Levocetirizine Dihydrochloride (levocetirizine dihydrochloride 5 mg) Dailymed

1 Indications And Usage

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

• The relief of symptoms associated with perennial allergic rhinitis (1.1)
• The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.2)

1.1 Perennial Allergic Rhinitis

Levocetirizine dihydrochloride tablets are indicated for the relief of symptoms associated with perennial allergic rhinitis in children 6 months to 2 years of age.

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 months of age and older.

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.


Chronic Idiopathic Urticaria (2.2)

• Adults and children 12 years of age and older: 5 mg once daily in the evening
• Children 6 to 11 years of age: 2.5 mg once daily in the evening
• Renal Impairment
  Adjust the dose in patients 12 years of age and older with decreased renal function (12.3)
  

2.2 Chronic Idiopathic Urticaria

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.  

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)].  

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.

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.  

Use of levocetirizine dihydrochloride 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. In subjects 1 to 5 years of age, the most common adverse reactions (rate ≥2% and > placebo) were pyrexia, diarrhea, vomiting, and otitis media. In subjects 6 to 11 months of age, the most common adverse reactions (rate ≥3% and > placebo) were diarrhea and constipation (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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 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 to 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 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 uls 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%Rounded to the closest unit percentage 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 to 6 Weeks in Duration

Adverse Reactions	LevocetirizineDihydrochloride2.5 mg(n = 421)	LevocetirizineDihydrochloride 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 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 uls 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%Rounded to the closest unit percentage of Subjects Aged 6 to 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%)

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 uls 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%Rounded to the closest unit percentage of Subjects Aged 1 to 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 mgTwice 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%)

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 uled 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.

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

• 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,  12.3).
• Pediatric UseDo not exceed the recommended dose of 2.5 mg once daily in children 6 to 11 years of age, respectively. Systemic exposure with these doses in respective pediatric age groups is comparable to that from a 5 mg once daily dose in adults. (12.3)

8.1 Pregnancy

Risk Summary

Available data from published literature and postmarketing experience with levocetirizine use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm with administration of levocetirizine by the oral route to pregnant rats and rabbits, during the period of organogenesis, at doses up to 390 times and 470 times, respectively, the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine had no effects on pup development at oral doses up to approximately 60 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine administered by the oral route to the dams had no effects on pup development at a dose that was approximately 25 times the MRHD in adults; however, lower pup weight gain during lactation was observed at a dose that was 95 times the MRHD in adults [see Data].  

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.  

Data

Animal data

In embryo-fetal development studies, pregnant rats received daily doses of levocetirizine up to 200 mg/kg/day from gestation days 6 to 15 and pregnant rabbits received daily doses of levocetirizine up to 120 mg/kg/day from gestation days 6 to 18. Levocetirizine produced no evidence of fetal harm in rats and rabbits at doses up to 390 and 470 times the MRHD, respectively (on a mg/m² basis with maternal oral doses of 200 and 120 mg/kg/day in rats and rabbits, respectively).  

No prenatal and postnatal development (PPND) studies in animals have been conducted with levocetirizine. In a PPND study conducted in mice, cetirizine was administered at oral doses up to 96 mg/kg/day from gestation day 15 through lactation day 21. Cetirizine lowered pup body weight gain during lactation at an oral dose in dams that was approximately 95 times the MRHD (on a mg/m² basis with a maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an oral dose in dams that was approximately 25 times the MRHD (on a mg/m² basis with a maternal oral dose of 24 mg/kg/day). In a PPND study conducted in rats, cetirizine was administered at oral doses up to 180 mg/kg/day from gestation day 17 to lactation day 22. Cetirizine did not have any adverse effects on rat dams or offspring development at doses up to approximately 60 times the MRHD (on a mg/m² basis with a maternal oral dose of 30 mg/kg/day). Cetirizine caused excessive maternal toxicity at an oral dose in dams that was approximately 350 times the MRHD (on a mg/m² basis with a maternal oral dose of 180 mg/kg/day).

8.2 Lactation

Risk Summary

There are no data on the presence of levocetirizine dihydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production. However, cetirizine has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine was excreted in milk [see Dat a]. When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levocetirizine dihydrochloride and any potential adverse effects on the breastfed child from levocetirizine dihydrochloride or from the underlying maternal condition.  

Data  

Animal data  

Cetirizine was detected in the milk of mice. No adverse developmental effects on pups were seen when cetirizine was administered orally to dams during lactation at a dose that was approximately 25 times the MRHD in adults [see Use in Specific Populations (8.1)]. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use

The recommended dose of levocetirizine dihydrochloride 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 [see Clinical Studies (14) ].

The recommended dose of levocetirizine dihydrochloride in patients 6 months to 2 years of age for the treatment of the symptoms of perennial allergic rhinitis and 6 months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons 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 months 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. The safety of levocetirizine dihydrochloride 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 dihydrochloride 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 (6.1) ].

The effectiveness of levocetirizine dihydrochloride 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 perennial allergic rhinitis and 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. 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 (2.2) , Clinical Studies (14) , and Clinical Pharmacology (12.3) ]. 

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) ].