Kytril Paediatric Liquid

1. Name Of The Medicinal Product

Kytril Paediatric Liquid.

2. Qualitative And Quantitative Composition

Granisetron hydrochloride equivalent to 200μg granisetron (free base equivalent) per 1ml.

3. Pharmaceutical Form

An orange coloured and flavoured clear solution equivalent to 200μg of granisetron free base per 1ml.

4. Clinical Particulars

4.1 Therapeutic Indications

Kytril Paediatric Liquid is indicated for the prevention of nausea and vomiting induced by cytostatic therapy.

4.2 Posology And Method Of Administration

Children

A single dose of 20μg/kg bodyweight (up to 1mg)twice a day up to 5 days during cytostatic therapy. The first dose of Kytril should be administered within one hour before the start of cytostatic therapy.

Patients with renal or hepatic impairment

No special requirements apply.

4.3 Contraindications

Hypersensitivity to granisetron, or related substances, or any of the other constituents.

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.

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.

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.

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 orally prophylactically in prevention of 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 9 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.

In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalised for body-weight.

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

Sorbitol Ph Eur.

Sodium Benzoate (E211) Ph Eur.

Citric Acid Anhydrous Ph Eur.

Orange Flavour D3798 HSE.

Orange Flavour D2362 HSE.

F.D. & C Yellow No. 6 (E110) HSE.

Purified Water Ph Eur.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Unopened: 4 years.

After opening for the first time: one month.

6.4 Special Precautions For Storage

Kytril Paediatric Liquid should be stored at or below 30°C and capped after partial use.

6.5 Nature And Contents Of Container

Kytril Paediatric Liquid is supplied in a 30ml amber glass bottle with a child resistant high density polyethylene cap with a PVdC faced boxboard wad. The bottle contains 30ml of solution and is enclosed in an outer carton.

6.6 Special Precautions For Disposal And Other Handling

Administering the Oral Solution

Children: To administer the dose of 20μg/kg, 0.1ml of solution per one kilogram of body weight should be withdrawn from the bottle up to a maximum of 5ml per dose.

An oral dosing syringe should be used. When administering the measured dose, insert the syringe tip into the child's mouth and drip the medicine in slowly.

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 00031/0593

9. Date Of First Authorisation/Renewal Of The Authorisation

15 August 2001

10. Date Of Revision Of The Text

September 2005

LEGAL STATUS

POM

Kytril is a registered trade mark

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