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Generic Name: Granisetron Hydrochloride
Class: 5-HT3 Receptor Antagonists
Chemical Name: endo-1-Methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide monohydrochloride
Molecular Formula: C18H24N4O•ClH
CAS Number: 107007-99-8

Introduction

Antiemetic; selective inhibitor of type 3 serotonergic (5-HT3) receptors.1 2 3

Uses for Kytril

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin.1 33

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Postoperative Nausea and Vomiting

Prevention and treatment of postoperative nausea and vomiting.1

Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.1

Recommended for patients who, in the clinician’s judgment, must avoid nausea and/or vomiting postoperatively, even when anticipated incidence is low.1

Radiation-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with radiation, including total body irradiation and daily fractionated abdominal radiation.33

Kytril Dosage and Administration

Administration

Administer orally, by IV infusion, or by direct IV injection.1 33

Oral Administration

May use oral solution and tablets interchangeably.33

For prevention of nausea and vomiting associated with chemotherapy, administer once or twice daily.33 Administer only on days when emetogenic chemotherapy is administered.33

For prevention of radiation-induced nausea and vomiting, administer within 1 hour of radiation.33

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

For prevention of nausea and vomiting associated with chemotherapy, administer approximately 30 minutes before administration of emetogenic drug, only on days when emetogenic chemotherapy is administered.1

For prevention of postoperative nausea and vomiting, administer before induction of or immediately before reversal of anesthesia.1

Dilution

IV infusion: Dilute in 5% dextrose or 0.9% sodium chloride injection1 to a total volume of 20–50 mL.HID

Rate of Administration

Direct IV injection: Administer undiluted over 30 seconds.1

IV infusion: Infuse over 5 minutes.1

Dosage

Available as granisetron hydrochloride; dosage expressed in terms of granisetron.1 33

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
IV

Children 2–16 years of age: 10 mcg/kg by IV infusion or direct IV injection within 30 minutes before administration of chemotherapy.1

Adults

Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
Oral

2 mg once daily up to 1 hour before administration of chemotherapy.33

Alternatively, 1 mg twice daily (first dose up to 1 hour before chemotherapy and second dose 12 hours after first dose).33

IV

10 mcg/kg by IV infusion or direct IV injection within 30 minutes before administration of chemotherapy.1

Postoperative Nausea and Vomiting
Prevention
IV

1 mg as a single dose by direct IV injection before induction of or immediately before reversal of anesthesia.1

Treatment
IV

1 mg as a single dose by direct IV injection.1

Radiation-induced Nausea and Vomiting
Prevention
Oral

2 mg once daily within 1 hour of radiation.33

Special Populations

Hepatic Impairment

No dosage adjustment required.1 33

Geriatric Patients

No dosage adjustment required.1 33

Cautions for Kytril

Contraindications

  • Known hypersensitivity to granisetron or any ingredient in the formulation.1 33

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including anaphylactic reaction, shortness of breath, hypotension, and urticaria, reported rarely.1 33

Possible hypersensitivity reactions in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.1 33

General Precautions

GI Precautions

Does not stimulate gastric or intestinal peristalsis; do not use as a substitute for nasogastric suction.1

May mask progressive ileus and/or gastric distention when used in patients undergoing abdominal surgery or in those with chemotherapy-induced nausea and vomiting.1

Specific Populations

Pregnancy

Category B.1 33

Lactation

Not known whether granisetron is distributed into milk.1 33 Caution advised if used in nursing women.1 33

Pediatric Use

Safety and efficacy of IV granisetron for chemotherapy-induced nausea and vomiting not established in children <2 years of age; safety and efficacy of IV granisetron for prevention and treatment of postoperative nausea and vomiting not established in children of any age.1

Safety and efficacy of oral granisetron not established in children of any age.33

Geriatric Use

No substantial differences in safety and efficacy for chemotherapy-induced nausea and vomiting in geriatric patients relative to younger adults.1 33

Insufficient experience with IV granisetron for postoperative nausea and vomiting in patients≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Common Adverse Effects

Headache1 33 , constipation1 33 , pain1 , diarrhea1 33 , fever1 , abdominal pain1 33 , increased hepatic enzymes1 33 , asthenia1 33 , dyspepsia33 .

Interactions for Kytril

Apparently metabolized by CYP3A; does not induce or inhibit CYP isoenzymes.1 33

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered granisetron clearance and half-life) with inhibitors or inducers of CYP isoenzymes.1 33

Specific Drugs

Drug

Interaction

Antineoplastic agents

No apparent interaction with emetogenic cancer chemotherapies1 33

Ketoconazole

Inhibition of granisetron metabolism in vitro33

Kytril Pharmacokinetics

Absorption

Bioavailability

Dose of oral solution is bioequivalent to corresponding dose of oral tablets.33

Food

Food has minimal effect on extent of absorption; may increase peak plasma concentration by 30%.33

Distribution

Extent

Distributes freely between plasma and red blood cells.1 33 Not known whether granisetron distributed into milk.1 33

Plasma Protein Binding

Approximately 65%.1 33

Elimination

Metabolism

Metabolized via N-demethylation and aromatic ring oxidation followed by conjugation; metabolism appears to be mediated by CYP3A subfamily.1 33

Elimination Route

Excreted in urine as unchanged drug (11–12%) and metabolites (48–49%) and in feces as metabolites (34–38%).1 33

Half-life

IV administration: Terminal half-life is approximately 9 hours in adult cancer patients or adults undergoing surgery.1

Oral administration: Terminal half-life is approximately 6.2 hours in healthy adults.1

Special Populations

In pediatric cancer patients, pharmacokinetic profile is similar to that in adult cancer patients.1

In geriatric patients, mean clearance may be decreased and half-life increased compared with younger adults.1

In patients with hepatic impairment due to neoplastic liver involvement, total clearance following a single IV dose is reduced by approximately 50% compared with patients without hepatic impairment.1

In patients with severe renal impairment, total clearance following a single 40-mcg/kg IV dose is not altered.1

Stability

Storage

Oral

Tablets

Tight container at 15–30°C; protect from light.33

Solution

Tight container at 25°C (may be exposed to 15–30°C).33 Store in upright position; protect from light.33

Parenteral

Injection

25°C (may be exposed to 15–30°C).1 Do not freeze; protect from light.1 Once multiple-dose vial is penetrated, use contents within 30 days.1

Following dilution with sodium chloride 0.9% or dextrose 5% injection, stable for at least 24 hours at room temperature under normal lighting conditions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in sodium chloride 0.45 or 0.9%HID

Dextrose 5% in waterHID

Sodium chloride 0.9%HID

Drug Compatibility
Admixture CompatibilityHID

Compatible

Dexamethasone sodium phosphate

Methylprednisolone sodium succinate

Y-Site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Amikacin sulfate

Aminophylline

Amphotericin B cholesteryl sulfate complex

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefazolin sodium

Cefepime HCl

Cefotaxime sodium

Cefotetan disodium

Cefoxitin sodium

Ceftaroline fosamil

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Chlorpromazine HCl

Ciprofloxacin

Cisplatin

Cladribine

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Dactinomycin

Daunorubicin HCl

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Diphenhydramine HCl

Dobutamine HCl

Docetaxel

Dopamine HCl

Doripenem

Doxorubicin HCl

Doxorubicin HCl liposome injection

Doxycycline hyclate

Droperidol

Enalaprilat

Etoposide

Etoposide phosphate

Famotidine

Fenoldopam mesylate

Filgrastim

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gallium nitrate

Ganciclovir sodium

Gemcitabine HCl

Gentamicin sulfate

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Imipenem–cilastatin sodium

Leucovorin calcium

Linezolid

Lorazepam

Magnesium sulfate

Mechlorethamine HCl

Melphalan HCl

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Mitomycin

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Oxaliplatin

Paclitaxel

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Propofol

Ranitidine HCl

Sargramostim

Sodium bicarbonate

Streptozocin

Teniposide

Thiotepa

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Topotecan HCl

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Amphotericin B

Variable

Acyclovir sodium

Actions

  • Antiemetic activity appears to be mediated both centrally (in medullary chemoreceptor trigger zone) and peripherally (in GI tract) via inhibition of 5-HT3 receptors.4 5 6 8 11 12 13 29 30

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Granisetron Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

1 mg (of granisetron) per 5 mL

Kytril

Roche

Tablets, film-coated

1 mg (of granisetron)

Kytril

Roche

Parenteral

Injection, for IV use

0.1 mg (of granisetron) per mL (0.1 mg)

Kytril

Roche

1 mg (of granisetron) per mL (1 and 4 mg)

Kytril

Roche

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Granisetron HCl 1MG Tablets (TEVA PHARMACEUTICALS USA): 2/$45.99 or 6/$125.96

Kytril 1MG Tablets (GENENTECH): 2/$131.98 or 6/$385.97

Sancuso 3.1MG/24HR Patches (PROSTRAKAN): 1/$403.33 or 2/$771.92

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Roche. Kytril (granisetron hydrochloride) injection prescribing information. Nutley, NJ; 2002 Aug.

2. Jay GT, Wallace M, DeFusco P et al. Focus on granisetron: the second 5-HT3 receptor antagonist approved for chemotherapy-induced emesis. Hosp Formul. 1994; 29:191-201.

3. Seynaeve C, De Mulder PHM, Verweij J. Pathophysiology of cytotoxic drug-induced emesis: far from crystal-clear. Pharm Weekbl [Sci]. 1991; 13:1-6. [IDIS 278161] [PubMed 1674600]

4. McKeage MJ. Comparative adverse effect profile of platinum drugs. Drug Saf. 1995; 13:228-44. [PubMed 8573296]

5. Cubeddu LX, Hoffmann IS. Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol. 1993; 33:691-7. [IDIS 319277] [PubMed 7691898]

6. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst. 1991; 83:613-20. [PubMed 1850806]

7. du Bois A, Meerpohl HG, Vach W et al. Course, patterns, and risk-factors for chemotherapy-induced emesis in cisplatin pretreated patients: a study with ondansetron. Eur J Cancer. 1992; 28:450-7. [PubMed 1534250]

8. Gebbia V, Cannata G, Testa A et al. Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Results of a prospective randomized trial. Cancer. 1994; 74:1945-52. [IDIS 336138] [PubMed 8082100]

9. Perez EA. Review of the preclinical pharmacology and comparative efficacy of 5- hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol. 1995; 13:1036-43. [IDIS 344879] [PubMed 7707101]

10. Ruff P, Paska W, Goedhals L et al for the Ondansetron and Granisetron Emesis Study Group. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. Oncology. 1994; 51:113-8. [PubMed 8265095]

11. Gralla RJ. Adverse effects of treatment: antiemetic therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: J.B. Lippincott Company; 1993:2338-48.

12. De Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med. 1990; 113:834-40. [IDIS 274419] [PubMed 2146911]

13. Kris MG, Pisters KM, Hinkley L. Delayed emesis following anticancer chemotherapy. Support Care Cancer. 1994; 2:297-300. [PubMed 8000726]

14. Italian Group for Antiemetic Research. Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet. 1992; 340:96-99. [IDIS 298926] [PubMed 1352024]

15. du Bois A, Vach W, Thomssen C et al. Comparison of emetogenic potential between cisplatin and carboplatin in combination with akylating agents. Acta Oncol. 1994; 33:531-5. [PubMed 7917367]

16. Smith DB, Newlands ES, Rustin GJS et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet. 1991; 338:487-90. [IDIS 284481] [PubMed 1714532]

17. Anon. Ondansetron vs dexamethasone for chemotherapy-induced emesis. Lancet. 1991; 338:478-9. [PubMed 1714531]

18. Navari R, Gandara D, Hesketh P et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group. J Clin Oncol. 1995; 13:1242-8. [IDIS 347756] [PubMed 7738628]

19. Marty M. A comparison of granisetron as a single agent with conventional combination antiemetic therapies in the treatment of cytostatic-induced emesis. The Granisetron Study Group. Eur J Cancer. 1992; 28A(Suppl 1):S12-6.

20. Ohmatsu H, Eguchi K, Shinkai T et al. A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin. Jpn J Cancer Res. 1994; 85:1151-8. [PubMed 7829401]

21. Heron JF, Goedhals L, Jordaan JP et al. Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin- induced emesis. The Granisetron Study Group. Ann Oncol. 1994; 5:579-84. [PubMed 7993831]

22. The Granisetron Study Group. The antiemetic efficacy and safety of granisetron compared with metoclopramide plus dexamethasone in patients receiving fractionated chemotherapy over 5 days. J Cancer Res Clin Oncol. 1993; 119:555-9. [PubMed 8392077]

23. Cunningham D, Hill M, Dicato M et al. Optimal anti-emetic therapy for cisplatin induced emesis over repeat courses. Proc Ann Meet Am Soc Clin Oncol. 1994; 13:A1553.

24. Tyson LB, Gralla RJ, Clark RA et al. Combination antiemetic trials with metoclopramide. Proc Am Soc Clin Oncol. 1983; 2:91.

25. Ahn MJ, Lee JS, Lee KH et al. A randomized double-blind trial of ondansetron alone versus in combination with dexamethasone versus in combination with dexamethasone and lorazepam in the prevention of emesis due to cisplatin-based chemotherapy. Am J Clin Oncol. 1994; 17:150-6. [IDIS 329909] [PubMed 8141107]

26. Bruera ED, Roca E, Cedaro L et al. Improved control of chemotherapy- induced emesis by the addition of dexamethasone to metoclopramide in patients resistant to metoclopramide. Cancer Treat Rep. 1983; 67:381-3. [IDIS 171263] [PubMed 6342770]

27. Malik IA, Khan WA, Qazilbash M et al. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol. 1995; 18:170-5. [IDIS 344756] [PubMed 7900711]

28. Clerico M, Bertetto O, Cardinali C et al. Antiemetic activity of lorazepam in the prophylactic treatment of vomiting induced by cisplatin: a double-blind placebo controlled study with cross-over design. Ann Oncol. 1992; 3(Suppl 5):188.

29. Plosker GL, Goa KL. Granisetron: a review of its pharmacological properties and therapeutic use as an antiemetic. Drugs. 1991;42:805-24.

30. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993; 329:1790-6. [IDIS 322575] [PubMed 8232489]

31. Mitchelson F. Pharmacological agents affecting emesis: a review (part I). Drugs. 1992; 43:295-315. [PubMed 1374316]

32. Aapro MS. 5- HT3 receptor antagonists: an overview of their present status and future potential in cancer therapy-induced emesis. Drugs. 1991; 42:551-68. [PubMed 1723361]

33. Roche. Kytril (granisetron hydrochloride) tablets and oral solution prescribing information. Nutley, NJ; 2001 Jun.

34. Spitzer TR, Friedman CJ, Bushnell W et al. Oral granisetron (Kytril) and ondansetron (Zofran) in the prevention of hyperfractionated total body irradiation induced emesis: the results of a double-blind, randomized parallel group study. Blood. 1998; 92(Suppl 1):278a.

35. Lanciano R, Sherman DM, Michalski J et al. The efficacy and safety of Kytril tablets (2 mg) once daily in patients receiving at least 10 fractions of uppper abdominal radiation for malignancy. Int J Radiat Oncol Biol Phys. 1998; 42(Suppl 1)204. Abstract.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:573-9.

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