Levocetirizine Dihydrochloride (levocetirizine dihydrochloride 5 mg) Dailymed

Recent Major Changes Section

Warnings and Precautions, Urinary Retention (5.2) [09/2012]

Boxed Warning Section

1 Indications And Usage

Levocetirizine dihydrochloride tablets are a histamine H₁-receptor antagonist indicated for:

• The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.3)

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) is approved for UCB Inc.'s levocetirizine dihydrochloride drug product labeling. 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 is 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 is 5 mg (1 tablet) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (½ tablet) once daily in the evening.

2.2 Children 6 to 11 Years of Age

The recommended dose of levocetirizine is 2.5 mg (½ 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 labeling. 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 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 to 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, oval-shaped, scored tablets and contain 5 mg levocetirizine dihydrochloride. One side of the tablet is scored in half and debossed with the number "9" on one side of the score and "3" on the other. The other side of the tablet is debossed with the number "7701."

• 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

• Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine (5.1).
• Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine (5.1).
• Use with caution in patients with predisposing factors of urinary retention (e.g., spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine if urinary retention occurs (5.2).

5.1 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.

5.2 Urinary Retention

Urinary retention has been reported postmarketing 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.

6 Adverse Reactions

Use of levocetirizine 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 (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; 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 in 12 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 (162 males and 81 females 6 to 12 years of age) were treated with levocetirizine 5 mg once daily for 4 to 6 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) were exposed to treatment with levocetirizine 5 mg once daily.

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 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 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 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%Rounded to the closest unit percentage of Subjects Aged 12 Years and Older Exposed to Levocetirizine 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1 to 6 Weeks in Duration

Adverse Reactions	Levocetirizine Dihydrochloride 2.5 mg (n = 421)	Levocetirizine Dihydrochloride 5 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%)

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 uls 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%Rounded to the closest unit percentage of Subjects Aged 6 to 12 Years Exposed to Levocetirizine 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

Adverse Reactions	Levocetirizine Dihydrochloride 5 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%)

Clinical trial information in pediatric patients (age 6 months to 5 years) is approved for UCB Inc.'s levocetirizine dihydrochloride drug product labeling. 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 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 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 Postmarketing 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. 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, increased appetite, angioedema, fixed drug eruption, pruritus, rash and urticaria, convulsion, paraesthesia, dizziness, tremor, dysgeusia, vertigo, aggression and agitation, hallucinations, depression, insomnia, suicidal ideation, visual disturbances, blurred vision, palpitations, tachycardia, dyspnea, nausea, vomiting, hepatitis, dysuria, urinary retention, myalgia, and edema have been reported.

Besides these events reported under treatment with levocetirizine, other potentially severe adverse events have been reported from the postmarketing 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: orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and stillbirth.