Skip to Content

GRANISETRON 1MG/ML SOLUTION FOR INJECTION

Active substance(s): GRANISETRON HYDROCHLORIDE

PDF options:  View Fullscreen   Download PDF

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Granisetron, 1mg/ml, solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

The active substance is granisetron.
Each ml solution for injection contains 1 mg of granisetron (as the hydrochloride).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for injection
The solution for injection is a clear, colourless liquid.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Granisetron solution for injection is indicated in adults for the prevention or
treatment of
- acute nausea and vomiting associated with chemotherapy and radiotherapy.
- post-operative nausea and vomiting.
Granisetron solution for injection is indicated for the prevention of delayed nausea
and vomiting associated with chemotherapy and radiotherapy.
Granisetron solution for injection is indicated in children aged 2 years and above for
the prevention and treatment of acute nausea and vomiting associated with
chemotherapy.

4.2

Posology and method of administration

Posology
Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV)
Prevention (acute and delayed nausea)

A dose of 1-3 mg (10-40 µg/kg) of Granisetron solution for injection should be
administered either as a slow intravenous injection or as a diluted intravenous infusion
5 minutes prior to the start of chemotherapy. The solution should be diluted to 5 ml
per mg.
Treatment (acute nausea)
A dose of 1-3 mg (10-40 µg/kg) of Granisetron solution for injection should be administered
either as a slow intravenous injection or as a diluted intravenous infusion and administered
over 5 minutes. The solution should be diluted to 5 ml per mg. Further maintenance doses of
Granisetron solution for injection may be administered al least 10 minutes apart. The
maximum dose to be administered over 24 hours should not exceed 9 mg.

Combination with adrenocortical steroid
The efficacy of parenteral granisetron may be enhanced by an additional intravenous dose of
an adrenocortical steroid e.g. by 8-20 mg dexamethasone administered before the start of the
cytostatic therapy or by 250 mg methyl-prednisolone administered prior to the start and
shortly after the end of the chemotherapy.
Paediatric population
The safety and efficacy of Granisetron solution for injection in children aged 2 years and
above has been well established for the prevention and treatment (control) of acute nausea
and vomiting associated with chemotherapy and the prevention of delayed nausea and
vomiting associated with chemotherapy. A dose of 10 – 40 µg/kg body weight (up to 3 mg)
should be administered as an i.v. infusion, diluted in 10 to 30 ml infusion fluid and
administered over 5 minutes prior to the start of chemotherapy. One additional dose may be
administered within a 24 hour-period if required. This additional dose should not be
administered until at least 10 minutes after the initial infusion.

Post-operative nausea and vomiting (PONV)
A dose of 1 mg (10µg/kg) of Granisetron solution for injection should be administered by
slow intravenous injection. The maximum dose of Granisetron to be administered over 24
hours should not exceed 3 mg.

For the prevention of PONV, administration should be completed prior to induction
of anaesthesia.
Paediatric population
Currently available data are described in section 5.1 but no recommendation on a posology
can be made. There is insufficient clinical evidence to recommend administration of the
solution for injection to children in prevention and treatment of Post-operative nausea and
vomiting (PONV).
Elderly and renal impairment

There are no special precautions required for its use in either elderly patients or those
patients with renal or hepatic impairment.
Hepatic impairment

There is no evidence to date for an increased incidence of adverse events in patients
with hepatic disorders. On the basis of its kinetics, whilst no dosage adjustment is
necessary, granisetron should be used with a certain amount of caution in this patient
group (see section 5.2.).
Method of administration
Administration may be either as a slow intravenous injection (over 30 seconds) or as an
intravenous infusion diluted in 20 to 50 ml infusion fluid and administered over 5 minutes.
For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use
As granisetron may reduce lower bowel motility, patients with signs of sub-acute
intestinal obstruction should be monitored following its administration.
As for other 5-HT3 antagonists, ECG changes including QT interval prolongation
have been reported with granisetron. 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 cardiotoxic
chemotherapy and/or with concomitant electrolyte abnormalities (see section 4.5).
Cross-sensitivity between 5-HT3 antagonists (e.g. dolasetron, ondansetron) has been
reported
This medicinal product contains 1.37 mmol sodium (or 31.5 mg) per maximum daily
dose of 9 mg. This should be taken into consideration by patients on a controlled
sodium diet.
Serotonin syndrome
There have been reports of serotonin syndrome with the use of 5-HT3 antagonists
either alone, but mostly in combination with other serotonergic drugs (including
selective serotonin reuptake inhibitors (SSRIs), and serotonin noradrenaline reuptake
inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like
symptoms is advised.

4.5

Interaction with other medicinal products and other forms of interaction
As for other 5-HT3 antagonists, cases of ECG modifications including QT
prolongation have been reported with granisetron. In patients concurrently treated
with medicinal products known to prolong QT interval and/or which are
arrhythmogenic, this may lead to clinical consequences (see section 4.4).
In studies in healthy subjects, no evidence of any interaction has been indicated
between granisetron and benzodiazepines (lorazepam), neuroleptics (haloperidol) or

anti-ulcer medicinal products (cimetidine). Additionally, granisetron has not shown
any apparent medicinal product interaction with emetogenic cancer chemotherapies.
No specific interaction studies have been conducted in anaesthetised patients.
Serotonergic medicinal products (e.g. SSRIs and SNRIs)
There have been reports of serotonin syndrome following concomitant use of 5-HT3
antagonists and other serotonergic medicinal products (including SSRIs and SNRIs)
(see section 4.4).

4.6

Fertility, pregnancy and lactation
Pregnancy
There is limited amount of data from the use of granisetron in pregnant
women. Animal studies do not indicate direct or indirect harmful effects with
respect to reproductive toxicity (see section 5.3). As a precautionary measure,
it is preferable to avoid the use of granisetron during pregnancy.
Breast-feeding
It is unknown whether granisetron or its metabolites are excreted in human milk. As a
precautionary measure, breast-feeding should not be advised during treatment with
Granisetron.
Fertility
In rats, granisetron had no harmful effects on reproductive performance or fertility.

4.7

Effects on ability to drive and use machines

Granisetron has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions for Granisetron are headache and
constipation which may be transient. ECG changes including QT prolongation have
been reported with granisetron (see sections 4.4 and 4.5).
Tabulated list of adverse reactions
The following table of listed adverse reactions is derived from clinical trials and
post-marketing data associated with granisetron and other 5-HT3 antagonists.
The frequencies used in the table below are: very common (≥1/10), common (≥1/100
to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to < 1/1,000) and very
rare (<1/10,000).

Immune system disorders
Uncommon
Psychiatric disorders
Common
Nervous system disorders
Very common
Uncommon

Hypersensitivity reactions e.g., anaphylaxis,
urticaria
Insomnia
Headache
Extrapyramidal Reactions,
Serotonin syndrome

Cardiac disorders
Uncommon
QT prolongation
Gastrointestinal disorders
Very common
Constipation
Common
Diarrhoea
Hepatobiliary disorders
Common
Elevated hepatic transaminases*
Skin and subcutaneous tissue disorders
Uncommon
Rash
* Occurred at a similar frequency in patients receiving comparator therapy
Description of selected adverse reactions
As for other 5-HT3 antagonists, ECG changes including QT prolongation have been
reported with granisetron (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
There is no specific antidote for Granisetron. In the case of overdose with the
injection, symptomatic treatment should be given. Doses of up to 38.5 mg of
granisetron as a single injection have been reported, with symptoms of mild headache
but no other reported sequelae.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists,
ATC code: A04AA02
Neurological mechanisms, serotonin-mediated nausea and vomiting

Serotonin is the main neurotransmitter responsible for emesis after chemo- or radio-therapy.
The 5-HT3 receptors are located in three sites: vagal nerve terminals in the gastrointestinal
tract and chemoreceptor trigger zones located in the area postrema and the nucleus tractus
solidarius of the vomiting center in the brainstem. The chemoreceptor trigger zones are
located at the caudal end of the fourth ventricle (area postrema). This structure lacks an
effective blood-brain barrier, and will detect emetic agents in both the systemic circulation
and the cerebrospinal fluid. The vomiting centre is located in the brainstem medullary
structures. It receives major inputs from the chemoreceptor trigger zones, and a vagal and
sympathetic input from the gut.
Following exposure to radiation or catotoxic substances, serotonin (5-HT) is released from
enterochromaffine cells in the small intestinal mucosa, which are adjacent to the vagal
afferent neurons on which 5-HT3 receptors are located. The released serotonin activates vagal
neurons via the 5-HT3 receptors which lead ultimately to a severe emetic response mediated
via the chemoreceptor trigger zone within the area postrema.
Mechanism of action
Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine
(5-HT3) receptors. Radioligand binding studies have demonstrated that granisetron has
negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites.
Chemotherapy- and radiotherapy-induced nausea and vomiting
Granisetron administered intravenously has been shown to prevent nausea and vomiting
associated with cancer chemotherapy in adults and children 2 to 16 years of age.
Post-operative nausea and vomiting
Granisetron administered intravenously has been shown to be effective for prevention and
treatment of post-operative nausea and vomiting in adults.
Pharmacological properties of granisetron
Interaction with neurotropic and other active substances through its activity on P 450cytochrome has been reported (see section 4.5).
In vitro studies have shown that the cytochrome P450 sub-family 3A4 (involved in the
metabolism of some of the main narcotic agents) is not modified by granisetron. Although
ketoconazole was shown to inhibit the ring oxidation of granisetron in vitro, this action is not
considered clinically relevant.
Although QT-prolongation has been observed with 5-HT3 receptor antagonists (see section
4.4), this effect is of such occurrence and magnitude that it does not bear clinical significance
in normal subjects. Nonetheless it is advisable to monitor both ECG and clinical
abnormalities when treating patients concurrently with drugs known to prolong the QT (see
section 4.5).
Paediatric population
Clinical application of granisetron was reported by Candiotti et al. A prospective,
multicentre, randomized, double-blind, parallel-group study evaluated 157 children 2 to 16
years of age undergoing elective surgery. Total control of postoperative nausea and vomiting
during the first 2 hours after surgery was observed in most patients.

5.2

Pharmacokinetic properties

Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose
in adults. It is clear from the extensive dose-finding program that the antiemetic efficacy is
not unequivocally correlated with either administered doses or plasma concentrations of
granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in
terms of either the proportion of patient responding to treatment or in the duration of
symptom control.
Distribution
Granisetron is extensively distributed, with a mean volume of distribution of approximately 3
L/kg. Plasma protein binding is approximately 65%.
Biotransformation
Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The
major compounds are 7-OH-granisetron and its sulphate and glycuronide conjugates.
Although antiemetic properties have been observed for 7-OH-granisetron and indazoline Ndesmethyl granisetron, it is unlikely that these contribute significantly to the pharmacological
activity of granisetron in man.
In vitro liver microsomal studies show that granisetron’s major route of metabolism is
inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A
subfamily (see section 4.5).
Elimination
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged
granisetron averages 12% of dose while that of metabolites amounts to about 47% of dose.
The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients by the
oral and intravenous route is approximately 9 hours, with a wide inter-subject variability.
Pharmacokinetic relationship(s)
Renal failure
In patients with severe renal failure, data indicate that pharmacokinetic parameters after a
single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment
In patients with hepatic impairment due to neoplasic liver involvement, total plasma clearance
of an intravenous dose was approximately halved compared to patients without hepatic
involvement. Despite these changes, no dosage adjustment is necessary (see section 4.2).
Elderly
In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the
range found for non-elderly subjects.
Paediatric population

In children, after single intravenous doses, pharmacokinetics are similar to those in adults
when appropriate parameters (volume of distribution, total plasma clearance) are normalized
for body weight.

5.3

Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity.
Carcinogenicity studies revealed no special hazard for humans when used in the
recommended human dose. However when administered in higher doses and over a
prolonged period of time the risk of carcinogenicity cannot be ruled out.
A study in cloned human cardiac ion channels has shown that granisetron has the potential to
affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been
shown to block both sodium and potassium channels, which potentially affects both
depolarisation and repolarisation through prolongation of PR, QRS, and QT intervals. This
data helps to clarify the molecular mechanisms by which some of the ECG changes
(particularly QT and QRS prolongation) associated with this class of agents occur. However,
there is no modification of the cardiac frequency, blood pressure or the ECG trace. If changes
do occur, they are generally without clinical significance.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Citric acid, monohydrate
Hydrochloric acid (for pH adjustment)
Sodium chloride
Sodium hydroxide (for pH adjustment)
Water for injections

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products except
those mentioned in section 6.6.

6.3

Shelf life
Shelf life of the finished medicinal product:
3 years
After first opening:
Once opened the product should be used immediately.
After dilution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 25 ºC
protected from direct sunlight.

From a microbiological point of view, the product should be used immediately. 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 to 8°C,
unless dilution has taken place in controlled and validated aseptic conditions

6.4

Special precautions for storage

Keep the ampoules in the outer carton in order to protect from light. Do not freeze.
For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

3 ml, type I clear glass ampoules
1 ml, type I clear glass ampoules
Pack sizes:
5 x 1 ml, 10 x 1 ml
5 x 3 ml, 10 x 3 ml
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

For single use only. Any unused portion should be discarded.
The diluted injections and infusions are to be inspected visually for particulate matter prior to
administration. They should only be used if the solution is clear and free from particles.
Preparing the infusion
Adults
The solution should be diluted to 5 ml per mg. i.e the contents of a 1 ml ampoule can be
diluted to a volume of 5 ml; the contents of a 3 ml ampoule can be diluted to a volume of 15
ml.
Granisetron can also be diluted in 20 to 50 ml compatible infusion fluid and then given over
five minutes as an intravenous infusion in any of the following solutions:
0.9 % w/v sodium chloride injection
5 % w/v glucose injection
Lactated Ringer’s Solution;
No other diluents should be used.
Use in the paediatric population
Children 2 years of age and older: To prepare the dose of 10 - 40 µg/kg, the appropriate
volume is withdrawn and diluted with infusion fluid (as for adults) to a total volume of 10 to
30 ml.

As a general precaution, Granisetron should not be mixed in solution with other drugs.
Granisetron 1 mg / ml is compatible with Dexamethasone dihydrogenphosphate dinatrium in
a concentration of 10-60 µg/ml of Granisetron and 80-480 µg/ml Dexamethasonphosphate
diluted in sodium chloride 0.9 % or Glucose 5 % solution over a period of 24 hours.
Any unused medicinal product or waste material should be disposed of in accordance with
local requirements.

7

MARKETING AUTHORISATION HOLDER
Fresenius Kabi Limited
Cestrian Court
Eastgate Way
Manor Park
Runcorn
Cheshire
WA7 1NT
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 08828/0191

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 22nd January 2009
Date of latest renewal: 14th March 2013

10

DATE OF REVISION OF THE TEXT
13/03/2017

+ Expand Transcript

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Hide