Signifor LAR

Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.6 ) 7/2024

1 INDICATIONS AND USAGE SIGNIFOR LAR is a somatostatin analog 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. ( 1.1 ) Patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative. ( 1.2 ) 1.1 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. 1.2 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.

2 DOSAGE AND ADMINISTRATION Evaluate fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), liver enzyme tests, electrocardiogram (ECG), serum magnesium, and serum potassium prior to starting. ( 2.1 ) Optimize glucose control in patients with poorly controlled diabetes mellitus prior to starting. ( 2.1 ) Must be administered by a health care professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. ( 2.2 ) Initial Dose: Acromegaly: The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days). ( 2.3 ) Cushing's Disease: The initial dose is 10 mg by intramuscular injection once every 4 weeks (every 28 days). ( 2.3 ) Adjust dose based on response and tolerability. ( 2.4 ) Patients with Hepatic Impairment: Child-Pugh B : Acromegaly: Recommended initial dose is 20 mg once every 4 weeks and maximum dose is 40 mg once every 4 weeks ( 2.5 , 8.6 ) Cushing's Disease: Recommended initial dose is 10 mg once every 4 weeks and maximum dose is 20 mg once every 4 weeks ( 2.5 , 8.6 ) Child-Pugh C : Avoid use in these patients ( 2.5 , 8.6 ) Follow reconstitution and administration instructions. ( 2.6 ) 2.1 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) [see Warnings and Precautions (5.1)] Liver tests [see Warnings and Precautions (5.3)] Electrocardiogram (ECG), serum potassium and serum magnesium levels [see Warnings and Precautions (5.2)] 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)] . 2.2 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 [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. 2.3 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) [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) ]. 2.4 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 [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 adren …

3 DOSAGE FORMS AND STRENGTHS 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. SIGNIFOR LAR for injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg, powder in a vial to be reconstituted with the provided 2 mL diluent. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Hyperglycemia, Diabetes, and Ketoacidosis [see Warnings and Precautions (5.1)] Bradycardia and QT Prolongation [see Warnings and Precautions (5.2)] Liver Test Elevations [see Warnings and Precautions (5.3)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.4)] Pituitary Hormone Deficiency(ies) [see Warnings and Precautions (5.5)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.6) ] Adverse drug reactions associated with SIGNIFOR LAR and occurring in ≥ 20% of patients were diarrhea, cholelithiasis, hyperglycemia, and diabetes mellitus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 [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. 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 a Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus. b Sinus bradycardia includes the following PTs: bradycardia and sinus bradycardia. c 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. Adverse Reaction Type SIGNIFOR LAR (40-60 mg) % N = 178 Active Comparator % N = 180 Hyperglycemia Related Adverse Reactions Hyperglycemia 29 8 Diabetes mellitus a 26 4 Blood glucose increased 8 2 Glycosylated hemoglobin increased 6 2 Hypoglycemia 5 7 Gastrointestinal Related Adverse Reactions Diarrhea 39 45 Abdominal pain 18 22 Nausea 14 22 Abdominal distension 12 12 Vomiting 8 7 Abdominal pain upper 6 8 Hepatobiliary Related Adverse Reactions Cholelithiasis 26 36 Cardiac Related Adverse Reactions Sinus bradycardia b 10 7 Hypertension 8 7 Nervous System Related Adverse Reactions Headache 19 26 Dizziness 10 11 Skin Related Adverse Reactions Alopecia 18 19 Infections Related Adverse Reactions Nasopharyngitis 16 16 Influenza 8 4 Upper respiratory tract infection 7 3 Cough 5 8 Laboratory Related Adverse Reactions Blood creatine phosphokinase increased 13 12 Alanine aminotransferase increased 8 4 Aspartate aminotransferase increased 6 4 Lipase increased 6 7 Weight decreased 5 4 General and Injection-Site Related Adverse Reactions Fatigue 10 10 Injection-site reaction c 7 7 Musculoskeletal and Connective Tissue Related Adverse Reactions Arthralgia 10 12 Back pain 8 11 Pain in extremity 7 4 Blood Related Adverse Reactions Anemia 6 6 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 acro …

7 DRUG INTERACTIONS Drugs that Prolong QT: Use with caution in patients who are at significant risk of developing QTc prolongation. ( 5.2 , 7.1 ) Cyclosporine: Consider additional monitoring. ( 7.2 ) Bromocriptine: Consider bromocriptine dose reduction. ( 7.2 ) 7.1 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 [see Warnings and Precautions (5.2)] . 7.2 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.

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential : Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 ) 8.1 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. 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. 8.2 Lactation 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 [ 14 C]-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. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the thera …

12.1 Mechanism of Action 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). Table 4 – Binding Affinities of Somatostatin (SRIF-14) and Pasireotide to the Five Human SSTR Subtypes (SSTR 1-5) Results are the mean + SEM of IC 50 values expressed as nmol/l (nM). Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Somatostatin (SRIF-14) 0.93 ± 0.12 0.15 ± 0.02 0.56 ± 0.17 1.5 ± 0.4 0.29 ± 0.04 Pasireotide 9.3 ± 0.1 1.0 ± 0.1 1.5 ± 0.3 > 100 0.16 ± 0.01

11 DESCRIPTION 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. The molecular formula of pasireotide pamoate is C 58 H 66 N 10 O 9 • C 23 H 16 O 6 and the molecular weight is 1435.58 g/mol. 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). 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: *corresponds to 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg of pasireotide base, respectively. 10 mg 20 mg 30 mg 40 mg 60 mg Pasireotide pamoate 13.71 mg* 27.42 mg* 41.13 mg* 54.84 mg* 82.26 mg* Poly(D,L-lactide-co-glycolide) [50-60:40-50] 13.15 mg 26.29 mg 39.44 mg 52.58 mg 78.87 mg Poly(D,L-lactide-co-glycolide) [50:50] 13.15 mg 26.29 mg 39.44 mg 52.58 mg 78.87 mg Each diluent prefilled syringe contains: Mannitol 90 mg Carboxymethylcellulose sodium 14 mg Poloxamer 188 4 mg Water for injections add to 2 mL structural formula

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SIGNIFOR LAR for injectable suspension is supplied in a single-use kit containing the following: One 6-mL brownish glass vial with a grey rubber stopper of SIGNIFOR LAR containing slightly yellow to yellow powder with a flip-off cap One 3-mL glass barrel/grey rubber stopper prefilled syringe containing 2 mL of clear, colorless to slightly yellow/brown diluent solution for reconstitution One sterile 20G x 1.5" stainless steel, polypropylene safety injection needle One vial adapter made of polycarbonate for drug product reconstitution SIGNIFOR LAR kits are available in the following strengths: SIGNIFOR LAR Kit Final Concentration When Reconstituted (total product strength per total volume) Final Concentration When Reconstituted (per mL) Flip-off Cap Color NDC 10 mg 10 mg/2 mL 5 mg/mL Brown 55292-139-01 20 mg 20 mg/2 mL 10 mg/mL Gray 55292-140-01 30 mg 30 mg/2 mL 15 mg/mL Lilac 55292-141-01 40 mg 40 mg/2 mL 20 mg/mL Red 55292-142-01 60 mg 60 mg/2 mL 30 mg/mL Orange 55292-143-01 16.2 Storage and Handling 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.

16.1 How Supplied SIGNIFOR LAR for injectable suspension is supplied in a single-use kit containing the following: One 6-mL brownish glass vial with a grey rubber stopper of SIGNIFOR LAR containing slightly yellow to yellow powder with a flip-off cap One 3-mL glass barrel/grey rubber stopper prefilled syringe containing 2 mL of clear, colorless to slightly yellow/brown diluent solution for reconstitution One sterile 20G x 1.5" stainless steel, polypropylene safety injection needle One vial adapter made of polycarbonate for drug product reconstitution SIGNIFOR LAR kits are available in the following strengths: SIGNIFOR LAR Kit Final Concentration When Reconstituted (total product strength per total volume) Final Concentration When Reconstituted (per mL) Flip-off Cap Color NDC 10 mg 10 mg/2 mL 5 mg/mL Brown 55292-139-01 20 mg 20 mg/2 mL 10 mg/mL Gray 55292-140-01 30 mg 30 mg/2 mL 15 mg/mL Lilac 55292-141-01 40 mg 40 mg/2 mL 20 mg/mL Red 55292-142-01 60 mg 60 mg/2 mL 30 mg/mL Orange 55292-143-01

16.2 Storage and Handling 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.