Consumer medicine information

Kytril Tablets [8844]

Granisetron

BRAND INFORMATION

Brand name

Kytril Tablets

Active ingredient

Granisetron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kytril Tablets [8844].

What is in this leaflet

This leaflet answers some common questions about KYTRIL tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking KYTRIL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What KYTRIL is used for

KYTRIL contains the active ingredient granisetron.

It belongs to a group of medicines called anti-emetics.

KYTRIL is used to stop you feeling sick (nauseous) or being sick (vomiting). It is especially useful when you need to have medical treatment that may cause you to feel or be sick, for example, chemotherapy.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

Before you take KYTRIL

When you must not take it

Do not take KYTRIL if you have an allergy to:

  • any medicine containing granisetron
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or breathing difficulty; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take KYTRIL after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if:

  • you have allergies to any other medicines, foods, preservatives or dyes.
  • you have had an allergic reaction with other medicines used to prevent or treat nausea and vomiting, such as ondansetron and tropisetron. You may have an allergic reaction to KYTRIL as well.
  • you have severe constipation.
  • you are pregnant or plan to become pregnant or are breast-feeding.
    Your doctor can discuss with you the risks and benefits of taking KYTRIL if you are pregnant or breast-feeding.
  • you have used KYTRIL before, and you became unwell.
    You may need to be given another medicine instead.
  • you have a heart condition related to changes in the rhythm or rate of your heart beat.
  • you are intolerant to lactose or galactose or your body does not absorb glucose or galactose well.

If you have not told your doctor about any of the above, tell him/her before you start taking KYTRIL.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and KYTRIL may interfere with each other. These include:

  • phenobarbitone, a medicine used to treat epilepsy.
    Phenobarbitone may be affected by KYTRIL or may affect how well KYTRIL works. You may need different amounts of your medicine, or you may need to take a different medicine.
  • medicines that can affect the serotonin levels in your body. These may include: some antibiotics, medicines used to treat depression, medicines that treat or prevent pain, some medicines to treat Parkinson's disease, medicines to treat obesity; and medicines used to treat attention hyperactivity disorder.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking KYTRIL.

How to take KYTRIL

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

Your doctor or pharmacist will tell you how many KYTRIL tablets to take each day.

Chemotherapy Patients
For the prevention of nausea and vomiting associated with chemotherapy, the usual adult dose is one 2 mg tablet once a day, taken within 1 hour before the start of chemotherapy, and then daily for up to one week following chemotherapy.

Radiotherapy Patients
For the prevention of nausea and vomiting associated with radiotherapy, the usual adult dose of KYTRIL is one 2 mg tablet taken within 1 hour before the start of radiotherapy.

How to take it

Swallow the tablets whole with a full glass of water. Do not crush or chew the tablets.

When to take it

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking KYTRIL tablets for as long as your doctor tells you.

Your doctor will tell you when your treatment should be stopped.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much KYTRIL, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking KYTRIL

Things you must do

If you are about to start a new medicine, remind your doctor and pharmacist that you are taking KYTRIL.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking KYTRIL.

Tell your doctor immediately if you become pregnant while taking this medicine.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take KYTRIL to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dose without checking with your doctor.

Do not take any other medicines whether they require a prescription or not without first telling your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how KYTRIL affects you.

Be careful when drinking alcohol while you are taking KYTRIL.

Your doctor may suggest that you avoid alcohol or reduce the amount of alcohol you drink while you are taking KYTRIL.

If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking KYTRIL.

This medicine helps most people with nausea and vomiting, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • unusual tiredness or weakness
  • dizziness or light headedness
  • nervousness
  • drowsiness
  • difficulty in sleeping
  • abdominal pain
  • constipation
  • diarrhoea
  • altered taste
  • fever
  • skin rash.

The above list includes the more common side effects of your medicine.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • chest pain
  • changes in your heart beat
  • severe dizziness or fainting
  • seizures
  • symptoms of serotonin syndrome such as fever, sweating, fast heartbeat, agitation or confusion and loss of muscle coordination, which may lead to loss of consciousness
  • symptoms of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using KYTRIL

Storage

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store KYTRIL tablets, or any other medicine, in a bathroom or near a sink.

Do not leave KYTRIL tablets in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep KYTRIL tablets where children cannot reach them.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What KYTRIL looks like

KYTRIL 2 mg tablets are triangular, and white, with "K2" engraved on one side.

KYTRIL 2 mg tablets come in a:

  • pack containing 1 tablet; or
  • pack containing 5 tablets

KYTRIL is also available as an injection that is given by a healthcare professional.

Ingredients

Active Ingredients

Each 2 mg KYTRIL tablet contains 2 mg of granisetron.

Inactive Ingredients

  • microcrystalline cellulose
  • sodium starch glycollate
  • hypromellose
  • lactose
  • magnesium stearate
  • macrogol 400
  • polysorbate 80
  • titanium dioxide.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Atnahs Pharma Australia Pty Ltd
Level 10
10 Shelley Street,
SYDNEY, NSW, 2000, Australia

Supplier

KYTRIL is supplied by:

Clinect Pty Ltd
120 - 132 Atlantic Drive
Keysborough VIC 3173
Australia

Customer enquiries: 1 800 899 005

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Number (AUST R)
2 mg tablet: 60872.

This leaflet was prepared on 15 September 2017

BRAND INFORMATION

Brand name

Kytril Tablets

Active ingredient

Granisetron

Schedule

S4

 

Name of the medicine

Tablets.

Granisetron hydrochloride (≡ granisetron free base 2 mg).

Injection.

Granisetron hydrochloride (≡ granisetron free base 3 mg in 3 mL; and ≡ granisetron free base 1 mg in 1 mL).

Excipients.

Tablets.

Microcrystalline cellulose, sodium starch glycollate, hypromellose, lactose and magnesium stearate. The film coating contains hypromellose, macrogol 400, polysorbate 80 and titanium dioxide (171). Kytril tablets do not contain sucrose, gluten, tartrazine or azo dyes.

Injection.

Sodium chloride 0.9% in water for injections, citric acid monohydrate, sodium hydroxide and hydrochloric acid.

Description

CAS registry number: 107007-99-0.
Granisetron hydrochloride is a white to off-white crystalline solid with a bitter taste, which is freely soluble in water and 0.9% sodium chloride at 20°C.
Kytril tablets contain granisetron hydrochloride (equivalent to 2 mg of granisetron free base). Each tablet also contains microcrystalline cellulose, sodium starch glycollate, hypromellose, lactose and magnesium stearate. The film-coating contains hypromellose, macrogol 400, polysorbate 80 and titanium dioxide (171). Kytril tablets do not contain sucrose, gluten, tartrazine, or azo dyes.
Kytril injection is a sterile clear solution containing granisetron hydrochloride, sodium chloride 0.9% in water for injections, citric acid monohydrate, sodium hydroxide and hydrochloric acid. Kytril injection is available as an ampoule containing granisetron hydrochloride, equivalent to 3 mg of granisetron free base in 3 mL; and equivalent to 1 mg of granisetron free base in 1 mL.
The systematic chemical name is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride. The molecular weight of the salt is 348.9 and that of the base is 312.4.

Pharmacology

Kytril is a potent antiemetic and highly selective antagonist of 5-hydroxytryptamine-3 (5-HT3) receptors. Radioligand binding studies have demonstrated that Kytril has negligible affinity for other receptor types including 5-HT, α1 and α2, β-adrenoreceptors, histamine H1, picrotoxin, benzodiazepine, opioid and dopamine D2 binding sites.
Antagonism of 5-HT3 receptors located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone in the area postrema, is one of the most effective pharmacological methods of preventing cytotoxic induced emesis. Mucosal enterochromaffin cells release serotonin during chemotherapy induced emesis. Serotonin stimulates 5-HT3 receptors and evokes a vagal afferent discharge to subsequently induce emesis. Animal pharmacological studies have shown that in binding to 5-HT3 receptors, Kytril blocks serotonin stimulation, and is effective in alleviating the retching and vomiting evoked by cytostatic treatment. In the ferret animal model, a single Kytril injection prevented vomiting due to high dose cisplatin or arrested vomiting within 5 to 30 seconds.
In healthy subjects, Kytril produced no consistent or clinically important changes in pulse rate, blood pressure or ECG. Kytril did not affect the plasma levels of prolactin or aldosterone.
Kytril injection showed no effect on gut transit time in normal volunteers given single doses up to 200 microgram/kg. However, single and multiple doses of Kytril, given orally, slowed colonic transit time in normal volunteers.

Pharmacokinetics.

A linear pharmacokinetic relationship was found after oral administration of 2.5-fold the recommended dose and IV administration up to fourfold the recommended dose.
Granisetron is rapidly and completely absorbed with peak plasma concentrations being reached at approximately two hours following oral administration. An accurate assessment of its oral bioavailability and the effect of food on its oral bioavailability is complicated by high intrasubject and intersubject variability in pharmacokinetics. However, the bioavailability has been estimated by a variety of methods to be in the order of 60%.
Kytril is extensively distributed with a mean volume of distribution of approximately 3 L/kg; plasma protein binding is approximately 65%, and granisetron distributes freely between plasma and red blood cells.
Kytril clearance is predominantly via hepatic metabolism and is rapid in most subjects. Kytril metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest some metabolites of granisetron may also have 5-HT3 receptor antagonist activity. However, in humans the metabolites are present in very low concentrations and are thought not to contribute to the pharmacological action.
Mean plasma half-life of Kytril in patients is nine hours with wide intersubject variability. The plasma concentration of Kytril is not clearly correlated with antiemetic efficacy. Clinical benefit may be conferred even when granisetron is not detectable in plasma.
Urinary excretion of unchanged Kytril averages 12% of the dose in 48 hours, while the remainder is excreted as metabolites; 47% in the urine and 34% in the faeces.

Pharmacokinetics in special populations.

Elderly.

In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for younger healthy volunteers.

Renal impairment.

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 neoplastic liver involvement, total clearance of Kytril was approximately halved compared to patients without hepatic impairment. However, no dosage adjustment is recommended.

Clinical Trials

Intravenous administration.

Single day chemotherapy.

Cisplatin based chemotherapy.

In a double blind, placebo controlled study in 28 patients, Kytril injection administered as a single intravenous infusion of 40 microgram/kg was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin chemotherapy.
Kytril injection was also evaluated in a randomised dose response study of cancer patients receiving cisplatin > 75 mg/m2. Additional chemotherapeutic agents included anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydralazine, nitrogen mustard analogues, podophyllotoxin derivatives, pyrimidine analogues and vinca alkaloids. Kytril injection doses of 10 and 40 microgram/kg were superior to 2 microgram/kg in preventing cisplatin induced nausea and vomiting.

Moderately emetogenic chemotherapy.

Kytril injection 40 microgram/kg was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin > 300 mg/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide > 600 mg/m2. Kytril injection was superior to the chlorpromazine/ dexamethasone regimen in preventing nausea and vomiting.

Repeat cycle chemotherapy.

In an uncontrolled trial, 75 cancer patients received Kytril injection 40 microgram/kg, prophylactically, for three cycles of chemotherapy. 31 patients received it for at least four cycles and eight patients received it for at least six cycles. Kytril injection efficacy remained relatively constant over the first six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 65 to 70%. No patients were studied for more than nine cycles.
During the clinical trial program, there were 26 reports of cardiac arrest. Of these, 25 were considered to be unrelated to granisetron administration and were attributed to the underlying disease or concomitant cytostatic medication with time of onset up to four months after initiation of therapy.
In the one case where granisetron administration was causally related, the patient experienced cardiac arrest as part of a severe allergic reaction. This event was not related to any direct cardiotoxic effect of granisetron. A full recovery was made on discontinuation of therapy.
Of the 40 reports of renal failure, causality was assigned in 37 cases. All 37 were considered to be unrelated to granisetron administration and were attributed to the underlying disease or cisplatin, a known nephrotoxic agent.

Paediatric.

Kytril injection 20 microgram/kg was compared to chlorpromazine (0.5 mg/kg) plus dexamethasone (2 mg/m2) in 88 paediatric patients treated with ifosfamide > 3 g/m2 for two or three days. Kytril was administered on each day of ifosfamide treatment. At 24 hours, 22% of Kytril patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine/ dexamethasone regimen. The median number of vomiting episodes was significantly lower in patients receiving granisetron than in patients receiving the combination of chlorpromazine/ dexamethasone (1.5 versus 7).
The efficacy and safety of intravenous doses of 10, 20 and 40 microgram/kg were compared in 80 paediatric patients undergoing highly emetogenic chemotherapy. The median number of vomiting episodes were 2, 3 and 1, and the percentage of patients with no more than one vomiting episode were 48%, 42% and 56%, respectively. There were no dose related safety issues.
Kytril administered intravenously has been shown to be effective in paediatric patients aged 2 years and above for the prevention of nausea and vomiting induced by cytotoxic chemotherapy. There is insufficient information to recommend intravenous administration of Kytril for the treatment of paediatric patients with nausea and vomiting induced by cytotoxic chemotherapy.

Radiotherapy.

Kytril injection 3 mg was compared to a combination of intravenous (IV) metoclopramide (20 mg), dexamethasone (6 mg/m2) and lorazepam (2 mg) in 30 patients to assess the efficacy and safety of Kytril for prophylaxis and control of radiotherapy induced emesis. The study drug was administered one hour before starting radiation therapy. The antiemetic efficacy of Kytril was significantly more effective than the standard regimen of metoclopramide/ dexamethasone/ lorazepam in preventing radiotherapy induced emesis.
Very limited data are available on the use of Kytril in the treatment of nausea and vomiting induced by radiotherapy.

Postoperative nausea and vomiting.

Prevention.

Kytril injection 0.1, 1.0 or 3.0 mg was compared to placebo in a double blind study to assess the efficacy and safety of Kytril in the prevention of postoperative nausea and vomiting (PONV) in 538 patients. Kytril was given as a 30 second injection prior to induction of anaesthesia. Patient groups receiving Kytril 1.0 and 3.0 mg responded significantly better than those in the 0.1 mg group.

Treatment.

Kytril injection 0.1, 1.0 or 3.0 mg was compared to placebo in a double blind study to assess the efficacy and safety of Kytril in 519 patients experiencing postoperative vomiting or severe nausea. In the 24 hour period after the day of surgery, patients receiving Kytril were less likely to experience nausea and vomiting than those receiving placebo.

Oral administration.

High dose cisplatin.

Kytril 1.0 mg twice daily (b.d.) orally for seven days was compared with the combination of metoclopramide (7 mg/kg) and dexamethasone (12 mg), followed by metoclopramide 10 mg three times daily (t.d.s.) orally for six days. 230 cancer patients received high dose cisplatin (mean dose 80 mg/m2). Complete response rates (no vomiting, no more than mild nausea, no use of rescue therapy and not withdrawn from the study) at 24 hours were 52.1% for both treatment arms. Complete response rates at seven days showed a trend in favour of granisetron (34.5% granisetron; 26.4% metoclopramide/ dexamethasone), but this difference did not reach statistical significance.

Moderately emetogenic chemotherapy.

Oral doses of Kytril 0.25 to 2 mg b.d. for seven days were compared in a trial of 930 cancer patients receiving principally cyclophosphamide, carboplatin and cisplatin (20 to 50 mg/m2). At 24 hours postchemotherapy, all doses of Kytril were found to have antiemetic efficacy with 1.0 mg being significantly better than 0.25 and 0.5 mg. 2.0 mg was not significantly better than 1.0 mg b.d. Results over the seven day postchemotherapy period reflected those seen at 24 hours, i.e. 1.0 mg b.d. was significantly superior to 0.25 or 0.5 mg b.d.

Combination with corticosteroid.

Three studies demonstrated that in patients receiving chemotherapy, the addition of corticosteroids to prophylactic intravenous or oral Kytril resulted in significantly better control of nausea and vomiting over 24 hours. Doses of corticosteroid included dexamethasone 8 to 20 mg administered prior to the start of chemotherapy, or methylprednisolone 250 mg prior to the start of chemotherapy and again just after the end of chemotherapy. In one study an analysis of efficacy over seven days indicated that Kytril with dexamethasone was significantly more effective than Kytril alone.

Paediatric.

There is insufficient information to recommend the oral administration of Kytril for the prevention or treatment of paediatric patients with nausea and vomiting induced by cytotoxic chemotherapy.

Radiotherapy.

In a double blind, parallel, placebo controlled study, Kytril was found to be significantly more effective than placebo in the prevention of nausea and vomiting in 260 patients (from 38 centres), receiving at least ten (maximum 20) fractions of upper abdominal radiation. The dose of Kytril administered in this study was 2 mg orally once daily, given one hour before radiation.
The proportion of patients without emesis and those without nausea for Kytril tablets, compared to placebo, was statistically significant (p < 0.0001) at 24 hours after radiation, irrespective of the radiation dose. Kytril was significantly more effective than placebo in patients receiving up to ten daily fractions of radiation, but was not significantly more effective than placebo in patients receiving 20 fractions.
Patients treated with Kytril tablets (n = 134) had a significantly longer time to the first episode of vomiting (35 versus 9 days, p < 0.001) relative to those patients who received placebo (n = 126) and a significantly longer time to the first episode of nausea (11 days versus 1 day, p < 0.001).
Kytril was well tolerated and no significant differences in unexpected or clinically significant adverse events were observed between the treatment groups.

Indications

Adults.

Kytril (tablets and injection) is indicated for use in adults for:
The prevention of nausea and vomiting induced by cytotoxic chemotherapy;
The prevention of nausea and vomiting induced by radiotherapy.
Kytril (injection) is also indicated for use in the treatment of nausea and vomiting induced by cytotoxic chemotherapy; and prevention and treatment of postoperative nausea and vomiting.

Paediatric.

Kytril injection is indicated for the prevention of nausea and vomiting induced by cytotoxic chemotherapy.

Contraindications

Kytril is contraindicated in patients with known hypersensitivity to granisetron or to any of its excipients.

Precautions

As Kytril may reduce lower bowel motility, patients with signs of subacute intestinal obstruction should be monitored following administration of Kytril.
As with other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. The ECG changes with Kytril were minor, generally not of clinical significance and specifically, there was 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 comorbidities, on cardiotoxic chemotherapy and/or with concomitant electrolyte abnormalities.
In healthy subjects, no clinically relevant effects on resting EEG or on the performance of psychometric tests were observed after intravenous Kytril at any dose tested (up to 200 microgram/kg).
Cross-sensitivity between 5-HT3 antagonists has been reported.
It is recommended that Kytril film coated tablets are not taken by patients with the rare hereditary problems of galactose intolerance, lactase deficiency or glucose galactose malabsorption.
As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction and neuromuscular abnormalities) have been reported following the concomitant use of Kytril and other serotonergic drugs. If concomitant treatment with granisetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised (see Interactions with Other Medicines).
There are no data on the effect of Kytril on the ability to drive, however there have been occasional reports of somnolence in clinical studies which should be taken into account.
No special precautions are required for the elderly or patients with renal or hepatic impairment.

Use in pregnancy.

(Category B1)
There is no experience of granisetron in human pregnancy. Animal studies have shown no teratogenic effects in rats or rabbits at intravenous doses up to 9 and 3 mg/kg/day, respectively, or at oral doses up to 125 and 32 mg/kg/day, respectively. Time weighted systemic exposure (maternal plasma AUC) at the highest intravenous dose in rats was about seven times higher than that in humans at therapeutic dose levels, but insufficient data are available for a similar comparison in rabbits. Because of the low safety margin indicated by the animal studies and because animal reproduction studies are not always predictive of human response, Kytril should be used during pregnancy only if clearly needed.

Use in lactation.

A study in lactating rats showed that the rate of excretion in milk after IV dosing is less than 1% of the dose per hour, and that at least some of this is absorbed by the offspring.
There are no data on the excretion of granisetron in human breast milk, therefore use of the drug during lactation should be limited to situations where the potential benefit to the mother justifies the potential risk to the nursing infant.

Carcinogenicity.

In a 24 month carcinogenicity study, mice were treated with granisetron in the diet at 1, 5 or 50 mg/kg/day. There was a statistically significant increase in the incidence of hepatocellular carcinomas in males and of hepatocellular adenomas in females dosed with 50 mg/kg/day. The incidence of hepatic tumours was not affected at 1 mg/kg/day.
In a 24 month carcinogenicity study, rats were treated with granisetron in the diet at 1, 5 or 50 mg/kg/day (reduced to 25 mg/kg/day at week 59 because of toxicity). Systemic exposure at the highest dose level was 1.7 times higher than that in humans at the recommended dose. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males dosed with 5 mg/kg/day and above, and in females dosed with 50 mg/kg/day. No increase in liver tumours was observed in rats at a dose of 1 mg/kg/day in males and 5 mg/kg/day in females.
Experimental evidence in rats shows that granisetron exhibits the characteristics of a promoter of liver tumours with a clear no effect dose of 1 mg/kg. The probable mechanism for this effect is sustained liver cell hyperplasia. In a study in which rats were treated for 12 months with 100 mg/kg/day, the observed promoting effects were reversible upon cessation of treatment. Additionally, there was no adverse effect on the liver of dogs treated orally for 12 months with granisetron 5 mg/kg/day.

Genotoxicity.

Granisetron did not cause gene mutation in bacterial assays in Salmonella and Escherichia coli nor in a mouse lymphoma cell assay. No evidence of chromosomal damage was observed in human lymphocytes in vitro, or in a mouse micronucleus test. There was no evidence of DNA damage in assays of unscheduled DNA synthesis (UDS) in rat hepatocytes in vitro or ex vivo. There was an apparent increase in UDS in HeLa cells exposed to granisetron in vitro when DNA synthesis was measured by scintillation counting of incorporated radioactive thymidine. However, when this test was repeated using a more definitive autoradiographic method, the test was negative for UDS. It is likely that the apparent UDS in the initial study was, in fact, a reflection of DNA synthesis in cells undergoing normal division (mitogenic activity).

Interactions

Kytril does not induce or inhibit the cytochrome P450 drug metabolising enzyme system in rodent studies. In humans, hepatic enzyme induction with phenobarbital resulted in an increase in total plasma clearance of intravenous Kytril of approximately one-quarter.
In healthy human subjects, Kytril has been safely administered with benzodiazepines, neuroleptics and antiulcer medications commonly prescribed with antiemetic treatments. Additionally, Kytril has shown no apparent drug 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 subfamily 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. The ECG changes with Kytril were minor, generally not of clinical significance and specifically, there was 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.
As with other 5-HT3 antagonists, cases of serotonin syndrome have been reported following the concomitant use of Kytril and other serotonergic drugs. If concomitant treatment with granisetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised (see Precautions).

Adverse Effects

Kytril has been well tolerated in human studies. The most frequently reported adverse reactions for Kytril are headache and constipation which may be transient. ECD changes including QT prolongation have been reported with Kytril (see Precautions).
As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction and neuromuscular abnormalities) have been reported following the concomitant use of Kytril and other serotonergic drugs (see Precautions and Interactions with Other Medicines).
In patients receiving oral Kytril 1 mg b.d. for 1, 7 or 14 days, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are shown in Table 1.
Table 2 gives the comparative frequencies of the five commonly reported adverse events (> 3%) in patients receiving Kytril injection 40 microgram/kg, in single day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24 hour period following Kytril injection administration.
In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to Kytril, except for headache, which was clearly more frequent than in comparison groups.
Adverse events reported in clinical trials other than those in Tables 1 and 2 are listed below. All adverse experiences are included in the list except those reported in terms so general as to be uninformative and those experiences for which the drug cause was remote. It should, however, be noted that causality has not necessarily been established.
Events are listed within body systems and categorised by frequency according to the following definitions. Very common events reported at a frequency of ≥ 1/10 patients; common events reported at a frequency of ≥ 1/100 patients; uncommon events reported at a frequency of < 1/100 but ≥ 1/1,000 patients; rare events reported at a frequency of < 1/1,000 patients.

Body as a whole.

Common: fever.

Cardiovascular.

Common: hypertension. Uncommon: QT prolongation. Rare: hypotension, arrhythmias, sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including nonsustained tachycardia, ECG abnormalities, angina pectoris, syncope.

Gastrointestinal disorders.

Very common: constipation.

Hypersensitivity.

Uncommon: hypersensitivity reactions (e.g. anaphylaxis, shortness of breath, hypotension, urticaria).

Hepatic.

Common: transient increases in AST and ALT. These are generally within the normal range and have been reported at similar frequency in patients receiving comparator therapy.

Nervous system.

Very common: headache. Common: agitation, anxiety, CNS stimulation, dizziness, insomnia, somnolence. Uncommon: serotonin syndrome. Rare: extrapyramidal syndrome (only in the presence of other drugs associated with this syndrome).

Dermatological.

Uncommon: skin rashes.

Special senses.

Common: taste disorder.
Other common events often associated with chemotherapy also have been reported: leukopaenia, decreased appetite, anaemia, alopecia, thrombocytopaenia.

Dosage and Administration

Standard dosage by presentation and indication for adult and paediatric patients are shown as follows.

Indication: chemotherapy induced nausea and vomiting (CINV).

Adults. Oral administration.

Prevention of nausea and vomiting in adults.

The dose of Kytril is 2 mg once a day for up to one week following chemotherapy. The first dose of Kytril should be administered within 1 hour before the start of chemotherapy.

Treatment of established nausea and vomiting in adults.

There is insufficient information to recommend the oral administration of Kytril in the treatment of CINV in adult patients.

Intravenous administration.

Prevention of nausea and vomiting in adults.

A single dose of Kytril 3 mg should be administered as an intravenous infusion, diluted in 20 to 50 mL infusion fluid and administered over five minutes prior to the start of chemotherapy. The infusion should be commenced within 30 minutes before the start of chemotherapy.
Prophylactic administration of Kytril should be completed prior to the start of chemotherapy.
In clinical trials, the majority of patients have required only a single dose of Kytril to control nausea and vomiting over 24 hours.

Treatment of established nausea and vomiting in adults.

A single dose of Kytril 1 mg should be administered as a 5 minute infusion. Further treatment doses of Kytril may be administered, if required, at least ten minutes apart. The maximum dose of Kytril is 9 mg/24 hours.
In trials, patients have received a total dose of 160 microgram/kg of intravenous Kytril in one day. There is also clinical experience in patients receiving a total of 600 microgram/kg of intravenous Kytril over 5 days.

Paediatric. Oral administration.

There is insufficient information to recommend the oral administration of Kytril in the prevention or treatment of CINV in paediatric patients.

Intravenous administration.

Prevention of nausea and vomiting in paediatric patients.

The recommended intravenous dose of Kytril in paediatric patients is 20 microgram/kg bodyweight to 40 microgram/kg body weight (up to 3 mg), which should be administered as an intravenous infusion, diluted in 10 to 30 mL infusion fluid and administered over 5 minutes, no more than 30 minutes before the start of chemotherapy.

Indication: radiotherapy induced nausea and vomiting.

Adults. Oral administration.

Prevention of nausea and vomiting in adults.

The dose of Kytril is 2 mg once a day, one hour before radiotherapy.

Intravenous administration.

Prevention of nausea and vomiting in adults.

A single dose of 3 mg of Kytril should be administered as an intravenous infusion, diluted in 20 to 50 mL infusion fluid and administered over 5 minutes prior to the start of radiotherapy.

Treatment of nausea and vomiting in adults.

There is insufficient information to recommend the intravenous administration of Kytril in the treatment of RINV in adult patients.

Paediatric.

There is insufficient information to recommend the oral or intravenous administration of Kytril in the prevention or treatment of RINV in paediatric patients.

Indication: postoperative nausea and vomiting.

Adults. Oral administration.

Prevention and treatment of postoperative nausea and vomiting in adults.

There is insufficient information to recommend the oral administration of Kytril in the prevention or treatment of postoperative nausea and vomiting in adults.

Intravenous administration.

Prevention of postoperative nausea and vomiting in adults.

A single dose of 1 mg of Kytril should be administered as a 30 second intravenous injection prior to induction of anaesthesia.

Treatment of established postoperative nausea and vomiting in adults.

A single dose of 1 mg of Kytril should be administered by intravenous injection over 30 seconds.
Patients undergoing anaesthesia for elective surgery have received a total dose of 3 mg Kytril intravenous in one day.

Paediatric.

There is insufficient information to recommend the oral or intravenous use of Kytril in the prevention or treatment of postoperative nausea and vomiting in paediatric patients.

Special dosage instructions.

No dosage adjustment is required for the elderly, renally impaired or hepatically impaired (see Pharmacokinetics in special populations).

Combination with a corticosteroid.

The efficacy of IV or oral Kytril can be enhanced by the addition of an intravenous corticosteroid. For example, dexamethasone 8 to 20 mg administered prior to the start of cytostatic therapy, or methlyprednisolone 250 mg prior to the start of chemotherapy and again just after the end of chemotherapy.

Preparing the infusion.

Adults.

To prepare the dose of 3 mg, withdraw 3 mL from the ampoule and dilute with a compatible infusion fluid to a total volume of 20 to 50 mL, in any of the following solutions: sodium chloride 0.9%, sodium chloride 0.18% and glucose 4%, glucose 5%, Hartmann's solution, sodium lactate 1.85%, mannitol.

Paediatric patients.

To prepare the dose of 40 microgram/kg, the appropriate volume is withdrawn (up to 3 mL from the ampoule) and diluted with infusion fluid (as for adults) to a total volume of 10 to 30 mL.
The injectable presentations contain no antimicrobial agent. Use once and discard any residue.
In order to reduce microbiological hazards it is recommended that the prepared infusion be commenced as soon as practicable after its preparation and should be completed within 24 hours. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C.
As a general precaution, Kytril should not be mixed in solution with other drugs other than dexamethasone sodium phosphate.
Admixtures of granisetron hydrochloride and dexamethasone sodium phosphate are compatible at concentrations of granisetron 10 to 60 microgram/mL and dexamethasone phosphate 80 to 480 microgram/mL in either sodium chloride 0.9% or glucose 5% intravenous infusion fluids. Stability data have been provided to demonstrate the physical and chemical stability of these solutions when stored at 25°C exposed to strong light for up to 24 hours. To reduce microbiological contamination hazards, it is recommended that admixing should be effected immediately prior to use and infusion commenced as soon as practicable after preparation. The admixture will have a shelf life of 24 hours.
Parenteral drug products should be inspected visually for particulate matter and discolouration before administration whenever solution and container permit.

Overdosage

There is no specific antidote for Kytril. In the case of overdosage, symptomatic treatment should be given. Overdose with both the intravenous and oral formulations has occurred. Overdosage of up to Kytril 38.5 mg as a single injection has been reported without symptoms or only the occurrence of a slight headache.

Presentation

Tablets, 2 mg (white, triangular, film coated): 1's, 5's (opaque blister pack).
Injection (clear, sterile solution), 1 mg/1 mL: 5's; 3 mg/3 mL: 1's (ampoules).

Storage

Tablets.

Kytril tablets should be stored below 30°C.

Ampoules.

Kytril ampoules should be stored below 30°C and protected from direct sunlight. Ampoules removed from the pack should be stored protected from light.

Poison Schedule

S4.