Octreotide Teva 10 mg/20 mg/30 mg Suspension

Treatment of patients with acromegaly:

• who are adequately controlled on subcutaneous (s.c) treatment with a somatostatin analogue
• in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective (see section 4.2)

Treatment of patients with carcinoid tumours with:

• features of the carcinoid syndrome, in whom symptoms are adequately controlled on subcutaneous treatment with octreotide.
• VIPomas

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

Acromegaly: For patients who are adequately controlled with s.c. octreotide, it is recommended to start treatment with the administration of OCTREOTIDE TEVA 20 at 4-week intervals for 3 months. Treatment with OCTREOTIDE TEVA 20 can be started on the day after the last dose of s.c. octreotide. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor 1/somatomedin C (IGF 1) concentrations and clinical symptoms.

For patients in whom, within this 3-month period, clinical symptoms and biochemical parameters (GH; IGF 1) are not fully controlled (GH concentrations still above 2,5 microgram/L), the dose may be increased to 30 mg every 4 weeks. If after 3 months, GH, IGF 1, and/or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks.

For patients whose GH concentrations are consistently below 1 microgram/L whose IGF 1 serum concentrations normalised and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20 mg, 10 mg OCTREOTIDE TEVA may be administered every 4 weeks. However particularly in this group of patients it is recommended to closely monitor adequate control of serum GH and IGF 1 concentrations and clinical signs/symptoms at this low dose of OCTREOTIDE TEVA.

For patients on a stable dose of OCTREOTIDE TEVA assessment of GH and IFG 1 should be made every 6 months. For patients in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective, a short test dosing period of s.c. administration of octreotide is recommended to assess the response and systemic tolerability of octreotide prior to initiating treatment with OCTREOTIDE TEVA as described above.

Carcinoid tumours: For patients in whom symptoms are adequately controlled with s.c. octreotide, it is recommended to start treatment with the administration of OCTREOTIDE TEVA 20 at 4-week intervals. The treatment with s.c. octreotide should be continued at the previously effective dosage for 2 weeks after the first injection of OCTREOTIDE TEVA 20.

For patients who were not previously treated with s.c. octreotide, it is recommended to start with the administration of s.c. octreotide at a dosage of 0,1 mg three times daily for a short period (approximately 2 weeks) to assess the response and systemic tolerability of octreotide before initiating the treatment with OCTREOTIDE TEVA as described above.

For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10 mg OCTREOTIDE TEVA every 4 weeks. For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30 mg OCTREOTIDE TEVA every 4 weeks.

For days when symptoms associated with carcinoid tumours may increase during treatment with OCTREOTIDE TEVA, additional administration of s.c. octreotide is recommended at the dose used prior to the OCTREOTIDE TEVA treatment. This may occur mainly in the first 2 months of treatment until therapeutic concentrations of octreotide are reached.

Use in patients with impaired renal function: No dose adjustment of OCTREOTIDE TEVA is necessary.

Use in patients with impaired hepatic function: No data in patients with impaired hepatic function is available.

Use in elderly patients: No data is available.

Use in children: Safety and efficacy of OCTREOTIDE TEVA in children have not been established.

Method of administration: Instructions for preparation and intramuscular injection of OCTREOTIDE TEVA. FOR DEEP INTRAGLUTEAL INJECTION ONLY

Hypersensitivity to the active substance octreotide or to any of the excipients listed in section 6.1.

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 may be 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 childbearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see section 4.6).

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

Hepatic function should be monitored during OCTREOTIDE TEVA therapy.

Cardiovascular related events: Cases of bradycardia have been reported. Dose adjustment of medicines such as beta blockers, calcium channel blockers, or medicines to control fluid and electrolyte balance, may be necessary (see section 4.5).

Gallbladder and related events: Cholelithiasis is a very common event during OCTREOTIDE TEVA treatment and may be associated with cholecystitis and biliary duct dilatation (see section 4.8). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients taking octreotide in the post-marketing setting. Ultrasonic examination of the gallbladder before and at about 6-monthly intervals during OCTREOTIDE TEVA therapy is recommended.

Glucose metabolism: Because of its inhibitory action on growth hormone, glucagon, and insulin release, OCTREOTIDE TEVA may affect glucose regulation. Post-prandial glucose tolerance may be impaired. As reported for patients treated with s.c. octreotide, in some instances, the state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been reported.

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

In patients with insulinomas, octreotide as contained in OCTREOTIDE TEVA, 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 OCTREOTIDE TEVA in patients who have a history of vitamin B12 deprivation.

Pancreatic function: Pancreatic exocrine insufficiency (PEI) has been observed in some patients receiving octreotide therapy for gastroenteropancreatic neuroendocrine tumours. Symptoms of PEI can include steatorrhea, loose stools, abdominal bloating and weight loss. Screening and appropriate treatment for PEI according to clinical guidelines should be considered in symptomatic patients.

Mannitol: Patients with the rare hereditary condition of mannitol intolerance should not use OCTREOTIDE TEVA.

Dose adjustment of medicines such as beta blockers, calcium channel blockers, or medicines to control fluid and electrolyte balance may be necessary when OCTREOTIDE TEVA is administered concomitantly (see section 4.4).

Dose adjustments of insulin and antidiabetic medicines may be required when OCTREOTIDE TEVA is administered concomitantly (see section 4.4).

Octreotide as contained in OCTREOTIDE TEVA 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 analogues might decrease the metabolic clearance of compounds known to be metabolised 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 medicines mainly metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

Concomitant use of radiopharmaceuticals coupled to somatostatin analogues (peptide receptor radionuclide therapy (PRRT)) somatostatin and its analogues (e.g. octreotide) bind competitively to somatostatin receptors and may impair the efficacy of relevant radiopharmaceuticals (e.g. (177 Lu) oxodotreotide). Administration of OCTREOTIDE TEVA as a long-acting somatostatin analogue must therefore be interrupted 4 to 6 weeks before initiation of treatment with PRRT. If required, patients may be treated with short-acting somatostatin analogues up to 24 hours before administration of PRRT. Treatment with OCTREOTIDE TEVA may be resumed within 4 to 24 hours after administration of PRRT, but must be interrupted once again 4 to 6 weeks before the radiopharmaceutical is next administered.

Women of childbearing potential / Contraception in males and females: Female patients of childbearing potential should be advised to use adequate contraception during treatment with OCTREOTIDE TEVA.

Pregnancy: Experience with OCTREOTIDE TEVA in pregnant women is limited. Avoid the use of OCTREOTIDE TEVA during pregnancy (see section 4.4) as safety in pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Lactation: Experience with OCTREOTIDE TEVA in nursing women is limited. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breastfeed during OCTREOTIDE TEVA treatment.

Fertility: It is not known whether OCTREOTIDE TEVA has an effect on human fertility. Late descent of the testes was found for male off springs of dams treated during pregnancy and lactation. Octreotide, however, did not impair fertility in male and female rats at doses of up to 1 mg/kg body weight per day.

OCTREOTIDE TEVA can cause dizziness, asthenia/fatigue, or headache and may have no or negligible effect on mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision. Patients should be advised to be cautious when driving or using machines if they experience dizziness, asthenia/fatigue, or headache during treatment with OCTREOTIDE TEVA.

Summary of the safety profile: The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders. The most frequently 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, 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.

Table 1 Adverse drug reactions reported in clinical studies: The following adverse drug reactions, listed in Table 1, have been accumulated from reports from clinical studies with octreotide: Adverse medicine reactions (Table 1) are ranked under heading of frequency. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1 Adverse drug reactions reported in clinical studies:

Endocrine disorders: Frequent Hypothyroidism, thyroid disorder (e.g., decreased TSH, decreased total T4, and decreased free T4).

Metabolism and nutrition disorders: Frequent Hyperglycaemia, hypoglycaemia, impaired glucose tolerance, anorexia. Less frequent Dehydration.

Nervous system disorders: Frequent Headache, dizziness.

Cardiac disorders: Frequent Bradycardia. Less frequent Tachycardia.

Respiratory, thoracic and mediastinal disorders: Frequent Dyspnoea.

Gastrointestinal disorders: Frequent Diarrhoea, abdominal pain, nausea, constipation, flatulence, dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.

Hepato-biliary disorders: Frequent Cholelithiasis, cholecystitis, biliary sludge, hyperbilirubinaemia.

Skin and subcutaneous tissue disorders: Frequent Pruritus, rash, alopecia.

General disorders and administration site conditions: Frequent Injection site reactions, asthenia.

Investigations: Frequent Elevated transaminase levels.

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 medicine exposure.

Table 2 Adverse drug reactions derived from spontaneous reports:

Blood and lymphatic system disorders: Thrombocytopenia.

Immune system disorders: Anaphylaxis, allergy/hypersensitivity reactions.

Skin and subcutaneous tissue disorders: Urticaria.

Hepato-biliary disorders: Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.

Cardiac disorders: Dysrhythmias.

Investigations: Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.

Description of selected adverse events: Gallbladder and related reactions: Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Development of gallstones has been reported in 15 to 30 % of long-term recipients of s.c. octreotide. The incidence in the general population (aged 40 to 60 years) is about 5 to 20 %. Long-term exposure to OCTREOTIDE TEVA of patients with acromegaly or gastro-entero-pancreatic tumours suggests that treatment with OCTREOTIDE TEVA does not increase the incidence of gallstone formation, compared with s.c. treatment. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

Gastrointestinal disorders: Gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. The frequency of gastrointestinal adverse events is known to decrease over time with continued treatment.

Hypersensitivity and anaphylactic reactions: Hypersensitivity and allergic reactions have been reported during post-marketing. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.

Injection site reactions: Injection site related reactions including pain, redness, haemorrhage, pruritus, swelling or induration were commonly reported in patients receiving OCTREOTIDE TEVA; however, these events did not require any clinical intervention in the majority of the cases.

Metabolism and nutrition disorders: Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide as in OCTREOTIDE TEVA has led to nutritional deficiency due to malabsorption.

Pancreatic enzymes: Acute pancreatitis has been reported within the first hours or days of octreotide s.c. treatment and resolved on withdrawal of the medicine. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide s.c. treatment.

Cardiac disorders: Bradycardia is a common adverse reaction with somatostatin analogues. 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 4.4).

Thrombocytopenia: Thrombocytopenia has been reported during post-marketing experience, particularly during treatment with octreotide (i.v.) in patients with cirrhosis of the liver, and during treatment with OCTREOTIDE TEVA. This is reversible after discontinuation of treatment.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

The adverse events reported were hot flushes, dysrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis. The management of overdosage is symptomatic and supportive.