Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: NOVARTIS PHARMACEUTICALS UK LIMITED, Frimley Business Park, Frimley, Camberley, Surrey GU16 7SR
Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
Hepatic function should be monitored during octreotide therapy.
Common cases of bradycardia have been reported. Dose adjustments of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary (see section 4.5).
Cholelithiasis is a very common event during Sandostatin treatment and may be associated with cholecystitis and biliary duct dilatation (see section 4.8). Ultrasonic examination of the gallbladder before, and at about 6- to 12-month intervals during Sandostatin therapy is therefore recommended.
During the treatment of GEP endocrine tumours, there may be rare instances of sudden escape from symptomatic control by Sandostatin, with rapid recurrence of severe symptoms. If the treatment is stopped, symptoms may worsen or recur.
Because of its inhibitory action on growth hormone, glucagon, and insulin, Sandostatin may affect glucose regulation. Post-prandial glucose tolerance may be impaired and, 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 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 during initiation of Sandostatin therapy and at each change of dosage. Marked fluctuations in blood glucose concentration may possibly be reduced by smaller, more frequently administered doses.
Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by administration of Sandostatin. In non-diabetics and type II diabetics with partially intact insulin reserves, Sandostatin administration can result in post-prandial increases in glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Since, following bleeding episodes from oesophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.
In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the s.c. injection site only at the highest dose (about 8 times the maximum human dose based on body surface area). No hyperplastic or neoplastic lesions occurred at the s.c. injection site in a 52-week dog toxicity study. There have been no reports of tumour formation at the injection sites in patients treated with Sandostatin for up to 15 years. All the information available at present indicates that the findings in rats are species specific and have no significance for the use of the drug in humans (see section 5.3).
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 in patients who have a history of vitamin B12 deprivation.
Sandostatin contains less than 1 mmol (23 mg) sodium per dose, i.e is essentially “sodium-free”.
Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may be necessary when Sandostatin is administered concomitantly (see section 4.4).
Dose adjustments of insulin and antidiabetic medicinal products may be required when Sandostatin is administered concomitantly (see section 4.4).
Sandostatin 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 drugs mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. quinidine, terfenadine).
There is a limited amount of data (less than 300 pregnancy outcomes) from the use of octreotide in pregnant women, and in approximately one third of the cases the pregnancy outcomes are unknown. The majority of reports were received after post-marketing use of octreotide and more than 50% of exposed pregnancies were reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-1200 micrograms/day of Sandostatin s.c. or 10-40 mg/month of Sandostatin LAR. Congenital anomalies were reported in about 4% of pregnancy cases for which the outcome is known. No causal relationship to octreotide is suspected for these cases.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Sandostatin during pregnancy (see section 4.4).
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.
It is not known whether octreotide has an effect on human fertility. Late descent of the testes was found for male offsprings of dam 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 (see section 5.3).
Sandostatin has no or negligible influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience dizziness, asthenia/fatigue, or headache during treatment with Sandostatin.
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, 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.
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 studies:
Very common: Diarrhoea, abdominal pain, nausea, constipation, flatulence.
Common: Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.
Very common: Headache.
Common: Dizziness.
Common: Hypothyroidism, thyroid disorder (e.g. decreased TSH, decreased total T4, and decreased free T4).
Very common: Cholelithiasis.
Common: Cholecystitis, biliary sludge, hyperbilirubinaemia.
Very common: Hyperglycaemia.
Common: Hypoglycaemia, impaired glucose tolerance, anorexia.
Uncommon: Dehydration.
Very common: Injection site reactions.
Common: Asthenia.
Common: Elevated transaminase levels.
Common: Pruritus, rash, alopecia.
Common: Dyspnoea.
Common: Bradycardia
Uncommon: Tachycardia.
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:
Blood and lymphatic system disorders: Thrombocytopenia
Immune System disorders: Anaphylaxis, allergy/hypersensitivity reactions.
Skin and subcutaneous tissue disorders: Urticaria
Hepatobiliary disorders: Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.
Cardiac disorders: Arrhythmias.
Investigations: Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.
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. Sandostatin. The incidence in the general population (aged 40 to 60 years) is 5 to 20%. If gallstones do occur, they usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.
In rare instances, 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.
Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of Sandostatin s.c. administration, that is, by injecting between meals or on retiring to bed.
Hypersensitivity and allergic reactions have been reported during post-marketing experience. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.
Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection, or by injecting a smaller volume using a more concentrated solution.
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.
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 has been reported during post-marketing experience, particularly during treatment with Sandostatin (i.v.) in patients with cirrhosis of the liver. This is reversible after discontinuation of treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Octreotide acetate is not stable in Total Parenteral Nutrition (TPN) solutions.
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