Ambolev

Perennial Allergic Rhinitis

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

Chronic Idiopathic Urticaria

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

Ambolev is available as 2.5 mg/5 mL (0.5 mg/mL) oral solution and as 5 mg breakable (scored) tablets, allowing for the administration of 2.5 mg, if needed. Ambolev can be taken without regard to food consumption.

Perennial Allergic Rhinitis

Children 6 Months To 2 Years Of Age

The recommended initial dose of Ambolev is 1.25 mg (1/2 teaspoon oral solution) [2.5mL] 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 Ambolev is 5 mg (1 tablet or 2 teaspoons [10 mL] oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet or 1 teaspoon [5 mL] oral solution) once daily in the evening.

Children 6 To 11 Years Of Age

The recommended dose of Ambolev is 2.5 mg (1/2 tablet or 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.

Children 6 Months To 5 Years Of Age

The recommended initial dose of Ambolev is 1.25 mg (1/2 teaspoon oral solution) [2.5mL] 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 [CL_CR] = 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 Ambolev.

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 Ambolev is contraindicated in:

Patients With Known Hypersensitivity

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

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Ambolev. 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 Ambolev. Concurrent use of Ambolev 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.

Urinary Retention

Urinary retention has been reported post-marketing with Ambolev. Ambolev should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Ambolev may increase the risk of urinary retention. Discontinue Ambolev if urinary retention occurs.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults, approximately 4 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 6 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 2 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). The clinical significance of these findings during long-term use of Ambolev is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in mice.

In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m² basis).

Use In Specific Populations

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, Ambolev 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.

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 Ambolev in nursing mothers is not recommended.

Pediatric Use

The recommended dose of Ambolev 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 Ambolev 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 Ambolev in adults and pediatric patients and on the safety profile of Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 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 Ambolev to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of Ambolev 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..

Geriatric Use

Clinical studies of Ambolev 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.

Renal Impairment

Ambolev 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.

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.

Use of Ambolev has been associated with somnolence, fatigue, asthenia, and urinary retention.

Clinical Trials Experience

The safety data described below reflect exposure to Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 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 Ambolev 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 Ambolev-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 Ambolev 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 Ambolev 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 Ambolev 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with Ambolev than placebo.

Table 1 Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to Ambolev 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration

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 Ambolev 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 Ambolev 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 Ambolev 5 mg in placebo-controlled clinical trials and that were more common with Ambolev than placebo.

Table 2 Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to Ambolev 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

Pediatric Patients 1 To 5 Years Of Age

A total of 114 pediatric patients 1 to 5 years of age received Ambolev 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 Ambolev 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with Ambolev than placebo.

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

Pediatric Patients 6 To 11 Months Of Age

A total of 45 pediatric patients 6 to 11 months of age received Ambolev 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 Ambolev 1.25 mg once daily in the placebo-controlled safety trial and that were more common with Ambolev than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the Ambolev 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 Ambolev 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 Ambolev 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.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have also been identified during post-approval use of Ambolev. 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), paraesthesia, 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 Ambolev, 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 Ambolev.

• 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)

Overdosage has been reported with Ambolev.

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 Ambolev. Should overdose occur, symptomatic or supportive treatment is recommended. Ambolev 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/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, and approximately 370 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis).

Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown.

A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While a single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long post-marketing history of cetirizine without reports of QT prolongation.

Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.

A dose of 5 mg (10 mL) of Ambolev oral solution is bioequivalent to a 5 mg dose of Ambolev tablets. Following oral administration of a 5 mg dose of Ambolev oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose.

Distribution

The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.

Metabolism

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N-and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.

Elimination

The plasma half-life in adult healthy subjects was about 8 to 9 hours after administration of oral tablets and oral solution, and the mean oral total body clearance for levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of levocetirizine is reduced.