Sandostatin^® Safety Information

Contraindications

Known hypersensitivity to octreotide or to any of the excipients, (see list of excipients).

Special warnings and precautions for use

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures are advisable.

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see also section PREGNANCY AND LACTATION).

Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.

Cardiovascular related events

Uncommon cases of bradycardia have been reported. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.

Gallbladder and related events

Development of gallstones has been reported in 15 to 30% of long-term recipients of s.c. Sandostatin. The prevalence in the general population (aged 40 to 60 years) is about 5 to 20%. Long-term exposure to Sandostatin LAR of patients with acromegaly or gastro-entero-pancreatic tumours suggests that treatment with Sandostatin LAR does not increase the incidence of gallstone formation, compared with s.c. treatment. Ultrasonic examination of the gallbladder before and at about 6 monthly intervals during Sandostatin LAR therapy is however recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon and insulin release, Sandostatin LAR may affect glucose regulation. Post-prandial glucose tolerance may be impaired. As reported for patients treated with s.c. Sandostatin, in some instances, a state of persistent hyperglycaemia may be induced as a result of chronic administration.

In patients with concomitant Type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation, and insulin requirements may be reduced. In non-diabetics and type II diabetics with partially intact insulin reserves, Sandostatin s.c. administration may result in increases in post-prandial glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.

In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycaemia. These patients should be closely monitored.

Nutrition

Octreotide may alter absorption of dietary fats in some patients.

Depressed vitamin B₁₂ levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B₁₂ levels is recommended during therapy with Sandostatin LAR in patients who have a history of vitamin B₁₂ deprivation.

Interaction with other medicinal products and other forms of interaction

Octreotide has been found to reduce the intestinal absorption of ciclosporin and to delay that of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

Pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. In the post-marketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 micrograms/day of Sandostatin s.c. or 20 to 30 mg/month of Sandostatin LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies. In most of the cases with known outcome, normal newborns were reported but also several spontaneous abortions during the first trimester, and a few induced abortions.

There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see section PRECLINICAL SAFETY DATA).

Sandostatin should only be prescribed to pregnant women under compelling circumstances (see also section SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Lactation

It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during Sandostatin treatment.

Effects on ability to drive and use machines

No data exist on the effects of Sandostatin LAR on the ability to drive and use machines.

Undesirable effects

The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.

The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhoea, abdominal pain, nausea, flatulence headache, cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction (e.g., decreased thyroid stimulating hormone [TSH], decreased Total T4, and decreased Free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycaemia.

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

Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption.

In very rare instances, acute pancreatitis has been reported within the first hours or days of Sandostatin s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin s.c. treatment.

In both acromegalic and carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis shifts, early repolarisation, 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 diseases (see section SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies with octreotide:

Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Post-marketing

Spontaneously reported adverse reactions, presented in Table 2, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.

Overdose

A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100 mg to 163 mg/month of Sandostatin LAR. The only adverse event reported was hot flushes.

Cancer patients receiving doses of Sandostatin LAR up to 60 mg/month and up to 90 mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety, and lack of concentration.

The management of overdosage is symptomatic.

List of excipients

Vial

Poly (DL-lactide-co-glycolide) 78.35% of nominal fill weight; sterile mannitol 17.0% of nominal fill weight.

Prefilled syringe

Kit without vial adapter/safety needle

One prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg; water for injection qs ad 2.5 mL.

Kit with vial adapter/safety needle

One prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose (14 mg), mannitol (12 mg), poloxamer 188 (4 mg); water for injection qs ad 2 mL. Pharmaceutical formulations may vary between countries.