These Highlights Do Not Include All The Information Needed To Use Levocetirizine Dihydrochloride Tablets Safely And Effectively. See Full Prescribing Information For Levocetirizine Dihydrochloride Tablets.

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.

Adults and Adolescents 12 Years of Age and Older

In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian.

In these trials 43% and 42% of the subjects in the levocetirizine dihydrochloride 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.

In placebo-controlled trials of 1 to 6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with levocetrizine 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.

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%).

Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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).

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.

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 is a white, or almost white powder and is freely soluble in water, practically insoluble in acetone and methylene chloride.

Levocetirizine dihydrochloride tablets, 5 mg are formulated as immediate release, white, film-coated, oval, scored tablets for oral administration. The tablets are debossed with “S” on the left side of bisect and “G” on the right side of the bisect and other side “1” on the left side and “36” on the right side of the bisect. Inactive ingredients are: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. The film coating Opadry white YS-1-18202-A contains hypromellose, titanium dioxide, and macrogol/polyethylene glycol 400.

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.

Caution patients 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 tablets.

The recommended dose of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies (14) ].

The recommended dose of levocetirizine dihydrochloride in patients 6 months to 11 years of age for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria and in patients 2 to 11 years of age for the treatment of symptoms of seasonal allergic rhinitis is based on cross-study comparisons of the systemic exposure of levocetirizine dihydrochloride in adults and pediatric patients and on the safety profile of levocetirizine dihydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age.

The safety of levocetirizine dihydrochloride 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of levocetirizine dihydrochloride 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of levocetirizine dihydrochloride 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age [see Adverse Reactions (6.1) ].

The effectiveness of levocetirizine dihydrochloride 1.25 mg once daily (6 months to 5 years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine dihydrochloride 5 mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children.

Cross-study comparisons indicate that administration of a 5 mg dose of levocetirizine dihydrochloride to 6 to 12 year old pediatric seasonal allergic rhinitis patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of levocetirizine dihydrochloride was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 mg once daily in adults. [see Dosage and Administration (2.2); Clinical Studies (14); and Clinical Pharmacology (12.3) ].

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.

The use of levocetirizine dihydrochloride tablets is contraindicated in:

Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, asthenia, and urinary retention. [see Warnings and Precautions (5) ].

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.

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.

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) ].

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.

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.

Reproductive Toxicology Studies

In 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).

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) ].

Levocetirizine dihydrochloride tablets are a histamine H₁‑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)

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.

• 4.
  Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride (5.1).
• 5.
  Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride (5.1).
• 6.
  Use with caution in patients with predisposing factors of urinary retention (e.g., spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride if urinary retention occurs(5.2).

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.

Levocetirizine Dihydrochloride Tablets, 5 mg are white, oval, biconvex, film-coated functional scored tablets debossed with “S” on the left side of bisect and “G” on the right side of bisect and other side “1” on the left side and “36” on the right side of the bisect.

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 . 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, increased appetite, angioedema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, paraesthesia, dizziness, tremor, dysgeusia, vertigo, movement disorders (including dystonia and oculogyric crisis) aggression and agitation, hallucinations, depression, insomnia, suicidal ideation, visual disturbances, blurred vision, palpitations, tachycardia, dyspnea, nausea, vomiting, hepatitis, dysuria, urinary retention, myalgia and edema 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: orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, still birth, tic, myoclonus, and extrapyramidal symptoms.

• 3.
  Renal Impairment
  
  Because levocetirizine dihydrochloride is substantially excreted by the kidneys, the risk of adverse reactions to this drug may be greater in patients with impaired renal function (8.6 and 12.3).
• 4.
  Pediatric Use
  
  Do not exceed the recommended doses of 2.5 mg and 1.25 mg once daily in children 6 to 11 years and 6 months to 5 years of age, respectively. Systemic exposure with these doses in respective pediatric age groups is comparable to that from a 5 mg once daily dose in adults. (12.3).

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.

The safety data described below reflect exposure to levocetirizine dihydrochloride in 2708 patients with seasonal or perennial 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 seasonal or perennial allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with levocetirizine dihydrochloride 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine dihydrochloride 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with levocetirizine dihydrochloride 1.25 mg once daily for 2 weeks.

The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with levocetirizine dihydrochloride 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine dihydrochloride-treated subjects 12 to 24 months of age.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

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.

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.

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) ].

Levocetirizine Dihydrochloride Tablets, 5 mg are white, oval, biconvex, film-coated functional scored tablets debossed with “S” on the left side of bisect and “G” on the right side of bisect and other side “1” on the left side and “36” on the right side of the bisect. They are supplied in unit of use HDPE bottles.

NDC 63187-663-30:   Bottle of 30 tablets

NDC 63187-663-60:   Bottle of 60 tablets

NDC 63187-663-90:   Bottle of 90 tablets

NDC 63187-663-30

30 Tablets

Levocetirizine Dihydrochloride Tablets

5 mg

For oral administration

Rx only

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

The recommended dose of levocetirizine dihydrochloride tablets is 5 mg (1 tablet) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet) once daily in the evening.

Children 6 months to 11 years of age with impaired renal function

In adults and children 12 years of age and older with:

• 1.
  Mild renal impairment (creatinine clearance [CL_CR] = 50 to 80 mL/min): a dose of 2.5 mg once daily is recommended;
• 2.
  Moderate renal impairment (CL_CR = 30 to 50 mL/min): a dose of 2.5 mg once every other day is recommended;
• 3.
  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;
• 4.
  End-stage renal disease patients (CL_CR < 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine dihydrochloride tablets.

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.

Do not exceed the recommended daily dose in adults and adolescents 12 years of age and older of 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. Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride tablets because of the increased risk of somnolence at higher doses.

•  
  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/m ² 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/m ² 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/m ² 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).

Instruct patients to avoid concurrent use of levocetirizine dihydrochloride tablets with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.

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.

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.

Adults and Adolescents 12 Years of Age and Older

In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian.

In these trials 43% and 42% of the subjects in the levocetirizine dihydrochloride 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.

In placebo-controlled trials of 1 to 6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with levocetrizine 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.

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%).

Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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).

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.

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 is a white, or almost white powder and is freely soluble in water, practically insoluble in acetone and methylene chloride.

Levocetirizine dihydrochloride tablets, 5 mg are formulated as immediate release, white, film-coated, oval, scored tablets for oral administration. The tablets are debossed with “S” on the left side of bisect and “G” on the right side of the bisect and other side “1” on the left side and “36” on the right side of the bisect. Inactive ingredients are: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. The film coating Opadry white YS-1-18202-A contains hypromellose, titanium dioxide, and macrogol/polyethylene glycol 400.

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.

Caution patients 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 tablets.

The recommended dose of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies (14) ].

The recommended dose of levocetirizine dihydrochloride in patients 6 months to 11 years of age for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria and in patients 2 to 11 years of age for the treatment of symptoms of seasonal allergic rhinitis is based on cross-study comparisons of the systemic exposure of levocetirizine dihydrochloride in adults and pediatric patients and on the safety profile of levocetirizine dihydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age.

The safety of levocetirizine dihydrochloride 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of levocetirizine dihydrochloride 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of levocetirizine dihydrochloride 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age [see Adverse Reactions (6.1) ].

The effectiveness of levocetirizine dihydrochloride 1.25 mg once daily (6 months to 5 years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine dihydrochloride 5 mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children.

Cross-study comparisons indicate that administration of a 5 mg dose of levocetirizine dihydrochloride to 6 to 12 year old pediatric seasonal allergic rhinitis patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of levocetirizine dihydrochloride was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 mg once daily in adults. [see Dosage and Administration (2.2); Clinical Studies (14); and Clinical Pharmacology (12.3) ].

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.

The use of levocetirizine dihydrochloride tablets is contraindicated in:

Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, asthenia, and urinary retention. [see Warnings and Precautions (5) ].

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.

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.

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) ].

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.

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.

Reproductive Toxicology Studies

In 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).

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) ].

Levocetirizine dihydrochloride tablets are a histamine H₁‑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)

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.

• 4.
  Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride (5.1).
• 5.
  Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride (5.1).
• 6.
  Use with caution in patients with predisposing factors of urinary retention (e.g., spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride if urinary retention occurs(5.2).

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.

Levocetirizine Dihydrochloride Tablets, 5 mg are white, oval, biconvex, film-coated functional scored tablets debossed with “S” on the left side of bisect and “G” on the right side of bisect and other side “1” on the left side and “36” on the right side of the bisect.

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 . 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, increased appetite, angioedema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, paraesthesia, dizziness, tremor, dysgeusia, vertigo, movement disorders (including dystonia and oculogyric crisis) aggression and agitation, hallucinations, depression, insomnia, suicidal ideation, visual disturbances, blurred vision, palpitations, tachycardia, dyspnea, nausea, vomiting, hepatitis, dysuria, urinary retention, myalgia and edema 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: orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, still birth, tic, myoclonus, and extrapyramidal symptoms.

• 3.
  Renal Impairment
  
  Because levocetirizine dihydrochloride is substantially excreted by the kidneys, the risk of adverse reactions to this drug may be greater in patients with impaired renal function (8.6 and 12.3).
• 4.
  Pediatric Use
  
  Do not exceed the recommended doses of 2.5 mg and 1.25 mg once daily in children 6 to 11 years and 6 months to 5 years of age, respectively. Systemic exposure with these doses in respective pediatric age groups is comparable to that from a 5 mg once daily dose in adults. (12.3).

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.

The safety data described below reflect exposure to levocetirizine dihydrochloride in 2708 patients with seasonal or perennial 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 seasonal or perennial allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with levocetirizine dihydrochloride 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine dihydrochloride 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with levocetirizine dihydrochloride 1.25 mg once daily for 2 weeks.

The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with levocetirizine dihydrochloride 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine dihydrochloride-treated subjects 12 to 24 months of age.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

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.

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.

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) ].

Levocetirizine Dihydrochloride Tablets, 5 mg are white, oval, biconvex, film-coated functional scored tablets debossed with “S” on the left side of bisect and “G” on the right side of bisect and other side “1” on the left side and “36” on the right side of the bisect. They are supplied in unit of use HDPE bottles.

NDC 63187-663-30:   Bottle of 30 tablets

NDC 63187-663-60:   Bottle of 60 tablets

NDC 63187-663-90:   Bottle of 90 tablets

NDC 63187-663-30

30 Tablets

Levocetirizine Dihydrochloride Tablets

5 mg

For oral administration

Rx only

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

The recommended dose of levocetirizine dihydrochloride tablets is 5 mg (1 tablet) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet) once daily in the evening.

Children 6 months to 11 years of age with impaired renal function

In adults and children 12 years of age and older with:

• 1.
  Mild renal impairment (creatinine clearance [CL_CR] = 50 to 80 mL/min): a dose of 2.5 mg once daily is recommended;
• 2.
  Moderate renal impairment (CL_CR = 30 to 50 mL/min): a dose of 2.5 mg once every other day is recommended;
• 3.
  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;
• 4.
  End-stage renal disease patients (CL_CR < 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine dihydrochloride tablets.

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.

Do not exceed the recommended daily dose in adults and adolescents 12 years of age and older of 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. Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride tablets because of the increased risk of somnolence at higher doses.

•  
  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/m ² 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/m ² 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/m ² 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).

Instruct patients to avoid concurrent use of levocetirizine dihydrochloride tablets with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.

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.