`
`PHYSICIANS
`See
`RsrareNe=
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1012, 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 PHARMA LTD (IPR2020-01263) Ex. 1012, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1012, p. 002
`
`

`

`NOVARTIS PHARMACEUTICALS/2015
`PRODUCT INFORMATION
`
`BR
`
`[di-o-van]
`valsartan
`Capsules
`Rx only
`The following prescribing information is. based onofficial
`labeling in effect July 1999.
`Prescribing Information
`
`ly recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged
` DIOVAN®
`
`Valsartan is a white to practically white fine powder.
`It is soluble in ethanol and methanol andslightly soluble
`in water.
`:
`Diovanis available as capsules for oral administration, con-
`taining either 80 mg or 160 mgofvalsartan. The inactive
`ingredients of the capsules are cellulose compounds,
`crospovidone, gelatin, iron oxides, magnesium stearate,
`povidone, sodium lauryl sulfate, and titanium dioxide.
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Angiotensin II is formed from aena I in a reaction
`catalyzed by angiotensin-converting enzyme (ACE,kininase
`Il). Angiotensin II is the principal pressor agent of the
`renin-angiotensin system, with effects that include vasocon-
`striction, stimulation of synthesis and release of aldos-
`terone, cardiac stimulation, and renal reabsorption of so-
`dium.Valsartan blocks the vasoconstrictor and aldosterone-
`secreting effects of angiotensinII byselectively blocking the
`binding of angiotensin II to the AT, receptor in manytis-
`sues, such as vascular smooth muscle and the adrenal
`gland. Its action is therefore independentof the pathways
`for angiotensin II synthesis.
`There is also an AT, receptor found in many tissues, but
`AT, is not known to be associated with cardiovascular
`homeostasis. Valsartan has much greater affinity (about
`20,000-fold) for the AT, receptor than for the AT, receptor.
`The primary metabolite of valsartan is essentially inactive
`with an affinity for the AT, receptor about one 200th that
`of valsartanitself.
`Blockadeof the renin-angiotensin system with ACE inhibi-
`tors, which inhibit the biosynthesis of angiotensin II from
`angiotensin I, is widely used in the treatment of hyperten-
`sion. ACE inhibitors also inhibit the degradation of brady-
`kinin, a reaction also catalyzed by ACE. Because valsartan
`does not inhibit ACE (kininase I), it does not affect the
`responseto bradykinin. Whetherthis difference hasclinical
`relevance is not yet known. Valsartan does not bind to or
`block other hormonereceptors or ion channels known to be
`important in cardiovascular regulation.
`Blockadeofthe angiotensin II receptor inhibits the negative
`regulatory feedback of angiotensin II on renin secretion, but
`the resulting increased plasma renin activity and angio-
`tensin II circulating levels do not overcomethe effect of
`valsartan on blood pressure.
`Pharmacokinetics
`Valsartan peak plasma concentration is reached 2 to
`4 hours after dosing. Valsartan shows bi-exponential decay
`kinetics following intravenous administration, with an
`average eliminationhalf-life of about 6 hours. Absolute bio-
`availability for the capsule formulation is about 25% (range
`10%-35%). Food decreases the exposure (as measured by
`AUC)to valsartan by about 40% and peak plasma concen-
`tration (C,,,,) by about 50%. AUC and C,,,, values of val-
`sartan increase approximatelylinearly with increasing dose
`over theclinical dosing range. Valsartan does not accumu-
`late appreciably in plasma following repeated administra-
`tion.
`Metabolism and Elimination
`——* when administered as an oral solution, is pri-
`BIOCON PHARMA LTD (IPR202020.b263)2EXated<Qeb2supeOOiorrevisions
`
`drug, with only about 20% of dose recovered as metabolites.
`The primary metabolite, accounting for about 9% of dose, is
`valeryl 4-hydroxy valsartan. The enzyme(s) responsible for
`valsartan metabolism have not been identified but do not
`seem to be CYP 450 isozymes.
`Following intravenous administration, plasma clearance of
`valsartan is about 2 L/h andits renal clearance is 0.62 L/h
`(about 30% oftotal clearance).
`Distribution
`The steady state volume of distribution of valsartan after
`intravenous administration is small (17 L), indicating that
`valsartan does not distribute into tissues extensively.
`Valsartan is highly bound to serum proteins (95%), mainly
`serum albumin.
`Special Populations
`Pediatric: The pharmacokinetics of valsartan have not
`been investigated in patients <18 years of age.
`Geriatric: Exposure (measured by AUC)to valsartan is
`higher by 70% and the half-life is longer by 35% in the
`elderly than in the young. No dosage adjustment is neces-
`sary (see DOSAGE AND ADMINISTRATION).
`Gender: Pharmacokinetics of valsartan does notdiffer sig-
`nificantly between males and females.
`Renal Insufficiency: There is no apparent correlation
`between renal function (measured by creatinine clearance)
`and exposure (measured by AUC)to valsartan in patients
`with different degrees of renal impairment. Consequently,
`dose adjustment is not required in patients with mild-to-
`moderate renal dysfunction. No studies have been per-
`formedin patients with severe impairmentof renal function
`(creatinine clearance <10 mL/min). Valsartan is not
`removed from the plasma by hemodialysis. In the case of
`severe renal disease, exercise care with dosing of valsartan
`(see DOSAGE AND ADMINISTRATION).
`Hepatic Insufficiency: On average, patients with mild-to-
`moderate chronic liver disease have twice the exposure
`(measured by AUC values) to valsartan of healthy volun-
`teers (matched by age, sex and weight). In general, no dos-
`age adjustmentis needed in patients with mild-to-moderate
`liver disease. Care should be exercised in patients with liver
`disease (see DOSAGE AND ADMINISTRATION).
`PharmacodynamicsandClinical Effects
`Valsartan inhibits the pressor effect of angiotensin II infu-
`sions. An oral dose of 80 mg inhibits the pressor effect by
`about 80% at peak with approximately 30% inhibition per-
`sisting for 24 hours. No information on the effect of larger
`dosesis available.
`Removal of the negative feedback of angiotensin II causes
`a 2- to 3-fold rise in plasma renin and consequentrise in
`angiotensin II plasma concentration in hypertensive
`patients. Minimal decreases in plasma aldosterone were
`observed after administration of valsartan; very little effect
`on serum potassium wasobserved.
`In multiple-dose studies in hypertensive patients with sta-
`ble renal insufficiency and patients with renovascular
`hypertension, valsartan hadnoclinically significant effects
`on glomerular filtration rate,filtration fraction, creatinine
`clearance, or renal plasmaflow.
`Jn multiple-dose studies in hypertensivepatients, valsartan
`had no notable effects on total cholesterol, fasting triglycer-
`ides, fasting serum glucose, or uric acid.
`The antihypertensive effects of Diovan were demonstrated
`principally in 7 placebo-controlled, 4- to 12-week trials (one
`in patients over 65) of dosages from 10 to 320 mg/day in
`patients with baseline diastolic blood pressures of 95-115.
`The studies allowed comparison of once-daily and twice-
`daily regimens of 160 mg/day; comparison of peak and
`trough effects; comparison (in pooled data) of response by
`gender, age, and race; andevaluation of incremental effects
`of hydrochlorothiazide.
`Administration of valsartan to patients with essential
`hypertension results in a significant. reduction ofsitting,
`supine, and standing systolic and diastolic blood pressure,
`usually with little or no orthostatic change.
`In most patients, after administration of a single oral dose,
`onset of antihypertensive activity occurs at approximately
`2 hours, and maximum reduction of blood pressure is
`achieved within 6 hours. The antihypertensive effect per-
`sists for 24 hours after dosing, but there is a decrease from
`peak effect at lower doses (40 mg). presumably reflecting loss
`of inhibition of angiotensin II. At higher doses, however
`(160 mg), thereis little difference in peak andtrougheffect.
`During repeated dosing, the reduction in blood pressure
`with any dose is substantially present within 2 weeks, and
`maximal reduction is generally attained after 4 weeks.
`In long-term follow-up studies (without placebo control),
`the effect of valsartan appeared to be maintained for up to
`two years. The antihypertensive effect is independent of
`age, gender or race. The latter finding regarding race is
`based on pooled data and should be viewed with caution,
`because antihypertensive drugs that affect the renin-angio-
`tensin system (that is, ACE inhibitors and angiotensin-II
`blockers) have generally been found to be less effective in
`low-renin hypertensives. (frequently blacks) than in high-
`renin hypertensives (frequently whites). In pooled, random-
`ized, controlled trials of Diovan that included a total
`of 140 blacks and 830 whites, valsartan and an ACE-inhib-
`itor control were generally at least as effective in blacks as
`whites. The explanation for this difference from previous
`findings is unclear.
`
`Continued on next page
`
`USE IN PREGNANCY
`When used in pregnancy during the second and
`third trimesters, drugs that act directly on the renin-
`angiotensin system can cause injury and even death
`to the developing fetus. When pregnancyis detected,
`Diovan should be discontinued as soon as possible. See
`
`WARNINGS:Fetal/Neonatal Morbidity and Mortality.
`
`DESCRIPTION
`Diovan (valsartan) is a nonpeptide, orally active, and spe-
`cific angiotensin II antagonist acting on the AT, receptor
`subtype.
`Valsartan is chemically described as N-(1-oxopentyl)-N-{[2’-
`(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine. Its
`empirical formula is C,HjgN;O3, its molecular weight is
`435.5, and its structural formula is
`
`
`
`it with D.H.E. 45® (dihydroergotamine mesylate) Injection,
`USP unless at least 6 hours have elapsed since your last
`injection. No more
`than 6 mL of D.H.E.
`45®
`(dihydroergotamine mesylate) Injection, USP should be
`injected during a one-weekperiod.
`Learn what to do in case of an Overdose
`If you have used more medication than you have been
`instructed, contact your doctor, hospital emergency
`department, or nearest poison control center immediately.
`How to use the D.H.E. 45® (dihydroergotamine mesylate)
`Injection, USP
`1. Use available training materials.
`¢ Read andfollow the instructions in the patient instruc-
`tion booklet which is provided with the D.H.E. 45®
`(dihydroergotamine mesylate) Injection, USP package
`before attempting to use the product.
`¢ If there are any questions concerning the use of your
`D.H.E. 45® (dihydroergotamine mesylate) Injection,
`USP, ask your Doctor or pharmacist.
`2. Preparing for the Injection
`* Carefully examine the ampul(glass vial) of D.H.E. 45®
`(dihydroergotamine mesylate) Injection, USP for any
`cracks or breaks, and the liquid for discoloration, cloud-
`iness,or particles. If any of these defects are present,
`use a new ampul, makecertain it is intact, and return
`the defective ampul to your doctor or pharmacy. Once
`you open an ampul,if it is not used within an hour, it
`should be thrown away.
`8. Locating an Injection Site
`e Administer your subcutaneous Injection in the middle
`of your thigh, well above the knee.
`4. Drawing the Medication into the Syringe
`¢ Wash your hands thoroughly with soap and water.
`© Check the dose of your medication.
`© Look to see ifthere is any liquid at the top of the ampul.
`If there is, gently flick the ampul with your finger to get
`all the liquid into the bottom portion of the ampul.
`¢ Hold the bottom of the ampul in one hand. Clean the
`ampul neck with an alcohol wipe using your other
`hand. Then place the alcohol wipe around the neck of
`the ampul and break it open by pressing your thumb
`against the neck of the ampul.
`° Tilt the ampul down at a 45° angle. Insert the needle
`into the solution in the ampul.
`¢ Draw up the medication by pulling back the plunger
`slowly and steadily until you reach your dose.
`© Check the syringefor air bubbles. Holdit with the nee-
`dle pointing upward. If there are air bubbles, tap your
`finger against the barrel of the syringe to get the
`bubbles to the top. Slowly and carefully push the
`plungerup sothat the bubbles are pushed out through
`the needle and you see a drop of medication.
`¢ When there are no air bubbles, check the dose of the
`medication. If the dose is incorrect, repeat steps 6
`through 8 until you draw upthe right dose.
`5. Preparing the Injection Site
`¢ With a new alcohol wipe, clean the selected injection
`site thoroughly with a firm, circular motion from inside
`to outside. Wait for the injection site to dry before
`injecting.
`6. Administering the Injection
`© Hold the syringe/needle in your right hand.
`© With yourleft hand, firmly grasp about a 1-inch fold of
`skin at the injection site.
`¢ Push the needle shaft, bevel side up, all the way into
`the fold of skin at a 45° to 90° angle, then release the
`fold of skin.
`© While holding the syringe with your left hand, use your
`right hand to draw back slightly on the plunger.
`¢ If you do not see any blood coming back into the sy-
`ringe, inject the medication by pushing down on the
`plunger. If you doseeblood in the syringe, that means
`the needle has penetrated a vein. If this happens, pull
`the needle/syringe out of the skin slightly and draw
`back on the plunger again.If no bloodis seen this time,
`inject the medication.
`¢ Use yourright hand to pull the needle out of your skin
`quickly at the same angle youinjected it. Immediately
`press the alcohol wipe on the injection site and rub.
`Checkthe expiration date printed on the ampul containing
`medication.If the expiration date has passed, do‘notuseit.
`Answersto patients’ questions about D.H.E. 45®@ (dihydro-
`ergotamine mesylate) Injection, USP
`Whatif | need help in using my D.H.E. 45® (dihydroergot-
`amine mesylate} Injection, USP?
`If you have any questions or if you need help in opening,
`putting together, or using D.H.E. 45® (dihydroergotamine
`mesylate) Injection, USP, speak to your doctor or phar-
`macist.
`How much medication should | use and how often?
`Your doctor will have told you what dose to use for each
`migraine attack. Should you get another migraine attack
`in the same day as the attack you treated, you must not
`treat it with D.H.E. 45® (dihydroergotamine mesylate)
`Injection, USP unless at least 6 hours have-elapsed since
`your last injection. No more than 6 mL of D.H.E. 45®
`(dihydroergotamine mesylate) Injection, USP should be
`injected during a one-week period. Do not use more than
`this amount unless instructed to do so by your doctor.
`If you have any other unanswered question about D.H.E.
`45®@ (dihydroergotamine mesylate) Injection, USP, consult
`your doctor or pharmacist.
`*Trademark of Medical pp Company, Inc.
`REV: MAY 1998
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1012, p. 003
`
`

`

`2016/NOVARTIS PHARMACEUTICALS
`PHYSICIANS’ DESK REFERENCE®
`seSe
`Diovan—Cont.
`
` Hypotension in Volume- and /or Salt-Depleted Patients
`
` or safety of valsartan was observedin this patient popula-
`
`Excessive reduction of blood pressure was rarely seen
`tion, but greater sensitivity of someolder individuals cannot
`be ruled out.
`:
`(0.1%) in patients with uncomplicated hypertension. In
`Abrupt withdrawal of valsartan has not been associated
`patients with an activated renin-angiotensin system, such
`with a rapid increase in blood pressure.
`ADVERSE REACTIONS
`as volume- and/or salt-depleted patients receiving high
`The blood pressure lowering effect of valsartan and
`Diovan has been evaluated for safety in more than
`doses of diuretics, symptomatic hypotension may occur.
`thiazide-type diuretics are approximately additive.
`4000 patients,
`including over 400 treated for over
`This condition should be corrected prior to administration
`The 7 studies of valsartan monotherapy included over
`of Diovan,or the treatment shouldstart under close medical
`6 months, and more than 160 for over 1 year. Adverse expe-
`2000 patients randomized to variousdoses of valsartan and
`supervision.
`riences have generally been mild andtransient in nature
`about 800 patients randomized to placebo. Doses below
`and hayeonly infrequently required discontinuation ofther-
`If hypotension occurs, the patient should be placed in the
`80 mg werenot consistently distinguished from those of pla-
`apy. The overall incidence of adverse experiences. with
`supine position and, if necessary, given an intravenous
`cebo at trough, but doses of 80, 160 and 320 mg produced
`Diovan wassimilar to placebo.
`infusion of normalsaline. A transient hypotensive response
`dose-related decreases in systolic and diastolic blood pres-
`The overall frequency of adverse experiences was neither
`is not a contraindication to further treatment, which usu-
`sure, with the difference from placebo of approximately
`dose-related nor related to gender, age, race, or regimen.
`ally can be continued withoutdifficulty once the blood pres-
`6-9/3-5 mmHgat 80-160 mg and 9/6 mmHgat 320 mg.
`sure has stabilized.
`Discontinuation of therapy dueto side effects was required
`In a controlled trial the addition of HCTZ to valsartan
`in 2.3% of valsartan patients and 2.0% of placebo patients.
`PRECAUTIONS
`80 mg resulted in additional lowering of systolic and dia-
`The most common reasons for discontinuation of therapy
`General
`stolic blood pressure by approximately 6/3 and 12/5 mmHg
`with Diovan were headache anddizziness.
`:
`for 12.5 and 25 mg of HCTZ, respectively, compared to
`Impaired Hepatic Function: As the majority of valsartan
`The adverse experiences that occurred in placebo-controlled
`valsartan 80 mgalone.
`is eliminated in the bile, patients with mild-to-moderate
`clinical trials in at least 1% of patients treated with Diovan
`Patients with an inadequate response to 80 mg once daily
`hepatic impairment,includingpatients with biliary obstruc-
`and at a higher incidence in valsartan (n=2316) than pla-
`weretitrated to either 160 mg once daily or 80 mg twice
`tive disorders, showed lower valsartan clearance (higher
`cebo (n=888) patients included viral infection (3% vs. 2%),
`daily, which resulted in a comparable response in both
`groups.
`AUCs). Care shouldbe exercised in administering Diovan to
`fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%).
`these patients.
`Headache, dizziness, upper respiratory infection, cough,
`In controlled trials, the antihypertensive effect of once-daily
`Impaired Renal Function: As a consequence of inhibiting
`diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema,
`valsartan 80 mg wassimilar to that of once-daily enalapril
`and arthralgia occurred at a more than 1% rate but at about
`the renin-angiotensin-aldosterone system, changes in renal
`20 mgor once-daily lisinopril 10 mg.
`function may be anticipated in susceptible individuals. In
`the sameincidence in placebo and valsartan patients.
`There wasessentially no change in heart rate in valsartan-
`treated patients in controlledtrials.
`In trials in which valsartan was compared to an ACE inhib-
`patients whoserenal function may depend on the activity of
`the renin-angiotensin-aldosterone system (e.g., patients
`itor with or without placebo, the incidence of dry cough was
`INDICATIONS AND USAGE
`with severe congestive heart failure), treatment with angio-
`significantly greater in the ACE-inhibitor group (7.9%) than
`Diovan is indicated for the treatment of hypertension. It
`tensin-converting enzyme inhibitors and angiotensin recep-
`in the groups who received valsartan (2.6%) or placebo
`tor antagonists has been associated with oliguria and/or
`(1.5%). In a 129-patient trial limited to patients who. had
`maybeused aloneor in combination with other antihyper-
`tensive agents.
`progressive azotemia and (rarely) with acute renalfailure
`had dry cough when they had previously received ACE
`CONTRAINDICATIONS
`and/or death. Diovan would be expected to behave similarly.
`inhibitors, the incidences of cough in patients whoreceived
`In studies of ACE inhibitors in patients with unilateral or
`valsartan, HCTZ,orlisinopril were 20%, 19%, and 69%
`Diovanis contraindicated in patients who are hypersensi-
`respectively (p<0.001).
`bilateral renal artery stenosis, increases in serum creati-
`tive to any componentof this product.
`Dose-related orthostatic effects were seen in less than 1% of
`nine or blood urea nitrogen have been reported. In a 4-day
`WARNINGS
`patients. An increase in the incidence of dizziness was
`trial of valsartan in 12 patients with unilateral renal artery
`Fetal/Neonatal Morbidity and Mortality
`stenosis, no significant increases in serum creatinine or
`observedin patients treated with Diovan 320 mg (8%) com-
`Drugs that act directly on the renin-angiotensin system can
`pared to 10 to 160 mg (2% to 4%).
`blood urea nitrogen were observed. There has been no long-
`cause fetal and neonatal morbidity and death when admin-
`term use of Diovan in patients with unilateral or bilateral
`Diovan has been used concomitantly with hydrochloro-
`istered to pregnant women. Several dozen cases have been
`renalartery stenosis, but an effect similar to that seen with
`thiazide without evidenceofclinically important. adverse
`interactions.
`reported in the world literature in patients who were taking
`ACEinhibitors should be anticipated.
`Information for Patients
`angiotensin-converting enzymeinhibitors. When pregnancy
`Other adverse experiences that occurred in controlled
`is detected, Diovan should be discontinued as soon as
`clinical trials of patients treated with Diovan (>0.2% of
`Pregnancy: Fernale patients of childbearing age should be
`possible.
`valsartan patients) are listed below. It cannot be deter-
`told about the.consequencesof second- and third-trimester
`The use of drugs that act directly on the renin-angiotensin
`mined whether these events were causally related to
`exposure to drugs that act on the renin-angiotensin system,
`Diovan.
`system during the second andthird trimesters of pregnancy
`and they should also be told that these consequences do not
`has been associated with fetal and neonatal
`injury,
`Body as a Whole: Allergic reaction and asthenia
`appear to have resulted from intrauterine drug exposure
`including hypotension, neonatal skull hypoplasia, anuria,
`Cardiovascular: Palpitations
`that has been limited-to-the first trimester. These patients
`Dermatologic: Pruritus and rash
`reversible or irreversible renal failure, and death. Oligo-
`should be asked to report pregnanciesto their physicians as
`soon as possible.
`hydramnioshasalso been reported, presumably resulting
`Digestive: Constipation, dry mouth, dyspepsia, and
`flatulence
`Drug Interactions
`from decreasedfetal renal function; oligohydramniosin this
`setting has been associated with fetal limb contractures,
`Musculoskeletal: Back pain, muscle cramps, and myalgia
`Noclinically significant pharmacokinetic interactions were
`craniofacial deformation, and hypoplastic lung develop-
`Neurologic and Psychiatric: Anxiety, insomnia, paresthe-
`observed when valsartan was coadministered with amlo-
`sia, and somnolence
`ment. Prematurity, intrauterine growth retardation, and
`dipine, atenolol, cimetidine, digoxin, furosemide, glyburide,
`patent ductus arteriosus have also been reported, although
`Respiratory: Dyspnea
`hydrochlorothiazide, or
`indomethacin. The valsartan.
`it is not clear whether these occurrences were due to expo-
`Special Senses: Vertigo
`atenolol combination was more antihypertensive than
`sure to the drug.
`Urogenital:
`Impotence
`either component, but it did not lower the heart rate more
`These adverse effects do not appear to have resulted from
`than atenolol alone.
`Other reported events seen less frequently in clinical trials
`intrauterine drug exposure that has been limited to thefirst
`included chest pain, syncope, anorexia, vomiting, and
`Coadministration of valsartan and warfarin did not change
`angioedema.
`;
`trimester. Mothers whose embryos andfetuses are exposed ©
`the pharmacokinetics of valsartan or the time-courseof the
`to an angiotensin II receptor antagonist only during the
`Post-Marketing Experience
`anticoagulantproperties of warfarin.
`first trimester should be so informed. Nonetheless, when
`The following additional adverse reactions have been re-
`CYP 450 Interactions: The enzyme(s) responsible for
`patients become pregnant, physicians should advise the
`ported in post-marketing experience:
`<
`valsartan metabolism have not been identified but do not
`patient to discontinue the use of valsartan as soon as
`Hypersensitivity: There are rare reports of angioedema;
`possible.
`seem to be CYP 450 isozymes. The inhibitory or induction
`Digestive: Elevated liver enzymes and very rare reports of
`potential of valsartan on CYP 450 is also unknown.
`hepatitis.
`Rarely (probably less often than once in every thousand
`Carcinogenesis, Mutagenesis, Impairmentof Fertility
`pregnancies), no alternative to a drug acting on the renin-
`Clinical Laboratory Test Findings
`angiotensin system will be found. In these rare cases, the
`There was no evidence of carcinogenicity when valsartan
`In controlledclinicaltrials, clinically important changes in
`mothers shouldbe apprised of the potential hazardsto their
`was administered in the diet to mice and rats for up to
`standard laboratory parameters were rarely associated with
`administration of Diovan.
`fetuses, and serial ultrasound examinations should be per-
`2 years at doses up to 160 and 200 mg/kg/day, respectively.
`formedto assess the intra-amniotic environment.
`These doses in mice and rats are about 2.6 and 6 times,
`Creatinine: Minorelevations in creatinine occurred in
`respectively,
`the maximum recommended human dose
`If oligohydramniosis observed, valsartan should be discon-
`0.8% of patients taking Diovan and 0.6% given placebo in
`controlled clinical trials.
`on a mg/m”basis. (Calculations assume an oral dose of
`tinued unless it is considered life-saving for the mother.
`320 mg/day and a 60-kgpatient.)
`Contraction stress testing (CST), a nonstress test (NST), or
`Hemoglobin and Hematocrit: Greater than 20% decreases
`biophysical profiling (BPP) maybe appropriate, depending
`Mutagenicity assays did not reveal any valsartan-related
`in hemoglobin and hematocrit were observed in 0.4% and
`upon the weekof pregnancy. Patients and physicians should
`effects at either the gene or chromosomelevel. These assays
`0.8%, respectively, of Diovan patients, compared with 0.1%
`be aware, however, that oligohydramnios may not appear
`included bacterial mutagenicity tests with Salmonella
`and 0.1% in placebo-treated patients. One valsartan patient
`until after the fetus has sustainedirreversible injury.
`(Ames) and E coli; a gene mutation test with Chinese ham-
`discontinued treatmentfor microcytic anemia.
`Infants with historiesof in utero exposure to an angiotensin
`ster V79 cells; a cytogenetic test with Chinese hamster
`Liver function tests: Occasional elevations (greater than
`ovary cells; and a rat micronucleustest.
`II receptor antagonist should be closely observed for hypo-
`150%) of liver chemistries occurred in Diovan-treated
`tension, oliguria, and hyperkalemia. If oliguria occurs,
`Valsartan had no adverseeffects on the reproductive perfor-
`patients. Three patients (<0.1%) treated with valsartan dis-
`attention should be directed toward support of blood pres-
`continued treatment for elevated liver chemistries.
`mance ofmaleor female rats at oral doses up to 200 mg/kg/
`sure andrenal perfusion. Exchange transfusion or dialysis
`day. This dose is 6 times the maximum recommended
`Neutropenia: Neutropenia was observed in 1.9% of
`may be required as meansof reversing hypotension and/or
`human dose on a. mg/m? basis. (Calculations assume an
`patients treated with Diovan and 0.8% of patients treated
`substituting for disordered renal function.
`with placebo.
`oral dose of 320 mg/day and a 60-kg patient.)
`No teratogenic effects were observed when valsartan was
`Serum Potassium: Greater than 20% increases in serum
`PregnancyCategoriesC(first trimester) and D (second and
`third trimesters)
`administered to pregnant mice andrats at oral doses up to
`potassium were observed in 4.4% of Diovan-treated patients
`600 mg/kg/day and to pregnantrabbits at oral doses up to
`compared to 2.9% of placebo-treated patients. No patient
`See WARNINGS,Fetal/Neonatal Morbidity and Mortality.
`10 mg/kg/day. However, significant decreases in fetal
`Nursing Mothers
`treated with valsartan discontinued therapy for hyper-
`kalemia.
`weight, pup birth weight, pup survival rate, and slight
`It is not known whethervalsartan is excreted in human
`delays in developmental milestones were observed in stud-
`OVERDOSAGE
`milk, but valsartan was excreted in the milk of lactating
`ies in which parental rats were treated with valsartan at
`rats. Because of the potential for adverse effects on the
`Limited data are available related to overdosage in humans.
`oral, maternally toxic (reduction in body weight gain and
`nursing infant, a decision should be made whether to dis-
`The most likely manifestations of overdosage would be
`food consumption) doses’ of 600 mg/kg/day during organo-
`genesis or late gestation and lactation. In rabbits, fetotoxic-
`continue nursing or discontinue the drug, taking into
`hypotension and tachycardia, bradycardia could occur
`account the importance of the drug to the mother.
`Mwy G.e., resorptions, litter loss, abortions, and low body
`trom parasympathetic (vagal) stimulation, If symptomatic
`Pediatric Use
`weight) associated with maternal toxicity (mortality) was
`hypotension should occur, supportive treatment should be
`instituted,
`observed at doses of 5 and 10 mg/kg/day. The no observed
`Safety andeffectiveness