MYCAPSSA

MYCAPSSA delayed release capsules contain octreotide acetate, a somatostatin analog. Octreotide is known chemically as L-cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)]. The molecular weight of octreotide is 1019.3 (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: MYCAPSSA (octreotide) delayed-release capsules are enteric-coated capsules for oral use. Each capsule contains 20 mg of octreotide (provided as octreotide acetate). Octreotide is present as a salt with 1.4 to 2.5 molar equivalents of acetate. The capsules contain the following inactive ingredients: polyvinylpyrrolidone (PVP-12), sodium caprylate, magnesium chloride, polysorbate 80, glyceryl monocaprylate, glyceryl tricaprylate, gelatin, gelatin capsules, and Acryl-EZE ® (methacrylate). The capsule is printed with "OT 20" in Opacode ® black ink. Formula

MYCAPSSA is indicated for long-term maintenance treatment in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide. MYCAPSSA is a somatostatin analog indicated for long-term maintenance treatment in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide (‎ 1 ).

Take MYCAPSSA orally with a glass of water on an empty stomach, at least 1 hour before a meal or at least 2 hours after a meal (‎ 2.1 ). Initiate MYCAPSSA at a dosage of 40 mg daily, administered as 20 mg orally twice daily (‎ 2.2 ). Monitor insulin-like growth factor 1 (IGF-1) levels and patient's signs and symptoms every two weeks during the dose titration or as indicated (‎ 2.2 ). Titrate the MYCAPSSA dosage, based on IGF-1 levels and patient's signs and symptoms. Increase the dosage in increments of 20 mg ( 2.2 ). The maximum recommended dosage is 80 mg daily (‎ 2.2 ). Once the maintenance dosage of MYCAPSSA is achieved, monitor IGF-1 levels and patient's signs and symptoms monthly or as indicated (‎ 2.2 ). For patients with end-stage renal disease, initiate at a dosage of 20 mg orally once daily. Titrate and adjust the maintenance dosage based on IGF-1 levels, patient's signs and symptoms and tolerability (‎ 2.4 ). 2.1 Important Administration Instructions Take MYCAPSSA orally with a glass of water on an empty stomach, at least 1 hour before a meal or at least 2 hours after a meal. Swallow MYCAPSSA capsules whole. Do not crush or chew the capsules. 2.2 Recommended Dosage, Titration, and Monitoring Initiate MYCAPSSA at a dosage of 40 mg daily, administered as 20 mg orally twice daily. Monitor insulin-like growth factor 1 (IGF-1) levels and patient's signs and symptoms every two weeks during the dose titration or as indicated. Titrate the MYCAPSSA dosage based on IGF-1 levels and patient's signs and symptoms. Increase the dosage in increments of 20 mg daily. For MYCAPSSA dosages of 60 mg daily, administer as 40 mg in the morning and 20 mg in the evening. For MYCAPSSA dosages of 80 mg daily, administer as 40 mg twice daily. The maximum recommended dosage of MYCAPSSA is 80 mg daily. Once the maintenance dosage of MYCAPSSA is achieved, monitor IGF-1 levels and patient's signs and symptoms monthly or as indicated. 2.3 Dosage Interruptions and Modifications If IGF-1 levels remain above the upper normal limit after treatment with the maximum recommended dosage of 80 mg daily or the patient cannot tolerate treatment with MYCAPSSA, consider discontinuing MYCAPSSA and switching patient to another somatostatin analog. Withdraw MYCAPSSA therapy periodically to assess disease activity. If IGF-1 levels increase and signs and symptoms recur, resume MYCAPSSA therapy. 2.4 Recommended Dosage in Patients with End Stage Renal Disease For patients with end-stage renal disease, initiate MYCAPSSA at a dosage of 20 mg orally once daily. Titrate and adjust the maintenance dosage of MYCAPSSA based on IGF-1 levels, patient's signs and symptoms and tolerability [see Dosage and Administration (‎2.2 , ‎ 2.3) , Use in Specific Populations (‎8.6) ]. 2.5 Dosage Modifications with Concomitant Use of Proton Pump Inhibitors, H2-receptor Antagonists, or Antacids Patients taking proton pump inhibitors, H2-receptor antagonists, or antacids concomitantly with MYCAPSSA may require increased dosages of MYCAPSSA [see Drug Interactions (‎7.1) ] .

Hypersensitivity to octreotide or any of the components of MYCAPSSA. Anaphylactoid reactions, including anaphylactic shock, have been reported in patients receiving octreotide [see Adverse Reactions (‎6.3) ]. Hypersensitivity to octreotide or any of the components of MYCAPSSA.

The following important adverse reactions are described below and elsewhere in the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (‎5.1) ] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (‎5.2) ] Thyroid Function Abnormalities [see Warnings and Precautions (‎5.3) ] Cardiac Function Abnormalities [see Warnings and Precautions (‎5.4) ] Steatorrhea and Malabsorption of Dieatary Fats [see Warnings and Precautions (‎5.5) ] Changes in Vitamin B 12 Levels [ see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence >10 %) are nausea, diarrhea, headache, arthralgia, asthenia, hyperhidrosis, peripheral swelling, blood glucose increased, vomiting, abdominal discomfort, dyspepsia, sinusitis, osteoarthritis (‎ 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Chiesi Farmaceutici S.p.A. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MYCAPSSA has been evaluated in patients with acromegaly in a placebo-controlled study [see Clinical Studies (‎14) ] and an open-label baseline-controlled study . The data reflect exposure of 183 patients to MYCAPSSA for a mean duration of 29 weeks. In the overall study population, 56% were female and the average age of patients was 54.3 years. Adverse reactions occurring ≥ 5% and greater than placebo for the placebo-controlled study are presented in Table 1 and adverse reactions occurring ≥ 5% in the open-label study are presented in Table 2. Table 1: Adverse Reactions Occurring ≥ 5% and Greater than Placebo in a Placebo-Controlled Study with MYCAPSSA in Acromegaly Patients MYCAPSSA % (N=28) PLACEBO % (N=28) Diarrhea 29 21 Nausea 21 11 Blood glucose increased Includes blood glucose increased, hyperglycemia and glycosylated hemoglobin increased 14 7 Vomiting 14 0 Abdominal discomfort 14 11 Dyspepsia 11 4 Sinusitis 11 0 Osteoarthritis 11 0 Urinary tract infection 7 4 Pain 7 0 Large intestine polyp 7 0 Cholelithiasis 7 4 Table 2: Adverse Reactions Occurring ≥ 5% in an Open-Label Study with MYCAPSSA in Acromegaly Patients MYCAPSSA % (N=155) Headache 33 Nausea 30 Arthralgia 26 Asthenia 22 Hyperhidrosis 21 Diarrhea 18 Peripheral swelling 16 Dyspepsia 8 Abdominal pain upper 8 Abdominal distension 7 Nasopharyngitis 7 Influenza 7 Blood glucose increased Includes blood glucose increased, hyperglycemia and impaired fasting glucose 6 Vomiting 6 Flatulence 6 Back pain 6 Abdominal pain 5 Dizziness 5 Fatigue 5 Upper respiratory tract infection 5 Hypertension 5 Other Adverse Reactions Gallbladder Abnormalities In the placebo-controlled study, in patients treated with MYCAPSSA, acute cholecystitis occurred in 4% of patients. In the open-label study, cholelithiasis occurred in 4.5% of patients and bile duct obstruction, bile duct stone, acute cholecystitis and jaundice occurred in 1% of patients each. Hypoglycemia/Hyperglycemia In the placebo-controlled study, 18% of patients treated with MYCAPSSA and 4% of patients treated with placebo developed at least one glucose value above the upper normal limit. All patients with abnormal glucose values were asymptomatic. Asymptomatic hypoglycemia was reported in 4% of patients. In the open-label study 16% of patients developed a glucose value above the upper limit of normal. Asymptomatic hypoglycemia was reported in 4% and symptomatic hypoglycemia was reported in 1% of patients. Diabetes was reported in 1% of patients. Hypothyroidism In the open-label study, hypothyroidism, increased TSH, or decreased free T4 were reported in 1% of patients. Cardiac In the open-label study, bradycardia was reported in 2%, conduction abnormalities in 1%, and arrhythmias/tachycardia in 2% of patients. Gastrointestinal Gastrointestinal symptoms were the most commonly reported adverse reactions with MYCAPSSA. In the placebo-controlled study, gastrointestinal adverse reactions were reported in 68% of patients treated with MYCAPSSA. These adverse reactions were diarrhea, nausea, vomiting, abdominal discomfort, dyspepsia, large intestinal polyp, abdominal pain, constipation, and flatulence. The adverse reactions were mild to moderate, occurred mostly during the initial 3 months of treatment, and resolved on treatment within a median duration of 8 days. In the open-label study, gastrointestinal adverse reactions were reported in 57% of patients. Gastrointestinal adverse reactions occurring in ≥ 1% of patients were nausea, diarrhea, dyspepsia, abdominal pain, abdominal distention, vomiting, flatulence, constipation, gastroesophageal reflux disease, abdominal discomfort, frequent bowel movement, gastritis, hemorrhoids, dry mouth, and gastrointestinal motility disorder. Large intestinal polyp was reported in 1 patient. The adverse reactions were mostly mild to moderate, occurred during the initial 2 months of treatment, and resolved on treatment within a median of 13 days. Ten patients discontinued treatment due to gastrointestinal adverse reactions. 6.2 Immunogenicity As with all therapeutic peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other octreotide acetate products may be misleading. No antibodies to the octreotide peptide from MYCAPSSA were detected in 149 patients assessed in the open label study throughout 13 months of treatment. 6.3 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of octreotide acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic: pancytopenia, thrombocytopenia Cardiac: myocardial infarction, cardiac arrest, atrial fibrillation Ear and labyrinth: deafness Endocrine: diabetes insipidus, adrenal insufficiency in patients 18 months of age and under, pituitary apoplexy Eye: glaucoma, visual field defect, scotoma, retinal vein thrombosis Gastrointestinal: intestinal obstruction, peptic/gastric ulcer, abdomen enlarged General and administration site: generalized edema, facial edema Hepatobiliary: gallbladder polyp, fatty liver, hepatitis Immune: anaphylactoid reactions including anaphylactic shock Infections and infestations: appendicitis Laboratory abnormalities: increased liver enzymes, CK increased, creatinine increased Metabolism and nutrition: diabetes mellitus Musculoskeletal: arthritis, joint effusion, Raynaud's syndrome Nervous System: convulsions, aneurysm, intracranial hemorrhage, hemiparesis, paresis, suicide attempt, paranoia, migraines, Bell's palsy, aphasia Renal and urinary: renal failure, renal insufficiency Reproductive and breast: gynecomastia, galactorrhea, libido decrease, breast carcinoma Respiratory: status asthmaticus, pulmonary hypertension, pulmonary nodule, pneumothorax aggravated Skin and subcutaneous tissue: urticaria, cellulitis, petechiae Vascular: orthostatic hypotension, hematuria, gastrointestinal hemorrhage, arterial thrombosis of the arm

Proton Pump Inhibitors, H2-receptor Antagonists, or Antacids: may decrease bioavailability of MYCAPSSA and the MYCAPSSA dose may need to be increased (‎ 7 ). Cyclosporine : may have decreased bioavailability and require dose adjustment ( 7 ). Insulin and Antidiabetic Drugs: patients receiving insulin or antidiabetic drugs agents may require dose adjustment (‎ 7 ). Digoxin: exposure may be decreased and assessment of clinical response to digoxin should be performed (‎ 7 ). Lisinopril: bioavailability may be increased, monitor patient's blood pressure and adjust dose of lisinopril if needed (‎ 7 ). Levonorgestrel: counsel women to use an alternative non-hormonal method of contraception or a back-up method when MYCAPSSA is used with combined oral contraceptives (‎ 7 ). Bromocriptine: dose adjustment of bromocriptine may be necessary (‎ 7 ). Beta Blocker and Calcium Channel Blockers : dose adjustment of beta blockers or calcium channel blockers may be necessary (‎ 7 ). Drugs Metabolized by CYP 450 Enzymes: concomitant use with other drugs mainly metabolized by CYP3A4 that have a narrow therapeutic index (e.g., quinidine) should be used with caution and increased monitoring may be required (‎ 7 ). 7.1 Effects of Other Drugs on MYCAPSSA Proton Pump Inhibitors, H2-receptor Antagonists, or Antacids Clinical Impact: Concomitant administration of MYCAPSSA with esomeprazole resulted in a decrease in the bioavailability for MYCAPSSA [ See Clinical Pharmacology (‎12.3) ] . Drugs that alter the pH of the upper GI tract (e.g., other proton pump inhibitors (PPIs), H2-receptor antagonists, and antacids) may alter the absorption of MYCAPSSA and lead to a reduction in bioavailability. Intervention: Co-administration of MYCAPSSA with PPIs, H2-blockers, or antacids may require increased doses of MYCAPSSA. 7.2 Effects of MYCAPSSA on Other Drugs Cyclosporine Clinical Impact: Concomitant administration of MYCAPSSA with cyclosporine resulted in a decrease in cyclosporine bioavailability [see Clinical Pharmacology (‎12.3) ]. Intervention: Adjustment of cyclosporine dose to maintain therapeutic levels may be necessitated. Insulin and Antidiabetic Drugs Clinical Impact: MYCAPSSA inhibits the secretion of insulin and glucagon. Intervention: Monitor blood glucose levels in diabetic patients upon MYCAPSSA initiation and subsequent dose adjustment. Patients receiving insulin or antidiabetic drugs agents may require dose adjustment of these therapeutic agents. Digoxin Clinical Impact: Concomitant administration of MYCAPSSA with digoxin resulted in a decrease in digoxin peak exposure [see Clinical Pharmacology (‎12.3) ]. Intervention: Digoxin has a narrow therapeutic ratio and careful assessment of clinical response should be performed when digoxin is concomitantly administered with MYCAPSSA. Lisinopril Clinical Impact: Concomitant administration of MYCAPSSA increases lisinopril bioavailability [see Clinical Pharmacology (‎12.3) ] . Intervention: Monitor patient's blood pressure and adjust the dosage of lisinopril if needed. Levonorgestrel Clinical Impact: Concomitant administration of MYCAPSSA with levonorgestrel decreases levonorgestrel bioavailability [see Clinical Pharmacology (‎12.3) ] . Intervention: Decreased bioavailability may potentially diminish the effectiveness of combined oral contraceptives (COCs) or increase breakthrough bleeding. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when MYCAPSSA is used with COCs. Bromocriptine Clinical Impact: Concomitant administration of MYCAPSSA with bromocriptine may increase the systemic exposure of bromocriptine [see Clinical Pharmacology (‎12.3) ]. Intervention: Dose adjustment of bromocriptine may be necessary. Beta Blocker and Calcium Channel Blockers Clinical Impact: MYCAPSSA may cause bradycardia in acromegaly patients. Intervention: Patients receiving beta blockers or calcium channel blockers may require dose adjustments of these therapeutic agents. Drugs Metabolized by CYP 450 Enzymes Clinical Impact: Limited published data indicate that somatostatin analogs including MYCAPSSA may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. Intervention: Concomitant use with other drugs mainly metabolized by CYP3A4 that have a narrow therapeutic index (e.g., quinidine) should be used with caution and increased monitoring may be required.

Storage Until first use, store unopened wallets of MYCAPSSA refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. After first use, opened wallets may be stored at 20° to 25°C (68° to 77°F) for up to 1 month.