Included as part of the PRECAUTIONS section.

Cholelithiasis and Gallbladder Sludge

Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically [see ADVERSE REACTIONS].

Hyperglycemia and Hypoglycemia

Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly [See ADVERSE REACTIONS].

Thyroid Function Abnormalities

Octreotide suppresses the secretion of thyroid stimulating hormone, which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T₄) is recommended during chronic octreotide therapy [See ADVERSE REACTIONS].

Cardiac Function Abnormalities

In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other EKG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin® Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge [See ADVERSE REACTIONS].

Nutrition

Octreotide may alter absorption of dietary fats.

Depressed vitamin B₁₂ levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B₁₂ levels is recommended during therapy with Sandostatin LAR® Depot.

Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels.

Monitoring: Laboratory Tests

Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy [See DOSAGE AND ADMINISTRATION]:

Acromegaly: Growth Hormone, IGF-1 (somatomedin C)

Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P

VIPoma: VIP (plasma vasoactive intestinal peptide) Baseline and periodic total and/or free T₄ measurements should be performed during chronic therapy

Drug Interactions

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [See DRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin®. No mutagenic potential of the polymeric carrier in Sandostatin LAR® Depot, D,L-lactic and glycolic acids copolymer, was observed in the Ames mutagenicity test.

No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats administered octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin® Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.

Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and have revealed no evidence of harm to the fetus due to octreotide.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose and have revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [See Nonclinical Toxicology].

Nursing Mothers

It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR® Depot is administered to a nursing woman.

Pediatric Use

In pediatric patients with hypothalamic obesity, the mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR® Depot administered by IM injection every four weeks was approximately 3 ng/ml. Steady-state concentration was achieved after 3 injections of a 40 mg dose.

The efficacy and safety of Sandostatin LAR Depot were examined in a randomized, double-blind, placebo controlled six month study in 60 pediatric patients aged 6-17 years with hypothalamic obesity resulting from cranial insult. Mean BMI increased 0.1 kg/m² in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m² in saline control-treated subjects. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 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 Sandostatin LAR Depot was 10 to 30 mg once a month.

Geriatric Use

Clinical studies of Sandostatin 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.

Renal Impairment

In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in non renal patients [See CLINICAL PHARMACOLOGY].

Hepatic Impairment- Cirrhotic Patients

In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any non cirrhotic patients [See CLINICAL PHARMACOLOGY].

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