Octreotide Acetate: Package Insert and Label Information (Page 2 of 2)

Wockhardt USA LLC. 10 October 2012

Pediatric Use

Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate in pediatric under age 6 years. In post-marketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of octreotide acetate using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, six–month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by IM injection every four weeks was approximately 3 ng/ml. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m² in octreotide acetate for injectable suspension-treated subjects compared to 0 kg/m² in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adults indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 to 30 mg once a month.

Geriatric Use

Clinical studies of octreotide acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Gallbladder Abnormalities

Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide acetate injection therapy (see WARNINGS).

Cardiac

In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate therapy (see PRECAUTIONS – General).

Gastrointestinal

Diarrhea, loose stools, nausea and abdominal discomfort were each seen in 34%-61% of acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5%-10% of patients with other disorders.

The frequency of these symptoms was not dose-related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients.

In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

Hypo/Hyperglycemia

Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients.

Hypothyroidism

In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 6% during octreotide acetate therapy (see PRECAUTIONS – General). In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported.

Other Adverse Events

Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Pancreatitis was also observed (see WARNINGS and PRECAUTIONS).

Other Adverse Events 1%-4%

Other events (relationship to drug not established), each observed in 1%-4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance and depression.

Other Adverse Events <1%

Events reported in less than 1% of patients and for which relationship to drug is not established are listed: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary: rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint effusion, muscle pain, Raynaud’s phenomenon; Cardiovascular: chest pain, shortness of breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease, syncope, tremor, seizure, vertigo, Bell’s Palsy, paranoia, pituitary apoplexy, increased intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus, gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital: nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous: otitis, allergic reaction, increased CK, weight loss.

Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate were subsequently reported in three patients and resulted in prolonged duration of drug action in two patients. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide acetate.

Postmarketing Experience

The following adverse reactions have been identified during the postapproval 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.

Gastrointestinal: intestinal obstruction

Hematologic: thrombocytopenia

OVERDOSAGE

A limited number of accidental overdoses of octreotide acetate injection in adults have been reported. In adults, the doses ranged from 2,400–6,000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms t.i.d.). Adverse events in some patients included arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss.

Octreotide acetate injection given in intravenous boluses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients.

If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222.

Drug Abuse and Dependence

There is no indication that octreotide acetate has potential for drug abuse or dependence. Octreotide acetate levels in the central nervous system are negligible, even after doses up to 30,000 mcg.

DOSAGE AND ADMINISTRATION

Octreotide acetate injection may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of octreotide acetate for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination. Octreotide acetate is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

Octreotide acetate is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50-200 mL and infused intravenously over 15-30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis) it may be given by rapid bolus.

The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows.

Acromegaly

Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses. IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone levels at 0-8 hours after octreotide acetate injection administration permit more rapid titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females. The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be re-evaluated at 6-month intervals.

Octreotide acetate should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, octreotide acetate therapy may be resumed.

Carcinoid Tumors

The suggested daily dosage of octreotide acetate during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited.

VIPomas

Daily dosages of 200-300 mcg in 2-4 divided doses are recommended during the initial 2 weeks of therapy (range 150-750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.

HOW SUPPLIED

Octreotide acetate injection, containing octreotide (as acetate) 50 mcg per mL, is supplied in 1 ml Single Dose Vials; NDC 64679-636-01 (package of 1 Single Dose Vial), NDC 64679-636-02 (package of 10 Single Dose Vials)

Octreotide acetate injection, containing octreotide (as acetate) 100 mcg per mL, is supplied in 1 ml Single Dose Vials; NDC 64679-633-01 (package of 1 Single Dose Vial), NDC 64679-633-02 (package of 10 Single Dose Vials)

Octreotide acetate injection, containing octreotide (as acetate) 500 mcg per mL, is supplied in 1 ml Single Dose Vials; NDC 64679-635-01 (package of 1 Single Dose Vial), NDC 64679-635-02 (package of 10 Single Dose Vials)

Octreotide acetate injection, containing octreotide (as acetate) 200 mcg per mL, is supplied in 5 ml Multi Dose Vials; NDC 64679-634-01 (package of 1 Multi Dose Vial)

Octreotide acetate injection, containing octreotide (as acetate) 1000 mcg per mL, is supplied in 5 ml Multi Dose Vials; NDC 64679-632-01 (package of 1 Multi Dose Vial)

Storage

For prolonged storage, octreotide acetate single-dose and multi-dose vials should be stored at refrigerated temperatures 2°C-8°C (36°F-46°F) and store in outer carton in order to protect from light. At room temperature, (20°C-30°C or 70°F-86°F), octreotide acetate single dose and multi-dose vials are stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Single-dose vials should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly.

Manufactured by:

Wockhardt Limited

Mumbai, India.

Distributed by:

Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054

USA.

Iss.101012

(click image for full-size original)