Granisetron 1mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Granisetron 1 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg granisetron as granisetron hydrochloride. Excipient(s) with known effect:
Each 1 mg tablet contains 64.88 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
1 mg: White to off white, film coated, capsule shaped tablet, debossed with “93” on one side of the tablet and with “7485” on the other side of the tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Granisetron film-coated tablets are indicated for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy.
Granisetron film-coated tablets are indicated in adults for prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.
4.2 Posology and method of administration
Posology
1 mg tablet twice a day or 2 mg once a day for up to one week following radiotherapy or chemotherapy.
The first dose of granisetron should be administeredwithin 1 hour before the start of therapy. Dexamethasone has been used concomitantly at doses up to 20 mg once a day orally.
Paediatric population
The safety and efficacy of granisetron tablets in children have not yet been established. No data are available.
Elderly and renal impairment:
There are no special precautions required for its use in either elderly patients or those patients with renal or hepatic impairment.
Hepatic impairment:
There is no evidence to date for an increased incidence of adverse events in patients with hepatic disorders. On the basis of its kinetics, whilst no dosage adjustment is necessary, granisetron should be used with a certain amount of caution in this patient group (see section 5.2).
Method of administration
The tablets should be swallowed whole with water.
4.3 Contraindications
Hypersensitivity to granisetron or to any of the excipients (see section 6.1).
4.4 Special warnings and precautions for use
As granisetron may reduce bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following administration of granisetron.
As for other 5-HT3 antagonists, ECG changes including QT interval prolongation have been reported with granisetron. In patients with pre-existing arrhythmias or cardiac conduction disorders this might lead to clinical consequences. Therefore caution should be exercised in patients with cardiac co-morbidities, on cardiotoxic chemotherapy and/or with concomitant electrolyte abnormalities (see section 4.5).
Cross-sensitivity between 5-HT3 antagonists (e.g. dolasteron, ondansetron) has been reported.
Patients with rare hereditary problems of glucose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine
Paediatric population
There is insufficient clinical evidence to recommend administration of granisetron tablets to children.
4.5 Interaction with other medicinal products and other forms of interaction
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. In patients concurrently treated with medicinal products known to prolong QT interval and/or which are arrhythmogenic, this may lead to clinical consequences (see section 4.4).
In studies in healthy subjects, no evidence of any interaction has been indicated between granisetron and benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine). Additionally, granisetron has not shown any apparent medicinal product interaction with emetogenic cancer chemotherapies.
No specific interaction studies have been conducted in anaesthetised patients.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is limited amount of data from the use of granisetron in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see sectin 5.3). As precautionary measure, it is preferable to avoid use of granisetron during pregnancy.
Breastfeeding
It is unknown whether granisetron or its metabolites are excreted in human milk. As precautionary measure, breast-feeding should not be advised during treatment with granisetron.
Fertility
In rats, granisetron had no harmful effects on reproductive performance or fertility.
4.7 Effects on ability to drive and use machines
Granisetron has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions for granisetron are headache and constipation, which may be transient. ECG changes including QT prolongation have been reported with granisetron (see sections 4.4 and 4.5).
Tabulated list of adverse reactions
The following table of listed adverse reactions is derived from clinical trials and postmarketing data associated with granisetron and other 5-HT3 antagonists.
Frequency categories are as follows:
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)
|
Immune system disorders | |
|
Uncommon |
Hypersensitivity reactions, e.g. anaphylaxis, |
|
urticaria | |
|
Psychiatric disorders | |
|
Common |
Insomnia |
|
Nervous system disorders | |
|
Very common |
Headache |
|
Uncommon |
Extrapyramidal reactions |
|
Cardiac disorders | |
|
Uncommon |
QT prolongation |
|
Gastrointestinal disorders | |
|
Very common |
Constipation |
|
Common |
Diarrhoea |
|
Hepatobiliary disorders | |
|
Common |
Elevated hepatic transaminases* |
|
Skin and subcutaneous tissue disorders | |
|
Uncommon |
Rash |
*Occurred at a similar frequency in patients receiving comparator therapy Description of selected adverse reactions
As for other 5-HT3 antagonists, ECG changes including QT prolongation have been reported with granisetron (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard
4.9 Overdose
There is no specific antidote for granisetron. In the case of overdose with tablets, symptomatic treatment should be given. Doses of up to 38.5 mg of granisetron as a single injection have been reported, with symptoms of mild headache but no other reported sequelae.
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT3) antagonists
ATC code: A04A A02
Neurological mechanisms, serotonin-mediated nausea and vomiting Serotonin is the main neurotransmitter responsible for emesis after chemo- or radiotherapy. The 5-HT3 receptors are located in three sites: vagal nerve terminals in the gastrointestinal tract and chemoreceptor trigger zones located in the area postrema and the nucleus tractus solidarius of the vomiting center in the brainstem. The chemoreceptor trigger zones are located at the caudal end of the fourth ventricle (area postrema). This structure lacks an effective blood-brain barrier, and will detect emetic agents in both the systemic circulation and the cerebrospinal fluid. The vomiting centre is located in the brainstem medullary structures. It receives major inputs from the chemoreceptor trigger zones, and a vagal and sympathetic input from the gut.
Following exposure to radiation or catotoxic substances, serotonin (5-HT) is released from enterochromaffine cells in the small intestinal mucosa, which are adjacent to the vagal afferent neurons on which 5-HT3 receptors are located. The released serotonin activates vagal neurons via the 5-HT3 receptors which lead ultimately to a severe emetic response mediated via the chemoreceptor trigger zone within the area postrema.
Mechanism of action
Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types including 5-HT, and dopamine D2 binding sites.
Chemotherapy- and radiotherapy-induced nausea and vomiting
Granisetron administered orally has been shown to prevent nausea and vomiting
associated with cancer chemotherapy in adults.
Post-operative nausea and vomiting
Granisetron administered orally has been shown to be effective for prevention and treatment of post-operative nausea and vomiting in adults.
Pharmacological properties of granisetron
Interaction with neurotropic and other active substances through its activity on P 450-cytochrome has been reported (see section 4.5).
In vitro studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main narcotic agents) is not modified by granisetron. Although ketaconazole was shown to inhibit the ring oxidation of granisetron in vitro, this action is not considered clinically relevant.
Although QT-prolongation has been observed with 5-HT3 receptor antagonists (see section 4.4), this effect is of such occurrence and magnitude that it does not bear clinical significance in normal subjects. Nonetheless it is advisable to monitor both ECG and clinical abnormalities when treating patients concurrently with drugs known to prolong the QT (see section 4.5).
Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from the extensive dose-finding programme that the antiemetic efficacy is not unequivocally correlated with either administered doses or plasma concentrations of granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion of patient responding to treatment or in the duration of symptoms control.
Absorption
Absorption of granisetron is rapid and complete, though oral biovailability is reduced to about 60% as a result of first pass metabolism. Oral biovailability is not generally influenced by food.
Distribution
Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 l/kg. Plasma protein binding is approximately 65%..
Biotransformation
Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The major compounds are 7-OH-granisetron and its sulphate and glycuronide conjugates. Although antiemetic properties have been observed for 7-OH-granisetron and indazoline N-desmethyl granisetron, it is unlikely that these contribute significantly to the pharmacological activity of granisetron in man. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P450 3A subfamily (see section 4.5).
Elimination
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose, while that of metabolites amounts to about 47% of dose.The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide intersubject variability.
Pharmacokinetics in special populations Renal failure
In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment
In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared with patients without hepatic impairment. Despite these changes, no dosage adjustment is necessary (see section 4.2).
Paediatric population
These tablets are not recommended in children.
Elderyl patients
In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity, reproductive toxicity and genotoxicity. Carcinogenicity studies revealed no special hazard for humans when used in the recommended human dose. However, when administered in higher doses and over a prolonged period of time the risk of carcinogenicity cannot be ruled out.
A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which potentially affects both depolarization and repolarization through prolongation of PR, QRS, and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace. If changes do occur, they are generally without clinical significance.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core
Lactose monohydrate Hypromellose (E464)
Microcrytalline cellulose Sodium starch glycollate Magnesium stearate (E572)
Coating
Titanium dioxide (E171)
Hypromellose (E464)
Polysorbate 80 Macrogol 400
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Transparent and white opaque PVC/PVdC aluminium blisters.
Pack sizes:
1 mg: 1, 2, 5, 6, 10, 14, 50 and 100 film-coated tablets.
Hospital packs of 50 x 1, 10 x 1 and 100 x 1 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road,
Hampden Park,
Eastbourne, East Sussex,
BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0960
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/02/2008
10 DATE OF REVISION OF THE TEXT
14/10/2013