Granisetron

Granisetron is a Selective 5-HT₃ Receptor Antagonist belonging to Antiemetic agent.

Granisetron is a 5HT3 antagonist used to treat nausea and vomiting in cancer therapy and postoperatively.

Absorption of Granisetron is rapid and complete, though oral bioavailability is reduced to about 60% because of first pass metabolism. Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells. Granisetron hepatically metabolized via N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity.

Granisetron shows side effects like Headache, tiredness, heartburn, chills, less frequent urination.

Granisetron is available in the Oral tablet, Injectable solution, and Transdermal Film.

Granisetron is available in India, US, Spain, Canada, China, UK, Malaysia, Australia, and Italy.

Granisetron belongs to the Antiemetic agent acts as a Selective 5-HT₃ Receptor Antagonist.

Granisetron is a potent, selective antagonist of 5-HT₃ receptors. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone.

The Onset of action of Granisetron is about 1-3 minutes.

The Duration of action of Granisetron is 24 hours (via oral and IV) and about 7 days (via subcutaneous route).

The Tmax of Granisetron is via subcutaneous route is about 24 hours and via transdermal route is about 48 hours.

Granisetron is an antiemetic drug used to prevent nausea and vomiting caused by chemotherapy, radiation therapy as well as nausea and vomiting associated with surgeries. This medicine is not recommended for use in patients less than 2 years of age.

Granisetron is approved for use in the following clinical indications

• Nausea and vomiting associated with cancer chemotherapy
• Prophylaxis of nausea and vomiting associated with radiation therapy
• Treatment and prophylaxis of postoperative nausea and vomiting

• Nausea and vomiting associated with cancer chemotherapy

Adult Oral Dose: 1-2 mg within 1 hour prior to start of chemotherapy, then 2 mg daily as a single or in 2 divided doses for up to 1 week after chemotherapy. Max: 9 mg daily.

• Prophylaxis of nausea and vomiting associated with radiation therapy
• Adult Oral Dose: 2 mg once daily within 1 hours of irradiation.

• Nausea and vomiting associated with cancer chemotherapy

Adult IV Dose: 1-3 mg 5 min prior to start of chemotherapy, by infusion over 5 min or by bolus injection over at least 30 sec. Further doses may be given at least 10 min apart. Max: 9 mg daily.

Child IV Dose: 2–16-year 10-40 mcg/kg (max: 3,000 mcg) by infusion over 5 min to be given prior to start of chemotherapy. An additional dose may be given w/in 24 hours, at least 10 min after the 1st infusion.

• Treatment and prophylaxis of postoperative nausea and vomiting
• Adult IV Dose: 1 mg over 30 sec, to be given before induction of anaesth. May be repeated up to max of 3 mg in 24 hours.

• Prophylaxis of nausea and vomiting associated with radiation therapy

Adult IV Dose: 1-3 mg 5 min prior to start of radiotherapy, by infusion over 5 min or by bolus injection over at least 30 sec. Further doses may be given at least 10 min apart. Max: 9 mg daily.

• Nausea and vomiting associated with cancer chemotherapy

Adult Transdermal Dose: As patch releasing 3.1 mg/24 hours: Apply 1 patch at the upper arm 24-48 hours prior to chemotherapy; remove at least 24 hours after the end of chemotherapy. May be worn for up to 7 days depending on the duration of the chemotherapy regimen.

Granisetron is available in various strengths as 2 mg/10 ml; 1 mg/ml; 1 mg; 0.1 mg/ml; 3.1 mg/24 hours; 10 mg/0.4 ml.

Granisetron is available in the Oral tablet, Injectable solution, and Transdermal Film.

Granisetron is contraindicated in patients with

• Granisetron hydrochloride tablets are contraindicated in patients with known hypersensitivity to the drug or any of its components.

• Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagoinist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of granisetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue granisetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if granisetron is used concomitantly with other serotonergic drugs.

• Granisetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.
• An adequate QT assessment has not been conducted, but QT prolongation has been reported with granisetron hydrochloride. Therefore, granisetron hydrochloride should be used with caution in patients with preexisting arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when granisetron hydrochloride is administered to a nursing woman.

Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Common

Headache, insomnia, constipation, diarrhoea, elevated hepatic transaminases, QT prolongation, bradycardia, palpitations, sick sinus syndrome, chest pain. Application site reactions (transdermal), Rash, pain, erythema, pruritus, irritation, burn, vesicles, urticaria, discoloration.

• Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron in vitro.
• In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron. The clinical significance of this change is not known.
• QT prolongation has been reported with granisetron hydrochloride. Use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may result in clinical consequences. Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs).

The common side effects of Granisetron include the following

Common side effects

● Headache, tiredness, heartburn, chills, less frequent urination.

Rare side effects

● Hives, rash, itching, difficulty breathing or swallowing, chest pain, swelling of the face, changes in heartbeat or heart rhythm, dizziness or light-headedness, fainting, fast, slow or irregular heartbeat, agitation, confusion, nausea, vomiting, and diarrhoea, loss of coordination, stiff or twitching muscles, seizures, coma (loss of consciousness).

• Pregnancy

Pregnancy Category B

Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when granisetron hydrochloride is administered to a nursing woman.

• Pediatric Use

As per FDA, the safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

During clinical trials, 325 patients 65 years of age or older received granisetron hydrochloride tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.

There is no specific treatment for Granisetron hydrochloride overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of Granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

Pharmacodynamic

Granisetron is a selective inhibitor of type 3 serotonergic (5-HT₃) receptors. Granisetron has little or no affinity for other serotonin receptors, including 5-HT 1 , 5-HT 1A , 5-HT 1B/C , or 5-HT 2 ; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine D 2 receptors; for histamine H 1 receptors; for benzodiazepine receptors; for picrotoxin receptors; or for opioid receptors. In most human studies, granisetron has had little effect on blood pressure, heart rate, or electrocardiogram (ECG). The drug is structurally and pharmacologically related to ondansetron, another selective inhibitor of 5-HT₃ receptors. The serontonin 5-HT₃ receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.

Pharmacokinetics

• Absorption

Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% because of first pass metabolism.

• Distribution

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

• Metabolism and Excretion

Granisetron hepatically metabolized via N -demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020239s023lbl.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/078080Orig1s005lbl.pdf
• https://medlineplus.gov/druginfo/meds/a601211.html
• https://reference.medscape.com/drug/sustol-sancuso-granisetron-342050
• https://www.rxlist.com/kytril-drug.htm#warnings
• https://www.drugs.com/dosage/granisetron.html
• https://go.drugbank.com/drugs/DB00889
• https://www.mims.com/india/drug/info/granisetron?type=full&mtype=generic
• https://www.practo.com/medicine-info/granisetron-1588-api