Stadeltine

Levocetirizine dihydrochloride.

Each film-coated tablet contains: Levocetirizine dihydrochloride 5 mg.

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivatives. ATC code: R06A E09.
Pharmacology: Pharmacodynamics: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H₁-receptors.
It is 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 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. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg once daily dose, respectively. 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. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment.
In humans, 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 half-life is shorter in small children.
The mean apparent total body clearance in adults is 0.63 ml/min/kg.
The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces 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 anuric end stage renal disease patients, the total body clearance is decreased by approximately 80% when compared to normal patients. The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.
Paediatric population: Oral administration of a single dose of 5 mg levocetirizine in children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adults. The mean Cmax was 450 ng/ml, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this paediatric population than in adults.
Elderly: Limited pharmacokinetic data are available in elderly. The total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be 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: Pharmacokinetic results for the patients (both men and women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 hours ± 1.72 hours) than in men (8.62 hours ± 1.84 hours); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 ml/min/kg) appears to be comparable to that in men (0.59 ± 0.12 ml/min/kg). The same daily doses 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 the hepatically impaired 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 those who are healthy.

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

Adults and adolescents 12 years and above: The daily recommended dose is 5 mg (one film-coated tablet).
Elderly: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Renal impairment as follows).
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 patients with impaired renal function: (see table).

Click on icon to see table/diagram/image

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.
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 previously).
Paediatric population: Children aged 6 to 12 years: The daily recommended dose is 5 mg (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 paediatric formulation of levocetirizine.
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 clinical experience of use of cetirizine (racemate) for up to one year.
Administration: Oral use. Swallow whole with liquid and may be taken with or without food. It is recommended to take the daily dose in one single intake.

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

Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any of the excipients in the formula.
Severe renal impairment at less than 10ml/min creatinine clearance.

Precaution is recommended with concurrent intake of alcohol.
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.
Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.
Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 resolve when the treatment is restarted.
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 paediatric formulation of levocetirizine.
Effects on ability to drive and use machines: It has been revealed that 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.

Pregnancy: The use of levocetirizine may be considered during pregnancy, if necessary. There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto/neonatal toxicity.
Lactation: Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.

Nervous system disorders: Common: headache, somnolence.
Gastrointestinal disorders: Common: dry mouth. Uncommon: abdominal pain.
General disorders and administration site conditions: Common: fatigue. Uncommon: asthenia.
The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1 %) under levocetirizine 5 mg than under placebo (3.1%).
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: dyspnoea.
Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea.
Hepatobiliary disorders: Not known: hepatitis, abnormal liver function test.
Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, 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: oedema.
Skin reactions occurring after discontinuation of levocetirizine: After levocetirizine discontinuation, pruritus has been reported.

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). A small decrease in the clearance of cetirizine (16%) was observed with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.
The extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

Do not store above 30°C.

Antihistamines & Antiallergics

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

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