LEVOCETIRIZINE DIHYDROCHLORIDE tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
levocetirizine dihydrochloride (UNII: SOD6A38AGA) (levocetirizine - UNII:6U5EA9RT2O)
Available from:
ScieGen Pharmaceuticals, Inc.
INN (International Name):
levocetirizine dihydrochloride
Composition:
levocetirizine dihydrochloride 5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 use of levocetirizine dihydrochloride is contraindicated in: 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 (CLCR <10 mL/min) and patients undergoing hemodialysis Children 6 months to 11 years of age with impaired renal function Risk Summary Available data from published literature and postmarketing experience with levocetirizine use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm with administration of levoce
Product summary:
Levocetirizine dihydrochloride tablets, USP 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 the 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. 30 tablets (NDC 50228-136-30) 90 tablets (NDC 50228-136-90) 1,000 tablets (NDC 50228-136-10) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
50228-136-10, 50228-136-30, 50228-136-90

LEVOCETIRIZINE DIHYDROCHLORIDE- levocetirizine dihydrochloride tablet

ScieGen Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LEVOCETIRIZINE DIHYDROCHLORIDE

tablets safely and effectively. See full prescribing information for LEVOCETIRIZINE DIHYDROCHLORIDE

table ts.

LEVOCETIRIZINE DIHYDROCHLORIDE tablets, for oral use

Initial U.S. Approval: 1995

INDICATIONS AND USAGE

Levocetirizine dihydrochloride is a histamine H -receptor antagonist indicated for:

The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.2)

DOSAGE AND ADMINISTRATION

Chronic Idiopathic Urticaria (2.2)

Adults and children 12 years of age and older: 5 mg once daily in the evening

Children 6 to 11 years of age: 2.5 mg once daily in the evening

Renal Impairment

Adjust the dose in patients 12 years of age and older with decreased renal function (12.3)

DOSAGE FORMS AND STRENGTHS

Immediate release breakable (functional scored) tablets, 5 mg (3)

CONTRAINDICATIONS

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

tablets or to cetirizine (4.1)

Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis

(4.2)

Children 6 months to 11 years of age with renal impairment (4.3)

WARNINGS AND PRECAUTIONS

Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery

when taking levocetirizine dihydrochloride. (5.1)

Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride. (5.1)

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)

ADVERSE REACTIONS

The most common adverse reactions (rate ≥2% and > placebo) were somnolence, nasopharyngitis, fatigue, dry mouth, and

pharyngitis in subjects 12 years of age and older, and pyrexia, somnolence, cough, and epistaxis in children 6 to 12 years of

age. In subjects 1 to 5 years of age, the most common adverse reactions (rate ≥2% and > placebo) were pyrexia, diarrhea,

vomiting, and otitis media. In subjects 6 to 11 months of age, the most common adverse reactions (rate ≥3% and >

placebo) were diarrhea and constipation. (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

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, 12.3)

Pediatric Use

Do not exceed the recommended dose of 2.5 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)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.2 Chronic Idiopathic Urticaria

2 DOSAGE AND ADMINISTRATION

2.2 Chronic Idiopathic Urticaria

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Patients with Known Hypersensitivity

4.2 Patients with End-Stage Renal Disease

4.3 Pediatric Patients with Impaired Renal Function

5 WARNINGS AND PRECAUTIONS

5.1 Somnolence

5.2 Urinary Retention

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and

Pseudoephedrine

7.2 Ritonavir

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Perennial Allergic Rhinitis

14.2 Chronic Idiopathic Urticaria

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sections or subsections omitted from the full prescribing information are not listed.

1.2 Chronic Idiopathic Urticaria

Levocetirizine dihydrochloride tablets are indicated for the treatment of the uncomplicated skin

manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older.

2 DOSAGE AND ADMINISTRATION

Levocetirizine dihydrochloride tablets are available as 5 mg breakable (scored) tablets, allowing for

the administration of 2.5 mg, if needed. Levocetirizine tablets can be taken without regard to food

consumption.

2.2 Chronic Idiopathic Urticaria

Adults and Children 12 Years of Age and Older

The recommended dose of levocetirizine dihydrochloride tablet 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 to 11 Years of Age

The recommended dose of levocetirizine dihydrochloride tablet 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)].

Dose Adjustment for Renal and Hepatic Impairment

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

Mild renal impairment (creatinine clearance [CL

] = 50 to 80 mL/min): a dose of 2.5 mg once daily

is recommended;

Moderate renal impairment (CL

= 30 to 50 mL/min): a dose of 2.5 mg once every other day is

recommended;

Severe renal impairment (CL

= 10 to 30 mL/min): a dose of 2.5 mg twice weekly (administered

once every 3 to 4 days) is recommended;

End-stage renal disease patients (CL

<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.

3 DOSAGE FORMS AND STRENGTHS

Levocetirizine dihydrochloride tablets, USP 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.

4 CONTRAINDICATIONS

The use of levocetirizine dihydrochloride is contraindicated in:

4.1 Patients with Known Hypersensitivity

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)].

4.2 Patients with End-Stage Renal Disease

Patients with end-stage renal disease (CL

<10 mL/min) and patients undergoing hemodialysis

4.3 Pediatric Patients with Impaired Renal Function

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

5 WARNINGS AND PRECAUTIONS

5.1 Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients

under therapy with levocetirizine dihydrochloride. Patients should be cautioned against engaging in

hazardous occupations requiring complete mental alertness, and motor coordination such as operating

machinery or driving a motor vehicle after ingestion of levocetirizine dihydrochloride. Concurrent use

of levocetirizine dihydrochloride with alcohol or other central nervous system depressants should be

avoided because additional reductions in alertness and additional impairment of central nervous system

performance may occur.

5.2 Urinary Retention

Urinary retention has been reported post marketing with levocetirizine dihydrochloride. Levocetirizine

dihydrochloride should be used with caution in patients with predisposing factors of urinary retention

(e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine dihydrochloride may increase the risk

of urinary retention. Discontinue levocetirizine dihydrochloride if urinary retention occurs.

6 ADVERSE REACTIONS

Use of levocetirizine dihydrochloride has been associated with somnolence, fatigue, asthenia, and

urinary retention [see Warnings and Precautions (5)].

6.1 Clinical Trials Experience

The safety data described below reflect exposure to levocetirizine dihydrochloride in 2,708 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 1,896 patients (825 males and 1,071 females aged 12 years and older) were

treated with levocetirizine dihydrochloride 2.5 mg, 5 mg, or 10 mg once daily in the evening.

The short-term safety data from pediatric patients are based upon two clinical trials in which 243

children with allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with

levocetirizine dihydrochloride 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114

children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic

urticaria were treated with levocetirizine dihydrochloride 1.25 mg twice daily for 2 weeks, and one

clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of

allergic rhinitis or chronic urticaria were treated with levocetirizine dihydrochloride 1.25 mg once

daily for 2 weeks.

The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two

clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to

treatment with levocetirizine dihydrochloride 5 mg once daily. Long term safety data are also available

from an 18-month trial in 255 levocetirizine dihydrochloride -treated subjects 12 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.

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 levocetirizine dihydrochloride showed dose ordering between tested doses

of 2.5 mg, 5 mg and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).

Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12

years and older exposed to levocetirizine dihydrochloride 2.5 mg or 5 mg in eight placebo-controlled

clinical trials and that were more common with levocetirizine dihydrochloride than placebo.

Table 1: Adverse Reactions Reported in ≥2%* of Subjects Aged 12

Years and Older Exposed to Levocetirizine Dihydrochloride 2.5 mg or 5

mg Once Daily in Placebo-Controlled Clinical Trials 1 to 6 Weeks in

Duration

Advers e

Reactions

Levocetirizine

dihydrochloride

2.5 mg

(n = 421)

Levocetirizine

dihydrochloride 5

mg

(n = 1,070)

Placebo

(n = 912)

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%).

Pediatric Patients 6 to 12 Years of Age

A total of 243 pediatric patients 6 to 12 years of age received levocetirizine dihydrochloride 5 mg

once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was

9.8 years, 79 (32%) were 6 to 8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions

that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to

levocetirizine dihydrochloride 5 mg in placebo-controlled clinical trials and that were more common

with levocetirizine dihydrochloride than placebo.

Table 2: Adverse Reactions Reported in ≥2%* of Subjects Aged 6 to 12

Years Exposed to Levocetirizine Dihydrochloride 5 mg Once Daily in

Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

Adverse Reactions

Levocetirizine

dihydrochloride

5 mg

(n = 243)

Placebo

(n = 240)

Pyrexia

10 (4%)

5 (2%)

Cough

8 (3%)

2 (<1%)

Rounded to the closest unit percentage

Somnolence

7 (3%)

1 (<1%)

Epistaxis

6 (2%)

1 (<1%)

Pediatric Patients 1 to 5 Years of Age

A total of 114 pediatric patients 1 to 5 years of age received levocetirizine dihydrochloride 1.25 mg

twice daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients

was 3.8 years, 32% were 1 to 2 years of age, 71% were Caucasian and 18% were Black. Table 3 lists

adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years

exposed to levocetirizine dihydrochloride 1.25 mg twice daily in the placebo-controlled safety trial and

that were more common with levocetirizine dihydrochloride than placebo.

Table 3: Adverse Reactions Reported in ≥2%* of Subjects Aged 1 to 5

Years Exposed to levocetirizine dihydrochloride 1.25 mg Twice Daily in a

2-Week Placebo-Controlled Clinical Trial

Adverse Reactions

Levocetirizine

dihydrochloride

1.25 mg Twice Daily

(n = 114)

Placebo

(n = 59)

Rounded to the closest unit percentage

Pyrexia

5 (4%)

1 (2%)

Diarrhea

4 (4%)

2 (3%)

Vomiting

4 (4%)

2 (3%)

Otitis Media

3 (3%)

0 (0%)

Pediatric Patients 6 to 11 Months of Age

A total of 45 pediatric patients 6 to 11 months of age received levocetirizine dihydrochloride 1.25 mg

once daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was

9 months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than

1 subject (i.e. greater than or equal to 3% of subjects) aged 6 to 11 months exposed to levocetirizine

dihydrochloride 1.25 mg once daily in the placebo-controlled safety trial and that were more common

with levocetirizine dihydrochloride than placebo included diarrhea and constipation which were

reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the levocetirizine dihydrochloride and

placebo-treated groups, respectively.

Long-Term Clinical Trials Experience

In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were

treated with levocetirizine dihydrochloride 5 mg once daily for 4 or 6 months. The patient

characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%)

patients treated with levocetirizine dihydrochloride discontinued because of somnolence, fatigue or

asthenia compared to 2 (<1%) in the placebo group.

There are no long term clinical trials in children below 12 years of age with allergic rhinitis or chronic

idiopathic urticaria.

Laboratory Test Abnormalities

Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials.

The elevations were transient and did not lead to discontinuation in any patient.

6.2 Postmarketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following

adverse reactions have also been identified during postapproval use of levocetirizine dihydrochloride.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: palpitations, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: blurred vision, visual disturbances

Gastrointestinal disorders: nausea, vomiting

General disorders and administration site conditions: edema

Hepatobiliary disorders: hepatitis

Immune system disorders: anaphylaxis and hypersensitivity

Metabolism and nutrition disorders: increased appetite

Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia

Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including

dystonia and oculogyric crisis), 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 levocetirizine dihydrochloride, other potentially

severe adverse events have been reported from the postmarketing experience with cetirizine. Since

levocetirizine is the principal pharmacologically active component of cetirizine, one should take into

account the fact that the following adverse events could also potentially occur under treatment with

levocetirizine dihydrochloride.

Cardiac disorders: severe hypotension

Gastrointestinal disorders: cholestasis

Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic

Pregnancy, puerperium and perinatal conditions: stillbirth

Renal and urinary disorders: glomerulonephritis

Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP); rebound

pruritus - pruritus within a few days after discontinuation of cetirizine, usually after long-term use

(e.g. months to years) of cetirizine.

7 DRUG INTERACTIONS

In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through

inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug-drug interaction studies

have been performed with levocetirizine. Drug interaction studies have been performed with racemic

cetirizine.

7.1 Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and

Ps eudoephedrine

Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did

not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole, and cimetidine.

There was a small decrease (~16%) in the clearance of cetirizine caused by a 400 mg dose of

theophylline. It is possible that higher theophylline doses could have a greater effect.

7.2 Ritonavir

Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life

(53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by

concomitant cetirizine administration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published literature and postmarketing experience with levocetirizine use in

pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or

adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm

with administration of levocetirizine by the oral route to pregnant rats and rabbits, during the period of

organogenesis, at doses up to 390 times and 470 times, respectively, the maximum recommended human

dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine had no

effects on pup development at oral doses up to approximately 60 times the MRHD in adults. In mice

treated during late gestation and the lactation period, cetirizine administered by the oral route to the

dams had no effects on pup development at a dose that was approximately 25 times the MRHD in adults;

however, lower pup weight gain during lactation was observed at a dose that was 95 times the MRHD

in adults [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risks of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In embryo-fetal development studies, pregnant rats received daily doses of levocetirizine up to 200

mg/kg/day from gestation days 6 to 15 and pregnant rabbits received daily doses of levocetirizine up to

120 mg/kg/day from gestation days 6 to 18. Levocetirizine produced no evidence of fetal harm in rats

and rabbits at doses up to 390 and 470 times the MRHD, respectively (on a mg/m basis with maternal

oral doses of 200 mg/kg/day and 120 mg/kg/day in rats and rabbits, respectively).

No prenatal and postnatal development (PPND) studies in animals have been conducted with

levocetirizine. In a PPND study conducted in mice, cetirizine was administered at oral doses up to 96

mg/kg/day from gestation day 15 through lactation day 21. Cetirizine lowered pup body weight gain

during lactation at an oral dose in dams that was approximately 95 times the MRHD (on a mg/m basis

with a maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an

oral dose in dams that was approximately 25 times the MRHD (on a mg/m basis with a maternal oral

dose of 24 mg/kg/day). In a PPND study conducted in rats, cetirizine was administered at oral doses up

to 180 mg/kg/day from gestation day 17 to lactationday 22. Cetirizine did not have any adverse effects

on rat dams or offspring development at doses up to approximately 60 times the MRHD (on a mg/m

basis with a maternal oral dose of 30 mg/kg/day). Cetirizine caused excessive maternal toxicity at an

oral dose in dams that was approximately 350 times the MRHD (on a mg/m basis with a maternal oral

dose of 180 mg/kg/day).

8.2 Lactation

Risk Summary

There are no data on the presence of levocetirizine in human milk, the effects on the breastfed infant, or

the effects on milk production. However, cetirizine has been reported to be present in human breast

milk. In mice and beagle dogs, studies indicated that cetirizine was excreted in milk [see Data]. When a

drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and

health benefits of breastfeeding should be considered along with the mother’s clinical need for

levocetirizine dihydrochloride and any potential adverse effects on the breastfed child from

levocetirizine dihydrochloride or from the underlying maternal condition.

Data

Animal Data

Cetirizine was detected in the milk of mice. No adverse developmental effects on pups were seen when

cetirizine was administered orally to dams during lactation at a dose that was approximately 25 times the

MRHD in adults [see Use in Specific Populations (8.1)]. Studies in beagle dogs indicated that

approximately 3% of the dose of cetirizine was excreted in milk. The concentration of drug in animal

milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use

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 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 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 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 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)].

8.5 Geriatric Use

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.

8.6 Renal Impairment

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)].

8.7 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 [see Clinical

Pharmacology (12.3)].

10 OVERDOSAGE

Overdosage has been reported with levocetirizine dihydrochloride.

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 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/m basis). In rats

the maximal non-lethal oral dose was 240 mg/kg (approximately 390 times the maximum recommended

daily oral dose in adults, approximately 460 times the maximum recommended daily oral dose in

children 6 to 11 years of age, and approximately 370 times the maximum recommended daily oral dose

in children 6 months to 5 years of age on a mg/m basis).

11 DESCRIPTION

Levocetirizine dihydrochloride, USP the active component of levocetirizine dihydrochloride tablets,

USP is an orally active H -receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl)

phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is

the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The

empirical formula of levocetirizine dihydrochloride is C

H ClN O 2HCl. The molecular weight is

461.82 and the chemical structure is shown below:

Levocetirizine Dihydrochloride, USP is a white, or almost white powder and is freely soluble in water,

practically insoluble in acetone and methylene chloride.

Levocetirizine dihydrochloride tablets, USP 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

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