OCTREOTIDE: 23,724 Adverse Event Reports & Safety Profile

Octreotide acetate injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered acetic acid solution for administration by deep subcutaneous or IV injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl) propyl]-,cyclic (2 → 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. Octreotide acetate injection is available as sterile 1-mL single dose vials in 3 strengths, each mL containing 50 mcg, 100 mcg, or 500 mcg octreotide acetate, USP as the active ingredient and sterile 5-mL multi-dose vials in 2 strengths, containing 200 and 1,000 mcg/mL of octreotide acetate, USP as the active ingredient. Each mL of the single-dose vials also contains following inactive ingredients: glacial acetic acid, USP.......................................................................................................................................2 mg sodium acetate (trihydrate), USP........................................................................................................................2 mg sodium chloride, USP.........................................................................................................................................7 mg water for injection........................................................................................................... quantity sufficient to 1 mL Each mL of the multi-dose vials also contains following inactive ingredients: glacial acetic acid, USP......................................................................................................................................2 mg sodium acetate (trihydrate), USP........................................................................................................................2 mg sodium chloride, USP.........................................................................................................................................7 mg phenol, USP .......................................................................................................................................................5 mg water for injection............................................................................................................ quantity sufficient to 1 mL Glacial acetic acid, USP and sodium acetate (trihydrate), USP are added to provide a buffered solution, pH to 3.9 to 4.5. The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: chemical-structure

AND USAGE Octreotide acetate injection is a somatostatin analogue indicated:

• Acromegaly : To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. ( 1.1 )
• Carcinoid Tumors : For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. ( 1.2 )
• Vasoactive Intestinal Peptide Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. ( 1.3 ) Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide acetate injection; these trials were not optimally designed to detect such effects. ( 1.4 )

1.1 Acromegaly Octreotide acetate injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.

1.2 Carcinoid Tumors Octreotide acetate injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

1.3 Vasoactive Intestinal Peptide Tumors Octreotide acetate injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors.

1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide acetate injection; these trials were not optimally designed to detect such effects.

AND ADMINISTRATION

• Octreotide acetate for injectable suspension should be administered by a trained healthcare provider. It is important to closely follow the mixing instructions included in the packaging. Octreotide acetate for injectable suspension must be administered immediately after mixing. Discard unused portion.
• Do not directly inject diluent without preparing suspension.
• The recommended needle size for administration of octreotide acetate for injectable suspension is the 1½” 19 gauge safety injection needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a size 2” 19 gauge needle (not supplied) may be used.
• Octreotide acetate for injectable suspension should be administered intramuscularly (IM) in the gluteal region at 4-week intervals. Administration of octreotide acetate for injectable suspension at intervals greater than 4 weeks is not recommended.
• Injection sites should be rotated in a systematic manner to avoid irritation. Deltoid injections should be avoided due to significant discomfort at the injection site when given in that area.
• Octreotide acetate for injectable suspension should never be administered intravenously or subcutaneously. The following dosage regimens are recommended.

Patients Not Currently Receiving Octreotide

Acetate Injection Subcutaneously:

• Acromegaly: 50 mcg three times daily octreotide acetate injection subcutaneously for 2 weeks followed by octreotide acetate for injectable suspension 20 mg intragluteally every 4 weeks for 3 months ( 2.1 )
• Carcinoid Tumors and VIPomas: Octreotide acetate injection subcutaneously 100 mcg/day to 600 mcg/day in 2 to 4 divided doses for 2 weeks followed by octreotide acetate for injectable suspension 20 mg every 4 weeks for 2 months ( 2.2 )

Patients Currently Receiving Octreotide Acetate

Injection Subcutaneously:

• Acromegaly: 20 mg every 4 weeks for 3 months ( 2.1 )
• Carcinoid Tumors and VIPomas: 20 mg every 4 weeks for 2 months ( 2.2 )

Renal

Impairment, Patients on Dialysis: 10 mg every 4 weeks ( 2.3 )

Hepatic

Impairment, Patients With Cirrhosis: 10 mg every 4 weeks ( 2.4 )

2.1 Acromegaly Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with octreotide acetate injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily. Patients should be maintained on octreotide acetate injection subcutaneous for at least 2 weeks to determine tolerance to octreotide acetate. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug, can then be switched to octreotide acetate for injectable suspension in the dosage scheme described below (Patients Currently Receiving Octreotide Acetate Injection).

Patients Currently Receiving Octreotide Acetate

Injection Patients currently receiving octreotide acetate injection can be switched directly to octreotide acetate for injectable suspension in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months.

After

3 months, dosage may be adjusted as follows:

• GH ≤ 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain octreotide acetate for injectable suspension dosage at 20 mg every 4 weeks
• GH > 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase octreotide acetate for injectable suspension dosage to 30 mg every 4 weeks
• GH ≤ 1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce octreotide acetate for injectable suspension dosage to 10 mg every 4 weeks
• If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended. In patients who have received pituitary irradiation, octreotide acetate for injectable suspension should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide acetate for injectable suspension therapy may be resumed.

2.2 Carcinoid Tumors and VIPomas Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with octreotide acetate injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100 mcg/day to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg). Some patients may require doses up to 1,500 mcg/day. The suggested daily dosage for VIPomas is 200 mcg to 300 mcg in 2 to 4 divided doses (range, 150 mcg to 750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required. Octreotide acetate injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide acetate, and who tolerate the drug, may be switched to octreotide acetate for injectable suspension in the dosage regimen as described below (Patients Currently Receiving Octreotide Acetate Injection).

Patients Currently Receiving Octreotide Acetate

Injection Patients currently receiving octreotide acetate injection can be switched to octreotide acetate for injectable suspension in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of octreotide acetate for injectable suspension, carcinoid tumor and VIPoma patients should continue to receive octreotide acetate injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms (some patients may require 3 or 4 weeks of such therapy).

After

2 months, dosage may be adjusted as follows:

• If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10 mg dose every 4 weeks.
• If symptoms are not adequately controlled, increase octreotide acetate for injectable suspension to 30 mg every 4 weeks. Patients who achieve good control on a 20 mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
• Dosages higher than 30 mg are not recommended. Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on octreotide acetate injection or octreotide acetate for injectable suspension). During these periods, they may be given octreotide acetate injection subcutaneously for a few days at the dosage they were receiving prior to switching to octreotide acetate for injectable suspension. When symptoms are again controlled, the octreotide acetate injection subcutaneous can be discontinued.

2.3 Special Populations: Renal Impairment In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12) ]</span> .

2.4 Special Populations: Hepatic Impairment – Cirrhotic Patients In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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.

REACTIONS The following clinically significant adverse reactions are described 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 Dietary Fats [see Warnings and Precautions (5.5) ]
• Changes in Vitamin B12 Levels [see Warnings and Precautions (5.6) ]
• Changes in Zinc Levels [see Warnings and Precautions (5.7) ]
• Monitoring: Laboratory Tests [see Warnings and Precautions (5.8) ]
• Drug Interactions [see Warnings and Precautions (5.9) ] The most common adverse reactions, occurring in ≥ 20% of patients are:
• Acromegaly: diarrhea, cholelithiasis, abdominal pain, flatulence ( 6.1 )
• Carcinoid Syndrome: back pain, fatigue, headache, abdominal pain, nausea, dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Acromegaly

The safety of octreotide acetate for injectable suspension in the treatment of acromegaly has been evaluated in three Phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. Octreotide acetate for injectable suspension was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous octreotide acetate injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14 to 81 years old and 53% were female.

Approximately

35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10 mg to 60 mg every 4 weeks.

Table

1 below reflects adverse events from these studies regardless of presumed causality to study drug.

Table

1.

Adverse Events

Occurring in ≥ 10% of Acromegalic Patients in the Phase 3 Studies Abbreviation: AEs, adverse events.

Who

Preferred Term Phase 3 Studies (Pooled) Number (%) of Subjects with AEs 10 mg/20 mg/30 mg (n = 261) n (%)

Diarrhea

93 (35.6)

Abdominal Pain

75 (28.7)

Flatulence

66 (25.3) Influenza-Like Symptoms 52 (19.9)

Constipation

46 (17.6)

Headache

40 (15.3)

Anemia

40 (15.3) Injection-Site Pain 36 (13.8)

Cholelithiasis

35 (13.4)

Hypertension

33 (12.6)

Dizziness

30 (11.5)

Fatigue

29 (11.1) The safety of octreotide acetate for injectable suspension in the treatment of acromegaly was also evaluated in a postmarketing randomized Phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of octreotide acetate for injectable suspension. All the patients were treatment naïve ( ‘de novo’ ). Crossover was allowed according to treatment response and a total of 76 patients were exposed to octreotide acetate for injectable suspension. Approximately half of the patients initially randomized to octreotide acetate for injectable suspension were exposed to octreotide acetate for injectable suspension up to 1 year. The population age range was between 20 to 76 years old, 45% were female, 93% were Caucasian, and 1% Black. The majority of these patients were exposed to 30 mg every 4 weeks.

Table

2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug.

Table

2.

Adverse Events

Occurring in ≥ 10% of Acromegalic Patients in Phase 4 Study WHO Preferred Term Phase 4 Study Octreotide Acetate for Injectable Suspension N = 76 n (%)

Phase

4 Study Surgery N = 64 n (%)

Diarrhea

36 (47.4) 2 (3.1)

Cholelithiasis

29 (38.2) 3 (4.7)

Abdominal Pain

19 (25.0) 2 (3.1)

Nausea

12 (15.8) 5 (7.8)

Alopecia

10 (13.2) 5 (7.8) Injection-Site Pain 9 (11.8) 0 Abdominal Pain Upper 8 (10.5) 0 Headache 8 (10.5) 6 (9.4)

Epistaxis

0 7 (10.9)

Gallbladder Abnormalities

Single doses of octreotide acetate injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with octreotide acetate injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide acetate, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure. In clinical trials, 52% of acromegalic patients, most of whom received octreotide acetate for injectable suspension for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones. Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during octreotide acetate injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide acetate, 1% of patients developed acute symptoms requiring cholecystectomy.

Glucose

Metabolism - Hypoglycemia/Hyperglycemia In acromegaly patients treated with either octreotide acetate injection or octreotide acetate for injectable suspension, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions (5.2) ] . Hypothyroidism In acromegaly patients receiving octreotide acetate injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving octreotide acetate injection. In acromegalic patients treated with octreotide acetate for injectable suspension, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving octreotide acetate for injectable suspension required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5.3) ] . Cardiac In acromegalic patients, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate injection-therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4) ] .

Gastrointestinal

The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3.

Table

3. Number (%) of Acromegalic Patients With Common GI Adverse Events Adverse Event Octreotide Acetate Injection S.C.

Three Times

Daily n = 114 Octreotide Acetate for Injectable Suspension Every 28 Days n = 261 n % n % Diarrhea 66 (57.9) 95 (36.4)

Abdominal

Pain or Discomfort 50 (43.9) 76 (29.1)

Nausea

34 (29.8) 27 (10.3)

Flatulence

15 (13.2) 67 (25.7)

Constipation

10 (8.8) 49 (18.8)

Vomiting

5 (4.4) 17 (6.5)

Only

2.6% of the patients on octreotide acetate injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving octreotide acetate for injectable suspension discontinued therapy for a GI event. In patients receiving octreotide acetate for injectable suspension, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with octreotide acetate for injectable suspension. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity. In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding. Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4% to 6% of patients. In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27% to 38% and constipation or vomiting in 15% to 21% of patients treated with octreotide acetate for injectable suspension. Diarrhea was reported as an adverse event in 14% of patients, but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea. Pain at the Injection Site Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalic patients receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of octreotide acetate for injectable suspension. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20% to 25% at a 10 mg dose and about 30% to 50% at the 20 mg and 30 mg dose. Antibodies to Octreotide Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received octreotide acetate injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with octreotide acetate for injectable suspension. Carcinoid and VIPomas The safety of octreotide acetate for injectable suspension in the treatment of carcinoid tumors and VIPomas has been evaluated in one Phase 3 study.

Study

1 randomized 93 patients with carcinoid syndrome to octreotide acetate for injectable suspension 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label octreotide acetate injection subcutaneously. The population age range was between 25 to 78 years old and 44% were female, 95% were Caucasian and 3% Black. All the patients had symptom control on their previous octreotide acetate injection subcutaneous treatment. Eighty (80) patients finished the initial 24 weeks of octreotide acetate injection exposure in Study 1.

In Study

1, comparable numbers of patients were randomized to each dose.

Table

4 below reflects the adverse events occurring in ≥ 15% of patients regardless of presumed causality to study drug.

Table

4.

Adverse Events

Occurring in ≥ 15% of Carcinoid Tumor and VIPoma Patients in Study 1 Number (%) of Subjects With AEs (n = 93)

Who

Preferred Term S.C. N = 26 10 mg N = 22 20 mg N = 20 30 mg N = 25 Abdominal Pain 8 (30.8) 8 (35.4) 2 (10.0) 5 (20.0)

Arthropathy

5 (19.2) 2 (9.1) 3 (15.0) 2 (8.0)

Back Pain

7 (26.9) 6 (27.3) 2 (10.0) 2 (8.0)

Dizziness

4 (15.4) 4 (18.2) 4 (20.0) 5 (20.0)

Fatigue

3 (11.5) 7 (31.8) 2 (10.0) 2 (8.0)

Flatulence

3 (11.5) 2 (9.1) 2 (10.0) 4 (16.0)

Generalized Pain

4 (15.4) 2 (9.1) 3 (15.0) 1 (4.0)

Headache

5 (19.2) 4 (18.2) 6 (30.0) 4 (16.0)

Musculoskeletal Pain

4 (15.4) 0 1 (5.0) 0 Myalgia 0 4 (18.2) 1 (5.0) 1 (4.0)

Nausea

8 (30.8) 9 (40.9) 6 (30.0) 6 (24.0)

Pruritus

0 4 (18.2) 0 0 Rash 1 (3.8) 0 3 (15.0) 0 Sinusitis 4 (15.4) 0 1 (5.0) 3 (12.0) URTI 6 (23.1) 4 (18.2) 2 (10.0) 3 (12.0)

Vomiting

3 (11.5) 0 0 4 (16.0)

Gallbladder

Abnormalities In clinical trials, 62% of malignant carcinoid patients, who received octreotide acetate for injectable suspension for up to 18 months, developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.

Glucose

Metabolism - Hypoglycemia/Hyperglycemia In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with octreotide acetate for injectable suspension [see Warnings and Precautions (5.2) ] . Hypothyroidism In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5.3) ] .

Cardiac

Electrocardiograms were performed only in carcinoid patients receiving octreotide acetate for injectable suspension. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4) ] .

Other Clinical Studies Adverse Events

Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving octreotide acetate for injectable suspension were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.

6.2 Postmarketing Experience The following adverse reactions have been identified during the postapproval use of octreotide acetate for injectable suspension. 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, pancreatic exocrine insufficiency 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

AND PRECAUTIONS

• Cardiac Function Abnormalities : Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving Octreotide acetate injection intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. ( 5.1 )
• Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.2 )
• Glucose Metabolism : Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. ( 5.3 )
• Thyroid Function : Hypothyroidism may occur. Monitor thyroid levels periodically. ( 5.4 )
• Steatorrhea and Malabsorption of Dietary Fats: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. ( 5.5 )

5.1 Cardiac Function Abnormalities Complete Atrioventricular Block Patients who receive octreotide acetate injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving IV octreotide acetate injection during surgical procedures. In the majority of patients, octreotide acetate injection was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving octreotide acetate injection for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate injection intravenously.

Other Cardiac Conduction Abnormalities

Other cardiac conduction abnormalities have occurred during treatment with octreotide acetate injection. In acromegalic patients, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during octreotide acetate injection therapy [see Adverse Reactions (6) ] . Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of octreotide acetate injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.

5.2 Cholelithiasis and Complications of Cholelithiasis Octreotide acetate injection may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide acetate injection therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate injection for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide acetate injection therapy and died. If complications of cholelithiasis are suspected, discontinue octreotide acetate injection and treat appropriately.

5.3 Hyperglycemia and Hypoglycemia Octreotide acetate injection alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate injection therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate injection in 3% and 16% of acromegalic patients, respectively <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate injection therapy was reported in one patient with no history of hyperglycemia. Monitor glucose levels during octreotide acetate injection therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly.

5.4 Thyroid Function Abnormalities Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T4) is recommended during chronic therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including octreotide acetate injection. 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 octreotide acetate injection, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly .

5.6 Changes in Vitamin B12 Levels Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide acetate injection therapy, and monitoring of vitamin B12 levels is recommended during octreotide acetate injection therapy.

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (‎12.3) ]</span>. 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.