Claritin® (brand of loratadine)
Tablets
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
PRECAUTIONS
ADVERSE REACTIONS
DRUG ABUSE AND DEPENDENCE
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
DESCRIPTION
CLARITIN Tablets contain 10 mg micronized loratadine, an antihistamine, to be administered orally. They also contain the following inactive ingredients: corn starch, lactose, and magnesium stearate.Loratadine is a white to off-white powder not soluble in water, but very soluble in acetone, alcohol, and chloroform. It has a molecular weight of 382.89, and empirical formula of C22H23CIN2O2; its chemical na me is ethyl 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]cycloheptal[1,2-b]pyridin-11-ylidene)-1-piperidine-carboxylate and has the following structural formula:
Top of page CLINICAL PHARMACOLOGY
Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity.Human histamine skin wheal studies following single and repeated 10 mg oral doses of CLARITIN Tablets have shown that the drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with CLARITIN Tablets.
Pharmacokinetic studies following single and multiple oral doses of loratadine in 115 volunteers showed that loratadine is rapidly absorbed and extensively metabolized to an active metabolite (descarboethoxyloratadine). Approximately 80% of the total dos e administered can be found equally distributed between urine and feces in the form of metabolic products after 10 days. The mean elimination half-lives found in studies in normal adult subjects (n=54) were 8.4 hours (range=3 to 20 hours) for loratadine and 28 hours (range=8.8 to 92 hours) for the major active metabolite (descarboethoxyloratadine). In nearly all patients, exposure (AUC) to the metabolite is greater than exposure to parent loratadine. Loratadine and descarboethoxyloratadine reached stea dy-state in most patients by approximately the fifth dosing day. The pharmacokinetics of loratadine and descarboethoxyloratadine are dose independent over the dose range of 10 to 40 mg and are not significantly altered by the duration of treatment.
In vitro studies with human liver microsomes indicate that loratadine is metabolized to descarboethoxyloratadine premdominantly by P450 CYP3A4 and, to a lesser extnet, by P450 CYP2D6. In the presence CYP34A inhibitor ketoconazole, loratadine is me tabolized to descarboethoxyloratadine predominatly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with significantly increased plasma concentrations of loratadine (see Drug Interactions section).
In a study involving twelve healthy geriatric subjects (66 to 78 years old), the AUC and peak plasma levels (Cmax) of both loratadine and descarboethoxyloratadine were significantly higher (approximately 50% increased) than in studies of younger subject s. The mean elimination half-lives for the elderly subjects were 18.2 hours (range=6.7 to 3.7 hours) for loratadine and 17.5 hours (range=11 to 38 hours) for the active metabolite.
In the clinical efficacy studies, CLARITIN Tablets were administered before meals. In a single-dose study , food increased the AUC of loratadine by approximately 40% and of descarboethoxyloratadine by approximately 15%. The time to peak plasma concentra tion (Tmax) of loratadine and descarboethoxyloratadine was delayed by 1 hour with a meal.
In patients with chronic renal impairment (creatinine clearance < /= 30 mL/min) both the AUC and peak plaasma levels (Cmax) increased on average by approximately 73% for loratadine; and approximately by 120% for descarboethoxyloratadine, compared to ind ividuals with normal renal function. The mean elimination half-lives of loratadine (7.6 hours) and descarboethoxyloratadine (23.9 hours) were not significantly different from that observed in normal subjects. Hemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite (descarboethoxyloratadine) in subjects with chronic renal impairment.
In patients with chronic alcoholic liver disease the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite (descarboethoxyloratadine) was not significantly changed from that in normals. The elimination half-lives for loratadine and descarboethoxyloratadine were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.
There was considerable variability in the pharmacokinetic data in all studies of CLARITIN Tablets, probably due to the extensive first clearance, and volume of distribution showed a log normal distribution with a 25-fold range in distribution in healthy s ubjects.
Loratadine is about 97% bound to plasma proteins at the expected concentrations (2.5 to 100 ng/mL) after a therapeutic dose. Loratadine does not effect the plasma protein binding of warfarin and digoxin. The metabolite descarboethoxyloratadine is 73% t o 77% bound to plasma proteins (at 0.5 to 100 ng/mL).
Whole body autoradiographic studies in rats and monkeys, radio labeled tissue distribution studies in mice and rats, and in vivo radioligand studies in mice have shown that neither loratadine nor its metabolites readily cross the blood-brain barri er. Radioligantd binding studies with guinea pig pulmonary and brain H1-receptors indicate that there was preferential binding to peripheral versus central nervous system H1-receptors.
Clinical trials of CLARITIN Tablets involved over 10,700 patients who received either CLARITIN Tablets or another antihistamine and/or placebo in double-bind randomized controlled studies. In placebo-controlled trials, 10 mg once daily of CLARITIN Tablet s was superior to placebo and similar to clemastine (1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic rhinitis. In these studies, somnolence occurred less frequently with CLARITIN tablets than with clemastine an d at about the same frequency as terfenadine or placebo. In studies with CLARITIN Tablets at doses 2 to 4 times higher than the recommended dose of 10 mg, a dose-related increase in the incidence of somnolence was observed. Therefore, some patients, pa rticularly those with hepatic or renal impairment and the elderly, may experience somnolence.
Among those patients involved in double-blind, randomized controlled studies of CLARITIN Tablets, approximately 1000 patients were enrolled in studies of idiopathic chronic urticaria. In placebo-controlled clinical trials, CLARITIN Tablets 10 mg once dai ly were superior to placebo in the management of idiopathic chronic urticaria, as demonstrated by reduction of associated itching, erythema, and hives. In these studies, the incidence of somnolence seen with CLARITIN Tablets was similar to that seen with placebo.
In a study in which CLARITIN Tablets were administered at 4 times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs.
INDICATIONS AND USAGE
CLARITIN Tablets are indicated for the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the management of idiopathic chronic urticaria.CONTRAINDICATIONS
CLARITIN Tablets are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients.PRECAUTIONS
GENERAL: Patients with liver impairment of renal insufficiency (GFR < 30 mL/min) should be given a lower initial dose (10 mg every other day) because they have reduced clearance of CLARITIN Tablets.Drug Interactions: Loratadine (10 mg once daily) has been safely coadministered with therapeutic doses of erythromycin, cimetidine, and ketoconazole in controlled clinical pharmacology studies. Although increased plasma concentrations (AUC 0-24 h ours) of locatadine and/or descarboethoxyloratadine were observed following coadministration 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 QTc intervals, and no reports of sedation or syncope. No effects on plasma concentrations of ci metidine or ketoconazole were observed. Plasma concentrations (AUC 0-24 hrs) of erythromycin decreased 15% with coadministration of loratadine relative to that observed with erythromycin alone. The clinical relevance of this difference is unknown. Thes e above findings are summarized in the following table:
Effects on Plasma Concentrations (AUC 0-24 hrs) of Loratadine and
Descarboethoxyloratadine After 10 Days of Coadministration
(Loratadine 10 mg) in Normal VolunteersLoratadine Descarboethoxyloratadine Erythromycin +40% +46% (500 mg Q8h) Cimetidine +103% +6% (300 mg QID) Ketoconazole +307% +73% (200 mg Q12h)There does not appear to be an increase in adverse events in subjects who received oral contraceptives and loratadine.
Carcinogenesis, Mutagenesis, and Impairment of Fertilty: In an 18 month oncogenicity 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). In the carcinogenicity stud ies, pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUC data demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (active metabolite) times higher than a human given 10 mg /day. Exposure of rats given 25 mg/kg of ioratadine was 28 (loratadine) and 67 (active metabolite) 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 car cinomas) that concurrent controls. In rats, a significantly higher incidence on 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 find ings during long-term use of CLARITIN Tablets is not known.
In mutagenicity studies, there was no evidence of mutagenic potential in revere (Ames) or forward point mutation (CHOHGPRT) assays, or in the assay for DNA damage (Rat Primary Hepatocyte Unscheduled DNA Assay) or in two assays for chromosomal aberrations (Human Peripheral Blood Lymphocyte Clastogenesis Assay and the Mouse Bone Marrow Erythrocyte Micronucleus Assay). In the Mouse Lymphoma Assay, a positive finding occurred in the nonactivated but not the activated phase of the study.
Loratadine administration produced hepatic microsomal enzyme induction in the mouse at 40 mg/kg and rat at 25 mg/kg, but not at lower doses.
Decreased fertility in male rats, shown by lower female conception rates, occurred at approximately 64 mg/kg and was reversible with cessation of dosing. Loratadine had no effect on male or female fertility or reproduction in the rat at does approximately 24 mg/kg.
Pregnancy Category B: There was no evidence of animal teratogenicity in studies performed in rats and rabbits at oral doses up to 96 mg/kg (75 times and 150 times, respectively, the recommended daily human dose on a mg/m2 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 Tablets 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 AUCmilk/AUCplasma ratio of 1.17 and 0.85 for the p arent and active metabolite, respectively. Following a 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 over 48 hours). A decision should be made whether to discontin ue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when CLARITIN Tablets are administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below the age of 12 years have been established.
ADVERSE REACTIONS
Approximately 90,000 patients 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 prem ature withdrawal from these trials was approximately 2% in both the treated and placebo groups.REPORTED ADVERSE EVENTS WITH AN INCIDENCE OF
MORE THAN 2% IN PLACEBO-CONTROLLED
ALLERGIC RHINITIS CLINICAL TRIALSPERCENT OF PATIENTS REPORTING LORATADINE PLACEBO CLEMASTINE TERFENADINE 10 mg QD 1 mg BID 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 idiopathic chronic uticaria 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 non-white subjects was relatively small.
In addition to those adverse events reported above, the following adverse events have been reported in 2% or fewer patients.
Autonomic Nervous System: Altered lacrimation, altered salivation, flushing, hypoesthesia, impotence, increased sweating, thirst.
Body as a Whole: Angioneurotic edema, asthenia, back pain, blurred vision, chest pain, conjunctivitis, earache, eyepain, fever, leg cramps, malaise, rigors, tinnitus, upper respiratory infection, weight gain.
Cardiovascular System: Hypertension, hypotension, palpitations, syncope, tachycardia.
Central and Peripheral Nervous System: Blepharospasm, dizziness, dysphonia, hyperkinesia, migraine, paresthesia, tremor, vertigo.
Gastrointestinal System: Abdominal distress, altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, increased appetite, nausea, stomatitis, toothache, vomiting.
Musculoskeletal System: Arthralgia, myalgia.
Psychiatric: Agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, nervousness, paroniria.
Reproductive System: Breast pain, dysmenorrhea, menorhagia, vaginitis.
Respiratory System: Bronchitis, bronchospasm, coughing, dyspnea, epistaxis hemoptysis, laryngitis, nasal congestion, 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.
In addition, the following spontanious 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 multif orme; peripheral edema; seizures; and supraventricular tachyarrhythmias.DRUG ABUSE AND DEPENDENCE
There is no information to indicate that abuse or dependency occurs with CLARITIN Tablets.OVERDOSAGE
Somnolence, tachycardia, and headache have been reported with overdoses greater than 10 mg (40 to 180 mg). 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 reasonable consist of emesis (ipecac syrup), except in patients with impaired consciousness, followed by the administration of activated charcoal to absorb any remaining drug. If vomiting is unsuccessful, or contraindicatio n, 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 hemodialysis.
Oral LD50 values for loratadine were greater than 5000 mg/kg in rats and mice. Doses as high as 10 times the recommended clinical doses showed no effects in rats, mice and monkeys.
DOSAGE AND ADMINISTRATION
Adults and children 12 years of age and over: One 10 mg tablet daily.
In patients with liver failure or a renal insufficiency (GFR < 30mL/min), 10 mg every other day should be the starting dose.HOW SUPPLIED
CLARITIN Tablets, 10 mg, white to off-white compressed tablets; impressed with the product identification number “458” on one side and “CLARITIN 10” on the other; high density polyethylene plastic bottles of 100 (NDC 0085-0458-03) and 500 (NDC 0085-0458-0 6). Also available, CLARITIN Unit-of-Use packages of 14 tablets (7 tablets per blister card) (NDC 0085-0458-01) and 30 tablets (10 tablets per blister card) (NDC 0085-0458-05); and 10 x 10 tablet Unit Dose-Hospital Pack (NDC 0085-0458-04).Protect Unit-of-Use packaging and Unit Dose-Hospital Pack from excessive moisture. Store between 2o and 30oC (36o and 86oF).
Rev. 9/95
Schering Corporation
Kenilworth, NJ 07033 USA
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