`
`PHYSICIANS
`See
`RsrareNe=
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 001
`
`

`

`2000
`
`
`
`
` PDR
`eh
`
`EDITION
`
`
`
`
`PHYSICIANS
`OK
`REFERENCE
`
`
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`Director of Sales: Dikran N. Barsamian
`
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales:Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Managerof Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy,Ill
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`
`
`oe Copyright©2000 and published by Medical Economics Company,Inc. at Montvale, NJ 07645-1742. All rights reserved. Noneofthe contentofthis publication may
`
`be reproduced, stored in a retrieval system, resold,redistributed, or transmitted in any form or by any means(electronic, mechanical, photocopying, recording, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDR For Ophthalmology®, Pocket PDR®, and The PDR® Family
`Guide to Prescription Drugs® are registered trademarks used herein underlicense. PDR For Nonprescription Drugs and Dietary Supplements™, PDR Companion Guide™,
`PDR?for Herbal Medicines™, PDR® Medical Dictionary™, PDR® Nurse's Drug Handbook™, PDR® Nurse's Dictionary™, The PDR® Family Guide Encyclopedia of Medical
`Care™, The PDR® Family Guide to Natural Medicines and Healing Therapies™, The PDR® Family Guide to CommonAilments™, The PDR® Family Guide to Over-the-
`Counter Drugs™, and PDR?® Electronic Library™ are trademarks used herein underlicense.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler; Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: Jonn R. Ware; Senior Vice President, Internet Strategies: Raymond Zoeller
`
`3) Printed on recycled paper
`
`ISBN: 1-56363-330-2
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1019, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 002
`
`

`

`PHYSICIANS’DESK REFERENCE®
`
`2358/PFIZER INC
`
`Navane IM—Cont.
`
`Dosage of Navane shouldbe individually adjusted depend-
`ing on the chronicity and severity of the condition. In gen-
`eral, small doses should be used initially and gradually in-
`creased to the optimaleffective level, based on patient re-
`sponse.
`Usage in children under 12 years of age is not recom-
`mended.
`Where more rapid control and treatment of acute behavior
`is desirable, the intramuscular form of Navane maybe in-
`dicated. It is also of benefit where the very nature of the
`patient’s symptomatology, whether acute or chronic, renders
`oral administration impractical or even impossible.
`For treatment of acute symptomatology or in patients un-
`able or unwilling to take oral medication, the usual dose is
`4 mg of Navane Intramuscular For Injection administered
`2 to 4 timesdaily. Dosage may be increased or decreased
`depending on response. Most patients are controlled on a
`total daily dosage of 16 to 20 mg. The maximum recom-
`mended dosageis 30 mg/day. An oral form should supplant
`the injectable form as soon as possible. It may be necessary
`to adjust the dosage when changing from the intramuscular
`to oral dosage forms. Dosage recommendations for Navane
`Capsules and Concentrate can be found in the Navaneoral
`packageinsert.
`.
`OVERDOSAGE
`Manifestations include muscular twitching, drowsiness,
`and dizziness. Symptomsof gross overdosage may include
`CNSdepression,rigidity, weakness, torticollis, tremor, sali-
`vation, dysphagia, hypotension, disturbances of gait, or
`coma.
`Treatment: Essentially symptomatic and supportive. Keep
`patient undercareful observation and maintain an open air-
`way, since involvement of the extrapyramidal system may
`produce dysphagia and respiratory difficulty in severe over-
`dosage. If hypotension occurs, the standard measures for
`managingcirculatory shock shouldbe used (LV. fluids and/
`or vasoconstrictors).
`If a vasoconstrictor is needed, levarterenol and phenyleph-
`rine are the most suitable drugs. Other pressor agents, in-
`cluding epinephrine, are not recommended,since phenothi-
`azine derivatives may reverse the usual pressor elevating
`action of these agents and cause further lowering of blood
`pressure.
`If CNS depression is marked, symptomatic treatmentis in-
`dicated. Extrapyramidal symptoms maybetreated with an-
`tiparkinson drugs.
`Thereare no data on the useofperitoneal or hemodialysis,
`but they are knownto beoflittle value in phenothiazine
`intoxication.
`HOW SUPPLIED
`Navane(thiothixene hydrochloride) Intramuscular For In-
`jection is available in amberglass vialsin packages of 10
`vials (NDC 0049-5765-83). When reconstituted with 2.2 ml
`of STERILE WATER FOR INJECTION,each ml contains
`thiothixene hydrochloride equivalent to 5 mgof thiothixene,
`and 59.6 mg of mannitol. The reconstituted solution of Na-
`vane Intramuscular For Injection may be stored for 48
`hours at room temperature before discarding. 70-4177-00-4
`Revised January 1988
`
`
`
`
`NORVASC®
`[nor 'vask]
`(amlodipine besylate)
`Tablets
`
`R
`
`.
`DESCRIPTION
`NORVASC®is the besylate salt of amlodipine, a long-acting
`calcium channel blocker.
`NORVASCis chemically described as (R.S.) 3-ethy]-5-meth- ‘
`yl-2-(2-amino-ethoxymethyl)-4-(2-chlorophenyl)-1,4-dihy-
`dro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate.
`Its empirical formula is Cy9H);CIN,O;-CgH,0,S, and its
`structural formulais:
`
`addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: micro-
` For Intramuscular Use Only
`
`crystalline cellulose, dibasic calcium phosphate anhydrous,
`sodium starch glycolate, and magnesium stearate.
`ADVERSE REACTIONS
`CLINICAL PHARMACOLOGY
`NOTE:Notall of the following adverse reactions have been
`Mechanism of Action: NORVASC is a dihydropyridine cal-
`reported with Navane. However, since Navane has certain
`cium antagonist (calcium ion antagonist or slow-channel
`chemical and pharmacologic similarities to the phenothia-
`blocker) that inhibits the transmembraneinflux of calcium
`ions into vascular smooth muscle and cardiac muscle. Ex-
`zines, all of the knownside effects and toxicity associated
`with phenothiazine therapy should be borne in mind when
`perimental data suggest that NORVASC bindsto both dihy-
`Navaneis used.
`dropyridine and nondihydropyridine binding sites. The con-
`Cardiovascular Effects: Tachycardia, hypotension, light-
`tractile processes of cardiac muscle and vascular smooth
`headedness, and syncope. In the event hypotension occurs,
`muscle are dependent upon the movementof extracellular
`calcium ions into thesecells through specific ion channels.
`epinephrine should not be used as a pressor agent since a
`NORVASC inhibits calcium ion influx across cell mem-
`paradoxical further lowering of blood pressure may result.
`Nonspecific EKG changes have been observed in some pa-
`branesselectively, with a greater effect on vascular smooth
`musclecells than on cardiac muscle cells. Negative inotropic
`tients receiving Navane. These changes are usually revers-
`effects can be detected in vitro but such effects have not
`ible and frequently disappear on continued Navanetherapy.
`been seenin intact animals at therapeutic doses. Serum cal-
`Theclinical significance of these changes is not known.
`cium concentration is not affected by NORVASC.Within the
`CNSEffects: Drowsiness, usually mild, may occur although
`physiologic pH range, NORVASCis an ionized compound
`it usually subsides with continuation of Navane therapy.
`The incidence of sedation appears similar to that of the pi-
`(pKa=8.6), and its kinetic interaction with the calcium
`channelreceptor is characterized by a gradual rate of asso-
`perazine group of phenothiazines, but less than that of cer-
`ciation and dissociation with the receptor bindingsite, re-
`tain aliphatic phenothiazines. Restlessness, agitation and
`insomnia have been noted with Navane. Seizures and par-
`sulting in a gradualonsetofeffect.
`adoxical exacerbation of psychotic symptoms haveoccurred
`NORVASCis a peripheral arterial vasodilator that acts di-
`with Navaneinfrequently.
`rectly on vascular smooth muscle to cause a reduction in pe-
`ripheral vascular resistance and reduction in blood pres-
`Hyperreflexia has been reported in infants delivered from
`sure.
`mothers havingreceived structurally related drugs.
`The precise mechanisms by which NORVASC relieves an-
`In addition, phenothiazine derivatives have been associated
`with cerebral edema andcerebrospinal fluid abnormalities.
`gina have not been fully delineated, but are thought to in-
`clude the following:
`Extrapyramidal symptoms, such as pseudo-parkinsonism,
`Exertional Angina: In patients with exertional angina,
`akathisia, and dystonia have been reported. Managementof
`NORVASC reduces the total peripheral resistance (after-
`these extrapyramidal symptoms depends upon the type and
`load) against which the heart works and reduces the rate
`severity. Rapid relief of acute symptoms may require the
`pressure product, and thus myocardial oxygen demand,at
`use of an injectable antiparkinson agent. More slowly
`any given level of exercise.
`emerging symptoms may be managed by reducing the dos-
`Vasospastic Angina: NORVASC has been demonstrated. to
`age of Navane and/or administering an oral antiparkinson
`block constriction and restore blood flow in coronary arter-
`agent.
`ies and arterioles in response to calcium, potassium epi-
`Persistent Tardive Dyskinesia: As with all antipsychotic
`nephrine, serotonin, and thromboxane A, analog in experi-
`agents tardive dyskinesia may appear in somepatients on
`mental animal models and in human coronary vessels in vi-
`long term therapy or mayoccurafter drug therapy has been
`tro. This inhibition of coronary spasm is responsible for the
`discontinued. The syndromeis characterized by rhythmical
`effectiveness of NORVASC in vasospastic (Prinzmetal’s or
`involuntary movements of the tongue, face, mouth or jaw
`variant) angina.
`(e.g., protrusion of tongue, puffing of cheeks, puckering of
`Pharmacokinetics and Metabolism: After oral administra-
`mouth, chewing movements). Sometimes these may be ac-
`tion of therapeutic doses of NORVASC,absorption produces
`companied by involuntary movements of extremities.
`peak plasmaconcentrations between 6 and 12 hours. Abso-
`Since early detection of tardive dyskinesia is important, pa-
`tients should be monitored on an ongoing basis. It has been
`lute bioavailability has been estimated to be between 64 and
`90%. The bioavailability of NORVASCis notaltered by the
`reported that fine vermicular movementof the tongue may
`presenceoffood.
`:
`be anearly sign of the syndrome.If this or any other pre-
`NORVASCis extensively (about 90%) converted to inactive
`sentation of the syndromeis observed,the clinician should
`metabolites via hepatic metabolism with 10% of the parent
`considerpossible discontinuation of neuroleptic medication.
`(See WARNINGSsection.)
`compound and 60% of the metabolites excreted in the urine.
`Ex vivo studies have shown that approximately 93% of the
`Hepatic Effects: Elevations of serum transaminase and al-
`circulating drug is bound to plasma proteins in hyperten-
`kaline phosphatase, usually transient, have been infre-
`sive patients. Elimination from the plasmais biphasic with
`quently observed in somepatients. No clinically confirmed
`‘a terminal elimination half-life of about 30-50 hours.
`cases ofjaundice attributable to Navane(thiothixene hydro-
`Steady-state plasmalevels of NORVASCarereachedafter 7
`chloride) have been reported.
`to 8 days of consecutive daily dosing.
`Hematologic Effects: As is true with certain other psycho-
`The pharmacokinetics of NORVASCare not significantly in-
`tropic drugs, leukopenia andleucocytosis, which are usually.
`fluenced by renal impairment. Patients with renal failure
`transient, can occur occasionally with Navane. Other anti-
`maytherefore receive the usualinitial dose.
`psychotic drugs have been associated with agranulocytosis,
`Elderly patients and patients with hepatic insufficiency
`eosinophilia, hemolytic anemia, thrombocytopenia and pan-
`have decreased clearance of amlodipine with a resulting in-
`cytopenia.
`crease in AUCof approximately 40-60%,anda lowerinitial
`Allergic Reactions: Rash,pruritus, urticaria, and rare cases
`dose may be required. A similar increase in AUC was ob-
`of anaphylaxis have been reported with Navane. Undue ex-
`served in patients with moderate to severe heart failure.
`posure to sunlight should be avoided. Although not experi-
`Pharmacodynamics: Hemodynamics Following administra-
`enced with Navane, exfoliative dermatitis, contact dermati-
`tion of therapeutic doses to patients with hypertension,
`tis (in nursing personnel), have been reported with certain
`NORVASCproducesvasodilation resulting in a reduction of
`phenothiazines.
`Endocrine Disorders: Lactation, moderate breast enlarge-
`supine and standing blood pessures. These decreases in
`ment and amenorrhea haveoccurred in a small percentage
`blood pressure are not accompanied by a significant change
`in heart rate or plasma catecholaminelevels with chronic
`of females receiving Navane.If persistent, this may neces-
`dosing. Although the acute intravenous administration of
`sitate a reduction in dosage or the discontinuation of ther-
`amlodipine decreasesarterial blood pressure and increases
`apy. Phenothiazines have been associated with false posi-
`heart rate in hemodynamicstudies of patients with chronic
`tive pregnancy tests, gynecomastia, hypoglycemia, hyper-
`stable angina, chronic administration of oral amlodipine in
`glycemia, and glycosuria.
`clinical trials did not leadto clinically significant changes in
`Autonomic Effects: Dry mouth,blurred vision, nasal conges-
`heart rate or blood pressures in normotensivepatients with
`tion, constipation, increased sweating, increased salivation,
`angina.
`and impotence have occurred infrequently with Navane
`With chronic once daily oral administration, antihyperten-
`therapy. Phenothiazines have been associated with miosis,
`sive effectiveness is maintained for at least 24 hours.
`mydriasis, and adynamic ileus.
`Plasma concentrations correlate with effect in both young
`Other Adverse Reactions: Hyperpyrexia, anorexia, nausea,
`and elderly patients. The magnitude of reduction in blood
`vomiting, diarrhea, increase in appetite and weight, weak-
`pressure with NORVASCis also correlated with the height
`nessor fatigue, polydipsia and peripheral edema.
`of pretreatmentelevation; thus, individuals with moderate
`Although not reported with Navane, evidence indicates
`hypertension (diastolic pressure 105-114 mmHg) had about
`there is a relationship between phenothiazine therapy and
`a 50% greater response than patients with mild hyperten-
`the occurrence of a systemic lupus erythematosus-like syn-
`sion (diastolic pressure 90-104 mmHg). Normotensive sub-
`drome.
`jects experienced noclinically significant change in blood
`Neuroleptic Malignant Syndrome (NMS): Pleaserefer to the
`pressures (+1/— 2 mmHg).
`text regarding NMS in the WARNINGSsection.
`In hypertensive patients with normalrenal function, thera-
`NOTE: Sudden deaths have occasionally been reported in
`peutic doses of NORVASCresulted in a decrease in renal
`vascular resistance and anincrease in glomerularfiltration
`patients who have received certain phenothiazine deriva-
`tives. In some cases the cause of death was apparently car-
`rate and effective renal plasma flow without changein fil-
`diac arrest or asphyxia dueto failure of the cough reflex. In
`tration fraction or proteinuria.
`others, the cause could not be determined nor could it be
`As with other calcium channelblockers, hemodynamic mea-
`established that death was due to phenothiazine ad-
`surementsof cardiac function at rest and during exercise (or
`ministration.
`pacing) in patients with normal ventricular function treated
`DOSAGE AND ADMINISTRATION
`with NORVASC have generally demonstrated a small in-
`crease in cardiac index without significant influence on
`Preparation
`dP/dt or on left ventricular end diastolic pressure or volume.
`Navane(thiothixene hydrochloride) Intramuscular For In-
`In hemodynamic studies, NORVASC has not been associ-
`jection mustbe reconstituted with 2.2 mlof sterile water for
`ated with a negative inotropic effect when administered in
`injection.
`Information will be superseded by supplements and su3E.Q0.G6.N PHARMA LTD (IPR2020-0 1 263) Exe 1 0 1 9, p. 003
`
`CHg
`
`Cr
`9
`
`HC
`
`H3C
`
`NH
`
`=
`
`aeNH2
`
`CgH,0.8
`Amlodipine besylate is a white crystalline powder with a
`molecular weight of 567.1. It is slightly soluble in water and
`sparingly soluble in ethanol. NORVASC (amlodipine besy-
`late) tablets are formulated as white tablets equivalent to
`2.5, 5 and 10 mg of amlodipine for oral administration. In
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 003
`
`

`

`PRODUCT INFORMATION
`
`PFIZER INC/2359
`
`Adverse
`Event
`Rdémia
`Dizziness
`Flushing
`Palpitation
`
`2.5 mg
`N=275
`1.8
`EA
`0.7
`0.7
`
`5.0 mg
`N=296
`3.0
`3.4
`1.4
`1.4
`
`10.0 mg
`N=268
`10.8
`3.4
`2.6
`4.5
`
`Placebo
`N=520
`0.6
`1.5
`0.0
`0.6
`
`Other adverse experiences which were not clearly dose re-
`lated but which were reported with an incidence greater
`than 1.0% in placebo-controlled clinical trials include the
`following:
`
`Placebo-Controlled Studies
`NORVASC(%)
`PLACEBO(%)
`(N=1730)
`(N=1250)
`7.3
`7.8
`4.5
`2.8
`2.9
`19
`1.6
`0.3
`14
`0.6
`
`Headache
`Fatigue
`Nausea
`Abdominal Pain
`Somnolence
`
`For several adverse experiences that appear to be drug and
`dose related, there was a greater incidence in women than
`men associated with amlodipine treatment as shown in the
`following table:
`
`Edema
`Flushing
`Palpitations
`Somnolence
`
`
`
`|
`
`|
`
`|
`
`
`
` cardial infarction on starting calcium channel blocker ther-
`troglycerin, digoxin, warfarin, non-steroidal anti-inflamma-
`
`the therapeutic dose rangeto intact animals and man, even
`when co-administered with beta-blockers to man. Similar
`apy or at the time of dosage increase. The mechanism ofthis
`findings, however, have been observed in normals or well-
`effect has not been elucidated.
`compensated patients with heart failure with agents pos-
`PRECAUTIONS
`sessing significant negative inotropic effects.
`General: Since the vasodilation induced by NORVASC is
`Studies in Patients with Congestive Heart Failure: NOR-
`gradual in onset, acute hypotension has rarely been re-
`VASChasbeen comparedto placeboin four 8-12 week stud-
`ported after oral administration of NORVASC.Nonetheless,
`ies of patients with NYHA class II/III heart failure, involv-
`caution shouldbe exercised when administering NORVASC
`ing a total of 697 patients. In these studies, there was no
`evidence of worsened heart failure based on measuresof ex-
`as with any other peripheral vasodilator particularly in pa-
`tients with severe aortic stenosis.
`‘ercise tolerance, NYHA classification, symptoms, or LVEF.
`In general,
`Use in Patients with Congestive Heart Failure:
`In a long-term (follow-up at least 6 months, mean 13.8
`calcium channel blockers should be used with caution in pa-
`months) placebo-controlled mortality/morbidity study of
`NORVASC5-10 mgin 1153 patients with NYHA classesIII
`tients with heart failure. NORVASC (5-10 mgper day) has
`(n=931) or IV (n=222)heart failure on stable doses ofdiuret-
`been studied in a placebo-controlled trial of 1153 patients
`with NYHA Class III or IV heart failure (see CLINICAL
`ies, digoxin, and ACE inhibitors, NORVASC hadnoeffect on
`PHARMACOLOGY) on stable doses of ACE inhibitor, di-
`the primary endpointof the study which was the combined
`goxin, anddiuretics. Follow-up was at least 6 months, with
`endpointof all-cause mortality and cardiac morbidity (as de-
`a mean of about 14 months. There was no overall adverse
`fined bylife-threatening arrhythmia, acute myocardial in-
`effect on survival or cardiac morbidity (as defined by life-
`farction, or hospitalization for worsened heart failure), or on
`NYHA classification, or symptomsof heart failure. Total
`threatening arrhythmia, acute myocardial infarction, or
`hospitalization for worsened heart failure). NORVASC has
`combinedall-cause mortality and cardiac morbidity events
`were 222/571 (39%) for patients on NORVASC and 246/583
`been compared to placebo in four 8-12 week studies of pa-
`(42%) for patients on placebo; the cardiac morbid events
`tients with NYHA classII/III heart failure, involving a total
`of 697 patients. In these studies, there was no evidence of
`represented about 25% of the endpoints in the study.
`worsened heart failure based on measuresof exercise toler-
`Electrophysiologic Effects: NORVASC does not changesino-
`NORVASC
`PLACEBO.
`atrial nodal function or atrioventricular conduction in intact
`ance, NYHA classification, symptoms, or LVEF.
`Beta-Blocker Withdrawal:.NORVASCis not a beta-blocker
`ADR
`M=%
`Fe%
`M=%
`F=%
`animals or man. In patients with chronic stable angina,in-
`(N=1218)
`(N=512)
`(N=914)
`(N=336)
`travenous administration of 10 mg did not significantly al-
`and therefore gives no protection against the dangers of
`5.6
`14.6
`14
`5.1
`abrupt beta-blocker withdrawal; any such withdrawal
`ter A-H and H-V conduction andsinus node recovery time
`should be by gradual reduction of the dose of beta-blocker.
`1.5
`4.5
`0.3
`0.9
`after pacing. Similar results were obtained in patients re-
`ceiving NORVASCandconcomitant beta blockers. In clini-
`Patients with Hepatic Failure: Since NORVASCis exten-
`14
`3.3
`0.9
`0.9
`cal studies in which NORVASCwasadministered in combi-
`13
`16
`0.8
`0.3
`sively metabolized by the liver and the plasmaelimination
`nation with beta-blockers to patients with either hyperten-
`half-life (t 1/2) is 56 hours in patients with impaired hepatic
`The following events occurred in =1% but >0.1% of patients
`sion or angina, no adverse effects on electrocardiographic
`function, caution should be exercised when administering
`in controlledclinical trials or under conditionsof open trials
`parameters wereobserved.In clinical trials with anginapa-
`NORVASCto patients with severe hepatic impairment.
`or marketing experience where a causal relationship is un-
`tients alone, NORVASCtherapydid notalter electrocardio-
`Drug Interactions:
`Jn vitro data in human plasmaindicate
`certain; they are listed to alert the physician to a possible
`graphic intervals or produce higher degrees of AV blocks.
`that NORVASChasnoeffect on the protein bindingof drugs
`relationship:
`tested (digoxin, phenytoin, warfarin, and indomethacin).
`Effects in Hypertension: The antihypertensiveefficacy of
`Cardiovascular: arrhythmia (including ventricular tachy-
`NORVASChasbeen demonstrated in a total of 15 double-
`Special studies haveindicated that the co-administration of
`cardia andatrial fibrillation), bradycardia, chest pain, hy-
`NORVASCwithdigoxin did not change serum digoxin levels
`blind, placebo-controlled, randomized studies involving 800
`potension, peripheral ischemia, syncope, tachycardia, pos-
`patients on NORVASC and 538 on placebo. Once daily ad-
`or digoxin renal clearance in normal volunteers; that co-
`tural dizziness, postural hypotension.
`ministration producedstatistically significant placebo-cor-
`administration with cimetidine did not alter the pharmaco-
`Central and Peripheral Nervous System: hypoesthesia, par-
`kinetics of amlodipine; and that co-administration with
`rected reductions in supine andstanding blood pressuresat
`esthesia, tremor, vertigo.
`24 hours postdose, averaging about 12/6 mmHgin the
`warfarin did not change the warfarin prothrombin response
`time.
`Gastrointestinal: anorexia, constipation, dyspepsia,** dys-
`standingposition and 13/7 mmHgin the supine position in
`phagia,diarrhea,flatulence, vomiting, gingival hyperplasia.
`patients with mild to moderate hypertension. Maintenance
`In clinical trials, NORVASC has been safely administered
`General: asthenia,** back pain, hot flushes, malaise, pain,
`of the blood pressureeffect over the 24-hour dosing interval
`with thiazide diuretics, beta-blockers, angiotensin-convert-
`rigors, weight gain.
`wasobserved, with little difference in peak and troughef-
`ing enzyme inhibitors, long-acting nitrates, sublingual ni-
`Musculoskeletal System: arthralgia, arthrosis, muscle
`fect. Tolerance was not demonstrated in patients studied for
`cramps,** myalgia.
`up to 1 year. The3 parallel. fixed dose, dose response stud-
`tory drugs, antibiotics, and oral hypoglycemic drugs.
`Psychiatric: sexual dysfunction (male** and female), insom-
`Drug/Laboratory Test Interactions: None known.
`ies showed that the reduction in supine and standing blood
`lia, nervousness, depression, abnormal dreams, anxiety, de-
`pressures was dose-related within the recommended dosing
`personalization.
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`range. Effects on diastolic pressure were similar in young
`Rats and mice treated with amlodipine in the diet for two
`Respiratory System: dyspnea.** epistaxis.
`and older patients. The effect on systolic pressure was
`years, at concentrations calculated to provide daily dosage
`Skin and Appendages: pruritus.** rash** rash erythema-
`greater in older patients, perhaps because of greater base-
`levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of
`tous, rash maculopapular.
`line systolic pressure. Effects were similar in black patients
`**These events occurred in le
`carcinogenicity. The highest dose (for mice, similar to, and
`and in white patients.
`for rats twice* the maximum recommendedclinical dose of
`trolled trials, but the incidence
`Theeffectiveness of
`Effects in Chronic Stable Angina:
`10 mg on a mg/m?basis) was close to the maximum toler-
`tween 1% and 2% in all multip
`ated dose for mice but not for rats.
`5-10 mg/day of NORVASCin exercise-induced angina has
`
`Special Senses: abnormalvision, conjunctivit
`been evaluated in 8 placebo-controlled, double-blindclinical
`eye pain, tinnitus.
`Mutagenicity studies revealed no drugrelated effects at ei-
`trials of up to 6 weeks duration involving 1038 patients (684
`ther the gene or chromosomelevels.
`Urinary System: micturition frequency, micturition disor-
`NORVASC,354 placebo) with chronic stable angina. In 5 of
`der, nocturia.
`There was noeffect on thefertility of rats treated with am-
`the 8 studies significant increases in exercise time (bicycle
`Autonomic Nervous System: dry mouth, sweating in-
`lodipine (males for 64 days and females 14 days prior to
`creased.
`or treadmill) were seen with the 10 mg dose. Increases in
`mating) at doses up to 10 mg/kg/day(8 times* the maximum
`symptom-limited exercise time averaged 12.8% (63 sec) for
`Metabolic and Nutritional: thirst.
`recommended human doseof 10 mg on a mg/m”basis).
`NORVASC10 mg, and averaged 7.9% (38 sec) for NORVASC
`Hemopoietic: purpura.
`Pregnancy Category C: No evidence of teratogenicity or
`5 mg. NORVASC 10 mgalso increased time to 1 mm ST seg-
`The following events occurred in <0.1% of patients: cardiac
`other embryo/fetal toxicity was found when pregnant rats or
`ment deviation in several studies and decreased anginaat-
`failure, pulse irregularity, extrasystoles, skin discoloration,
`rabbits were treated orally with up to 10 mg/kg amlodipine
`tack rate. The sustainedefficacy of NORVASCin angina pa-
`urticaria, skin dryness, alopecia, dermatitis, muscle weak-
`(respectively 8 times* and 23 times* the maximum recom-
`tients has been demonstrated over long-term dosing. In pa-
`ness, twitching, ataxia, hypertonia, migraine, cold and
`mended human dose of 10 mg on a mg/m? basis) during
`tients with angina there were noclinically significant
`clammy skin, apathy, agitation, amnesia, gastritis,
`in-
`their respective periods of major organogenesis. However,
`reductions in blood pressures (4/1 mmHg) or changes in
`creased appetite, loose stools, coughing, rhinitis, dysuria,
`litter size was significantly decreased (by about 50%) and
`heart rate (+0.3 bpm).
`polyuria, parosmia, taste perversion, abnormal visual ac-
`the number of intrauterine deaths was significantly in-
`In a double-blind,placebo-
`Effects in Vasospastic Angina:
`commodation, and xerophthalmia.
`creased (about 5-fold) in rats administered 10 mg/kg amlo-
`controlled clinical trial of 4 weeks duration in 50 patients,
`Other reactions occurred sporadically and cannotbe distin-
`dipine for 14 days before mating and throughout mating
`NORVASC therapy decreased attacks by approximately
`guished from medications or concurrent disease states such
`and gestation. Amlodipine has been shown to prolong both
`4éweek compared with a placebo decrease of approximately
`as myocardial infarction and angina.
`the gestation period and the duration oflaborin rats at this
`Uweek (p<0.01). Two of 23 NORVASCand7of 27 placebo
`dose. There are no adequate and well-controlled studies in
`NORVASC therapy has not been associated with clinically
`patients discontinued from the study due to lack ofclinical
`significant changes in routine laboratory tests. Noclinically
`pregnant women, Amlodipine should be used during preg-
`improvement.
`relevant changes were noted in serum potassium, serum
`nancyonly if the potential benefit justifies the potential risk
`INDICATIONS AND USAGE
`to the fetus.
`glucose, total triglycerides, total cholesterol, HDL choles-
`1. Hypertension
`terol, uric acid, blood urea nitrogen, or creatinine.
`It is not known whether amlodipineis
`Nursing Mothers:
`NORVASCis indicatedfor the treatment of hypertension.It
`The following postmarketing event has been reported infre-
`excreted in human milk. In the absenceofthis information,
`maybe usedaloneor in combination with other antihyper-
`quently where a causal relationship is uncertain: gyneco-
`itis recommendedthat nursing be discontinued while NOR-
`tensive agents.
`VASCis administered.
`mastia.
`In postmarketing experience,
`jaundice and
`2. Chronic Stable Angina
`hepatic enzymeelevations (mostly consistent with cholesta-
`Pediatric Use: Safety and effectiveness of NORVASC in
`NORVASCis indicated for the treatment of chronic stable
`sis) in some cases severe enough to require hospitalization
`children have not been established.
`angina. NORVASC maybe used alone or in combination
`have beenreported in association with use of amlodipine.
`*Based on patient weight of50 kg.
`with other antianginal agents.
`NORVASChasbeen usedsafely in patients with chronic ob-
`ADVERSE REACTIONS
`3. Vasospastic Angina (Prinzmetal’s or Variant Angina)
`structive pulmonary disease, well-compensated congestive
`NORVASCis indicatedfor the treatment of confirmed or
`heart failure, peripheral vascular disease, diabetes melli-
`tus, and abnormallipid profiles.
`suspected vasospastic angina. NORVASC maybe used as
`monotherapy or in combination with other. antianginal
`OVERDOSAGE
`drugs.
`Single oral doses of 40 mg/kg and 100 mg/kg in mice and
`CONTRAINDICATIONS
`rats, respectively, caused deaths. A single oral dose of 4
`mg/kg or higher in dogs caused a marked peripheral vaso-
`dilation and hypotension.
`Overdosage might be expected to cause excessive peripheral
`vasodilation with marked hypotension andpossibly a reflex
`tachycardia. In humans, experience with intentional oyer-
`dosage of NORVASCis limited. Reports of intentional over-
`
`i
`
`NORVASChas been evaluated for safety in more than
`11,000 patients in U.S. andforeign clinical trials. In gen-
`eral, treatment with NORVASCwaswell-tolerated at doses
`up to 10 mg daily. Most adverse reactions reported during
`therapy with NORVASCwereof mild or moderate severity.
`In controlled clinical trials directly comparing NORVASC
`NORVASCis contraindicated in patients with knownsensi-
`(