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Xyzal (Levocetirizine Dihydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Levocetirizine dihydrochloride, the active component of XYZAL tablets and oral solution, is an orally active H1- receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C21H25ClN2O3•2HCl. The molecular weight is 461.82 and the chemical structure is shown below:

Levocetirizine dihydrochloride is a white, crystalline powder and is water soluble.

XYZAL 5 mg tablets are formulated as immediate release, white, film-coated, oval-shaped scored tablets for oral administration. The tablets are imprinted on both halves of the scored line with the letter Y in red (Opacode® Red). Inactive ingredients are: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and macrogol 400.

XYZAL 0.5 mg/mL oral solution is formulated as an immediate release, clear, colorless liquid. Inactive ingredients are: sodium acetate trihydrate, glacial acetic acid, maltitol solution, glycerin, methylparaben, propylparaben, saccharin, flavoring (consisting of triacetin, natural & artificial flavors, dl-alpha-tocopherol), purified water.

CLINICAL PHARMACOLOGY

Mechanism of Action

Levocetirizine, the active enantiomer of cetirizine, is an 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 Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.

    A dose of 5 mg (10 mL) of XYZAL oral solution is bioequivalent to a 5 mg dose of XYZAL tablets. Following oral administration of a 5 mg dose of XYZAL oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose.
  • 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 oral solution, 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 [see Dosage and Administration ].
  • 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 Cmax 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 [see Drug Interactions (7) ].
  • 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 Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. 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 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 XYZAL dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration (2) ].
  • 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 (CLCR < 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during a standard 4 hour hemodialysis procedure was <10%.

    The dosage of XYZAL 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 [see Dosage and Administration (2) ].
  • Hepatic Impairment
    XYZAL 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 [see Dosage and Administration (2) ].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenesis studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 16 times the maximum recommended daily oral dose in adults and approximately 20 times the maximum recommended daily oral dose in children on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 7 times the maximum recommended daily oral dose in adults and approximately 8 times the maximum recommended daily oral dose in children on a mg/m2 basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis). The clinical significance of these findings during long-term use of XYZAL is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in mice.

In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m2 basis).

CLINICAL STUDIES

Seasonal and Perennial Allergic Rhinitis

Adults and Adolescents 12 Years of Age and Older

The efficacy of XYZAL was evaluated in six randomized, placebo-controlled, double-blind clinical trials in adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis or perennial allergic rhinitis. The six clinical trials include three dose-ranging trials of 2 to 4 weeks duration, one 2-week efficacy trial in patients with seasonal allergic rhinitis, and two efficacy trials (one 6-week and one 6-month) in patients with perennial allergic rhinitis.

These trials included a total of 2412 patients (1068 males and 1344 females) of whom 265 were adolescents 12-17 years of age. Efficacy was assessed using a total symptom score from patient recording of 4 symptoms (sneezing, rhinorrhea, nasal pruritus, and ocular pruritus) in five studies and 5 symptoms (sneezing, rhinorrhea, nasal pruritus, ocular pruritus, and nasal congestion) in one study. Patients recorded symptoms using a 0-3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) once daily in the evening reflective of the 24 hour treatment period. In one study, patients also recorded these symptoms in an instantaneous (1 hour before the next dose) manner. The primary endpoint was the mean total symptom score averaged over the first week and over 2 weeks for seasonal allergic rhinitis trials, and 4 weeks for perennial allergic rhinitis trials.

The three dose-ranging trials were conducted to evaluate the efficacy of XYZAL 2.5, 5, and 10 mg once daily in the evening. One trial was 2 weeks in duration conducted in patients with seasonal allergic rhinitis, and two trials were 4 weeks in duration conducted in patients with perennial allergic rhinitis. In these trials, each of the three doses of XYZAL demonstrated greater decrease in the reflective total symptom score than placebo and the difference was statistically significant for all three doses in two of the studies. Results for two of these trials are shown in Table 3.

Table 3 Mean Reflective Total Symptom Score* in Allergic Rhinitis Dose-Ranging Trials
TreatmentNBaselineOn Treatment Adjusted MeanDifference from Placebo
Estimate95% CIp-value
*Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0-3 categorical severity scale.
Seasonal Allergic Rhinitis Trial – Reflective total symptom score
XYZAL 2.5 mg1167.834.270.91(0.37, 1.45)0.001
XYZAL 5 mg1157.454.061.11(0.57, 1.65)<0.001
XYZAL 10 mg1187.153.571.61(1.07, 2.15)<0.001
Placebo1187.945.17
Perennial Allergic Rhinitis Trial – Reflective total symptom score
XYZAL 2.5 mg1337.144.121.17(0.71, 1.63)<0.001
XYZAL 5 mg1277.184.071.22(0.76, 1.69) <0.001
XYZAL 10 mg1297.584.191.10(0.64, 1.57)<0.001
Placebo1287.225.29

One clinical trial was designed to evaluate the efficacy of XYZAL 5 mg once daily in the evening compared with placebo in patients with seasonal allergic rhinitis over a 2-week treatment period. In this trial, XYZAL 5 mg demonstrated a greater decrease from baseline in the reflective and instantaneous total symptom score than placebo, and the difference was statistically significant (see Table 4). The results of the instantaneous total symptom score support efficacy at the end of the dosing interval.

One clinical trial evaluated the efficacy of XYZAL 5 mg once daily in the evening compared to placebo in patients with perennial allergic rhinitis over a 6-week treatment period. Another trial conducted over a 6-month treatment period assessed efficacy at 4 weeks. XYZAL 5 mg demonstrated a greater decrease from baseline in the reflective total symptom score than placebo and the difference from placebo was statistically significant. Results of one of these trials are shown in Table 4.

Table 4 Mean Reflective Total Symptom Score* and Instantaneous Total Symptom Score in Allergic Rhinitis Trials
TreatmentNBaselineOn Treatment Adjusted MeanDifference from Placebo
Estimate95% CIp-value
*Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0-3 categorical severity scale.
Seasonal Allergic Rhinitis Trial – Reflective total symptom score
XYZAL 5 mg1188.405.200.89(0.30, 1.47)0.003
Placebo1178.506.09
Seasonal Allergic Rhinitis Trial – Instantaneous total symptom score
XYZAL 5 mg1187.244.580.73(0.17, 1.28) 0.011
Placebo1177.485.30
Perennial Allergic Rhinitis Trial – Reflective total symptom score
XYZAL 5 mg 1507.693.931.17(0.70, 1.64)<0.001
Placebo 1427.445.10

Onset of action was evaluated in two environmental exposure unit studies in allergic rhinitis patients with a single dose of XYZAL 2.5 or 5 mg. XYZAL 5 mg was found to have an onset of action 1 hour after oral intake. Onset of action was also assessed from the daily recording of symptoms in the evening before dosing in the seasonal and perennial allergic rhinitis trials. In these trials, onset of effect was seen after 1 day of dosing.

Pediatric Patients Less than 12 Years of Age

There are no clinical trials with XYZAL 2.5 mg once daily in pediatric patients under 12 years of age [see Use in Specific Populations ].

Chronic Idiopathic Urticaria

Adult Patients 18 Years of Age and Older

The efficacy of XYZAL for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria was evaluated in two multi-center, randomized, placebo-controlled, double-blind clinical trials of 4 weeks duration in adult patients 18 to 85 years of age with chronic idiopathic urticaria. The two trials included one 4-week dose-ranging trial and one 4-week single-dose level efficacy trial. These trials included 423 patients (139 males and 284 females). Most patients (>90%) were Caucasian and the mean age was 41. Of these patients, 146 received XYZAL 5 mg once daily in the evening. Efficacy was assessed based on patient recording of pruritus severity on a severity score of 0–3 (0 = none to 3 = severe). The primary efficacy endpoint was the mean reflective pruritus severity score over the first week and over the entire treatment period. Additional efficacy variables were the instantaneous pruritus severity score, the number and size of wheals, and duration of pruritus.

The dose-ranging trial was conducted to evaluate the efficacy of XYZAL 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of XYZAL demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (see Table 5).

The single dose level trial evaluated the efficacy of XYZAL 5 mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over a 4-week treatment period. XYZAL 5 mg demonstrated a greater decrease from baseline in the reflective pruritus severity score than placebo and the difference from placebo was statistically significant.

Duration of pruritus, number and size of wheals, and instantaneous pruritus severity score also showed significant improvement over placebo. The significant improvement in the instantaneous pruritus severity score over placebo confirmed end of dosing interval efficacy (see Table 5).

Table 5 Mean Reflective Pruritus Severity Score in Chronic Idiopathic Urticaria Trials
TreatmentNBaselineOn Treatment Adjusted MeanDifference from Placebo
Estimate95% CIp-value
Dose-Ranging Trial – Reflective pruitus severity score
XYZAL 2.5 mg 69 2.08 1.02 0.82 (0.58, 1.06) <0.001
XYZAL 5 mg622.070.920.91(0.66, 1.16)<0.001
XYZAL 10 mg552.040.731.11(0.85, 1.37)<0.001
Placebo602.251.84
Chronic Idiopathic Urticaria Trial – Reflective pruritus severity score
XYZAL 5 mg802.070.940.62(0.38, 0.86)<0.001
Placebo822.061.56

Pediatric Patients

There are no clinical trials in pediatric patients with chronic idiopathic urticaria [see Use in Specific Populations ].

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