`
`PHYSIOANS’
`
`#
`# DESK
`_
`PEEEEENCE‘
`
`_
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1012, p. 001
`
`

`

`
` 5g;
`5.3
`
`
`
`
`
`
`
`
`
`
`PHVSICIANS’
`DESK
`PEEEPENCE
`
`
`
`
`
`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 0- Keary
`Jeffrey F- Pth'
`Suzanne 5- Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales: Bill Gaffney
`Director °f 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
`Manager of 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. Cahiil
`Digital Imaging Coordinator: Frank J. McElroy,
`III
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`
`
`fl Copyright © 2000 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of the content of this 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
`othenivise) without the prior written permissibn of the publisher. PHYSICIANS' DESK REFERENCE®, PDR‘”, PDFt For Ophthalmology? Pocket PDR®, and The PDFt® Family
`Guide to Prescription Drugs® are registered trademarks used herein under license. PDR For Nonprescription Drugs and Dietary Supplements”, PDR Companion Guidem,
`PDFi® for Herbal MedicinesTM, PDFt°37 Medical DictionaryTM, PDFt® Nurse’s Drug HandbookTM, PDR® Nurse's DictionaryTM, The PDR® Family Guide Encyclopedia of Medical
`CareTM, The PDR® Family Guide to Natural Medicines and Healing TherapiesTM, The PDR® Family Guide to Common Ailmentsm, The PDR® Family Guide to Over-the-
`Counter DrugsTM, and PDR® Electronic LibraryTM are trademarks used herein under license.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDeII; 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 (3. Hope: Vice President, Business Integration: David A. Pitler,‘ Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: John R. Ware: Senior Vice President. Internet Strategies: Raymond Zoeller
`® 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 PHARMACE UTICALS/201 5
`PRODUCT INFORMATION
`
`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.
`Learn what to do in case of an Overdose
`If you have used more medication than you have been
`instructed, contact your d‘octOr, hospital emergency
`department, or nearest poison control center immediately.
`How to use the D.H.E. 458 (dihydroergotamine mesylatel
`Injection, USP
`1. Use available training materials.
`' Read and follow 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
`0 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, make certain 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.
`3. Locating an Injection Site
`0 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.
`0 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.
`O Tilt the ampul down at a 45° angle. Insert the needle
`into the solution in the ampul.
`0 Draw up the medication by pulling back the plunger
`slowly and steadily until you reach your dose.
`0 Check the syringe for air bubbles. Hold it 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
`plunger up so that the bubbles are pushed out through
`the needle and you see a drop of medication.
`0 When there are no air bubbles, check the dose of the
`CLINICAL PHARMACOLOGY
`medication. If the dose is incorrect, repeat steps 6
`Mechanism of Action
`,
`through 8 until you draw up the right dose.
`Angiotensin II is formed from angiotensin I in a reaction
`5. Preparing the Injection Site
`catalyzed by angiotensin-converting enzyme (ACE, kininase
`' With a new alcohol wipe, clean the selected injection
`II). Angiotensin II is the principal pressor agent of the
`site thoroughly with a firm, circular motion from inside
`renin-angiotensin system, with effects that include vasocon-
`to outside. Wait for the injection site to dry before
`striction, stimulation of synthesis and release of aldos-
`injecting.
`terone, cardiac stimulation, and renal reabsorption of so-
`6. Administering the Injection
`dium. Valsartan blocks the vasoconstrictor and aldosterone-
`0 Hold the syringe/needle in your right hand.
`secreting effects of angiotensin II by selectively blocking the
`O With your left hand, firmly grasp about a Linch fold of
`binding of angiotensin II to the AT1 receptor in many tis-
`skin at the injection site.
`sues, such as vascular smooth muscle and the adrenal
`' Push the needle shaft, bevel side up, all the way into
`gland. Its action is therefore independent of the pathways
`the fold of skin at a 45° to 90° angle, then release the
`fold of skin.
`for angiotensin II synthesis.
`There is also an AT2 receptor found in many tissues, but
`- While holding the syringe with your lefi hand, use your
`AT2 is not known to be associated with cardiovascular
`right hand to draw back slightly on the plunger.
`homeostasis. Valsartan has much greater alfinity (about
`0 If you do not see any blood coming back into the sy-
`20,000Afold) for the AT1 receptor than for the AT2 receptor.
`ringe, inject the medication by pushing down on the
`The primary metabolite of valsartan is essentially inactive
`plunger. If you do see blood in the syringe, that means
`with an aflinity for the AT1 receptor about one 200th that
`the needle has penetrated a vein. If this happens, pull
`of valsartan itself.
`the needle/syringe out of the skin slightly and draw
`Blockade of the renin-angiotensin system with ACE inhibi»
`back on the plunger again. If no blood is seen this time,
`tors, which inhibit the biosynthesis of angiotensin II from
`inject the medication.
`angiotensin I, is widely used in the treatment of hyperten-
`0 Use your right hand to pull the needle out of your skin
`sion. ACE inhibitors also inhibit the degradation of brady-
`quickly at the same angle you injected it. Immediately
`kinin, a reaction also catalyzed by ACE. Because valsartan
`press the alcohol wipe on the injection site and rub.
`does not inhibit ACE (kininase II), it does not afl'ect the
`Check the expiration date printed on the ampul containing
`response to bradykinin. Whether this difference has clinical
`medication. If the expiration date has passed, don’t use it.
`relevance is not yet known. Valsartan does not bind to or
`Answers to patients’ questions about D.H.E. 45® Idihydro-
`block other hormone receptors or ion channels known to be
`ergotamine mesylate) lniection, USP
`important in cardiovascular regulation.
`What if I need help in using my D.H.E. 456’ (dihydroergot-
`Blockade of the angiotensin II receptor inhibits the negative
`amine mesylate) Injection, USP?
`regulatory feedback of angiotensin II on renin secretion, but
`If you have any questions or if you need help in opening,
`the resulting increased plasma renin activity and angio-
`putting together, or using D.H.E. 45® (dihydroergotamine
`tensin II circulating levels do not overcome the efiect of
`mesylate) Injection, USP, speak to your doctor or phar-
`valsartan on blood pressure.
`macist.
`Pharmacokinetics
`How much medication should I use and how often?
`Valsartan peak plasma concentration is reached 2 to
`Your doctor will have told you what dose to use for each
`4 hours after dosing. Valsartan shows bi-exponential decay
`migraine attack. Should you get another migraine attack
`kinetics following intravenous administration, with an
`in the same day as the attack you treated, you must not
`average elimination half-life of about 6 hours. Absolute bio-
`treat it with D.H.E. 45® (dihydroergotamine mesylate)
`availability for the capsule formulation is about 25% (range
`Injection, USP unless at least 6 hours have‘elapsed since
`10%—35%). Food decreases the exposure (as measured by
`your last injection. No more than 6 mL of D.H.E. 45®
`AUC) to valsartan by about 40% and peak plasma concen-
`(dihydroergotamine mesylate) Injection, USP should be
`tration (Cum) by about 50%. AUC and Cmax values of val-
`injected during a one-week period. Do not use more than
`sartan increase approximately linearly with increasing dose
`this amount unless instructed to do so by your doctor.
`over the clinical dosing range. Valsartan does not accumu-
`If you have any other” unanswered question about D.H.E.
`late appreciably in plasma following repeated administra—
`tion.
`45® (dihydroergotamine mesylate) Injection, USP, consult
`your doctor or pharmacist.
`Metabolism and Elimination
`”Drademark ofMedical Economics Company, ham
`Valsartan, when administered as an oral solution, is pri-
`REV: MAY 1998
`marily recovered in feces (about 83% of dose) and urine
`BIOCON PHARMA LTD (IPMOZWWHfiWum
`
`(about 13% of dose). The recovery is mainly as unchanged
`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 and its renal clearance is 0.62 L/h
`(about 30% of total 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 not differ 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-
`formed'in patients with severe impairment of 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 Insufi‘iciency: 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 adjustment is needed in patients with mild-to—moderate
`liver disease. Care should be exercised in patients with liver
`disease (see DOSAGE AND ADMINISTRATION).
`Pharmacodynamics and Clinical Effects
`Valsartan inhibits the pressor efl'ect 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
`doses is available.
`Removal of the negative feedback of angiotensin II causes
`a 2— to 3-fold rise in plasma renin and consequent rise in
`angiotensin II plasma concentration in hypertensive
`patients. Minimal decreases in plasma aldosterone were
`observed after administration of valsartan; very little eifect
`on serum potassium was observed.
`In multiple-dose studies in hypertensive patients with sta-
`ble renal insufliciency and patients with renovascular
`hypertension, valsartan had no clinically significant elfects
`on glomerular filtration rate, filtration fraction, creatinine
`clearance, or renal plasma flow.
`In multiplevdose studies in hypertensive patients, valsartan
`had no notable effects on total cholesterol, fasting triglycer-
`ides, fasting serum glucose, or uric acid.
`The antihypertensive efl'ects 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; and evaluation of incremental effects
`of hydrochlorothiazide.
`Administration of valsartan to patients with essential
`hypertension results in a significant reduction of sitting,
`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), there is little difference in peak and trough elfect.
`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 afi'ect 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
`
`R
`
`DIOVAN®
`[di-o-vanl
`valsartan
`Capsules
`Rx only
`The following prescribing information is based on official
`labeling in efiect July 1999.
`Prescribing Information
`
`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 pregnancy is 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 AT1 receptor
`subtype.
`Valsartan is chemically described as N-(l-oxopentyl)—N—[[2’»
`(1H~tetrazol-5-yl)[1,1'-biphenyl]-4—yl]methyl]-L-valine. Its
`empirical formula is CZ4H29N503, its molecular weight is
`435.5, and its structural formula is
`
`
`
`Valsartan is a white to practically white fine powder.
`It is soluble in ethanol and methanol and slightly soluble
`in water.
`'
`Diovan is available as capsules for oral administration, con-
`taining either 80 mg or 160 mg of valsartan. The inactive
`ingredients of the capsules are cellulose compounds,
`crospovidone, gelatin, iron oxides, magnesium stearate,
`povidone, sodium lauryl sulfate, and titanium dioxide.
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1012, p. 003
`
`

`

`2016/NOVARTIS PHARMACEUTICALS
`PHYSICIANS' DESK REFERENCE®
`RE
`Diovan—Cont.
`Hypotension in Volume- and /or Salt-Depleted Patients
`Excessive reduction of blood pressure was rarely seen
`(0.1%) in patients with uncomplicated hypertension. In
`patients with an activated renin-angiotensin system, such
`as volume- and/or salt-depleted patients receiving high
`doses of diuretics, symptomatic hypotension may occur.
`This condition should be corrected prior to administration
`of Diovan, or the treatment should start under close medical
`supervision.
`If hypotension occurs, the patient should be placed in the
`supine position and, if necessary, given an intravenous
`infusion of normal saline. A transient hypotensive response
`is not a contraindication to further treatment, which usu-
`ally can be continued without difliculty once the blood pres-
`sure has stabilized.
`PRECAUTIONS
`General
`Impaired Hepatic Function: As the majority of Valsartan
`is eliminated in the bile, patients with mild-to-moderate
`hepatic impairment, including patients with biliary obstruc—
`tive disorders, showed lower valsartan clearance (higher
`AUCs). Care should be exercised in administering Diovan to
`these patients.
`Impaired Renal Function: As a consequence of inhibiting
`the renin-angiotensin-aldosterone system, changes in renal
`function may be anticipated in susceptible individuals. In
`patients whose renal function may depend on the activity of
`the renin-angiotensin-aldosterone system (e.g., patients
`with severe congestive heart failure), treatment with angio-
`tensin-converting enzyme inhibitors and angiotensin recep-
`tor antagonists has been associated with oliguria and/or
`progressive azotemia and (rarely) with acute renal failure
`and/or death. Diovan would be expected to behave similarly.
`In studies of ACE inhibitors in patients with unilateral or
`bilateral renal artery stenosis, increases in serum creati-
`nine or blood urea nitrogen have been reported. In a 4—day
`trial of valsartan in 12 patients with unilateral renal artery
`stenosis, no significant increases in serum creatinine or
`blood urea nitrogen were observed. There has been no long-
`term use of Diovan in patients with unilateral or bilateral
`renal artery stenosis, but an effect similar to that seen with
`ACE inhibitors should be anticipated.
`Information for Patients
`Pregnancy: Female patients of childbearing age should be
`told about theconsequences of second- and third-trimester
`exposure to drugs that act on the renin-angiotensin system,
`and they should also be told that these consequences do not
`appear to have resulted from intrauterine drug exposure
`that has been limited to the first trimester. These patients
`should be asked to report pregnancies to their physicians as
`soon as possible.
`Drug Interactions
`No clinically significant pharmacokinetic interactions were
`observed when valsartan was coadministered with amlo-
`dipine, atenolol, cimetidine, digoxin, furosemide, glyburide,
`hydrochlorothiazide, or
`indomethacin. The valsartan-
`atenolol combination was more antihypertensive than
`either component, but it did not lower the heart rate more
`than atenolol alone.
`
`or safety of valsartan was observed in this patient popula-
`tion, but greater sensitivity of some older individuals cannot
`be ruled out.
`'
`ADVERSE REACTIONS
`Diovan has been evaluated for safety in more than
`4000 patients,
`including over 400 treated for over
`6 months, and more than 160 for over 1 year. Adverse expe-
`riences have generally been mild and transient in nature
`and have only infrequently required discontinuation of ther-
`apy. The overall incidence of adverse experiences with
`Diovan was similar to placebo.
`The overall frequency of adverse experiences was neither
`dose-related nor related to gender, age, race, or regimen.
`Discontinuation of therapy due to side effects was required
`in 2.3% of valsartan patients and 2.0% of placebo patients.
`The most common reasons for discontinuation of therapy
`with Diovan were headache and dizziness.
`_
`The adverse experiences that occurred in placebo-controlled
`clinical trials in at least 1% of patients treated with Diovan
`and at a higher incidence in valsartan (n=2316) than pla-
`cebo (n=888)’ patients included viral infection (3% vs. 2%),
`fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%).
`Headache, dizziness, upper respiratory infection, cough,
`diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema,
`and arthralgia occurred at a more than 1% rate but at about
`the same incidence in placebo and valsartan patients.
`In trials in which valsartan was compared to an ACE inhib-
`itor with or without placebo, the incidence of dry cough was
`significantly greater in the ACE-inhibitor group (7.9%) than
`in the groups who received valsartan (2.6%) or placebo
`(1.5%). In a 129-patient trial limited to patients whohad
`had dry cough when they had previously received ACE
`inhibitors, the incidences of cough in patients who received
`valsartan, HCTZ, or lisinopril were 20%, 19%, and 69%
`respectively (p<0.001).
`Dose-related orthostatic effects were seen in less than 1% of
`patients. An increase in the incidence of dizziness was
`observed in patients treated with Diovan 320 mg (8%) com-
`pared to 10 to 160 mg (2% to 4%).
`Diovan has been used concomitantly with hydrochloro-
`thiazide without evidence of clinically important adverse
`interactions.
`Other adverse experiences that occurred in controlled
`clinical trials of patients treated with Diovan (>0.2% of
`valsartan patients) are listed below. It cannot be deter-
`mined whether these events were causally related to
`Diovan.
`Body as a Whole: Allergic reaction and asthenia
`Cardiovascular: Palpitations
`Dermatologic: Pruritus and rash
`Digestive: Constipation, dry mouth, dyspepsia, and
`flatulence
`
`
`
`Musculoskeletal: Back pain, muscle cramps, and myalgia
`Neurologic and Psychiatric: Anxiety, insomnia, paresthe-
`sia, and somnolence
`Respiratory: Dyspnea
`Special Senses: Vertigo
`Urogenital:
`Impotence
`Other reported events seen less frequently in clinical trials
`included chest pain, syncope, anorexia, vomiting, and
`angioedema.
`‘
`Post-Marketing Experience
`The following additional adverse reactions have been re-
`ported in post-marketing experience:
`,
`Hypersensitivity: There are rare reports of angioedema;
`Digestive: Elevated liver enzymes and very rare reports of
`hepatitis.
`Clinical Laboratory Test Findings
`In controlled clinical trials, clinically important changes in
`standard laboratory parameters were rarely associated with
`administration of Diovan.
`Creatinine: Minor elevations in creatinine occurred in
`0.8% of patients taking Diovan and 0.6% given placebo in
`controlled clinical trials.
`Hemoglobin and Hematocrit: Greater than 20% decreases
`in hemoglobin and hematocrit were observed in 0.4% and
`0.8%, respectively, of Diovan patients, compared with 0.1%
`and 0.1% in placebo-treated patients, One valsartan patient
`discontinued treatment for microcytic anemia.
`Liver function tests: Occasional elevations (greater than
`150%) of liver chemistries occurred in Diovan-treated
`patients. Three patients (<0.1%) treated with valsartan dis-
`continued treatment for elevated liver chemistries.
`Neutropenia: Neutropenia was observed in 1.9% of
`patients treated with Diovan and 0.8% of patients treated
`with placebo.
`Serum Potassium: Greater than 20% increases in serum
`potassium were observed in 4.4% of Diovan-treated patients
`compared to 2.9% of placebo-treated patients. No patient
`treated with valsartan discontinued therapy for hyper-
`kalemia.
`OVERDOSAGE
`
`Limited data are available related to overdosage in humans.
`The most likely manifestations of overdosage would be
`hypotension and tachycardia; bradycardia could occur
`from parasympathetic (vagal) stimulation. If symptomatic
`hypotension should occur, supportive treatment should be
`instituted.
`
`Valsartan is not removed from the plasma by hemodialysis.
`Valsartan was without grossly observable adverse effects
`at single oral doses up to 2000 mg/kg in rats and up to
`1000 mg/kg in marmosets, except for salivation and diarv
`rhea in the rat and vomiting in the marmoset at the highest
`1d§5e6(§0)arlr%)3(7 tirlneé,fiecfive1662anumprewm-
`
`Abrupt withdrawal of valsartan has not been associated
`with a rapid increase in blood pressure.
`The blood pressure lowering effect of valsartan and
`thiazide-type diuretics are approximately additive.
`The 7 studies of valsartan monotherapy included over
`2000 patients randomized to various doses of valsartan and
`about 800 patients randomized to placebo. Doses below
`80 mg were not consistently distinguished from those of pla-
`cebo at trough, but doses of 80, 160 and 320 mg produced
`dose-related decreases in systolic and diastolic blood pres-
`sure, with the difl'erence from placebo of approximately
`6—9/3—5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg.
`In a controlled trial the addition of HCTZ to valsartan
`80 mg resulted in additional lowering of systolic and dia-
`stolic blood pressure by approximately 6/3 and 12/5 mmHg
`for 12.5 and 25 mg of HCTZ, respectively, compared to
`valsartan 80 mg alone.
`Patients with an inadequate response to 80 mg once daily
`were titrated to either 160 mg once daily or 80 mg twice
`daily, which resulted in a comparable response in both
`groups.
`In controlled trials, the antihypertensive efi'ect of once-daily
`valsartan 80 mg was similar to that of once-daily enalapril
`20 mg or once-daily lisinopril 10 mg.
`There was essentially no change in heart rate in valsartan—
`treated patients in controlled trials.
`INDICATIONS AND USAGE
`Diovan is indicated for the treatment of hypertension. It
`may be used alone or in combination with other antihyper-
`tensive agents.
`CONTRAINDICATIONS
`Diovan is contraindicated in patients who are hypersensi-
`tive to any component of this product.
`WARNINGS
`Fetal/Neonatal Morbidity and Mortality
`Drugs that act directly on the renin-angiotensin system can
`cause fetal and neonatal morbidity and death when admin-
`istered to pregnant women. Several dozen cases have been
`reported in the world literature in patients who were taking
`angiotensin-converting enzyme inhibitors. When pregnancy
`is detected, Diovan should be discontinued as soon as
`possible.
`The use of drugs that act directly on the renin-angiotensin
`system during the second and third trimesters of pregnancy
`has been associated with fetal and neonatal
`injury,
`including hypotension, neonatal skull hypoplasia, anuria,
`reversible or irreversible renal failure, and death. Oligo-
`hydramnios has also been reported, presumably resulting
`from decreased fetal renal function; oligohydramnios in this
`setting has been associated with fetal limb contractures,
`craniofacial deformation, and hypoplastic lung develop—
`ment. Prematurity, intrauterine growth retardation, and
`patent ductus arteriosus have also been reported, although
`it is not clear whether these occurrences were due to expo-
`sure to the drug.
`These adverse effects do not appear to have resulted from
`intrauterine drug exposure that has been limited to the first
`trimester. Mothers whose embryos and fetuses are exposed ‘
`to an angiotensin II receptor antagonist only during the
`first trimester should be so informed. Nonetheless, when
`patients become pregnant, physicians should advise the
`patient to discontinue the use of valsartan as soon as
`possible.
`Rarely (probably less often than once in every thousand
`pregnancies), no alternative to a drug acting on the renin-
`angiotensin system will be found. In these rare cases, the
`mothers should be apprised of the potential hazards to their
`fetuses, and serial ultrasound examinations should be per-
`formed to assess the intra-amniotic environment.
`If oligohydramnios is observed, valsartan should be discon-
`tinued unless it is considered life-saving for the mother.
`Contraction stress testing (CST), a nonstress test (NST), or
`biophysical profiling (BPP) may be appropriate, depending
`upon the week of pregnancy. Patients and physicians should
`be aware, however, that oligohydramnios may not appear
`until after the fetus has sustained irreversible injury.
`Infants with histories of in utero exposure to an angiotensin
`II receptor antagonist should be closely observed for hypo-
`tension, oliguria, and hyperkalemia. If oliguria occurs,
`attention should be directed toward support of blood pres-
`sure and renal perfusion. Exchange transfusion or dialysis
`may be required as means of reversing hypotension and/or
`substituting for disordered renal function.
`No teratogenic effects were observed when valsartan was
`administered to pregnant mice and rats at oral doses up to
`600 mg/kg/day and to pregnant rabbits at oral doses up to
`10 mg/kgiday. However, significant decreases in fetal
`weight, pup birth weight, pup survival rate, and slight
`delays in developmental milestones were observed in stud-
`ies in which parental rats were treated with valsartan at
`oral, maternally toxic (reduction in body weight gain and
`food consumption) doses of 600 mglkg/day during organo—
`genesis or late gestation and lactation. in rabbits, femtoinc-
`ity (3.2., tesotptions, litter \oss, abortions, and low bod
`weight) associated with maternal toxicity (mortality) was
`observed at doses of 5 and 10 mg/kg/day. The no observed
`adverse efl'ect doses of 600, 200 and 2 mg/kg/day in mice,
`rats and rabbits represent 9, 6, and 0.1 times, respectively,
`the maximum recommended human dose on a mg/m2 basis.
`(Calculations assume an oral dose of 320 mg/day and a
`GO-kg patient).
`
`
`
`Coadministration of valsartan and warfarin did not change
`the pharmacokinetics of valsartan or the time-course of the
`anticoagulant properties of warfarin.
`CYP 450 Interactions: The enzyme(s) responsible for
`valsartan metabolism have not been identified but do not
`seem to be CYP 450 isozymes. The inhibitory or induction
`potential of valsartan on CYP 450 is also unknown.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`There was no evidence of carcinogenicity when valsartan
`was administered in the diet to mice and rats for up to
`2 years at doses up to 160 and 200 mg/kg/day, respectively.
`These doses in mice and rats are about 2.6 and 6 times,
`respectively,
`the maximum recommended human dose
`on a mg/m2 basis. (Calculations assume an oral dose of
`320 mg/day and a 60-kg patient.)
`Mutagenicity assays did not reveal any valsartan-related
`effects at either the gene or chromosome level. These assays
`included bacterial mutagenicity tests with Salmonella
`(Ames ) and E coli; a gene mutation test with Chinese ham-
`ster V79 cells; a cytogenetic test with Chinese hamster
`ovary cells; and a rat micronucleus test.
`Valsartan