Signifor Lar Drug Information

Acromegaly 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.

Cushing's Disease 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.

Recommended Baseline Evaluations Prior to Initiation of SIGNIFOR LAR Prior to the initiation of SIGNIFOR LAR, it is recommended that patients have the following baseline evaluations: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) Liver tests Electrocardiogram (ECG), serum potassium and serum magnesium levels Patients with poorly controlled diabetes mellitus, who have inadequate glucose control, should have anti-diabetic therapy optimized prior to starting SIGNIFOR LAR.

Important Administration Instructions SIGNIFOR LAR must be reconstituted by a trained healthcare professional immediately before use. Illustrations on reconstitution are found in Instructions for Use. 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.

Recommended Initial Dose 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).

Dose Adjustment and Monitoring 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.

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.

Dose in Patients With Hepatic Impairment

• For patients with moderately impaired hepatic function (Child-Pugh B): Acromegaly: The recommended initial dose for acromegaly patients with moderately impaired hepatic function is 20 mg once every 4 weeks and the maximum recommended dose is 40 mg once every 4 weeks.
• Cushing's Disease: The recommended initial dose for Cushing's disease patients with moderately impaired hepatic function is 10 mg once every 4 weeks and the maximum recommended dose is 20 mg once every 4 weeks. Avoid use in patients with severe hepatic impairment (Child-Pugh C).

Reconstitution and Intramuscular Injection Instructions

After reconstitution of the SIGNIFOR LAR vial with the provided 2 mL diluent, the intramuscular injectable suspension will have a final concentration of: The entire contents of the reconstituted solution should be administered immediately. 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. Included in the injection kit: Step 1 Step 2 Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging. Step 3 Slowly push the plunger all the way down to transfer all the diluent solution in the vial.

Step 4 Step 5 Unscrew the syringe from the vial adapter. Step 6 Pull the protective cover straight off the needle. Step 7 Step 8

Missed Dose 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.

Clinical Trials Experience

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. 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.

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. 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. In the overall study population, 79% of patients were female and the average age was 39 years at study entry.

Hyperglycemia The average FPG levels in patients with acromegaly naïve to drug therapy study across visits is shown in Figure 2 below. Figure 2. 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.

Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy*

Postmarketing Experience

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. Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy

Effect of Other Drugs on SIGNIFOR LAR 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.

Effect of SIGNIFOR LAR on Other Drugs 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.

Pregnancy 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.

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.

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

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. In the event of an overdose, contact the National Capital Poison Center at 1-800-222-1222 or www.poison.org.