National Geographic : 1999 Apr
CLARITIN® brand of loratadine TABLETS, SYRUP, and RAPIDLY-DISINTEGRATING TABLETS BRIEFSUMMARY(For full Prescribing Information, see package insert.) INDICATIONS ANDUSAGE:CLARITIN is indicated for the relief of nasal and non nasal symptoms of seasonal allergic rhinitis and for the treatment of chronic idiopathic urticaria in patients 6years of age or older. CONTRAINDICATIONS: CLARITINis contraindicated in patients who are hypersensitive to this medication or to any of its ingredients. PRECAUTIONS: General: Patients with liver impairment or renal insufficiency (GFR< 30 mL/min) should be given a lower initial dose (10 mg every other day). (See CLINICAL PHARMACOLOGY: Special Populations.) Drug Interactions: Loratadine (10 mg once daily) has been coadministered with therapeutic doses of erythromycin, cimetidine, and ketoconazole in controlled clinical pharmacology studies in adult volunteers. Although increased plasma concentrations (AUC 0-24 hrs) of loratadine and/or descarboethoxyloratadine were observed following coad ministration of loratadine with each of these drugs in normal volunteers (n = 24 in each study), there were no clinically relevant changes in the safety profile of loratadine, as assessed by electrocardiographic parameters, clinical laboratory tests, vital signs, and adverse events. There were no significant effects on QT,intervals, and no reports of seda tion or syncope. Noeffects on plasma concentrations of cimetidine or ketoconazole were observed. Plasma concentrations (AUC0-24 hrs) of erythromycin decreased 15% with coadministration of loratadine relative to that observed with erythromycin alone. The clin ical relevance of this difference is unknown. These above findings are summarized in the following table: Effects on Plasma Concentrations (AUC0-24 hrs) of Loratadine and Descarboethoxyloratadine After 10 Days of Coadministration (Loratadine 10 mq) in Normal Volunteers Loratadine Descarboethoxyloratadine Erythromycin (500 mg Q8h) + 40% +46% Cimetidine (300 mg QID) +103% +6% Ketoconazole (200 mg Q12h) +307% +73% There does not appear to be an increase in adverse events in subjects who received oral contraceptives and loratadine. Carcinogenesis, Mutagenesis, and Impairment of Fertility: In an 18-month car cinogenicity study in mice and a 2-year study in rats, loratadine was administered in the diet at doses up to 40 mg/kg (mice) and 25 mg/kg (rats). Inthe carcinogenicity studies, pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUCdata demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (descarboethoxyloratadine) times higher than in humans given the maximum recommended daily oral dose. Exposure of rats given 25 mg/kg of loratadine was 28 (loratadine) and 67 (descarboethoxyloratadine) times higher than inhumans given the maximum recommended daily oral dose. Male mice given 40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls. Inrats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg and males and females given 25 mg/kg. The clinical significance of these findings during long term use of CLARITIN is not known. In mutagenicity studies, there was no evidence of mutagenic potential in reverse (Ames) or forward point mutation (CHO-HGPRT) assays, or inthe assay for DNAdam age (rat primary hepatocyte unscheduled DNAassay) or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenesis assay and the mouse bone marrow erythrocyte micronucleus assay). Inthe mouse lymphoma assay, a positive find ing occurred in the nonactivated but not the activated phase of the study. Decreased fertility in male rats, shown by lower female conception rates, occurred at an oral dose of 64 mg/kg (approximately 50 times the maximum recommended human daily oral dose on a mg/m2 basis) and was reversible with cessation of dosing. Loratadine had no effect on male or female fertility or reproduction in the rat at an oral dose of approximately 24 mg/kg (approximately 20 times the maximum recommended human daily oral dose on a mg/m 2 basis). Pregnancy Category B:There was no evidence of animal teratogenicity in studies per formed in rats and rabbits at oral doses up to 96 mg/kg (approximately 75 times and 150 times, respectively, the maximum recommended human daily oral dose on a mg/m 2 basis). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CLARITIN should be used during pregnancy only if clearly needed. Nursing Mothers: Loratadine and its metabolite, descarboethoxyloratadine, pass easily into breast milk and achieve concentrations that are equivalent to plasma levels with an AUC,,JAUCp, ratio of 1.17 and 0.85 for loratadine and descarboethoxyloratadine, respectively. Fol)wing a single oral dose of 40 mg, a small amount of loratadine and descarboethoxyloratadine was excreted into the breast milk (approximately 0.03% of 40 mg over 48 hours). Adecision should be made whether to discontinue nursing or to dis continue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when CLARITIN isadministered to a nursing woman. Pediatric Use: The safety of CLARITINSyrup at a daily dose of 10 mg has been demonstrated in 188 pediatric patients 6-12 years of age in placebo-controlled 2-week trials. The effectiveness of CLARITINfor the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria in this pediatric age group is based on an extrapolation of the demonstrated efficacy of CLARITINin adults in these conditions and the likelihood that the disease course, pathophysiology, and the drug's effect are substantially similar to that of the adults. The recommended dose for the pediatric population is based on cross-study comparison of the pharmacokinetics of CLARITINin adults and pediatric subjects and on the safety profile of loratadine in both adults and pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness of CLARITINin pedi atric patients under 6 years of age have not been established. ADVERSEREACTIONS:CLARITIN Tablets: Approximately 90,000 patients, aged 12 and older, received CLARITIN Tablets 10 mg once daily in controlled and uncontrolled studies. Placebo-controlled clinical trials at the recommended dose of 10 mg once a day varied from 2 weeks' to 6 months' duration. The rate of premature withdrawal from these trials was approximately 2% in both the treated and placebo groups. REPORTED ADVERSE EVENTSWITHANINCIDENCE OFMORE THAN2% IN PLACEBO-CONTROLLED ALLERGIC RHINITIS CLINICAL TRIALS INPATIENTS 12 YEARS OFAGEANDOLDER PERCENT OFPATIENTS REPORTING LORATADINE PLACEBO CLEMASTINETERFENADINE 10mgQD 1mgBID 60 mg BID n=1926 n =2545 n=536 n= 684 Headache 12 11 8 8 Somnolence 8 6 22 9 Fatigue 4 3 10 2 Dry Mouth 3 2 4 3 Adverse events reported in placebo-controlled chronic idiopathic urticaria trials were similar to those reported in allergic rhinitis studies. Adverse event rates did not appear to differ significantly based on age, sex, or race, although the number of nonwhite subjects was relatively small. CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): Approximately 500 patients received CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in controlled clinical trials of 2 weeks' duration. Inthese studies, adverse events were sim ilar in type and frequency to those seen with CLARITINTablets and placebo. Administration of CLARITINREDITABS (loratadine rapidly-disintegrating tablets) did not result in an increased reporting frequency of mouth or tongue irritation. CLARITIN Syrup: Approximately 300 pediatric patients 6 to 12 years of age received 10 mg loratadine once daily in controlled clinical trials for a period of 8-15 days. Among these, 188 children were treated with 10 mg loratadine syrup once daily in placebo controlled trials. Adverse events in these pediatric patients were observed to occur with type and frequency similar to those seen in the adult population. The rate of premature discontinuance due to adverse events among pediatric patients receiving loratadine 10 mg daily was less than 1%. ADVERSE EVENTSOCCURRING WITHAFREQUENCY OF> 2% INLORATADINE SYRUP-TREATED PATIENTS (6-12 YEARS OLD)INPLACEBO-CONTROLLED TRIALS, ANDMORE FREQUENTLY THANINTHEPLACEBO GROUP PERCENT OFPATIENTS REPORTING LORATADINE PLACEBO CHLORPHENIRAMINE 10mgQD 2-4 mg BID/TID n=188 n=262 n =170 Nervousness 4 2 2 Wheezing 4 2 5 Fatigue 3 2 5 Hyperkinesia 3 1 1 Abdominal Pain 2 0 0 Conjunctivitis 2 <1 1 Dysphonia 2 <1 0 Malaise 2 0 1 Upper Respiratory Tract Infection 2 <1 0 Inaddition to those adverse events reported above (>2%), the following adverse events have been reported in at least one patient in CLARITIN clinical trials inadult and pediatric patients: Autonomic Nervous System: Altered lacrimation, altered salivation, flushing, hypoes thesia, impotence, increased sweating, thirst. BodyAsA Whole: Angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus, viral infection, weight gain. CardiovascularSystem: Hypertension, hypotension, palpitations, supraventricular tachyarrhythmias, syncope, tachycardia. Central and Peripheral Nervous System: Blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia, tremor, vertigo. GastrointestinalSystem: Altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, hiccup, increased appetite, nausea, stomatitis, toothache, vomiting. MusculoskeletalSystem: Arthralgia, myalgia. Psychiatric: Agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, irritability, paroniria. Reproductive System: Breast pain, dysmenorrhea, menorrhagia, vaginitis. Respiratory System: Bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis, nasal dryness, pharyngitis, sinusitis, sneezing. Skin and Appendages: Dermatitis, dry hair, dry skin, photosensitivity reaction, pruritus, purpura, rash, urticaria. Urinary System: Altered micturition, urinary discoloration, urinary incontinence, urinary retention. In addition, the following spontaneous adverse events have been reported rarely during the marketing of loratadine: abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis; alopecia; anaphylaxis; breast enlargement; erythema multiforme; peripheral edema; and seizures. OVERDOSAGE: Inadults, somnolence, tachycardia, and headache have been reported with overdoses greater than 10 mg with the Tablet formulation (40 to 180 mg). Extra pyramidal signs and palpitations have been reported in children with overdoses of greater than 10 mg of CLARITIN Syrup. Inthe event of overdosage, general symptomatic and sup portive measures should be instituted promptly and maintained for as long as necessary. Treatment of overdosage would reasonably consist of emesis (ipecac syrup), except in patients with impaired consciousness, followed by the administration of activated char coal to absorb any remaining drug. If vomiting is unsuccessful, or contraindicated, gastric lavage should be performed with normal saline. Saline cathartics may also be of value for rapid dilution of bowel contents. Loratadine is not eliminated by hemodialysis. It is not known if loratadine is eliminated by peritoneal dialysis. Nodeaths occurred at oral doses up to 5000 mg/kg in rats and mice (greater than 2400 and 1200 times, respectively, the maximum recommended human daily oral dose on a mg/m 2 basis). Single oral doses of loratadine showed no effects in rats, mice, and monkeys at doses as high as 10 times the maximum recommended human daily oral dose on a mg/m 2 basis. Schering Corporation Kenilworth, NJ 07033 USA Rev.3/98 19628426T-JBS CLARITINREDITABS(loratadine rapidly-disintegrating tablets) are manufactured for Schering Corporation by Scherer DDS, England. U.S. Patent Nos. 4,282,233 and 4,371,516. Copyright © 1997, 1998, Schering Corporation. Allrights reserved.