CIP2051
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`1
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`F2?
`54
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`_EDlTlON
`2000
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`ll'
`DES _
`REFERENCE
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`Senior Vice President, irectory Services: Paul Walsh
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`

` PRODUCT INFORMATION
`
`SCHERING/2783
`
`wwh
`
`cunnsm REDITABS (loratadéne rapidw-désintegraiing-tab-
`letsl are manufactured for Schering Corporation by Scherer
`DDS, England.
`US. Patent Nos. 4,282,233 and 4,371,516.
`Copyright © 1997, 1998, sobering Corporation. All rights
`reserved.
`'
`1
`Shown in Product Identification Guide, pages 335 and 336'
`
`
`CLARlTiN-D® 12 HOUR
`brand of loratadéne and
`pseudoephedrine sulfate, USP
`Extended Release Tablets
`
`E
`
`CAUTION: Federal Law Prohibi‘ts Dispensing Without
`Prescription
`DESCRDVI‘ION
`CLARITlN-D 12 HOUR Extended Release Tablets contain 5
`mg loratadinein the tablet coating for immediate release
`and 120 mg pseudoephedrine sulfate. USP equally distrib-
`uted between the tablet coating for immediate release and
`the barrieracoated extended release core.
`Loratadine is a white to off-white powder, not soluble in wa-
`ter, but very soluble'in acetone, alcohol, and- chloroform. Lo~
`ratadine has-a molecular weight of382.89 and empirical for-
`mula o'f szHégClNZOQ; the chemical name, ethyl 4-(8-
`chloro»5,6-dihydro-11H-ben20l5,6lcyclohepta [1,2-blpyr-idin-
`11-.ylideneJ-1 piperidinemrboxylate;.and has the following
`chemical structure:
`
`ogc/ocsz
`'
`I
`
`N O
`
`(5ll
`
`.6!
`
`Pseudoephedrine sulfate is the synthetic salt of one of the
`naturally occurring dextaorotatory diastereomers of ephed-
`line and is classified as an indirect sympathomimetic
`amine. The empirical formula for pseudoephedrine sulfate
`is (C10HL5NO)Z.-H2504; the chemical name is [S-(R*,R*)l-q¢-
`[1(methylamino)ethyl] benzenemethanol sulfate (2:1) (salt),
`and the following chemical structure:
`
`H NHCH3
`l
`I
`C-C-CHa
`
`I IOHH
`
`'- H2304
`
`2
`
`The molecular weight of pseuduephedrine sulfate is 428.54.
`It is a white powder, freely soluble in water and methanol
`and sparingly soluble in chloroform.
`The inactive ingredients for CLARITTN-D 12 HGUR Ex-
`tended Release Tablets are acacia, butylparaben, calcium
`sulfate, carnauba wax, corn starch, lactose, magnesium
`stearate, microcrystalline cellulose, neutral soap, oleic acid,
`povidone, rosin, sugar, talc, titanium dioxide, white wax,
`and zein.
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`-
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`._
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`:
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`1
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`enemas and carcinomas) was observed in males given 10
`Cardiovascular System: Hypertension. hypotension, palpi-
`Lug/kg and males and females given 25 mglkg. The clinical
`tatibns, supraventricular tachyarrhytbmias, syncope, tach-
`ycardia
`significance of these findings during long-term use of
`GLA'RlTIN is>not known-
`"
`'
`‘
`Centml and Peripheral Nervous. System; Blepharospasm,
`In mutagenicity studies, there was no evide‘nce of muta-
`dizziness, dysphonia, hypertoniar, migraine, paresthesia,
`genie potential in reverse (Amos) or forward point mutation
`tremor, vertigo.
`(CHO-HGPRT) assaysy'or in the assay for DNA damage (rat
`Gastrointestinal Syitem: Altered taste, anorexia, constipa-
`primary hepatocyte unscheduled DNA assay) or in two as
`tion, diarrhea, dyspepsia, flatulence, gastritis, hiccup, in-
`. Says for chromosomal aberrations (human peripheral blood
`creased appotite, nausea, 'stomatitis‘, toothache, vomiting.
`lymphocyte clastogenesis assay and the mouse bone marrow
`Musculoskeletal System: Arthralgia, myalgia.
`erythrocyte micronucleus assay). In the mouselymphoma
`Psychiatric: lAgitdtion, amnesia, anxiety, confusion, de:
`assay, 'a positive finding oocoired in the nonactivated but
`creased libido, depression, impaired concentration, insom-
`not the activated phase of the study
`nia, irritability‘ paron’efia.
`Decreased fertility in male rats, shown by lower female con-
`Reproductive System: Breast pain, dysmenorrhea, manor--
`ception rates, occurred at an oral dose of 64 mg/kg (approx—
`rhagia, vagiuités.
`imately 50 times the maximum recommended humaana'jly
`Respiratory System: Bronchitis, bronchospasm. coughing,
`oral dose on a rug/m2 basis) and was reversible with cessa~
`dyspnea, epistaxls, hemoptysis, laryngitis, nasal dryness,
`gion of dosmg. Loratadme had no efi'ect on male or'female ; ph
`gifis, sinusitis, sneezing?
`” ,
`fertility or reproduction in the rat at an oral dose ofapprox-
`Skin and Appendages: Dermatitis, dry hair, dry skin, pho-
`mately 24 mg/kg (approximately 20 times the maximum
`'
`tosensitivity reaction, prurétus, purpura, rash, urticaria.
`recommended human daily oral dose on a rug/1p2 basis).
`Urinary System: I Altei'ed micturition, urinary discolor:
`Pregnancy Category B: There was no evidence ofapimal
`ation, minary.incontinen,ce,
`retention.
`'
`teratogeuicity in studies performed in ratsand rabbits at
`oral doses up to 96 rug/kg (approximately 75 timesaand 150
`In addition, the following spontaneous adverse events have
`been'igeportedgarely duiing the marketing ofloratadine: ab-
`times, respectively. the maximum recommended human
`normalihepati‘clfimctio including jaundice, h‘epaeas, and
`daily oral dose..on a rug/m2 basis). There are, however-,pno
`Hepatic necrosis; ellipsoid; amphylaxis; breast enlargement;
`adequate. and well-controlled studies in pregna'nt‘women.
`. A
`.
`B€cause firfimal'reproductlon sturh’és are not always predic2
`erythema m_ultlforme; peripheral 2edema; and séizures'.
`'
`five of human response, _CLARITEN'“should 'be"used diuing‘
`J
`DRUG ABU‘SEuAl‘fD D‘EPIINDEN‘; E
`pregnancy only if clearly-needed. {“3‘5 "'4‘?
`i" ,
`There is 313 (information to indicate that abuse or depen-
`Nursing Mothers: Loratadine and its metabolite, des'car~
`dency occurs with CLARITlN.
`'
`boethoxylor'atadine, pass easily ‘into breast milk and
`OVERDOSAGE
`achieve concentrations that are equivalent to plasma levels
`In adults, somnolence, tachycardia, and headache have '
`with anAUlek/AUCNasma ratio of 1.17 and 0.85 for Iorata-
`been reported with overdoses" greater than 10 mg' with the
`dine and descarboethoxyloratadine, respectively. Following
`a single oral dose of a 40 mg, a small amount of loratadine
`Tablet formulation (40 to 180 mg). Extrapyramidal signs
`and descarboethoxylor'atadine was excreted into the breast
`and palpitations have been reported in children with over-
`milk (approximately 0.03% of 40 mg over 48 home). A deci-
`doses of greater than 10 mg of CIARITIN Syrupjn the
`sion should be made whether to discontinue nursing or to
`event of overdosage, gener‘al symptomatic and 'supp'ortive
`discontinue the drug, taking into account the importance of
`measures should be instituted promptly and-maintained for
`the drug to the mother. Caution should be exercised when
`as long as necessary.
`CLARITIN is administered to a nursing woman.
`Treatment ofoverdosage would reasonably consist ofemesis
`Pediatric Use: The safety of CLARITTN Syrup at a daily
`(ipecac syrup), except in patients with impaired conscious-
`ness, followed by the administration of activated charcoal to
`dose of 10mg has been demonstrated in 188 pediatric pa-
`tlents 6—12 years of age in placebo-controlled 2‘week trials.
`absorb any remaining drug. vaomiting is unsuccessful, or
`The edectiveness of CLARle for the treatment of 'Sea-
`contraindicated, gastric lavage should be performed with
`sonal allergic rhinitis and chronic idiopathic urticaria in
`normal saline. Saline cathartics may also be of value for
`rapid dilution of bowel contents. Loratadine is not elimi-
`this pediatric age group is based on an extrapolation of the
`demonstrated elficacy of CLARITIN in adults in these con-
`nated by hemodialysis. It is not known if loratadine is elim-
`ditions and the likelihood that the disease course, patho—
`inated by peritoneal dialysis.
`physiology, and the drug’s effect are substantially similar to
`No deaths occurred at oral doses up to 5000 mg/kg in rats
`that of the adults. The recommended dose for the pediatric
`and mice (greater than 2400 and 1200 times, respectiver
`population is based on cross-study comparison of the phar-
`the maximum recommended human daily oral dose on a
`macoldnetics of CLARITDI in adults and pediatric subjects
`rug/m2 basis). Single oral doses of loratadine showed no ef-
`and on the safety profile of loratadine in both adults and
`fects in rats, mice, and monkeys at doses as high as 10 times
`pediatric patients at dpses equal to or higher than the rec-
`the maximum recommended human daily oral dose on 3
`ommended doses. The safety and eli'ectiveness of CLARI‘TIN
`mg/m2 basis.
`in pediatfic patients under 6 years of age have not been es-
`DOSAGE AND ADMfflSTiiATION
`tablished.
`Adults and children 12 years of age and over: The recom-
`ADVERSE REACTIONS
`mended dose of CLARITlN is 10 mg once daily.
`CLARITIN Tablets: Approximately 90,000 patients, aged 12
`Children 6—11 years of age: The recommended dose of
`and older, received CLARITIN Tablets 10 mg once daily in
`CLARITIN is 10 mg (2 teaspoonfuls) once daily.
`controlled and uncontrolled studies. Placebo-controlled clin-
`In patients with liver failure or renal insufliciency (GFR
`ical
`at the recomménded dose of 10mg once a. day var-
`<30 mllmin), one tablet or two teaspoonfuls every other
`ied from 2 weeks’ to 6 months’ duration. The rate of prema-
`day should be the starting dose.
`ture withdrawal from these trials was approximame 2% in
`Administration of CLARlTlN REDITABS (loratadine rapidly-
`both the treated and placebo groups.
`disintegrating tablets): Place CLARlTlN REDITABS (lo-
`[See first table at top of previous page] r
`ratadine rapidlydismtegratmg tablets) on the tongue. Tab-
`Adverse events reported in placebo-controlled chronic idio-
`let disintegration uccurs rapidly. Administer with or without
`pathic urticaria trials were similar to those reported in al-
`water.
`lergic rhinitis studies.
`HOW SUPPLIED
`Adverse event rates did not appear to differ significantly
`. CLARITIN Tablets:
`based on age, sex, or race, although the number ofnonwhite
`10 mg, white to off-white compressed
`subjects was relatively small.
`tablets; impressed with the product identification number
`-
`CLARlTlN REDITABS_(loratadEéne rapidFy-disintegrating tab-
`“458” on one side and “CLARITIN 10” on the other; higflr
`lats): Approximately 500 patients received CLARITIN -
`density polyethylene plastic bottles of 100 (NDC 0085-0458—
`REDITABS- (loratadine rapidly-disintegrating tablets) in
`03) and 500 (NDC 0085-0458-06). Also available, CLARITIN
`Controlled clinical trials of 2 weeks’ duration. In these stud-
`Unit‘of-Use packages of 14 tablets (7 tablets per blister
`ies, adverse events were similar in type and frequency to
`card) (NDC 0085-0458431) and 30 tablets (10 tablets per
`those seen with CLARITIN Tablets and placebo.
`.
`blister card) (NDC 0085-0458-05); and 10 x 10 tablet; Unit
`Administration of CLARITIN REDITABS (loratadine rapid:
`Dose-Hospital Pack (NDC 0085-0458-04).
`ly—disintegi'ating tablets) did not result in an increased re-
`Protect Unlt-of-Use packaging and UnitDosc-Hosp'rtal Pack
`from excessive moisture.
`Porting frequency of mouth or tongue imitation.
`CLARlTlN Swap: Approximately 300 pediatric patients 6
`Store between 2° and 3050 (36“ and 86°F).
`to 12 years of age received. 10 mg loratadine once daily in
`CLARITIN Syrup: Clear, colorless to light-yellow liquid,
`Controlled clinical trials for a period of 8—15 days. Among
`containing 1 mg loratadine per mL; amber glass bottles of
`these, 188 children were treated with 10 mg loratadine
`16 fluid ounces (NDC 0085—1223-01).
`W111]: once daily in placebo-controlled trials. Adverse events
`Store between 2" and 25°C (36° and 77°F].
`111 these pediatric patients were observed to occur with type -
`CLARITIN REDITABS [loratadEne rapidly-disintegrating 12b-
`and frequency-‘similar to those seen in the adult population.
`lets): CLARITIN REDITABS (loratadine rapidly-disinte—
`The rate of premature discontinuance due to adverse events
`grating tablets), 10 mg, white to oE—white blister-formed
`among pediatric patients receiving loratadine 10 mg daily
`Was less than 1%.
`tablet: Unit‘of—Use polyvinyl chloride blister packages of 30
`tablets (3 laminated foil pouches, each containing one bhs—
`[See second table on previous page]
`ter card‘ of 10 tablets) supplied with Patient’s Insnuctions
`In addition to those adverse events reported above (22%),
`for Use (NDC 0085-1128202).
`the following adverse events have been reported in at least
`Keep CLAFllT REDITABS (Ioratadine rapidly-désintegrat-
`one patient in CLARITIN clinical trials in adult and pedi-
`ing tablets) in a dry place.
`atric patients:
`Store between 2’ and 25"0 (36“ and 77°F). Use within 6
`Autonomic Nervous System; Altered lacrimation, altered
`months of opening laminated foil pouch, and immediately
`Salivation, flushing, hypoesthesia, impotence, increased
`upon opening individual tablet blister.
`sWeating, thirst.
`Schering Corporation
`Body As A Whole: Angioneurotic edema, asthenia, back
`Kenilworth, NJ 07033 USA
`Pain, blurred vision, chest pain, earache, eye pain, fever, leg
`Rev. 3/98
`crcoups, malaise, rigors, tinnitus, viral infection, weight
`gain.
`
`CLINICAL PHARMACOLOGY
`The following information is based upon studies of lorata-
`dine alone or psudosphediine alone, except as indicated.
`Loratadineris a long-acu'ng tricyclic antihistamine with se-
`lective peripheral histamine Hfreeeptor antagonistic act??-
`ity
`Human histamine skin wheel studies following single and
`repeated oral doses of loratadine have shown. that the drug
`exhibits an antihistaminjc efiect 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 developing after 28 days of dosing with lorata-
`dine.
`Pharniacokinetic studies following single and multiple oral
`doses ofloratadine in 115 volunteers showed that loratadine
`is rapidly absorbed and extensively metabolized to an active
`metabolite (descarboetboxyloratadine). Approximately 80%
`of the total dose administesed can be found equally distrib~
`uted between urine and feces in the form of metabolic prod-
`ucts alter 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 themajor active metabolite (descaIboeth-
`. oxyloratadine). In nearly all patients. exposure (AUC) to the
`metabolite is mater than exposure to parent loratadine.
`Loratadine and descarboethoxyloratadine reached steady-
`state in most patients by approximately the fifth dosing day
`The pharmacokinetics of loratadine and descarboetr'l-
`oxyloratadine are close independent over the dose range of
`10 to 40 mg and are not significantly altered by the duration
`of treatment.
`Ir}. vitro studies with human liver microsomes indicate that
`loratadine is, metabolized to descarboethoxyloratadine pre-
`dominantly by P450 CYP3A4 and, to a lesser extent, by
`
`_
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`-
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`19628434T
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`continued on next page
`Information on Scheréng products appearing on these pages
`is effective as of August 15, 1999.
`
`consult 2 0 o o FDRd supplements and future editions for revisions
`
`3
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`rev—w...
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`2784ISCHERING
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`PHYSICIANS’ DESK HEFERENCE® '
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`il
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`Ii
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`Claritin-D 12 hr.—-Cont.
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`thatthisproductshouldheusedinpregnancyorduringlac-
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`Information will be superseded by supplements and subsequent editions
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`4
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`rhinorrhea, nasal pruritus, and eye tearing more than pseu-
`doephedrine and reduced the intensity of nasal congestion
`more than loratadine, demonstrating a contribution of
`P450 CYPZDG. In the presence of a CYP3A4 inhibitor keto-
`each of the components. The onset of antihistamine and use |
`conazole, loratadine is metabolized to descarboethoxylorata-
`sal decongestant actions occurred after the first dose of
`dine predominantly by CYP2D6. Concurrent administration
`CLARIITN-D 12 HOUR Extended Release Tablets,
`of loratadine with either ketoconazole, erythromycin (both
`CLARITIN—D 12 HOUR Extended Release Tablets were
`CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4
`well tolerated, with a frequency of sedation similar to that
`inhibitor) to healthy volunteers was associated with signif-
`seen with placebo, and an adverse event profile clinically
`icantly increased plasma concentrations of loratadine (see
`similar to that of pseudoephedrine.
`Drug Interactions section).
`In a 6-week, placebo-controlled study of 193 patients with ,
`|
`In a study involving twelve healthy geriatric subjects (66 to
`seasonal allergic rhinitis and concomitant mild to moderate
`78 years old), the AUC and peak plasma levels (Cum) of
`asthma, CLARITTN-D 12 HOUR Extended Release fl‘ablets
`'
`both loratadine and descarboethoxyloratadine were signifi-
`twice daily improved seasonal allergic rhinitis signs and
`cantly higher (approximately 50% increased) than "in studs
`symptoms with no decrease in pulmonary function or ad—
`ies of younger subjects. The mean elimination half-lives for
`verse efl'ects of asthma symptoms. This supports the safety
`the elderly subjects were 18.2 hours (range = 6.7 to 37
`of administering CLARITDI—D 12 HOUR Extended Release
`hours) forl satadine and 17.5 hours (range = 11 to 38 hours)
`
`Tablets to seasonal allergic rhinitis patients with asthma.
`for the a
`metabolite.
`INDICATIONS AND USAGE
`In the clinical eflicacy studies, loratarine was administered
`before meals. In a single-dose study, food increased the AUC
`CLARITIN-D 12 HOUR Extended Release Tablets are indi-
`of loratadine by approximately 40% and of descarboethoxy—
`cated for the relief of symptoms of seasonal allergic rhinitis.
`loratadine by approximately 15%. The time of peak plasma
`CLARITIN-D 12 HOUR Extended Release Tablets should
`concentration (Tm) of loratadine and descarboetboxylora-
`be administered when both the antihistaminic properties of
`tadine was delayed by 1 hour with a meal.
`CLARITIN (loratadine) and the nasal decongestant activity
`In patients with chronic renal impairment (creatinine clear-
`of pseudoephedrine are designed (see CLINICAL PHAR-
`MACOLOGY).
`ance s 30 mL/min) both the AUC and peak plasma levels
`(Cm) incéeased on average by approximately 73% for lora-
`CONTRADIDICATIONS
`tadine; and approximately by 120% for descarboethoxylora-
`CLARITIN—D 12 HOUR Extended Release Tablets are con-
`tadine, compared to individuals with normal renal function.
`traindicated in patients who are hypersensitive to this med-
`The mean elimination half-lives of loratadine (7.6 hours)
`ication or to any of its ingredients.’
`and descarhoetboxyloratadine (23.9 hours) were not signif»
`This product, due to its pseudoephediine component, is con;
`icantly different from that observed in normal subjects. He-
`traindicated in patients with narrow-angle glaucoma or uri-
`modialysis does not have an eEect on the pharmacokinetics
`nary retention, and in patients receiving monoamine oxi-
`of loratadine or its active metabolite (descarboethoxylorata—
`dase (MAO) inhibitor therapy or within fourteen (14) days
`dine) in subjects with chronic renal impairment.
`of stopping such treatment (see Drug Interactions section).
`In patients vn'th chronic alcoholic liver disease the AUC and
`It is also contraindicated in patients with severe hyperten-
`peak plasma levels (Cm) of loratadine were double while
`sion, severe coronary artery disease, and in those who have
`the pharmacokinetic profile of the active metabolite (descar-
`shown hypersensitivity or idiosyncrasy to its components, to
`boethoxyloratadine) was not significantly changed fiom
`that in normals. The elimination half-lives for loratadine
`adrenergic agents, or to other drugs of similar chemical
`structures. Manifestations of patient idiosyncrasy to adren-
`and descarboethoxyloratadine were 24 hours and 37 hours,
`ergic agents include: insomnia, dizziness, weakness. tremor,
`respectively, and increased with increasing severity of liver
`disease.
`or mhythnuas.
`WARNINGS
`There was considerable variability in the pharmacokinetic
`CLARITIN-D 12 HOUR Extended Release Tablets should
`data in all studies'of loratadine, probably due to the exten-
`sive first-pass metabolism. Individual histograms of area
`be used with caution in patients with hypertension, diabe«
`under the curve, clearance, and volume of distribution
`tes mellitus, ischemic heart disease, increased intraocular
`showed a log normal distribution with a 25-fold range in '
`pressure, hyperthyroidism, renal impairment, or prustatic
`distribution in healthy subjects.
`hypertrophy. Central nervous system stimulation with con-
`Loratadine is about 97% bound to plasma proteins at the
`vulsions or cardiovascular collapse with accompanying hy-
`expected concentrations (2.5 to 100 ng/mL) after a thera-
`potension may be produced by sympathomimetic amines.
`peutic dose. Loratadine does not affect the plasma protein
`Use in Patients Approximately 60 Years and Older: The
`binding of warfarin and digoxin. The metabolite descarbo-
`safety and efficacy of CLARITl'N—D 12 HOUR Extended Re-
`ethoxyloratadjne is 73% to 77% bound to plasma proteins
`lease Tablets in patients greater than 60 years old have not
`(at 0.5 to 100 ng/mL).
`been investigated in placebo-controlled clinical trials. The
`Whole body autoradiographic studies in rats and monkeys,
`elderly are more likely to have adverse reactions to sympa<
`thomimetic amines.
`»
`radiolabeled tissue distribution studies in mice and rats,
`and in viva radioligand studies in mice have shown that nei-
`PRECAUTIONS .
`ther loratadine nor its metabolites readily cross the blood-
`General: Because the doses of this fixed combination prod-
`brain barrier, Radioligand binding studies with guinea pig
`uct cannot be individually titrated and hepatic insufficiency
`pulmonary and brain Hivreceptors indicate that there was
`results in a reduced clearance of loratadine to a much
`preferential binding to peripheral versus central nervous
`greater extent than ps'eudoephedrine, CLARITIN-D 12
`system Hl-receptors.
`HOUR Extended Release Tablets should generally be
`In a study in which Ioratadine was administered at four
`avoided in patients with hepatic insufiiciency. Patients with
`times the clinical dose for 90 days, no clinically significant
`renal insufliciency (GFR < 30 ml/min) should be given a
`increase in the Q’I‘c was seen on ECGs.
`lower initial dose (one tablet per day) because they have re
`In a Single-rising dose study of loratadine alone in which
`duced clearance of loratadine and pseudoephediine.‘
`
`doses up to 160 mg (16 times the clinical dose) were admin-
`Infor
`ion for Patients: Patients taking CLARl'l'LN-D 12
`istered, no clinically significant changes on the QTc interval
`HOUR Extended Release Tablets should receive the follow-
`in the ECGs were observed.
`ing information: CLARITlN-D 12 HOUR Extended Release
`P'seudoephedrine sulfate (d-isoephedrine sulfate) is an
`Tablets are prescribed for the relief of symptoms of seasonal
`orally active sympathomimetic amine which exerts a decon-
`allergic rhinitis. Patients should be instructed to take
`gestant action on the nasal mucosa. It is recognized as an
`CLARITIN-D 12 HOUR Extended Release Tablets only as
`effective agent for the relief ofnasal congestion due to aller-
`prescribed and not to exceed the prescribed dose. Patients
`gic rhinitis. Pseudoephedrine produces peripheral effects
`should also be advised against the concurrent use of
`similar to those of ephedrine and central effects similar to,
`CLARITIN—D 12 HOUR Extended Release Tablets with
`but less intense than, amphetamines. It has the potential
`over-thecounter antihistamines and decongestants.
`for excitatory side effects,
`This product should not be used by patients who are hyper-
`The pseudoephedn'ne component of CLARITIN—D 12 HOUR
`sensitive to it or to any of its ingredients. Due to its pseu-
`Extended Release Tablets were absorbed at a similar rate
`doephedrlne component, this product should not be used by
`and was equally available from the combination tablet as
`patients with narrow-angle glaucoma, urinary retention, or
`from a pseudoephedrine sulfate repetabs 120 mg tablet.
`by patients receiving a monoamine oxidase (MAO) inhibitor
`Mean (%CV) steady-state peak plasma concentration of 464
`or within 14 days of stopping use of an MAO inhibitor. It
`ug/mL (22) was attained at 3.9 hours (50). The terminal
`also should not be used by patients with severe hyperten—
`half-life ofpseudoephedrine fiom the combination tablet ad-
`sion or severe coronary artery disease.
`ministered twice daily was 6.3 hours (23). The ingestion of
`Patients who are or may become pregnant should be told I
`food was found not to affect the absorption of pseudoephed-
`Tine from CLARITlN-D 12 HOUR Extended Release Tab-
`tation only if the potential‘benefit justifies the potential risk
`lets. Loratadine and pseudoephedrine sulfate do not influ-
`to the fetus or nursing infant.
`ence the pharmacokinetics of each other when administered
`Patients shsuld be instructed not to break or chew the tab-
`let.
`concomitantly.
`Clinical Studies: Clinical trials of CLARITl'N-D 12 HOUR
`Drug Interactions: No specific interaction studies have
`been conducted with CLARITIN—D 12 HOUR Extended Re—
`Extended Release Tablets in seasonal allergic rhinitis in-
`volved appcoximately 3700 patients who received either the
`lease Tablets. However, loratadine (10 mg once daily) has
`combination product, a comparative treatment, or placebo,
`been safely coadministered with therapeutic doses of eryth—
`in double-blind, randomized controlled studies, Four of the
`romycin, :rimetidine, and ketoconazole in controlled clinical
`largest studies involved approximately 1600 patients in
`pharmacology studies. Although increased plasma concen-
`trations (AUC 024 hrs) or loratadine and/or descarbo-
`comparisons of the combination product, loratadine (5 mg
`bid), pseudoephedrine sulfate (120 mg bid), and placebo. Im-
`ethoxyloratadine were observed following coadministration
`provement in symptoms of seasonal aliergic rhinitis for pa-
`of loratadine with each of these drugs in normal volunteers
`tients receiving CLARITH‘I—D 12 HOUR Extended Release
`(n = 24 in each study), there were no clinically relevant
`Tablets was significantly greater than the improvement in I changes in the safety profile of loratadiue, as assessed by
`those patients who received the individual components or
`electrocardiograpbic parameters, clinical laboratory tests,
`placebo. The combination reduced the intensity of sneezing,
`vital signs, and adverse events. There were no significant
`
`efi'ects on QT, intervals, and no reports of sedation or syfi
`cope. No efl’ects on plasma concentrations of cimetidine or
`ketoconazole were observed. Plasma concentrations (AUC
`0-24 hrs) of erythromycin decreased 15% with coadministra;
`tion of loratadine relative to that observed with erythromyg
`cin alone. The clinical relevance of this dili‘erence is u“~
`known. These above findings «are summarized in the follow.
`ing table:
`
`Efi'ects on Piasma Concentrations (AUC 0_—_2_4_h_gs) _of
`Loratadine and Descarboetbgyloratadine After
`'
`10Days of Cgadministration (Loratadine 10 mg)
`in Normal Volunteers
`
`Erythromym'n
`(500 mg QSh)
`Cimetidine
`(300 mg QID)
`Ketoconazole
`(200 mg Q12h)
`
`Loratadine Descar-boethoxyloratadine
`+ 40%
`+46%
`‘
`+103%
`+ 6%
`
`+307%
`
`+73%
`
`‘
`
`There does not appear to be an increase in adverse events in
`subjects who received oral contraceptives and loratadine_
`CLARITIN-D 12 HOUR Extended Release Tablets (pseudo.
`ephedrine component) are contraindicated in patients tak.
`ing monoamine orddase inhibitors and for 2 weeks afier
`stopping use of an MAO inhibitor. The antihyperteusive ef.
`fects of beta—adrenergic blocking agents, methyldopa, mesa.
`mylamine, reserpine, and veratmm alkaloids may be re.
`. duced by sympathomimetics. Increased ectopic pacemaker
`i
`activity can occur when pseudoephedrine is used concomi.
`I
`_
`tantly with digitalis.
`Drug/Laboratory Test Interactions: The in vitro addition
`of pseudoephedriue to Sam containing the cardiac isoen_
`zyme MB of serum creatinine phosphokinase progressiver
`inhibits the activity of the enzyme. The inhibition becomes
`complete over 6 hours.
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`There are no animal laboratory studies on the combination
`product loratadine and pseudoephedrine sulfate to evaluate
`carcinogenesis, mutagenesis, or impairment of fertility.
`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 rug/kg (rats). In the car-
`cinogenicity studies pharmacokinefic assessments were car
`ried out to determine animal exposure to the drug. AUC
`data demonstrated that the exposure of mice given 40
`rug/kg of loratadine was 3.6 (loratadine) and 18 (active me
`tabolite) times higher than a human given 10 nag/day. Ex-
`posure of rats given 25 mg/kg of loratadine was 28 (lorata-
`dine) and 67 (active metabolite) times higher than a human
`given 10 mg/day. Male mice given 40 mg/kg had a signifi-
`cantly higher incidence of hepatocellular tumors (combined
`adenomas and carcinomas) than concurrent controls. In
`rats, a significantly higher incidence of hepatocellular tu-
`mors (combined adenomas and carcinomas) was observed in
`males given 10 rug/kg and males and females given 25 mg]
`kg. The clinical significance of these findings during long-
`term use of loratadine is not known.
`In mutageuicity studies with loratadine alone, there was no
`evidence of mutagenic potential in reverse (Ames) or for-
`ward point mutation (CI-IOJ‘IGPRT) 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 As-
`say). In the Mouse Lymphoma Assay