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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): 20 mL multidose vials. (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 ondansetronin 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*




FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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


[see Clinical Studies (14.1)].

1.2 Prevention of Postoperative Nausea and/or Vomiting


[see Clinical Studies (14.3)].



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




Adults:
undilutedundiluted

Pediatrics:

2.3 Stability and Handling






Note:


Precaution:

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function


[see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS


4 CONTRAINDICATIONS


[See Adverse Reactions (6.2).]

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions


3

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







Chemotherapy-Induced Nausea and Vomiting:


Table 1. Adverse Reactions Reported in > 5% of Adult Patients Who Received Ondansetron at a Dosage of Three 0.15 mg/kg Doses
  Adverse Reaction
Number of Adult Patients With Reaction
Ondansetron Injection
0.15 mg/kg x 3
n = 419
Metoclopramide
n = 156
Placebo
n = 34
  Diarrhea
16%
44%
18%
  Headache
17%
7%
15%
  Fever
8%
5%
3%
Cardiovascular:

Gastrointestinal:

Hepatic:


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


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



3
Ondansetron
181932





12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


3

12.2 Pharmacodynamics



QTc interval prolongation was studied in a double blind, single intravenous dose, placebo- and positive-controlled, crossover study in 58 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline-correction was 19.5 (21.8) ms and 5.6 (7.4) ms after 15 minute intravenous infusions of 32 mg and 8 mg ondansetron, respectively. A significant exposure-response relationship was identified between ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship, 24 mg infused intravenously over 15 min had a mean predicted (95% upper prediction interval) ΔΔQTcF of 14 (16.3) ms. In contrast, 16 mg infused intravenously over 15 min using the same model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) ms.

In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. In another study in six normal male volunteers, a 16 mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.

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 Therapya 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 Therapya 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

Cyclophosphamide-Based Chemotherapy:2
Table 8. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cyclophosphamide Therapya 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
Treatment Response Over
24 Hours
      Ondansetron      
n (%)
      Placebo      
n (%)
      P Value      
a Failure was one or more emetic episodes, rescued, or withdrawn.
         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










Store at

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 - 40 mg/20 mL Container Label


Rx only            NDC 55150-126-20
ONDANSETRON
INJECTION, USP

40 mg/20 mL
(2 mg/mL)

For Intravenous or
Intramuscular Injection.

Sterile
20 mL Multidose Vial
AUROMEDICS

Ondansetron



PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 40 mg/20 mL Container-Carton (1 Vial)




Rx only            NDC 55150-126-20
ONDANSETRON
INJECTION, USP

40 mg/20 mL
(2 mg/mL)

For Intravenous or
Intramuscular Injection.

Sterile
20 mL Multidose Vial
AUROMEDICS

Ondansetron

Ondansetron

Ondansetron Hydrochloride INJECTION, SOLUTION

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:55150-126
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:55150-126-20 1 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202599 2012-12-21


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