Cetizal 5

Levocetirizine dihydrochloride.

Each film coated tablet contains: Levocetirizine dihydrochloride 5 mg.

Pharmacotherapeutic group: Antihistamine for systemic use, piperazine derivative.
Pharmacology: Levocetirize, the (R) enantiomer of Cetirizine, is a potent and selective antagonist of peripheral H₁-receptors. Levocetirizine has high affinity for human H₁-receptors. Levocetirizine dissociates from H₁-receptors with a half-life of 115 ± 38 min. After single administration, Levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.
Pharmacokinetics: The pharmacokinetics of Levocetirizine are 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. In adults, peak plasma concentrations are achieved 0.9 hour after dosing. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans, neither concerning the passage of Levocetirizine through the blood-brain-barrier.
Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 L/Kg.
Metabolism: The extent of metabolism of Levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of 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 half-life is shorter in small children.
The major route of excretion of Levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Special population: 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 creatinine clearance in patients with moderate and severe renal impairment. In end-stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects.
Pediatric population: In children 6 to 11 years of age, C_max and AUC volumes were about 2 fold greater than in adults. Total body clearance was 30% greater and elimination half-life was 24% shorter when compared with adults.
Elderly: The disposition of racemic Cetirizine is dependent on renal function rather than on age. This finding would also be applicable for Levocetirizine, as Levocetirizine and Cetirizine are both predominantly excreted in urine. Therefore, the Levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
Gender: Half-life was slightly shorter in women than in men. However, the body-weight adjusted oral clearance in women appeared to be comparable with that in men. The same daily dosage and dosing intervals are applicable for men and women with normal renal function.
Race: The effect of race on Levocetirizine has not been studied. As Levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of Levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic Cetirizine have been observed.
Hepatic impairment: The pharmacokinetics of Levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound Cetirizine as a single dose had a 50% increase in half life along with a 40% decrease in clearance compared to healthy subjects.
Pharmacokinetic/pharmacodynamic relationship: The action on histamine-induced skin reactions is out of phase with the plasma concentrations.

Levocetirizine is indicated for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and chronic idiopathic urticaria.

Posology: Adults and adolescents 12 years and above: The daily recommended dose is 5 mg once daily (one film coated tablet).
Elderly: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Renal impairment below).
Renal impairment: The dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed. The CLcr (mL/min) may be estimated from serum creatinine (mg/dL) determination using the following formula: (See equation.)

Click on icon to see table/diagram/image

Dosing adjustments for adult patients with impaired renal function: (See table.)

Click on icon to see table/diagram/image

In pediatric 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.
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 (see Renal impairment as previously mentioned).
Pediatric population: Children aged 6 to 12 years: The daily recommended dose is 5 mg once daily (one film coated tablet).
Children aged 2 to 6 years: No adjusted dosage is possible with the film coated tablet formulation. It is recommended to use a pediatric formulation of Levocetirizine.
Method of administration: The film coated tablet 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.
Duration of use: Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) 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 experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens.
There is clinical experience with the use of Levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is a clinical experience of use of Cetirizine (racemate) for up to one year.

Symptoms: Symptoms of overdose may include drowsiness in adults. In children agitation and restlessness may initially occur, followed by drowsiness.
Management of overdoses: There is no known specific antidote to Levocetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered shortly after ingestion of the drug.
Levocetirizine is not effectively removed by hemodialysis.

Hypersensitivity to the Levocetirizine, to Cetirizine, to Hydroxyzine, to any other piperazine or to any of the other excipients.
Severe renal impairment at less than 10 mL/min creatinine clearance.

This preparation contains Sodium metabisulfite that may cause serious allergic type reactions in certain susceptible patients. Do not use if known to be hypersensitive to bisulfites.

Alcohol: Precaution is recommended with concurrent intake of alcohol (see Interaction).
Risk of urinary retention: Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Levocetirizine may increase the risk of urinary retention.
Risk of seizure aggravation: Caution should be taken in patients with epilepsy and patients at risk of convulsion as Levocetirizine may cause seizure aggravation.
Allergy skin tests: Response to allergy skin tests are inhibited by antihistamines and a wash out period (of 3 days) is required before performing them.
Excipients: Lactose: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Withdrawal syndrome: Pruritus may occur when Levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should be resolved when the treatment is started.
Effects on Ability to Drive and Use Machine: 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.
Use in Children: 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 pediatric formulation of Levocetirizine.

Fertility: There are no relevant data available.
Pregnancy: Caution should be exercised when prescribing to pregnant women. For Levocetirizine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ fetal development, parturition or postnatal development.
Lactation: Caution should be exercised when prescribing to lactating women. Cetirizine is excreted in human breast milk. Levocetirizine is also expected to be excreted in human milk.

Adverse drug reactions (ADRs) are listed below by system organ class: Nervous system disorders: Common: Headache, somnolence.
Gastrointestinal disorders: Common: Dry mouth. Uncommon: Abdominal pain.
General disorders and administration site conditions: Common: Fatigue. Uncommon: Asthenia.
Post Marketing Data: Immune system disorders: Not known: Hypersensitivity including anaphylaxis.
Metabolism and nutrition disorders: Not known: Increased weight, increased appetite.
Psychiatric disorders: Not known: Aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmares.
Nervous system disorders: Not known: Convulsions, paraesthesia, dizziness, syncope, tremor, dysgeusia.
Eyes disorders: Not known: Visual disturbances, blurred vision, oculogyration.
Ear and labyrinth disorders: Not known: Vertigo.
Cardiac disorders: Not known: Palpitations, tachycardia.
Respiratory, thoracic, and mediastinal disorders: Not known: Dyspnea.
Gastrointestinal disorders: Not known: Nausea, vomiting, diarrhea.
Hepatobiliary disorders: Not known: Hepatitis, abnormal liver function test.
Skin and subcutaneous tissue disorders: Not known: Angioneurotic edema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal and connective tissues disorders: Not known: Myalgia, arthralgia.
Renal and urinary disorders: Not known: Dysuria, urinary retention.
General disorders and administration site conditions: Not known: Edema.
Skin reactions occurring after discontinuation of Levocetirizine: After Levocetirizine discontinuation, pruritus has been reported (see Warnings and Precaution).

No interaction studies have been performed with Levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound Cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, Pseudoephedrine, Cimetidine, Ketoconazole, Erythromycin, Azithromycin, Glipizide and Diazepam).
Theophylline: A small decrease in the clearance of Cetirizine can be observed with Theophylline (400 mg once a day); while the disposition of Theophylline cannot be altered by concomitant Cetirizine administration.
Ritonavir: The extent of exposure to Cetirizine is possible to increase while the disposition of Ritonavir can be slightly altered further to concomitant Cetirizine administration.
Food: The extent of absorption of Levocetirizine is not reduced with food, although the rate of absorption is decreased.
Alcohol: The concurrent administration of Cetirizine or Levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

Store at temperature of not more than 30°C.

Antihistamines & Antiallergics

R06AE09 - levocetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.

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