Granisetron - instructions for use, dose, side effects, contraindications

Active substance:
Granisetron hydrochloride in terms of base	1.12 mg
(granisetron)	1.0 mg
ATExcipients:
Sodium chloride	9.0 mg
Citric acid monohydrate	2.0 mg
Water for injections	up to 1.0 ml
Hydrochloric acid *	q.s.
Sodium hydroxide *	q.s.

* Used when necessary in the process to adjust the pH value of 5.3 ± 0.3.

Description:A clear, colorless solution.

Pharmacotherapeutic group:Antiemetic means - serotonin receptor antagonist

ATX: & nbsp

A.04.A.A.02 Granizetron

Pharmacodynamics:

Granisetron is a selective antagonist of 5-hydroxytryptamine (5-HT₃) receptors located in the endings of the vagus nerve (n.vagus) and the trigger zone of the bottom of the IV ventricle of the brain (practically does not affect other receptors of serotonin), with pronounced antiemetic effect. Has a slight affinity for other receptor types, including 5-HT₁, 5-HT₂, 5-HT₄ and dopamine (D₂) receptors.

Eliminates the vomiting that occurs when the parasympathetic nervous system is excited, due to the release of serotonin by enterochromaffine cells.

Granisetron does not affect the concentration of prolactin and aldosterone in the blood plasma.

Pharmacokinetics:

Distribution

Volume of distribution (V_d) is 3 l / kg. Binding to plasma proteins is approximately 65%. The average value of the clearance of granisetron is approximately 27 l / h. The maximum concentration in serum (C_max) with intravenous administration of 63.8 ng / ml. It is distributed in plasma and erythrocytes. The concentration of granisetron in plasma does not have a clear correlation with the severity of the antiemetic effect. Clinical effect can be observed, even if granisetron is not found in the blood plasma.

Metabolism

Biotransformation occurs mainly in the liver by N-detylation and oxidation of the aromatic ring, followed by conjugation. The main metabolites are 7-OH-granisetron, 7-OH-granisetron sulfate and glucuronic conjugates. Some of them, for example 7-OH-granisetron and indazoline N-desmet granisetron, have an antiemetic effect, but the probability of a significant manifestation of their effect on the human body is small.

In studies in vitro shown, that ketoconazole inhibits granisetron metabolism, which involves the participation of the isoenzyme of the subfamily FROMYP3A4 systems of cytochrome P450. Research in vitro showed that granisetron does not affect the activity of the isoenzyme FROMYP3A4 systems of cytochrome P450.

Excretion

The half-life (T_1/2) with intravenous administration is 9 h with wide individual variability. On average, 12% of the administered dose is unchanged in the kidneys and 47% in the form of metabolites, the remainder of the drug is excreted by the intestines in the form of metabolites.

Pharmacokinetics in specific patient groups

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

Have patients with severe renal insufficiency pharmacokinetic parameters after a single intravenous administration did not differ from those in patients with normal renal function.

Have patients with hepatic insufficiency, caused by neoplastic changes, the total level of plasma clearance is about half as compared with patients with normal liver function. Despite these changes, dose adjustment is not required.

Have children when granisetron was administered at a dose of 20 mcg / kg body weight, there were no clinically significant differences in pharmacokinetic parameters from adult indices.

Indications:

- Prevention and therapy of nausea and vomiting in cytostatic chemotherapy in adults and children over 2 years of age;

- Profilaktika and therapy of nausea and vomiting during radiation therapy in adults;

- tTherapy of postoperative nausea and vomiting in adults.

Contraindications:

- Hypersensitivity to granisetron or any of the components of the drug;

- hypersensitivity reactions to other selective 5-HT antagonists₃-receptors in the anamnesis;

- breastfeeding (no data on efficacy and safety);

- Children under 2 years of age (no data on efficacy and safety when using the drug in children under 2 years of age).

Carefully:

- Partial intestinal obstruction;

- concomitant heart disease, cardiotoxic chemotherapy and / or associated electrolyte disorders.

Pregnancy and lactation:

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

Dosing and Administration:

In the form of intravenous infusion

Preparation of a solution for infusion

To obtain the drug solution Granisetron The following infusion solutions are used for intravenous administration:

- 0.9% solution of sodium chloride;

- 0.18% solution of sodium chloride and 4% dextrose solution;

- 5% dextrose solution;

- Hartman's solution;

- a solution of sodium lactate or a solution of mannitol.

Use of other solutions is not allowed.

Concentrate for the preparation of solution for infusion should be used immediately after opening the vial, it is forbidden to continue using the remaining amount of the drug in the vial.

It is recommended to inject the infusion solution immediately after its preparation. The finished solution is stable for 24 hours at a temperature of 15 ° C to 25 ° C under normal room lighting.

Intravenous administration of the drug without dilution is permissible.

Standard dosing regimen

Adults

Cytostatic chemotherapy (prophylaxis)

Patients with a body weight of more than 50 kg: one bottle (3 mg / 3 ml) is diluted in 20-50 ml of the infusion solution and injected for 5 minutes before the start of cytostatic chemotherapy; one vial (3 mg / 3 ml) can also be administered bolus (within 30 seconds).

Patients weighing less than 50 kg: 20-40 mcg / kg; Infusion should be completed before the start of cytostatic therapy.

Clinical studies have shown that for control of nausea and vomiting for 24 hours, most patients needed only one dose of the drug.

Radiation therapy (prevention)

The dosage regimen is the same as in the prevention of nausea and vomiting in the conduct of cytostatic chemotherapy.

Cytostatic chemotherapy and radiotherapy (therapy)

A small number of patients may experience vomiting and nausea.

If necessary, you can make 2 additional infusions (5 minutes each), each at a dose of not more than 3 mg, with an interval of at least 10 minutes for 24 hours. The maximum daily dose should not exceed 9 mg.

Postoperative nausea and vomiting (therapy)

Once 1 mg slowly (not less than 30 seconds). There is an experience of using granisetron in a dose of up to 3 mg in patients who underwent elective surgery under anesthesia.

Patients receiving granisetron infusion, after eliminating nausea and vomiting for the purpose of prophylaxis, may be prescribed tablets.

Children

Cytostatic chemotherapy (prophylaxis)

A single infusion at a dose of 20 mcg / kg in 10-30 ml of a solution for infusions within 5 minutes prior to the onset of cytostatic therapy.

Cytostatic chemotherapy (therapy)

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

Postoperative nausea and vomiting (therapy)

Data on the use of granisetron for the therapy of postoperative nausea and vomiting in children are absent.

Special dosing regimen

Patients with renal or hepatic insufficiency, elderly patients

Correction of the dose is not required.

Side effects:

In most cases, side effects with granisetron are not severe and are tolerated by patients without discontinuing therapy.

Rare and sometimes severe cases of hypersensitivity (for example, anaphylaxis) are noted.

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, < 1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, set the frequency appearance was not possible.

From the nervous system: very often - headache; rarely - serotonin syndrome (including changes in mental state, autonomic dysfunction and disorders of the nervous and muscular systems); rarely - anxiety, restlessness, dizziness.

From the digestive system: very often constipation; often - an increase in the activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)) usually within their normal values; rarely - heartburn, a change in taste.

From the immune system: rarely - hypersensitivity reactions, including anaphylaxis and hives.

From the skin and subcutaneous tissues: infrequent skin rash; very rarely - edema, including face.

From the side of the cardiovascular system: infrequent - lengthening QT interval.

As with the use of other antagonists of serotonin 5-HT₃-receptors, granisetron therapy reported cases of changes in ECG parameters, including cases of lengthening the interval QT, These changes were insignificant and, as a rule, did not have clinical significance, in particular, had no signs of pro-arrhythmogenic effect.

From the body as a whole: very rarely - flu-like syndrome, including fever and chills.

If any of the side effects listed in the manual are aggravated or you notice any other side effects not listed in the instructions, inform the doctor about it.

Post-registration experience with granisetron

From the nervous system: frequency is unknown - insomnia, drowsiness, weakness.

From the digestive system: frequency unknown - abdominal pain, diarrhea, flatulence, indigestion.

From the immune system: the frequency is unknown - hyperthermia, bronchospasm, itchy skin.

From the cardiovascular system: frequency unknown - arrhythmia, chest pain, decrease or increase in blood pressure.

Overdose:

Symptoms: reported cases of overdose. With a single intravenous the introduction of 38 mg of granisetron did not show the development of serious adverse effects other than mild headache.

Treatment: the specific antidote is unknown. Conduct symptomatic therapy.

Interaction:

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

Research in vitro showed that ketoconazole inhibits the metabolism of granisetron, by acting on the isoenzyme 3A of the cytochrome P450 system.

Special studies on the effect of granisetron on patients under anesthesia, was not carried out, but granisetron well tolerated with simultaneous administration with similar drugs and narcotic analgesics.

When induction of hepatic enzymes phenobarbital an increase in the clearance of granisetron was observed by about a quarter.

There was no interaction with concomitant administration with benzodiazepines (for example, lorazepam), neuroleptics (for example, haloperidol), tranquilizers, antiulcer drugs from the group of blockers H₂-gistaminovyh receptors (for example, cimetidine) and cytostatic medicines that cause vomiting.

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

As with other antagonists of serotonin 5-HT₃-receptors, with the use of granisetron in combination with other serotonergic drugs, there have been cases of the development of serotonin syndrome (including changes in mental state, autonomic dysfunction and disorders of the nervous and muscular systems).

Special instructions:

Patients with signs of partial intestinal obstruction after drug administration Granisetron should be under the supervision of a doctor, since granisetron can reduce bowel motility.

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

Granisetron with intravenous administration at a dose of up to 200 μg / kg does not have a clinically significant effect on the electroencephalogram or the results of psychometric tests. As with other 5-NT₃ antagonists, granisetron therapy reported changes in ECG parameters, including cases of lengthening the interval QT. These changes were insignificant and, as a rule, did not have clinical significance, in particular, had no signs of pro-arrhythmogenic effect. However, in patients with pre-existing arrhythmias or diseases accompanied by cardiac conduction disorders, the observed changes in ECG parameters during granisetron therapy can lead to clinically significant consequences. In this regard, caution should be exercised in prescribing patients with concomitant heart disease who receive cardiotoxic chemotherapy and / or have associated electrolyte disturbances.

Cases of cross-sensitivity between antagonists have been reported sirotonin 5-HT₃receptors.

It is necessary to observe the patient's condition in the case of clinical necessity, oneatbelt application of granisetron with other serotonergic drugs.

Effect on the ability to drive transp. cf. and fur:

Data on the effect of granisetron on the ability to drive a vehicle are missing. However, it is necessary to warn about the possibility of occurrence during treatment with granisetron of drowsiness, asthenia and dizziness. If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion, 1 mg / ml.

Packaging:

1 ml or 3 ml in vials of colorless glass I hydrolytic class, hermetically sealed with rubber stoppers and crimped with aluminum or combined caps.

For 5 or 10 bottles together with the instructions for use are placed in a pack of cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003064

Date of registration:29.06.2015 / 08.12.2015

Expiration Date:29.06.2020

Date of cancellation:2020-06-29

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

R-PHARM, JSC Russia

Information update date: & nbsp07.05.2017

Illustrated instructions

Instructions

Granisetron (Granisetrone)