Granisetron, 1 mg/ml 3 ml

Pharmacotherapeutic group

An anti-emetic – serotonin receptor antagonist

ATX code

A04AA02

Pharmacodynamics:

Granisetron is a selective antagonist of the 5-hydroxytryptamine (5-HT3) receptors located in the vagus nerve (n.vagus) and the trigger zone of the bottom of the IV ventricle of the brain (practically has no effect on other serotonin receptors) with a pronounced antiemetic effect. It has negligible affinity for other types of receptors including 5-HT1 5-HT2 5-HT4 and dopamine (D2) receptors.

It relieves vomiting resulting from excitation of the parasympathetic nervous system due to the release of serotonin by enterochromaffin cells.

Granisetron has no effect on plasma concentrations of prolactin and aldosterone.

Pharmacokinetics:

Distribution

The volume of distribution (Vd) is 3 l/kg. Binding to plasma proteins is approximately 65%. The average clearance of granisetron is approximately 27 l/h. Maximum serum concentration (Cmax) when administered intravenously is 638 ng/ml. It is distributed in plasma and erythrocytes. Plasma concentration of granisetron has no clear correlation with the severity of antiemetic effect. Clinical effect can be observed even if granisetron is not detected in plasma.

Metabolism

Biotransformation occurs mainly in the liver by N-demethylation and oxidation of the aromatic ring followed by conjugation. The main metabolites of 7-OH-granisetron are 7-OH-granisetron sulfate and glucuron conjugates. Some of them such as 7-OH-granisetron and indazolin N-desmethyl granisetron have antiemetic effects but the probability of their significant effect on the human body is small.

In vitro studies have shown that ketoconazole inhibits the metabolism of granisetron, which suggests the involvement of the CYP3A4 subfamily isoenzyme of the cytochrome P450 system. In vitro studies have shown that granisetron has no effect on the activity of the CYP3A4 isoenzyme of the cytochrome P450 system.

The elimination half-life (T1/2) when administered intravenously is 9 hours with wide individual variability. On average, 12% of the administered dose is excreted unchanged by the kidneys and 47% – as metabolites; the remaining part of the drug is excreted as metabolites in the intestine.

Pharmacokinetics in special patient groups

In elderly patients the pharmacokinetic parameters after single intravenous administration did not differ from those in younger patients.

In patients with severe renal impairment the pharmacokinetic parameters after single intravenous administration did not differ from those in patients with normal renal function.

In patients with hepatic impairment due to neoplastic changes, total plasma clearance is approximately half that of patients with normal hepatic function. Despite these changes, no dose adjustment is required.

In children when administering granisetron at a dose of 20 mcg/kg body weight there were no clinically significant differences in pharmacokinetic parameters from those observed in adults.

Indications

Prevention and therapy of nausea and vomiting during cytostatic chemotherapy in adults and children over 2 years old;

Prevention and therapy of nausea and vomiting during radiation therapy in adults;

Therapy of postoperative nausea and vomiting in adults.

Active ingredient

Granisetron

Composition

1 ml of the drug contains:

Active ingredient:

Granisetron hydrochloride in recalculation on the base 1.12 mg (granisetron) 1.0 mg,

Excipients:

Sodium chloride – 9.0 mg,

Citric acid monohydrate – 2.0 mg,

Water for injection to 1.0 ml,

Chloric acid* q.s.

Sodium hydroxide* q.s.

* Used if necessary in the technological process to correct the pH value of 5.3±0.3.

How to take, the dosage

In the form of intravenous infusion

Preparation of solution for infusion

The following infusion solutions are used to prepare Granisetron solution for intravenous administration:

– 09% sodium chloride solution;

– 018% sodium chloride solution and 4% dextrose solution;

– 5% dextrose solution;

– Hartmann’s solution;

– sodium lactate solution or mannitol solution.

The use of other solutions is not allowed.

The concentrate for preparation of the solution for infusion must be used immediately after opening the bottle no further use of the remaining amount of the drug in the bottle is allowed.

The solution for infusion is recommended to be administered immediately after preparation. The prepared solution is stable for 24 hours at a temperature of 15 ° C to 25 ° C in normal room light.

Intravenous administration of the drug without dilution is allowed.

The standard dosing regimen

Adults

Cytostatic chemotherapy (prophylaxis)

Patients with a body weight greater than 50 kg: One vial (3 mg/3 mL) diluted in 20-50 mL of infusion solution and administered within 5 minutes before cytostatic chemotherapy; one vial (3 mg/3 mL) may also be administered bolus (within 30 seconds).

Patients with body weight less than 50 kg: 20-40 mcg/kg; infusion should be finished before the start of cytostatic therapy.

The data of clinical studies showed that only one dose of the drug was required to control nausea and vomiting for 24 hours in most patients.

Radiation therapy (prophylaxis)

The dosing regimen is the same as for the prevention of nausea and vomiting with cytostatic chemotherapy.

Cytostatic chemotherapy and radiation therapy (therapy)

A small number of patients may experience uncontrollable vomiting and severe nausea.

If necessary, 2 additional infusions (5 minutes each) of no more than 3 mg at intervals of at least 10 minutes over 24 hours may be given. The maximum daily dose should not exceed 9 mg.

Postoperative nausea and vomiting (therapy)

Once 1 mg slowly (at least 30 seconds). There is experience with the use of granisetron in doses up to 3 mg in patients undergoing elective surgery under anesthesia.

Patients receiving infusions of granisetron after nausea and vomiting have resolved may be prescribed tablets for prophylaxis.

Children

Cytostatic chemotherapy (prophylaxis)

A single infusion of 20 mcg/kg in 10-30 ml infusion solution for 5 minutes before cytostatic therapy.

Cytostatic chemotherapy (therapy)

No more than 2 additional infusions (within 5 minutes) each dose of 20 mcg/kg at intervals of at least 10 minutes. The maximum daily dose should not exceed 60 mcg/kg.

Postoperative nausea and vomiting (therapy)

There are no data on the use of granisetron for the therapy of postoperative nausea and vomiting in children.

Special dosing regimen

Patients with renal or hepatic impairment elderly patients

Dose adjustment is not required.

Interaction

Granisetron does not affect the activity of CYP3A4 isoenzyme of cytochrome P450 system (responsible for metabolism of some narcotic analgesics). The effectiveness of granisetron may be enhanced by intravenous administration of dexamethasone (8-20 mg) before the start of chemotherapy.

In vitro studies have shown that ketoconazole inhibits the metabolism of granisetron through its effect on cytochrome P450 isoenzyme 3A.

There have been no specific studies on the effect of granisetron on patients under anesthesia, but granisetron is well tolerated when administered concomitantly with similar drugs and narcotic analgesics.

Induction of hepatic enzymes with phenobarbital increased clearance of granisetron by approximately one-quarter.

There were no identified interactions with benzodiazepines (e.g. lorazepam) neuroleptics (e.g. haloperidol) tranquilizers with anti-ulcer drugs from the group of H2-histamine receptor blockers (e.g. cimetidine) and cytostatic drugs that cause vomiting.

In patients receiving concomitant therapy with drugs with known ability to prolong the QT interval and/or arrhythmogenic activity, observed ECG changes during therapy with granisetron may lead to clinically significant consequences.

As with other serotonin 5-NT3 receptor antagonists, the use of granisetron in combination with other serotonergic medications has reported cases of serotonin syndrome (including altered mental status autonomic dysfunction and nervous and muscular system disorders).

Special Instructions

Patients with signs of partial bowel obstruction after administration of Granisetron should be kept under medical supervision because Granisetron may decrease bowel motility.

Granisetron is safe for use in the elderly and patients with renal or hepatic impairment.

Granisetron when administered intravenously in doses up to 200 mcg/kg has no clinically significant effect on the electroencephalogram or the results of psychometric tests. As with the use of other 5-HT3 antagonists, changes in ECG parameters have been reported during granisetron therapy, including cases of prolongation of the QT interval. These changes were not significant and, as a rule, had no clinical significance, in particular, there were no signs of proarrhythmogenic action. However, in patients with pre-existing arrhythmias or diseases accompanied by cardiac conduction abnormalities the observed changes of ECG parameters during granisetron therapy may lead to clinically significant consequences. Therefore, caution should be exercised when prescribing the drug to patients with concomitant cardiac diseases receiving cardiotoxic chemotherapy and/or having concomitant electrolyte disturbances.

Cases of cross-sensitivity between serotonin 5-NT3 receptor antagonists have been reported.

The patient’s condition should be monitored if it is clinically necessary to use granisetron concomitantly with other serotonergic drugs.

Influence on ability to drive motor vehicles:

There are no data on the effect of granisetron on the ability to drive a motor vehicle. However, you should be cautioned about the possibility of asthenia drowsiness and dizziness during treatment with granisetron. If these symptoms occur, patients are advised to refrain from driving and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

– Hypersensitivity to granisetron or any of the drug components;

– history of hypersensitivity reactions to other selective 5-NT3 receptor antagonists;

– breastfeeding (no data on efficacy and safety);

– childhood age less than 2 years (no data on efficacy and safety in children younger than 2 years).

With caution:

– Partial intestinal obstruction;

– Concomitant heart disease cardiotoxic chemotherapy and/or concomitant electrolyte disorders.

Side effects

In most cases, the side effects of granisetron are not severe and are tolerated by patients without interruption of therapy.

Rare and sometimes severe cases of hypersensitivity have been reported (e.g., anaphylaxis).

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: Very common (>1/10) common (>1/100 < 1/10) infrequent (>1/1000 < 1/100) rare (>1/10000 < 1/1000) and very rare (< 1 /10000); frequency unknown – it was not possible to determine the incidence from available data.

Nervous system disorders: very common – headache; infrequent – serotonin syndrome (including altered mental status autonomic dysfunction and disorders of the nervous and muscular systems); rare – anxiety anxiety anxiety dizziness.

The digestive system: very often – constipation; often – increased activity of “liver” transaminases (alanine aminotransferase (ALT) aspartate aminotransferase (ACT)) usually within their normal values; rarely – heartburn change of taste.

The immune system: rare – hypersensitivity reactions including anaphylaxis and urticaria.

Skin and subcutaneous tissue: infrequent – skin rash; very rare – swelling, including of the face.

Cardiovascular system: infrequent – prolongation of the QT interval.

As with other serotonin 5-NT3 receptor antagonists, there have been reports of changes in ECG parameters including prolongation of the QT interval during therapy with granisetron These changes were not significant and generally had no clinical significance, particularly with no evidence of proarrhythmogenic effects.

In general body: very rarely flu-like syndrome including fever and chills.

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Post-registration experience with granisetron

Nervous system side effects: frequency unknown – insomnia sleepiness weakness.

Gastrointestinal system: frequency unknown – abdominal pain diarrhea flatulence dyspepsia.

The immune system: frequency unknown – hyperthermia bronchospasm skin itching.

Cardiovascular system: frequency unknown – arrhythmia chest pain decreased or increased blood pressure.

Overdose

Symptoms: cases of overdose have been reported. No serious adverse effects other than mild headache have been observed with a single intravenous injection of 38 mg of granisetron.

Treatment: no specific antidote is known. Symptomatic therapy is administered.

Pregnancy use

The safety of treatment with granisetron in pregnancy has not been established. Granisetron should be used in pregnant women only if the estimated benefit to the mother exceeds the potential risk to the fetus.