Octreotide 50 Micrograms/Ml Solution For Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Octreotide 50 micrograms/ml solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial of 1 ml solution for injection contains octreotide acetate equivalent to 50 micrograms octreotide.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless to slightly brownish solution. pH of the solution: 3.9 - 4.5
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
• GEP tumours
For the relief of symptoms associated with functional gastro enteropancreatic endocrine tumours including:
carcinoid tumours with features of carcinoid syndrome
VIPomas
glucagonomas
Octreotide is not an anticancer agent and is not curative in the above-mentioned patients.
• Acromegaly
Symptomatic treatment and reduction of plasma levels of growth hormone (GH) and IGF-1 in patients with acromegaly who respond inadequately to treatment with surgery or radiotherapy. Octreotide may also be administered to patients with acromegaly who are not able or willing to undergo surgery, or in the initial stage of radiotherapy treatment until it becomes effective.
Prevention of complications following pancreatic surgery.
4.2 Posology and method of administration
GEP tumours
Initially 50 micrograms subcutaneously once or twice daily.
Depending on the clinical response, the effect on the concentrations of hormones produced by the tumour (in carcinoid tumours on the excretion of 5-hydroxy-indolacetic acid in urine) and on the tolerability, the dose may be gradually increased to 100 - 200 micrograms three times daily. In exceptional circumstances, higher doses may be required. The maintenance doses should be determined individually.
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 octreotide may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring cardiac rhythm.
If no favourable response occurs within 1 week after treatment at the maximum tolerable dose in carcinoid tumours, the therapy should be discontinued.
Acromegaly
Initially 50 - 100 micrograms subcutaneously every 8 or 12 hours.
The dose should be adjusted on the basis of a monthly evaluation of its effects on the plasma levels of GH and IGF-1 (target: GH < 2.5 ng/ml; IGF-1 within the normal limits) and on the clinical symptoms and adverse effects.
The optimum daily dose will be 200 to 300 micrograms in most patients. The maximum daily dose is 1500 micrograms. In patients stabilised on an octreotide dose, the GH level should be assessed every 6 months. If after 3 months’ treatment no relevant reduction in GH levels or improvement of clinical symptoms has been achieved, the therapy should be discontinued.
Prevention of complications following pancreatic surgery
Three times daily 100 micrograms subcutaneously for 7 days, to be started on the day of surgery, at least one hour before the laparotomy.
Patients with impaired renal function
In subcutaneous administration, a reduced renal function did not affect the total exposure (AUC) to octreotide. A dose adjustment is therefore not necessary.
Patients with impaired hepatic function
In patients with liver cirrhosis, the half-life of octreotide may be prolonged, requiring an adjustment of the maintenance dose.
Elderly
In elderly patients treated with octreotide, there is no evidence for reduced tolerability or altered dosage requirements.
Paediatric population
No data are available. Currently no recommendation on a posology can be made.
Method of administration Subcutaneous or intravenous use.
For instructions on dilution of the medicinal product before intravenous administration, see section 6.6.
This medicinal product is for single use only.
4.3
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 considered.
Life-long therapy may be required in patients with growth hormones-producing tumours if surgery or radiotherapy is not possible.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation the insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female acromegalic patients of childbearing potential should be advised, if necessary, to use appropriate contraception during treatment with octreotide (see section 4.6).
Thyroid function should be monitored in patients receiving long-term octreotide therapy.
The occurrence of gastrointestinal adverse effects can be reduced by not eating at the time of injection, i.e. by administering the injections between meals or at bedtime.
Adverse effects at the injection site usually last no longer than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection, or by using a smaller volume of a more concentrated solution.
Cardiovascular events
Bradycardia is a commonly reported side effect (see section 4.8). Dose adjustment of medicinal products such as beta-blockers, calcium channel blockers or agents that control fluid and electrolyte balance may be necessary.
GEP endocrine tumours
Sudden escape of gastro-enteropancreatic endocrine tumours from symptomatic control by octreotide may occur rarely, 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, a state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been observed. Consider routine checks of blood glucose.
In patients with insulinoma 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 duration of hypoglycaemia. If octreotide is given to a patient with insulinoma, close monitoring is necessary particularly at initiation of treatment or when the dose is changed. Consider clinical therapy initiation at hospital. Marked fluctuations of blood glucose concentrations may be reduced by more frequent administration of lower doses of octreotide.
Octreotide may reduce requirements for insulin or oral hypoglycaemic agents in patients with type I diabetes mellitus. In non-diabetics and type II diabetics with partially intact insulin reserves, octreotide administration may result in prandial increases in glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Gallbladder and related incidents
Octreotide 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 octreotide treatment is estimated to be between 15 - 30%.
Ultrasonic examination of the gallbladder, before and at about 6 to 12 month intervals during octreotide 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 dose adjustment may be necessary (see section 4.2).
Administration site reactions
In a 52-week toxicity study in rats (predominantly males) sarcomas were observed at the subcutaneous injection site only at the highest dose (about 40 times the maximum human dose). No hyperplastic or neoplastic lesions occurred at the subcutaneous injection site in a 52-week toxicity study in dogs. There have been no reports of tumour formation at the injection site in patients treated for up to 15 years with octreotide. All the information currently available indicates that the rat findings are species-specific and are not significant for use of the medicinal product in humans.
Nutrition
Octreotide can alter the absorption of dietary fats in some patients.
Although nutritional deficiencies as a result of absorption disorders have not been described to date, it is advisable to check the fat excretion in faeces in prolonged therapy and, if necessary, to consider appropriate therapeutic measures (see section 4.8).
Reduced vitamin B12 levels and an abnormal Schilling test have been observed in some patients receiving octreotide therapy. It is therefore recommended to monitor vitamin B12 levels during treatment with octreotide in patients with a previous history of vitamin B12 deficiency.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per ml solution, i.e. essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Octreotide has been reported 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 active substances mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. quinine, carbamazepine, digoxin, phenprocoumon and terfenadine).
Octreotide reduces hepatic blood flow by about 30%. Consideration should therefore be given to the risk of interactions with active substances whose metabolism is dependent on hepatic blood flow.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of octreotide in pregnant women. Because of the inhibitory effect on growth hormone, octreotide may be assumed to constitute a risk to the foetus.
Studies in animals showed transient growth retardation of offsprings (see section 5.3), possibly as a consequence of the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic or other reproduction effects. The potential risk to humans is not known. Octreotide should therefore not be used during pregnancy unless the clinical condition of the woman requires treatment with octreotide. Women of childbearing potential have to use effective contraception during treatment.
Breastfeeding
It is unknown whether octreotide/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Women receiving treatment with octreotide should not breast-feed their infants. Animal studies have shown that octreotide is excreted in milk.
Fertility
Impaired fertility may be resolved during octreotide therapy of acromegaly.
4.7 Effects on ability to drive and use machines
No studies on the effects of octreotide on the ability to drive and use machines have been conducted.
4.8 Undesirable effects
Summary of the safety profile
The most frequent occurring adverse reactions reported during treatment with octreotide include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders and metabolism and nutrition disorders.
The most commonly reported adverse reactions in clinical trials involving the administration of octreotide were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and constipation. Other frequently reported adverse reactions were dizziness, local pain, biliary sludge, thyroid dysfunction (e.g. lower thyroid-stimulating hormone [TSH], total T4 and free T4 values), loose stools, reduced 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 subcutaneous 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 fate excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption.
The risk of gastro-intestinal 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.
There have been rare reports of acute pancreatitis. This effect is generally observed within the first few hours or days of treatment with octreotide and resolves upon withdrawal of the medicinal product. Cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide treatment.
There have been isolated cases of biliary colic following the abrupt withdrawal of the medicinal product in acromegalic patients in whom biliary sludge or gallstones had developed.
ECG changes such as QT prolongation, axis deviations, early repolarisation, low voltage, R/S transition, early R wave progression and non-specific ST-T wave changes were observed in both acromegalic patients and patients with carcinoid syndrome. The relationship between these incidents and octreotide acetate is not proven, as many of these patients had underlying heart disease (see section 4.4).
Tabulated list of adverse drug reactions
The following undesirable effects (see table 1) have been gathered from clinical trials with octreotide. Undesirable effects are classified according to the following convention:
Very common Common Uncommon Rare
Very rare Not known
(>1/10);
(>1/100 to <1/10);
(>1/1,000 to <1/100);
(>1/10,000 to <1/1,000);
(<1/10,000)
(cannot be estimated from the available data).
Within each frequency group undesirable effects are ranked in decreasing order of seriousness.
Table 1 - Adverse drug reactions as reported in clinical trials
|
Endocrine disorders | |
|
Common: |
Hypothyroidism, thyroid dysfunction (e.g. TSH decreased, total T4 decreased, free T4 decreased) |
|
Metabolism and nutrition disorders | |
|
Very common: |
Hyperglycaemia |
|
Common: |
Hypoglycaemia, reduced glucose tolerance, anorexia |
|
Uncommon: |
Dehydration |
|
Nervous system disorders | |
|
Very common: |
Headache |
|
Common: |
Dizziness |
|
Cardiac disorders | |
|
Common: |
Bradycardia |
|
Uncommon: |
Tachycardia |
|
Respiratory, thoracic and mediastinal disorders | |
|
Common: |
Dyspnoea |
|
Gastrointestinal disorders | |
|
Very common: |
Diarrhoea, abdominal pain, nausea, constipation, flatulence |
|
Common: |
Dyspepsia, vomiting, abdominal distension, steatorrhoea, loose stools, discoloured stools |
|
Rare: |
Acute intestinal obstruction, severe epigastric pain, abdominal tenderness, abdominal guarding, acute pancreatitis, cholelithiasis-induced pancreatitis |
|
Hepatobiliary disorders | |
|
Very common: |
Cholelithiasis |
|
Common: |
Cholecystitis, biliary sludge, hyperbilirubinaemia |
|
Skin and subcutaneous tissue disorders | |
|
Common: |
Pruritus, rash, alopecia |
|
General disorders and administration site conditions | |
|
Very common: |
Local pain at injection site |
|
Investigations | |
|
Common: |
Transaminases increased |
Postmarketing
Spontaneously reported adverse reactions listed in table 2 are reported voluntarily and it is not always possible to establish reliably how often these occur and whether there is a causal relationship between the adverse reaction and use of the medicinal product.
Table 2 - Spontaneously reported adverse reactions
|
Immune system disorders |
Anaphylaxis, allergic/hypersensitivity reactions |
|
Cardiac disorders |
Cardiac arrhythmias |
|
Hepatobiliary disorders |
Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice |
|
Skin and subcutaneous tissue disorders |
Urticaria |
|
Investigations |
Alkaline phosphatase increased, gamma-glutamyl transferase increased |
4.9 Overdose
There have been a limited number of reports of accidental overdose of octreotide in adults and children. In adults, the doses ranged from 2,400 to 6,000 micrograms/day, administered by continuous infusion (100 to 250 micrograms/hour) or subcutaneously (1500 micrograms three times daily). The reported adverse reactions were arrhythmia, hypotension, cardiac arrest, cerebral hypoxia, pancreatitis, steatosis, hepatitis, diarrhoea, asthenia, lethargy, weight loss, hepatomegaly and lactic acidosis.
In children the doses ranged from 50 to 3,000 micrograms/day, administered by continuous infusion (2.1 to 500 micrograms/hour) or subcutaneously (50 to 100 micrograms). The only reported adverse reaction was mild hyperglycaemia.
No unexpected adverse reactions have been reported in cancer patients receiving octreotide at doses of 3,000 to 30,000 micrograms/day (divided doses, subcutaneously).
The management of overdosage is symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, Somatostatin and analogues, ATC code: H01CB02.
Mechanism of action
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 gastro-enteropancreatic endocrine (GEP) system.
Pharmacodynamic effects
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 healthy subjects octreotide, like somatostatin, has been shown to inhibit:
- release of growth hormone stimulated by arginine, exercise and insulin-induced hypoglycaemia;
- post-prandial release of insulin, glucagon, gastrin, other peptides of the gastro-enteropancreatic 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).
Clinical efficacy and safety
For patients undergoing pancreatic surgery, the peri- and postoperative administration of octreotide reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).
In patients with acromegaly, octreotide consistently lowers GH and normalises IGF-1 plasma levels in the majority of patients. In most patients, octreotide markedly reduces the clinical symptoms of the disease, such as headache, perspiration, paraesthesia, fatigue, osteo-arthralgia and carpal tunnel syndrome. In individual patients with GH-secreting pituitary adenoma, octreotide was reported to lead to shrinkage of the tumour mass.
For patients with functional tumours of the gastro-enteropancreatic endocrine system, treatment with octreotide can provide continuous control of symptoms related to the underlying disease. The effects of octreotide in different types of gastro-enteropancreatic tumours are as follows:
The effect of octreotide on tumour size and growth and on the development of metastases is not yet clearly documented.
Carcinoid tumours
Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.
VIPomas
The biochemical characteristic of these tumours is overproduction of vaso-active 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 to within the normal reference range.
Glucagonomas
Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash that 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.
Prevention of complications following pancreatic surgery
Studies have shown that the incidence of fistula formation in particular is reduced by perioperative or postoperative administration of octreotide in pancreatic surgery. The incidence of other specific postoperative complications, such as abscess formation with the risk of emerging sepsis and acute pancreatitis, is affected to a lesser extent. The patients studied were those due to undergo elective pancreatic resection and/or pancreaticojejunostomy for a pancreatic tumour, peri-ampullary carcinoma or chronic pancreatitis.
5.2 Pharmacokinetic properties Absorption
After subcutaneous injection, octreotide is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.
Distribution
The volume of distribution is 0.27 l/kg bodyweight 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 administration is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and 90 minutes, respectively. About 32% is excreted unchanged in the urine.
Renal impairment had no effect on the total exposure (AUC) to octreotide following subcutaneous administration. The elimination capacity may be reduced in patients with hepatic cirrhosis, but not in patients with fatty liver disease.
5.3 Preclinical safety data
Non-clinical data reveal no special 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 offsprings, possibly a consequence of 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
(S)-Lactic acid
Sodium hydrogen carbonate (for pH adjustment) Mannitol
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
Unopened vial:
2 years
The product should be used immediately after opening the vial.
Diluted solution:
Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature. From a microbiological point of view, the product should be used immediately after it is diluted. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C).
Keep the vial in the outer carton in order to protect from light.
For day-to-day use unopened vials may be stored at room temperature for up to two weeks.
For storage conditions after dilution of the medicinal product see section 6.3.
6.5 Nature and contents of container
2 ml colourless type I glass vials, closed with chlorobutyl stoppers coated with a fluorocarbon barrier film and aluminium flip off caps containing 1 ml solution for injection.
Pack size: 1 vial.
5 vials. 30 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Vials should be opened immediately prior to use. Any unused solution should be discarded.
Prior to administration the solution should be inspected visually for discolouration or particulate matters.
To reduce local discomfort, it is recommended to let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same injection site.
Subcutaneous administration:
For subcutaneous use Octreotide should not be diluted.
Intravenous administration:
For intravenous use octreotide should be diluted with 9 mg/ml sodium chloride solution to a ratio of not less than 1 vol : 1 vol and not more than 1 vol : 9 vol. Dilution of octreotide with glucose solution is not recommended.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Fresenius Kabi Limited Cestrian Court,
Eastgate Way,
Manor Park,
Runcorn,
Cheshire,
WA7 1NT
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 08828/0242
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/03/2013
10 DATE OF REVISION OF THE TEXT
22/06/2013