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

Excipients (core): lactose monohydrate (sugar milk) - 75.38 mg; cellulose microcrystalline - 20,00 mg; sodium carboxymethyl starch - 2.00 mg; hypromellose - 1.00 mg; magnesium stearate 0.50 mg.

Auxiliary substances (shell): hypromellose - 1.74 mg; Macrogol-4000 - 0.42 mg; titanium dioxide - 0.84 mg.

Description:TOrifle, biconvex tablets, covered with a film shell of white or almost white color. On the cross section of the tablet, two layers are visible: the nucleus is almost white and the film membrane.

Pharmacotherapeutic group:Antiemetic means - serotonin receptor antagonist

ATX: & nbsp

A.04.A.A.02 Granizetron

Pharmacodynamics:

Granisetron is a selective antagonist of serotonin (5-hydroxytryptamine) 5-HT₃-receptors located in the endings of the vagus nerve 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. Studies have shown that granisetron has low affinity for other receptor types, including other types of serotonin receptors and D₂dopamine receptors.

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

Granisetron eliminates nausea and vomiting caused by cytotoxic chemotherapy,radiotherapy, as well as postoperative nausea and vomiting.

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

Granisetron blocks potassium hERG cardiac channels, affecting the repolarization of the myocardium. On the parameters of the electrocardiogram (ECG), this manifests itself in a change PR, QRS and especially in elongation QT interval.

Does not have a mutagenic effect in vivo and in vitro. When administered for life in high doses, it increases the risk of hepatocellular tumors in animals.

Pharmacokinetics:

Suction

Absorption of granisetron after oral administration is rapid and complete, but absolute bioavailability is reduced to 60% due to the effect of "first passage" through the liver. Eating does not affect the bioavailability of granisetron.

Distribution

Granisetron is distributed to organs and tissues (including plasma and erythrocytes), the average volume of distribution is 3 l / kg. The connection with plasma proteins is approximately 65%.

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. Research in vitro showed that ketoconazole inhibits the metabolism of granisetron, which involves the participation of isoenzymes of the subfamily CYP3A. Other studies in vitro showed that granisetron does not affect the activity of the isoenzyme CYP3A4.

Excretion

Kidneys in unmodified form are displayed on average 12% and in the form of metabolites 47% of the dose. The remaining 41% is excreted by the intestines in the form of metabolites.

The half-life (T_1/2) for oral administration is 9 hours, from broad individual variability.

Concentrations of granisetron in plasma are indistinctly correlated with its antiemetic effect. Therapeutic effect is observed even when granisetron is no longer found in plasma.

The pharmacokinetics of granisetron when administered orally remains linear in a dose range up to 2.5 times that recommended.

Special patient groups

In patients with hepatic insufficiency caused by neoplastic changes, the values of total plasma clearance are approximately half of the values of plasma clearance compared to patients with normal liver function. Despite the research data, dose adjustment is not required.

Indications:

Prevention of nausea and vomiting in the conduct of cytostatic chemotherapy in adults.

Prevention and treatment of nausea and vomiting during radiotherapy in adults.

Contraindications:

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

- hypersensitivity reactions to other selective antagonists serotonin 5-HT₃-receptors in the anamnesis;

- breast-feeding;

- Children under 12 years of age (there is not enough data to establish the optimal dosing regimen for this age group).

Carefully:

- Partial intestinal obstruction;

- pregnancy;

- concomitant heart disease, especially with arrhythmia in the syndrome of an elongated interval QT;

- with cardiotoxic chemotherapy and / or associated electrolyte imbalance;

- deficiency of lactase, hereditary intolerance to galactose, glucose-galactose malabsorption.

Pregnancy and lactation:

In pregnancy, the drug is used only if the intended benefit to the mother exceeds the potential risk to the fetus. The drug does not have a teratogenic effect on animals, studies in pregnant women have not been conducted.

The drug is contraindicated in the period of breastfeeding.

Dosing and Administration:

Tablets should be swallowed whole, washed down with water.

Cytostatic chemotherapy (prophylaxis)

Inside 1 mg 2 times a day or 2 mg 1 time a day not more than 7 days after the start of cytostatic therapy. The first dose should be taken 1 hour before the start of cytostatic therapy.

Radiation therapy (prevention and treatment)

Inside to 2 mg 1 time a day not more than 7 days after the start of radiation therapy. In this case, the first dose should be taken 1 hour before the start of radiotherapy.

Special dosing regimen

The drug in the form of tablets is not recommended for use in children under 12 years of age, There is insufficient data to establish the optimal dosing regimen for this age group. For the prevention and treatment of nausea and vomiting during the cytostatic therapy in children, another dosage form of granisetron is used - a concentrate for the preparation of a solution for infusions.

Elderly age, kidney failure

Special precautions when using the drug in elderly patients or patients with renal insufficiency is not provided.

Liver failure

There is no evidence of an increased incidence of side effects in patients with liver disease.In patients with impaired liver function, dose adjustment is not required.

Side effects:

In most cases, adverse reactions with granisetron were not severe and were tolerated by patients without discontinuing therapy.

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

From the immune system: reactions of increased sensitivity, for example, skin rash, hyperthermia, bronchospasm, urticaria, pruritus.

From the nervous system: headache, insomnia, drowsiness, weakness, anxiety, restlessness, dizziness, serotonin syndrome (including changes in mental state, autonomic dysfunction and disorders of the nervous and muscular systems), extrapyramidal disorders.

From the side of the cardiovascular system: interval lengthening QT, arrhythmia, chest pain, decreased or increased blood pressure.

As with the use of other antagonists of serotonin 5-NT₃-receptors, granisetron therapy reported cases of changes in the parameters of the electrocardiogram (ECG), including cases of increasing 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 digestive system: constipation, abdominal pain, diarrhea, flatulence, increased activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)) usually within their normal values, dyspepsia, heartburn, a change in taste sensations.

From the skin and subcutaneous fat: skin rash, swelling, including swelling of the face.

On the part of the body as a whole: flu-like syndrome, including fever and chills.

Overdose:

Symptoms: The use of 38 mg of granisetron in the form of a single intravenous injection was not accompanied by the development of serious undesirable effects other than mild headache.

Treatment: The specific antidote for granisetron is unknown. Symptomatic therapy is indicated.

Interaction:

Granisetron does not affect isoenzyme activity CYP3A4 (responsible for the metabolism of some narcotic analgesics). The efficacy of granisetron may be enhanced by intravenous administration of dexamethasone (8-20 mg) prior to chemotherapy. Research in vitro showed that ketoconazole inhibits the metabolism of granisetron, which involves the participation of isoenzymes of the subfamily CYP3A.

Special studies to interact with funds for general anesthesia have not been carried out, but granisetron well tolerated with simultaneous use with similar drugs and narcotic analgesics.

When induction of "liver" enzymes with phenobarbital, an increase in the clearance of granisetron (with intravenous administration) was observed by approximately a quarter.

There was no interaction with concomitant use with benzodiazepines (eg, lorazepam), tranquilizers, neuroleptics (eg, haloperidol), antiulcer drugs from the H blocker group₂-gistaminovyh receptors (for example, cimetidine) and cytostatic drugs 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 the use of 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 obstruction of the intestine after the administration of the drug should be under the supervision of a physician, since the drug can reduce intestinal motility.

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

As with the use of other antagonists of serotonin 5-HT₃-receptors, 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 when using the drug in patients with concomitant cardiac diseases receiving cardiotoxic chemotherapy and / or having associated electrolyte imbalance,

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

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

Patients with a rare hereditary intolerance to galactose, a deficiency of lactase, or a violation of absorption of glucose-galactose are not recommended to use the drug.

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

Data on the effect of the drug on the ability to drive vehicles are missing. However, care should be taken, given that when the drug has been reported on the occurrence of drowsiness 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:

Tablets, film-coated, 1.0 mg.

Packaging:

For 10, 30, 50 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

10, 20, 30, 40, 50 or 100 tablets in cans of polyethylene terephthalate for medicinal products sealed with caps screwed with a first opening control or a "push-turn" system made of polypropylene or polyethylene, or cans of polypropylene for medicinal products sealed with lids with the control of the first opening from polyethylene, or polypropylene cans for medicines, sealed with caps tightened with the control of the first opening of high pressure polyethylene.

One jar or 1, 2, 3, 4, 5 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003586

Date of registration:25.04.2016

Expiration Date:25.04.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp07.05.2017

Illustrated instructions

Instructions

Granisetron (Granisetron)