LEVORID Tablets / Syrup (Levocetirizine dihydrochloride)

Table of Content

Composition

LEVORID Tablets

Each film-coated tablet contains

Levocetirizine dihydrochloride IP..........5 mg

LEVORID Syrup

Each 5 ml contains

Levocetirizine dihydrochloride IP.......2.5 mg

Dosage Form

Oral tablets and syrup

Pharmacology

Pharmacodynamics

Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.

Binding studies have revealed that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115±38 minutes. After single administration, levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: Inhibition of VCAM-1 release, modulation of vascular permeability, and a decrease in eosinophil recruitment.

The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis, including nasal obstruction in some studies.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose levocetirizine has comparable activity to cetirizine, both in the skin and in the nose. Pharmacokinetic/pharmacodynamic relationship 5 mg levocetirizine provide a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg cetirizine. As for cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations. ECGs did not show relevant effects of levocetirizine on QT interval.

Pharmacokinetics

The pharmacokinetics of levocetirizine is linear with dose and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 hours after dosing. Steady state is achieved after 2 days. Peak concentrations are typically 270ng/mL and 308ng/mL, following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed. A dose of 5 mg (10ml) of levocetirizine dihydrochloride oral solution is bioequivalent to a 5 mg dose of levocetirizine tablets. Following oral administration of a 5 mg dose of levocetirizine oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hours post-dose.

Distribution

No tissue distribution data are available in humans, concerning the passage of levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue levels are found in the liver and kidneys, and the lowest in the central nervous system (CNS) compartment. Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and, therefore, differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances or vice-versa is unlikely.

Elimination

The plasma half-life in adults is 7.9 ± 1.9 hours. The mean apparent total body clearance is 0.63 ml/min/kg. The major route of excretion of levocetirizine and its metabolites is via the urine, accounting for a mean of 85.4% of the dose. Excretion via the faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

Renal Impairment

The apparent body clearance of levocetirizine is correlated to the creatinine clearance. It is, therefore, recommended to adjust the dosing intervals of levocetirizine, based on the creatinine clearance in patients with moderate and severe renal impairment. In anuric end-stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects. The amount of levocetirizine removed during a standard 4-hour haemodialysis procedure was <10%.

Indications

LEVORID Tablets and Syrup is indicated in the symptomatic treatment of perennial and seasonal allergic rhinitis and chronic idiopathic urticaria.

Dosage and Administration

LEVORID Tablets and Syrup must be taken orally, swallowed whole with liquid and may be taken with or without food. It is recommended to take the daily dose in one single intake.

LEVORID Tablets

Adults and adolescents 12 years and above

The daily recommended dose is 5 mg (1 tablet).

Children aged 6 to 12 years

The daily recommended dose is 5 mg (1 tablet).

LEVORID Syrup

Adults and adolescents 12 years and above

The daily recommended dose is 5 mg (10 ml of solution).

Children aged 6 to 12 years

The daily recommended dose is 5 mg (10 ml of solution).

Children aged 6 Months to 5 years

The recommended initial dose is 1.25 mg (2.5 ml of solution) once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure   to adults receiving 5 mg.

Duration of use

Intermittent allergic rhinitis (symptoms <4days/week or during less than 4 weeks) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms >4days/week and during more than 4 weeks), continuous therapy can be proposed to the patient during the period of exposure to allergens. Clinical experience with 5 mg levocetirizine as a film-coated tablet formulation is currently available for a 6-month treatment period. For chronic urticaria and chronic allergic rhinitis, up to one year's clinical experience is available for the racemate.

Contraindications

Hypersensitivity to levocetirizine, cetirizine, or its parent compound hydroxyzine. Patients with severe renal impairment (<10 ml/min creatinine clearance), and patients undergoing hemodialysis and children 6 months to 11 years of age with impaired renal function should not be administered LEVORID Tablets and Syrup. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Warnings and Precautions

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirine. The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirizine. The administration of levocetirizine to infants and toddlers aged less than 2 years is not recommended.

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive.

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine. 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. Concurrent use of levocetirizine with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

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

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.

Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin glipizide and diazepam, 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.

The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.

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.

In sensitive patients the simultaneous administration of cetirizine or levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system, although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol.

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive. Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

Renal Impairment

Since the body clearance of levocetirizine is correlated to the creatinine clearance, it is, therefore, recommended that the dosing intervals of levocetirizine be adjusted, based on the creatinine clearance in patients with moderate and severe renal impairment. The dosing intervals must be individualized according to renal function.

Dosing Adjustments for Patients with Impaired Renal Function

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Group   

Creatinine Clearance (ml/min)

Dosage and Frequency

Normal

≥80                                                  

5 mg once daily

Mild      

50–79                                                  

5 mg once daily

Moderate   

30–49                                                

5 mg once every 2 days

Severe                             

<30                                                    

5mg once every 3 days

End-stage renal disease  

Patients undergoing dialysis

<10                                                  

Contraindicated

Hepatic Impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended.

Pregnancy

Pregnancy category B

There are no adequate and well-controlled studies of levocetirizine in pregnant women. Because animal reproduction studies are not always predictive of human response, LEVORID Tablets and Syrup should be used during pregnancy only if clearly needed.

Lactation

Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of LEVORID Tablets and Syrup in nursing mothers is not recommended.

Pediatric Use

For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet formulation. It is recommended to use a paediatric formulation of levocetirizine.

Geriatric Use

Clinical studies of levocetirizine 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. Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.

Undesirable Effects

Use of levocetirizine has been associated with somnolence, headache, fatigue, nasopharyngitis, 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 clinical trials. Further uncommon incidences of adverse reactions like asthenia or abdominal pain and urinary retention were observed. 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 are syncope (0.2%) and weight increased (0.5%).

Adverse reactions reported in subjects 1 to 5 years of age and in 6 months to 11 months of age were pyrexia, diarrhoea, vomiting, otitis media, constipation, salivary hypersecretion, thirst, hunger, fatigue, anorexia, somnolence, psychomotor hyperactivity, sleep disorder, middle insomnia, epistaxis, pruritius, headache.

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported in post-marketing experience

Immune System Disorders: Hypersensitivity including anaphylaxis

Metabolism and Nutrition Disorders: Increased appetite

Psychiatric Disorders: Aggression, agitation, hallucinations, depression, insomnia, suicidal ideation.

Nervous System Disorders: Convulsion, paraesthesia, dizziness, syncope, tremor, dysguesia.

Ear and Labyrinth Disorder: Vertigo

Eyes Disorders: Visual disturbances, blurred vision

Cardiac Disorders: Palpitations, tachycardia

Respiratory, Thoracic, and Mediastinal Disorders: Dyspnoea

Gastrointestinal Disorders: Nausea, vomiting, diarrhoea

Hepatobiliary Disorders: Hepatitis

Skin and Subcutaneous Tissue Disorders: Angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria

Musculoskeletal, Connective Tissues, and Bone Disorders: Myalgia, Arthralgia

Investigations: Weight increased, abnormal liver function tests

Renal and Urinary Disorders: dysuria, urinary retention

General Disorders and Administration Site Conditions: oedema

Besides these events reported under treatment with levocetirizine, 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: suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

Overdosage

Symptoms of overdose may include drowsiness in adults, and in children, initially agitation and restlessness, followed by drowsiness. There is no known specific antidote to levocetirizine. Should overdose occur consider standard measures to remove any unabsorbed drug. Gastric lavage should be considered following short-term ingestion. Levocetirizine is not effectively removed by haemodialysis.

Packaging Information

LEVORID Tablets……………………… Blister pack of 10 tablets

LEVORID Syrup…………………………. 30 ml bottle

Last updated:  Mar 2016
Last reviewed: Mar 2016