Octreotide 100 Micrograms/Ml Solution For Injection In Prefilled Syringe
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
OCTREOTIDE 100 micrograms/ml, solution for injection in prefilled syringe
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prefilled syringe with l ml of solution for injection contains 100 micrograms of octreotide as octreotide acetate.
This medicinal product contains less than 1 mmol (23 mg) of sodium per 1 ml of solution (i.e., essentially sodium free)
For a full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Solution for injection in prefilled syringe.
Clear, colourless solution .
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
a) For the relief of symptoms associated with gastroenteropancreatic tumours (GEP tumours) including:
• Carcinoid tumours with features of carcinoid syndrome
• VIPomas
• Glucagonomas
OCTREOTIDE is not an antitumour therapy and is therefore not curative in these patients.
b) Acromegaly:
For symptomatic control and reduction of growth hormone (GH) and Insulin-like growth factor number-1 (IGF-1) plasma levels in patients with acromegaly who are not adequately controlled by surgery or radiotherapy:
- In short term treatment, prior to pituitary surgery, or
- In long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, dopamine agonist treatment, or in the interim period until radiotherapy becomes effective.
- OCTREOTIDE is indicated for acromegalic patients for whom surgery is inappropriate.
Evidence from short term studies demonstrates 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.
c) Prevention of complications following pancreatic surgery.
4.2 Posology and method of administration
To reduce discomfort, let OCTREOTIDE injection reach room temperature before administration. Avoid multiple injections at short intervals at the same administration site.
OCTREOTIDE injection should be inspected prior to administration and only clear solutions without particles should be used.
Gastroenteropancreatic (GEP) endocrine tumours:
Initially a dose of 50 micrograms once or twice daily by subcutaneous injection is recommended. Depending on clinical response the dosage can be gradually increased to 100-200 micrograms three times daily. Under exceptional circumstances, higher doses may be necessary. Maintenance doses are variable. The recommended maximum daily dosage is 600 micrograms.
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 the cardiac rhythm through ECG.
In carcinoid tumours, if there is no beneficial response with the maximum tolerated dose of OCTREOTIDE within a week, the therapy should be discontinued.
Acromegaly:
Initially doses of 50-100 micrograms three times daily by subcutaneous injection. For most patients the optimal daily dose is normally 200-300 micrograms daily. More than 1500 micrograms per day should not be given. Dose adjustment should be made based on monthly measurements of the amount of circulating growth hormones (GH or IGF-1), changes to the clinical picture and possible adverse events.
If no significant reduction of growth hormone (GH) levels and no improvement of clinical symptoms have been achieved within three months of starting treatment with OCTREOTIDE, therapy should be discontinued.
Prevention of complications following pancreatic surgery:
A dose of 100 micrograms three times daily by subcutaneous injection for seven consecutive days is recommended, starting on the day of the operation at least one hour before laparotomy.
Use in patients with renal insufficiency:
Renal insufficiency did not affect the total exposure (AUC: area under the curve) to OCTREOTIDE when administered subcutaneously, and therefore no dose adjustment of OCTREOTIDE is necessary.
Use in patients with hepatic insufficiency:
In patients with liver cirrhosis the half-life of OCTREOTIDE may be increased, requiring an adjustment of the maintenance dose.
Use in the elderly:
In elderly patients treated with OCTREOTIDE, there was no evidence for reduced tolerability or altered dosage requirements.
Use in children:
Experience with the use of OCTREOTIDE in children is limited.
4.3 Contraindications
Hypersensitivity to octreotide or to any of the excipients of Octreotide (see section 6.1 Full list of excipients).
4.4 Special warnings and precautions for use
General
OCTREOTIDE should only be used under specialist hospital supervision with appropriate facilities available for diagnosis and evaluation of response.
As growth hormone secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defect), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures should be considered.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization 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 Pregnancy and lactation).
Thyroid function should be monitored in patients receiving long-term Octreotide therapy.
In patients with cirrhosis, dosage adjustment may be necessary (see section 4.2. Posology and Method of Administration).
GEP endocrine tumours
Sudden escape of gastroenteropancreatic 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, octreotide 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.
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 Octreotide therapy and at each change of dosage.
OCTREOTIDE may reduce insulin requirements in patients receiving treatment for type I diabetes mellitus. In non-diabetics and type II diabetics with partially intact insulin reserves, OCTREOTIDE administration can result in prandial increases in glycaemia.
Blood glucose levels should therefore be carefully monitored particularly at the initiation of treatment with OCTREOTIDE or when the dose is changed. Unstable blood sugar concentrations may be avoided by dividing the daily dose into several injections.
Gallbladder and related events
The development of gallstones has been reported (estimated at between 15% and 30%) in association with OCTREOTIDE treatment. The incidence in the general population is 5 to 20%. Ultrasonic examination for gallstones before, and at 6 to 12 month intervals during prolonged OCTREOTIDE treatment is recommended. The presence of gallstones in patients treated with OCTREOTIDE is usually asymptomatic; symptomatic stones should be treated in normal manner.
Liver function should be monitored during treatment with OCTREOTIDE.
Cardiovascular related events
Bradycardia has been reported. This should be taken into account in patients with a history of, or risk factors for bradycardia. Dose adjustments of drugs such as betablockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.
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 Octreotide 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 the absorption of fat from food in some patients.
Decreased vitamin B12 levels and abnormal Schilling’s test have been observed in some patients treated with Octreotide. In patients who previously have experienced vitamin B12 deficiency, monitoring of vitamin B12 levels are recommended during treatment with Octreotide.
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 bioavailability of bromocriptine.
Limited published data indicate that somatostatin analogs 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 (e.g. quinine, terfenadine) should therefore be used with caution.
4.6 Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. In the postmarketing 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 octreotide s.c. or 20-30 mg/month of the slow-release form of octreotide. 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).
Octreotide should only be prescribed to pregnant woman under compelling circumstances (see section 4.4 Special warnings and precautions for use).
Lactation
It is not known whether OCTREOTIDE passes into breast milk. Animal studies have shown excretion of octreotice in breast milk. Patients should not breast-feed during octreotide treatment.
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 performed.
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, localized 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, 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 longterm 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 s.c. administration, that is, by injecting between meals or on retiring to bed.
In very rare instances, acute pancreatitis has been reported within the first hours or days of Octreotide s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasisinduced pancreatitis has been reported for patients on long-term Octreotide s.c. 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 (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 ^ 1/10); 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
Gastrointestinal disorders
Very common:
Common:
Diarrhoea, abdominal pain, nausea, constipation, flatulence.
Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.
Nervous system disorders
Very common: Headache.
Common: Dizziness.
Endocrine disorders
Common: Hypothyroidism, thyroid dysfunction (e.g., decreased TSH,
decreased Total T4, and decreased Free T4).
Hepatobiliary disorders
Very common: Cholelithiasis.
Common: Cholecystitis, biliary sludge, hyperbilirubinaemia.
Metabolism and nutrition disorders
Very common: Hyperglycaemia
Common: Hypoglycaemia, impaired glucose tolerance, anorexia.
Uncommon: Dehydration.
General disorders and administration site
Very common: Injection site localized pain.
Investigations
Common: Elevated transaminase levels.
Skin and subcutaneous tissue disorders
Common: Pruritus, rash , alopecia.
Respiratory disorders
Common: Dyspnoea.
Cardiac disorders
Common: Bradycardia
Uncommon: Tachycardia.
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
Anaphylaxis, allergy/hypersensitivity reactions.
Skin and subcutaneous tissue disorders
Urticaria.
Hepatobiliary disorders
Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis.
Cholestasis, j aundice, cholestatic j aundice.
Cardiac disorders Arrhythmias.
Investigations
Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.
4.9 Overdose
A limited number of accidental overdoses of Octreotide in adults and children have been reported. In adults, the doses ranged from 2,400-6,000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 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 50-3,000 microgram/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 Octreotide at doses of 3,000-30,000 micrograms/day in divided doses subcutaneously.
Treatment
The management of overdosage is symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antigrowth Hormones.
ATC code: H01CB02
Octreotide is a synthetic octapeptide analog of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the
gastroenteropancreatic (GEP) endocrine system, stomach, intestine and pancreas (for example, gastrin, insulin and glucagon).
Octreotide gives symptomatic relief of the symptoms caused by functional tumours of the gastroenteropancreatic (GEP) endocrine system (stomach, intestine and pancreas) in patients whose symptoms have not been relieved by other forms of treatment such as surgery, hepatic artery embolisation or chemotherapy.
The effect of octreotide on tumour size, rate of growth or on the formation of metastases has not yet been clearly documented. In healthy volunteers octreotide has been shown to inhibit the release of GH stimulated by arginine, exercise and insulin-induced hypoglycaemia, and thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).
Unlike somatostatin, octreotide inhibits growth hormone (GH) and glucagon preferentially over insulin.
Discontinuation of treatment is not followed by a rebound effect with hypersecretion of hormones.
In patients with carcinoid tumours, octreotide may result in relief 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 (5-HIAA).
In patients with VIPomas, the biochemical characteristic is overproduction of vasoactive intestinal peptide (VIP). In most cases, octreotide alleviates 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, such as hypokalaemia. The need for administration of fluids and electrolytes is reduced. In some patients, computer tomography scanning reveals a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.
In glucagonomas, administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of this condition. The effect of octreotide on the moderate 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 affected patients. 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.
In patients with acromegaly, octreotide reduces GH and IGF-1 plasma levels. A GH reduction by around 50% or more occurs in over 90% of patients, and a reduction of plasma GH to < 5 ng/ml can be achieved in about half of the cases. In most patients, octreotide significantly reduces clinical symptoms such as headache, swelling of skin and soft tissues, hyperhidrosis, arthralgia and paraesthesia. In patients with large volume pituitary adenomas, octreotide may lead to shrinkage of the tumour mass.
For patients undergoing pancreatic surgery, the peri- and post-operative administration of octreotide generally reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).
5.2 Pharmacokinetic properties Absorption
After subcutaneous administration, octreotide is rapidly and completely absorbed. The peak plasma concentration is reached after 30 minutes.
Distribution
The volume of distribution is around 0.27 l/kg and the total body clearance is 160 ml/min. Plasma protein binding is approximately 65%. The amount of octreotide bound to blood cells is negligible.
Elimination
The elimination half-life after subcutaneous administration is 100 minutes.
After intravenous administration, the elimination is biphasic with half-lives of 10 and 90 minutes. Most of the administered dose is eliminated in the faeces and approximately 32% is excreted in unchanged form in the urine.
Renal insufficiency did not affect the total exposure (AUC) to octreotide when administered in the form of a subcutaneous injection. The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver.
5.3 Preclinical safety data Acute toxicity
Acute toxicity studies performed with octreotide in the guinea-pig showed that LD50 is 72 mg/kg by IV and 470 mg/kg subcutaneously. In the mouse, LD50 was 18 mg/kg ( IV). Octreotide acetate was well tolerated by dogs that received up to 1 mg/kg by IV bolus.
Toxicity after repeated administration
A 26 weeks toxicity study in dogs, with IV doses up to 0.5 mg/kg, bid, showed progressive changes in acidophilic pituitary cells that contain prolactin. Further investigations showed that this variation was within the physiologic range and apparently not related to octreotide administration. No significant changes were seen in plasma level of hormones. Rhesus monkey females receiving 0.5 mg/kg bid for 3 weeks did not show pituitary changes nor changes in plasma levels of GH, prolactin or glucose.
Local tolerance
While acidic vehicle produced inflammation and fibroplasias in mouse after repeated injections, no evidence of octreotide acetate causing hypersensitivity reactions was found in the guinea-pig model after intradermal administration.
In a toxicology study on predominantly male rats, sarcomas were observed at the subcutaneous injection site after 52 weeks, but only with the highest dose (around forty times the maximum dose used in humans). In a 52-week toxicology study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. No cases of tumour formation at the injection site have been reported in patients treated with octreotide for periods of up to 15 years. All of the available information to date indicates that the results obtained in rats are species-specific and are not relevant for the use of the drug in humans.
Mutagenicity
Octreotide and/or its metabolites were without mutagenic potential in standard in vitro tests. An increase of chromosomic changes in V79 Chinese hamster cells was seen, in vitro, although only with high and cytotoxic concentrations. In human lymphocytes incubated with octreotide acetate in vitro the chromosomal changes were not increased. Blastogenic activity in vivo (micronuclei test in guinea pigs) was not observed .
Carcinogenicity
Studies with mice treated with subcutaneous octreotide in daily doses up to 1.25 mg/kg of body weight, the presence of fibrosarcomas, after 52, 104 and 113/116 weeks was observed in some animals, mainly males. Local tumours in control group of mice also appeared, however the tumours were related to disorganized fibroplasias produced by irritant effects of the acid vehicle. In guinea-pigs that received daily SC injections of octreotide in doses up to 2 mg/kg for 98 weeks, neoplastic lesions were not observed.
The mouse carcinogenicity study also revealed endometrial carcinomas, statistically significant for the highest subcutaneous dose of 1.25 mg/kg/day. This observation was associated with an increase in endometritis, a reduced number of luteal bodies, a reduction of breast adenomas and the presence of luminal dilation and glandular uterus, suggesting a hormonal imbalance. The available data indicates that the observed hormone-dependent tumours in mice are species specific and therefore not relevant for humans.
Reproduction toxicity
The fertility study as well as the studies of pre-, peri- and post-natal effects in rats did not reveal adverse events on the reproductive ability or on foetal development with doses up to 1 mg/kg/day subcutaneously. Some delay of offspring growth, which was transient and may be due the GH inhibition due to the excessive pharmacodynamic activity, was observed
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 due to the pharmacodynamic action of octreotide, but there was no evidence of foetotoxic, teratogenic, or other reproductive effects.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
(S)-Lactic acid,
Sodium chloride,
Sodium hydroxide for pH adjusting
Water for injection.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
6.3 Shelf life
3 years
Storage conditions after dilution in sodium chloride 0.9% solution when stored in glass bottles :
Chemical and physical in-use stability has been demonstrated for 24 hours at 25° From a microbiological point of view, the product should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze. Store the pre-filled syringe in the blister in order to protect the product from light. For day by day use the product may be stored below 30 degree Celsius for up to 30 days.
For storage conditions after dilution, see section 6.3.
6.5 Nature and contents of container
1 ml of solution in type I glass syringe barrel with needle and rigid needle shield with plunger stopper (bromobutyl).
Five, six or thirty prefilled syringes are packaged in thermoformed white, opaque PVC blister, sealed with an aluminum foil.
1 ml of solution in type I glass syringe barrel with needle and rigid needle shield with
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Prior to administration the solution should be inspected visually for changes of colour or solid particles.
It is not recommended to mix or dilute OCTREOTIDE solutions for injection except with 0.9% sodium chloride solution.
For single use only.
Administration by the subcutaneous route:
Octreotide should be administered by the subcutaneous route without reconstitution or dilution.
Administration by the intravenouse route:
GEP tumour where a rapid response is needed (i.v. administration as a bolus): OCTREOTIDE should be diluted with 0.9% (w/v) sodium chloride solution for injection at a ratio not exceeding 1:100.
Any unused solution or waste material should be disposed of in accordance with local requirements
7 MARKETING AUTHORISATION HOLDER
CHEMI SPA
VIA DEI LAVORATORI
54-20092 CINSIELLO BALSAMO
MILAN
ITALY
8 MARKETING AUTHORISATION NUMBER(S)
PL 04465/0006
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/07/2010
10 DATE OF REVISION OF THE TEXT
16/04/2012