Xyzal Drug Information

Perennial Allergic Rhinitis

XYZAL is indicated for the relief of symptoms associated with perennial allergic rhinitis in children 6 months to 2 years of age.

Chronic Idiopathic Urticaria

XYZAL is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.

Perennial Allergic Rhinitis Children 6 months to 2 Years of Age

The recommended initial dose of XYZAL is 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure to adults receiving 5 mg .

Chronic Idiopathic Urticaria Adults and Children 12 Years of Age and Older

The recommended dose of XYZAL is 5 mg (1 tablet or 2 teaspoons oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet or 1 teaspoon oral solution) once daily in the evening. Children 6 to 11 Years of Age The recommended dose of XYZAL is 2.5 mg (1/2 tablet or 1 teaspoon oral solution) 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 . Children 6 months to 5 Years of Age The recommended initial dose of XYZAL is 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure to adults receiving 5 mg . Dose Adjustment for Renal and Hepatic Impairment In adults and children 12 years of age and older with: Mild renal impairment (creatinine clearance = 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 XYZAL. 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.

Clinical Trials Experience

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 trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to XYZAL 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 XYZAL 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 XYZAL 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 XYZAL 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 XYZAL 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 XYZAL 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 XYZAL-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 XYZAL 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 XYZAL 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 XYZAL 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with XYZAL than placebo. Table 1: Adverse Reactions Reported in ≥2%* of Subjects Aged 12 Years and Older Exposed to XYZAL 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration Adverse Reactions XYZAL 2.5 mg (n = 421) XYZAL 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 XYZAL 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 XYZAL 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 XYZAL 5 mg in placebo-controlled clinical trials and that were more common with XYZAL than placebo. Table 2: Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to XYZAL 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration Adverse Reactions XYZAL 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 XYZAL 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 XYZAL 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with XYZAL than placebo. Table 3: Adverse Reactions Reported in ≥2%* of Subjects Aged 1-5 Years Exposed to XYZAL 1.25 mg Twice Daily in a 2-Week Placebo-Controlled Clinical Trial Adverse Reactions XYZAL 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 XYZAL 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 XYZAL 1.25 mg once daily in the placebo-controlled safety trial and that were more common with XYZAL than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the XYZAL 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 XYZAL 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 XYZAL 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.

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 XYZAL. 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, urticaria, and new onset pruritus within a few days after discontinuation of XYZAL, usually after long-term use (e.g., few months to years) of XYZAL Besides these reactions reported under treatment with XYZAL, other potentially severe adverse reactions 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 reactions could also potentially occur under treatment with XYZAL. 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)

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.

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.

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 . 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis with a maternal oral dose of 180 mg/kg/day).

Pediatric Use The recommended dose of XYZAL 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 . The recommended dose of XYZAL 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 XYZAL in adults and pediatric patients and on the safety profile of XYZAL 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 XYZAL 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 XYZAL 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 XYZAL 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age . The effectiveness of XYZAL 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 XYZAL 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 XYZAL to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of XYZAL 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. .

Patients with Known Hypersensitivity Patients with known hypersensitivity to levocetirizine or any

of the ingredients of XYZAL, or to cetirizine. Observed reactions range from urticaria to anaphylaxis .

Patients with End-Stage Renal Disease Patients with end-stage renal disease (CL CR

<10 mL/min) and patients undergoing hemodialysis

Pediatric Patients with Impaired Renal Function Children 6 months to 11 years

of age with impaired renal function

Overdosage has been reported with XYZAL. Symptoms of overdose may include drowsiness in adults. In children agitation and restlessness may initially occur, followed by drowsiness. There is no known specific antidote to XYZAL. Should overdose occur, symptomatic or supportive treatment is recommended.

XYZAL 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, and approximately 180 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m 2 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, and approximately 370 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m 2 basis).