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PRODUCT INFORMATION

NAME OF THE MEDICINE
Granisetron Kabi Concentrated Injection
Granisetron Kabi Concentrated Injection contains granisetron hydrochloride
equivalent to granisetron free base 1mg/mL. It also contains sodium chloride,
citric acid monohydrate, hydrochloric acid, sodium hydroxide and water for
injections.
Granisetron hydrochloride has the following chemical structure:

The systematic chemical name is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-
yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride.

DESCRIPTION
Granisetron hydrochloride is a white to off-white crystalline powder which is
freely soluble in water and sodium chloride 0.9% at 20°C.

PHARMACOLOGY
Granisetron is a potent anti-emetic and highly selective antagonist of 5-
hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have
demonstrated that granisetron has negligible affinity for other receptor types,
including 5-HT, alpha1 and alpha2, beta-adrenoreceptors, histamine H1,
picrotoxin, benzodiazepine, opioid and dopamine D2 binding sites.
Antagonism of 5-HT 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-HT 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 injection showed no effect on gut transit time in normal volunteers given single doses up to 200 µg/kg. Pharmacokinetics A linear pharmacokinetic relationship was found after IV administration up to 4-fold the recommended dose. Granisetron is extensively distributed, with a mean volume of distribution of approximately 3L/kg; plasma protein binding is approximately 65%, and granisetron distributes freely between plasma and red blood cells. 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. Mean plasma half-life of granisetreon in patients is approximately 9 hours, with a wide inter-subject variability. The plasma concentration of granisetron is not clearly correlated with anti-emetic efficacy. Clinical benefit may be conferred even when granisetron is not detectable in plasma. Urinary excretion of unchanged granisetron averages 12% of 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 dose adjustment is recommended. CLINICAL TRIALS
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 µg/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 µg/kg were superior to 2 µg/kg in
preventing cisplatin-induced nausea and vomiting.
Moderately Emetogenic Chemotherapy: Granisetron Injection, 40 µg/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. Granisetron 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 Injection, 40
µg/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 µg/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 µg/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 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 drug was administered 1 hour before starting radiation therapy. The anti-emetic efficacy of granisetron was significantly more effective than the standard regimen of metoclopramide/dexamethasone/lorazepam induced emesis.
Very limited data are available on the use of granisetron in the treatment of
nausea and vomiting induced by radiotherapy.
INDICATIONS
Prevention and treatment of nausea and vomiting induced by cytotoxic Prevention of nausea and vomiting induced by radiotherapy in adults only.
CONTRAINDICATIONS
Hypersensitivity to the active substance granisetron hydrochloride, or to any of
the excipients in Granisetron Kabi.
PRECAUTIONS
As Granisetron may reduce lower bowel motility, patients with signs of sub-
acute intestinal obstruction should be monitored following administration of
Granisetron Kabi.
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 co-morbidities, on cardio-toxic 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 µg/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 renally and/or hepatically impaired patient. Carcinogenicity and genotoxicity 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. 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
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 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 with other medicines
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 anti-ulcer medications commonly
prescribed with anti-emetic 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 injections have 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 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.
The following table gives the comparative frequencies of the five commonly
reported adverse events (>3%) in patients receiving granisetron injection, 40
µg/kg, in single-day chemotherapy trials. These patients received
chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour
period following granisetron injection administration.

Table Principal adverse events in clinical trials single-day
chemotherapy
Granisetron Injection
Comparator
Adverse Event
40 µg/kg
(n = 1,268)
1 Adverse events were generally recorded over 7 days post-granisetron Injection administration.
2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
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:
arrhythmias, sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including 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,
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: thrombocytopaenia.

DOSAGE AND ADMINISTRATION
Granisetron Kabi is for intravenous administration only.
Chemotherapy induced nausea and vomiting
Adults: For prevention of nausea and vomiting in adults, a single dose of 3
mg of Granisetron Kabi 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 Kabi 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 Kabi should be administered as a 5 minute infusion.
Further treatment doses of Granisetron Kabi may be administered if required
at least 10 minutes apart. The maximum dose of Granisetron Kabi is 9 mg/24
hours.
In trials, patients have received a total dose of 160 µg/kg of intravenous
granisetron in one day. There is also clinical experience in patients receiving a
total of 600 µg/kg of intravenous Granisetron Kabi over 5 days.
Children: The recommended intravenous dose of Granisetron Kabi in children
is 20 µg to 40 µg/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 Adults: For prevention of nausea and vomiting in adults, a single dose of 3 mg of Granisetron Kabi 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 Kabi 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. Preparation and administration Granisetron Kabi is for single use in one patient only. Discard any residue. The injectable presentations contain no antimicrobial agent. 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 to 50 mL, in any of the following solutions: sodium chloride 0.9%, glucose 5%, Lactated Ringers Solution. Children: To prepare the dose of 40 µg/kg, the appropriate volume (up to 3 mL from the ampoule) is diluted with infusion fluid (as for adults) to a total volume of 10 to 30 mL. Granisetron Kabi 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 Kabi should not be mixed in solution with other drugs other than dexamethasone sodium phosphate. Granisetron is compatible with dexamethasone sodium phosphate in a concentration of 10-60 µg/mL of Granisetron and 80-480 µg/mL dexamethasone phosphate diluted in sodium chloride 0.9% or Glucose 5% solution over a period of 24 hours. Parenteral drug products should be inspected visually for particulate matter
and discolouration before administration wherever solution and container
permit.
OVERDOSAGE
There is no specific antidote for Granisetron Kabi. In the case of overdosage,
symptomatic treatment should be given. Overdose with the intravenous
formulation has occurred. 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 AND STORAGE CONDITIONS
Granisetron Kabi is a concentrated solution for infusion intended for dilution
with Sodium Chloride 0.9% Injection, Glucose 5% Injection or Lactated
Ringer’s Solution prior to intravenous infusion. It is a clear, colourless solution
free of visible particles.
Granisetron Kabi is available in packs of 5 ampoules in the following
presentations:
Granisetron Kabi 1 mg/1 mL
Store the ampoules in the original carton below 25ºC. Protect from light. Do not freeze. Single use only. Discard unused portion. 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. The expiry date (month/year) is stated on the package after the word EXP.
NAME AND ADDRESS OF THE SPONSOR
Fresenius Kabi Australia Pty Limited
964 Pacific Highway
Pymble NSW 2073
Australia
POISON SCHEDULE OF THE MEDICINE
S4

DATE OF APPROVAL
Date of TGA approval: 2 August 2010

Source: http://www.fresenius-kabi.com.au/files/granisetron_medical.pdf