EDITION
`
`PDIZ
`46
`1992
`PHYSIC A\S'
`DISK
`T\CEm
`
`F
`
`4
`
`NOVARTIS EXHIBIT 2114
`Par v Novartis, IPR 2016-00084
`Page 1 of 303
`
`

`
`PDR®
`
`EDITION
`
`1992
`
`RECEIVED
`
`DEC 3 1 1991
`
`FITZPATRICK, CELLA, HARPER & SCSI
`
`Ys C A\ S/
`D
`S
`\C
`
`Director of Production:
`MARJORIE A. DUFFY
`
`Assistant Director of Production:
`CARRIE WILLIAMS
`
`Manager of Production Services:
`ELIZABETH H. CARUSO
`
`Format Editor:
`MILDRED M. SCHUMACHER
`
`Production Coordinator:
`ELIZABETH A. KARST
`
`Art Associate:
`JOAN K. AKERLIND
`
`Medical Consultant:
`LOUIS V. NAPOLITANO, MD
`
`Product Manager:
`JOHN A. MALCZYNSKI
`Sales Manager:
`CHARLIE J. MEITNER
`
`Account Managers:
`CHAD E. ALCORN
`MICHAEL S. SARAJIAN
`JOANNE C. TERZIDES
`
`Commercial Sales Manager:
`ROBIN B. BARTLETT
`Direct Marketing Manager:
`ROBERT W. CHAPMAN
`
`Manager, Professional Data:
`MUKESH MEHTA, R.Ph.
`Index Editor:
`ADELE L. DOWD
`
`O.Copyright ,r,1992 and published by Medical Economics Data, a division of Medical Economics Company Inc., at Montvale, N.J. 07645. All rights reserved. None of the content
`$1 of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, or otherwise) without
`the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE PDR''', PDR For Ophthalmology , PDR For Nonprescription Drugs', PDR Drug Interactions and
`Side Effects'. and PDR Indications Index are trademarks of Medical Economics Company Inc., registered in the United States Patent and Trademark Office.
`
`Officers of Medical Economics Data, a division of Medical Economics Company Inc.: President and Chief Executive Officer: Norman R. Snesil; Senior Vice President and Chief
`Financial Officer: Joseph T. Deithorn; Senior Vice President of Business Development, Stephen J. Sorkenn; Senior Vice President of Operations: Mark L. Weinstein; Vice President,
`Sales and Marketing: Thomas F. Rice; Vice President of Circulation: Scott I. Rockman; Vice President of Information Services: Edward J. Zecchini.
`
`ISBN 1-56363-003-6
`
`NOVARTIS EXHIBIT 2114
`Par v Novartis, IPR 2016-00084
`Page 2 of 303
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Consult 1992 Supplements for revisions (cid:9)
`
`creased fetal weights in rabbits and rats at maternally toxic
`doses approximately 1052 and 5264 times the maximum
`recommended human dose (10 mg/70 kg/day), respectively.
`A dose-related increase in wavy ribs was noted in the devel-
`oping rat fetus when pregnant females received daily doses
`of approximately 212 times the maximum recommended
`human dose. No such effects were noted in pregnant mice
`subjected to up to 1052 times the maximum recommended
`human dose. There are no adequate and well-controlled stud-
`' ies in pregnant women. CARTROL (carteolol hydrochloride)
`should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`Nursing Mothers:
`Studies have not been conducted in lactating humans and,
`therefore, it is not known whether carteolol is excreted in
`human milk. Studies in lactating rats indicate that CAR-
`TROL (carteolol hydrochloride) is excreted in milk. Because
`many drugs are excreted in human milk, caution should be
`exercised when CARTROL (carteolol hydrochloride) is ad-
`ministered to a nursing woman.
`Pediatric Use:
`Safety and effectiveness in children have not been estab-
`lished.
`ADVERSE REACTIONS
`The prevalence of adverse reactions has been ascertained
`from clinical studies conducted primarily in the United
`States. All adverse experiences (events) reported during
`these studies were recorded as adverse reactions. The preva-
`lence rates presented below are based on combined data from
`nineteen placebo-controlled studies of patients with hyper-
`tension, angina or dysrhythmias, using once-daily carteolol
`at doses up to 60 mg. Table 1 summarizes those adverse ex-
`periences reported for patients in these studies where the
`prevalence in the carteolol group is 1% or greater and ex-
`ceeds the prevalence in the placebo group. Asthenia and
`muscle cramps were the only symptoms that were signifi-
`cantly more common in patients receiving carteolol than in
`patients receiving placebo. Patients in clinical trials were
`carefully selected to exclude those, such as patients with
`asthma or known bronchospasm, or congestive heart failure,
`who would be at high risk of experiencing beta-adrenergic
`blocker adverse effect (See WARNINGS and CONTRA-
`INDICATIONS):
`
`TABLE 1
`Adverse Reactions During
`Placebo-Controlled Studies
`Placebo
`(n=448)
`
`Body as a Whole
`tAsthenia
`Abdominal Pain
`Back Pain
`Chest Pain
`Digestive System
`Diarrhea
`Nausea
`Metabolic/Nutritional
`Disorders
`Abnormal Lab Test
`Peripheral Edema
`Musculoskeletal System
`Arthralgia
`Muscle Cramps
`Lower Extremity Pain
`Nervous System
`Insomnia
`Paresthesia
`Respiratory System
`Nasal Congestion
`Pharyngitis
`Skin and Appendages
`Rash
`
`4.0
`0.4
`1.6
`1.8
`
`2.0
`1.8
`
`1.1
`1.1
`
`1.1
`0.2
`0.2
`
`0.7
`1.1
`
`0.9
`0.9
`
`1.1
`
`Carteolol
`(n=781)
`
`7.1'
`1.3
`2.1
`2.2
`
`2.1
`2.1
`
`1.2
`17
`
`1.2
`2.6'
`1.2
`
`1.7
`2.0
`
`1.1
`1.1
`
`1.3
`
`t Includes weakness, tiredness, lassitude and fatigue
`• Statistically significant at p =0.05 level.
`The adverse experiences were usually mild or moderate in
`intensity and transient, but sometimes were serious enough
`to interrupt treatment. The adverse reactions that were
`most bothersome, as judged by their being reported as rea-
`sons for discontinuation of therapy by at least 0.4% of the
`carteolol group are shown in Table 2. [See table above.]
`Additional adverse reactions have been reported, but these
`are, in general, not distinguishable from symptoms that
`might have occurred in the absence of exposure to carteolol.
`The following additional adverse reactions were reported by
`at least 1% of 1568 patients who received carteolol in con-
`trolled or open, short- or long-term clinical studies, or repre-
`sent less common,, but potentially important, reactions re-
`ported in clinical studies or marketing experience (these rare
`reactions are shown in italics): Body as a Whole: fever, infec-
`tion, injury, malaise, pain, neck pain, shoulder pain; Cardio-
`vascular System: angina pectoris, arrhythmia, heart failure,
`palpitations, second degree heart block, vasodilation; Diges-
`
`Physicians' Desk Reference® (cid:9)
`TABLE 2
`Discontinuations During
`Placebo-Controlled Studies
`Placebo
`(n=448)
`
`Carteolol
`(n=781)
`
`Body as a Whole
`Asthenia
`Headache
`Chest Pain
`Skin and Appendages
`Rash
`Sweating
`Digestive System
`Nausea
`
`0.2
`0.7
`0.2
`
`D.0
`0.2
`
`0.0
`
`0.5
`0.7
`0.4
`
`0.4
`0.4
`
`0.4
`
`3.3
`4.2
`Overall Adverse Reactions
`tine System.• acute hepatitis with jaundice, constipation, dys-
`pepsia, flatulence, gastrointestinal disorder; Metabolic/Nu-
`tritional Disorder: gout, Musculoskeletal System: pain in ex-
`tremity, joint disorder, arthritis; Nervous System: abnormal
`dreams, anxiety, depression, dizziness, nervousness, somno-
`lence; Respiratory System• bronchitis, bronchospasm, cold
`symptoms, cough, dyspnea, flu symptoms, lung disorder,
`rhinitis, sinusitis, wheezing; Skin and Appendages: sweating;
`Special Senses: blurred vision, conjunctivitis, eye disorder,
`tinnitus; Urogenital: impotence, urinary frequency, urinary
`tract infection.
`In studies of patients with hypertension or angina pectoris
`where carteolol and positive reference beta-adrenergic
`blocking agents [nadolol (n=82) and propranolol (n=50)]
`have been compared, the differences in prevalence rates
`between the carteolol group and the reference agent group
`were statistically significant (p 50.05) for the adverse reac-
`tions listed in Table 3.
`
`TABLE 3
`Adverse Reactions During
`Positive-Controlled Studies
`Reference
`Agents (cid:9)
`(n= 132)
`
`Body as a Whole
`Chest Pain
`Cardiovascular System
`Bradycardia
`Digestive System
`Diarrhea
`Nervous System
`Somnolence
`Skin and Appendages
`Sweating
`
`5.3
`
`4.5
`
`11.4
`
`0.8
`
`5.3
`
`Ca rteolot
`(n= 135)
`
`0.7
`
`0.0
`
`4.4
`
`7.4
`
`0.7
`
`POTENTIAL ADVERSE REACTIONS
`In addition, other adverse reactions not listed above have
`been reported with other beta-adrenergic blocking agents
`and should be considered potential adverse reactions of CAR-
`TROL (carteolol hydrochloride).
`Body as a Whole:
`Fever combined with aching and sore throat.
`Cardiovascular System:
`Intensification of AV block. (See CONTRAINDICATIONS.)
`Digestive System:
`Mesenteric arterial thrombosis, ischemic colitis.
`Hemic/Lymphatic System•
`Agranulocytosis, thrombocytopenic and non-thrombocyto-
`penic purpura.
`Nervous System:
`Reversible mental depression progressing to catatonia; an
`acute reversible syndrome characterized by disorientation to
`time and place, short-term memory loss, emotional lability,
`slightly clouded sensorium, and decreased performance on
`neuropsychometric testing.
`Respiratory System•
`Laryngospasm, respiratory distress.
`Skin and Appendages•
`Erythematous rash, reversible alopecia.
`Urogenital System:
`Peyronie's disease.
`The oculomucocutaneous syndrome associated with the beta-
`adrengeric blocking agent practolol has not been reported
`with carteolol
`OVERDOSAGE
`No specific information on emergency treatment of overdos-
`age in humans is available. The most common effects ex-
`pected with overdosage of a beta-adrenergic blocking agent
`are bradycardia, bronchospasm, congestive heart failure and
`hypotension.
`In case of overdosage, treatment with CARTROL (carteolol
`hydrochloride) should be discontinued and gastric lavage
`considered. The patient should be closely observed and vital
`signs carefully monitored. The prolonged effects of carteolol
`must be considered when determining the duration of correc-
`tive therapy. On the basis of the pharmacologic profile, the
`
`509
`
`following additional measures should be considered as
`appropriate.
`Symptomatic Bradycardia•
`Administer atropine. If there is no response to vagal block-
`ade, administer isoproterenol cautiously.
`Bronchospasm:
`Administer a betarstimulating agent such as isoproterenol
`and/or a theophylline derivative:
`Congestive Heart Failure:
`Administer diuretics and digitalis glycosides as necessary.
`Hypotension:
`Administer vasopressors such as intravenous dopamine,
`epinephrine or norepinephrine bitartrate.
`DOSAGE AND ADMINISTRATION
`Dosage must be individualized. The initial dose of CARTROL
`(carteolol hydrochloride) is 2.5 mg given as a single daily oral
`dose either alone or added to diuretic therapy. If an adequate
`response is not achieved, the dose can be gradually increased
`to 5 mg and 10 mg as single daily doses. Increasing the dose
`above 10 mg per day is unlikely to produce further substan-
`tial benefits and, in fact, may decrease the response. The
`usual maintenance dose of carteolol is 2.5 or 5 mg once daily.
`Dosage Adjustment in Renal Impairment
`Carteolol is excreted principally by the kidneys. When ad-
`ministering CARTROL (carteolol hydrochloride) to patients
`with renal impairment, the dosage regimen should be ad-
`justed individually by the physician. Guidelines for dose
`interval adjustment are shown below:
`Creatinine Clearance (cid:9)
`(mL/min) (cid:9)
`>60 (cid:9)
`20-60 (cid:9)
`<20 (cid:9)
`HOW SUPPLIED
`CARTROL (carteolol hydrochloride) is supplied as:
`2.5 mg gray tablets:
`Bottles of 100 (cid:9)
`5 mg white tablets:
`(NDC 0074-1665-13).
`Bottles of 100 (cid:9)
`Recommended storage: Avoid exposure to temperatures in
`excess of 104°F (40'C).
`07-5664-R1
`Shown in Product Identification Section, page 403
`
`Dosage Interval
`(hours)
`24
`48
`72
`
`(NDC 0074-1664-13).
`
`CEFOL® Filmtab® Tablets
`[c full ]
`(B-Complex, folic acid, vitamin E
`with 760 mg vitamin C)
`
`•
`
`K
`
`750 mg
`100 mg
`20 mg
`15 mg
`10 mg
`5 mg
`500 mcg
`6 mcg
`
`DESCRIPTION
`Each oral Cefol Filmtab vitamin tablet provides:
`Ascorbic Acid (C) (cid:9)
`Niacinamide (cid:9)
`Calcium Pantothenate
`Thiamine Mononitrate (Br)
`Riboflavin (BO (cid:9)
`Pyridoxine Hydrochloride (B& (cid:9)
`Folic Acid .
`Cyanocobalamin (B12) (cid:9)
`Vitamin E (as dl-alpha
`30 IU
`tocopheryl acetate) (cid:9)
`Inactive Ingredients: Cellulosic polymers, colloidal silicon
`dioxide, corn starch, D&C Yellow No. 10, FD&C Blue No. 1,
`magnesium stearate, microcrystalline cellulose, polyethyl-
`ene glycol, povidone, propylene glycol, titanium dioxide, and
`vanillin.
`CLINICAL PHARMACOLOGY
`The vitamin components of Cefol are absorbed by the active
`transport process. All but Vitamin E are rapidly eliminated
`and not stored in the body. Vitamin E is stored in body
`tissues.
`INDICATIONS AND USAGE
`Cefol is indicated in non-pregnant' adults for the treatment
`of Vitamin C deficiency states with an associated deficient
`intake or increased need for Vitamin B-Complex, Folic Acid,
`and Vitamin E.
`CONTRAINDICATIONS
`Rare hypersensitivity to Folic Acid.
`WARNINGS
`Folic Acid alone is improper treatment of perniciouls anemia
`and other megaloblastic anemias where Vitamin Biz is
`deficient.
`'Pregnancy may require greater Folic Acid intake.
`
`Continued on next page
`
`If desired, additional literature on any Abbott Product will be
`provided upon request to Abbott Laboratories.
`
`NOVARTIS EXHIBIT 2114
`Par v Novartis, IPR 2016-00084
`Page 3 of 303
`
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`(cid:9)
`(cid:9)
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`(cid:9)
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`(cid:9)
`

`
`510
`
`Abbott—Cont.
`
`PRECAUTIONS
`Folic Acid above 0.1 mg daily may obscure pernicious anemia
`(hematologic remission may occur while neurological mani-
`festations remain progressive).
`ADVERSE REACTIONS
`Allergic sensitization has been reported following oral and
`parenteral administration of Folic Acid.
`DOSAGE
`Usual adult dose is one tablet daily.
`HOW SUPPLIED
`Cefol is supplied as green Filmtab tablets in bottles of 100
`(NDC 0074-6089-13).
`Filmtab—Film-sealed tablets, Abbott.
`Ref. 03-1869-2/R19
`Shown in Product Identification Section, page 403
`
`CHLORTHALIDONE Tablets, USP
`[clor-thal 1i-done ]
`
`HOW SUPPLIED
`Abbott Chlorthalidone Tablets, USP are available as scored
`tablets in two dosage strengths:
`25 mg, peach colored:
`Bottles of 100 (NDC 0074-4325-13).
`50 mg, lavender-colored:
`Bottles of 100 (NDC 0074-4338-13).
`Bottles of 500 (NDC 0074-4338-53).
`Inactive Ingredients
`25 mg tablet: Corn starch, FD&C Yellow No. 6, lactose,
`magnesium stearate, povidone, pregelatinized starch (con-
`tains corn starch) and talc.
`50 mg tablet: Corn starch, MC Red No 33, FD&C Blue No.
`2, lactose, magnesium stearate, povidone, pregelatinized
`starch (contains corn starch) and talc.
`Ref. 01-2472-R-5
`Shown in Product Identification Section, page 403
`
`CYLERT® Tablets
`[cf 'lert
`(Pemoline)
`
`DESCRIPTION
`CYLERT (pemoline) is a central nervous system stimulant.
`Pemoline is structurally dissimilar to the amphetamines and
`methylphenidate.
`It is an oxazolidine compound and is chemically identified
`as 2-amino-5-phenyl-2-oxazolin-4-one.
`Pemoline is a white, tasteless, odorless powder, relatively
`insoluble (less than 1 mg/mL) in water, chloroform, ether,
`acetone, and benzene; its solubility in 95% ethyl alcohol is
`2.2 mg/mL.
`CYLERT (pemoline) is supplied as tablets containing 18.75 mg,
`37.5 mg or 75 mg of pemoline for oral administration. CYLERT
`is also available as chewable tablets containing 37.5 mg of
`pemoline.
`Inactive Ingredients
`18.75 mg tablet: corn starch, gelatin, lactose, magnesium
`hydroxide, polyethylene glycol and talc.
`37.5 mg tablet: corn starch, FD&C Yellow No. 6, gelatin,
`lactose, magnesium hydroxide, polyethylene glycol and talc.
`37.5 mg chewable tablet: corn starch, FD&C Yellow No. 6,
`magnesium hydroxide, magnesium stearate, mannitol, poly-
`ethylene glycol, povidone, talc and artificial flavor.
`75 mg tablet: corn starch, gelatin, iron oxide, lactose, mag-
`nesium hydroxide, polyethylene glycol and talc.
`CLINICAL PHARMACOLOGY
`CYLERT (pemoline) has a pharmacological activity similar to
`that of other known central nervous system stimulants; how-
`ever, it has minimal sympathomimetic effects. Although
`studies indicate that pemoline may act in animals through
`dopaminergic mechanisms, the exact mechanism and site of
`action of the drug in man is not known.
`There is neither specific evidence which clearly establishes
`the mechanism whereby CYLERT produces its mental and
`behavioral effects in children, nor conclusive evidence re-
`garding how these effects relate to the condition of the cen-
`tral nervous system.
`Pemoline is rapidly absorbed from the gastrointestinal tract.
`Approximately 50% is bound to plasma proteins The serum
`half-life of pemoline is approximately 12 hours. Peak serum
`levels of the drug occur within 2 to 4 hours after ingestion of
`a single dose. Multiple dose studies in adults at several dose
`levels indicate that steady state is reached in approximately
`2 to 3 days. In animals given radiolabeled pemoline, the drug
`was widely and uniformly distributed throughout the tis-
`sues, including the brain.
`Pemoline is metabolized by the liver. Metabolites of pemo-
`line include pemoline conjugate, pemoline dione, mandelic
`
`Physicians' Desk Reference® (cid:9)
`acid, and unidentified polar compounds. CYLERT is excreted
`primarily by the kidneys with approximately 50% excreted
`unchanged and only minor fractions present as metabolites.
`CYLERT (pemoline) has a gradual onset of action. Using the
`recommended schedule of dosage titration, significant clini-
`cal benefit may not be evident until the third or fourth week
`of drug administration.
`INDICATIONS AND USAGE
`CYLERT (pemoline) is indicated in Attention Deficit Disorder
`(ADD) with hyperactivity as an integral part of a total treat-
`ment program which typically includes other remedial mea-
`sures (psychological, educational, social) for a stabilizing
`effect in children with a behavioral syndrome characterized
`by the following group of developmentally inappropriate
`symptoms• moderate to severe distractibility, short attention
`span, hyperactivity, emotional lability, and impulsivity. The
`diagnosis of this syndrome should not be made with finality
`when these symptoms are only of comparatively recent ori-
`gin. Nonlocalizing (soft) neurological signs, learning disabil-
`ity, and abnormal EEG may or may not be present, and a
`diagnosis of central nervous system dysfunction may or may
`not be warranted.
`CONTRAINDICATIONS
`CYLERT (pemoline) is contraindicated in patients with known
`hypersensitivity or idiosyncrasy to the drug. CYLERT should
`not be administered to patients with impaired hepatic func-
`tion. (See "ADVERSE REACTIONS" section.)
`WARNINGS
`Decrements in the predicted growth (i.e., weight gain and/or
`height) rate have been reported with the long-term use of
`stimulants in children. Therefore, patients requiring long-
`term therapy should be carefully monitored.
`•
`PRECAUTIONS
`General: Clinical experience suggests that in psychotic
`children, administration of CYLERT may exacerbate symp-
`toms of behavior disturbance and thought disorder.
`CYLERT should be administered with caution to patients with
`significantly impaired renal function.
`Laboratory Tests: Liver function testa should be performed
`prior to and periodically during therapy with Crum' The
`drug should be discontinued if abnormalities are revealed
`and confirmed by follow-up tests. (See "ADVERSE REAC-
`TIONS" section regarding reports of abnormal liver function
`tests, hepatitis and jaundice.)
`Drug Interactions: The interaction of Crum. (pemoline)
`with other drugs has not been studied in humans. Patients
`who are receiving CYLERT concurrently with other drugs,
`especially drugs with CNS activity, should be monitored
`carefully.
`Decreased seizure threshold has been reported in patients
`receiving CYLERT concomitantly with antiepileptic medi-
`cations.
`Carcznogeriesis: Long-term studies have been conducted in
`rats with doses as high as 150 mg/kg/day for eighteen
`months There was no significant difference in the incidence
`of any neoplasm between treated and control animals.
`Mutageriesis: Data are not available concerning long-term
`effects on mutagenicity in animals or humans.
`Impairment of Fertility: The results of studies in which rats
`were given 18.75 and 37.5 mg/kg/day indicated that pemo-
`line did not affect fertility in males or females at those doses.
`Pregnancy. Teratogenic effects: Pregnancy Category B.
`Reproduction studies have been performed in rats and rab-
`bits at doses of 18.75 and 37.5 mg/kg/day and have revealed
`no evidence of impaired fertility or harm to the fetus. There
`are, however, no adequate and well-controlled studies in
`pregnant women. Because animal reproduction studies are
`not always predictive of human response, this drug should be
`used during pregnancy only if clearly needed.
`Nonteratogenic effects: Studies in rats have shown an in-
`creased incidence of stillbirths and cannibalization when
`pemoline was administered at a dose of 37.5 mg/kg/day.
`Postnatal survival of offspring was reduced at doses of 18.75
`and 37.5 mg/kg/day.
`Nursing Mothers: It is not known whether this drug is ex-
`creted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when CYLERT is
`administered to a nursing woman.
`Pediatric Use: Safety and effectiveness in children below
`the age of 6 years have not been established.
`Long-term effects of CYLERT in children have not been estab-
`lished (See "WARNINGS" section).
`CNS stimulants, including pemoline, have been reported to
`precipitate motor and phonic tics and Tourette's syndrome.
`Therefore, clinical evaluation for tics and Tourette's syn-
`drome in children and their families should precede use of
`stimulant medications.
`Drug treatment is not indicated in all cases of ADD with
`hyperactivity and should be considered only in light of com-
`plete history and evaluation of the child. The decision to pre-
`scribe CYLERT (pemoline) should depend on the physician's
`assessment of the chronicity and severity of the child's symp-
`toms and their appropriateness for his/her age. Prescription
`
`Consult 1992 Supplements for revisions
`
`should not depend solely on the presence of one or more of
`the behavioral characteristics.
`ADVERSE REACTIONS
`The following are adverse reactions in decreasing order of
`severity within each category associated with CYLERT
`Hepatic: There have been reports of hepatic dysfunction
`including elevated liver enzymes, hepatitis and jaundice in
`patients taking Cyteirr. The occurrence of elevated liver
`enzymes is not rare and these reactions appear to be revers-
`ible upon drug discontinuance. Most patients with elevated
`liver enzymes were asymptomatic. Although no causal rela-
`tionship has been established, there have been rare reports
`of hepatic-related fatalities involving patients taking
`CYLERT.
`Hematopozetic: There have been isolated reports of aplastic
`anemia.
`Central Nervous System: The following CNS effects have
`been reported with the use of CYLERT: convulsive seizures;
`literature reports indicate that CYLERT may precipitate at-
`tacks of Gilles de la Tourette syndrome; hallucinations; dys-
`kinetic movements of the tongue, lips, face and extremities;
`abnormal oculomotor function including nystagmus and
`oculogyric crisis; mild depression; dizziness; increased irrita-
`bility; headache; and drowsiness.
`Insomnia is the most frequently reported side effect of CY-
`LERT. it usually occurs early in therapy prior to an optimum
`therapeutic response. In the majority of cases it is transient
`in nature or responds to a reduction in dosage.
`Gastrointestinal: Anorexia and weight loss may occur dur-
`ing the first weeks of therapy. In the majority of cases it is
`transient in nature; weight gain usually resumes within
`three to six months.
`Nausea and stomach ache have also been reported.
`Genitourinary: A case of elevated acid phosphatase in asso-
`ciation with prostatic enlargement has been reported in a 63
`year old male who was treated with CYLERT for sleepiness.
`The acid phosphatase normalized with discontinuation of
`CYLERT and was again elevated with rechallenge.
`Miscellaneous: Suppression of growth has been reported
`with the long-term use of stimulants in children (See
`"WARNINGS" section.) Skin rash has been reported with
`CYLERT
`Mild adverse reactions appearing early during the course of
`treatment with CYLERT often remit with continuing therapy
`If adverse reactions are of a significant or protracted nature,
`dosage should be reduced or the drug discontinued.
`DRUG ABUSE AND DEPENDENCE
`Controlled Substance: CYLERT is subject to control under
`DEA schedule IV.
`Abuse: CvLEirr failed to demonstrate a potential for self-
`administration in primates. However, the pharmacologic
`similarity of pemoline to other psychostimulants with
`known dependence liability suggests that psychological and/
`or physical dependence might also occur with CYLERT There
`have been isolated reports of transient psychotic symptoms
`occurring in adults following the long-term misuse of exces-
`sive oral doses of pemoline. CYLERT should be given with cau-
`tion to emotionally unstable patients who may increase the
`dosage on their own initiative.
`OVERDOSAGE
`Signs and symptoms of acute overdosage, resulting princi-
`pally from overstimulation of the central nervous system
`and from excessive sympathomimetic effects, may include
`the following: vomiting, agitation, tremors, hyperreflexia,
`muscle twitching, convulsions (may be followed by coma),
`euphoria, confusion, hallucinations, delirium, sweating,
`flushing, headache, hyperpyrexia, tachycardia, hyperten-
`sion and mydriasis. Treatment consists of appropriate sup-
`portive measures. The patient must be protected against self-
`injury and against external stimuli that would aggravate
`overstimulation already present. If signs and symptoms are
`not too severe and the patient is conscious, gastric contents
`may be evacuated. Chlorpromazine has been reported in the
`literature to be useful in decreasing CNS stimulation and
`sympathomimetic effects.
`Efficacy of peritoneal dialysis or extracorporeal hemodialy-
`sis for CYLERT overdosage has not been established.
`DOSAGE AND ADMINISTRATION
`CYLERT (pemoline) is administered as a single oral dose each
`morning. The recommended starting dose is 37.5 mg/day.
`This daily dose should be gradually increased by 18.75 mg at
`one week intervals until the desired clinical response is ob-
`tained. The effective daily dose for most patients will range
`from 56.25 to 75 mg. The maximum recommended daily dose
`of pemoline is 112.5 mg.
`Clinical improvement with CYLERT is gradual. Using the
`recommended schedule of dosage titration, significant bene-
`fit may not be evident until the third or fourth week of drug
`administration.
`Where possible, drug administration should be interrupted
`occasionally to determine if there is a recurrence of behav-
`ioral symptoms sufficient to require continued therapy.
`
`NOVARTIS EXHIBIT 2114
`Par v Novartis, IPR 2016-00084
`Page 4 of 303
`
`(cid:9)
`

`
`Consult 1992 Supplements for revisions
`
`Physicians' Desk Reference® (cid:9)
`
`511
`
`HOW SUPPLIED
`Crwrr (pemoline) is supplied as monogrammed, grooved
`tablets in three dosage strengths:
`18.76 mg tablets (white) in bottles of 100 (NDC 0074-
`6025-13),
`37.5 mg tablets (orange-colored) in bottles of 100 (NDC 0074-
`6057-13),
`75 mg tablets (tan-colored) in bottles of 100 (NDC 0074-
`6073-13).
`CyLzirr (pemoline) Chewable is supplied as 37.5 mg mono-
`grammed, grooved tablets (orange-colored) in bottles of 100
`(NDC 0074-6088-13).
`Ref. 03-4375-R14
`Shown in Product Identification Section, page 403
`
`DAYALETS® Fllmtab®
`[ay la-lets ]
`Multivitamin Supplement for adults and
`children 4 or more years of age
`DAYALETS® PLUS IRON FIlmtab0
`Multivitamin Supplement with Iron for adults
`and children 4 or more years of age
`
`OTC
`
`(See PDR For Nonprescription Drugs.)
`
`DEPAKENEO Capsules and Syrup
`(dep 'a-keine )
`(Valproic Add)
`
`WARNING
`HEPATIC FAILURE RESULTING IN FATALITIES
`HAS OCCURRED IN PATIENTS RECEIVING VAL-
`PROIC ACID. EXPERIENCE HAS INDICATED THAT
`CHILDREN UNDER THE AGE OF TWO YEARS ARE
`AT A CONSIDERABLY INCREASED RISK OF DE-
`VELOPING FATAL HEPATOTOXICITY. ESPE-
`CIALLY THOSE ON MULTIPLE ANTICONVUL-
`SANTS, THOSE WITH CONGENITAL METABOLIC
`DISORDERS, THOSE WITH SEVERE SEIZURE DIS-
`ORDERS ACCOMPANIED BY MENTAL RETARDA-
`TION, AND THOSE WITH ORGANIC BRAIN DIS-
`EASE. WHEN DEPAKENE PRODUCTS ARE USED
`IN THIS PATIENT GROUP, IT SHOULD BE USED
`WITH EXTREME CAUTION AND AS A SOLE
`AGENT. THE BENEFITS OF SEIZURE CONTROL
`SHOULD BE WEIGHED AGAINST THE RISKS.
`ABOVE THIS AGE GROUP, EXPERIENCE HAS INDI-
`CATED THAT THE INCIDENCE OF FATAL HEPA-
`TOTOXICITY DECREASES CONSIDERABLY IN
`PROGRESSIVELY OLDER PATIENT GROUPS.
`THESE INCIDENTS USUALLY HAVE OCCURRED
`DURING THE FIRST SIX MONTHS OF TREAT-
`MENT. SERIOUS OR FATAL HEPATOTOXICITY
`MAY BE PRECEDED BY NON-SPECIFIC SYMP-
`TOMS SUCH AS LOSS OF SEIZURE CONTROL, MAL-
`AISE, WEAKNESS, LETHARGY, FACIAL EDEMA,
`ANOREXIA AND VOMITING. PATIENTS SHOULD
`BE MONITORED CLOSELY FOR APPEARANCE OF
`THESE SYMPTOMS. LIVER FUNCTION TESTS
`SHOULD BE PERFORMED PRIOR TO THERAPY
`AND AT FREQUENT INTERVALS THEREAFTER,
`ESPECIALLY DURING THE FIRST SIX MONTHS.
`
`DESCRIPTION
`DEPAKENE (valproic acid) is a carboxylic acid designated as
`2-propylpentanoic acid. It is also known as dipropylacetic
`acid.
`Valproic acid (pKa 4.8) has a molecular weight of 144 and
`occurs as a colorless liquid with a characteristic odor. It is
`slightly soluble in water (1.3 mg/mL) and very soluble in
`organic solvents.
`DEPAKENE capsules and syrup are antiepileptics for oral ad-
`ministration Each soft elastic capsule contains 250 mg val-
`proic acid. The syrup contains the equivalent of 250 mg val-
`proic acid per 5 mL as the sodium salt.
`Inactive Ingredients:
`250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glyc-
`erin, iron oxide, methylparaben, propylparaben and tita-
`nium dioxide.
`Syrup: FD&C Red No. 40, glycerin, methylparaben, propyl-
`paraben, sorbitol, sucrose, water and natural and artificial
`flavors.
`CLINICAL PHARMACOLOGY
`Valproic acid is an antiepileptic agent which dissociates to
`the valproate ion in the gastrointestinal tract. The mecha-
`nism by which valproate exerts its antiepileptic effects has
`not been established. It has been suggested that its activity is
`related to increased brain levels of gamma-aminobutyric
`acid (GABA).
`Valproic acid is rapidly absorbed after oral administration.
`Peak plasma concentrations of valproate ion are observed
`
`one to four hours after a single oral dose of valproic acid. A
`slight delay in absorption occurs when the drug is adminis-
`tered with meals but this does not affect the total absorption.
`Accordingly, administration of oral valproate products with
`food, and substitution among the various DEPAKENE(valproic
`acid) and DEPAKOTE® (divalproex sodium) products should
`be without consequence. Nonetheless, any changes in dosage
`administration, or the addition or discontinuance of con-
`comitant drugs, should ordinarily be accompanied by close
`monitoring of clinical status and valproate plasma
`concentrations.
`The plasma half-life of valproate is typically in the range of
`six to sixteen hours. Half-lives in the lower part of the range
`are usually found in patients taking other antiepileptic
`drugs capable of enzyme induction.
`Valproate is primarily metabolized in the liver. The major
`metabolic routes are glucuronidation, mitochrondrial beta
`oxidation, and microsomol oxidation. The major metabolites
`formed are the glucuronide conjugate, 2-propyl-3-keto-pen-
`tanoic acid, and 2-propylhydroxypentanoic acids. Other un-
`saturated metabolites have been reported. The major route
`of elimination of these metabolites is in the urine.
`Patients on monotherapy will generally have longer half-
`lives and higher concentrations of valproate at a given dos-
`age than patients receiving polytherapy. This is primarily
`due to enzyme induction caused by other antiepileptics,
`which results in enhanced clearance of valproate by
`glucuronidation and microsomal oxidation. Because of these
`changes in valproate clearance, monitoring of antiepileptic
`concentrations should be intensified whenever concomitant
`antiepileptics are introduced or withdrawn.
`The therapeutic range is commonly considered to be 50 to
`100 mcg/mL of total valproate, although some patients may
`be controlled with plasma concentrations that fall outside
`this range. Valproate is highly bound (90%) to plasma pro-
`teins in the therapeutic range; however, protein binding is
`concentration-dependent and decreases at high valproate
`concentrations. The binding is variable among patients, and
`may be affected by fatty acids or by highly bound drugs su