National Geographic : 1995 Oct
CLARITIN -D brand of loratadine and pseudoephedrine sulfate, USP Long-Acting Antihistamine/Extended ReleaseDecongestant Tablets BRIEF SUMMARY (For full Prescribing Information, see package insert.) CAUTION: Federal Law Prohibits Dispensing Without Prescription INDICATIONS ANDUSAGE:OLARITIN-D Tabletsare indicatedforthe reliefofsymptoms of sea sonal allergicrhinitis.CLARITIN-D Tablets should be administered whenboththe antihistaminic properties of CLARITIN(loratadine) andthe nasal decongestant activityof pseudoephedrine are desired(see CLINICAL PHARMACOLOGY). CONTRAINDICATIONS: CLARITIN-DTablets are contraindicated inpatients who are hypersensi tiveto this medication or to any of its ingredients. This product, due to its pseudoephedrine component, is contraindicated in patients with narrow-angle glaucoma or urinaryretention, andin patients receivingmonoamine oxidase (MAO) inhibitortherapy or withinfourteen (14)days of stopping such treatment (see DrugInteractions section). It is also contraindicated in patients withsevere hypertension, severe coronary artery disease, and in those who haveshown hypersensitivity or idiosyncrasy to its components, to adrenergic agents, or to other drugs of similar chemical structures. Manifestations ofpatient idio syncrasy to adrenergic agents include:insomnia, dizziness, weakness, tremor, or arrhythmias. WARNINGS:CLARITIN-DTablets should be used withcaution in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy. Centralnervous system stimulation withconvulsions or cardiovascular collapse withaccompanying hypotension maybe produced by sympathomimetic amines. Use inPatients Approximately60 YearsandOlder:The safety and efficacyof CLARITIN-D Tablets in patients greater than 60 years old have not been investigated inplacebo-controlled clinical trials. The elderlyare more likelyto haveadverse reactions to sympathomimetic amines. PRECAUTIONS:General:Because the doses of this fixedcombination product cannot beindi viduallytitrated and hepatic insufficiencyresults in a reduced clearance of loratadine to a much greater extent than pseudoephedrine, CLARITIN-D Tablets should generally beavoidedinpatients withhepatic insufficiency.Patients withrenalinsufficiency(GFR< 30 mL/min)should begivena 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 onlyas 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 beused by patients who are hypersensitive to it or to any ofits ingre dients. Dueto its pseudoephedrine component, this product should not be used bypatients with narrow-angle glaucoma, urinaryretention, or by patients receivinga monoamine oxidase (MAO) inhibitoror within 14 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 maybecome pregnant should betold that this product should be used in pregnancy or during lactationonlyifthe 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 with CLARITIN-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 witheachofthese drugs in nor mal volunteers (n = 24 in each study), there were no clinicallyrelevant changes inthe safety profileof loratadine, as assessed by electrocardiographic parameters, clinicallaboratory tests, vitalsigns, and adverse events. Therewere 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) of erythromycin decreased 15% withcoadmin istration of loratadine relativeto that observed witherythromycin alone. The clinicalrelevance of this differenceis unknown. These above findingsare summarized inthe followingtable: Effectson Plasma Concentrations (AUC0-24 hrs) of LoratadineandDescarboethoxvloratadine After10 Daysof Coadministration (Loratadine10 ma) inNormalVolunteers Loratadine Descarboethoxvloratadine Erythromycin(500 mgQ8h) + 40% +46% Cimetidine(300 mgdID) +103% +6% Ketoconazole(200 mg012h) +307% +73% There does not appear to bean increaseinadverseevents in subjects who receivedoral con traceptives and loratadine. CLARITIN-DTablets (pseudoephedrine component) are contraindicated in patients taking monoamine oxidase inhibitors and for 2 weeks after stopping use ofan 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 vitroaddition ofpseudoephedrine 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, or impairment offertility. In an 18-month oncogenicity study inmice and a 2-year study in rats loratadine was adminis tered inthe dietat doses up to 40 mg/kg(mice)and 25 mg/kg(rats). Inthe carcinogenicity stud ies pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUCdata demonstrated that the exposure of micegiven40 mg/kgof loratadine was 3.6 (lorata dine) and 18 (activemetabolite) times higher than a human given10 mg/day. Exposure of rats given 25 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 given10 mg/kgand males and females given25 mg/kg.The clinicalsig nificanceofthese 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 forwardpointmutation (CHO-HGPRT)assays, or inthe assay for DNAdamage (RatPrimary Hepatocyte Unscheduled DNAAssay)or intwo assays for chromosomal aberrations (Human Peripheral Blood Lymphocyte Clastogenesis Assay and the Mouse Bone Marrow ErythrocyteMicronucleus Assay).In the Mouse Lymphoma Assay, a positivefindingoccurred in the nonactivated but not the activated phase ofthe study. Loratadine administration produced hepatic microsomal enzyme induction in the mouse at 40 mg/kgand rat at 25 mg/kg, but not at lowerdoses. Decreased fertilityin male rats, shown by lowerfemaleconception rates, occurred at approxi mately64 mg/kgof loratadine and was reversiblewithcessation of dosing. Loratadinehad no effecton maleor female fertilityor reproduction inthe ratat 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 dailyhuman dosage of 250 mg or 185 mg/m 2 ), and 120 mg/kg (1416 mg/m 2 or 8 times the recommended dailyhuman dosage), respectively. Thereare, how ever, no adequate and well-controlledstudies in pregnant women. Because animal reproduction studies are not alwayspredictiveof human response, CLARITIN-D Tablets should beused during pregnancy onlyifclearlyneeded. NursingMothers:It is not known if this combination product is excreted in human milk. However,loratadine when administered alone and its metabolite descarboethoxyloratadine pass easily into breast milkand achieveconcentrations that are equivalent to plasma levels,withan AUCmik/AUCpiasma ratio of 1.17 and 0.85 for the parent and active metabolite, respectively. Followinga single oraldose of 40 mg, a smallamount 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 intobreast milkof the lactatinghuman female. Pseudoephedrine con centrations in milkare consistently higher than those inplasma. The total amount of drug in milk as judged by the area under the curve (AUC)is 2 to 3 times greater than in plasma. The fraction of a pseudoephedrine dose excreted inmilkis estimated to be 0.4% 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 childrenbelowthe 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 every12 hours, 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 Headache Insomnia DryMouth Somnolence Nervousness Dizziness Fatigue Dyspepsia Nausea Pharyngitis Anorexia Thirst PERCENT OFPATIENTS REPORTING CLARITIN-D Loratadine Pseudoephedrine n=1023 n=543 n=548 19 18 17 16 4 19 14 4 9 7 8 5 5 3 7 4 1 5 4 6 3 3 2 3 Placebo n=922 19 3 3 4 2 2 3 1 Adverseevent rates didnot appear to differsignificantlybased onage, sex, or race, although the number of non-white subjects was relativelysmall. In addition to those adverse events reported above (>2%), the followingless frequent adverse events have been 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. Central and 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 andBiliarySystem: Hepaticfunction abnormal. Musculoskeletal System: Arthralgia,myalgia,torticollis. Psychiatric: Aggressive reaction, agitation, anxiety, apathy, confusion, decreased libido, depression, emotional lability,euphoria, impairedconcentration, irritability,paroniria. Reproductive System: Dysmenorrhea, impotence, intermenstrual bleeding,vaginitis. Respiratory System: Bronchitis, bronchospasm, chest congestion, coughing, drythroat, 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. Thefollowingadditionaladverse events have beenreported withthe use of CLARITINTablets: alopecia, altered salivation,amnesia, anaphylaxis, angioneurotic edema, blepharospasm, breast enlargement, breast pain,dermatitis, dry hair,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 withother untoward effects, such as fear, anxiety,tenseness, tremor, hallucinations, seizures, pallor,respiratory difficulty,dysuria, and car diovascular collapse. OVERDOSAGE:Inthe event of overdosage, general symptomatic and supportive measures should beinstituted promptly and maintained foras long as necessary. Treatment of overdosage wouldreasonably consist of emesis (ipecacsyrup), except in patients with impaired conscious ness, followedbythe administration of activated charcoal to absorb any remaining drug. Ifvomit ing is unsuccessful, or contraindicated, gastric lavageshould be performed withnormal saline. Salinecathartics mayalso be ofvaluefor rapiddilutionof bowelcontents. Loratadineis not elimi nated by hemodialysis. It is notknownif loratadine is eliminated by peritoneal dialysis. Somnolence, tachycardia, and headache have been reported with doses of 40 to 180 mg of CLARITINTablets. Inlargedoses, sympathomimetics may giverise to giddiness, headache, nau sea, vomiting, sweating, thirst, tachycardia, precordialpain, palpitations, difficultyinmicturition, muscular weakness andtenseness, anxiety,restlessness, and insomnia. Manypatients can pre sent a toxicpsychosis withdelusions and hallucinations. Some may develop cardiac arrhythmias, circulatorycollapse, convulsions, coma, and respiratory failure. The oralLDsovalues for the mixtureof the two drugs were greater than 525 and 1839 mg/kgin mice and rats, respectively. Oral LDsovalues for loratadine were greater than 5000 mg/kgin rats and mice. Doses of loratadine as highas 10 times the recommended dailyclinicaldose showed no effectin rats, mice,and monkeys. A- #47 Schering Corporation Kenilworth, NJ07033 USA Rev.1/95 17798626-JBS Copyright1994,1995,ScheringCorporation. Allrightsreserved.