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Granisetron

Pronunciation

(gra NI se tron)

Index Terms

  • BRL 43694
  • Granisetron HCl
  • Granisetron Hydrochloride
  • Granisol
  • Kytril
  • Sustol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Patch, Transdermal:

Sancuso: 3.1 mg/24 hr (1 ea)

Solution, Intravenous:

Generic: 0.1 mg/mL (1 mL); 1 mg/mL (1 mL); 4 mg/4 mL (4 mL)

Solution, Intravenous [preservative free]:

Generic: 0.1 mg/mL (1 mL); 1 mg/mL (1 mL)

Solution, Oral:

Granisol: 2 mg/10 mL (30 mL [DSC]) [contains fd&c yellow #6 (sunset yellow), sodium benzoate; orange flavor]

Tablet, Oral:

Generic: 1 mg

Brand Names: U.S.

  • Granisol [DSC]
  • Sancuso

Pharmacologic Category

  • Antiemetic
  • Selective 5-HT3 Receptor Antagonist

Pharmacology

Selective 5-HT3-receptor antagonist, blocking serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone

Absorption

Oral: Tablets and oral solution are bioequivalent; Transdermal patch: ~66% over 7 days

Distribution

Vd: 2 to 4 L/kg; widely throughout body

Metabolism

Hepatic via N-demethylation, oxidation, and conjugation; some metabolites may have 5-HT3 antagonist activity

Excretion

Urine (11% to 12% as unchanged drug, 48% to 49% as metabolites); feces (34% to 38% as metabolites)

Onset of Action

IV: 1-3 minutes

Time to Peak

Transdermal patch: Maximum systemic concentrations: ~48 hours after application (range: 24 to 168 hours)

Duration of Action

Oral, IV: Generally up to 24 hours

Half-Life Elimination

Oral: 6 hours; IV: Mean range: 5 to 9 hours

Protein Binding

~65%

Special Populations: Hepatic Function Impairment

Total Cl decreased by about 50%.

Special Populations: Elderly

Mean values were lower for Cl and longer for half-life.

Special Populations: Gender

Men had a higher Cmax, but there was no difference in AUC.

Use: Labeled Indications

Chemotherapy-associated nausea and vomiting: Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin (injection and tablets); prevention of nausea and vomiting associated with moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days of duration (transdermal).

Radiation-associated nausea and vomiting: Prevention of nausea and vomiting associated with radiation therapy, including total body radiation and fractionated abdominal radiation (tablets).

Use: Unlabeled

Management of breakthrough treatment of nausea and vomiting associated with chemotherapy; prevention of postoperative nausea and vomiting (PONV)

Contraindications

Hypersensitivity to granisetron or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Concomitant use with apomorphine

Dosing: Adult

Note: Granisol oral solution has been discontinued in the US for more than 1 year.

Prevention of chemotherapy-associated nausea and vomiting:

Oral: 2 mg once daily up to 1 hour before chemotherapy or 1 mg twice daily; the first 1 mg dose should be given up to 1 hour before chemotherapy (with the second 1 mg dose 12 hours later). Administer only on the day(s) chemotherapy is given.

IV: 10 mcg/kg 30 minutes prior to chemotherapy; only on the day(s) chemotherapy is given.

Transdermal patch: Prophylaxis of chemotherapy-related emesis: Apply 1 patch at least 24 hours prior to chemotherapy; may be applied up to 48 hours before chemotherapy. Remove patch a minimum of 24 hours after chemotherapy completion. Maximum duration: Patch may be worn up to 7 days, depending on chemotherapy regimen duration.

Adult guideline recommendations:

American Society of Clinical Oncology (ASCO; Basch 2011): High emetic risk:

IV: 1 mg or 10 mcg/kg on the day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone and aprepitant or fosaprepitant)

Oral: 2 mg on the day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone and aprepitant or fosaprepitant)

Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) (Roila 2010):

Highly emetic chemotherapy:

IV: 1 mg or 10 mcg/kg (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant) prior to chemotherapy on day 1

Oral: 2 mg (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant) prior to chemotherapy on day 1

Moderately emetic chemotherapy:

IV: 1 mg or 10 mcg/kg (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant for AC chemotherapy regimen]) prior to chemotherapy on day 1

Oral: 2 mg (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant for AC chemotherapy regimen]) prior to chemotherapy on day 1

Low emetic risk:

IV: 1 mg or 10 mcg/kg prior to chemotherapy on day 1

Oral: 2 mg prior to chemotherapy on day 1

Prophylaxis of radiation therapy-associated emesis: Oral: 2 mg once daily within 1 hour of radiation therapy.

Prevention of postoperative nausea and vomiting (off-label use): IV: 0.35 to 3 mg (5 to 20 mcg/kg) administered at the end of surgery (Gan 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Granisol oral solution has been discontinued in the US for more than 1 year.

Prevention of chemotherapy-associated nausea and vomiting: Children ≥2 years and Adolescents: IV: 10 mcg/kg 30 minutes prior to chemotherapy; only on the day(s) chemotherapy is given.

Pediatric guideline recommendations:

Prevention of chemotherapy-induced nausea and vomiting (off-label dosing; Dupuis 2013):

Highly emetogenic chemotherapy: Infants ≥1 month and Children <12 years: IV: 40 mcg/kg as a single daily dose prior to chemotherapy. Antiemetic regimen also includes dexamethasone.

Highly emetogenic chemotherapy: Children ≥12 years and Adolescents: IV: 40 mcg/kg as a single daily dose prior to chemotherapy. Antiemetic regimen includes dexamethasone and (if no known or suspected drug interactions) aprepitant.

Moderately emetogenic chemotherapy: Infants ≥1 month, Children, and Adolescents:

IV: 40 mcg/kg as a single daily dose. Antiemetic regimen also includes dexamethasone

Oral: 40 mcg/kg every 12 hours. Antiemetic regimen also includes dexamethasone

Low emetogenic chemotherapy: Infants ≥1 month, Children, and Adolescents:

IV: 40 mcg/kg as a single daily dose.

Oral: 40 mcg/kg every 12 hours.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Kinetic studies in patients with hepatic impairment showed that total clearance was approximately halved; however, standard doses were very well tolerated, and dose adjustments are not necessary.

Reconstitution

IV: May be given undiluted or may be further diluted in NS or D5W.

Extemporaneously Prepared

Note: Commercial oral solution is available (0.2 mg/mL)

A 0.2 mg/mL oral suspension may be made with tablets. Crush twelve 1 mg tablets in a mortar and reduce to a fine powder. Add 30 mL distilled water, mix well, and transfer to a bottle. Rinse the mortar with 10 mL cherry syrup and add to bottle. Add sufficient quantity of cherry syrup to make a final volume of 60 mL. Label “shake well”. Stable 14 days at room temperature or refrigerated (Quercia 1997).

A 50 mcg/mL oral suspension may be made with tablets and one of three different vehicles (Ora-Sweet®, Ora-Plus®, or a mixture of methylcellulose 1% and Simple Syrup, N.F.). Crush one 1 mg tablet in a mortar and reduce to a fine powder. Add 20 mL of the chosen vehicle and mix to a uniform paste; transfer to a calibrated bottle. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (Nahata 1998).

Nahata MC, Morosco RS, and Hipple TF, "Stability of Granisetron Hydrochloride in Two Oral Suspensions," Am J Health Syst Pharm, 1998, 55(23):2511-3.9853637Quercia RA, Zhang J, Fan C, et al, "Stability of Granisetron Hydrochloride in an Extemporaneously Prepared Oral Liquid," Am J Health Syst Pharm, 1997, 54(12):1404-6.9194985

Administration

Oral: Doses should be given up to 1 hour prior to initiation of chemotherapy/radiation

IV: Administer IV push over 30 seconds or as a 5-minute infusion

Transdermal (Sancuso): Apply patch to clean, dry, intact skin on upper outer arm. Do not use on red, irritated, or damaged skin. Remove patch from pouch immediately before application. Do not cut patch. Cover patch application site with clothing to protect from natural or artificial sunlight exposure while patch is applied and for 10 days following removal; granisetron may potentially be affected by natural or artificial sunlight. Do not apply heat (eg, heating pad) over or in area of the transdermal patch; avoid prolonged exposure to heat (may increase plasma concentrations).

Compatibility

Stable in D51/2NS, D5NS, D5W, NS, bacteriostatic water.

Y-site administration: Incompatible with amphotericin B.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

IV: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Do not freeze vials. Stable when mixed in NS or D5W for at least 24 hours at room temperature.

Oral: Store tablet or oral solution at 15°C to 30°C (59°F to 86°F). Protect from light.

Transdermal patch: Store at 20°C to 25°C (68°F to 77°F). Keep patch in original packaging until immediately prior to use.

Drug Interactions

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Panobinostat: Granisetron may enhance the arrhythmogenic effect of Panobinostat. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Serotonin Modulators: Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Tapentadol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of Tapentadol. Monitor therapy

TraMADol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of TraMADol. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (oral and IV: 3% to 21%; transdermal: <1%)

Gastrointestinal: Nausea (20%), constipation (oral and IV: 3% to 18%; transdermal: 5%), vomiting (12%)

Neuromuscular & skeletal: Weakness (oral: 14% to 18%; IV: 5%)

1% to 10%:

Cardiovascular: Prolonged Q-T interval on ECG (1% to 3%; >450 milliseconds, not associated with any arrhythmias), hypertension (oral and IV: 1% to 2%)

Central nervous system: Dizziness (5%), insomnia (oral and IV: ≤5%), drowsiness (1% to 4%), anxiety (oral and IV: ≤2%), agitation (IV: <2%), central nervous system stimulation (IV: <2%)

Dermatologic: Alopecia (3%), skin rash (IV: 1%)

Gastrointestinal: Diarrhea (oral and IV: 4% to 9%), decreased appetite (6%), dyspepsia (oral: 6%), abdominal pain (4% to 6%), dysgeusia (IV: 2%)

Hematologic & oncologic: Leukopenia (9%), anemia (4%), thrombocytopenia (2%)

Hepatic: Increased serum ALT (>2 x ULN: 3% to 6%), increased serum AST (>2 x ULN: 3% to 5%)

Miscellaneous: Fever (3% to 9%)

<1% (Limited to important or life-threatening): Angina pectoris, application site reaction (transdermal: including allergic rash, burn, discoloration, erythema, erythematous rash, irritation, macular rash, pain, papular rash, pruritus, urticaria, vesicles), atrial fibrillation, atrioventricular block (IV), bradycardia, cardiac arrhythmia, chest pain, ECG abnormality (IV), extrapyramidal reaction (oral), hypersensitivity reaction (includes anaphylaxis, dyspnea, hypotension, urticaria), hypotension, palpitations, serotonin syndrome, sick sinus syndrome, sinus bradycardia (IV), syncope, ventricular ectopy (IV; includes non-sustained tachycardia)

Warnings/Precautions

Concerns related to adverse effects:

• Allergic reactions: Use with caution in patients allergic to other 5-HT3 receptor antagonists; cross-reactivity has been reported.

• ECG effects: Selective 5-HT3 antagonists, including granisetron, have been associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT), usually occurring 1 to 2 hours after IV administration. In general, these changes are not clinically relevant, however, when used in conjunction with other agents that prolong these intervals, arrhythmia may occur. When used with agents that prolong the QT interval (eg, Class I and III antiarrhythmics), clinically relevant QT interval prolongation may occur resulting in torsade de pointes. A number of trials have shown that 5-HT3 antagonists produce QT interval prolongation to variable degrees. Use with caution in patients at risk of QT prolongation and/or ventricular arrhythmia. Reduction in heart rate may also occur with the 5-HT3 antagonists. IV formulations of 5-HT3 antagonists have more association with ECG interval changes, compared to oral formulations.

• Serotonin syndrome: Serotonin syndrome has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT3 receptor antagonist have occurred in a postanesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of another 5-HT3 receptor antagonist. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonist treatment and begin supportive management.

Disease-related concerns:

• Long QT syndrome: Use with caution in patients with congenital long QT syndrome or other risk factors for QT prolongation (eg, medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], and cumulative high-dose anthracycline therapy).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

• Transdermal patch: Do not apply to red, irritated, or damaged skin. Application-site reactions have occurred with use; local reactions were generally mild and did not require discontinuation. If skin reaction is severe or generalized (allergic rash including erythematous, macular, or papular rash or pruritus), remove patch. Cover patch application site with clothing to protect from natural or artificial sunlight exposure while patch is applied and for 10 days following removal; granisetron may potentially be affected by natural or artificial sunlight. Do not apply heat (eg, heating pad) over or in area of the transdermal patch; avoid prolonged exposure to heat (may increase plasma concentrations).

Other warnings/precautions:

• Chemotherapy-associated emesis: Antiemetics are most effective when used prophylactically (Roila 2010). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease, concurrent morbidities and medications to assure antiemetic regimen is optimized (Basch 2011).

• Ileus or gastric distention: Does not stimulate gastric or intestinal peristalsis (should not be used instead of nasogastric suction); may mask progressive ileus and/or gastric distension.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Injection (1 mg/mL strength) may contain benzyl alcohol which may cross the placenta.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, insomnia, or constipation. Have patient report immediately to prescriber severe dizziness, passing out, shortness of breath, angina, tachycardia, abnormal heartbeat, severe loss of strength and energy, chills, pharyngitis, abnormal movements, abdominal edema, abdominal pain, severe skin irritation, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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