Kytril Infusion 3mg / 3ml

1. Name Of The Medicinal Product

Kytril Infusion 3mg/3ml.

2. Qualitative And Quantitative Composition

Each 3ml contains 3.0mg granisetron (as the hydrochloride).

For excipients, see 6.1.

3. Pharmaceutical Form

An ampoule containing a sterile, clear, colourless or slightly straw-coloured solution equivalent to 1mg of granisetron per 1ml of solution. The content allows withdrawal of 3ml.

Concentrate for solution for infusion, or bolus injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Kytril is indicated for the prevention or treatment of nausea and vomiting induced by cytostatic therapy.

4.2 Posology And Method Of Administration

Adults

Kytril ampoules are for intravenous administration only.

3mg Kytril, which should be administered either in 15ml infusion fluid as an intravenous bolus over not less than 30 seconds or diluted in 20 to 50ml infusion fluid and administered over five minutes.

Prevention:In clinical trials, the majority of patients have required only a single dose of Kytril to control nausea and vomiting over 24 hours. Up to two additional doses of 3mg Kytril may be administered within a 24-hour period. There is clinical experience in patients receiving daily administration for up to five consecutive days in one course of therapy. Prophylactic administration of Kytril should be completed prior to the start of cytostatic therapy.

Treatment:The same dose of Kytril should be used for treatment as prevention. Additional doses should be administered at least 10 minutes apart.

Maximum daily dosage

Up to three doses of 3mg Kytril may be administered within a 24-hour period. The maximum dose of Kytril to be administered over 24 hours should not exceed 9mg.

Concomitant use of dexamethasone

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

Children

Prevention:A single dose of 40 μg/kg body weight (up to 3mg) should be administered as an intravenous infusion, diluted in 10 to 30ml infusion fluid and administered over five minutes. Administration should be completed prior to the start of cytostatic therapy.

Treatment: The same dose of Kytril as above should be used for treatment as prevention.

One additional dose of 40 μg/kg body weight (up to 3mg) may be administered within a 24-hour period. This additional dose should be administered at least 10 minutes apart from the initial infusion.

Elderly

No special requirements apply to elderly patients.

Patients with renal or hepatic impairment

No special requirements apply to those patients with renal or hepatic impairment.

4.3 Contraindications

Hypersensitivity to granisetron, related substances or the excipients (see section 6.1).

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.

No special precautions are required for the elderly or renally or hepatically impaired patient.

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 conducted.

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 (5₃) receptors. Radioligand binding studies have demonstrated that Kytril has negligible affinity for other receptor types including 5₂ binding sites.

Kytril is effective intravenously, either prophylactically or by intervention, in abolishing the retching and vomiting evoked by administration of cytotoxic drugs or by whole body X

5.2 Pharmacokinetic Properties

General characteristics

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.

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

Sodium Chloride

Water for Injection

Citric acid, monohydrate

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

As a general precaution, Kytril should not be mixed in solution with other drugs. Prophylactic administration of Kytril should be completed prior to the start of cytostatic therapy.

6.3 Shelf Life

Kytril ampoules have a shelf-life of three years.

6.4 Special Precautions For Storage

Kytril ampoules should be stored protected from light. Do not freeze.

6.5 Nature And Contents Of Container

Kytril is supplied in clear glass ampoules packaged in boxes of 5 or 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Preparing the infusion

Adults: To prepare a dose of 3mg, 3ml is withdrawn from the ampoule and diluted either to 15ml with 0.9% w/v Sodium Chloride Injection BP (for bolus administration) or in infusion fluid to a total volume of 20 to 50ml in any of the following solutions: 0.9% w/v Sodium Chloride Injection BP; 0.18% w/v Sodium Chloride and 4% w/v Glucose Injection BP; 5% w/v Glucose Injection BP; Hartmann's Solution for Injection BP; Sodium Lactate Injection BP; or 10% Mannitol Injection BP (for infusion). No other diluents should be used.

Children: To prepare the dose of 40μg/kg the appropriate volume (up to 3ml) is withdrawn from the ampoule and diluted with infusion fluid (as for adults) to a total volume of 10 to 30ml.

Ideally, intravenous infusions of Kytril should be prepared at the time of administration. After dilution (see above) the shelf life is 24 hours when stored at ambient temperature in normal indoor illumination protected from direct sunlight. It must not be used after 24 hours. If to be stored after preparation, Kytril infusions must be prepared under appropriate aseptic conditions.

As a general precaution, Kytril should not be mixed in solution with other drugs.

7. Marketing Authorisation Holder

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

8. Marketing Authorisation Number(S)

PL 00031/0594

9. Date Of First Authorisation/Renewal Of The Authorisation

15 October 2001

10. Date Of Revision Of The Text

23 December 2009

Legal STATUS

POM

Kytril is a registered trade mark

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