1. Name Of The Medicinal Product
Kytril Ampoules 1mg/1ml
2. Qualitative And Quantitative Composition
Each 1ml contains 1mg granisetron (as the hydrochloride). For excipients, see section 6.1.
3. Pharmaceutical Form
A glass ampoule containing a sterile, clear colourless solution. The content allows withdrawal of 1ml.
Concentrate for solution for infusion or injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Kytril is indicated for the prevention or treatment of nausea and vomiting induced by cytostatic therapy and for the prevention and treatment of post-operative nausea and vomiting.
4.2 Posology And Method Of Administration
Cytostatic therapy
Children
Prevention: A single dose of 40μg/kg bodyweight (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 40μg/kg bodyweight (up to 3mg) may be administered within a 24-hour period if required. This additional dose should be administered at least 10 minutes apart from the initial infusion.
Renally impaired
No special requirements apply.
Hepatically impaired
No special requirements apply.
Post-operative nausea and vomiting
Adults
For prevention in adults, a single dose of 1mg of Kytril should be diluted to 5ml and administered as a slow intravenous injection (over 30 seconds). Administration should be completed prior to induction of anaesthesia.
For the treatment of established post-operative nausea and vomiting in adults, a single dose of 1mg of Kytril should be diluted to 5ml and administered by slow intravenous injection (over 30 seconds).
Maximum dose and duration of treatment
Two doses (2mg) in one day.
Children
There is no experience in the use of Kytril in the prevention and treatment of post-operative nausea and vomiting in children. Kytril is not therefore recommended for the treatment of post-operative nausea and vomiting in this age group.
Elderly
As for adults.
Renally impaired
As for adults.
Hepatically impaired
As for adults.
4.3 Contraindications
Hypersensitivity to granisetron or related substances.
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.
No specific interaction studies have been conducted in anaesthetised patients, but Kytril has been safely administered with commonly used anaesthetic and analgesic agents. In addition, in vitro human microsomal studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by 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 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
Kytril is effective, intravenously, in the prevention and treatment of post-operative nausea and vomiting.
5.2 Pharmacokinetic Properties
General characteristics
Distribution
Kytril is extensively distributed, with a mean volume of distribution of approximately 3L/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 or induction of anaesthesia.
6.3 Shelf Life
Kytril ampoules have a shelf-life of three years.
Once opened 24 hours.
6.4 Special Precautions For Storage
Do not store above 30°C. Keep container in the outer carton. Do not freeze.
6.5 Nature And Contents Of Container
Kytril is supplied in clear glass ampoules in packs of five, with an outer carton.
6.6 Special Precautions For Disposal And Other Handling
Preparing the infusion
Children: To prepare the dose of 40 μg/kg, the appropriate volume is withdrawn and diluted with infusion fluid to a total volume of 10 to 30ml. Any one of the following solutions may be used: 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. No other diluents should be used.
Ideally, intravenous infusions of Kytril should be prepared at the time of administration. After dilution (see above), or when the container is opened for the first time, 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.
Adults: to prepare a dose of 1mg, 1ml should be withdrawn from the ampoule and diluted to 5ml with 0.9% w/v Sodium Chloride Injection BP. No other diluent should be used.
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 00031/0595
9. Date Of First Authorisation/Renewal Of The Authorisation
23rd October 1995/23rd October 2000.
10. Date Of Revision Of The Text
23 December 2009
LEGAL STATUS
POM
Kytril is a registered trade mark
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