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

Active substance:
Granisetron hydrochloride	1.12 mg
in terms of granisetron	1.00 mg
Excipients:
Microcrystalline cellulose	36.00 mg
Lactose Monohydrate	57.6 mg
Pregelatinized starch	5.00 mg
Magnesium stearate	0.25 mg
Film Sheath:
Aquarius Prime VAR218010 white
[hypromellose 65%, titanium dioxide 25%, macrogol 10%]	3.00 mg

Description:

Tablets are round, biconvex, covered with a film coat of white color, two layers are visible on a cross section.The core of the tablet is white or almost white.

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 (n.vagus) and the trigger zone of the emetic center of the bottom of the IV ventricle of the brain (practically does not affect other types of serotonin receptors and D₂dopamine receptors), with pronounced antiemetic effect. Eliminates the vomiting that occurs when the parasympathetic nervous system is excited, due to the release of serotonin by enterochromaffine cells.

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

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 intervals.

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

In studies in vitro shown, that ketoconazole inhibits the metabolism of granisetron, which involves the participation of isoenzymes of the subfamily CYP3A systems of cytochrome P450.

Other studies in vitro showed that granisetron does not affect the activity of the metabolizing enzymes of the subfamily CYP3A4 systems of cytochrome P450.

Excretion

Granisetron is mainly metabolized in the liver. 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 at oral intake is 9 hours with a wide individual variability.

Concentrations of granisetron in plasma do not clearly correlate with its antiemetic effect. Therapeutic effect is observed even when granisetron is no longer found in plasma. When the dose of granisetron was increased 4-fold, the dose-dependent nature of the antiemetic effect was not detected.

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

Pharmacokinetics in specific patient groups

In patients with renal insufficiency pharmacokinetic parameters after a single intravenous dose did not differ from those in patients with normal renal function.

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

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.

In elderly patients pharmacokinetic parameters after a single intravenous dose, as a rule, correspond to the parameters of the norm of adult patients.

Indications:

Prevention of nausea and vomiting in cytostatic chemotherapy in adults, as well as the prevention and treatment of nausea and vomiting in 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 of serotonin 5-HT₃ receptors in the anamnesis;

- breastfeeding (there is no data on efficacy and safety when using the drug during breastfeeding);

- Children under 12 years of age (no data on efficacy and safety when using the drug in children under 12 years of age).

Carefully:

Care should be taken when prescribing Granisetron-TL for patients with:

- with partial intestinal obstruction, with liver diseases;

- with hereditary intolerance to galactose, with lactase deficiency of Lappa, with glucose-galactose malabsorption;

- concomitant diseases of the heart, especially with arrhythmia in the syndrome of elongated QT-Interval;

- with cardiotoxic chemotherapy and / or concomitant disorders of electrolyte balance.

Pregnancy and lactation:

The safety of treatment with granisetron during pregnancy is not established, so the application is only possible in cases where the intended benefit to the mother exceeds the potential risk to the fetus.

For the duration of treatment, breastfeeding should be discontinued (no data on penetration into breast milk).

Dosing and Administration:

Tablets should be swallowed whole, washed down with water

Standard dosing regimen

Cytostatic chemotherapy (prevention and treatment)

Inside 1 mg 2 times a day or 2 mg 1 time per day no more than 7 days after the start of cytostatic therapy. The first dose should be taken 1 hour before the start of cytostatic therapy. To enhance the action of granisetron simultaneously orally used dexamethasone in doses up to 20 mg once a day.

Radiation therapy (prevention and treatment)

Inside 2 mg 1 time per day no more than 7 days after the start of radiation therapy; The first dose should be taken 1 hour before the start of radiotherapy.

Special dosing regimen

Children

Granisetron-TL tablets are not recommended for use in children under 12 years of age, since there is insufficient data to establish the optimal dosing regimen for this age group. For the prevention and treatment of nausea and vomiting in the conduct of cytostatic therapy in children, it is necessary to use another dosage form of the drug - concentrate for the preparation of a solution for infusions.

Elderly age and kidney failure

Special precautions for therapy in elderly patients or patients with renal failure are not provided.

Liver failure

There is no evidence of an increased incidence of adverse events in patients with liver disease. But given the pharmacokinetics data in this group of patients, granisetron should be used with a certain degree of caution, if necessary, adjust the dose of the drug.

Side effects:

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

The most common side effects with granisetron are headache, constipation, temporary ECG changes, including elongation QT interval. Rare and sometimes severe cases of hypersensitivity (for example, anaphylaxis) are noted.

The frequency of adverse reactions listed below was determined by the following criteria: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000), very rarely (<1/10000).

From the immune system
Rarely	Hypersensitivity reactions, such as skin rash, hyperthermia, bronchospasm, urticaria, pruritus
From the nervous system
Often	Headache
Often	Insomnia, drowsiness, anxiety, anxiety, dizziness,weakness, serotonin syndrome (including changes in mental state, autonomic dysfunction and disorders of the nervous and muscular systems)
Rarely	Extrapyramidal disorders
From the side of the cardiovascular system
Rarely	Elongation QT interval, arrhythmia, chest pain, decrease or increase in blood pressure. As with the use of other antagonists of serotonin 5-HT₃-receptors, granisetron therapy reported cases of changes in ECG parameters, including cases of prolongation of the QT interval. 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
Often	Abdominal pain, constipation
Often	Diarrhea, flatulence, increased activity of "hepatic" transaminases [alanine aminotransferase (ALT) and aminotransferase (ACT)] usually within their normal values
Rarely	Dyspepsia, heartburn, changes in taste
From the skin and subcutaneous tissues
Rarely	Skin rash, swelling, including face
From the body as a whole
Rarely	Flu-like syndrome, including fever and chills

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

Overdose:

Symptoms: slight headache is possible. There is no specific antidote for granisetron.

Treatment: symptomatic.

Interaction:

Granisetron does not affect isoenzyme activity CYP3A4 (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.

Study in vitro showed that ketoconazole inhibits the metabolism of granisetron, which involves the participation of isoenzyme CYP3A systems of cytochrome P450.

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

When induction of hepatic enzymes phenobarbital an increase in the clearance of granisetron (with intravenous injection) was observed approximately by a quarter.

There was no interaction with simultaneous use with benzodiazepines (for example, lorazepam), neuroleptics (for example, haloperidol), tranquilizers, antiulcer drugs from the blocker group H₂-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 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 granisetron administration should be under the supervision of a physician, since granisetron can reduce bowel motility.

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

As with the application of other 5-HT₃ antagonists (for example ondansetron), when granisetron therapy was 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 of serotonin 5-HT₃receptors.

Patients with a rare hereditary intolerance to galactose, lactase deficiency, or impaired glucose-galactose absorption should not be taken.

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.

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:Tablets, film-coated, 1 mg.

Packaging:

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

For 30 tablets in a can of polymer for medicines or a bottle for medicines made of plastic.

Free space in the jar, bottle is filled with cotton wool hygroscopic. Each jar, bottle,1 or 3 contour mesh packages together with the instruction for use are placed in a pack of cardboard box.

Storage conditions:

In a dry, 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-002741

Date of registration:02.12.2014 / 22.07.2016

Expiration Date:02.12.2019

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-TL (Granisetrone-TL)