Levocet

Levocetirizine dihydrochloride.

Active Ingredient: Levocetirizine Dihydrochloride 0.5 mg/mL.
Excipients/Inactive Ingredients: (See Table 1.)

Click on icon to see table/diagram/image

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives. ATC Code: R06AE09.
Pharmacology: Pharmacodynamics: Mechanism of action: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.
Binding studies 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: Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. ln adults, peak plasma concentrations are achieved 0.9 h 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 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.
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, 2El 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 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 The amount of levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.
Pediatric population: The paediatric patient with oral administration of a single dose of 5 mg Levocetirizine in 14 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 in paediatric population than in healthy adult. 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: The total body clearance on elderly was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine is dependent on renal function rather than on age.
This was also applicable to levocetirizine and cetirizine which are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
Gender: The half-life was slightly shorter in women than in men, however the body weight-adjusted oral clearance in women appears to be comparable to that in men. The same daily doses and dosing intervals are applicable for men and women with normal renal function.
Race: As levocetirizine is primarily renal 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: 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 person.
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.

Instruction for use: Appropriate volume of oral solution should be measured with the oral syringe, and poured in a spoon or in a glass of water. The oral solution must be taken orally immediately after dilution, and may be taken with or without food.
Adults and adolescents 12 years and above: The daily recommended dose is 5 mg (10 ml of solution).
Elderly: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Patients with renal impairment as follows).
Children aged 2 to 6 years: The daily recommended dose is 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 ml of solution twice daily).
Children aged 6 to 12 years: The daily recommended dose is 5 mg (10 ml of solution), Due to the lack of data in this population, the administration of the product to infants and toddlers aged less than 2 years is not recommended.
Patients with 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 patients 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: CLcr = {[140 - age (years)] x weight (kg)} ÷ {72 x serum creatinine (mg/dl)} x {0.85 for women}.
Dosing adjustments for patients with impaired renal function: (See Table 2.)

Click on icon to see table/diagram/image

Patients with 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 Patients with renal impairment as previously mentioned).
Duration of use: Intermittent allergic rhinitis (symptoms <4 days/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 >4 days/week and during more than 4 weeks), continuous therapy can be proposed to the patient during the period of exposure to allergens.
Route of Administration: Oral.

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 may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by hemodialysis.

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

Precaution is recommended with concurrent intake of alcohol.
Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.
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.
Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
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.
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.

Pregnancy: The use of levocetirizine may be considered during pregnancy, if necessary.
Breast-feeding: Cetirizine, the race mate 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.

Adverse reactions from post-marketing experience are per System Organ Class and per frequency.
The frequency is defined as follows: very common; common; uncommon; rare; very rare, not known.
Immune system disorders: Not known: hypersensitivity including anaphylaxis.
Metabolism and nutrition disorders: Not known: increased appetite.
Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare.
Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia.
Ear and labyrinth disorders: Not known: vertigo.
Eye disorders: Not known: visual disturbances, blurred vision, oculogyration.
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.
Renal and urinary disorders: Not known: dysuria, urinary retention.
Skin and subcutaneous tissue disorders: Not known: angioneurotic edema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia.
General disorders and administration site conditions: Not known: edema.
Investigations: Not known: weight increased, abnormal liver function tests.

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.

Instructions for Use: Appropriate volume of oral solution should be measured with the oral syringe, and poured in a spoon or in a glass of water. The oral solution must be taken orally immediately after dilution, and may be taken with or without food.

The In-use Storage Condition: Discard 3 months After Opening.
Shelf Life: 3 years.

Antihistamines & Antiallergics

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

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