Consumer medicine information

Granisetron-AFT

Granisetron

BRAND INFORMATION

Brand name

Granisetron-AFT

Active ingredient

Granisetron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Granisetron-AFT.

What is in this leaflet

This leaflet answers some common questions about Granisetron-AFT.

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 having this medicine against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

What Granisetron-AFT is used for

Granisetron-AFT contains the active ingredient granisetron. Granisetron belongs to a group of medicines called anti-emetics.

Granisetron-AFT is used to prevent nausea (feeling sick) and vomiting. It is especially useful when you need to have medical treatment that may cause you to feel or be sick, for example, chemotherapy or radiotherapy.

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.

Granisetron-AFT is only available with a doctor's prescription. It is not addictive.

Before you are given Granisetron-AFT

When you must not be given it

You must not be given Granisetron-AFT if you have ever had an allergy to:

  • granisetron (the active ingredient in Granisetron-AFT)
  • any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction include 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.

If you are unsure if you should be given Granisetron-AFT, talk to your doctor.

Before you are given it

Tell your doctor if you have any of the following health problems / medical conditions:

  • if you have allergies to any other medicines, foods, dyes or preservatives.
  • 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 using Granisetron-AFT while you are pregnant or breast-feeding.
  • you have been given granisetron 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.

If you have not told your doctor about any of the above, tell him/her before you are given Granisetron-AFT.

Taking other medicines

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

Some medicines and Granisetron-AFT may interfere with each other. These include:

  • Phenobarbitone - a medicine used to treat epilepsy.
    Phenobarbitone may be affected by Granisetron-AFT or may affect how well Granisetron-AFT works. You may need different amounts of your medicine, or you may need to take a different medicine.

Your doctor and pharmacist have more information on medicines to be careful of or avoid while being given Granisetron-AFT.

If you have not told your doctor about any of these things, tell him/her before you are given this medicine.

How Granisetron-AFT is given

How much is given

Granisetron-AFT will only be given by a doctor or nurse. Your doctor will decide what dose and how long you will receive Granisetron-AFT. This depends on your condition and other factors such as your weight.

How it is given

Granistron-AFT is given as a fast or slow injection into a vein (intravenous 'drip'). It must only be given by a nurse or doctor.

If you take too much (overdose)

Because Granisetron-AFT will be given in hospital by a doctor or nurse it is unlikely that you will be given too large a dose. However, if you experience severe side effects tell your doctor immediately.

Symptoms of an overdose may include the side effects listed below in the 'Side Effects' section but are usually of a more severe nature. Ask your doctor or pharmacist if you have any concerns.

While you are being given Granisetron-AFT

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Granisetron-AFT.

Tell your doctor immediately if you become pregnant while you are being treated with Granisetron-AFT.

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

Things you must not do

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, operating machinery or doing jobs that require you to be alert until you know how Granisetron-AFT affects you.

Be careful when drinking alcohol while you are being given this medicine. 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 being given Granisetron-AFT. 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.

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
  • agitation
  • 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
  • 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 else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

Storage

Granisetron-AFT will be stored in the pharmacy or on the ward. The solution for injection should be kept in a cool place, protected from light where the temperature stays below 30°C.

Product description

What it looks like

Granisetron-AFT ampoules are 1 mL and 3 mL glass ampoules containing a clear, colourless or faintly yellow-brown solution. It is supplied in packs of 1 or 5 ampoules.

Ingredients

Granisetron-AFT ampoules contain 1 mg/1 mL or 3 mg/3 mL of the active ingredient granisetron. They also contain:

  • citric acid monohydrate
  • sodium chloride
  • sodium citrate dihydrate
  • water for injections

Supplier

AFT Pharmaceuticals Pty Ltd
113 Wicks Road
North Ryde
NSW 2113

Australian Registration Numbers:

1 mg/1 mL: AUST R 300321.

3 mg/3 mL: AUST R 300322.

This leaflet was prepared on: 31 May 2018.

Published by MIMS August 2018

BRAND INFORMATION

Brand name

Granisetron-AFT

Active ingredient

Granisetron

Schedule

S4

 

1 Name of Medicine

Granisetron-AFT granisetron (as hydrochloride) 1 mg/mL concentrated solution for injection.
Granisetron-AFT granisetron (as hydrochloride) 3 mg/3 mL concentrated solution for injection.

2 Qualitative and Quantitative Composition

Granisetron-AFT 1 mg/mL injection.

Each 1 mL concentrated solution for injection contains 1.12 mg granisetron hydrochloride, equivalent to 1 mg granisetron.

Granisetron-AFT 3 mg/3 mL injection.

Each 3 mL concentrated solution for injection contains 3.36 mg granisetron hydrochloride, equivalent to 3 mg granisetron.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated solution for injection.
Sterile, clear, colourless solution, practically free of visible particles.
Granisetron-AFT contains no antimicrobial preservative.

4 Clinical Particulars

4.1 Therapeutic Indications

Granisetron-AFT, concentrated solution for injection, is indicated in:

Adults.

For the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy;
for the prevention of nausea and vomiting induced by radiotherapy.

Paediatric patients.

For the prevention of nausea and vomiting induced by cytotoxic chemotherapy.

4.2 Dose and Method of Administration

Dose.

Granisetron-AFT must be diluted in accordance with the directions below before being administered.

Chemotherapy induced nausea and vomiting (CINV).

Intravenous administration.

Adults.

For prevention of nausea and vomiting in adults, a single dose of 3 mg of Granisetron-AFT should be administered as an intravenous infusion, diluted in 20 - 50 mL infusion fluid and administered over 5 minutes prior to the start of chemotherapy. The infusion should be commenced within 30 minutes before the start of chemotherapy.
Prophylactic administration of Granisetron-AFT should be completed prior to the start of chemotherapy.
In clinical trials, the majority of patients have required only a single dose of Granisetron-AFT to control nausea and vomiting over 24 hours.
For treatment of established nausea and vomiting in adults, a single dose of 1 mg of Granisetron-AFT should be administered as a 5 minute infusion. Further treatment doses of Granisetron-AFT may be administered if required at least 10 minutes apart. The maximum dose of Granisetron-AFT is 9 mg/24 hours.
In trials, patients have received a total dose of 160 microgram/kg of intravenous Granisetron-AFT in one day. There is also clinical experience in patients receiving a total of 600 microgram/kg of intravenous Granisetron-AFT over 5 days.

Paediatric patients.

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

Radiotherapy induced nausea and vomiting (RINV).

Intravenous administration.

Adults.

For prevention of nausea and vomiting in adults, a single dose of 3 mg of Granisetron-AFT should be administered as an intravenous infusion, diluted in 20 - 50 mL infusion fluid and administered over 5 minutes prior to the start of radiotherapy.

Special dosage instructions.

No dosage adjustment is required for the elderly, renally impaired or hepatically impaired (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Combination with a corticosteroid.

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

Method of administration.

Adults.

To prepare the dose of 3 mg, withdraw 3 mL from the ampoule and dilute with a compatible infusion fluid (see below) to a total volume of 20 - 50 mL, in any of the following solutions: 0.9% sodium chloride, 0.18% sodium chloride and 4% glucose, 5% glucose, Hartmann's solution, 1.85% sodium lactate, 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 - 30 mL.
The injectable presentations contain no antimicrobial agent. Use once and discard any residue.
Granisetron-AFT has been shown to be stable for at least 24 hours in the cited solutions when stored at ambient temperature in normal indoor illumination (natural daylight supplemented by fluorescent light). 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.
As a general precaution, Granisetron-AFT should not be mixed in solution with other medicines other than dexamethasone sodium phosphate.
Admixtures of granisetron hydrochloride and dexamethasone sodium phosphate are compatible at concentrations of 10 - 60 microgram/mL granisetron and 80 - 480 microgram/mL dexamethasone phosphate in either 0.9% sodium chloride or 5% glucose 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 storage period for the admixture is not more than 6 hours when stored at room temperature.
Parenteral medicine products should be inspected visually for particulate matter and discolouration before administration whenever solution and container permit.

4.3 Contraindications

Granisetron-AFT is contraindicated in patients hypersensitive to granisetron or any of the excipients.

4.4 Special Warnings and Precautions for Use

As Granisetron-AFT may reduce lower bowel motility, patients with signs of subacute intestinal obstruction should be monitored following administration of Granisetron-AFT.
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. The ECG changes with granisetron 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 IV granisetron at any dose tested (up to 200 microgram/kg).
Cross-sensitivity between 5-HT3 antagonists has been reported.
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 granisetron and other serotonergic medicines. If concomitant treatment with granisetron and other serotonergic medicines are clinically warranted, appropriate observation of the patient is advised (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No special precautions are required for the elderly (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Paediatric use.

See Section 4.2 Dose and Method of Administration for information on dose and method of administration in paediatric patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Granisetron 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 granisetron of approximately one quarter.
In healthy human subjects, granisetron has been safely administered with benzodiazepines, neuroleptics, and antiulcer medications commonly prescribed with antiemetic treatments. Additionally, granisetron has shown no apparent medicine interaction with emetogenic cancer chemotherapies.
No specific interaction studies have been conducted in anaesthetised patients, but granisetron 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 granisetron.
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. The ECG changes with granisetron were minor, generally not of clinical significance and specifically, there was no evidence of proarrhythmia. However, in patients concurrently treated with medicines 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 granisetron and other serotonergic medicines. If concomitant treatment with granisetron and other serotonergic medicines is clinically warranted, appropriate observation of the patient is advised (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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 7 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, Granisetron-AFT should be used during pregnancy only if clearly needed.
 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 medicine during lactation should be limited to situations where the potential benefit to the mother justifies the potential risk to the nursing infant.

4.7 Effects on Ability to Drive and Use Machines

There are no data on the effect of Granisetron-AFT on the ability to drive, however there have been occasional reports of somnolence in clinical studies which should be taken into account.

4.8 Adverse Effects (Undesirable Effects)

Granisetron has been well tolerated in human studies. In common with other medicines of this class, headache and constipation have been the most frequently noted adverse events, but the majority have been mild or moderate in nature and tolerated by patients. ECG changes including QT prolongation have been reported with granisetron (see Section 4.4 Special Warnings and Precautions for Use).
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 granisetron and other serotonergic medicines (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Table 1 gives the comparative frequencies of the five commonly reported adverse events (> 3%) in patients receiving granisetron injection, 40 microgram/kg, in single day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24 hour period following granisetron injection administration.
In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron except for headache, which was clearly more frequent than in comparison groups.
Adverse events reported in clinical trials other than those in the tables above 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 medicine 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 greater or equal to 1/10 patients; common events reported at a frequency of greater or equal to 1/100 patients; uncommon events reported at a frequency of less than 1/100 but greater or equal to 1/1,000 patients; rare events reported at a frequency of less than 1/1,000 patients.

Body as a whole.

Common: fever.

Cardiovascular disorders.

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 disorders.

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 disorders.

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

Dermatological disorders.

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.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific antidote for Granisetron-AFT. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron as a single injection has been reported without symptoms or only the occurrence of a slight headache.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: serotonin (5HT3) antagonists. ATC classification: A04AA0.

Mechanism of action.

Granisetron is a potent antiemetic 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, alpha1 and alpha2, beta-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, granisetron blocks serotonin stimulation, and is effective in alleviating the retching and vomiting evoked by cytostatic treatment. In the ferret animal model, a single granisetron injection prevented vomiting due to high dose cisplatin or arrested vomiting within 5 - 30 seconds.
In healthy subjects, granisetron produced no consistent or clinically important changes in pulse rate, blood pressure or ECG. Granisetron did not affect the plasma levels of prolactin or aldosterone.
Granisetron injection showed no effect on gut transit time in normal volunteers given single doses up to 200 microgram/kg.

Clinical trials.

Intravenous administration.

Single day chemotherapy.

Cisplatin based chemotherapy.

In a double blind, placebo controlled study in 28 patients, granisetron 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.
Granisetron 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 analogs, podophyllotoxin derivatives, pyrimidine analogs and vinca alkaloids. Granisetron injection doses of 10 and 40 microgram/kg were superior to 2 microgram/kg in preventing cisplatin induced nausea and vomiting.

Moderately emetogenic chemotherapy.

Granisetron injection, 40 microgram/kg, was compared with the combination of chlorpromazine (50 - 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin > 300 mg/m2, cisplatin 20 - 50 mg/m2 and cyclophosphamide > 600 mg/m2. Granisetron injection was superior to the chlorpromazine/ dexamethasone regimen in preventing nausea and vomiting.
Combination with corticosteroid. Three studies demonstrated that in patients receiving chemotherapy, the addition of corticosteroids to prophylactic intravenous or oral granisetron resulted in significantly better control of nausea and vomiting over 24 hours. Doses of corticosteroid included 8-20 mg dexamethasone administered prior to the start of chemotherapy, or 250 mg methylprednisolone 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 granisetron with dexamethasone was significantly more effective than granisetron alone.
Repeat cycle chemotherapy. In an uncontrolled trial, 75 cancer patients received granisetron injection, 40 microgram/kg prophylactically, for three cycles of chemotherapy. 31 patients received it for at least four cycles and 8 patients received it for at least six cycles. Granisetron 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 65-70%. No patients were studied for more than 9 cycles.
During the clinical trial programme, 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 4 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. Granisetron 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. Granisetron was administered on each day of ifosfamide treatment. At 24 hours, 22% of granisetron 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 vs 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.
Granisetron 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 granisetron for the treatment of paediatric patients with nausea and vomiting induced by cytotoxic chemotherapy.
Radiotherapy. Granisetron 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 granisetron for prophylaxis and control of radiotherapy induced emesis. The study medicine was administered 1 hour before starting radiation therapy. The antiemetic efficacy of granisetron 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 granisetron in the treatment of nausea and vomiting induced by radiotherapy.

5.2 Pharmacokinetic Properties

Absorption.

A linear pharmacokinetic relationship was found after IV administration up to 4-fold the recommended dose.

Distribution.

Granisetron 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.

Metabolism.

Granisetron clearance is predominantly via hepatic metabolism and is rapid in most subjects.
Granisetron 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.

Excretion.

Mean plasma half-life of Granisetron-AFT in patients is 9 hours with wide intersubject variability. The plasma concentration of Granisetron-AFT is not clearly correlated with antiemetic efficacy. Clinical benefit may be conferred even when granisetron is not detectable in plasma.
Urinary excretion of unchanged Granisetron-AFT averages 12% of the dose in 48 hours, whilst the remainder is excreted as metabolites; 47% in the urine and 34% in the faeces.

Pharmacokinetics in special populations.

Elderly patients.

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

Patients with 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.

Patients with hepatic impairment.

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

5.3 Preclinical Safety Data

Genotoxicity.

Granisetron did not cause gene mutation in bacterial assays in Salmonella and E. coli or 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).

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Citric acid monohydrate (pH adjusting agent), sodium chloride, sodium citrate dihydrate (pH adjusting agent), water for injections.

6.2 Incompatibilities

Granisetron-AFT may be diluted using the instructions and compatible infusion solutions provided in Section 4.2 Dose and Method of Administration, Method of administration. As a general precaution, Granisetron-AFT should not be mixed in solution with medicines other than dexamethasone sodium phosphate (see Section 4.2 Dose and Method of Administration, Combination with a corticosteroid).

6.3 Shelf Life

In Australia, information on shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Shelf life following dilution.

To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, store at 2-8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.
For storage conditions after dilution of the product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Granisetron-AFT 1 mg/mL.

1 mL solution packaged in a 1 mL clear, colourless borosilicate Type I glass ampoule.
Pack size: 1 or 5 ampoules per carton.
AUST R 300321.

Granisetron-AFT 3 mg/3 mL.

3 mL solution packaged in a 5 mL clear, colourless borosilicate Type I glass ampoule.
Pack size: 1 or 5 ampoules per carton.
AUST R 300322.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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.
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.

Chemical structure.


CAS number.

107007-99-8 (granisetron hydrochloride) and 109889-09-0 (granisetron base).

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).