrule Toprule">16</td><td align="center" class="Rrule Toprule">19</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal pain</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Toprule">3</td> </tr> <tr> <td align="left" class="Rrule Toprule">Nausea</td><td align="center" class="Rrule Toprule">3</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">3</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Hepatobiliary Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Cholelithiasis</td><td align="center" class="Rrule Toprule">10</td><td align="center" class="Rrule Toprule">13</td><td align="center" class="Toprule">14</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Cardiac Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Atrioventricular block first degree</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Rrule Toprule">0</td><td align="center" class="Toprule">0</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Nervous System Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Headache</td><td align="center" class="Rrule Toprule">14</td><td align="center" class="Rrule Toprule">3</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Rrule Toprule">Dizziness</td><td align="center" class="Rrule Toprule">8</td><td align="center" class="Rrule Toprule">2</td><td align="center" class="Toprule">3</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Skin and Subcutaneous Tissue Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Alopecia</td><td align="center" class="Rrule Toprule">2</td><td align="center" class="Rrule Toprule">7</td><td align="center" class="Toprule">0</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Infections Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Nasopharyngitis</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Rrule Toprule">11</td><td align="center" class="Toprule">3</td> </tr> <tr> <td align="left" class="Toprule" colspan="4"><span class="Bold">Blood Related Adverse Reactions</span></td> </tr> <tr class="Last"> <td align="left" class="Rrule Toprule">Anemia</td><td align="center" class="Rrule Toprule">6</td><td align="center" class="Rrule Toprule">3</td><td align="center" class="Toprule">3</td> </tr> </tbody> </table></div>

Other notable adverse reactions which occurred with a frequency of 5% or less in the SIGNIFOR LAR 40 mg, SIGNIFOR LAR 60 mg arm, respectively, were adrenal insufficiency (2% and 0%) and glucose tolerance impaired (3% and 5%).

Patients With Cushing's Disease

The data described in Table 3 are derived from a randomized clinical study in 150 patients with Cushing's disease [see Clinical Studies (14.3)]. These data reflect exposure of 74 and 76 patients to SIGNIFOR LAR at a starting dose of 10 mg and 30 mg once every 28 days, respectively, for a mean duration of 68 weeks. In the overall study population, 79% of patients were female and the average age was 39 years at study entry.

Table 3 presents common adverse reactions which were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR.

<div class="scrollingtable"><table> <caption> <span>Table 3 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Cushing's Disease</span> </caption> <colgroup> <col width="150"/> <col width="50"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="2"><span class="Sup">a</span>Diabetes mellitus consists of the two terms: diabetes mellitus and type 2 diabetes mellitus.<br/> <br/> <span class="Sup">b</span>Abdominal pain includes the term abdominal pain upper.<br/> <br/> <span class="Sup">c</span>Sinus bradycardia includes the term bradycardia.<br/> <br/> <span class="Sup">d</span>Fatigue includes the term asthenia.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Rrule Toprule"><span class="Bold">Adverse Reactions</span></td><td align="center" class="Toprule"><span class="Bold">Overall<br/> <br/> %<br/> <br/> N = 150 </span></td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Endocrine Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Adrenal insufficiency</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Blood cortisol decreased</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Hyperglycemia Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Hyperglycemia</td><td align="center" class="Toprule">47</td> </tr> <tr> <td align="left" class="Rrule Toprule">Diabetes mellitus<span class="Sup">a</span></td><td align="center" class="Toprule">27</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypoglycemia</td><td align="center" class="Toprule">15</td> </tr> <tr> <td align="left" class="Rrule Toprule">Blood glucose increased</td><td align="center" class="Toprule">9</td> </tr> <tr> <td align="left" class="Rrule Toprule">Glycosylated hemoglobin (HbA1C) increased</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Gastrointestinal Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Diarrhea</td><td align="center" class="Toprule">39</td> </tr> <tr> <td align="left" class="Rrule Toprule">Nausea</td><td align="center" class="Toprule">21</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal pain<span class="Sup">b</span></td><td align="center" class="Toprule">23</td> </tr> <tr> <td align="left" class="Rrule Toprule">Constipation</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Abdominal distension</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Rrule Toprule">Flatulence</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Rrule Toprule">Vomiting</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Hepatobiliary Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Cholelithiasis</td><td align="center" class="Toprule">33</td> </tr> <tr> <td align="left" class="Rrule Toprule">Gamma-glutamyltransferase increased</td><td align="center" class="Toprule">9</td> </tr> <tr> <td align="left" class="Rrule Toprule">Alanine aminotransferase increased</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Cardiac Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypertension</td><td align="center" class="Toprule">15</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypotension</td><td align="center" class="Toprule">6</td> </tr> <tr> <td align="left" class="Rrule Toprule">Sinus bradycardia<span class="Sup">c</span></td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">General Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Fatigue<span class="Sup">d</span></td><td align="center" class="Toprule">27</td> </tr> <tr> <td align="left" class="Rrule Toprule">Edema peripheral</td><td align="center" class="Toprule">14</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Musculoskeletal and Connective Tissue Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Back pain</td><td align="center" class="Toprule">11</td> </tr> <tr> <td align="left" class="Rrule Toprule">Arthralgia</td><td align="center" class="Toprule">8</td> </tr> <tr> <td align="left" class="Rrule Toprule">Pain in extremity</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Myalgia</td><td align="center" class="Toprule">5</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Metabolism and Nutrition Related Adverse Reactions</span></td> </tr> <tr> <td align="left" class="Rrule Toprule">Decreased appetite</td><td align="center" class="Toprule">10</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hyperuricemia</td><td align="center" class="Toprule">7</td> </tr> <tr> <td align="left" class="Rrule Toprule">Hypercholesterolemia</td><td align="center" class="Toprule">6</td> </tr> <tr> <td align="left" class="Toprule" colspan="2"><span class="Bold">Blood Related Adverse Reactions</span></td> </tr> <tr class="Last"> <td align="left" class="Rrule Toprule">Anemia</td><td align="center" class="Toprule">5</td> </tr> </tbody> </table></div>

Other adverse reactions which occurred at a frequency less than 5% were cholestasis (4%), glucose tolerance impaired (3%), aspartate aminotransferase increased (3%), vomiting (3%), lipase increased (3%), injection-site reactions (2%), ECG QT prolonged (1%), cholecystitis (1%), amylase increased (1%), and prothrombin time prolonged (1%).

Hyperglycemia

The average FPG levels in patients with acromegaly naïve to drug therapy study [see Clinical Studies (14.1)] across visits is shown in Figure 2 below.

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Numbers of patients with a glucose value at the given timepoint in the SIGNIFOR LAR/Active comparator arms are displayed as xxx/xxx on the x axis.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span></td> </tr> <tr> <td align="center"><img alt="Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy* " src="/dailymed/image.cfm?name=signiforLAR-02.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> </tbody> </table></div>

Pancreatic Enzyme Elevation and Pancreatitis

Asymptomatic elevations in lipase and alpha amylase were observed in 30% and 20% of patients receiving SIGNIFOR LAR in the drug naïve study in acromegaly, and in 1% and 3% of patients receiving SIGNIFOR LAR in the study of acromegaly patients previously treated. In the drug-naïve study, 2 acromegaly patients receiving SIGNIFOR LAR developed pancreatitis. In the Cushing's disease study, increased lipase was observed in 4% of patients, and 1 patient developed pancreatitis. Pancreatitis is a potential adverse reaction associated with the use of SIGNIFOR LAR due to the association between cholelithiasis and acute pancreatitis.

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

Drugs That Prolong QT

Co-administration of drugs that prolong the QT interval with SIGNIFOR LAR may have additive effects on the prolongation of the QT interval. Monitoring effects on the QT interval at 21 days is recommended [see Warnings and Precautions (5.2)].

Cyclosporine

Concomitant administration of cyclosporine with SIGNIFOR LAR may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary.

Bromocriptine

Co-administration of SIGNIFOR LAR with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

Risk Summary

The limited data with SIGNIFOR LAR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryo-fetal development studies in rabbits, findings indicating a developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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

In embryo-fetal development studies in rats given 1 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 12 times higher than that at the maximum therapeutic dose based on area under the curve (AUC) comparisons across species. An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 106 times the exposure in humans at the highest recommended dose of 60 mg SIGNIFOR LAR administered as an intramuscular injection once every 4 weeks.

In embryo-fetal development studies in rabbits given 0.05 mg/kg/day, 1 mg/kg/day, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 5 times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose.

In pre- and post-natal developmental studies in rats given subcutaneous doses of 2 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (9 times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay.

Risk Summary

There is no information available on the presence of SIGNIFOR LAR in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that pasireotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SIGNIFOR LAR, and any potential adverse effects on the breastfed child from SIGNIFOR LAR or from the underlying maternal condition.

Data

Available data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg [14C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity was 0.28, based on AUC0-∞ values.

Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of IGF-1 in acromegalic females treated with pasireotide may lead to improved fertility.

Similarly, the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing's disease treated with pasireotide may also lead to improved fertility.

Safety and effectiveness of SIGNIFOR LAR have not been established in pediatric patients.

Clinical studies of SIGNIFOR LAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Clinical studies of SIGNIFOR LAR in patients with renal impairment have not been conducted. On the basis of studies with pasireotide given subcutaneously, dosage adjustment is not needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.

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Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. In the event of an overdose, contact the National Capital Poison Center at 1-800-222-1222 or www.poison.org.

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SIGNIFOR LAR (pasireotide) for injectable suspension is a long-acting release form of pasireotide pamoate, as powder to be suspended in the provided diluent immediately prior to intramuscular injection. SIGNIFOR LAR contains pasireotide, a somatostatin analog in the form of pasireotide pamoate (pamoic acid salt). Pasireotide is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Pasireotide pamoate has a chemical name of (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester pamoic acid salt.

{ "type": "p", "children": [], "text": "SIGNIFOR LAR (pasireotide) for injectable suspension is a long-acting release form of pasireotide pamoate, as powder to be suspended in the provided diluent immediately prior to intramuscular injection. SIGNIFOR LAR contains pasireotide, a somatostatin analog in the form of pasireotide pamoate (pamoic acid salt). Pasireotide is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Pasireotide pamoate has a chemical name of (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester pamoic acid salt. \t\t\t\t\t\t" }

The molecular formula of pasireotide pamoate is C58H66N10O9 • C23H16O6 and the molecular weight is 1435.58 g/mol.

{ "type": "p", "children": [], "text": "The molecular formula of pasireotide pamoate is C58H66N10O9 • C23H16O6 and the molecular weight is 1435.58 g/mol. " }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

The drug product consists of pasireotide pamoate uniformly distributed within microspheres which are made of biodegradable copolymers of poly (D,L-lactide-co-glycolide) acids (PLGA).

{ "type": "p", "children": [], "text": "The drug product consists of pasireotide pamoate uniformly distributed within microspheres which are made of biodegradable copolymers of poly (D,L-lactide-co-glycolide) acids (PLGA)." }

SIGNIFOR LAR is available in a vial containing the sterile pasireotide pamoate, PLGA microspheres powder, 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg to be reconstituted with the provided 2 mL sterile diluent.

{ "type": "p", "children": [], "text": "SIGNIFOR LAR is available in a vial containing the sterile pasireotide pamoate, PLGA microspheres powder, 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg to be reconstituted with the provided 2 mL sterile diluent." }

Each vial contains:

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

<div class="scrollingtable"><table> <col width="325"/> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> <tfoot> <tr class="First Last"> <td colspan="4">*corresponds to 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg of pasireotide base, respectively.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td class="Toprule"><span class="Bold">10 mg</span></td><td class="Toprule"><span class="Bold">20 mg</span></td><td class="Toprule"><span class="Bold">30 mg</span></td><td class="Toprule"><span class="Bold">40 mg</span></td><td class="Toprule"><span class="Bold">60 mg</span></td> </tr> <tr> <td class="Toprule">Pasireotide pamoate</td><td class="Toprule">13.71 mg* </td><td class="Toprule">27.42 mg* </td><td class="Toprule">41.13 mg* </td><td class="Toprule">54.84 mg* </td><td class="Toprule">82.26 mg* </td> </tr> <tr> <td>Poly(D,L-lactide-co-glycolide) [50-60:40-50] </td><td>13.15 mg</td><td>26.29 mg</td><td>39.44 mg</td><td>52.58 mg</td><td>78.87 mg</td> </tr> <tr class="Last"> <td>Poly(D,L-lactide-co-glycolide) [50:50]</td><td>13.15 mg</td><td>26.29 mg</td><td>39.44 mg</td><td>52.58 mg</td><td>78.87 mg</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"325\"/>\n<col width=\"200\"/>\n<col width=\"200\"/>\n<col width=\"200\"/>\n<col width=\"200\"/>\n<col width=\"200\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td colspan=\"4\">*corresponds to 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg of pasireotide base, respectively.</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\"></td><td class=\"Toprule\"><span class=\"Bold\">10 mg</span></td><td class=\"Toprule\"><span class=\"Bold\">20 mg</span></td><td class=\"Toprule\"><span class=\"Bold\">30 mg</span></td><td class=\"Toprule\"><span class=\"Bold\">40 mg</span></td><td class=\"Toprule\"><span class=\"Bold\">60 mg</span></td>\n</tr>\n<tr>\n<td class=\"Toprule\">Pasireotide pamoate</td><td class=\"Toprule\">13.71 mg* \t\t\t\t\t\t\t\t\t</td><td class=\"Toprule\">27.42 mg* \t\t\t\t\t\t\t\t\t</td><td class=\"Toprule\">41.13 mg* \t\t\t\t\t\t\t\t\t</td><td class=\"Toprule\">54.84 mg* \t\t\t\t\t\t\t\t\t</td><td class=\"Toprule\">82.26 mg* \t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr>\n<td>Poly(D,L-lactide-co-glycolide) [50-60:40-50] </td><td>13.15 mg</td><td>26.29 mg</td><td>39.44 mg</td><td>52.58 mg</td><td>78.87 mg</td>\n</tr>\n<tr class=\"Last\">\n<td>Poly(D,L-lactide-co-glycolide) [50:50]</td><td>13.15 mg</td><td>26.29 mg</td><td>39.44 mg</td><td>52.58 mg</td><td>78.87 mg</td>\n</tr>\n</tbody>\n</table></div>" }

Each diluent prefilled syringe contains:

{ "type": "p", "children": [], "text": "Each diluent prefilled syringe contains: \t\t\t\t\t\t" }

<div class="scrollingtable"><table> <col width="275"/> <col width="200"/> <tbody class="Headless"> <tr class="First"> <td>Mannitol</td><td>90 mg</td> </tr> <tr> <td>Carboxymethylcellulose sodium</td><td>14 mg</td> </tr> <tr> <td>Poloxamer 188</td><td>4 mg</td> </tr> <tr class="Last"> <td>Water for injections</td><td>add to 2 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"275\"/>\n<col width=\"200\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>Mannitol</td><td>90 mg</td>\n</tr>\n<tr>\n<td>Carboxymethylcellulose sodium</td><td>14 mg</td>\n</tr>\n<tr>\n<td>Poloxamer 188</td><td>4 mg</td>\n</tr>\n<tr class=\"Last\">\n<td>Water for injections</td><td>add to 2 mL</td>\n</tr>\n</tbody>\n</table></div>" }

SIGNIFOR LAR is an injectable cyclohexapeptide, somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTR). There are 5 known human somatostatin receptor subtypes: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogs bind to SSTRs with different potencies. Pasireotide binds with high affinity to 4 of the 5 SSTRs (see Table 4).

<div class="scrollingtable"><table> <caption> <span>Table 4 – Binding Affinities of Somatostatin (SRIF-14) and Pasireotide to the Five Human SSTR Subtypes (SSTR 1-5)</span> </caption> <col width="175"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <col width="100"/> <tfoot> <tr class="First Last"> <td colspan="4">Results are the mean + SEM of IC<span class="Sub">50</span> values expressed as nmol/l (nM).</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"><span class="Bold">Compound</span></td><td align="center" class="Toprule"><span class="Bold">SSTR1</span></td><td align="center" class="Toprule"><span class="Bold">SSTR2</span></td><td align="center" class="Toprule"><span class="Bold">SSTR3</span></td><td align="center" class="Toprule"><span class="Bold">SSTR4</span></td><td align="center" class="Toprule"><span class="Bold">SSTR5</span></td> </tr> <tr> <td class="Toprule">Somatostatin (SRIF-14)</td><td align="center" class="Toprule">0.93 ± 0.12</td><td align="center" class="Toprule">0.15 ± 0.02</td><td align="center" class="Toprule">0.56 ± 0.17</td><td align="center" class="Toprule">1.5 ± 0.4</td><td align="center" class="Toprule">0.29 ± 0.04</td> </tr> <tr class="Last"> <td>Pasireotide</td><td align="center">9.3 ± 0.1</td><td align="center">1.0 ± 0.1</td><td align="center">1.5 ± 0.3</td><td align="center">&gt; 100</td><td align="center">0.16 ± 0.01</td> </tr> </tbody> </table></div>

Somatostatin receptors are expressed in many tissues including neuroendocrine tumors (e.g., growth hormone or adrenocorticotropic hormone secreting pituitary adenomas).

Acromegaly

Pasireotide binds to SSTR2 and SSTR5 subtype receptors which may be relevant for inhibition of GH secretion. In vivo studies show that SIGNIFOR LAR lowers GH and IGF-1 levels in patients with acromegaly.

Cushing's Disease

Corticotroph tumor cells from Cushing's disease patients frequently over-express SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

Cardiac Electrophysiology

Individually corrected QT (QTcI) interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide subcutaneous doses of 0.6 mg and 1.95 mg twice daily, respectively. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg twice daily, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg twice daily.

The predicted pasireotide peak concentration (25.8 ng/mL) following SIGNIFOR LAR 60-mg dose in acromegaly patients is similar to the observed peak concentration (24.3 mg/mL) of the subcutaneous SIGNIFOR 0.6 mg twice daily dose and below the observed peak concentration (80.6 ng/mL) of the subcutaneous SIGNIFOR 1.95 mg twice daily dose. The predicted pasireotide peak concentration for the SIGNIFOR LAR dose of 40 mg in Cushing's disease patients is 14 ng/mL.

Pasireotide for intramuscular use is formulated as microspheres for long-acting release. After a single injection, the plasma pasireotide concentration shows an initial burst release on the injection day, followed by a dip from Day 2 to Day 7, then a slow increase to the maximum concentration around Day 21, and a slow declining phase over the next weeks, concomitant with the terminal degradation phase of the polymer matrix of the dosage form.

Absorption and Distribution

No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR LAR is administered via a parenteral route.

In healthy volunteers, pasireotide administered as SIGNIFOR LAR is widely distributed with large apparent volume of distribution (Vz/F > 100 L). Distribution between blood and plasma is concentration-independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.

Pasireotide has low passive permeability and is likely to be a substrate of P-glycoprotein (P-gp), but the impact of P-gp on the ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition did not affect the rate or extent of pasireotide availability [see Drug Interactions (7.1)]. At therapeutic dose levels, pasireotide is not expected to be a substrate of BCRP (breast cancer resistance protein), OCT1 (organic cation transporter 1), or OATP (organic anion-transporting polypeptides) 1B1, 1B3, or 2B1.

Elimination

Metabolism and Excretion

Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of GH secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study with subcutaneous SIGNIFOR with a single dose 0.6 mg, 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine.

The apparent clearance (CL/F) of SIGNIFOR LAR in healthy volunteers is on average 4.5-8.5 L/hour.

Steady-State Pharmacokinetics

PK steady-state for SIGNIFOR LAR is achieved after 3 monthly doses. Following multiple intramuscular doses every 4 weeks (every 28 days), SIGNIFOR LAR demonstrates approximately dose-proportional PK exposures (steady-state trough; Ctrough, ss) in the dose range of 10 mg to 60 mg every 4 weeks.

Special Populations

Population PK analyses of SIGNIFOR LAR suggest that race, gender, and body weight do not have clinically relevant influence on circulating levels of pasireotide. No dose adjustment is required for demographics.

Pediatric Patients

No studies have been performed in pediatric patients [see Use in Specific Populations (8.4)].

Geriatric Patients

Age is not a significant covariate in the population PK analysis. Therefore age is not expected to significantly impact circulating levels of pasireotide.

Efficacy and safety data on patients older than 65 years are limited [see Use in Specific Populations (8.5)].

Hepatic Impairment

In a clinical study with a single subcutaneous dose of 600 µg pasireotide in subjects with impaired hepatic function (Child-Pugh A, B, and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparing with the control group, AUCinf was increased by 12%, 56%, and 42%; and Cmax was increased by 3%, 46%, and 33% respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations (8.6), Dosage and Administration (2.5)].

Renal Impairment

Clinical studies have not been performed in patients with renal impairment. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function (creatinine clearance and estimated glomerular filtration rate) is not a covariate in the population PK analysis. Therefore, renal function is not expected to significantly impact the circulating levels of pasireotide [see Use in Specific Populations (8.7)].

Carcinogenesis

A lifetime carcinogenicity study was conducted in rats and transgenic mice. Rats were given daily subcutaneous doses of pasireotide at 0.01 mg/kg/day, 0.05 mg/kg/day, and 0.3 mg/kg/day for 104 weeks. There were no drug-related tumors in rats at exposures up to 5-times higher than the maximum recommended clinical exposure of the pasireotide LAR 60 mg dose. Mice were given subcutaneous doses of pasireotide at 0.5 mg/kg/day, 1 mg/kg/day, and 2.5 mg/kg/day for 26 weeks and did not identify any carcinogenic potential.

Mutagenesis

Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and Escherichia coli and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test.

Impairment of Fertility

Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in rats at exposures less than the human clinical exposure based on body surface area comparisons across species resulted in statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (4-fold higher than the maximum therapeutic exposure of pasireotide LAR based on surface area, comparisons across species).

A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of SIGNIFOR LAR in patients with active acromegaly. A total of 358 patients naïve to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR LAR or another somatostatin analog active comparator. Randomization was stratified based on previous pituitary surgical status (e.g., at least 1 prior pituitary surgery versus no prior pituitary surgery).

In the overall study population, 52% were female and the average age of patients was 45 years. Sixty percent of patients were Caucasian, 23% Asian, 12% Other, 3% American Indian, and 2% were Black. Forty-two percent of patients had previous pituitary surgery, and 1 patient had a history of pituitary radiation therapy. Median time between diagnosis and trial participation was 6 months. Median GH was 8.8 mcg/L (range: 0.8-200 mcg/L) and 10.1 mcg/L (range: 0.6-169.6 mcg/L) for SIGNIFOR LAR and active comparator, respectively at baseline. Median standardized IGF-1, defined as IGF-1 value divided by the ULN (i.e., fold above the ULN), was 2.9 (range: 0.9-6.9) and 2.9 (range: 0.8-7.3), for SIGNIFOR LAR and active comparator, respectively, at baseline.

The starting dose of SIGNIFOR LAR was 40 mg. Dose increase was allowed in both arms, at the discretion of investigators, after 3 and 6 months of treatment if mean GH was greater than or equal to 2.5 mcg/L and/or IGF-1 was greater than the ULN for age and sex. The maximum allowed dose for SIGNIFOR LAR was 60 mg. The maximum dose of the active comparator was not used in this trial because the trial was multi-national and the maximum dose approved in the US was not approved in all participating countries.

The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5 mcg/L and a normal IGF-1 levels at month 12 (age- and sex-adjusted) (see Table 5, Figure 3, and Figure 4). The proportion of patients achieving this level of control was 31.3% and 19.2% for SIGNIFOR LAR and active comparator, respectively. The changes in mean GH and IGF-1 levels by study visits in subjects with a measurement at these visits (observed cases) are shown in Figures 3 and 4.

<div class="scrollingtable"><table border="0" width="93%"> <caption> <span>Table 5 – Results at Month 12 in Drug-Naïve Patients Study</span> </caption> <tbody class="Headless"> <tr class="First"> <td></td><td> <p class="First"> <span class="Bold">SIGNIFOR LAR</span> </p> <p></p> <p> <span class="Bold">(40-60 mg)</span> </p> <p></p> <p> <span class="Bold">%</span> </p> <p></p> <p> <span class="Bold">N = 176</span> </p> </td><td> <p class="First"> <span class="Bold">Active Comparator<span class="Sup">c</span></span> </p> <p></p> <p> <span class="Bold">%</span> </p> <p></p> <p></p> <p></p> <p> <span class="Bold">N = 182</span> </p> </td> </tr> <tr> <td class="Toprule">GH &lt; 2.5 mcg/L and normalized IGF-1<span class="Sup">a</span></td><td class="Toprule">31.3%<span class="Sup">b</span></td><td class="Toprule">19.2%</td> </tr> <tr> <td>GH &lt; 2.5 mcg/L and IGF-1 ≤ ULN</td><td>35.8%</td><td>20.9%</td> </tr> <tr> <td>Normalized IGF-1</td><td>38.6%<span class="Sup">b</span></td><td>23.6%</td> </tr> <tr> <td>GH &lt; 2.5 mcg/L</td><td>48.3%</td><td>51.6%</td> </tr> <tr class="Last"> <td colspan="3"><span class="Sup">a</span>Primary endpoint [patients with IGF-1&lt; lower limit of normal (LLN) were not considered as "responders"]. <p class="First">ULN = Upper limit of normal.</p> <p></p> <p> <span class="Sup">b</span>p-value &lt; 0.01 for treatment difference.</p> <p></p> <p> <span class="Sup">c</span>The maximum dose approved for use in the United States was not used in this trial but the majority of patients were receiving the dose most commonly used in the United States to treat acromegaly.</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Numbers of patients with a GH value at the given timepoint for SIGNIFOR LAR/Active comparator arm are displayed as xxx/xxx on the x-axis.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 3. Mean GH (mcg/L) Levels By Visit in Drug Naïve Patient Study</span><a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></td> </tr> <tr> <td align="center"><img alt="Figure 3: Mean GH (mcg/L) Levels By Visit in Drug Naïve Patient Study*" src="/dailymed/image.cfm?name=signiforLAR-17.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Fold above the upper limit of normal for the assay</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Numbers of patients with an IGF-1 value at the given timepoint for SIGNIFOR LAR/Active comparator arm are displayed as xxx/xxx on the x axis.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 4. Mean Standardized IGF-1 Levels<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> By Visit in Drug Naïve Patient Study<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></span></td> </tr> <tr> <td align="center"><img alt="Figure 4: Mean Standardized IGF-1 Levels* By Visit in Drug Naïve Patient Study** " src="/dailymed/image.cfm?name=signiforLAR-18.jpg&amp;setid=a0aad470-3f38-af97-e053-2995a90a383a"/></td> </tr> </tbody> </table></div>

Biochemical control was achieved by Month 3 in 30.1% of patients in the SIGNIFOR LAR arm. Ninety-eight percent of patients treated with SIGNIFOR LAR had either a reduction or no change in tumor volume from baseline assessed by MRI at Month 12. The median (range) change in tumor volume was a reduction of 39.8% (-97.6% to 16.9%).

Additionally, ring size and acromegaly symptoms score (i.e., headache, fatigue, perspiration, paresthesia, and osteoarthralgia) were followed. At Month 12, reductions in ring size and in symptom severity scores in both treatment groups compared to baseline were noted.

A multicenter, randomized, 3-arm study was conducted in patients with acromegaly inadequately controlled on somatostatin analogs. Patients were randomized to double-blind SIGNIFOR LAR 40 mg (n = 65) or SIGNIFOR LAR 60 mg (n = 65) or to continued open-label pretrial somatostatin analog therapies at maximal or near maximal doses (n = 68). A total of 181 patients completed the 6-month trial.

Inadequate control was defined as a GH concentration of greater than 2.5 mcg/L (i.e., mean of 5 samples over 2 hours) and a sex- and age-adjusted IGF-1 level greater than 1.3 times the upper limit of normal. Patients were required to have been treated with other somatostatin analogs for at least 6 months prior to randomization. Note that the maximum dose for one of the active comparators approved for use in the United States was not used in this multinational trial; approximately 75% of the population in the comparator group was receiving this active comparator.

In the overall study population, 56% were female and the average age of patients was 45 years. Eighty-one percent of patients were Caucasian, 7% Other, 8% Black, 2% American Indian, and 2% Asian. The percentage of patients with previous pituitary surgery in the SIGNIFOR LAR 40 mg and 60 mg arms, and in the active control arm was 77%, 63%, and 60%, respectively. Three percent of patients in the SIGNIFOR LAR groups and 7% of patients in the active control arm had prior radiation therapy. Median (range) time from diagnosis to participation in this trial was 50 (10-337) months, 55 (8-357) months, and 54 (8-357) months in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively. At baseline, median (range) GH was 7.1 (1.0-200) mcg/L, 5.3 (1.4-113.8) mcg/L and 6.1 (1.0-92.4) mcg/L in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively. Baseline median standardized IGF-1 (defined as IGF-1 value divided by the ULN) values were 2.3, 2.6 and 2.9 in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively.

The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5 mcg/L and normal IGF-1 levels at week 24. The primary analysis compared SIGNIFOR LAR 60 mg and 40 mg to continued pretrial therapy (i.e., no change in treatment). The proportion of patients achieving biochemical control was 15.4% and 20.0% for SIGNIFOR LAR 40 mg and 60 mg, respectively, at 6 months.

Biochemical control was achieved by Month 3 in 15.4% and 18.5% of patients in the SIGNIFOR LAR 40 mg and 60 mg arms, respectively.

<div class="scrollingtable"><table> <caption> <span>Table 6 – Results at 6 Months in Inadequately Controlled Patient Study</span> </caption> <colgroup> <col width="250"/> <col width="200"/> <col width="200"/> <col width="200"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">a</span>Primary endpoint (patients with IGF-1 &lt; lower limit of normal (LLN) were not considered as "responders").<br/> <br/> <span class="Sup">b</span>For one of the active comparators, the maximum dose approved for use in the United States was not used in this trial but the majority of patients were receiving the dose most commonly used in the United States to treat acromegaly.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">SIGNIFOR LAR 40 mg<br/> <br/> <br/> <br/> %<br/> <br/> N = 65 </span></td><td align="center" class="Toprule"><span class="Bold">SIGNIFOR LAR 60 mg<br/> <br/> <br/> <br/> %<br/> <br/> N = 65 </span></td><td align="center" class="Toprule" valign="top"><span class="Bold">Continued<br/> <br/> Pre-Trial Therapy<br/> <br/> Control Arm<span class="Sup">b</span></span> <br/> <br/> <span class="Bold">%<br/> <br/> N = 68 </span></td> </tr> <tr> <td class="Toprule">GH &lt; 2.5 mcg/L and normalized IGF-1<span class="Sup">a</span></td><td align="center" class="Toprule">15.4%</td><td align="center" class="Toprule">20.0%</td><td align="center" class="Toprule">0%</td> </tr> <tr> <td>Normalization of IGF-1</td><td align="center">24.6%</td><td align="center">26.2%</td><td align="center">0%</td> </tr> <tr class="Last"> <td>GH &lt; 2.5 mcg/L</td><td align="center">35.4%</td><td align="center">43.1%</td><td align="center">13.2%</td> </tr> </tbody> </table></div>

Eighty-one percent and 70% of patients treated with SIGNIFOR LAR 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline assessed by MRI at Month 6. The median (range) change in tumor volume was a reduction of -10.4% (-74.5% to 19.4%) and -6.3% (-66.7% to 14.5%) from baseline for SIGNIFOR LAR 40 mg and 60 mg, respectively.

A Phase 3, randomized, double-blind, multicenter study was conducted to evaluate the safety and efficacy of two dose regimens of SIGNIFOR LAR over a 12-month treatment period in patients with persistent or recurrent Cushing's disease, or de novo patients who were not considered candidates for pituitary surgery.

The study enrolled 150 patients with a screening mean urinary free cortisol level (mUFC) ≥ 1.5 and ≤ 5 x ULN, who were randomized in a 1:1 ratio to receive a SIGNIFOR LAR starting dose of either 10 mg intramuscularly once every 28 days or 30 mg intramuscularly once every 28 days. Randomization was stratified by values of mUFC at screening (1.5 to < 2 x ULN versus 2 to 5 x ULN, respectively).

After four months of treatment, patients who had a mUFC ≤ 1.5 x ULN continued on the blinded dose to which they were randomized. Patients with a mUFC > 1.5 x ULN at Month 4 had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided there were no tolerability concerns. Additional dose increases were allowed at Month 7 and Month 9 (by one dose level if the mUFC was > 1 x ULN).

Dose reduction by one dose level for tolerability was allowed in a blinded fashion for the first seven months, with a minimum dose level of 5 mg. After the first seven months, blinded down titration of more than one dose level was allowed at any month.

After twelve months of treatment (core phase), patients had the option to enter an extension to continue to receive SIGNIFOR LAR if they benefited from treatment.

The primary efficacy endpoint was the proportion of patients in each arm who were mUFC responders (mUFC ≤ ULN) after seven months of treatment, with or without up-titration at Month 4. The key secondary endpoint was the proportion of patients in each arm who were mUFC responders after seven months of treatment and who did not up-titrate the dose prior to Month 7. The pre-specified boundary of the lower limit of the 95% confidence interval (CI) for efficacy for both the primary and key secondary endpoints was 15%. Patients with missing mUFC assessment at Month 7 were classified as non-responders. Other secondary endpoints included changes from baseline in 24-hour UFC, plasma ACTH, and serum cortisol levels. All analyses were conducted based on the randomized dose groups.

Baseline demographics and disease history were well balanced between the two randomized dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 38.5 years with a predominance of female patients (78.7%). The majority of the patients had persistent or recurrent Cushing's disease (82.0%). The median value of the baseline 24-hour mUFC for all patients was 396.9 nmol/24 hours (ULN: 166.5 nmol/24 hours). About three-quarters of all randomized patients completed seven months of treatment, and about two-thirds of all randomized patients completed twelve months of treatment.

The study met the primary efficacy objective for both dose groups. Patients were considered responders if they remained on treatment until at least Month 7 and achieved a Month 7 mUFC ≤ 1 x ULN, regardless of up-titration at Month 4. The proportion of patients with mUFC response at Month 7 was 39.2% (95% CI: 28.0, 51.2) in the 10 mg arm and 40.8% (95% CI: 29.7, 52.7) in the 30 mg arm. The responder rate at Month 12 was 35.1% (26/74) and 25.0% (19/76) in the 10 mg and 30 mg starting dose groups, respectively.

<div class="scrollingtable"><table> <caption> <span>Table 7 – Response Rates at Month 7 per Randomized Dose Group and According to Screening mUFC</span> </caption> <colgroup> <col width="250"/> <col width="200"/> <col width="200"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">There were 17 (23.0%) patients in 10 mg arm and 9 (11.8%) in the 30 mg arm with missing value mUFC assessments at Month 7 who were classified as non-responders.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR<br/> <br/> 10 mg Every 28 Days </span></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR<br/> <br/> 30 mg Every 28 Days </span></td> </tr> <tr> <td class="Toprule">Screening mUFC category</td><td align="center" class="Toprule">n/N (%)<br/> <br/> 95% CI</td><td align="center" class="Toprule">n/N (%)<br/> <br/> 95% CI</td> </tr> <tr> <td class="Toprule">All patients</td><td align="center" class="Toprule">29/74 (39.2)<br/> <br/> (28.0, 51.2)</td><td align="center" class="Toprule">31/76 (40.8)<br/> <br/> (29.7, 52.7)</td> </tr> <tr> <td class="Toprule">≥ 1.5 x ULN to &lt; 2 x ULN</td><td align="center" class="Toprule">11/25 (44.0)<br/> <br/> (24.4, 65.1)</td><td align="center" class="Toprule">13/25 (52.0)<br/> <br/> (31.3, 72.2)</td> </tr> <tr class="Last"> <td class="Toprule">≥ 2 x ULN to ≤ 5 x ULN</td><td align="center" class="Toprule">18/49 (36.7)<br/> <br/> (23.4, 51.7)</td><td align="center" class="Toprule">18/51 (35.3)<br/> <br/> (22.4, 49.9)</td> </tr> </tbody> </table></div>

The study met the key secondary efficacy objective for both dose groups. At Month 4, 31/74 (41.9%) and 28/76 (36.8%) patients were up-titrated in the pasireotide LAR 10 mg and 30 mg arms, respectively. When all patients who up-titrated prior to Month 7 were counted as non-responders, Month 7 mUFC response was observed in 25.7% (95% CI: 16.2 to 37.2) and 31.6% (95% CI: 21.4 to 43.3) of patients randomized to pasireotide LAR at a starting dose of 10 mg once every 28 days and 30 mg once every 28 days, respectively.

A secondary efficacy analysis was conducted for the combined proportion of patients who attained mUFC ≤ ULN (controlled) or had at least 50% reduction in mUFC (partially controlled) in the core phase of the study. The combined rate of controlled or partially controlled responders at Month 7 constituted 44.6% and 53.9% of patients randomized to the 10 mg and 30 mg dose groups, respectively (Table 8).

<div class="scrollingtable"><table> <caption> <span>Table 8 – Response Rates at Month 7 per Randomized Dose Group - Supportive Efficacy Analysis</span> </caption> <colgroup> <col width="275"/> <col width="225"/> <col width="225"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Toprule" valign="top"><span class="Bold">Response Category</span></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR<br/> <br/> 10 mg Every 28 Days<br/> <br/> (N = 74)<br/> <br/> n (%) </span></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR<br/> <br/> 30 mg Every 28 Days<br/> <br/> (N = 76)<br/> <br/> n (%) </span></td> </tr> <tr> <td class="Toprule">Controlled (mUFC ≤ ULN)</td><td align="center" class="Toprule">29 (39.2%)</td><td align="center" class="Toprule">31 (40.8%)</td> </tr> <tr> <td>Partially controlled (≥ 50% reduction in mUFC)</td><td align="center">4 (5.4%)</td><td align="center">10 (13.2%)</td> </tr> <tr class="Last"> <td>Combined</td><td align="center">33 (44.6%)</td><td align="center">41 (53.9%)</td> </tr> </tbody> </table></div>

Decreases in median mUFC levels at Month 7 compared to baseline, as measured by overall percentage of reduction, are shown in Table 9. Reductions in serum cortisol and plasma ACTH levels were also observed at Months 7 and 12 for each dose group.

<div class="scrollingtable"><table> <caption> <span>Table 9 – Median Percentage Change from Baseline in Mean Urinary Free Cortisol (mUFC) at Month 7 by Randomized Dose Group</span> </caption> <colgroup> <col width="250"/> <col width="200"/> <col width="200"/> <col width="200"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4">Note: Median % change from baseline in mUFC at Month 7 are calculated by imputing missing values with the worst observed % change in mUFC at Month 7 within each treatment group.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule"></td><td class="Toprule"></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR 10 mg Every 28 Days<br/> <br/> % change </span></td><td align="center" class="Toprule"><span class="Bold">Pasireotide LAR 30 mg Every 28 Days<br/> <br/> % change </span></td> </tr> <tr> <td class="Toprule">mUFC levels (nmol/24hr)<br/> <br/> Baseline</td><td align="center" class="Toprule">N<br/> <br/> Mean (SD)<br/> <br/> Median</td><td align="center" class="Toprule">74<br/> <br/> 462.6 (256.41)<br/> <br/> 409.8</td><td align="center" class="Toprule">76<br/> <br/> 477.1 (331.75)<br/> <br/> 371.6</td> </tr> <tr class="Last"> <td class="Toprule">Median change in mUFC (% from baseline)</td><td align="center" class="Toprule">Month 7</td><td align="center" class="Toprule">-41.3%</td><td align="center" class="Toprule">-41.4%</td> </tr> </tbody> </table></div>

SIGNIFOR LAR for injectable suspension is supplied in a single-use kit containing the following:

SIGNIFOR LAR kits are available in the following strengths:

<div class="scrollingtable"><table> <colgroup> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> <col width="200"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="top"><span class="Bold">SIGNIFOR LAR Kit</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">Final Concentration When Reconstituted<br/> <br/> (total product strength per total volume) </span></td><td align="center" class="Toprule" valign="top"><span class="Bold">Final Concentration When Reconstituted<br/> <br/> (per mL) </span></td><td align="center" class="Toprule" valign="top"><span class="Bold">Flip-off Cap Color</span></td><td align="center" class="Toprule" valign="top"><span class="Bold">NDC</span></td> </tr> <tr> <td align="center" class="Toprule">10 mg</td><td align="center" class="Toprule">10 mg/2 mL</td><td align="center" class="Toprule">5 mg/mL</td><td align="center" class="Toprule">Brown</td><td align="center" class="Toprule">55292-139-01</td> </tr> <tr> <td align="center" class="Toprule">20 mg</td><td align="center" class="Toprule">20 mg/2 mL</td><td align="center" class="Toprule">10 mg/mL</td><td align="center" class="Toprule">Gray</td><td align="center" class="Toprule">55292-140-01</td> </tr> <tr> <td align="center" class="Toprule">30 mg</td><td align="center" class="Toprule">30 mg/2 mL</td><td align="center" class="Toprule">15 mg/mL</td><td align="center" class="Toprule">Lilac</td><td align="center" class="Toprule">55292-141-01</td> </tr> <tr> <td align="center" class="Toprule">40 mg</td><td align="center" class="Toprule">40 mg/2 mL</td><td align="center" class="Toprule">20 mg/mL</td><td align="center" class="Toprule">Red</td><td align="center" class="Toprule">55292-142-01</td> </tr> <tr class="Last"> <td align="center" class="Toprule">60 mg</td><td align="center" class="Toprule">60 mg/2 mL</td><td align="center" class="Toprule">30 mg/mL</td><td align="center" class="Toprule">Orange</td><td align="center" class="Toprule">55292-143-01</td> </tr> </tbody> </table></div>

Store at 2°C to 8°C (36°F-46°F). Do not freeze.

SIGNIFOR LAR should be stored at refrigerated temperatures between 2°C to 8°C (36°F-46°F) until the time of use. SIGNIFOR LAR drug product kit should remain at room temperature for a minimum of 30 minutes before reconstitution, but should not exceed 24 hours at room temperature. However, after preparation of the drug suspension, it must be administered immediately.

Steatorrhea and Malabsorption of Dietary Fats

Manufactured for:Recordati Rare Diseases Inc., Bridgewater, NJ 08807 U.S.A

<div class="scrollingtable"><table width="100%"> <colgroup> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 7/2024</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="4"><span class="Bold">Patient Information<br/>SIGNIFOR<span class="Sup">®</span> LAR (sig-na-for L.A.R.)<br/>(pasireotide)<br/>for injectable suspension, for intramuscular use </span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First">Read this Patient Information before you start receiving SIGNIFOR LAR, and each time you receive it. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">What is SIGNIFOR LAR?</span> </p> <p>SIGNIFOR LAR is a prescription medicine used to treat people with:</p> <ul> <li>acromegaly for whom surgery has not worked well enough or who cannot have surgery.</li> <li>Cushing's disease for whom surgery has not worked well enough or who cannot have surgery.</li> </ul> <p>It is not known if SIGNIFOR LAR is safe and effective for use in children.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before receiving SIGNIFOR LAR?</span> </p> <p> <span class="Bold">Before you receive SIGNIFOR LAR, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <ul> <li>have high blood sugar (hyperglycemia).</li> <li>have diabetes.</li> <li>have or have had heart problems, including an abnormal heart rate or rhythm or problems with the electrical system of your heart (QT prolongation).</li> <li>have a low level of potassium or magnesium in your blood.</li> <li>have liver problems.</li> <li>have gallstones (cholelithiasis).</li> <li>are pregnant or plan to become pregnant. It is not known if SIGNIFOR LAR will harm your unborn baby.</li> <li>are breastfeeding or plan to breastfeed. It is not known if SIGINFOR LAR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take SIGNIFOR LAR.</li> </ul> <p>Treatment with SIGNIFOR LAR may result in improved fertility and the possibility of unplanned pregnancy in females who have acromegaly or Cushing's disease and have not gone through menopause. Talk to your healthcare provider about birth control methods that may be right for you during treatment with SIGNIFOR LAR.</p> <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.<br/> <br/> SIGNIFOR LAR and other medicines may affect each other, causing side effects. SIGNIFOR LAR may affect the way other medicines work, and other medicines may affect how SIGNIFOR LAR works. Your healthcare provider may need to change your dose of SIGNIFOR LAR or your other medicines. Especially tell your healthcare provider if you take:</p> <ul> <li>medicines to control your heart beat (antiarrhythmics)</li> <li>medicines to control your blood pressure (such as beta-blockers or calcium channel blockers)</li> <li>medicines to control the potassium and magnesium (electrolytes) levels in your body</li> <li>medicines that may affect the way the electrical system of your heart works (QT prolongation)</li> <li>cyclosporine</li> <li>bromocriptine</li> </ul> <p>Ask your healthcare provider for a list of these medicines if you are not sure.<br/> <br/> Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">How will I receive SIGNIFOR LAR? </span> </p> <ul> <li>SIGNIFOR LAR must be given by a trained healthcare provider as an injection into the muscle of your buttocks (intramuscularly).</li> <li>Your healthcare provider will tell you how much SIGNIFOR LAR you will receive and when you will receive it.</li> <li>Your healthcare provider may change your dose of SIGNIFOR LAR or the length of time between your injections. Your healthcare provider will tell you how long you need to receive SIGNIFOR LAR.</li> <li>Before you receive SIGNIFOR LAR for the first time, your healthcare provider should do a blood test to check your fasting blood sugar level, hemoglobin A1c level, electrolyte levels, and your liver function.</li> <li>You will need to check your blood sugar levels during treatment with SIGNIFOR LAR, especially after you start treatment with SIGNIFOR LAR and after your dose is increased. Your healthcare provider will tell you how often you should check your blood sugar levels.</li> <li>Before you receive SIGNIFOR LAR for the first time and during your treatment, your healthcare provider should do a test to check your heart (electrocardiogram).</li> <li>If you miss a dose of SIGNIFOR LAR, you may receive your missed dose up to 14 days before your next dose.</li> <li>It is important that you keep your scheduled appointments with your healthcare provider during treatment with SIGNIFOR LAR.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">What are the possible side effects of SIGNIFOR LAR?</span> </p> <p> <span class="Bold">SIGNIFOR LAR may cause serious side effects, including: </span> </p> <ul> <li> <span class="Bold">high blood sugar (hyperglycemia), diabetes, and increased ketones in your urine or blood (ketoacidosis). </span>High blood sugar and diabetes are serious but common side effects of SIGNIFOR LAR. Ketoacidosis is a serious condition that should be evaluated and treated promptly.Your healthcare provider should check your blood sugar level before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider right away if you have any of these symptoms:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <p class="First">o feel very thirsty<br/> <br/> o urinate more than usual</p> <p></p> <p></p> <p></p> <p>o nausea<br/> <br/>o vomiting<br/>o abdominal pain</p> </td><td> <p class="First">o increased appetite with weight loss<br/> <br/> o tiredness</p> <p></p> <p></p> <p></p> <p>o fruity scented breath<br/> <br/> o trouble breathing</p> <p></p> <p></p> <p></p> <p>o confusion</p> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <p class="First">If you get hyperglycemia while receiving SIGNIFOR LAR, your healthcare provider may give you another medicine to lower your blood sugar. Your healthcare provider may also change your dose of SIGNIFOR LAR or advise you to stop receiving it.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <ul> <li> <span class="Bold">slow heart rate (bradycardia). </span>SIGNIFOR LAR can cause your heart to beat slower. People who have, or have had heart problems, or take certain medicines used to treat slow heart rate or that may cause a slow heart rate, are at higher risk for bradycardia. Tell your healthcare provider if you get any of these symptoms:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <p class="First">o weakness<br/> <br/> o dizziness</p> </td><td> <p class="First">o fainting or near fainting spells</p> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <ul> <li> <span class="Bold">changes in the electrical system of your heart (QT interval prolongation). </span>Tell your healthcare provider if you get any of these symptoms:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <p class="First">o weakness<br/> <br/> o dizziness</p> </td><td> <p class="First">o fainting or near fainting spells</p> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <ul> <li> <span class="Bold">higher than normal liver function tests. </span>Your healthcare provider should do blood tests to check your liver while you receive SIGNIFOR LAR.</li> <li> <span class="Bold">gallstones (cholelithiasis) and complications that can happen if you have gallstones. </span>Gallstones are a serious but common side effect of SIGNIFOR LAR. Possible complications of gallstones include inflammation and infection of the gall bladder. Your healthcare provider should do a test (ultrasound) to check your gall bladder before and during your treatment with SIGNIFOR LAR. Tell your healthcare provider if you get any of these symptoms:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <p class="First">o sudden pain in your upper right stomach area (abdomen)<br/> <br/> o sudden pain in your right shoulder or between your shoulder blades</p> </td><td> <p class="First">o yellowing of your skin and whites of your eyes<br/> <br/> o fever with chills<br/> <br/> o nausea</p> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <ul> <li> <span class="Bold">low levels of pituitary hormones (pituitary insufficiency). </span>SIGNIFOR LAR may reduce the pituitary hormones in your body. Your healthcare provider should do a blood test to check your pituitary hormone levels before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider if you get any of these symptoms:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <p class="First">o nausea and vomiting<br/> <br/> o tiredness<br/> <br/> o dizziness<br/> <br/> o diarrhea</p> </td><td> <p class="First">o low blood sugar levels<br/> <br/> o loss of appetite<br/> <br/> o weight loss</p> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <ul> <li> <span class="Bold">fatty stool.</span> SIGNIFOR LAR may cause your body to have issues absorbing dietary fats. Tell your healthcare provider if you have any new or worsening symptoms including fatty stools, changes in the color of your stools, loose stools, stomach (abdominal) bloating or weight loss.</li> </ul> <p class="First"> <span class="Bold">The most common side effects of SIGNIFOR LAR include:</span> </p> </td> </tr> <tr> <td class="Lrule">• diarrhea<br/> <br/> • headache<br/> <br/> • stomach-area pain<br/> <br/> • hair loss<br/> <br/> • stuffy nose and sore throat<br/> <br/> • low blood sugar<br/> <br/> • limb swelling<br/> <br/> • loss of appetite</td><td></td><td>• nausea<br/> <br/> • increase in the level of an enzyme in your blood called creatine phosphokinase (CPK)<br/> <br/> • tiredness<br/> <br/> • stomach bloating<br/> <br/> • high blood pressure<br/> <br/> • back pain</td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"> <p class="First">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of SIGNIFOR LAR. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">How should I store SIGNIFOR LAR?</span> </p> <ul> <li>Store SIGNIFOR LAR in the refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li> <span class="Bold">Do not</span> freeze SIGNIFOR LAR.</li> <li>Take SIGNIFOR LAR out of the refrigerator at least <span class="Bold">30 minutes</span> before you will receive it to allow it to come to room temperature.</li> <li> <span class="Bold">Do not</span> use SIGNIFOR LAR if it has been out of the refrigerator and at room temperature for more than 24 hours.</li> <li>Your healthcare provider should give you SIGNIFOR LAR right away after it is mixed.</li> </ul> <p> <span class="Bold">Keep SIGNIFOR LAR and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">General information about the safe and effective use of SIGNIFOR LAR.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SIGNIFOR LAR for a condition for which it was not prescribed. Do not give SIGNIFOR LAR to other people, even if they have the same symptoms that you have. It may harm them.</p> <p>This Patient Information leaflet summarizes the most important information about SIGNIFOR LAR. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SIGNIFOR LAR that is written for health professionals.</p> <p>For more information go to www.SIGNIFORLAR.com or call 1-888-575-8344.</p> </td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">What are the ingredients in SIGNIFOR LAR?</span> </p> <p> <span class="Bold">Active ingredient: </span>pasireotide pamoate</p> <p> <span class="Bold">Inactive ingredients: </span> </p> <p> <span class="Bold">Vial: </span>Poly(D,L-lactide-co-glycolide)</p> <p> <span class="Bold">Prefilled syringe: </span>Mannitol, carboxymethylcellulose sodium, poloxamer 188, and water for injections</p> <p>Manufactured for:<br/> Recordati Rare Diseases Inc., Bridgewater, NJ 08807 U.S.A</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col width=\"25%\"/>\n<col width=\"25%\"/>\n<col width=\"25%\"/>\n<col width=\"25%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First Last\">\n<td colspan=\"3\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 7/2024</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"4\"><span class=\"Bold\">Patient Information<br/>SIGNIFOR<span class=\"Sup\">®</span> LAR (sig-na-for L.A.R.)<br/>(pasireotide)<br/>for injectable suspension, for intramuscular use </span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">Read this Patient Information before you start receiving SIGNIFOR LAR, and each time you receive it. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What is SIGNIFOR LAR?</span>\n</p>\n<p>SIGNIFOR LAR is a prescription medicine used to treat people with:</p>\n<ul>\n<li>acromegaly for whom surgery has not worked well enough or who cannot have surgery.</li>\n<li>Cushing's disease for whom surgery has not worked well enough or who cannot have surgery.</li>\n</ul>\n<p>It is not known if SIGNIFOR LAR is safe and effective for use in children.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before receiving SIGNIFOR LAR?</span>\n</p>\n<p>\n<span class=\"Bold\">Before you receive SIGNIFOR LAR, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<ul>\n<li>have high blood sugar (hyperglycemia).</li>\n<li>have diabetes.</li>\n<li>have or have had heart problems, including an abnormal heart rate or rhythm or problems with the electrical system of your heart (QT prolongation).</li>\n<li>have a low level of potassium or magnesium in your blood.</li>\n<li>have liver problems.</li>\n<li>have gallstones (cholelithiasis).</li>\n<li>are pregnant or plan to become pregnant. It is not known if SIGNIFOR LAR will harm your unborn baby.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if SIGINFOR LAR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take SIGNIFOR LAR.</li>\n</ul>\n<p>Treatment with SIGNIFOR LAR may result in improved fertility and the possibility of unplanned pregnancy in females who have acromegaly or Cushing's disease and have not gone through menopause. Talk to your healthcare provider about birth control methods that may be right for you during treatment with SIGNIFOR LAR.</p>\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.<br/>\n<br/>\t\t\tSIGNIFOR LAR and other medicines may affect each other, causing side effects. SIGNIFOR LAR may affect the way other medicines work, and other medicines may affect how SIGNIFOR LAR works. Your healthcare provider may need to change your dose of SIGNIFOR LAR or your other medicines. Especially tell your healthcare provider if you take:</p>\n<ul>\n<li>medicines to control your heart beat (antiarrhythmics)</li>\n<li>medicines to control your blood pressure (such as beta-blockers or calcium channel blockers)</li>\n<li>medicines to control the potassium and magnesium (electrolytes) levels in your body</li>\n<li>medicines that may affect the way the electrical system of your heart works (QT prolongation)</li>\n<li>cyclosporine</li>\n<li>bromocriptine</li>\n</ul>\n<p>Ask your healthcare provider for a list of these medicines if you are not sure.<br/>\n<br/>\t\t\tKnow the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">How will I receive SIGNIFOR LAR? </span>\n</p>\n<ul>\n<li>SIGNIFOR LAR must be given by a trained healthcare provider as an injection into the muscle of your buttocks (intramuscularly).</li>\n<li>Your healthcare provider will tell you how much SIGNIFOR LAR you will receive and when you will receive it.</li>\n<li>Your healthcare provider may change your dose of SIGNIFOR LAR or the length of time between your injections. Your healthcare provider will tell you how long you need to receive SIGNIFOR LAR.</li>\n<li>Before you receive SIGNIFOR LAR for the first time, your healthcare provider should do a blood test to check your fasting blood sugar level, hemoglobin A1c level, electrolyte levels, and your liver function.</li>\n<li>You will need to check your blood sugar levels during treatment with SIGNIFOR LAR, especially after you start treatment with SIGNIFOR LAR and after your dose is increased. Your healthcare provider will tell you how often you should check your blood sugar levels.</li>\n<li>Before you receive SIGNIFOR LAR for the first time and during your treatment, your healthcare provider should do a test to check your heart (electrocardiogram).</li>\n<li>If you miss a dose of SIGNIFOR LAR, you may receive your missed dose up to 14 days before your next dose.</li>\n<li>It is important that you keep your scheduled appointments with your healthcare provider during treatment with SIGNIFOR LAR.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of SIGNIFOR LAR?</span>\n</p>\n<p>\n<span class=\"Bold\">SIGNIFOR LAR may cause serious side effects, including: </span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">high blood sugar (hyperglycemia), diabetes, and increased ketones in your urine or blood (ketoacidosis). </span>High blood sugar and diabetes are serious but common side effects of SIGNIFOR LAR. Ketoacidosis is a serious condition that should be evaluated and treated promptly.Your healthcare provider should check your blood sugar level before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider right away if you have any of these symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\">\n<p class=\"First\">o feel very thirsty<br/>\n<br/>\t\t\to urinate more than usual</p>\n<p></p>\n<p></p>\n<p></p>\n<p>o nausea<br/>\n<br/>o vomiting<br/>o abdominal pain</p>\n</td><td>\n<p class=\"First\">o increased appetite with weight loss<br/>\n<br/>\t\t\to tiredness</p>\n<p></p>\n<p></p>\n<p></p>\n<p>o fruity scented breath<br/>\n<br/>\t\t\to trouble breathing</p>\n<p></p>\n<p></p>\n<p></p>\n<p>o confusion</p>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">If you get hyperglycemia while receiving SIGNIFOR LAR, your healthcare provider may give you another medicine to lower your blood sugar. Your healthcare provider may also change your dose of SIGNIFOR LAR or advise you to stop receiving it.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<ul>\n<li>\n<span class=\"Bold\">slow heart rate (bradycardia). </span>SIGNIFOR LAR can cause your heart to beat slower. People who have, or have had heart problems, or take certain medicines used to treat slow heart rate or that may cause a slow heart rate, are at higher risk for bradycardia. Tell your healthcare provider if you get any of these symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\">\n<p class=\"First\">o weakness<br/>\n<br/>\t\t\to dizziness</p>\n</td><td>\n<p class=\"First\">o fainting or near fainting spells</p>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<ul>\n<li>\n<span class=\"Bold\">changes in the electrical system of your heart (QT interval prolongation). </span>Tell your healthcare provider if you get any of these symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\">\n<p class=\"First\">o weakness<br/>\n<br/>\t\t\to dizziness</p>\n</td><td>\n<p class=\"First\">o fainting or near fainting spells</p>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<ul>\n<li>\n<span class=\"Bold\">higher than normal liver function tests. </span>Your healthcare provider should do blood tests to check your liver while you receive SIGNIFOR LAR.</li>\n<li>\n<span class=\"Bold\">gallstones (cholelithiasis) and complications that can happen if you have gallstones. </span>Gallstones are a serious but common side effect of SIGNIFOR LAR. Possible complications of gallstones include inflammation and infection of the gall bladder. Your healthcare provider should do a test (ultrasound) to check your gall bladder before and during your treatment with SIGNIFOR LAR. Tell your healthcare provider if you get any of these symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\">\n<p class=\"First\">o sudden pain in your upper right stomach area (abdomen)<br/>\n<br/>\t\t\to sudden pain in your right shoulder or between your shoulder blades</p>\n</td><td>\n<p class=\"First\">o yellowing of your skin and whites of your eyes<br/>\n<br/>\t\t\to fever with chills<br/>\n<br/>\t\t\to nausea</p>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<ul>\n<li>\n<span class=\"Bold\">low levels of pituitary hormones (pituitary insufficiency). </span>SIGNIFOR LAR may reduce the pituitary hormones in your body. Your healthcare provider should do a blood test to check your pituitary hormone levels before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider if you get any of these symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\">\n<p class=\"First\">o nausea and vomiting<br/>\n<br/>\t\t\to tiredness<br/>\n<br/>\t\t\to dizziness<br/>\n<br/>\t\t\to diarrhea</p>\n</td><td>\n<p class=\"First\">o low blood sugar levels<br/>\n<br/>\t\t\to loss of appetite<br/>\n<br/>\t\t\to weight loss</p>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<ul>\n<li>\n<span class=\"Bold\">fatty stool.</span> SIGNIFOR LAR may cause your body to have issues absorbing dietary fats. Tell your healthcare provider if you have any new or worsening symptoms including fatty stools, changes in the color of your stools, loose stools, stomach (abdominal) bloating or weight loss.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of SIGNIFOR LAR include:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">• diarrhea<br/>\n<br/>\t\t\t• headache<br/>\n<br/>\t\t\t• stomach-area pain<br/>\n<br/>\t\t\t• hair loss<br/>\n<br/>\t\t\t• stuffy nose and sore throat<br/>\n<br/>\t\t\t• low blood sugar<br/>\n<br/>\t\t\t• limb swelling<br/>\n<br/>\t\t\t• loss of appetite</td><td></td><td>• nausea<br/>\n<br/>\t\t\t• increase in the level of an enzyme in your blood called creatine phosphokinase (CPK)<br/>\n<br/>\t\t\t• tiredness<br/>\n<br/>\t\t\t• stomach bloating<br/>\n<br/>\t\t\t• high blood pressure<br/>\n<br/>\t\t\t• back pain</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\">\n<p class=\"First\">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all the possible side effects of SIGNIFOR LAR. For more information, ask your healthcare provider or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store SIGNIFOR LAR?</span>\n</p>\n<ul>\n<li>Store SIGNIFOR LAR in the refrigerator between 36°F to 46°F (2°C to 8°C).</li>\n<li>\n<span class=\"Bold\">Do not</span> freeze SIGNIFOR LAR.</li>\n<li>Take SIGNIFOR LAR out of the refrigerator at least <span class=\"Bold\">30 minutes</span> before you will receive it to allow it to come to room temperature.</li>\n<li>\n<span class=\"Bold\">Do not</span> use SIGNIFOR LAR if it has been out of the refrigerator and at room temperature for more than 24 hours.</li>\n<li>Your healthcare provider should give you SIGNIFOR LAR right away after it is mixed.</li>\n</ul>\n<p>\n<span class=\"Bold\">Keep SIGNIFOR LAR and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of SIGNIFOR LAR.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SIGNIFOR LAR for a condition for which it was not prescribed. Do not give SIGNIFOR LAR to other people, even if they have the same symptoms that you have. It may harm them.</p>\n<p>This Patient Information leaflet summarizes the most important information about SIGNIFOR LAR. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SIGNIFOR LAR that is written for health professionals.</p>\n<p>For more information go to www.SIGNIFORLAR.com or call 1-888-575-8344.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in SIGNIFOR LAR?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient: </span>pasireotide pamoate</p>\n<p>\n<span class=\"Bold\">Inactive ingredients: </span>\n</p>\n<p>\n<span class=\"Bold\">Vial: </span>Poly(D,L-lactide-co-glycolide)</p>\n<p>\n<span class=\"Bold\">Prefilled syringe: </span>Mannitol, carboxymethylcellulose sodium, poloxamer 188, and water for injections</p>\n<p>Manufactured for:<br/>\t\t\tRecordati Rare Diseases Inc., Bridgewater, NJ 08807 U.S.A</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 55292 139 01

{ "type": "p", "children": [], "text": "NDC 55292 139 01" }

Signifor® LAR(pasireotide)

{ "type": "p", "children": [], "text": "Signifor® LAR(pasireotide)" }

For Injectable Suspension

{ "type": "p", "children": [], "text": "For Injectable Suspension" }

For Intramuscular Use

{ "type": "p", "children": [], "text": "For Intramuscular Use" }

Should only be administered by a trained health care professional.

{ "type": "p", "children": [], "text": "Should only be administered by a trained health care professional." }

Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours.

{ "type": "p", "children": [], "text": "Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours." }

RECORDATIRARE DISEASESGROUP

{ "type": "p", "children": [], "text": "RECORDATIRARE DISEASESGROUP" }

Rx only

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

10 mg

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

Each carton contains:

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

{ "type": "ul", "children": [ "One vial containing Signifor® LAR powder", "One prefilled syringe containing diluentsolution for reconstitution", "One vial adapter for drug product reconstitution", "One 20G x 1.5\" safety injection needle" ], "text": "" }

NDC 55292 140 01

{ "type": "p", "children": [], "text": "NDC 55292 140 01" }

Signifor® LAR(pasireotide)

{ "type": "p", "children": [], "text": "Signifor® LAR(pasireotide)" }

For Injectable Suspension

{ "type": "p", "children": [], "text": "For Injectable Suspension" }

For Intramuscular Use

{ "type": "p", "children": [], "text": "For Intramuscular Use" }

Should only be administered by a trained health care professional.

{ "type": "p", "children": [], "text": "Should only be administered by a trained health care professional." }

Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours.

{ "type": "p", "children": [], "text": "Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours." }

RECORDATIRARE DISEASESGROUP

{ "type": "p", "children": [], "text": "RECORDATIRARE DISEASESGROUP" }

Rx only

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

20 mg

{ "type": "p", "children": [], "text": "20 mg" }

Each carton contains:

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

{ "type": "ul", "children": [ "One vial containing Signifor® LAR powder", "One prefilled syringe containing diluentsolution for reconstitution", "One vial adapter for drug product reconstitution", "One 20G x 1.5\" safety injection needle" ], "text": "" }

NDC 55292 141 01

{ "type": "p", "children": [], "text": "NDC 55292 141 01" }

Signifor® LAR(pasireotide)

{ "type": "p", "children": [], "text": "Signifor® LAR(pasireotide)" }

For Injectable Suspension

{ "type": "p", "children": [], "text": "For Injectable Suspension" }

For Intramuscular Use

{ "type": "p", "children": [], "text": "For Intramuscular Use" }

Should only be administered by a trained health care professional.

{ "type": "p", "children": [], "text": "Should only be administered by a trained health care professional." }

Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours.

{ "type": "p", "children": [], "text": "Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours." }

RECORDATIRARE DISEASESGROUP

{ "type": "p", "children": [], "text": "RECORDATIRARE DISEASESGROUP" }

Rx only

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

30 mg

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

Each carton contains:

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

{ "type": "ul", "children": [ "One vial containing Signifor® LAR powder", "One prefilled syringe containing diluentsolution for reconstitution", "One vial adapter for drug product reconstitution", "One 20G x 1.5\" safety injection needle" ], "text": "" }

NDC 55292 142 01

{ "type": "p", "children": [], "text": "NDC 55292 142 01" }

Signifor® LAR(pasireotide)

{ "type": "p", "children": [], "text": "Signifor® LAR(pasireotide)" }

For Injectable Suspension

{ "type": "p", "children": [], "text": "For Injectable Suspension" }

For Intramuscular Use

{ "type": "p", "children": [], "text": "For Intramuscular Use" }

Should only be administered by a trained health care professional.

{ "type": "p", "children": [], "text": "Should only be administered by a trained health care professional." }

Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours.

{ "type": "p", "children": [], "text": "Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours." }

RECORDATIRARE DISEASESGROUP

{ "type": "p", "children": [], "text": "RECORDATIRARE DISEASESGROUP" }

Rx only

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

40 mg

{ "type": "p", "children": [], "text": "40 mg" }

Each carton contains:

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

{ "type": "ul", "children": [ "One vial containing Signifor® LAR powder", "One prefilled syringe containing diluentsolution for reconstitution", "One vial adapter for drug product reconstitution", "One 20G x 1.5\" safety injection needle" ], "text": "" }

NDC 55292 143 01

{ "type": "p", "children": [], "text": "NDC 55292 143 01" }

Signifor® LAR(pasireotide)

{ "type": "p", "children": [], "text": "Signifor® LAR(pasireotide)" }

For Injectable Suspension

{ "type": "p", "children": [], "text": "For Injectable Suspension" }

For Intramuscular Use

{ "type": "p", "children": [], "text": "For Intramuscular Use" }

Should only be administered by a trained health care professional.

{ "type": "p", "children": [], "text": "Should only be administered by a trained health care professional." }

Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours.

{ "type": "p", "children": [], "text": "Remove the injection kit from the refrigerator and let the kit stand at roomtemperature for a minimum of 30 minutes before reconstitution,but do not exceed 24 hours." }

RECORDATIRARE DISEASESGROUP

{ "type": "p", "children": [], "text": "RECORDATIRARE DISEASESGROUP" }

Rx only

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

60 mg

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

Each carton contains:

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

{ "type": "ul", "children": [ "One vial containing Signifor® LAR powder", "One prefilled syringe containing diluentsolution for reconstitution", "One vial adapter for drug product reconstitution", "One 20G x 1.5\" safety injection needle" ], "text": "" }