ONDANSETRON HYDROCHLORIDE

WOCKHARDT USA LLC

PRESCRIBING INFORMATION ONDANSETRON INJECTION USP

FULL PRESCRIBING INFORMATION: CONTENTS*

• ONDANSETRON HYDROCHLORIDE DESCRIPTION
• CLINICAL PHARMACOLOGY
• CLINICAL TRIALS
• ONDANSETRON HYDROCHLORIDE INDICATIONS AND USAGE
• ONDANSETRON HYDROCHLORIDE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• ONDANSETRON HYDROCHLORIDE ADVERSE REACTIONS
• DRUG ABUSE AND DEPENDENCE
• OVERDOSAGE
• ONDANSETRON HYDROCHLORIDE DOSAGE AND ADMINISTRATION
• HOW SUPPLIED

FULL PRESCRIBING INFORMATION

ONDANSETRON HYDROCHLORIDE DESCRIPTION

The active ingredient in Ondansetron Injection is ondansetron hydrochloride (HCl), the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT₃ receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:

The empirical formula is C₁₈H₁₉N_3O•HCl•2H₂O, representing a molecular weight of 365.9.

Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration: Each 1 mL of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.
Ondansetron Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection solution is 3.3 to 4.0.

CLINICAL PHARMACOLOGY

CLINICAL TRIALS

Re-treatment: ²

Pediatric Studies:



Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and Vomiting: Adult Studies:

Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients

	Ondansetron 4 mg I.V.	Placebo	P Value
Study 1
Emetic episodes:
Number of patients	136	139
Treatment response over 24-h postoperative period
0 Emetic episodes	103 (76%)	64 (46%)	<0.001
1 Emetic episode	13 (10%)	17 (12%)
More than 1 emetic episode/rescued	20 (15%)	58 (42%)
Nausea assessments:
Number of patients	134	136
No nausea over 24-h postoperative period	56 (42%)	39 (29%)
Study 2
Emetic episodes:
Number of patients	136	143
Treatment response over 24-h postoperative period
0 Emetic episodes	85 (63%)	63 (44%)	0.002
1 Emetic episode	16 (12%)	29 (20%)
More than 1 emetic episode/rescued	35 (26%)	51 (36%)
Nausea assessments:
Number of patients	125	133
No nausea over 24-h postoperative period	48 (38%)	42 (32%)

P
PP
Pediatric Studies:

Table 9. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of Age

Treatment Response Over 24 Hours	Ondansetron n (%)	Placebo n (%)	P Value
Study 1
Number of patients	205	210
0 Emetic episodes	140 (68%)	82 (39%)	≤0.001
Failure*	65 (32%)	128 (61%)
Study 2
Number of patients	112	110
0 Emetic episodes	68 (61%)	38 (35%)	≤0.001
Failure*	44 (39%)	72 (65%)
Study 3
Number of patients	206	206
0 Emetic episodes	123 (60%)	96 (47%)	≤0.01
Failure*	83 (40%)	110 (53%)
Nausea assessments†:
Number of patients	185	191
None	119 (64%)	99 (52%)	≤0.01

^*
†


P

Prevention of Further Postoperative Nausea and Vomiting: Adult Studies:

Table 10. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients

	Ondansetron 4 mg I.V.	Placebo	P Value
Study 1
Emetic episodes:
Number of patients	104	117
Treatment response 24 h after study drug
0 Emetic episodes	49 (47%)	19 (16%)	<0.001
1 Emetic episode	12 (12%)	9 (8%)
More than 1 emetic episode/rescued	43 (41%)	89 (76%)
Median time to first emetic episode (min)*	55.0	43.0
Nausea assessments:
Number of patients	98	102
Mean nausea score over 24-hpostoperative period†	1.7	3.1
Study 2
Emetic episodes:
Number of patients	112	108
Treatment response 24 h after study drug
0 Emetic episodes	49 (44%)	28 (26%)	0.006
1 Emetic episode	14 (13%)	3 (3%)
More than 1 emetic episode/rescued	49 (44%)	77 (71%)
Median time to first emetic episode (min)*	60.5	34.0
Nausea assessments:
Number of patients	105	85
Mean nausea score over 24-hpostoperative period†	1.9	2.9

^*
†



Repeat Dosing in Adults:

Pediatric Study:

Table 11. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of Age

Treatment Response Over 24 Hours	Ondansetron n (%)	Placebo n (%)	P Value
Number of patients	180	171
0 Emetic episodes	96 (53%)	29 (17%)	≤0.001
Failure*	84 (47%)	142 (83%)

^*

ONDANSETRON HYDROCHLORIDE INDICATIONS AND USAGE

• Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not been established.
• Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ondansetron injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic ondansetron injection and experience nausea and/or vomiting postoperatively, ondansetron injection may be given to prevent further episodes (see CLINICAL TRIALS).

ONDANSETRON HYDROCHLORIDE CONTRAINDICATIONS

WARNINGS

₃

PRECAUTIONS

General:

Drug Interactions:
Apomorphine:
Phenytoin, Carbamazepine, and Rifampicin: ^1,3
Tramadol: ^4,5
Chemotherapy:

Carcinogenesis, Mutagenesis, Impairment of Fertility:
Pregnancy: Teratogenic Effects:
Nursing Mothers:
Pediatric Use:



Geriatric Use:

ONDANSETRON HYDROCHLORIDE ADVERSE REACTIONS

Chemotherapy-Induced Nausea and Vomiting:

Table 12. Principal Adverse Events in Comparative Trials in Adults

	Number of Adult Patients With Event
	Ondansetron Injection 0.15 mg/kg x 3 n = 419	Ondansetron Injection 32 mg x 1 n = 220	Metoclopramide n = 156	Placebo n = 34
Diarrhea	16%	8%	44%	18%
Headache	17%	25%	7%	15%
Fever	8%	7%	5%	3%
Akathisia	0%	0%	6%	0%
Acute dystonic reactions*	0%	0%	5%	0%

^*


Cardiovascular:
Gastrointestinal:
Hepatic:
Integumentary:
Neurological:
Other:
Postoperative Nausea and Vomiting:

Table 13. Adverse Events in ≥ 2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V. over 2 to 5 Minutes in Clinical Trials

	Ondansetron Injection 4 mg I.V. n = 547 patients	Placebo n = 547 patients
Headache	92 (17%)	77 (14%)
Dizziness	67 (12%)	88 (16%)
Musculoskeletal pain	57 (10%)	59 (11%)
Drowsiness/sedation	44 (8%)	37 (7%)
Shivers	38 (7%)	39 (7%)
Malaise/fatigue	25 (5%)	30 (5%)
Injection site reaction	21 (4%)	18 (3%)
Urinary retention	17 (3%)	15 (3%)
Postoperative CO2-related pain*	12 (2%)	16 (3%)
Chest pain (unspecified)	12 (2%)	15 (3%)
Anxiety/agitation	11 (2%)	16 (3%)
Dysuria	11 (2%)	9 (2%)
Hypotension	10 (2%)	12 (2%)
Fever	10 (2%)	6 (1%)
Cold sensation	9 (2%)	8 (1%)
Pruritus	9 (2%)	3 (<1%)
Paresthesia	9 (2%)	2 (<1%)

^*

Pediatric Use:

Table 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to 12 Years of Age

Adverse Event	Ondansetron n = 755 Patients	Placebo n = 731 Patients
Wound problem	80 (11%)	86 (12%)
Anxiety/agitation	49 (6%)	47 (6%)
Headache	44 (6%)	43 (6%)
Drowsiness/sedation	41 (5%)	56 (8%)
Pyrexia	32 (4%)	41 (6%)

Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment Group) in Pediatric Patients 1 Month to 24 Months of Age

Adverse Event	Ondansetron n = 336 Patients	Placebo n = 334 Patients
Pyrexia	14 (4%)	14 (4%)
Bronchospasm	2 (< 1%)	6 (2%)
Post-procedural pain	4 (1%)	6 (2%)
Diarrhea	6 (2%)	3 (< 1%)

Observed During Clinical Practice:
Cardiovascular:
General:
Hepatobiliary:
Local Reactions:
Lower Respiratory:
Neurological:
Skin:
Special Senses:
Eye Disorders:

DRUG ABUSE AND DEPENDENCE

OVERDOSAGE

ONDANSETRON HYDROCHLORIDE DOSAGE AND ADMINISTRATION

Prevention of Chemotherapy-Induced Nausea and Vomiting: Adult Dosing:

Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING.
Pediatric Dosing:

Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING.
Geriatric Dosing:
Prevention of Postoperative Nausea and Vomiting: Adult Dosing: undilutedundiluted

Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE NAUSEA AND VOMITING.
Pediatric Dosing:

Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE NAUSEA AND VOMITING.
Geriatric Dosing:
Dosage Adjustment for Patients With Impaired Renal Function:
Dosage Adjustment for Patients With Impaired Hepatic Function:
Stability:

Note:
Precaution:

HOW SUPPLIED

Ondansetron Injection,



Store at 20°-25°C (68°-77°F) (See USP Controlled Room Temperature). Protect from light.
Retain in carton until time of use.

REFERENCES

• Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
• Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
• Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381.
• De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
• Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.

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ONDANSETRON HYDROCHLORIDE ONDANSETRON HYDROCHLORIDE INJECTION Product Information Product Type Human prescription drug label Item Code (Source) NDC:64679-726 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ONDANSETRON HYDROCHLORIDE ONDANSETRON 2 mg Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE CITRIC ACID MONOHYDRATE TRISODIUM CITRATE DIHYDRATE water Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 2 in 1 VIAL, SINGLE-DOSE 2 NDC:64679-726-01 5 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077716 2006-12-27

ONDANSETRON HYDROCHLORIDE ONDANSETRON HYDROCHLORIDE INJECTION Product Information Product Type Human prescription drug label Item Code (Source) NDC:64679-727 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ONDANSETRON HYDROCHLORIDE ONDANSETRON 2 mg Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE CITRIC ACID MONOHYDRATE TRISODIUM CITRATE DIHYDRATE METHYLPARABEN PROPYLPARABEN water Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 20 in 1 VIAL, MULTI-DOSE 2 NDC:64679-727-01 1 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077577 2006-12-27