National Geographic : 1995 Aug
CLARITIN -D brand of loratadine and pseudoephedrine sulfate, USP Long-Acting Antihistamine/Extended Release Decongestant Tablets BRIEF SUMMARY (For full Prescribing Information, see package insert.) CAUTION: Federal Law Prohibits Dispensing Without Prescription INDICATIONS ANDUSAGE:CLARITIN-DTablets are indicatedforthe reliefof symptoms of sea sonal allergicrhinitis.CLARITIN-DTablets should be administered when boththe antihistaminic properties of CLARITIN(loratadine) and the nasaldecongestantactivityof pseudoephedrine are desired (see CLINICAL PHARMACOLOGY). CONTRAINDICATIONS: CLARITIN-D Tablets are contraindicated inpatients who are hypersensi tiveto this medication or to any ofits ingredients. This product, due to its pseudoephedrine component, is contraindicated in patients with narrow-angle glaucoma or urinaryretention, and inpatients receivingmonoamine oxidase (MAO) inhibitor therapy or withinfourteen (14) days ofstopping such treatment (see DrugInteractions section). It is also contraindicated in patients withsevere hypertension, severe coronary artery disease, and in those who have shown hypersensitivity or idiosyncrasy to its components, to adrenergic agents, or to other drugs ofsimilar chemical structures. Manifestations of patient idio syncrasy to adrenergic agents include:insomnia, dizziness, weakness, tremor, or arrhythmias. WARNINGS:CLARITIN-DTablets should be used withcaution in patients withhypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy. Central nervous system stimulation withconvulsions or cardiovascular collapse withaccompanying hypotension may be produced by sympathomimetic amines. Use inPatients Approximately60 YearsandOlder:The safety and efficacyof CLARITIN-DTablets in patients greater than 60 years old have not been investigated in placebo-controlled clinical trials. The elderlyare more likelyto haveadverse reactions to sympathomimetic amines. PRECAUTIONS:General:Because the doses of this fixedcombination product cannot be indi viduallytitrated and hepatic insufficiencyresults in a reduced clearance of loratadine to a much greater extent than pseudoephedrine, CLARITIN-D Tablets should generallybeavoided in patients withhepatic insufficiency.Patients withrenalinsufficiency(GFR< 30 mL/min)should be givena lower initialdose (one tablet per day) because they have reduced clearance of loratadine and pseudoephedrine. Informationfor Patients: Patients taking CLARITIN-DTablets should receivethe following information: CLARITIN-D Tablets are prescribed for the reliefof symptoms of seasonal allergic rhinitis. Patients should be instructed to take CLARITIN-DTablets only as prescribed and not to exceed the prescribed dose. Patients should also be advised against the concurrent use of CLARITIN-DTablets withover-the-counter antihistamines and decongestants. Thisproduct should not be used bypatients who are hypersensitive to it or to any ofits ingre dients. Dueto its pseudoephedrine component, this product should not be used by patients with narrow-angle glaucoma, urinaryretention, or by patients receivinga monoamine oxidase (MAO) inhibitor or within14 days of stopping use of an MAOinhibitor.It also should not be used by patients withsevere hypertension or severe coronary artery disease. Patients who are or may become pregnant should betold that this product should be used in pregnancy or during lactationonlyif the potentialbenefitjustifies the potentialriskto the fetus or nursing infant. Patients should beinstructed not to breakor chew the tablet. DrugInteractions: No specific interaction studies have been conducted withCLARITIN-D Tablets. However,loratadine (10 mg once daily)has been safelycoadministered withtherapeutic doses oferythromycin, cimetidine, and ketoconazole in controlled clinicalpharmacology studies. Althoughincreased plasma concentrations (AUC0-24 hrs) of loratadine and/or descarboethoxy loratadine were observed followingcoadministration ofloratadine witheach ofthese drugs in nor mal volunteers (n = 24 in each study), there were no clinicallyrelevant changes in the safety profileof loratadine, as assessed by electrocardiographic parameters, clinicallaboratory tests, vitalsigns, and adverse events. There were no significant effects on QTcintervals, and no reports of sedation or syncope. No effects on plasma concentrations of cimetidine or ketoconazole were observed. Plasma concentrations (AUC0-24 hrs) oferythromycin decreased 15%withcoadmin istration of loratadine relativeto that observed witherythromycin alone. The clinicalrelevance of this differenceis unknown. These above findings are summarized inthe followingtable: Effectson Plasma Concentrations (AUC0-24 hrs) of Loratadineand Descarboethoxyloratadine After10 DaysofCoadministration (Loratadine10 mo) in NormalVolunteers Loratadine Descarboethoxyloratadine Erythromycin(500 mg Q8h) + 40% +46% Cimetidine(300 mg QID) +103% +6% Ketoconazole(200 mg 012h) +307% +73% Theredoes not appear to be an increase in adverse events in subjects who receivedoralcon traceptives and loratadine. CLARITIN-DTablets (pseudoephedrine component) are contraindicated in patients taking monoamine oxidase inhibitors and for 2 weeks after stopping use of an MAOinhibitor.The anti hypertensive effects of beta-adrenergic blockingagents, methyldopa, mecamylamine, reserpine, and veratrum alkaloids may be reduced by sympathomimetics. Increased ectopic pacemaker activitycan occur when pseudoephedrine is used concomitantly withdigitalis. Drug/Laboratory Test Interactions: Thein vitro addition of pseudoephedrine to sera containing the cardiac isoenzyme MBof serum creatinine phosphokinase progressively inhibitsthe activityof the enzyme. The inhibitionbecomes complete over 6 hours. Carcinogenesis, Mutagenesis, Impairment of Fertility:There are no animal or laboratory studies on the combination product loratadine and pseudoephedrine sulfate to evaluate carcino genesis, mutagenesis, orimpairment of fertility. Inan 18-month oncogenicity study in mice and a 2-year study inrats loratadine was adminis tered inthe diet at doses upto 40 mg/kg(mice) and25 mg/kg(rats). Inthe carcinogenicity stud ies pharmacokinetic assessments were carried out to determine animalexposure to the drug. AUCdata demonstrated that the exposure of micegiven40 mg/kg of loratadine was 3.6 (lorata dine)and 18 (activemetabolite) times higher than a human given 10 mg/day. Exposure of rats given25 mg/kg of loratadine was 28 (loratadine) and 67 (activemetabolite) times higher than a human given 10 mg/day. Male mice given 40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls. In rats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kgand males andfemales given25 mg/kg.The clinicalsig nificanceof these findings during long-term use of loratadine is not known. In mutagenicity studies withloratadine alone, there was no evidence of mutagenic potentialin reverse (Ames) or forward pointmutation (CHO-HGPRT)assays, or inthe assay for DNAdamage (Rat Primary Hepatocyte Unscheduled DNAAssay)or intwo assays for chromosomal aberrations (Human Peripheral Blood Lymphocyte Clastogenesis Assay and the Mouse Bone Marrow ErythrocyteMicronucleus Assay). Inthe Mouse Lymphoma Assay, a positive findingoccurred in the nonactivated but not the activated phase ofthe study. Loratadine administration produced hepatic microsomal enzyme induction in the mouse at 40 mg/kg and rat at 25 mg/kg, but not at lowerdoses. Decreased fertilityinmale rats, shown by lowerfemale conception rates, occurred at approxi mately 64 mg/kg of loratadine and was reversiblewith cessation of dosing. Loratadinehad no effecton male orfemale fertilityor reproduction inthe rat at doses approximately 24 mg/kg. PregnancyCategoryB:Therewas no evidence ofanimalteratogenicity inreproduction studies performed on rats and rabbits withthis combination at oraldoses up to 150 mg/kg (885 mg/m 2 or 5 times the recommended daily human dosage of 250 mg or 185 mg/m2),and 120 mg/kg (1416 mg/m 2 or 8 times the recommended dailyhuman dosage), respectively. Thereare, how ever, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictiveof humanresponse,CLARITIN-DTabletsshouldbe usedduring pregnancyonlyif clearlyneeded. NursingMothers: It is not known if this combination product is excreted in human milk. However,loratadine when administered alone and its metabolite descarboethoxyloratadine pass easilyinto breast milkand achieveconcentrations that are equivalent to plasma levels,withan AUCmilk/AUCpiasma ratio of 1.17 and 0.85 for the parent and active metabolite, respectively. Followinga single oral dose of 40 mg, a small amount of loratadine and metabolite was excreted into the breast milk(approximately 0.03% of 40 mg after 48 hours). Pseudoephedrine adminis tered alone also distributes into breast milkofthe lactatinghuman female. Pseudoephedrine con centrations in milkare consistently higher than those inplasma. The total amount of drug inmilk as judged bythe area under the curve (AUC)is 2 to 3 times greater than inplasma. The fraction of a pseudoephedrine dose excreted in milkis estimated to be0.4% to 0.7%. A decision should be made whether to discontinue nursing or to discontinue the drug, takinginto account the impor tance of the drug to the mother. Caution should be exercised when CLARITIN-DTablets are administered to a nursing woman. Pediatric Use: Safetyand effectiveness in children belowthe age of 12 years have not been established. ADVERSEREACTIONS:Experiencefrom controlled and uncontrolled clinicalstudies involving approximately 10,000 patients who receivedthe combination of loratadine and pseudoephedrine sulfate for a periodof up to 1 month provides information on adverse reactions. The usual dose was one tablet every12 hours for up to 28 days. In controlled clinicaltrials using the recommended dose of one tablet every 12hours, the inci dence of reported adverse events was similar to those reported withplacebo, withthe exception of insomnia (16%)and drymouth (14%). REPORTED ADVERSEEVENTSWITHANINCIDENCE OF>2% ON CLARITIN-D INPLACEBO-CONTROLLED CLINICAL TRIALS PERCENT OFPATIENTS REPORTING Headache Insomnia DryMouth Somnolence Nervousness Dizziness Fatigue Dyspepsia Nausea Pharyngitis Anorexia Thirst CLARITIN-D n=1023 19 Loratadine Pseudoephedrine Placebo n=543 n=548 n=922 18 17 19 4 19 3 4 9 3 8 5 4 3 7 2 1 5 2 6 3 3 2 3 1 2 3 2 3 2 3 1 2 1 1 2 1 Adverse event rates did not appear to differsignificantlybased on age, sex, or race, although the number of non-white subjects was relativelysmall. Inan additionto those adverse events reported above (>2%), the followingless frequent adverse events havebeen reported in at least one CLARITIN-D treated patient: Autonomic Nervous System: Abnormal lacrimation, dehydration, flushing, hypoesthesia, increased sweating, mydriasis. Body As A Whole: Asthenia, back pain,blurredvision,chest pain,conjunctivitis, earache, ear infection,eye pain,fever, flu-likesymptoms, leg cramps, lymphadenopathy, malaise, photopho bia,rigors, tinnitus, viralinfection,weight gain. CardiovascularSystem: Hypertension, hypotension, palpitations, peripheral edema, syncope, tachycardia, ventricular extrasystoles. Centraland PeripheralNervous System: Dysphonia, hyperkinesia, hypertonia, migraine, pares thesia, tremors, vertigo. GastrointestinalSystem: Abdominaldistension, abdominal distress, abdominal pain,altered taste, constipation, diarrhea, eructation, flatulence, gastritis, gingival bleeding, hemorrhoids, increased appetite, stomatitis, taste loss, tongue discoloration, toothache, vomiting. Liver and BiliarySystem: Hepaticfunction abnormal. Musculoskeletal System: Arthralgia,myalgia,torticollis. Psychiatric: Aggressive reaction, agitation, anxiety, apathy, confusion, decreased libido, depression, emotional lability,euphoria, impaired concentration, irritability,paroniria. ReproductiveSystem: Dysmenorrhea, impotence, intermenstrual bleeding,vaginitis. RespiratorySystem: Bronchitis, bronchospasm, chest congestion, coughing, dry throat, dys pnea, epistaxis, halitosis, nasal congestion, nasal irritation,sinusitis, sneezing, sputum increased, upper respiratory infection,wheezing. Skin and Appendages: Acne,bacterial skin infection, dry skin, eczema, edema, epidermal necrolysis, erythema, hematoma, pruritus, rash, urticaria. UrinarySystem: Dysuria,micturition frequency, nocturia, polyuria,urinaryretention. The followingadditional adverse events havebeen reported withthe use of CLARITINTablets: alopecia, altered salivation,amnesia, anaphylaxis, angioneurotic edema, blepharospasm, breast enlargement, breast pain,dermatitis, dryhair, erythema multiforme, hemoptysis, hepatic necro sis, hepatitis, jaundice, laryngitis,menorrhagia, nasal dryness, photosensitivity reaction, purpura, seizures, supraventricular tachyarrhythmias, and urinarydiscoloration. Pseudoephedrine may cause mildCNSstimulation in hypersensitive patients. Nervousness, excitability,restlessness, dizziness, weakness, or insomnia may occur. Headache, drowsiness, tachycardia, palpitation, pressor activity, and cardiac arrhythmias have been reported. Sympathomimetic drugs have also been associated with other untoward effects, such as fear, anxiety,tenseness, tremor, hallucinations, seizures, pallor,respiratory difficulty,dysuria, and car diovascular collapse. OVERDOSAGE:In the event of overdosage, general symptomatic and supportive 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 withimpaired conscious ness, followedbythe administration of activated charcoal to absorb any remaining drug. Ifvomit ing is unsuccessful, or contraindicated, gastric lavageshould be performed with normal saline. Salinecathartics mayalso be of valuefor rapiddilutionofbowelcontents. Loratadine is not elimi nated byhemodialysis. It is not knownif loratadine is eliminatedbyperitoneal dialysis. Somnolence, tachycardia, and headache have been reported withdoses of 40 to 180 mg of CLARITINTablets. Inlargedoses, sympathomimetics may give rise to giddiness, headache, nau sea, vomiting, sweating, thirst, tachycardia, precordial pain,palpitations, difficultyin micturition, muscular weakness andtenseness, anxiety,restlessness, and insomnia. Manypatients can pre sent a toxicpsychosis withdelusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure. The oral LDsovalues for the mixtureofthe two drugs were greater than 525 and 1839 mg/kg in miceand rats, respectively. OralLDsovalues for loratadine were greater than 5000 mg/kg in rats and mice. Doses of loratadine as highas 10 times the recommended dailyclinicaldose showed noeffect inrats, mice,and monkeys. Schering Corporation <t Kenilworth, NJ07033 USA Rev.1/95 17798626-JBS Copyright©1994,1995,ScheringCorporation. Allrightsreserved.