LEVOCETIRIZINE DIHYDROCHLORIDE: Package Insert and Label Information

LEVOCETIRIZINE DIHYDROCHLORIDE- levocetirizine dihydrochloride tablet, film coated
Preferred Pharmaceuticals Inc.

1 INDICATIONS & USAGE

1.2 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.

2 DOSAGE & ADMINISTRATION

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

2.2 Chronic Idiopathic Urticaria

Adults and Children 12 Years of Age and Older
The recommended dose of levocetirizine dihydrochloride 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.

Children 6 to 11 Years of Age
The recommended dose of levocetirizine dihydrochloride 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)].

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 dihydrochloride.
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 & STRENGTHS

Levocetirizine dihydrochloride tablets, USP are white to off-white, film-coated, biconvex, oval-shaped, scored on both sides and imprinted with ‘M 17’ on one side, and contain 5 mg levocetirizine dihydrochloride.

4 CONTRAINDICATIONS

The use of levocetirizine dihydrochloride is contraindicated in:

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 (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 WARNINGS AND PRECAUTIONS

5.1 Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine dihydrochloride. 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. Concurrent use of levocetirizine dihydrochloride 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 dihydrochloride. Levocetirizine dihydrochloride should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine dihydrochloride may increase the risk of urinary retention. Discontinue levocetirizine dihydrochloride if urinary retention occurs.

6 ADVERSE REACTIONS

Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, asthenia, and urinary retention [see Warnings and Precautions (5) ].

6.1 Clinical Trials Experience

The safety data described below reflect exposure to levocetirizine dihydrochloride in 2708 patients with 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 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 12-24 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 1-6 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 Aged 12 Years and Older Exposed to Levocetirizine Dihydrochloride 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 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%)

*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 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 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 dihydrochloride 5 mg in placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride than placebo.Table 2: Adverse Reactions Reported in ≥ 2%* of Subjects Aged 6-12 Years Exposed to Levocetirizine Dihydrochloride 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%)

*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 dihydrochloride 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 dihydrochloride 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with levocetirizine dihydrochloride than placebo.

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

Adverse Reactions

Levocetirizine Dihydrochloride 1.25 mg Twice Daily (n = 114)

Placebo (n = 59)

Pyrexia

5 (4%)

1 (2%)

Diarrhea

4 (4%)

2 (3%)

Vomiting

4 (4%)

2 (3%)

Otitis Media

3 (3%)

0 (0%)

*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 dihydrochloride 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 dihydrochloride 1.25 mg once daily in the placebo-controlled safety trial and that were more common with levocetirizine dihydrochloride 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 dihydrochloride 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 dihydrochloride 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 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 Postmarketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have also been identified during postapproval use of levocetirizine dihydrochloride. Because these reactions 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.
Cardiac disorders: palpitations, tachycardia
Ear and labyrinth disorders: vertigo
Eye disorders: blurred vision, visual disturbances
Gastrointestinal disorders: nausea, vomiting
General disorders and administration site conditions: edema
Hepatobiliary disorders: hepatitis
Immune system disorders: anaphylaxis and hypersensitivity
Metabolism and nutrition disorders: increased appetite
Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia
Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paresthesia, seizure (reported in subjects with and without a known seizure disorder),
tremor
Psychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideation
Renal and urinary disorders: dysuria, urinary retention
Respiratory, thoracic, and mediastinal disorders: dyspnea
Skin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritus, rash and urticaria
Besides these reactions reported under treatment with levocetirizine dihydrochloride, 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 dihydrochloride.
Cardiac disorders: severe hypotension
Gastrointestinal disorders: cholestasis
Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic
Pregnancy, puerperium and perinatal conditions: stillbirth
Renal and urinary disorders: glomerulonephritis
Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP); rebound pruritus — pruritus within a few days after discontinuation of cetirizine, usually after long-term use (e.g. months to years) of cetirizine.

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