Kytril Tablets 1mg and 2mg

1. Name Of The Medicinal Product

Kytril Tablets 1mg and 2mg.

2. Qualitative And Quantitative Composition

Each tablet contains 1mg or 2mg granisetron (as hydrochloride).

Excipients include lactose (see section 4.3 Contraindications).

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated Tablet.

White triangular film-coated tablets marked 'K1' or 'K2' on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Kytril tablets are indicated for the prevention of nausea and vomiting induced by cytostatic therapy.

4.2 Posology And Method Of Administration

Adults

The dose of Kytril is 1mg twice a day or 2mg once a day during cytostatic therapy.

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

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.

Children

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

As for adults.

Renally Impaired

As for adults.

Hepatically Impaired

As for adults.

4.3 Contraindications

Hypersensitivity to granisetron, related substances, or 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 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.

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 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.

4.6 Pregnancy And Lactation

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.

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)

4.9 Overdose

There is no specific antidote for Kytril. In the case of overdosage, symptomatic treatment should be given. One patient has received 30mg of Kytril intravenously. The patient reported a slight headache but no other sequelae were observed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Absorption

Absorption of Kytril 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

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

Biotransformation

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

Elimination

Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Kytril 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 is approximately nine 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.

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.

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 Tablets 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 Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.

8. Marketing Authorisation Number(S)

PL 00031/0591 (1mg)

PL 00031/0592 (2mg)

9. Date Of First Authorisation/Renewal Of The Authorisation

15 September 2001

10. Date Of Revision Of The Text

23 December 2009

Legal STATUS

POM

Kytril is a registered trade mark