Levocetirizine Dihydrochloride (Page 2 of 5)

6.2 Postmarketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have also been identified during postapproval use of levocetrizine dihydrochloride. Because these reactions 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.

Cardiac disorders: palpitations, tachycardia
Ear and labyrinth disorders: vertigo
Eye disorders: blurred vision, visual disturbances
Gastrointestinal disorders: nausea, vomiting
General disorders and administration site conditions: edema
Hepatobiliary disorders: hepatitis
Immune system disorders: anaphylaxis and hypersensitivity
Metabolism and nutrition disorders: increased appetite
Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia
Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paresthesia, seizure (reported in subjects with and without a known seizure disorder), tremor
Psychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideation
Renal and urinary disorders: dysuria, urinary retention
Respiratory, thoracic, and mediastinal disorders: dyspnea
Skin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritis, rash and urticaria

Besides these reactions reported under treatment with levocetirizine dihydrochloride, other potentially severe adverse events have been reported from the postmarketing 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 dihydrochloride.

Cardiac disorders: severe hypotension
Gastrointestinal disorders: cholestasis
Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic
Pregnancy, puerperium and perinatal conditions: stillbirth
Renal and urinary disorders: glomerulonephritis
Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP); rebound pruritus — pruritus within a few days after discontinuation of cetirizine, usually after long-term use (e.g. months to years) of cetirizine.

7 DRUG INTERACTIONS

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.

7.1 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.

7.2 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published literature and postmarketing experience with levocetirizine use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm with administration of levocetirizine by the oral route to pregnant rats and rabbits, during the period of organogenesis, at doses up to 390 times and 470 times, respectively, the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine had no effects on pup development at oral doses up to approximately 60 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine administered by the oral route to the dams had no effects on pup development at a dose that was approximately 25 times the MRHD in adults; however, lower pup weight gain during lactation was observed at a dose that was 95 times the MRHD in adults [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal data

In embryo-fetal development studies, pregnant rats received daily doses of levocetirizine up to 200 mg/kg/day from gestation days 6 to 15 and pregnant rabbits received daily doses of levocetirizine up to 120 mg/kg/day from gestation days 6 to 18. Levocetirizine produced no evidence of fetal harm in rats and rabbits at doses up to 390 and 470 times the MRHD, respectively (on a mg/m2 basis with maternal oral doses of 200 mg/kg/day and 120 mg/kg/day in rats and rabbits, respectively).

No prenatal and postnatal development (PPND) studies in animals have been conducted with levocetirizine. In a PPND study conducted in mice, cetirizine was administered at oral doses up to 96 mg/kg/day from gestation day 15 through lactation day 21. Cetirizine lowered pup body weight gain during lactation at an oral dose in dams that was approximately 95 times the MRHD (on a mg/m2 basis with a maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an oral dose in dams that was approximately 25 times the MRHD (on a mg/m2 basis with a maternal oral dose of 24 mg/kg/day). In a PPND study conducted in rats, cetirizine was administered at oral doses up to 180 mg/kg/day from gestation day 17 to lactation day 22. Cetirizine did not have any adverse effects on rat dams or offspring development at doses up to approximately 60 times the MRHD (on a mg/m2 basis with a maternal oral dose of 30 mg/kg/day). Cetirizine caused excessive maternal toxicity at an oral dose in dams that was approximately 350 times the MRHD (on a mg/m2 basis with a maternal oral dose of 180 mg/kg/day).

8.2 Lactation

Risk Summary

There are no data on the presence of levocetirizine in human milk, the effects on the breastfed infant, or the effects on milk production. However, cetirizine has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine was excreted in milk (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levocetirizine dihydrochloride and any potential adverse effects on the breastfed child from levocetirizine dihydrochloride or from the underlying maternal condition.

Data

Animal data

Cetirizine was detected in the milk of mice. No adverse developmental effects on pups were seen when cetirizine was administered orally to dams during lactation at a dose that was approximately 25 times the MRHD in adults [see Use in Specific Population (8.1)]. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

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