Somatostatin analogues.

octreotide

The active substance is octreotide* free peptide, 10 mg, 20 mg or 30 mg nominally 4.15% of fill weight equivalent to 4.65% of octreotide acetate. Following suspension of the powder (microspheres) with the supplied vehicle solution, Sandostatin LAR suspension contains less than 1mmol (23mg) of sodium per dose, i.e. essentially “sodium-free”.

Powder and solvent for suspension for injection. Powder: white to off-white powder. Solvent for suspension for injection: clear, colourless solution. Sandostatin LAR is a long-acting depot injection form of octreotide. Powder (microspheres for suspension for injection) to be suspended in a vehicle immediately prior to i.m. injection.

Treatment of patients with acromegaly:

For symptomatic control and reduction of growth hormone and IGF-1 levels in patients with acromegaly

• who are adequately controlled on s.c. treatment with Sandostatin; in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective.

• in short term treatment (3-12 months) prior to pituitary surgery.

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

• Carcinoid tumours with features of carcinoid syndrome

• VIPomas

• Glucagonomas

in patients whose symptoms are adequately controlled on s.c. treatment with Sandostatin.

Currently data does not support the use of Sandostatin as antitumour therapy in patients with pancreatic neuroendocrine tumours.

Sandostatin LAR may only be administered by deep intragluteal injection. The site of repeat intragluteal injections should be alternated between the left and right gluteal muscle (see 6.6 Instructions for use/handling).

Acromegaly

For patients who have not received prior treatment with subcutaneous Sandostatin, a test dose of s.c. Sandostatin (50-100mcg) is recommended to assess any adverse reaction to octreotide prior to initiating treatment with Sandostatin LAR.

For de novo patients who have received a test dose and for patients who are adequately controlled with s.c. Sandostatin, treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals for 3 months. Treatment with Sandostatin LAR can be started on the day after the last dose of s.c. Sandostatin. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor l (IGF 1)/somatomedin C concentrations and clinical symptoms.

For patients in whom clinical symptoms and biochemical parameters (GH; IGF 1) are not fully controlled (GH concentrations still above 2.5μg/L{5mU/L}), the dose may be increased to 30mg every 4 weeks.

For patients whose GH concentrations are consistently below 1μg/L (2mU/L), whose IGF 1 serum concentrations have normalised, and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20mg, the dose may be reduced to 10mg every 4 weeks. However, in this group of patients serum GH and IGF 1 concentrations, and clinical signs/symptoms should be monitored particularly closely.

For patients on a stable dose of Sandostatin LAR, assessment of GH and IGF should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less adequate.

In order to permit successful endocrine testing of the completeness of tumour removal 5-6 weeks post surgery, the last injection of Sandostatin LAR should be administered at least 3-4 weeks prior to surgery.

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded

The recommended dose of Sandostatin LAR is 30mg administered every 4 weeks. Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours.

After adequate control has been established with Sandostatin s.c., treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals. Treatment with Sandostatin s.c. should be continued at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR. Response should be assessed after 3 months of treatment.

For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30mg Sandostatin LAR every 4 weeks.

For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10mg Sandostatin LAR every 4 weeks.

For days when symptoms associated with gastroenteropancreatic tumours may increase during treatment with Sandostatin LAR, additional administration of s.c. Sandostatin is recommended at the dose used prior to the Sandostatin LAR treatment.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. as Sandostatin. Therefore, no dose adjustment of Sandostatin LAR is necessary.

Use in patients with impaired hepatic function

In a study with Sandostatin administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In certain cases patients with liver impairment may require dose adjustment.

There is very limited experience with use of Sandostatin LAR in children.

In a study with Sandostatin administered s.c., no dose adjustment was necessary in patients 65 years of age. Therefore, no dose adjustment is necessary in this group with Sandostatin LAR.

Known hypersensitivity to octreotide or to any of the excipients.

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications (eg. 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 normalisation of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of child-bearing potential should be advised to use adequate contraception if necessary during treatment with octreotide.

Thyroid function (TSH and thyroid hormone levels) 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

The incidence of gallstone formation with Sandostatin treatment is estimated to be between 15-30%. Long term exposure to Sandostatin LAR of patients with acromegaly or gastroenteropancreatic 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. Hypoglycaemia has also been observed.

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 receiving Sandostatin LAR.

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 the 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.

Octreotide has been found to reduce the intestinal absorption of cyclosporin 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, caution should be exercised during co-administration of octreotide and drugs mainly metabolized by CYP3A4, which have a low therapeutic index (e.g. carbamazepine, digoxin, warfarin and terfenadine).

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, localised pain, bilary 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 s.c. Sandostatin treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term s.c. Sandostatin 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.

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.

Table 1 Adverse drug reactions reported in clinical trials

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.

Table 2 Adverse drug reactions derived from spontaneous reports

Novartis Pharmaceuticals UK Ltd

(POM)

17 February 2012