Download summary of product characteristics

SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Octreotide 100 micrograms /ml Solution for Injection or Concentrate for Solution for
Infusion
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of Octreotide solution for injection or concentrate for solution for infusion
contains 100 micrograms octreotide (as octreotide acetate).
Octreotide solution for injection or concentrate for solution for infusion contains less
than 1 mmol (23 mg) 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.
pH:
Osmolality:
3.7 to 4.7
315 to 350 mOsmol/kg
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
Octreotide is not an 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.
Octreotide 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.
4.2
Posology and method of administration
Route of administration
Subcutaneous or intravenous use.
To reduce local discomfort, let the solution reach room temperature before injection.
Avoid multiple injections at short intervals at the same time.
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 Octreotide 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 2.5 ng/ml,
5mU/I; IGF-1 within normal range) and clinical symptoms, and on tolerability.
For patients on a stable dose of Octreotide, 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 subcutaneously, and therefore no dose adjustment of
Octreotide 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 Octreotide, there was no evidence for reduced
tolerability or altered dosage requirements.
Paediatric population:
Experience with the use of Octreotide 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).
Thyroid function (TSH and thyroid hormone levels) should be monitored in patients
receiving long-term Octreotide 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 Octreotide 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 Octreotide 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 Octreotide.
Octreotide 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, Octreotide administration can result in prandial increases in
glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic
treatment.
Gallbladder and related events
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, dosage adjustment may be necessary (see Section 4.2).
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 52week 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 absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in
some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is
recommended during therapy with Octreotide 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 ciclosporin 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, terfenadine).
4.6
Fertility, pregnancy and lactation
Pregnancy
Octreotide should only be prescribed to pregnant women under compelling
circumstances (see also section 4.4).
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 Octreotide 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).
Lactation
Patients should not breastfeed during Octreotide 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 Octreotide 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 Octreotide treatment and resolves on withdrawal of
the drug. In addition, 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
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).
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 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000);
very rare (≤1/10,000); Not known (cannot be estimated from the available data)
including isolated reports. Within each frequency grouping adverse reactions are
ranked in order of decreasing seriousness.
Table - Adverse drug reactions
Endocrine disorders
Common:
Metabolism and nutrition
disorders:
Very common:
Common:
Uncommon:
Cardiac disorders
Common:
Uncommon:
Not Known:
Respiratory disorders
Common:
Gastrointestinal disorders
Very common:
Common:
Nervous system disorders
Very common:
Common:
Hepatobillary disorders
Very common:
Common:
Not known
Skin and subcutaneous tissue
disorder
Common:
Hypothyroidism, thyroid dysfunction (e.g.,
decreased TSH, decreased Total T4 and
decreased Free T4)
Hyperglycaemia
Hypoglycaemia, impaired glucose tolerance,
anorexia
Dehydration
Bradycardia
Tachycardia
Arrhythmias
Dyspnoea
Diarrhoea, abdominal pain, nausea,
constipation, flatulence
Dyspepsia, vomiting, abdominal bloating,
steatorrhoea, loose stools, discolouration of
faeces
Headache
Dizziness
Cholelithiasis
Cholecystitis, biliary sludge,
hyperbilirubinaemia
Acute pancreatitis, acute hepatitis without
cholestasis, cholestatic hepatitis, cholestasis,
jaundice, cholestatic jaundice
Pruritus, rash, alopecia
Not known
General disorders and
administration site
Very common:
Investigations
Common:
Urticaria
Not known
Increased alkaline phosphatase levels,
increased gamma glutamyl transferase levels
Immune disorders
Not known
Injection site localised pain
Elevated transaminase levels
Anaphylaxis, allergy/hypersensitivity
reactions
4.9
Overdose
A limited number of accidental overdoses of Octreotide 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
Octreotide 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: H01CB02.
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 Octreotide reduces the incidence of typical post-operative complications (e.g.
pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).
In patients with acromegaly, Octreotide consistently lowers GH and normalises IGF-1
serum concentrations in the majority of patients. In most patients, Octreotide
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, Octreotide 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 administration, Octreotide is rapidly and completely absorbed.
The peak plasma concentration is 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 is approximately 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.
About 32% is excreted unchanged in 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
Glacial acetic acid (for pH adjustment)
Sodium acetate trihydrate (for pH adjustment) (E262)
Mannitol (E421)
Water for injections
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
Unopened vials: 3 years
Shelf life after first opening: The product must be used immediately and any unused
drug product must be discarded.
Storage conditions after dilution: The chemical and physical stability of Octreotide
solution diluted in 9 mg/ml (0.9%) sodium chloride solution for infusion has been
demonstrated for 24 hours when stored below 25°C. From a microbiological point of
view, the product should be used immediately, if not used immediately, storage times
and conditions are the responsibility of the user, unless dilution has taken place in
controlled and validated aseptic conditions.
6.4
Special precautions for storage
Unopened vial: Store in a refrigerator between 2-8°C, protected from light. Do not
freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
Octreotide solution for injection or concentrate for solution for infusion is filled into
clear glass vials closed with rubber stoppers and sealed with aluminium flip-off caps
fitted with plastic flip-off discs. The product is packaged in cardboard boxes.
Packs sizes of 1, 3, 5, 6, 10, 20 and 30 vials.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
For i.v. use Octreotide 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 Octreotide with glucose is
not recommended.
If Octreotide has been diluted, the prepared solution may be kept at room temperature
but should be administered within 24 hours of preparation.
Single use only.
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local
requirements.
7
MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex BN22 9AG
UNITED KINGDOM
8
MARKETING AUTHORISATION NUMBER(S)
PL 00289/1264
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/12/2011
10
DATE OF REVISION OF THE TEXT
11/11/2014