Levocetirizine Dihydrochloride

American Health Packaging

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use levocetirizine dihydrochloride safely and effectively. See full prescribing information for levocetirizine dihydrochloride. Levocetirizine Dihydrochloride Tablets for Oral useInitial U.S. Approval: 1995 INDICATIONS AND USAGELevocetirizine dihydrochloride is a histamine H1-receptor antagonist indicated for: •The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.3) DOSAGE AND ADMINISTRATION •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 ImpairmentAdjust the dose in patients 12 years of age and older with decreased renal function (2.4, 12.3) DOSAGE FORMS AND STRENGTHS •Immediate release breakable (scored) tablets, 5 mg (3) CONTRAINDICATIONS •Patients with a known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablets 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 to 11 years of age with renal impairment (4.3)  WARNINGS AND PRECAUTIONS •Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride (5.1). •Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride (5.1). •Use with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride if urinary retention occurs (5.2). Side Effects 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 Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS •Renal ImpairmentBecause 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 once daily in children 6 to 11 years. Systemic exposure with this dose in pediatric age groups is comparable to that from a 5 mg once daily dose in adults. (12.3).   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.  

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 INDICATIONS & USAGE
  • 1.3 Chronic Idiopathic Urticaria
• 2 DOSAGE & ADMINISTRATION
  • 2.1 Adults and Children 12 Years of Age and Older
  • 2.2 Children 6 to 11 Years of Age
  • 2.3 Children 6 months to 5 Years of Age
  • 2.4 Dose Adjustment for Renal and Hepatic Impairment
• 3 DOSAGE FORMS & STRENGTHS
• 4 LEVOCETIRIZINE DIHYDROCHLORIDE CONTRAINDICATIONS
  • 4.1 Patients with known hypersensitivity
  • 4.2 Patients with end-stage renal disease
  • 4.3 Pediatric patients with impaired renal function
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Somnolence
  • 5.2 Urinary Retension
• 6 LEVOCETIRIZINE DIHYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Post-Marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine
  • 7.2 Ritonavir
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 LEVOCETIRIZINE DIHYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology
• 14 CLINICAL STUDIES
  • 14.2 Chronic Idiopathic Urticaria
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Somnolence
  • 17.2 Concomitant Use of Alcohol and other Central Nervous System Depressants
  • 17.3 Dosing of Levocetirizine Dihydrochloride
• PACKAGING INFORMATION
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS & USAGE

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 & 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.

2.1 Adults and Children 12 Years of Age and Older

The recommended dose of levocetirizine dihydrochloride tablets are 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 are 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 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 & STRENGTHS

Levocetirizine dihydrochloride tablets are white film coated, scored, round shaped, standard concave tablets debossed with ‘161’ on one side and ‘H’ on other side.

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 (CL_CR < 10 mL/min) and patients undergoing hemodialysis.

4.3 Pediatric patients with impaired renal function

Children 6 to 11 years of age with impaired renal function.

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.

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 Retension

Urinary retention has been reported post-marketing 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, and astheniaand urinary retention [see Warnings and Precautions (5) ].

6.1 Clinical Trials Experience

The safety data described below reflect exposure to levocetirizine dihydrochloride 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 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 (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.

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 dihydrochloride 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 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.

* 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.

* 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 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 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 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 listed above, adverse events have also been identified during post-approval use of levocetirizine dihydrochloride. 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, movement disorders (including dystonia and oculogyric crisis), 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 dihydrochloride, 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: orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth, tic, myoclonus, and extrapyramidal symptoms.

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

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 approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on a mg/m² 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/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 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 12 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 to 11 years of age for the treatment of the symptoms of chronic idiopathic urticaria is based on cross-study 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 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. [see Adverse Reactions (6.1) ].

The effectiveness of levocetirizine dihydrochloride 2.5 mg once daily (6 to 11 years of age) for the treatment of the 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 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. [see Dosage and Administration (2.2) ; Clinical Studies (14) ; and Clinical Pharmacology (12.3) ].
 
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.

8.5 Geriatric Use

Clinical studies of levocetirizine dihydrochloride 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.

8.6 Renal Impairment

Levocetirizine dihydrochloride 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 (2) and Clinical Pharmacology (12.3) ].

8.7 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 [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Overdosage has been reported with levocetirizine dihydrochloride.

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 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 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 on a mg/m² basis).
 
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.

11 DESCRIPTION

Levocetirizine dihydrochloride, the active component of levocetirizine dihydrochloride tablets, 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 empirical formula of levocetirizine dihydrochloride is C₂₁H₂₅ClN₂O₃•2HCl. The molecular weight is 461.82 and the chemical structure is shown below: