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
6.1Clinical 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.
6.3Postmarketing 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
