Underlined text has been added, text with strike through deleted:
1. NAME OF THE MEDICINAL PRODUCT
Kytril Ampoule 1mg/1ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
The active substance is granisetron.
Each 1ml solution for injection contains 1 mg of granisetron (as the hydrochloride).
For a full list of 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.
Solution for injection.
The solution for injection is a clear, colourless liquid.
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.
Kytril solution for injection is indicated in adults for the prevention and treatment of
- acute nausea and vomiting associated with chemotherapy and radiotherapy.
- post-operative nausea and vomiting.
Kytril solution for injection is indicated for the prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.
Kytril solution for injection is indicated in children aged 2 years and above for the prevention and treatment of acute nausea and vomiting associated with chemotherapy.
4.2 Posology and method of administration
Cytostatic therapy
Children
Prevention: A single dose of 40mg/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 40mg/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.
Posology
Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV)
Prevention (acute and delayed nausea)
A dose of 1-3 mg (10-40 µg/kg) of Kytril solution for injection should be administered either as a slow intravenous injection or as a diluted intravenous infusion 5 minutes prior to the start of chemotherapy. The solution should be diluted to 5ml per mg.
Treatment (acute nausea)
A dose of 1-3 mg (10-40 µg/kg) of Kytril solution for injection should be administered either as a slow intravenous injection or as a diluted intravenous infusion and administered over 5 minutes. The solution should be diluted to 5 ml per mg. Further maintenance doses of Kytril solution for injection may be administered at least 10 minutes apart. The maximum dose to be administered over 24 hours should not exceed 9 mg.
Combination with adrenocortical steroid
The efficacy of parenteral granisetron may be enhanced by an additional intravenous dose of an adrenocortical steroid e.g. by 8-20 mg dexamethasone administered before the start of the cytostatic therapy or by 250 mg methyl-prednisolone administered prior to the start and shortly after the end of the chemotherapy.
Paediatric population
The safety and efficacy of Kytril solution for injection in children aged 2 years and above has been well established for the prevention and treatment (control) of acute nausea and vomiting associated with chemotherapy and the prevention of delayed nausea and vomiting associated with chemotherapy. A dose of 10-40 μg/kg body weight (up to 3 mg) should be administered as an i.v. infusion, diluted in 10-30 ml infusion fluid and administered over 5 minutes prior to the start of chemotherapy. One additional dose may be administered within a 24 hour-period if required. This additional dose should not be administered until at least 10 minutes after the initial infusion.
Post-operative nausea and vomiting (PONV)
A dose of 1 mg (10 µg/kg) of Kytril solution for injection should be administered by slow intravenous injection. The maximum dose of Kytril to be administered over 24 hours should not exceed 3 mg.
For the prevention of PONV, administration should be completed prior to induction of anaesthesia.
Paediatric population
Currently available data are described in section 5.1, but no recommendation on a posology can be made. There is insufficient clinical evidence to recommend administration of the solution for injection to children in prevention and treatment of Post-operative nausea and vomiting (PONV).
Special populations
Elderly and renal impairment
There are no special precautions required for its use in either elderly patients or those patients with renal or hepatic impairment.
Hepatic impairment
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
Administration may be as either a slow intravenous injection (over 30 seconds) or as an intravenous infusion diluted in 20 to 50 ml infusion fluid and administered over 5 minutes.
4.3 Contra-indications
Hypersensitivity to the active substance or any of the excipientsgranisetron or related substances.
4.4 Special warnings and special precautions for use
As Kytrilgranisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following its 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 changes modifications 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 5HT3 antagonists (e.g. dolasetron, ondansetron) has been reported..
4.5 Interaction with other medicinal products aments and other forms of interaction
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. In patients concurrently treated with medicinal products 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 granisetronKytril and benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine) or lorazepam. No evidence of drug interactions has been observed in clinical studies conducted. Additionally, granisetron has not shown any apparent medicinal product interaction with emetogenic cancer chemotherapies.
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 Fertility, pPregnancy 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.
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.
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 is not expected to impair the ability to drive or to 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 summary 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)
|
Immune system disorders
|
|
Uncommon
|
Hypersensitivity reactions e.g. anaphylaxis, urticaria
|
|
Psychiatric disorders
|
|
Common
|
Insomnia
|
|
Nervous system disorders
|
|
Very common
|
Headache
|
|
Uncommon
|
Extrapyramidal Reactions
|
|
Cardiac disorders
|
|
Uncommon
|
QT prolongation
|
|
Gastrointestinal disorders
|
|
Very common
|
Constipation
|
|
Common
|
Diarrhoea
|
|
Hepatobiliary disorders
|
|
Common
|
Elevated hepatic transaminases*
|
|
Skin and subcutaneous tissue disorders
|
|
Uncommon
|
Rash
|
*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 injection, symptomatic treatment should be given. Doses of up to 38.5 mg of One 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
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 intravenously, either prophylactically or by intervention, in abolishing the retching and vomiting evoked by administration of cytotoxic drugs or by whole body X‑irradiation.
Kytril is effective, intravenously, in the prevention and treatment of post-operative nausea and vomiting.
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) 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 intravenously has been shown to prevent nausea and vomiting associated with cancer chemotherapy in adults and children 2 to 16 years of age.
Post-operative nausea and vomiting
Granisetron administered intravenously 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 receptors 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).
Paediatric use
Clinical application of granisetron was reported by Candiotti et al. A prospective, multicentre, randomized, double-blind, parallel-group study evaluated 157 children 2 to 16 years of age undergoing elective surgery. Total control of postoperative nausea and vomiting during the first 2 hours after surgery was observed in most patients.
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.
DistributionDistribution
KytrilGranisetron is extensively distributed, with a mean volume of distribution of approximately 3L/kg.; pPlasma protein binding is approximately 65%.
BiotransformationBiotransformation
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).
EliminationElimination
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Kytrilgranisetron 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.
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).
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.
Paediatrics
In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalized 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.
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
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 in order to protect from light. Do not freeze.
6.5 Nature and contents of container
The solution for injection is primary packed in standard colourless glass ampoules with 1 mgl nominal volume.
Kytril 1mg/ml is supplied in clear glass ampoules in packs of five, with an outer carton.
6.6 Special precautions for disposalInstructions for use/handling
Preparing the infusion
Children: To prepare the dose of 40 mg/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.
Any unused product or waste material should be disposed of in accordance with local requirements.
|
