Levocetirizine dihydrochloride (levocetirizine dihydrochloride 5 mg) Dailymed

1 Indications And Usage

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Levocetirizine dihydrochloride tablets are a histamine H₁-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 6 years of age and older.

Pediatric use information in pediatric patients (age 2 to 5 years) with seasonal allergic rhinitis is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

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 years of age and older.

Pediatric use information in pediatric patients (age 6 months to 5 years) with perennial allergic rhinitis is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

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 years of age and older.

Pediatric use information in pediatric patients (age 6 months to 5 years) with chronic idiopathic urticaria is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

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) ].

2.3 Children 6 months to 5 Years of Age

Pediatric use information in pediatric patients (age 6 months to 5 years) is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

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] = 50-80 mL/min): a dose of 2.5 mg once daily is recommended;
• Moderate renal impairment (CL_CR = 30-50 mL/min): a dose of 2.5 mg once every other day is recommended;
• Severe renal impairment (CL_CR = 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 (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 to off-white, film-coated, scored, oval, biconvex, debossed with "L9CZ 5" on the unscored side and nothing on the scored side, and contain 5 mg levocetirizine dihydrochloride.

• Immediate release breakable (scored) tablets, 5 mg (3)

4 Contraindications

The use of levocetirizine dihydrochloride tablets is contraindicated in:

• Patients with a known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablets or to cetirizine (4)
• Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis (4)
• Children 6 months to 11 years of age with renal impairment (4)

4.1 Patients with known hypersensitivity

Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablets, 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

5 Warnings And Precautions

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• Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride tablets (5.1).
• Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride tablets (5.1).

5.1 Activities Requiring Mental Alertness

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine dihydrochloride tablets. 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 dihydrochloride tablets. Concurrent use of levocetirizine dihydrochloride tablets 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.

6 Adverse Reactions

Use of levocetirizine dihydrochloride tablets has been associated with somnolence, fatigue, and asthenia [see Warnings and Precautions (5.1) ].


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. (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine dihydrochloride tablets-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 dihydrochloride tablets 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 dihydrochloride tablets 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 uls adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to levocetirizine dihydrochloride tablets 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride tablets than placebo.

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

Adverse Reactions	Levocetirizine dihydrochloride Tablets2.5 mg(n = 421)	Levocetirizine dihydrochloride Tablets5 mg(n = 1070)	Placebo(n = 912)
Somnolence	22 (5%)	61 (6%)	16 (2%)
Nasopharyngitis	25 (6%)	40 (4%)	28 (3%)
Fatigue	5 (1%)	46 (4%)	20 (2%)
Dry Mouth	12 (3%)	26 (2%)	11 (1%)
Pharyngitis	10 (2%)	12 (1%)	9 (1%)

*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 dihydrochloride tablets 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 dihydrochloride tablets 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 uls adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to levocetirizine dihydrochloride tablets 5 mg in placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride tablets than placebo.

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

Adverse Reactions	Levocetirizine dihydrochloride Tablets5 mg(n = 243)	Placebo(n = 240)
Pyrexia	10 (4%)	5 (2%)
Cough	8 (3%)	2 (<1%)
Somnolence	7 (3%)	1 (<1%)
Epistaxis	6 (2%)	1 (<1%)

*Rounded to the closest unit percentage
Clinical trial information in pediatric patients (age 6 months to 5 years) is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

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 dihydrochloride tablets 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 dihydrochloride tablets 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.

6.2 Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and uled above, adverse events have also been identified during post-approval use of levocetirizine dihydrochloride tablets 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, angioneurotic edema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, aggression and agitation, visual disturbances, palpitations, dyspnea, nausea, hepatitis, and myalgia have been reported.

Besides these events reported under treatment with levocetirizine dihydrochloride tablets, 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 dihydrochloride tablets: hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

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12.1 Mechanism of Action

Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; 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.

12.2 Pharmacodynamics

Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown.

A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While a single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long post-marketing history of cetirizine without reports of QT prolongation.

12.3 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 T_max was delayed by about 1.25 hours and C_max 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 dihydrochloride oral solution is bioequivalent to a 5 mg dose of levocetirizine dihydrochloride tablets. Following oral administration of a 5 mg dose of levocetirizine dihydrochloride 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 (2.3) ].

• Drug Interaction Studies

In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above C_max level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4.

No formal in vivo drug interaction studies have been performed with levocetirizine. Studies have been performed with the racemic cetirizine [see Drug Interactions (7) ].

• 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 C_max and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean C_max 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.

Pharmacokinetic information in pediatric patients (age 1 to 5 years) is approved for UCB Inc.'s levocetirizine dihydrochloride drug product. However, due to UCB Inc.'s marketing exclusivity rights; this drug product is not labeled for such use in pediatric patients.

• 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 dihydrochloride tablets dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration (2) ].

• 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 (CL_CR < 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure was <10%.

The dosage of levocetirizine dihydrochloride tablets 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 (2.4) ].

• Hepatic Impairment

Levocetirizine dihydrochloride tablets have 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 (2) ].