Granisetron (Pf) (granisetron HCl/PF)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Granisetron, a selective, first-generation inhibitor of type 3 serotonergic (5-HT3) receptors, is an antiemetic.
Granisetron hydrochloride, a selective inhibitor of type 3 serotonergic (5-HT3) receptors, is an antiemetic. The antiemetic activity of granisetron appears to be mediated both centrally and peripherally via inhibition of 5-HT3 receptors. Current evidence indicates that 5-HT3 receptors play a major role in acute emesis, but only a minor role in delayed nausea and vomiting.
The role of serotonin as a mediator of acute chemotherapy (e.g., cisplatin)-induced emesis has been strongly suggested by the temporal relationship between the emetogenic action of such drugs and the release (e.g., from GI enterochromaffin cells) of serotonin (e.g., as reflected by increases in plasma and urine concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA)) as well as by the clinical efficacy of antiemetic agents that act as inhibitors of 5-HT3 receptors (e.g., granisetron, metoclopramide, ondansetron). Studies in animals have shown that such chemotherapy-induced emesis can be prevented completely by ablation of the area postrema (the locus of the chemoreceptor trigger zone (CTZ)) or depletion of serotonin from this area; in addition, high levels of 5-HT3 receptors have been demonstrated in this area, and direct injection of 5-HT3 receptor antagonists into the area postrema also can prevent such chemotherapy-induced emesis. Therefore, current evidence suggests that the emetogenic action of such chemotherapy may be initiated by degenerative changes in the GI tract (e.g., small intestine) induced by these drugs and associated increases in endogenous serotonin release; serotonin then stimulates vagal and splanchnic nerve receptors that project to the medullary vomiting (emetic) center of the brain and also appears to stimulate 5-HT3 receptors in the area postrema.
Thus, 5-HT3 receptor antagonists appear to prevent or ameliorate acute chemotherapy-induced emesis by inhibiting visceral (from the GI tract) afferent stimulation of the emetic center probably indirectly at the level of the area postrema and by directly inhibiting serotonin activity within the area postrema and CTZ.
Alternative mechanisms appear to be principally responsible for delayed nausea and vomiting induced by such chemotherapy (e.g., cisplatin), since similar temporal relationships between serotonin and emesis beyond the first day after a dose have not been established, and inhibitors of 5-HT3 receptors do not appear to be effective alone in preventing or ameliorating delayed effects.
Administration of granisetron tablets with food has a minimal effect on extent of absorption; peak plasma concentration may be increased by 30%. Following a single-dose administration of subcutaneous granisetron in healthy subjects, granisetron is released from the polymer over an extended period of time and remains detectable in plasma for 7 days post-dose. The terminal elimination half-life is approximately 24 hours.
Following a 7-day application of granisetron transdermal system in 24 healthy subjects, high inter-subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following application. Based on the measure of residual content of the transdermal system after removal, approximately 66% of granisetron is delivered following transdermal system application for 7 days.
Following a single 5-minute IV infusion of 40 mcg/kg in cancer patients, the mean terminal half-life of granisetron was 8.95 hours. In healthy volunteers after a single 1 mg oral dose, the half-life was 6.23 hours. Plasma protein binding of granisetron is approximately 65%, with free distribution between plasma and red blood cells.
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Clearance is predominantly by hepatic metabolism, likely CYP1A1 and CYP3A4. In normal volunteers, approximately 12% of the administered dose is eliminated unchanged in the urine in 48 hours.
The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.
USES: This medication is used alone or with other medications to prevent nausea and vomiting caused by cancer drug treatment (chemotherapy). It is also used to prevent and treat nausea and vomiting after surgery in adults. Granisetron works by blocking one of the body's natural substances (serotonin) that can cause vomiting.
Generic name: granisetron HCl/PF
Pronunciation: (gra-NIS-e-tron)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Granisetron (Pf)
Indications
The following indications are listed for Granisetron (Pf):
- Post-Operative Nausea And Vomiting
- Prevention Of Cancer Chemotherapy-Induced Nausea And Vomiting
- Prevention Of Post-Operative Nausea And Vomiting
Also known as: Cancer Chemotherapy-Induced N & V Prophylaxis, Post Op Nausea And Vomiting, Postop Nausea And Vomiting Prophylaxis, Postoperative Nausea And Vomiting, Postoperative Nausea And Vomiting Prophylaxis.
Dosing
Some preparations are available as granisetron hydrochloride; dosage is expressed in terms of granisetron.
Granisetron is administered orally, by IV infusion, IV injection, subcutaneous injection, and transdermally.
Granisetron is commercially available as an injection containing 1.12 mg granisetron hydrochloride per mL equivalent to 1 mg of granisetron for IV administration, as an extended-release injection containing 10 mg of granisetron/0.4 mL in pre-filled syringes for subcutaneous administration, as a transdermal system that releases 3.1 mg of granisetron per 24 hours, and as oral tablets containing 1.12 mg granisetron hydrochloride equivalent to 1 mg of granisetron.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
There is no enhanced messaging for this drug.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Known hypersensitivity to granisetron or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects reported with IV granisetron in >=3% of patients when used for prevention of CINV include headache and constipation.
The most common adverse effects reported with IV granisetron in >=2% of patients when used for PONV include pain, headache, fever, abdominal pain, and increased hepatic enzymes.
The most common adverse effects reported with subcutaneous granisetron in >=3% of patients are injection site reactions, constipation, fatigue, headache, diarrhea, abdominal pain, insomnia, dyspepsia, dizziness, asthenia, and gastroesophageal reflux.
The most common adverse effect reported with granisetron transdermal system in >=3% of patients is constipation.
The most common adverse effects reported with granisetron oral tablets in >=5% of patients when used for prevention of CINV include headache, constipation, asthenia, diarrhea, abdominal pain, and dyspepsia.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
The safety and effectiveness of IV granisetron for the prevention of chemotherapy-induced nausea and vomiting (CINV) have been established in pediatric patients 2-16 years of age. This indication is supported by evidence from a randomized clinical trial in 80 pediatric patients 2-16 years of age who received a single IV dose of granisetron 10, 20, or 40 mcg/kg with a complete response in 21, 31, and 32% of patients, respectively. Another study of 88 pediatric patients compared IV granisetron 20 mcg/kg to chlorpromazine plus dexamethasone for prevention of CINV, which demonstrated a complete response in 22% of granisetron-treated patients compared to 10% among patients administered the chlorpromazine regimen.
Safety and efficacy of IV granisetron have not been established in pediatric patients younger than 2 years of age for the prevention of CINV.
Safety and efficacy of IV granisetron have not been established in pediatric patients for the prevention of postoperative nausea and vomiting (PONV). The manufacturer does not recommend its use due to the lack of efficacy and QT prolongation observed in a pediatric clinical trial.
Safety and efficacy of granisetron oral tablets, subcutaneous injection, and transdermal system have not been in established in pediatric patients.
There are no available clinical data regarding the use of granisetron in pregnant women to assess potential drug-related risks.
In animal studies, no evidence of impaired fertility or fetal harm was observed when pregnant rats received IV doses of granisetron up to 9 mg/kg per day (equivalent to 146 times the recommended human dose based on body surface area (BSA)), or when pregnant rabbits were given IV doses up to 3 mg/kg per day (96 times the human dose based on BSA). Similarly, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron during organogenesis at IV doses up to 61 and 41 times, respectively, the maximum recommended human dose (MRHD) of subcutaneous granisetron 10 mg/week and at IV doses up to 24 times and 16 times, respectively, the MRHD delivered by the granisetron transdermal system based on BSA. No evidence of impaired fertility or fetal harm was observed when pregnant rats received oral doses of granisetron up to 125 mg/kg per day (equivalent to 507 times the recommended human dose based on BSA), or when pregnant rabbits were given oral doses up to 32 mg/kg per day (255 times the human dose based on BSA).
Use granisetron during pregnancy only when clearly needed.
It is not known whether granisetron is distributed into human milk; its effects on milk production or on the breast-fed infant are also unknown.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug in addition to any possible adverse effects on the nursing infant from the drug or underlying maternal condition. Use with caution when administered during lactation.
The manufacturers makes no recommendations for dosage adjustment in geriatric patients.
In CINV clinical trials, 713 patients receiving IV granisetron were >=65 years of age; safety and effectiveness of the drug were similar in patients of various ages. Amongpatients who received IV granisetron in PONV clinical trials, 168 patients were >=65 years of age, of which 47 were >=75 years of age. Clinical studies of IV granisetron did not include sufficient numbers of subjects >=65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients.
Among patients receiving granisetron tablets in clinical trials, 325 were >=65 years of age,298 were 65-74 years of age, and 27 were >=75 years of age. Efficacy and safety were maintained with increasing age.
Among the 738 patients receiving subcutaneous granisetron in clinical trials, 177 (24%) were >=65 years of age and 39 (5%) were >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Clinical studies of granisetron transdermal system did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. In general, select dosage with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Pharmacokinetic parameters in geriatric patients were generally similar to younger patients.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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