Meclizine Hydrochloride

6 ADVERSE REACTIONS The following adverse reactions associated with the use of meclizine hydrochloride were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylactic reaction, drowsiness, dry mouth, headache, fatigue, and vomiting. On rare occasions blurred vision has been reported. Common adverse reactions are anaphylactic reaction, drowsiness, dry mouth, headache, fatigue, and vomiting. On rare occasions blurred vision has been reported ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Meclizine hydrochloride tablets are contraindicated in patients with a hypersensitivity to meclizine or any of the inactive ingredients [see Adverse Reactions (6) and Description (11) ] . Meclizine hydrochloride tablets are contraindicated in patients with hypersensitivity to meclizine or any of the inactive ingredients ( 4 ).

11 DESCRIPTION Meclizine hydrochloride, a histamine (H1) receptor antagonist, is a white or slightly yellowish, crystalline powder. It has the following structural formula: Chemically, meclizine hydrochloride is 1-( p -chloro-α-phenylbenzyl)-4-( m -methylbenzyl) piperazine dihydrochloride monohydrate. Inactive ingredients for the tablets are: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and talc. The 12.5 mg tablets also contain FD&C Blue #1 Aluminum Lake. The 25 mg tablets also contain D&C Yellow #10 Aluminum Lake. Each meclizine hydrochloride 12.5 mg tablet contains 12.5 mg of meclizine dihydrochloride equivalent to 10.53 mg of meclizine free base. Each meclizine hydrochloride 25 mg tablet contains 25 mg of meclizine dihydrochloride equivalent to 21.07 mg of meclizine free base. Each meclizine hydrochloride 50 mg tablet contains 50 mg of meclizine dihydrochloride equivalent to 42.14 mg of meclizine free base. 1

2 DOSAGE AND ADMINISTRATION Recommended dosage: 25 mg to 100 mg daily, in divided doses ( 2.1 ). Tablets: Swallow whole ( 2.2 ). 2.1 Recommended Dosage The recommended dosage is 25 mg to 100 mg daily administered orally, in divided doses, depending upon clinical response. 2.2 Administration Instructions Tablets Meclizine hydrochloride tablets must be swallowed whole.

1 INDICATIONS AND USAGE Meclizine hydrochloride tablets are indicated for the treatment of vertigo associated with diseases affecting the vestibular system in adults. Meclizine hydrochloride tablets are indicated for the treatment of vertigo associated with diseases affecting the vestibular system in adults ( 1 ).

7 DRUG INTERACTIONS Co-administration of meclizine hydrochloride with other CNS depressants, including alcohol, may result in increased CNS depression ( 7.1 ). CYP2D6 inhibitors: As meclizine is metabolized by CYP2D6, there is a potential for drug-drug interactions between meclizine hydrochloride and CYP2D6 inhibitors ( 7.2 ). 7.1 CNS Depressants There may be increased CNS depression when meclizine hydrochloride is administered concurrently with other CNS depressants, including alcohol [see Warnings and Precautions (5.1) ] . 7.2 CYP2D6 Inhibitors Based on in-vitro evaluation, meclizine is metabolized by CYP2D6. Therefore, there is a possibility for a drug interaction between meclizine hydrochloride and CYP2D6 inhibitors. Therefore, monitor for adverse reactions and clinical effect accordingly.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which meclizine exerts its therapeutic effect is unknown but is presumed to involve antagonism of the histamine H1 receptor. 12.2 Pharmacodynamics There are no relevant pharmacodynamic data regarding meclizine. 12.3 Pharmacokinetics The available pharmacokinetic information for meclizine following oral administration has been summarized from published literature. Absorption Meclizine is absorbed after oral administration with maximum plasma concentrations reaching at a median T max value of 3 hours post-dose (range: 1.5 to 6 hours) for the tablet dosage form. Distribution Drug distribution characteristics for meclizine in humans are unknown. Elimination Meclizine has a plasma elimination half-life of about 5 to 6 hours in humans. Metabolism In an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme, CYP2D6 was found to be the dominant enzyme for metabolism of meclizine.

12.1 Mechanism of Action The precise mechanism by which meclizine exerts its therapeutic effect is unknown but is presumed to involve antagonism of the histamine H1 receptor.

12.2 Pharmacodynamics There are no relevant pharmacodynamic data regarding meclizine.

12.3 Pharmacokinetics The available pharmacokinetic information for meclizine following oral administration has been summarized from published literature. Absorption Meclizine is absorbed after oral administration with maximum plasma concentrations reaching at a median T max value of 3 hours post-dose (range: 1.5 to 6 hours) for the tablet dosage form. Distribution Drug distribution characteristics for meclizine in humans are unknown. Elimination Meclizine has a plasma elimination half-life of about 5 to 6 hours in humans. Metabolism In an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme, CYP2D6 was found to be the dominant enzyme for metabolism of meclizine.

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3 DOSAGE FORMS AND STRENGTHS 12.5 mg: light blue colored, oval shaped tablets with “AN 441” debossed on one side and plain on the other side. 25 mg: light yellow colored, oval shaped tablets with “AN 442” debossed on one side and plain on the other side. 50 mg: white, oval shaped, partially bisected tablets with “AN 444” debossed on one side and plain on the other side. Tablets: 12.5 mg, 25 mg, and 50 mg ( 3 ).

Meclizine Hydrochloride Meclizine MECLIZINE HYDROCHLORIDE MECLIZINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO TALC FD&C BLUE NO. 1 Light AN;441 Meclizine Hydrochloride Meclizine Hydrochloride MECLIZINE HYDROCHLORIDE MECLIZINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO TALC D&C YELLOW NO. 10 Light AN;442 Meclizine Hydrochloride Meclizine Hydrochloride MECLIZINE HYDROCHLORIDE MECLIZINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO TALC AN;444

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to assess the carcinogenic potential of meclizine have not been conducted. Mutagenesis Genetic toxicology studies of meclizine have not been conducted. Impairment of Fertility Animal studies to assess the effects of meclizine on fertility and early embryonic development have not been conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to assess the carcinogenic potential of meclizine have not been conducted. Mutagenesis Genetic toxicology studies of meclizine have not been conducted. Impairment of Fertility Animal studies to assess the effects of meclizine on fertility and early embryonic development have not been conducted.

ANDA201451

Meclizine Hydrochloride

Meclizine Hydrochloride

65162-442

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 65162-441-03 Meclizine Hydrochloride Tablets, USP 12.5 mg Rx Only Container Label Amneal Pharmaceuticals LLC NDC 65162-442-03 Meclizine Hydrochloride Tablets, USP 25 mg Rx Only Container Label Amneal Pharmaceuticals LLC NDC 65162-444-03 Meclizine Hydrochloride Tablets, USP 50 mg Rx Only Container Label Amneal Pharmaceuticals LLC 0 0 0

17 PATIENT COUNSELING INFORMATION Administration Instructions Advise patients that the tablets must be swallowed whole [see Dosage and Administration (2.1) ]. Adverse Reactions Advise patients that meclizine hydrochloride may cause anaphylactic reaction, drowsiness, dry mouth, headache, fatigue, vomiting and, on rare occasions, blurred vision [see Warnings and Precautions (5.1) , Adverse Reactions (6) ]. Inform patients that meclizine hydrochloride may impair their ability to engage in potentially dangerous activities, such as operating machinery or vehicles. Concomitant Drug Interactions Advise patients regarding medications that should not be taken in combination with meclizine hydrochloride or that may necessitate increased monitoring [see Drug Interactions (7.1 , 7.2 )]. Inform patients that alcohol may increase adverse reactions. Concurrent Medical Conditions Advise patients to notify their healthcare provider about all of their medical conditions, including if they are pregnant or plan to become pregnant or if they are breastfeeding [see Warnings and Precautions (5.2) , Use in Specific Populations (8.1 , 8.2 )] . Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2023-06

8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.2 Lactation Risk Summary There are no data on the presence of meclizine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meclizine hydrochloride and any potential adverse effects on the breastfed infant from meclizine hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Data from epidemiological studies have not generally indicated a drug-associated risk of major birth defects with meclizine during pregnancy. However, in a published study, an increased incidence of fetal malformations was observed following oral administration of meclizine to pregnant rats during the period of organogenesis, at doses similar to those used clinically. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human Data Epidemiological studies reporting on pregnancies exposed to meclizine have not identified an association between the use of meclizine during pregnancy and an increased risk of major birth defects. Animal Data In a published study, oral administration of meclizine (25 mg/kg to 250 mg/kg) to pregnant rats during the period of organogenesis resulted in a high incidence of fetal malformations. These effects occurred at doses as low as 25 mg/kg, which is approximately 2 times the maximum recommended human dose (100 mg) on a body surface area (mg/m 2 ) basis.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Data from epidemiological studies have not generally indicated a drug-associated risk of major birth defects with meclizine during pregnancy. However, in a published study, an increased incidence of fetal malformations was observed following oral administration of meclizine to pregnant rats during the period of organogenesis, at doses similar to those used clinically. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human Data Epidemiological studies reporting on pregnancies exposed to meclizine have not identified an association between the use of meclizine during pregnancy and an increased risk of major birth defects. Animal Data In a published study, oral administration of meclizine (25 mg/kg to 250 mg/kg) to pregnant rats during the period of organogenesis resulted in a high incidence of fetal malformations. These effects occurred at doses as low as 25 mg/kg, which is approximately 2 times the maximum recommended human dose (100 mg) on a body surface area (mg/m 2 ) basis. 8.2 Lactation Risk Summary There are no data on the presence of meclizine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meclizine hydrochloride and any potential adverse effects on the breastfed infant from meclizine hydrochloride or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of meclizine has not been evaluated. As meclizine hydrochloride undergoes metabolism, hepatic impairment may result in increased systemic exposure of meclizine. Treatment with meclizine hydrochloride should be administered with caution in patients with hepatic impairment. 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of meclizine has not been evaluated. Because of a potential for drug/metabolite accumulation, meclizine hydrochloride should be administered with caution in patients with renal impairment and in the elderly, as renal function generally declines with age. 8.8 Genetic CYP2D6 Polymorphism The genetic polymorphism of CYP2D6 that results in poor-, intermediate-, extensive-, and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure. Therefore, when meclizine hydrochloride is administered to patients with CYP2D6 polymorphism, monitor for adverse reactions and clinical effect accordingly.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Meclizine Hydrochloride Tablets USP, 12.5 mg are supplied as light blue colored, oval shaped tablets with “AN 441” debossed on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-441-03 Bottles of 100: NDC 65162-441-10 Bottles of 500: NDC 65162-441-50 Bottles of 1000: NDC 65162-441-11 Meclizine Hydrochloride Tablets USP, 25 mg are supplied as light yellow colored, oval shaped tablets with “AN 442” debossed on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-442-03 Bottles of 100: NDC 65162-442-10 Bottles of 500: NDC 65162-442-50 Bottles of 1000: NDC 65162-442-11 Meclizine Hydrochloride Tablets USP, 50 mg are supplied as white, oval shaped, partially bisected tablets with “AN 444” debossed on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-444-03 Bottles of 100: NDC 65162-444-10 Bottles of 500: NDC 65162-444-50 Bottles of 1000: NDC 65162-444-11 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Keep this and all medication out of the reach of children.