Levocetin

Each tablet contains 5 mg levocetirizine dihydrochloride.

Pharmacology: Mechanism of Action: Levocetirizine, the active enantiomer of cetirizine, is anti-histamine; its principal effects are mediated via selective inhibition of H₁ receptors. The antihistaminic activity of levocetirizine has been documented in a variety of animal and human models. In vitro binding studies revealed that levocetirizine has an affinity for the human H₁-receptor 2-fold higher than that of cetirizine (Ki=3 nmol/L vs. 6 nmol/L, respectively). The clinical relevance of this finding is unknown.
Pharmacodynamics: Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown.
A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While a single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long post-marketing history of cetirizine without reports of QT prolongation.
Pharmacokinetics: Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the levocetirizine tablet, but T_max was delayed by about 1.25 hours and C_max was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.
Distribution: The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.
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 hepatic drug metabolizing 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 involves multiple and/or unidentified CYP isoforms.
Elimination: The plasma half-life in adult healthy subjects was about 8 to 9 hours after administration of oral tablets, and the mean oral total body clearance for levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its 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. Renal clearance of levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of levocetirizine is reduced.
Drug Interaction Studies: In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above C_max level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4.
No formal in vivo drug interaction studies have been performed with levocetirizine. Studies have been performed with the racemic cetirizine.
Pediatric Patients: Data from a pediatric pharmacokinetic study 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 C_max and AUC values are about 2-fold greater than that reported in healthy adult subjects in across study comparison. The mean C_max 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 pediatric population than in adults.
Geriatric Patients: Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65-74 years of age), 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 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); 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.
Renal Impairment: Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2.0-, 2.9-, and 4-fold, respectively.
The total body clearance of levocetirizine after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment. Therefore, it is recommended to adjust the dose and dosing intervals of levocetirizine based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CL_cr < 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during a standard 4 hour hemodialysis procedure was <10%.
The dosage of levocetirizine should be reduced in patients with mild renal impairment. Both the dosage and frequency of administration should be reduced in patients with moderate or severe renal impairment.
Hepatic Impairment: Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance(indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration.
As levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment.

Levocetirizine is indicated for the treatment of symptoms associated with allergic conditions such as: Seasonal allergic rhinitis (including ocular symptoms); Perennial allergic rhinitis; Persistent allergic rhinitis; Chronic urticaria.

Recommended Dose: Adults and adolescents 12 years and above: The daily recommended dose is 5 mg (1 tablet).
Elderly: Use caution with dose selection and start at low end of dosage range.
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 (CL_cr) in mL/min is needed. The CL_cr (mL/min) may be estimated from serum creatinine (mg/dL) determination using the following formula: See equation.

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Dosing adjustments for patients with impaired renal function: See Table 1.

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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 previously).
Pediatric population: Children aged 6 to 12 years: The daily recommended dose is 5 mg (1 tablet).
Method of Administration: The tablet must be taken orally, swallowed whole with liquid and may be taken with or without food.
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.

Overdosage has been reported with levocetirizine.
Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness, followed by drowsiness in children. There is no known specific antidote to levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine 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/m² 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/m² basis).

The use of levocetirizine is contraindicated in: Patients with known hypersensitivity: Patients with known hypersensitivity to levocetirizine or any of the ingredients of Levocetin, or to cetirizine. Observed reactions range from urticaria to anaphylaxis.
Patients with end-stage renal disease: Patients with end-stage renal disease (CL_cr < 10 mL/min) and patients undergoing hemodialysis.
Pediatric patients with impaired renal function: Children 6 months to 11 years of age with impaired renal function.

Somnolence: 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: 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 levocetirizine If urinary retention occurs.
Galactose Intolerance: This Levocetin contains Lactose. Patient with rare hereditary problem of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine or seek medical professional advice before use.
Renal Impairment: Levocetirizine 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.
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.
Use in Children: The recommended dose of levocetirizine 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.
The recommended dose of levocetirizine in patients 6 months to 11 years of age for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria and in patients 2 to 11years of age for the treatment of the symptoms of seasonal allergic rhinitis is based on cross-study comparisons of the systemic exposure of levocetirizine in adults and pediatric patients and on the safety profile of levocetirizine 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 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 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 1.25 mg once daily was evaluated in one 2- week clinical trial in 45 pediatric patients 6 to 11 months of age.
The effectiveness of levocetirizine 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 seasonal and perennial allergic rhinitis and chronic idiopathic urticarial is supported by the extrapolation of demonstrated efficacy of levocetirizine 5 mg once daily in patients 12 years of age and older and based on the pharmacokinetic comparison between adults and children.
Cross-study comparisons indicate that administration of a 5 mg dose of levocetirizine to 6 to 12 year old pediatric seasonal allergic rhinitis patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of levocetirizine 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.
Use in the Elderly: 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.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, levocetirizine should be used during pregnancy only if clearly needed.
Teratogenic Effects: In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390 times, respectively, the maximum recommended daily oral dose in adults on a mg/m² basis.
Nursing Mothers: No peri- and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of levocetirizine in nursing mothers is not recommended.

Use of levocetirizine has been associated with somnolence, fatigue, and asthenia.
Clinical Trials Experience: The safety data described as follows reflect exposure to levocetirizine in 2708 patients with seasonal or perennial 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 1896 patients (825 males and 1071 females aged 12 years and older) were treated with levocetirizine 2.5, 5, 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 seasonal or perennial allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with levocetirizine 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 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 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 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine-treated subjects 12-24 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 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 1-6 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 showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).
Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to levocetirizine 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with levocetirizine than placebo. (See Table 2.)

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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%).
Pediatric Patients 6 to 12 Years of Age: A total of 243 pediatric patients 6 to 12 years of age received levocetirizine 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 3 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to levocetirizine 5mg in placebo-controlled clinical trials and that were more common with levocetirizine than placebo. (See Table 3.)

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Pediatric Patients 1 to 5 Years of Age: A total of 114 pediatric patients 1 to 5 years of age received levocetirizine 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 4 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years exposed to levocetirizine 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with levocetirizine than placebo. (See Table 4.)

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Pediatric Patients 6 to 11 Months of Age: A total of 45 pediatric patients 6 to 11 months of age received levocetirizine 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 XYZAL 1.25 mg once daily in the placebo-controlled safety trial and that were more common with XYZAL than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the XYZAL 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 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 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.
Post-Marketing Experience: In addition to the adverse reactions reported during clinical trials and listed previously, adverse events have also been identified during post-approval use of levocetirizine in other countries. Because these events 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. Adverse events of hypersensitivity and anaphylaxis, angioneurotic edema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, aggression and agitation, visual disturbances, palpitations, dyspnea, nausea, hepatitis, and myalgia have been reported.
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: hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

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.
Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine: 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.
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.

Store below 30°C and keep in dry place.

Antihistamines & Antiallergics

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

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