1.                     NAME OF THE MEDICINAL PRODUCT

Kytril 1 mg or 2 mg film-coated Ttablets

2.                     QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 mg or 2 mg granisetron (as the hydrochloride).

Excipients

1mg -  Each tablet contains 69.38 mg of include lactose monohydrate (see section 4.3 Contraindications).

2mg - Each tablet contains 138.76 mg of lactose monohydrate

For full list of excipients, see section 6.1.

3.                     PHARMACEUTICAL FORM

Film-coated Ttablet.

The tablets are Wwhite to almost white triangular biconvex film-coated tablets imprinted with marked 'K1' or ’K2’ on one side.

4.                     CLINICAL PARTICULARS

4.1                 Therapeutic indications

Kytril film-coated tablets are indicated in adults for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapyinduced by cytostatic therapy.

Kytril 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

Adults

Posology

The dose of Kytril is 1 mg twice a day or 2 mg once a day for up to one week following radiotherapy or chemotherapy.during cytostatic therapy.

The first dose of Kytril should be administered within one 1 hour before the start of cytostatic therapy.

Dexamethasone has been used concomitantly at doses up to 20 mg once a day orally.

Concomitant use of dexamethasone: The efficacy of Kytril may be enhanced by the addition of dexamethasone.

Maximum Dose and Duration of Treatment

Kytril is also available as ampoules for intravenous administration.  The maximum dose of Kytril administered orally and/or intravenously over 24 hours should not exceed 9mg.

ChildrenPaediatric population

The safety and efficacy of granisetron tablets in children have not yet been established.  No data are available.

There is insufficient evidence on which to base appropriate dosage regimens for children under
12 years old.  Kytril Tablets are therefore not recommended in this age group.

Elderly and renal impairment

As for adults.There are no special precautions required for its use in either elderly patients or those patients with renal or hepatic impairment.

Renally Impaired

As for adults.

Hepatically iImpairmented

As for adults.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, relatedthe active substances, or to any of the excipients (see section 6.1).

Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.4                 Special warnings and precautions for use

As granisetron Kytril may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following its administration of Kytril.

As for other 5-HT₃ antagonists, cases of ECG changesmodifications including QT interval prolongation have been reported with granisetronKytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, Iin 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 cardio-toxic 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 galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population

There is insufficient clinical evidence to recommend administration of these tablets to children.

4.5                 Interaction with other medicinal products and other forms of         interaction

In studies in healthy subjects, no evidence of any interaction has been indicated between Kytril and cimetidine or lorazepam.  No evidence of drug interactions has been observed in clinical studies.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with granisetronKytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, iIn patients concurrently treated with medicinal productsdrugs 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, pPregnancy 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 section 5.3). As a precautionary measure, it is preferable to avoid the use of granisetron during pregnancy.

Breastfeeding

It is unknown whether granisetron or its metabolites are excreted in human milk. As a precautionary measure, breast-feeding should not be advised during treatment with Kytril.

Fertility

In rats, granisetron had no harmful effects on reproductive performance or fertility.

Whilst animal studies have shown no teratogenic effects, there is no experience of Kytril in human pregnancy.  Therefore Kytril should not be administered to women who are pregnant unless there are compelling clinical reasons.  There are no data on the excretion of Kytril in breast milk.  Breast feeding should therefore be discontinued during therapy.

4.7                 Effects on ability to drive and use machines

There has been no evidence from human studies that Kytril has any adverse effect on alertness.

Kytril has no or negligible influence on the ability to drive and use machines.

4.8                 Undesirable effects

Kytril has been generally well tolerated in human studies.  As reported with other drugs of this class, headache and constipation have been the most frequently noted adverse events, but the majority have been mild or moderate in nature.  Rare cases of hypersensitivity reaction, occasionally severe (e.g. anaphylaxis), have been reported.  Other allergic reactions including minor skin rashes have also been reported.  In clinical trials, transient increases in hepatic transaminases, generally within the normal range, have been seen.

Dystonias and dyskinesias have been reported with medicines in the 5-HT₃ antagonist class.   Such events have been reported rarely with Kytril.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. (See section 4.4 Special Warnings and Precautions for Use and 4.5 Interactions with other Medicinal Products and other Forms of Interaction)

Summary of the safety profile

The most frequently reported adverse reactions for Kytril are headache and constipation, which may be transient. ECG changes including QT prolongation have been reported with Kytril (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 post-marketing data associated with Kytril 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)

*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).

4.9                 Overdose

There is no specific antidote for Kytril.  In the case of overdosage with the tablets, symptomatic treatment should be given.  Doses of up to 38.5 mg ofOne patient has received 30mg of Kytril as a single injection have been reported, with symptoms of mild headache but no other reported sequelae. intravenously.  The patient reported a slight headache but no other sequelae were observed.

5.                     PHARMACOLOGICAL PROPERTIES

5.1                 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT3) antagonists.

ATC code: A04AA02.

Neurological mechanisms, serotonin-mediated nausea and vomiting

Serotonin is the main neurotransmitter responsible for emesis after chemo- or radio-therapy. 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).

Kytril is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT₃) receptors. Radioligand binding studies have demonstrated that Kytril has negligible affinity for other receptor types including 5-HT and dopamine D₂ binding sites.

Kytril is effective orally prophylactically in abolishing the retching and vomiting evoked by cytostatic therapy.

5.2                 Pharmacokinetic properties

General Characteristics

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 granisetronKytril is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism.  Oral bioavailability is generally not influenced by food.

Distribution

GranisetronKytril is extensively distributed,, with a mean volume of distribution of approximately 3 l/kg; Pplasma protein binding is approximately 65%.

Biotransformation

Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation.

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 P-450 3A subfamily (see section 4.5).

Elimination

Clearance is predominantly by hepatic metabolism.  Urinary excretion of unchanged granisetronKytril averages 12% of dose whilst 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 nine9 hours, with a wide inter-subject variability.

The pharmacokinetics of Kytril demonstrate no marked deviations from linear pharmacokinetics at oral doses up to 2.5-fold of the recommended clinical dose.

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 neoplasic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary (see section 4.2).

Paediatric population

These tablets are not recommended in children.

Elderly patients

Characteristics in Patients

The plasma concentration of Kytril is not clearly correlated with anti-emetic efficacy.  Clinical benefit may be conferred even when Kytril is not detectable in plasma.

In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.  In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.  In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement.  Despite these changes, no dosage adjustment is necessary.

5.3                 Preclinical safety data

Data from two-year carcinogenicity studies have shown an increase in hepatocellular carcinoma and/or adenoma in rats and mice of both sexes given 50mg/kg (rat dosage reduced to 25mg/kg/day at week 59).  Increases in hepatocellular neoplasia were also detected at 5mg/kg in male rats.  In both species, drug-induced effects (hepatocellular neoplasia) were not observed in the low-dose group (1mg/kg).

In several in vitro and in vivo assays, Kytril was shown to be non-genotoxic in mammalian cells.

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, 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

Microcrystalline Cellulose (E460)

Sodium Starch Glycolate

Hypromellose (E464)

Lactose monohydrate

Magnesium Stearate (E572)

Film coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

Polysorbate 80 (E433)

6.2                 Incompatibilities

None.

6.3                 Shelf life

Kytril Ttablets have a shelf-life of three years.

6.4                 Special precautions for storage

None.

6.5                 Nature and contents of container

Opaque PVC/aluminium foil blister packs packed in cartons containing 10 tablets (1mg) or 5 tablets (2mg).

6.6                 Special precautions for disposalInstructions for use/handling

None.

Any unused product or waste material should be disposed of in accordance with local requirements.

Kytril

1.                     NAME OF THE MEDICINAL PRODUCT

Kytril 1 mg or 2 mg Film-coated Tablets

2.                     QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 mg or 2 mg granisetron (as the hydrochloride).

Excipients

1mg -  Each tablet contains 69.38 mg of include lactose monohydrate (see section 4.3 Contraindications).

2mg - Each tablet contains 138.76 mg of lactose monohydrate

For full list of excipients, see section 6.1.

3.                     PHARMACEUTICAL FORM

Film-coated Tablet.

The tablets are Wwhite to almost white triangular biconvex film-coated tablets imprintedmarked 'K1' or ’K2’ on one side.

4.                     CLINICAL PARTICULARS

4.1                 Therapeutic indications

Kytril film-coated tablets are indicated in adults for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapyinduced by cytostatic therapy.

Kytril film-coated tablets are indicated for prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.

4.2                 Posology and method of administration

Adults

Posology

Underlined text has been added

Special warnings and precautions for use

As Kytril may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following administration of Kytril.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, 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 cardio-toxic chemotherapy and/or with concomitant electrolyte abnormalities.

Interaction with other medicinal products and other forms of interaction

In studies in healthy subjects, no evidence of any interaction has been indicated between Kytril and cimetidine or lorazepam.  No evidence of drug interactions has been observed in clinical studies.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, in patients concurrently treated with drugs known to prolong QT interval and/or are arrhythmogenic, this may lead to clinical consequences.

Undesirable effects

Kytril has been generally well tolerated in human studies.  As reported with other drugs of this class, headache and constipation have been the most frequently noted adverse events, but the majority have been mild or moderate in nature.  Rare cases of hypersensitivity reaction, occasionally severe (e.g. anaphylaxis), have been reported.  Other allergic reactions including minor skin rashes have also been reported.  In clinical trials, transient increases in hepatic transaminases, generally within the normal range, have been seen.

Dystonias and dyskinesias have been reported with medicines in the 5-HT₃ antagonist class.   Such events have been reported rarely with Kytril.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. (See section 4.4 Special Warnings and Precautions for Use and 4.5 Interactions with other Medicinal Products and other Forms of Interaction)