LEVOCETIRIZINE DIHYDROCHLORIDE
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levocetirizine dihydrochloride tablet, coated
Dr.Reddy's laboratories Ltd.
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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.
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.
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.
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)].
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.
In adults and children 12 years of age and older with:
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.
Levocetirizine dihydrochloride tablets are white, oval, film coated, biconvex tablets debossed ‘R & 5’ separated with break line on one side and break line on other side and contain 5 mg levocetirizine dihydrochloride.
The use of levocetirizine dihydrochloride tablets are contraindicated in:
• 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)].
• Patients with end-stage renal disease (CLCR < 10 mL/min) and patients undergoing hemodialysis.
• Pediatric patients 6 months to 11 years of age with impaired renal function [See Use in Specific Populations (8.4)].
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.
Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, and asthenia [see Warnings and Precautions (5.1)].
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.
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.
Adverse Reactions | levocetirizine dihydrochloride2.5 mg (n = 421) | levocetirizine dihydrochloride 5 mg (n = 1070) | Placebo (n = 912) |
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* Rounded to the closest unit percentage | |||
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%).
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 6-12 years exposed to levocetirizine dihydrochloride 5 mg in placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride than placebo.
Adverse Reactions | levocetirizine dihydrochloride 5 mg/day (n = 243) | Placebo (n = 240) |
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* Rounded to the closest unit percentage | ||
Pyrexia | 10 (4%) | 5 (2%) |
Cough | 8 (3%) | 2 (<1%) |
Somnolence | 7 (3%) | 1 (<1%) |
Epistaxis | 6 (2%) | 1 (<1%) |
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.
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.
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.
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 in other countries. 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, angioneurotic edema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, aggression and agitation, visual disturbances, palpitations, dyspnea, nausea, hepatitis, and myalgia 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 : hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.
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.
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 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 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 up to 200 and 120 mg/kg, respectively (approximately 320 and 390 times the maximum recommended daily oral dose in adults on a mg/m2 basis).
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.
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 seasonal and perennial allergic rhinitis and 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 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 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 5years) 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.
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.
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)].
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)].
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, 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).
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:
Levocetirizine dihydrochloride white or almost white powder and is freely soluble in water, practically insoluble in acetone and in methylene chloride. Levocetirizine dihydrochloride 5 mg tablets are formulated as immediate release, white, oval, film coated, scored tablets for oral administration. The tablets are debossed ‘R & 5’ separated with break line on one side and break line on other side. Inactive ingredients are: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, and titanium dioxide.
Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of levocetirizine has been documented in a variety of animal and human models. In vitro binding studies revealed that levocetirizine has an affinity for the human H1-receptor 2-fold higher than that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively. The clinical relevance of this finding is unknown.
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.
No carcinogenesis 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 and 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 and approximately 4 times the maximum recommended daily oral dose in children 6 to11 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 levocetirizine dihydrochloride 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).
Reproductive Toxicology StudiesIn rats and rabbits, levocetirizine was not teratogenic at oral doses up to 200 and 120 mg/kg, respectively, (approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on a mg/m2 basis).
In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m2 basis).
The efficacy of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria was evaluated in two multi-center, randomized, placebo-controlled, double-blind clinical trials of 4 weeks duration in adult patients 18 to 85 years of age with chronic idiopathic urticaria. The two trials included one 4-week dose-ranging trial and one 4-week single-dose level efficacy trial. These trials included 423 patients (139 males and 284 females). Most patients (>90%) were Caucasian and the mean age was 41. Of these patients, 146 received levocetirizine dihydrochloride 5 mg once daily in the evening. Efficacy was assessed based on patient recording of pruritus severity on a severity score of 0–3 (0 = none to 3 = severe). The primary efficacy endpoint was the mean reflective pruritus severity score over the first week and over the entire treatment period. Additional efficacy variables were the instantaneous pruritus severity score, the number and size of wheals, and duration of pruritus.
The dose-ranging trial was conducted to evaluate the efficacy of levocetirizine dihydrochloride 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of levocetirizine dihydrochloride demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (see Table 6).
The single dose level trial evaluated the efficacy of levocetirizine dihydrochloride 5 mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over a 4-week treatment period. Levocetirizine dihydrochloride 5 mg demonstrated a greater decrease from baseline in the reflective pruritus severity score than placebo and the difference from placebo was statistically significant.
Duration of pruritus, number and size of wheals, and instantaneous pruritus severity score also showed significant improvement over placebo. The significant improvement in the instantaneous pruritus severity score over placebo confirmed end of dosing interval efficacy (see Table 6).
Treatment | N | Baseline | On Treatment Adjusted Mean | Difference from Placebo | ||
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Estimate | 95% CI | p-value | ||||
Dose-Ranging Trial – Reflective pruitus severity score | ||||||
Levocetirizine dihydrochloride 2.5 mg | 69 | 2.08 | 1.02 | 0.82 | (0.58, 1.06) | <0.001 |
Levocetirizine dihydrochloride 5 mg | 62 | 2.07 | 0.92 | 0.91 | (0.66, 1.16) | <0.001 |
Levocetirizine dihydrochloride 10 mg | 55 | 2.04 | 0.73 | 1.11 | (0.85, 1.37) | <0.001 |
Placebo | 60 | 2.25 | 1.84 | |||
Chronic Idiopathic Urticaria Trial – Reflective pruritus severity score | ||||||
Levocetirizine dihydrochloride 5 mg | 80 | 2.07 | 0.94 | 0.62 | (0.38, 0.86) | <0.001 |
Placebo | 82 | 2.06 | 1.56 |
There are no clinical efficacy trials in pediatric patients with chronic idiopathic urticaria [see Use in Specific Populations (8.4)].
Levocetirizine dihydrochloride tablets are white, oval, film coated, biconvex tablets debossed ‘R & 5’ separated with break line on one side and break line on other side and contain 5 mg levocetirizine dihydrochloride. They are supplied in unit of use HDPE bottles and unit of use blisters.
Bottles of 30 NDC 55111-282-30
Bottles of 60 NDC 55111-282-60
Bottles of 90 NDC 55111-282-90
Bottles of 100 NDC 55111-282-01
Bottles of 180 NDC 55111-282-18
Bottles of 500 NDC 55111-282-05
Unit dose package of 100 (10 x 10) NDC 55111-282-78
Storage:
Store at 20-25°C (68-77°F); [see USP Controlled Room Temperature].
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 reduction in mental alertness may occur.
The daily dose in adults and adolescents 12 years of age and older should not exceed 5 mg once daily in the evening. In children 6 to 11 years of age the recommended dose is 2.5 mg once daily in the evening. Patients should be advised to not ingest more than the recommended dose of levocetirizine dihydrochloride because of the increased risk of somnolence at higher doses.
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.
RX Only
Manufactured by:
Dr. Reddy’s Laboratories Limited
Bachepalli – 502 325 INDIA
Issued: 0211
Container
Container Label 90's
Carton
LEVOCETIRIZINE DIHYDROCHLORIDE
levocetirizine dihydrochloride tablet, coated |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA090392 | 02/24/2011 |
Labeler - Dr.Reddy's laboratories Ltd. (862179079) |
Establishment | |||
Name | Address | ID/FEI | Operations |
Dr.Reddy's Laboratories Limited | 918608162 | analysis, manufacture |