Granisetron Hydrochloride Tablets USP 1mg Taj Pharma

This information is intended for use by health professionals

  1. Name of the medicinal product

Granisetron Hydrochloride Tablets USP 1 mg Taj Pharma
Granisetron Hydrochloride Tablets USP 2 mg Taj Pharma

  1. Qualitative and quantitative composition

a) Each film coated tablet contains:
Granisetron Hydrochloride USP 1.12 mg
Equivalent to Granisetron 1 mg
Excipients: Q.S.

b) Granisetron Hydrochloride Tablets USP 2 mg (Taj Pharma)
Each film coated tablet contains:

Granisetron Hydrochloride USP 2.24 mg
Equivalent to Granisetron 2 mg
Excipients: Q.S.

Excipient with known effect:

Each tablet contains 55.78 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet.

White to off-white tablet embossed “GS” on one side and plain on the reverse

  1. Clinical particulars

4.1 Therapeutic indications

Granisetron tablets are indicated in adults for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy.

Granisetron tablets are indicated in adults for prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.

4.2 Posology and method of administration

Posology

1 mg twice a day or 2 mg once a day for up to one week following radiotherapy or chemotherapy. The first dose of granisetron should be administered within one hour before the start of therapy.

Dexamethasone has been used concomitantly at doses up to 20 mg once a day orally.

Maximum Dose and Duration of Treatment

Granisetron is also available as ampoules for intravenous administration. The maximum dose of granisetron administered orally and/or intravenously over 24 hours should not exceed 9 mg.

Paediatric population

The safety and efficacy of granisetron tablets in children have not yet been established. No data are available.

Older people and renal impairment

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

The tablets should be swallowed whole with water.

4.3 Contraindications

Granisetron is contra-indicated in patients hypersensitive to the active substance or to 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 administration of granisetron.

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.

Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Granisetron is essentially ‘sodium free’ as it contains less than 1 mmol sodium (23 mg) per dose (2 mg). To be used with caution in children or in patients on a low sodium diet.

Paediatric population

There is insufficient clinical evidence to recommend administration of these tablets to children.

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 measureit 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.

Frequency categories are as follows:

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)

Very rare (<1/10,000)

Immune system disorders
Uncommon Hypersensitivity reactions e.g. anaphylaxis, urticaria
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Headache
Uncommon Extrapyramidal Reactions
Uncommon Serotonin Syndrome (see also sections 4.4 and 4.5)
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).

As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction and neuromuscular abnormalities) have been reported following the concomitant use of granisetron and other serotonergic drugs (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.

4.9 Overdose

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

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT3) antagonists. 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 cytotoxic 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. Radio-ligand 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 orally has been shown to prevent nausea and vomiting associated with cancer chemotherapy in adults.

Post-operative nausea and vomiting

Granisetron administered orally 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 450-cytochrome 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).

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 programme 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 symptoms control.

Absorption

Absorption of granisetron is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. Oral bioavailability is generally not influenced by food.

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 N-desmethyl 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 whilst that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients is approximately 9 hours, with a wide inter-subject variability.

Pharmacokinetics in special populations

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 neoplastic 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).

Paediatric population

These tablets are not recommended in children.

Older people

In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.

5.3 Preclinical safety data

Preclinical 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 depolarization and repolarization 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.

  1. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Lactose Monohydrate

Cellulose, Microcrystalline

Hypromellose

Sodium Starch Glycolate (type A)

Magnesium Stearate

Film coat:

Titanium Dioxide

Hypromellose

Macrogol 400

Polysorbate 80

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

This product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC aluminium foil opaque blisters in a cardboard carton and HDPE bottle with PE cap containing 1,2,4,5,6,7,10,14,20,28,30,50,90,100,150,200,250 and 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED

At SURVEY NO.188/1 TO 189/1,190/1 TO 4,

ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

Package leaflet: Information for the user
Granisetron Hydrochloride Tablets USP 1 mg (Taj Pharma)
Granisetron Hydrochloride Tablets USP 2 mg (Taj Pharma)

Film-coated tablets

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
  • If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any
  • possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Granisetron is and what it is used for
  2. What you need to know before you take Granisetron
  3. How to take Granisetron
  4. Possible side effects
  5. How to store Granisetron
  6. Contents of the pack and information
  7. What Granisetron is and what it is used for

Granisetron belongs to a group of medicines known as ‘5-HT3 receptor antagonists’ or anti-emetics or anti-sickness medicines. These tablets are only for use in adults. It is used to prevent or treat nausea (feeling sick) and vomiting (being sick) caused by other medical treatments, such as chemotherapy or radiation treatment for cancer.

  1. What you need to know before you take Granisetron

Do not take granisetron

  • if you are allergic (hypersensitive) to granisetron or any of the other ingredients of this medicine (listed in section 6). If you are not sure, talk to your doctor, nurse or pharmacist before taking these tablets.

Warnings and precautions

Talk to your doctor, nurse or pharmacist before using these tablets, especially if you:

  • have a blockage in the intestine (gut) causing symptoms such as stomach ache, wind, feeling or being sick, or difficulty passing stools.
  • have heart problems, are being treated for cancer with a medicine that is known to damage your heart or have problems with levels of salts, such as potassium, sodium or calcium, in your body (electrolyte abnormalities)
  • are taking other ‘5-HT3 receptor antagonist’ medicines. These include dolasetron, ondansetron used like granisetron in the treatment and prevention of nausea and vomiting.

Serotonin Syndrome is an uncommon but potentially life-threatening reaction that can occur with granisetron (see section 4). It can cause serious changes in how your brain, muscles, and digestive system work. The reaction can occur if you take granisetron alone but is more likely to occur if you take granisetron with certain other medicines (in particular fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram,  escitalopram, venlafaxine, duloxetine). Be sure to tell your doctor, nurse or pharmacist all the medicines you are taking.

Children

Children should not take these tablets.

Other medicines and granisetron

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

This is because granisetron can affect the way some medicines work. Also some other medicines can affect the way these tablets work.

In particular, tell your doctor or pharmacist if you are taking the following medicines:

  • medicines used to treat an irregular heartbeat, other ‘5-HT3 receptor antagonist’ medicines such as dolasetron or ondansetron (see “Warnings and precautions” above)
  • SSRIs (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety.Examples are fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram
  • SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety.

Examples are venlafaxine, duloxetine.

Pregnancy and breast-feeding

You should not take these tablets if you are pregnant, trying to get pregnant or are breast-feeding unless your doctor has told you to.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor, nurse or pharmacist for advice before taking this medicine.

Driving and using machines

Granisetron should not affect your ability to drive or operate machinery.

Granisetron tablets contain lactose

This medicine contains lactose (a type of sugar). If your doctor has told you that you have an intolerance to some sugars, such as lactose, contact your doctor before taking this medicine.

Granisetron is essentially ‘sodium free’ as it contains less than 1 mmol sodium (23 mg) per dose (2 mg).

  1. How to take Granisetron

Always take Granisetron exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Swallow the tablets with a glass of water.

The recommended dose of granisetron varies from one patient to another. It depends on your age, weight, and whether you are being given the medicine to prevent, or treat, nausea and vomiting. The doctor will work out how much to give you.

Prevention of feeling or being sick

Your first dose of granisetron will usually be given an hour before your radio- or chemotherapy. The dose will be either one or two 1 mg tablets or one 2 mg tablet once a day for up to a week after your radio- or chemotherapy.

Treatment of feeling or being sick

The dose will usually be either one or two 1 mg tablets or one 2 mg tablet once a day, but your doctor may decide to increase your dose to upto nine 1 mg tablets a day.

Your doctor may also give you another medicine called dexamethasone to take as well.

Children

Granisetron is not suitable for children.

If you take more Granisetron than you should

Contact your doctor or go to the nearest hospital casualty department immediately. Take the container and any remaining tablets with you. The symptoms of overdose include mild headaches. You will be treated depending on your symptoms.

If you forget to take Granisetron

If you think you have forgotten to take your medicine speak to your doctor or nurse.Do not take two doses together to make up for the one you have missed.

If you stop taking Granisetron

Do not stop taking your medicine before the treatment is finished. If you do stop taking your medicine, your symptoms may return. Speak to your doctor first if you wish to stop taking this medicine.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice the following problem you must see a doctor straight away:

  • Allergic reactions (anaphylaxis). The signs may include swelling of the throat, face, lips and mouth, difficulty in breathing or swallowing.

Other side effects that may be experienced while taking this medicine are:

Very common: may affect more than 1 in 10 people

  • Headache
  • Your doctor will monitor your condition.
  • Common: may affect up to 1 to 10 people
  • Problems sleeping (insomnia)
  • Changes in how your liver is working shown by blood tests

Uncommon: may affect up to 1 in 100 people

 Skin rashes or an allergic skin reaction or “nettle-rash” or “hives” (urticaria). The signs may include red, raised itchy bumps

 Changes in the heartbeat (rhythm) and changes seen on ECG readings (electrical recordings of the heart)

 Abnormal involuntary movements, such as shaking, muscle rigidity and muscle contractions.

 Serotonin Syndrome. The signs may include diarrheoa, nausea, vomiting, high temperature and blood pressure, excessive sweating and rapid heartbeat, agitation, confusion, hallucination, shivering, muscles shakes, jerks or stiffness, loss of coordination and restlessness.

Reporting of side effects

If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store granisetron

Keep this medicine out of the sight and reach of children.

Do not use Granisetron after the expiry date which is stated on the carton or label after EXP. The expiry date refers to the last day of that month.

There are no special storage conditions for this medicine.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

  1. Contents of the pack and other information

What Granisetron contains

 The active substance is 1 mg of granisetron, as hydrochloride.

 The other ingredients are lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, titanium dioxide (E171), macrogol and polysorbate.

What Granisetron looks like and contents of the pack

Granisetron is available in plastic bottles or blister packs of 1, 2, 4, 5, 6, 7, 10, 14, 20, 28, 30, 50, 90, 100, 150, 200, 250 and 500 tablets.

Not all pack sizes may be marketed.

Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED

At SURVEY NO.188/1 TO 189/1,190/1 TO 4,

ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

 

 

Related Products

Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.