1. Name Of The Medicinal Product
Sandostatin®Ampoules 50 mcg/ml solution for injection or concentrate for solution for infusion
Sandostatin®Ampoules 100 mcg/ml solution for injection or concentrate for solution for infusion
Sandostatin®Ampoules 500 mcg/ml solution for injection or concentrate for solution for infusion
Sandostatin®Multidose Vial 1mg/5ml solution for injection or concentrate for solution for infusion
2. Qualitative And Quantitative Composition
The active substance is octreotide acetate.
0.05 mg octreotide (INN) per ml.
0.1 mg octreotide (INN) per ml.
0.5 mg octreotide (INN) per ml.
0.2 mg octreotide (INN) per ml.
Sandostatin solution for injection contains less than 1mmol (23mg) sodium per dose, i.e essentially “sodium-free”.
For a full list of excipients see section 6.1.
3. Pharmaceutical Form
Solution for injection (s.c) or concentrate for solution for infusion.
The solution is clear and colourless.
4. Clinical Particulars
4.1 Therapeutic Indications
GEP tumours:
For the relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:
- carcinoid tumours with features of carcinoid syndrome
- VIPomas
- glucagonomas
Sandostatin is not antitumour therapy and is not curative in these patients.
Acromegaly:-
For symptomatic control and reduction of growth hormone and somatomedin c plasma levels in patients with acromegaly:
- in short term treatment, prior to pituitary surgery, or
- in long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, or in the interim period until radiotherapy becomes effective.
Sandostatin is indicated for acromegalic patients for whom surgery is inappropriate.
Evidence from short term studies demonstrate that tumour size is reduced in some patients (prior to surgery); further tumour shrinkage however cannot be expected as a feature of continued long term treatment.
Prevention of complications following pancreatic surgery.
Route of administration
Subcutaneous or intravenous use.
4.2 Posology And Method Of Administration
GEP tumours
Initially 0.05 mg once or twice daily by s.c. injection. Depending on response, dosage can be gradually increased to 0.2 mg three times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses are variable.
The recommended route of administration is subcutaneous, however, in instances where a rapid response is required, e.g. carcinoid crises, the initial recommended dose of Sandostatin may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring the cardiac rhythm.
In carcinoid tumours, if there is no beneficial effect within a week, continued therapy is not recommended.
Acromegaly
0.1 – 0.2 mg three times daily by s.c. injection. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH less than 2.5ng/ml, 5mU/l; IGF-1 within normal range) and clinical symptoms, and on tolerability. For patients on a stable dose of Sandostatin, assessment of GH should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is adequate.
If no relevant reduction of growth hormone levels and no improvement of clinical symptoms have been achieved within three months of starting treatment, therapy should be discontinued.
For the prevention of complications following pancreatic surgery
0.1 mg three times daily by subcutaneous injection for 7 consecutive days, starting on the day of operation at least one hour before laparotomy.
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. therefore, no dose adjustment of Sandostatin is necessary.
Use in patients with impaired liver function
In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage.
Use in the elderly
In elderly patients treated with Sandostatin, there is no evidence for reduced tolerability or altered dosage requirements.
Use in children
Experience with Sandostatin in children is very limited.
4.3 Contraindications
Known hypersensitivity to octreotide or to any of the excipients.
4.4 Special Warnings And Precautions For Use
General
As growth hormone 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 child bearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see also section 4.6 Pregnancy and lactation).
Thyroid function (TSH and thyroid hormone levels) should be monitored in patients receiving long-term Sandostatin therapy.
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.
GEP endocrine tumours
Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by Sandostatin may occur infrequently, with rapid recurrence of severe symptoms.
Glucose metabolism
Because of its inhibitory action on growth hormone, glucagon, and insulin release, octreotide may affect glucose regulation. Postprandial 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 observed.
Octreotide may increase the depth and duration of hypoglycaemia in patients with insulinoma. This is because it is relatively more potent in inhibiting growth hormone and glucagon secretion than in inhibiting insulin and because its duration of insulin inhibition is shorter. If Sandostatin is given to a patient with insulinoma, close monitoring is necessary on introduction of therapy and at each change of dosage. Marked fluctuations of blood glucose may be reduced by more frequent administration of Sandostatin.
Sandostatin may reduce insulin or oral hypoglycaemic requirements in patients with type I diabetes mellitus. In non-diabetics and type II diabetics with particularly intact insulin reserves, Sandostatin administration can result in prandial increases in glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Gallbladder and related events
Sandostatin exerts an inhibiting effect on gallbladder motility, bile acid secretion and bile flow and there is an acknowledged association with the development of gallstones. The incidence of gallstone formation with Sandostatin treatment is estimated to be between 15 – 30 %.
Ultrasonic examination of the gallbladder, before and at about 6 to 12 month intervals during Sandostatin therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated in the normal manner with due attention to abrupt withdrawal of the drug.
In patients with cirrhosis, dosage adjustment may be necessary (see Section 4.2 Posology and Method of Administration).
Local Site Reactions
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 40 times the maximum human dose). 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.
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 in patients who have a history of vitamin B12 deprivation.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine.
Concomitant administration of octreotide and bromocriptine increases the availability 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 metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. carbamazepine, digoxin, warfarin and terfenadine).
4.6 Pregnancy And Lactation
Pregnancy
Sandostatin should only be prescribed to pregnant women under compelling circumstances (see also section 4.4 Special warnings and precautions for use).
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 100-300 micrograms/day of Sandostatin s.c. or 20-30 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 5.3 Preclinical safety data).
Lactation
Patients should not breastfeed during Sandostatin treatment. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk.
4.7 Effects On Ability To Drive And Use Machines
No data exists on the effects of Sandostatin on the ability to drive and use machines.
4.8 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, 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.
In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.
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.
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.
Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.
In rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hours or days of Sandostatin treatment and resolves on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin treatment.
There have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.
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 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 ( 1/1,000, 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
Endocrine disorders
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Common:
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Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased Total T4 and decreased Free T4).
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Metabolism and nutrition disorders
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Very common:
Common:
Uncommon:
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Hyperglycaemia.
Hypoglycaemia, impaired glucose tolerance, anorexia.
Dehydration.
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Cardiac disorders
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Common:
Uncommon:
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Bradycardia.
Tachycardia.
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Respiratory disorders
Common:
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Dyspnoea.
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Gastrointestinal disorders
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Very common:
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Diarrhoea, abdominal pain, nausea, constipation, flatulence.
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Common:
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Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.
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Nervous system disorders
Very common:
Common:
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Headache.
Dizziness.
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Hepatobiliary disorders
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Very common:
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Cholelithiasis
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Common:
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Cholecystitis, biliary sludge, hyperbilirubinaemia.
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Skin and subcutaneous tissue disorder
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Common:
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Pruritus, rash, alopecia.
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General disorders and administration site
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Very common:
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Injection site localised pain.
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Investigations
Common:
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Elevated transaminase levels.
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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
Immune disorders
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Anaphylaxis, allergy/hypersensitivity reactions.
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Skin and subcutaneous tissue disorders
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Urticaria.
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Hepatobiliary disorders
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Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.
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Cardiac disorders
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Arrhythmias.
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Investigations
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Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.
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4.9 Overdose
A limited number of accidental overdoses of Sandostatin in adults and children have been reported. In adults, the doses ranged from 2400-6000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1500 micrograms t.i.d.). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly and lactic acidosis.
In children, the doses ranged from 50-3000 micrograms/day administered by continuous infusion (2.1-500 micrograms/hour) or subcutaneously (50-100 micrograms). The only adverse event reported was mild hyperglycaemia.
No unexpected adverse events have been reported in cancer patients receiving Sandostatin at doses of 3000-30,000 micrograms/day in divided doses subcutaneously.
The management of overdosage is symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antigrowth hormones (ATC code H01BC02).
Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone and of peptides and serotonin produced within the gastroenteropancreatic endocrine (GEP) system.
In animals, octreotide is a more potent inhibitor of growth hormone, glucagon and insulin release than somatostatin with greater selectivity for growth hormone and glucagon suppression.
In normal healthy subjects octreotide, like somatostatin, has been shown to inhibit
- release of growth hormone stimulated by arginine, exercise and insulin-induced hypoglycaemia;
- postprandial release of insulin, glucagon, gastrin other peptides of the gastroenteropancreatic system; arginine-stimulated release of insulin and glucagon and
- thyrotropin-releasing hormone (TRH) - stimulated release of thyroid stimulating hormone (TSH).
Unlike somatostatin, octreotide inhibits growth hormone preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. growth hormone in patients with acromegaly).
For patients undergoing pancreatic surgery, the peri and post-operative administration of Sandostatin reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).
In patients with acromegaly, Sandostatin consistently lowers GH and normalises IGF-1 serum concentrations in the majority of patients. In most patients, Sandostatin markedly reduces the clinical symptoms of the disease , such as headache, perspiration, paresthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In individual patients with GH-secreting pituitary adenoma, Sandostatin was reported to lead to shrinkage of the tumour mass.
For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with octreotide provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastroenteropancreatic tumours are as follows:
Carcinoid tumours: Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a falling plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.
VIPomas: The biochemical characteristics of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.
Glucagonomas: Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
5.2 Pharmacokinetic Properties
Absorption
After subcutaneous injection, Sandostatin is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.
Distribution
The volume of distribution is 0.27 l/kg and the total body clearance 160 ml/min. Plasma protein binding amounts to 65 %. The amount of octreotide bound to blood cells is negligible.
Elimination
The elimination half-life after subcutaneous administrations is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and 90 minutes respectively. About 32 % is excreted unchanged into the urine.
5.3 Preclinical Safety Data
Preclinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Studies in animals showed transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic, or other reproduction effects.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sandostatin Ampoules and Multidose vials:
Lactic acid, phenol (multidose vials only), mannitol, sodium hydrogen carbonate, water for injections.
6.2 Incompatibilities
None known
6.3 Shelf Life
Ampoules: 3 years
Multidose vials: 4 years unopened. Opened vials may be stored for 2 weeks at room temperature for day to day use.
6.4 Special Precautions For Storage
For prolonged storage Sandostatin Ampoules and Multidose vials should be stored between 2oC and 8oC. For day-to-day use they may be stored at room temperature for up to two weeks. Protect from light. Do not freeze.
6.5 Nature And Contents Of Container
Ampoules: 1 ml vial of uncoloured glass containing clear colourless solution.
Boxes of 5 ampoules.
Multidose vials: 5 ml vial of uncoloured glass containing clear colourless solution.
Boxes of 1 vial.
6.6 Special Precautions For Disposal And Other Handling
For i.v. use Sandostatin should be diluted with normal saline to a ratio of not less than 1 vol : 1 vol and not more than 1 vol : 9 vol . Dilution of Sandostatin with glucose solution is not recommended.
If Sandostatin has been diluted, the prepared solution may be kept at room temperature but should be administered within 8 hours of preparation.
To prevent contamination, it is recommended to puncture the cap of the vial not more than 10 times (Multidose vials only).
To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
NOVARTIS PHARMACEUTICALS UK LIMITED
(trading as Sandoz Pharmaceuticals)
Frimley Business Park
Frimley
Camberley
Surrey, GU16 7SR
8. Marketing Authorisation Number(S)
Sandostatin Ampoules 0.05 mg/ml
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- PL 00101/0212
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Sandostatin Ampoules 0.1 mg/ml
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- PL 00101/0213
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Sandostatin Ampoules 0.5 mg/ml
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- PL 00101/0214
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Sandostatin Multidose Vials 1 mg/5 ml
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- PL 00101/0300
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9. Date Of First Authorisation/Renewal Of The Authorisation
Ampoules:
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03 April 1989 / 07 June 2007
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Multidose vials:
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20 October 1990 / 07 June 2007
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10. Date Of Revision Of The Text
18 February 2010
Legal Category
POM
