LEVOCETIRIZINE: 10,782 Adverse Event Reports & Safety Profile

Levocetirizine dihydrochloride, the active component of XYZAL tablets and oral solution, is an orally active H 1 -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 C 21 H 25 ClN 2 O 3

• 2HCl. The molecular weight is 461.82 and the chemical structure is shown below: Levocetirizine dihydrochloride is a white, crystalline powder and is water soluble. XYZAL 5 mg tablets are formulated as immediate release, white, film-coated, oval-shaped scored tablets for oral administration. The tablets are imprinted on both halves of the scored line with the letter Y in red (Opacode ® Red). Inactive ingredients are: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and macrogol 400. XYZAL 0.5 mg/mL oral solution is formulated as an immediate release, clear, colorless liquid. Inactive ingredients are: sodium acetate trihydrate, glacial acetic acid, maltitol solution, glycerin, methylparaben, propylparaben, saccharin, flavoring (consisting of triacetin, natural & artificial flavors, dl-alpha-tocopherol), purified water. The molecular weight is 461.82 and the chemical structure is shown below: Levocetirizine dihydrochloride, the active component of XYZAL tablets and oral solution, 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.

AND USAGE Levocetirizine dihydrochloride tablets are a histamine H 1 ‑receptor antagonist indicated for:

• The relief of symptoms associated with seasonal and perennial allergic rhinitis ( 1.1 , 1.2 )
• The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria ( 1.3 )

1.1 Seasonal Allergic Rhinitis Levocetirizine dihydrochloride tablets are indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older.

1.2 Perennial Allergic Rhinitis Levocetirizine dihydrochloride tablets are indicated for the relief of symptoms associated with perennial allergic rhinitis in adults and children 6 years of age and older.

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.

AND ADMINISTRATION Levocetirizine dihydrochloride is available as 2.5 mg/5 mL (0.5 mg/mL) oral solution. Levocetirizine dihydrochloride oral solution can be taken without regard to food consumption.

Perennial Allergic

Rhinitis (2.1)

• Children 6 months to 2 years of age: 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening 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
• Children 6 months to 5 years of age: 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening
• Renal Impairment Adjust the dose in patients 12 years of age and older with decreased renal function (12.3)

2.1 Perennial Allergic Rhinitis Children 6 months to 2 Years of Age The recommended initial dose of levocetirizine dihydrochloride 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 [see Clinical Pharmacology ( 12.3)].

2.2 Chronic Idiopathic Urticaria Adults and Children 12 Years of Age and Older The recommended dose of levocetirizine dihydrochloride is 5 mg (2 teaspoons [10 mL] oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1 teaspoon [5 mL] oral solution) once daily in the evening.

Children

6 to 11 Years of Age The recommended dose of levocetirizine dihydrochloride is 2.5 mg (1 teaspoon [5 mL] 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 [see Clinical Pharmacology (12.3) ].

Children

6 months to 5 Years of Age The recommended initial dose of levocetirizine dihydrochloride 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 [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 oral solution. 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.

The use of levocetirizine dihydrochloride tablets are contraindicated in: Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine , or to cetirizine. Observed reactions range from urticaria to anaphylaxis [see Adverse Reactions (6.2) ]. Patients with end-stage renal disease (CL CR < 10 mL/min) and patients undergoing hemodialysis. Pediatric patients 6 to 11 years of age with impaired renal function [see Use in Specific Populations (8.4) ]. Patients with a known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride 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 months to 11 years of age with renal impairment (4.3)

4.1 Patients with known hypersensitivity

• Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride, 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

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:

• Somnolence [see Warnings and Precautions ( 5.1 )]
• Urinary Retention [see Warnings and Precautions ( 5.2 )]
• Risk of New Onset Pruritus After Discontinuation of Levocetirizine Dihydrochloride Tablets. [ see Warnings and Precautions ( 5.3 )] 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 Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

AND PRECAUTIONS Somnolence: Somnolence, fatigue, and asthenia have been reported with use of levocetirizine dihydrochloride tablets in some patients in clinical trials. Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride tablets. Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride tablets. ( 5.1 )

Urinary

Retention: Urinary retention has been reported with use of levocetirizine dihydrochloride tablets. Use with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride tablets if urinary retention occurs. ( 5.2 ) Risk of New Onset Pruritus After Discontinuation of Levocetirizine dihydrochloride tablets: New onset pruritus within a few days after discontinuation of Levocetirizine dihydrochloride tablets has been reported, usually after long-term use (e.g., few months to years) of Levocetirizine dihydrochloride tablets. Symptoms may improve with restarting or tapering Levocetirizine dihydrochloride tablets ( 5.3 ).

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 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.

5.3 Risk of New Onset Pruritus After Discontinuation of Levocetirizine Dihydrochloride Tablets Cases of pruritus after discontinuation of levocetirizine dihydrochloride tablets have been reported in the postmarketing setting in patients where pruritus was not present before initiation of levocetirizine dihydrochloride tablets. Pruritus occurred within a few days of discontinuing levocetirizine dihydrochloride tablets among patients who used levocetirizine dihydrochloride tablets long-term (e.g., few months to years). Reported cases of pruritus were infrequent, but some were serious with patients experiencing widespread severe pruritus <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . If pruritus occurs after discontinuation of levocetirizine dihydrochloride tablets, symptoms may improve with restarting or tapering levocetirizine dihydrochloride tablets.

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.

Active ingredient (in each tablet) LEVOCETIRIZINE DIHYDROCHLORIDE USP 5 MG Purpose Antihistamine

INACTIVE INGREDIENTS colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide.