Ondansetron

AuroMedics Pharma LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ondansetron injection safely and effectively. See full prescribing information for ondansetron injection. ONDANSETRON INJECTION, USP for intravenous or intramuscular useInitial U.S. Approval: 1991RECENT MAJOR CHANGES2.15.2INDICATIONS AND USAGE3 Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy. (1.1) Prevention of postoperative nausea and/or vomiting. (1.2) DOSAGE AND ADMINISTRATIONPrevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (2.1): Adults and Pediatric patients (6 months to 18 years): Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes. The first dose should be administered 30 minutes before the start of chemotherapy. Subsequent doses are administered 4 and 8 hours after the first dose. Prevention of postoperative nausea and/or vomiting (2.2): Population Age Ondansetron  Injection Dosage Intravenous Infusion Rate Adults > 12 yrs 4 mg x 1 over 2 to 5 min Pediatrics(> 40 kg) 1 mo. to 12 yrs 4 mg x 1 over 2 to 5 min Pediatrics(≤ 40 kg) 1 mo. to 12 yrs 0.1 mg/kg x 1 over 2 to 5 min In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. (2.4) DOSAGE FORMS AND STRENGTHSOndansetron injection (2 mg/mL): 2 mL single dose vial. (3)CONTRAINDICATIONS Patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. (4) Concomitant use of apomorphine. (4) WARNINGS AND PRECAUTIONS Hypersensitivity reactions including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. (5.1) QT prolongation occurs in a dose-dependent manner. Cases of Torsade de Pointes have been reported. Avoid ondansetron in patients with congenital long QT syndrome. (5.2) Use in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention. (5.3)(5.4) Side Effects The most common adverse reactions (≥ 7%) in adults are diarrhea, headache, and fever. (6.1) Postoperative Nausea and Vomiting –   The most common adverse reaction (≥ 10%) which occurs at a higher frequency compared to placebo in adults is headache. (6.1) The most common adverse reaction (≥ 2%) which occurs at a higher frequency compared to placebo in pediatric patients 1 to 24 months of age is diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AuroMedics Pharma LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Apomorphine – profound hypotension and loss of consciousness. Concomitant use with ondansetron is contraindicated. (7.2)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 ONDANSETRON INDICATIONS AND USAGE
  • 1.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Cancer Chemotherapy
  • 1.2 Prevention of Postoperative Nausea and/or Vomiting
• 2 ONDANSETRON DOSAGE AND ADMINISTRATION
  • 2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy
  • 2.2 Prevention of Postoperative Nausea and Vomiting
  • 2.3 Stability and Handling
  • 2.4 Dosage Adjustment for Patients with Impaired Hepatic Function
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ONDANSETRON CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 QT Prolongation
  • 5.3 Masking of Progressive Ileus and Gastric Distension
  • 5.4 Effect on Peristalsis
• 6 ONDANSETRON ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Drugs Affecting Cytochrome P-450 Enzymes
  • 7.2 Apomorphine
  • 7.3 Phenytoin, Carbamazepine, and Rifampin
  • 7.4 Tramadol
  • 7.5 Chemotherapy
  • 7.6 Temazepam
  • 7.7 Alfentanil and Atracurium
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 9 DRUG ABUSE AND DEPENDENCE
• 10 OVERDOSAGE
• 11 ONDANSETRON DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Chemotherapy-Induced Nausea and Vomiting
  • 14.2 Prevention of Postoperative Nausea and/or Vomiting
  • 14.3 Prevention of Further Postoperative Nausea and Vomiting
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 4 mg/2 mL Container Label
• PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 4 mg/2 mL Container-Carton (25 Vials)

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Cancer Chemotherapy

1.2 Prevention of Postoperative Nausea and/or Vomiting

2 DOSAGE AND ADMINISTRATION

2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Adults: The recommended adult intravenous dosage of ondansetron injection is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron injection.

Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron injection is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1) and Clinical Pharmacology (12.2 and 12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron injection. The drug should be infused intravenously over 15 minutes.

2.2 Prevention of Postoperative Nausea and Vomiting

2.3 Stability and Handling

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

5.2 QT Prolongation

Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical Pharmacology (12.2)]. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation.

5.3 Masking of Progressive Ileus and Gastric Distension

5.4 Effect on Peristalsis

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Integumentary:

Neurological:

Other:

Postoperative Nausea and Vomiting:

Table 2. Adverse Reactions Reported in ≥ 2% (and With Greater Frequency than the Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous over 2 to 5 Minutes

Adverse Reactiona,b	Ondansetron Injection 4 mg Intravenous n = 547 patients	Placebo n = 547 patients
a Adverse Reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups b Patients were receiving multiple concomitant perioperative and postoperative medications
Headache	92 (17%)	77 (14%)
Drowsiness/sedation	44 (8%)	37 (7%)
Injection site reaction	21 (4%)	18 (3%)
Fever	10 (2%)	6 (1%)
Cold sensation	9 (2%)	8 (1%)
Pruritus	9 (2%)	3 (< 1%)
Paresthesia	9 (2%)	2 (< 1%)

Pediatric Use:

6.2 Postmarketing Experience

Cardiovascular:[see Warnings and Precautions (5.2)].

General:

Hepatobiliary:

Local Reactions:

Lower Respiratory:

Neurological:

Skin:

Eye Disorders:

7 DRUG INTERACTIONS

7.1 Drugs Affecting Cytochrome P-450 Enzymes

[see Clinical Pharmacology (12.3)].

7.2 Apomorphine

[see Contraindications (4)].

7.3 Phenytoin, Carbamazepine, and Rifampin

[see Clinical Pharmacology (12.3)].

7.4 Tramadol

7.5 Chemotherapy

7.6 Temazepam

7.7 Alfentanil and Atracurium

Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

[See Clinical Studies (14.2)]. [See Clinical Studies (14.1) and Dosage and Administration (2).]

[See Clinical Pharmacology (12.3).]

8.5 Geriatric Use

[see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

[see Clinical Pharmacology (12.3)].[see Dosage and Administration (2.3)].

8.7 Renal Impairment

[see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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12.2 Pharmacodynamics

12.3 Pharmacokinetics

Table 3. Pharmacokinetics in Normal Adult Volunteers

Age-group (years)	n	Peak Plasma Concentration (ng/mL)	Mean Elimination Half-life (h)	Plasma Clearance (L/h/kg)
19 to 40	11	102	3.5	0.381
61 to 74	12	106	4.7	0.319
≥ 75	11	170	5.5	0.262

Absorption:

Distribution:in vitro

Metabolism:



In vitro in vivoin vivo

in vivo

Elimination:

Geriatrics:

Pediatrics:

Table 4. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age

Subjects and Age Group	N	CL       (L/h/kg)	Vdss       (L/kg)	T½       (h)
a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
		Geometric Mean		Mean
Pediatric Cancer Patients    4 to 18 years of age	N = 21	0.599	1.9	2.8
Population PK Patientsa    1 month to 48 months of age	N = 115	0.582	3.65	4.9

,

Table 5. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age

Subjects and Age Group	N	CL       (L/h/kg)	Vdss       (L/kg)	T½       (h)
		Geometric Mean		Mean
Pediatric Surgery Patients          3 to 12 years of age	N = 21	0.439	1.65	2.9
Pediatric Surgery Patients          5 to 24 months of age	N = 22	0.581	2.3	2.9
Pediatric Surgery Patients          1 month to 4 months of age	N = 19	0.401	3.5	6.7

Renal Impairment:

Hepatic Impairment:

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Chemotherapy-Induced Nausea and Vomiting

Adults:

Cisplatin-Based Chemotherapy:

Table 6. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cisplatin Therapy^a in Adults

	Ondansetron Injection (0.15 mg/kg x 3)	Placebo	P Valueb
a Chemotherapy was high dose (100 and 120 mg/m2; ondansetron injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m2; ondansetron injection n = 8, placebo n = 9). Other chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response. b Efficacy based on "all patients treated" analysis. c Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes. d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Number of patients	14	14
Treatment response
0 Emetic episodes       1 to 2 Emetic episodes       3 to 5 Emetic episodes	2 (14%) 8 (57%) 2 (14%)	0 (0%) 0 (0%) 1 (7%)
More than 5 emetic episodes/rescued	2 (14%)	13 (93%)	0.001
Median number of emetic episodes	1.5	Undefinedc
Median time to first emetic episode (h)	11.6	2.8	0.001
Median nausea scores (0 to 100)d	3	59	0.034
Global satisfaction with control of nausea and vomiting (0 to 100)e	96	10.5	0.009

²

Table 7. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin (≥ 100 mg/m²) Single-Day Therapy^a in Adults

	Ondansetron Injection	Metoclopramide	P Value
a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response. b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
Dose	0.15 mg/kg x 3	2 mg/kg x 6
Number of patients in efficacy population	136	138
Treatment response
0 Emetic episodes       1 to 2 Emetic episodes       3 to 5 Emetic episodes       More than 5 emetic episodes/rescued	54 (40%) 34 (25%) 19 (14%) 29 (21%)	41 (30%) 30 (22%) 18 (13%) 49 (36%)
Comparison of treatments with respect to
0 Emetic episodes       More than 5 emetic episodes/rescued	54/136 29/136	41/138 49/138	0.083 0.009
Median number of emetic episodes	1	2	0.005
Median time to first emetic episode (h)	20.5	4.3	< 0.001
Global satisfaction with control of nausea and vomiting (0 to 100)b	85	63	0.001
Acute dystonic reactions	0	8	0.005
Akathisia	0	10	0.002

²

Table 8. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cyclophosphamide Therapy^a in Adults

	Ondansetron Injection (0.15 mg/kg x 3)	Placebo	P Valueb
a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between treatments in the type of chemotherapy that would account for differences in response. b Efficacy based on "all patients treated" analysis. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Number of patients	10	10
Treatment response
0 Emetic episodes	7 (70%)	0 (0%)	0.001
1 to 2 Emetic episodes       3 to 5 Emetic episodes	0 (0%) 2 (20%)	2 (20%) 4 (40%)
More than 5 emetic episodes/rescued	1 (10%)	4 (40%)	0.131
Median number of emetic episodes	0	4	0.008
Median time to first emetic episode (h)	Undefinedc	8.79
Median nausea scores (0 to 100)d	0	60	0.001
Global satisfaction with control of nausea and vomiting (0 to 100)e	100	52	0.008

Re-treatment:²

Pediatrics:

14.2 Prevention of Postoperative Nausea and/or Vomiting

Adults:

Table 9. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in Adult Patients

	Ondansetron 4 mg Intravenous	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       More than 1 emetic episode/rescued	13 (10%) 20 (15%)	17 (12%) 58 (42%)
Nausea assessments:
Number of patients    No nausea over 24-h postoperative period	134 56 (42%)	136 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       More than 1 emetic episode/rescued	16 (12%) 35 (26%)	29 (20%) 51 (36%)
Nausea assessments:
Number of patients    No nausea over 24-h postoperative period	125 48 (38%)	133 42 (32%)

P

PP

Pediatrics:

Table 10. Therapeutic Response in 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
a Failure was one or more emetic episodes, rescued, or withdrawn. b Nausea measured as none, mild, or severe.
Study 1
Number of patients	205	210
0 Emetic episodes	140 (68%)	82 (39%)	≤ 0.001
Failurea	65 (32%)	128 (61%)
Study 2
Number of patients	112	110
0 Emetic episodes	68 (61%)	38 (35%)	≤ 0.001
Failurea	44 (39%)	72 (65%)
Study 3
Number of patients	206	206
0 Emetic episodes	123 (60%)	96 (47%)	≤ 0.01
Failurea	83 (40%)	110 (53%)
Nausea assessmentsb:
Number of patients	185	191
None	119 (64%)	99 (52%)	≤ 0.01

P

14.3 Prevention of Further Postoperative Nausea and Vomiting

Adults:

Table 11. Therapeutic Response in Prevention of Further Postoperative Nausea and Vomiting in Adult Patients

	Ondansetron 4 mg Intravenous	Placebo	P Value
a After administration of study drug. b Nausea measured on a scale of 0 to 10 with 0 = no nausea, 10 = nausea as bad as it can be.
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       More than 1 emetic episode/rescued    Median time to first emetic episode (min)a	12 (12%) 43 (41%) 55	9 (8%) 89 (76%) 43
Nausea assessments:
Number of patients    Mean nausea score over 24-h postoperative periodb	98 1.7	102 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       More than 1 emetic episode/rescued    Median time to first emetic episode (min)a	14 (13%) 49 (44%) 60.5	3 (3%) 77 (71%) 34
Nausea assessments:
Number of patients    Mean nausea score over 24-h postoperative periodb	105 1.9	85 2.9

Repeat Dosing in Adults:

Pediatrics:

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

a  Failure was one or more emetic episodes, rescued, or withdrawn.
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
Failurea	84 (47%)	142 (83%)

16 HOW SUPPLIED/STORAGE AND HANDLING

Retain in carton until time of use.

17 PATIENT COUNSELING INFORMATION

 

• Patients should be informed that ondansetron may cause serious cardiac arrhythmias such as QT prolongation. Patients should be instructed to tell their health care provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.
• Patients should be informed that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:
  • Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome;
  • Patients who take medications, such as diuretics, which may cause electrolyte abnormalities
  • Patients with hypokalemia or hypomagnesemia

Ondansetron should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.

• Inform patients that ondansetron may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems.
• The patient should report the use of all medications, especially apomorphine, to their health care provider. Concomitant use of apomorphine and ondansetron may cause a significant drop in blood pressure and loss of consciousness.
• Inform patients that ondansetron may cause headache, drowsiness/sedation, constipation, fever and diarrhea.

 

Manufactured for:
AuroMedics Pharma LLC
6 Wheeling Road
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
IDA, Pashamylaram - 502307
AP., India

Revised: December 2012

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 4 mg/2 mL Container Label

NDC 55150-125-02
ONDANSETRON
INJECTION, USP
4 mg/2 mL (2 mg/mL)
For I.V. or I.M. Injection.
Rx only         2 mL Single-dose Vial
AUROMEDICS
 
 

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 4 mg/2 mL Container-Carton (25 Vials)

Rx onlyNDC 55150-125-02
ONDANSETRON
INJECTION, USP
4 mg/2 mL
(2 mg/mL)
For Intravenous or Intramuscular Injection.
Sterile             25 x 2 mL Single-dose Vials
AUROMEDICS

 
 
 

Ondansetron Ondansetron Hydrochloride INJECTION, SOLUTION Product Information Product Type Human prescription drug label Item Code (Source) NDC:55150-125 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:55150-125-02 25 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202600 2012-12-21