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Levocetirizine Dihydrochloride Tablet and Oral Solution

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Levocetirizine dihydrochloride is an orally active H1- 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 structural formula is:

Molecular formula: C21H25ClN2O3•2HCl- Molecular weight: 461.82

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, scored tablets for oral administration. The tablets are debossed ‘R & 5’ separated with break line on one side and break line on other side.

Inactive ingredients are: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, and titanium dioxide.

Levocetirizine dihydrochloride 0.5 mg/mL oral solution is formulated as an immediate release, clear, colorless liquid.

Inactive ingredients are: sodium acetate trihydrate, glacial acetic acid, maltitol solution, glycerin, methylparaben, propylparaben, saccharin, flavoring (consisting of triacetin, natural & artificial flavors, dl-alpha-tocopherol), purified water.

2. INDICATIONS AND USAGE

2.1 Seasonal Allergic Rhinitis

Levocetirizine is indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 2 years of age and older.

2.2 Perennial Allergic Rhinitis

Levocetirizine is indicated for the relief of symptoms associated with perennial allergic rhinitis in adults and children 6 months of age and older.

2.3 Chronic Idiopathic Urticaria

Levocetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older.

3. DOSAGE AND ADMINISTRATION

Levocetirizine is available as 2.5 mg/5 mL (0.5 mg/mL) oral solution and as 5 mg breakable (scored) tablets, allowing for the administration of 2.5 mg, if needed. Levocetirizine can be taken without regard to food consumption.

3.1 Adults and Children 12 Years of Age and Older

The recommended dose of levocetirizine is 5 mg (1 tablet or 2 teaspoons [10 mL] oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet or 1 teaspoon [5 mL] oral solution) once daily in the evening.

3.2 Children 6 to 11 Years of Age

The recommended dose of levocetirizine is 2.5 mg (1/2 tablet or 1 teaspoon [5 mL] oral solution) 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.

3.3 Children 6 months to 5 Years of Age

The recommended initial dose of levocetirizine is 1.25 mg (1/2 teaspoon oral solution) [2.5mL] once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure to adults receiving 5 mg.

3.4 Dose Adjustment for Renal and Hepatic Impairment

In adults and children 12 years of age and older with:

• Mild renal impairment (creatinine clearance [CLCR] = 50-80 mL/min): a dose of 2.5 mg once daily is recommended;

• Moderate renal impairment (CLCR = 30-50 mL/min): a dose of 2.5 mg once every other day is recommended;

• Severe renal impairment (CLCR = 10-30 mL/min): a dose of 2.5 mg twice weekly (administered once every 3-4 days) is recommended;

• End-stage renal disease patients (CLCR < 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine.

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.

4. CONTRAINDICATIONS

The use of levocetirizine is contraindicated in:

4.1 Patients with known hypersensitivity

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].

4.2 Patients with end-stage renal disease

Patients with end-stage renal disease (CLCR < 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.

5. MECHANISM OF ACTION

Levocetirizine, the active enantiomer of cetirizine, is an antihistamine; its principal effects are mediated via selective inhibition of H1 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 H1-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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in 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 should be used during pregnancy only if clearly needed.

Teratogenic Effects: In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on a mg/m2 basis.

6.2 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/m2 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 in nursing mothers is not recommended.

6.3 Pediatric Use

The recommended dose of levocetirizine 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.

The recommended dose of levocetirizine 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 in adults and pediatric patients and on the safety profile of levocetirizine 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 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 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 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].

The effectiveness of levocetirizine 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 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 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 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. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 mg once daily in adults. [see Dosage and Administration].

6.4 Geriatric Use

Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

6.5 Renal Impairment

Levocetirizine is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see Dosage and Administration].

6.6 Hepatic Impairment

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment.

7. WARNINGS AND PRECAUTIONS

7.1 Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of levocetirizine. Concurrent use of levocetirizine with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

7.2 Urinary Retention

Urinary retention has been reported post-marketing with levocetirizine. Levocetirizine should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention. Discontinue levocetirizine if urinary retention occurs.

8. ADVERSE REACTIONS

Use of levocetirizine has been associated with somnolence, fatigue, and asthenia [see Warnings and Precautions].

8.1 Clinical Trials Experience

The safety data described below reflect exposure to levocetirizine 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 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 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 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 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 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine-treated subjects 12-24 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 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 1-6 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 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 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with levocetirizine than placebo.

Table 1: Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to Levocetirizine 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration

* Rounded to the closest unit percentage

Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to levocetirizine are syncope (0.2%) and weight increased (0.5%).

Pediatric Patients 6 to 12 Years of Age

A total of 243 pediatric patients 6 to 12 years of age received levocetirizine 5 mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were 6 to 8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to levocetirizine 5 mg in placebo-controlled clinical trials and that were more common with levocetirizine than placebo.

Table 2: Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to Levocetirizine 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

* Rounded to the closest unit percentage

Pediatric Patients 1 to 5 Years of Age

A total of 114 pediatric patients 1 to 5 years of age received levocetirizine 1.25 mg twice daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 3.8 years, 32% were 1 to 2 years of age, 71% were Caucasian and 18% were Black. Table 3 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years exposed to levocetirizine 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with levocetirizine than placebo.

Table 3: Adverse Reactions Reported in ≥2%* of Subjects Aged 1-5 Years Exposed to Levocetirizine 1.25 mg Twice Daily in a 2-Week Placebo-Controlled Clinical Trial

* Rounded to the closest unit percentage

Pediatric Patients 6 to 11 Months of Age

A total of 45 pediatric patients 6 to 11 months of age received levocetirizine 1.25 mg once daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 9 months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than 1 subject (i.e. greater than or equal to 3% of subjects) aged 6 to 11 months exposed to levocetirizine 1.25 mg once daily in the placebo-controlled safety trial and that were more common with levocetirizine than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the levocetirizine and placebo-treated groups, respectively.

Long-Term Clinical Trials Experience

In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with levocetirizine 5 mg once daily for 4 or 6 months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with levocetirizine discontinued because of somnolence, fatigue or asthenia compared to 2 (< 1%) in the placebo group.

There are no long term clinical trials in children below 12 years of age with allergic rhinitis or chronic idiopathic urticaria.

Laboratory Test Abnormalities

Elevations of blood bilirubin and transaminases were reported in < 1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.

8.2 Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, adverse events have also been identified during post-approval use of levocetirizine in other countries. Because these events are 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. Adverse events of hypersensitivity and anaphylaxis, angioedema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, paraesthesia, dizziness, aggression and agitation, hallucinations, depression, visual disturbances, blurred vision, palpitations, tachycardia, dyspnea, nausea, vomiting, hepatitis, dysuria, and myalgia have been reported.

Besides these events reported under treatment with levocetirizine, other potentially severe adverse events have been reported from the post-marketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with levocetirizine: suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

9. OVERDOSAGE

Overdosage has been reported with levocetirizine.

Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness, followed by drowsiness in children. There is no known specific antidote to levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine 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/m2 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/m2 basis).

10. 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.

10.1 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.

10.2 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.

11. PHARMACOKINETICS

Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.

• Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.

A dose of 5 mg (10 mL) of levocetirizine oral solution is bioequivalent to a 5 mg dose of levocetirizine tablets. Following oral administration of a 5 mg dose of levocetirizine oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose.

• Distribution

The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.

• Metabolism

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.

• Elimination

The plasma half-life in adult healthy subjects was about 8 to 9 hours after administration of oral tablets and oral solution, and the mean oral total body clearance for levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of levocetirizine is reduced [see Dosage and Administration].

• Pediatric Patients

Data from a pediatric pharmacokinetic study with oral administration of a single dose of 5 mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this pediatric population than in adults.

Dedicated pharmacokinetic studies have not been conducted in pediatric patients younger than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years of age results in plasma concentrations similar to those of adults receiving 5 mg once daily.

• Geriatric Patients

Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration].

• Gender

Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

• Race

The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

• Renal Impairment

Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2.0-, 2.9-, and 4-fold, respectively.

The total body clearance of levocetirizine after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment. Therefore, it is recommended to adjust the dose and dosing intervals of levocetirizine based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CLCR < 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.

The dosage of levocetirizine should be reduced in patients with mild renal impairment. Both the dosage and frequency of administration should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration].

• Hepatic Impairment

Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration.

As levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment [see Dosage and Administration].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: XYZAL, by UCB INC.

b) Generic drugs:

Tablet: Levocetirizine dihydrochloride, by various manufacturers.

Oral solution: Levocetirizine dihydrochloride, by Synthon Pharms.

2) How Supplied:

Levocetirizine dihydrochloride tablets (by DR REDDYS LABS) are white, oval, film coated, biconvex tablets debossed ‘R & 5’ separated with break line on one side and break line on other 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

_____________________________________________________________________

XYZAL oral solution is a clear, colorless liquid containing 0.5 mg of levocetirizine dihydrochloride per mL.

Oral solution in 5 oz glass bottles (NDC 0024-5801-20)

Oral Solution in 5 oz polypropylene bottles (NDC 0024-5801-21)

3) Storage:

Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature].

Rx only

Rev 09/12