Name of the medicine
Granisetron hydrochloride.
Excipients Sodium chloride, citric acid monohydrate, sodium hydroxide, hydrochloric acid and water for injections. https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSGRAHYD.gif
Description
Chemical name:1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo [3.3.1] non-3-yl]-1H-indazole-3-carboxamide hydrochloride. Chemical formula: C18H24N4O.HCl. CAS: 107007-99-8 (granisetron hydrochloride); 109889-09-0 (granisetron free base). MW: 348.9 (granisetron hydrochloride); 312.4 (granisetron free base). Granisetron hydrochloride is a white or almost white powder, which is freely soluble in water and 0.9% sodium chloride at 20°C.
Pharmacology
Pharmacodynamics. Granisetron is a potent antiemetic and highly selective antagonist of 5-hydroxytryptamine (5-HT)3 receptors. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types including 5-HT, α1and 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, 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 to 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 concentrated injection showed no effect on gut transit time in normal volunteers given single doses up to 200 microgram/kg.
Pharmacokinetics. 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.
Elimination. Mean plasma half-life of granisetron in patients is 9 hours with wide intersubject variability.
The plasma concentration of granisetron 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 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. 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 granisetron 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, granisetron concentrated 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 concentrated 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 concentrated 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 concentrated 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/m2and cyclophosphamide > 600 mg/m2. Granisetron concentrated injection was superior to the chlorpromazine/ dexamethasone regimen in preventing nausea and vomiting.
Repeat cycle chemotherapy. In an uncontrolled trial, 75 cancer patients received granisetron concentrated 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 concentrated 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 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 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 concentrated 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 children 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.
Very limited data are available on the use of granisetron in the treatment of children with nausea and vomiting induced by cytostatic chemotherapy.
Radiotherapy. Granisetron concentrated injection 3 mg was compared to a combination of intravenous (i.v.) 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 drug 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.
Indications
Adults. Granisetron Sandoz concentrated injection is indicated for use in adults for: the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy; the prevention of nausea and vomiting induced by radiotherapy.
Children. Granisetron Sandoz concentrated injection is indicated for the prevention of nausea and vomiting induced by cytotoxic chemotherapy.
Contraindications
Granisetron Sandoz is contraindicated in patients hypersensitive to granisetron or any of the excipients.
Precautions
As granisetron may reduce lower bowel motility, patients with signs of subacute intestinal obstruction should be monitored following administration of Granisetron Sandoz.
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).
There are no data on the effect of granisetron 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.
Carcinogenicity/ mutagenicity. 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 1mg/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.
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).
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. 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 Sandoz 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.
Interactions
Granisetron Sandoz 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 drug 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 drugs known to prolong QT interval and/or are arrhythmogenic, this may lead to clinical consequences.
Adverse effects
Granisetron Sandoz has been well tolerated in human studies. In common 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 and tolerated by patients.
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.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/GRASAN01.gif 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 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: 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. Common: hypertension.
Rare: hypotension, arrhythmias, sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including nonsustained tachycardia, ECG abnormalities, angina pectoris, syncope.
Hypersensitivity. Rare: 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. Common: agitation, anxiety, CNS stimulation, dizziness, insomnia, somnolence.
Rare: extrapyramidal syndrome (only in presence of other drugs associated with this syndrome).
Dermatological. Common: skin rashes.
Special senses. Common: taste disorder.
Other common events often associated with chemotherapy also have been reported: leucopenia, decreased appetite, anaemia, alopecia, thrombocytopenia.
Dosage and Administration
Chemotherapy induced nausea and vomiting. Intravenous administration. Adults. For prevention of nausea and vomiting in adults, a single dose of 3 mg of Granisetron Sandoz 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 chemotherapy. The infusion should be commenced within 30 minutes before the start of chemotherapy.
Prophylactic administration of Granisetron Sandoz should be completed prior to the start of chemotherapy.
In clinical trials, the majority of patients have required only a single dose of granisetron 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 Sandoz should be administered as a 5 minute infusion. Further treatment doses of Granisetron Sandoz may be administered if required at least 10 minutes apart. The maximum dose of Granisetron Sandoz is 9 mg/24 hours.
In trials, patients have received a total dose of 160 microgram/kg of intravenous granisetron in one day. There is also clinical experience in patients receiving a total of 600 microgram/kg of intravenous granisetron over 5 days.
Children. The recommended intravenous dose of Granisetron Sandoz in children is 20 microgram 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.
Radiotherapy induced nausea and vomiting. Intravenous administration. Adults. For prevention of nausea and vomiting in adults, a single dose of 3 mg of Granisetron Sandoz 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.
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 granisetron 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.
Preparing the infusion Adults. To prepare the dose of 3 mg, withdraw 3 mL from the vial and dilute with a compatible infusion fluid (see below) to a total volume of 20 to 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 i.v. solutions.
Children. To prepare the dose of 40 microgram/kg, the appropriate volume is withdrawn (up to 3 mL from the vial) 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 in one patient on one occasion only. Discard any unused portion.
Granisetron Sandoz concentrated injection has been shown to be stable for 24 hours in the cited solutions when stored at ambient temperature in normal room lighting conditions. To reduce microbiological hazard, use as soon as possible after dilution. If storage is necessary, hold at 2-8°C for not more than 24 hours.
As a general precaution, granisetron should not be mixed in solution with other drugs.
Admixtures of granisetron hydrochloride and dexamethasone sodium phosphate are compatible at concentrations of 10 to 60 microgram/mL granisetron and 80 to 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 affected 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
Contact the Poisons Information Centre on 131 126 for advice on management of overdose.
There is no specific antidote for Granisetron Sandoz. 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.
Presentation
Concentrate for injection (clear, colourless to slightly yellow), 1 mg/mL:1's*, 5's; 3 mg/3 mL: 1's, 5's* (clear glass vial with rubber stopper and flip off aluminium seal).
*Not currently marketed in Australia.
Storage
Stored below 25°C. Protect from light. Do not freeze.
