levocetirizine dihydrochloride

1 INDICATIONS AND USAGE Levocetirizine dihydrochloride is a histamine H 1 -receptor antagonist indicated for: The relief of symptoms associated with seasonal and perennial allergic rhinitis ( 1.1 , 1.2 ) The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.3) 1.1 Seasonal Allergic Rhinitis Levocetirizine dihydrochloride tablets are indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 2 years of age and older. 1.2 Perennial Allergic Rhinitis Levocetirizine dihydrochloride tablets are indicated for the relief of symptoms associated with perennial allergic rhinitis in adults and children 6 months of age and older. 1.3 Chronic Idiopathic Urticaria Levocetirizine dihydrochloride tablets are indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.

Purpose Antihistamine

2 DOSAGE AND ADMINISTRATION Levocetirizine dihydrochloride tablets are available as 5 mg breakable (scored) tablets, allowing for the administration of 2.5 mg, if needed. Levocetirizine dihydrochloride tablets can be taken without regard to food consumption. Adults and children 12 years of age and older: 5 mg once daily in the evening (2.1) Children 6 to 11 years of age: 2.5 mg once daily in the evening (2.2) Renal Impairment Adjust the dose in patients 12 years of age and older with decreased renal function (2.4 , 12.3 ) 2.1 Adults and Children 12 Years of Age and Older The recommended dose of levocetirizine dihydrochloride tablets is 5 mg (1 tablet ) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet ) once daily in the evening. 2.2 Children 6 to 11 Years of Age The recommended dose of levocetirizine dihydrochloride tablets is 2.5 mg (1/2 tablet ) once daily in the evening. The 2.5 mg dose should not be exceeded because the systemic exposure with 5 mg is approximately twice that of adults [see Clinical Pharmacology (12.3) ]. 2.4 Dose Adjustment for Renal and Hepatic Impairment In adults and children 12 years of age and older with: Mild renal impairment (creatinine clearance [CL CR ] = 50 to 80 mL/min): a dose of 2.5 mg once daily is recommended; Moderate renal impairment (CL CR = 30 to 50 mL/min): a dose of 2.5 mg once every other day is recommended; Severe renal impairment (CL CR = 10 to 30 mL/min): a dose of 2.5 mg twice weekly (administered once every 3-4 days) is recommended; End-stage renal disease patients (CL CR < 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine dihydrochloride tablets. No dose adjustment is needed in patients with solely hepatic impairment. In patients with both hepatic impairment and renal impairment, adjustment of the dose is recommended.

3 DOSAGE FORMS AND STRENGTHS Levocetirizine dihydrochloride tablets are white, oval, film coated biconvex tablets with breakline on both sides and debossed with 'R' &'5' separated by breakline on one side. and contain 5 mg levocetirizine dihydrochloride. Immediate release breakable (scored) tablets, 5 mg (3)

4 CONTRAINDICATIONS The use of levocetirizine dihydrochloride tablets are contraindicated in: Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine , or to cetirizine. Observed reactions range from urticaria to anaphylaxis [see Adverse Reactions (6.2) ]. Patients with end-stage renal disease (CL CR < 10 mL/min) and patients undergoing hemodialysis. Pediatric patients 6 to 11 years of age with impaired renal function [see Use in Specific Populations (8.4) ]. Patients with a known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride or to cetirizine (4.1) Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis (4.2) Children 6 months to 11 years of age with renal impairment (4.3) 4.1 Patients with known hypersensitivity • Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride, or to cetirizine. Observed reactions range from urticaria to anaphylaxis [see Adverse Reactions (6.2) ]. 4.2 Patients with end-stage renal disease • Patients with end-stage renal disease (CL CR < 10 mL/min) and patients undergoing hemodialysis. 4.3 Pediatric patients with impaired renal function Children 6 months to 11 years of age with impaired renal function

Do not use if you have kidney disease if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing cetirizine

Ask a doctor before use if you have ever had trouble urinating or emptying your bladder

Stop use and ask doctor if you have trouble urinating or emptying your bladder an allergic reaction to this product occurs. Seek medical help right away.

6 ADVERSE REACTIONS Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, asthenia, and urinary retention [see Warnings and Precautions (5) ]. The most common adverse reactions (rate ≥2% and > placebo) were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis in subjects 12 years of age and older, and pyrexia, somnolence, cough, and epistaxis in children 6 to 12 years of age. In subjects 1 to 5 years of age, the most common adverse reactions (rate ≥2% and > placebo) were pyrexia, diarrhea, vomiting, and otitis media. In subjects 6 to 11 months of age, the most common adverse reactions (rate ≥3% and > placebo) were diarrhea and constipation. (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The safety data described below reflect exposure to levocetirizine dihydrochloride in 2708 patients with seasonal or perennial allergic rhinitis or chronic idiopathic urticaria in 14 controlled clinical trials of 1 week to 6 months duration. The short-term (exposure up to 6 weeks) safety data for adults and adolescents are based upon eight clinical trials in which 1896 patients (825 males and 1071 females aged 12 years and older) were treated with levocetirizine dihydrochloride 2.5, 5, or 10 mg once daily in the evening. The short-term safety data from pediatric patients are based upon two clinical trials in which 243 children with seasonal or perennial allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with levocetirizine dihydrochloride 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine dihydrochloride 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with levocetirizine dihydrochloride 1.25 mg once daily for 2 weeks. The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with levocetirizine dihydrochloride 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine dihydrochloride-treated subjects 12 to 24 months of age. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 years of Age and Older In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian. In these trials 43% and 42% of the subjects in the levocetirizine dihydrochloride 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group. In placebo-controlled trials of 1 to 6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with levocetirizine dihydrochloride showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%). Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to levocetirizine dihydrochloride 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride than placebo. Table 1 Adverse Reactions Reported in ≥ 2%* of Subjects …

7 DRUG INTERACTIONS In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug-drug interaction studies have been performed with levocetirizine. Drug interaction studies have been performed with racemic cetirizine. 7.1 Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole, and cimetidine. There was a small decrease (∼16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect. 7.2 Ritonavir Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

8 USE IN SPECIFIC POPULATIONS Renal Impairment Because levocetirizine dihydrochloride is substantially excreted by the kidneys, the risk of adverse reactions to this drug may be greater in patients with impaired renal function ( 8.6 and 12.3 ). Pediatric Use Do not exceed the recommended doses of 2.5 mg and 1.25 mg once daily in children 6 to 11 years and 6 months to 5 years of age, respectively. Systemic exposure with these doses in respective pediatric age groups is comparable to that from a 5 mg once daily dose in adults. ( 12.3 ). 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, levocetirizine dihydrochloride should be used during pregnancy only if clearly needed. Teratogenic Effects In rats and rabbits, levocetirizine was not teratogenic at oral doses up to 200 and 120 mg/kg, respectively (approximately 320 and 390 times the maximum recommended daily oral dose in adults on a mg/m 2 basis). 8.3 Nursing Mothers No peri- and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on a mg/m 2 basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of levocetirizine dihydrochloride in nursing mothers is not recommended. 8.4 Pediatric Use The recommended dose of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies (14) ]. The recommended dose of levocetirizine dihydrochloride in patients 6 months to 11 years of age for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria and in patients 2 to 11 years of age for the treatment of symptoms of seasonal allergic rhinitis is based on cross-study comparisons of the systemic exposure of levocetirizine dihydrochloride in adults and pediatric patients and on the safety profile of levocetirizine dihydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age. The safety of levocetirizine dihydrochloride 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of levocetirizine dihydrochloride 1.25 mg twice daily was evaluated in one 2 week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of levocetirizine dihydrochloride 1.25 mg once daily was evaluated in one 2 week clinical trial in 45 pediatric patients 6 to 11 months of age [see Adverse Reactions ( 6.1 ) ]. The effectiveness of levocetirizine dihydrochloride 1.25 mg once daily (6 months to 5 years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine dihydrochloride 5 mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children. Cross-study comparisons indicate that administration of a 5 mg dose of levocetirizine dihydrochloride to 6 to 12 year old pediatric seasonal allergic rhinitis patients resulted in about 2 fold the systemic exposure (AUC) observed when 5 mg of levocetirizine dihydrochloride was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. …

12.1 Mechanism of Action Levocetirizine, the active enantiomer of cetirizine, is an antihistamine; its principal effects are mediated via selective inhibition of H 1 receptors. The antihistaminic activity of levocetirizine has been documented in a variety of animal and human models. In vitro binding studies revealed that levocetirizine has an affinity for the human H 1 -receptor 2-fold higher than that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively. The clinical relevance of this finding is unknown.

11 DESCRIPTION Levocetirizine dihydrochloride, the active component of levocetirizine dihydrochloride tablets is an orally active H 1 - receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C 21 H 25 ClN 2 O 3 •2HCl. The molecular weight is 461.82 and the chemical structure is shown below: Levocetirizine dihydrochloride white or almost white powder and is freely soluble in water, practically insoluble in acetone and in methylene chloride. Levocetirizine dihydrochloride 5 mg tablets are formulated as immediate release, white, oval, film coated biconvex tablets with breakline on both sides and debossed with 'R' &'5' separated by breakline on one side for oral administration. Inactive ingredients are: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, and titanium dioxide. structure

Active ingredient (in each tablet) Levocetirizine dihydrochloride USP, 5 mg

10 OVERDOSAGE Overdosage has been reported with levocetirizine dihydrochloride. Symptoms of overdose may include drowsiness in adults. In children agitation and restlessness may initially occur, followed by drowsiness. There is no known specific antidote to levocetirizine dihydrochloride. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine dihydrochloride is not effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested. The acute maximal non-lethal oral dose of levocetirizine was 240 mg/kg in mice (approximately 190 times the maximum recommended daily oral dose in adults, approximately 230 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 180 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m 2 basis). In rats the maximal non-lethal oral dose was 240 mg/kg (approximately 390 times the maximum recommended daily oral dose in adults, approximately 460 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 370 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m 2 basis).

16 HOW SUPPLIED/STORAGE AND HANDLING Levocetirizine dihydrochloride tablets are white, oval, film coated biconvex tablets with breakline on both sides and debossed with 'R' &'5' separated by breakline on one side and contain 5 mg levocetirizine dihydrochloride. They are supplied in unit of use HDPE bottles and unit of use blisters. Bottles of 30 NDC 55111-282-30 Bottles of 60 NDC 55111-282-60 Bottles of 90 NDC 55111-282-90 Bottles of 100 NDC 55111-282-01 Bottles of 180 NDC 55111-282-18 Bottles of 500 NDC 55111-282-05 Unit dose package of 100 (10 x 10) NDC 55111-282-78 Storage: Store at 20-25°C (68-77°F); [see USP Controlled Room Temperature].