1 of 8 Celltrion, Inc., Exhibit 1012

PDR® ~ tiH 1995

PHYS CANS' DESK

REFERENCE Medical Consultant Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School

President and Chief Operating Officer, Drug Information Services Group: William J. Gale

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Director of Corporate Communications: Gregory J. Thomas

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Digital Prepress Processing: Joanne Mccloskey, Richard Weinstock

Editor, Special Projects: David w. Sitton

!!!II!! Copyright© 1995 and published by Medical Economics Data Production Company 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 otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDR For Nonprescription Drugs®, PDR For Ophthalmology® and The PDR® Family Guide to Prescription Drugs® are trademarks of Medical Economics Data Production Company, registered In the United States Patent and Trademark Office. PDR Guide to Drug lnteractions•Side Effects•lndications™, The PDR® Family Guide to Women's Health and Prescription Drugs™, PDR® Library on CD-ROM™, PDR® Drug Interactions/Side Effects/ Indicat ions Diskettes™, and Pocket PDR™ are trade­marks of Medical Economics Data Production Company.

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@Printed on recycled paper ISBN: 1-56363-087 7

2 of 8 Celltrion, Inc., Exhibit 1012

FOREWORD

Welcome to the 49th edition of PHYSICIANS' DESK REFERENCE, America's first and only compendium of official, FDA-approved prescription drug labeling. For authoritative information on current indications and prescribing guidelines, there is no better source .

This year's edition of PDR provides the latest available information on nearly 3,000 specific pharmaceutical products, including 150 completely new listings. Through PDR's three convenient indices you can locate prescribing information on nearly every therapeutic enti­ty in general use today.

PHYSICIANS' DESK REFERENCE is published annually by Medical Economics in cooperation with participating manufacturers. PDR is the cornerstone in a library of drug references that includes:

• PDR Guide to Drug lnteractions•Side Effects• Indications rM

• PDR For Nonprescription Drugs®

• PDR For Ophthalmology®

• PDR® Medical Dictionary™

• PDR Supplements

Data from these printed references is also available in a variety of electronic formats:

• Pocket PDR™ - A handheld personal database of key sections from the prescription-drug listings in PDR ..

• PDR Library on CD-ROM™ - Complete prescrib­ing information from all PDR volumes - with the full contents of The Merck Manual and Stedman's Medical Dictionary as optional enhancements - all on one convenient CD-ROM for use on PC networks and individual PCs.

• PDR Drug Interactions/Side Effects/Indications

Diskettes™ - A powerful screening program for patient regimens of up to 20 drugs.

• PDR Tape Services - A preformatted text file suitable for integration in large mainframe-based information systems.

For more information on any of these products, please

call, toll-free, 1-800-232-7379 or fax 201-573-4956.

Under the federal Food, Drug & Cosmetics (FD&C) Act,

a drug approved for marketing may be labeled, promot­

ed, and advertised by the manufacturer for only those

uses for which the drug's safety and effectiveness have been established. The Code of Federal Regulations 201.100(d)(1) pertaining to labeling for prescription products requires that for PDR content "indications, effects, dosages, routes, methods, and frequency and duration of administration and any rele­vant warnings, hazards, contraindications, side effects, and precautions" must be in the "same language and

emphasis" as the approved labeling for the products. FDA regards the words same language and emphasis

as requiring VERBATIM use of the approved labeling providing such information. Furthermore, information that is emphasized in the approved labeling by the use of type set in a box, or in capitals , boldface, or italics, must be given the same emphasis in PDR.

The FDA has also recognized that the FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may choose to pre­scribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. The FDA has also observed that accepted medical prac­tice includes drug use that is not reflected in approved drug labeling. For products that do not have official package circulars, the publisher has emphasized the necessity of describing such products comprehensively,

so that physicians can have access to all information essential for intelligent and informed decision making.

The function of the publisher is the compilation, organi­

zation, and distribution of this information. Each prod­uct description has been prepared by the manufacturer,

and edited and approved by the manufacturer's medical department, medical director, and/or medical_ consul­

tant. In organizing and presenting the material in PHYSI­

CIANS' DESK REFERENCE, the publisher does not war­

rant or guarantee any of the products described, or per­

form any independent analysis in connection with any of the product information contained herein. PHYSICIANS'

DESK REFERENCE does not assume, and expressly dis­

claims, any obligation to obtain and include any infor­

mation other than that provided to it by the manufactur­

er. It should be understood that by making this materi­

al available the publisher is not advocating the use of

any product described herein, nor is the publisher

responsible for misuse of a product due to typographi­

cal error. Additional information on any product may be

obtained from the manufacturer.

3 of 8 Celltrion, Inc., Exhibit 1012

CONTENTS

Manufacturers' Index (White Pages)

Section 1 Lists all pharmaceutical manufacturers participating in PHYSICIANS' DESK REFERENCE.

Includes addresses, phone numbers, and emergency contacts. Shows each manufacturer's

products and the page number of those described in PDR.

Brand and Generic Name Index (Pink Pages)

Section 2 Gives the page number of each product by brand and generic name.

Product Category Index (Blue Pages)

Section 3 Lists all fully described products by prescribing category. An overview of the headings

appears on pages 201 and 202.

Product Identification Guide (Gray Pages)

Section 4 Presents full-color, actual-size photos of tablets and capsules, plus pictures of a variety of other

dosage forms and packages. Arranged alphabetically by manufacturer.

Product Information (White Pages)

Section 5

1

101

201

301

401

The main section of the book. Provides prescribing information on nearly 3,000 pharmaceuticals. Entries are arranged

alphabetically by manufacturer.

Diagnostic Product Information (Green Pages) 2769

Section 6 Gives usage guidelines for a variety of common diagnostic agents. Arranged alphabetically by manufacturer.

Certified Poison Control Centers ............................................................................................................ 2789

A directory to facilities accredited by the American Association of Poison Control Centers.

Arranged alphabetically by state.

Discontinued Products ........................................................................................................................... 2793

An alphabetical list of products withdrawn from the market during the past year.

U.S. Food and Drug Administration Telephone Directory ................... ....................................................... 2795

Gives numbers of key reporting programs and information services

Key to Controlled Substances Categories ............................................................................................... 2797

Gives the definition of each category and the prescribing limitations that apply.

Key to FDA Use-in-Pregnancy Ratings .................................................................................................... 2797

Provides the exact interpretation of each risk/benefit rating.

Adverse Event Report Forms .................................................................................................................. 2799

Contains master copies and instructions for completion.

4 of 8 Celltrion, Inc., Exhibit 1012

682/PHYSICIANS' DESK REFERENCE®

Bristol-Myers Squibb-Cont. 5. Clinical Oncological Society of Australia . Guidelines and

Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426428.

6. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; (Sept/Oct) 258-263.

7. American Society of Hospital Pharmacists Technical As­sistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.

8. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antfneoplastic) Drugs. Am J Hosp Pharm 1986; 43:1193-1204.

January 1994 3351DIM-03

TAXOL® [taks 10 l J (paclitaxell for Injection Concentrate

WARNING TAXOL® (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate manage­ment of complications is possible only when adequate diagnostic and treatment facilities are readily available. · ' Severe hypersensitivity reactions characterized by dys­pnea and hypotension requiring treatment, angioe­dema, and generalized urticaria have occurred in 2% of patients receiving TAXOL. One of these reactions was fatal in a patient treated without premedication in a Phase 1 study. Patients receiving TAXOL should lie pretreated with corticosteroids, diphenhydramine, and H2 antagonists to prevent these reactions. (See "DOS­AGE AND ADMINISTRATION" section.) Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug. TAXOL therapy should not be given to patients with baseline neutrophil counts of less than 1.500 cells/mm3. In order to monitor the occurrence of bone marrow SUP" pression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving T AXOL.

DESCRIPTION T AXOL (paclitaxel) for Injection Concentrate is a clear col­orless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. TAXOL is available in 30mg15 mLl single-dose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of Cremophor® EL• (polyoxyethylated castor oill and 49.7% lv/v) dehydrated alcohol, USP. Paclitaxel is a natural product with antitumor activity. The chemical name for paclitaxel is 5/3, 20-Epoxy-1,2a,4,7/3, 10/3, 13a-hexahydroxytax-ll-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following structural formula:

0

HCA '

~A $ -OHOO 0 CH, 0 y ~ ~ 0

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51N014 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216--217' C.

CLINICAL PHARMACOLOGY Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabil­izes microtubules by preventing depolymerization. This sta­bility results in the inhibition of the normal dynamic reorga­nization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, pa­clitaxel induces abnormal arrays or nbundles" of mi­crotubules throughout the cell cycle and multiple asters of microtubules during mitosis.

'Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.

Summary of Non-Compartment Pharmacoklnetic Parameters Mean (% Coefficient of Variation) Values by, Single-Dose and Infusion

Dose Infusion N Cm ax AUC !0-oo) T-HALF (mg/m2) · Duration (h) (patients) (ng/ml) (ng-h/ml) (h)

135 24 2 195 6300 52.7 175 24 4 365 (33) 7993 (29) 15.7 (56)

21.7 23.8 (35) 17.7 (20) 12.2 (25)

135 3 7 2170 (21) 7952 (23) 13.1145) 175 3 5 3650 (30) 15007 (27) 20.2 (85)

Cm8 x- Maximum plasma concentration AUC (0-oo) • Area under the plasma concentration-time curve from time 0 to infinity CLr- Total body clearance

Key Efficacy Parameters in the Phase 3 Ovarian Carcinoma Study

175/3 (n=96) • Response

rate (percent) 14.6 95% Confidence Interval (8.5-23.6)

• Time to Progression median (months) 4.4 95% Confidence Interval (3.0-5.6) • Survival median (months) 11.5 95% Confidence Interval (8.4-14.4)

Following intravenous administration ofTAXOL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table: [See first table above.] It appeared that with the 24-hour infusion ofTAXOL, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87% whereas the AUC (0-oo) remained propor­tional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC (0-oo) were increased by 68% and 89%, respectively. The mean apparent volume of distribu­tion at steady state, with the 24-hour infusion of TAXOL ranged from 227 to 688 L/m2, indicating extensive extravas­cular distribution and/or tissue binding of paclitaxel. The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions ln=54) in Phase 1 & 2 studies.Values for total body clearance and volume of distribution were consistent with the findings in the Phase 3 study. In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydra­mine did not affect protein binding of paclitaxel.

1 The disposition of paclitaxel has not been fully elucidated in humans. After intravenous administration ofl5-275 mg/m2 doses ofTAXOL as 1, 6, or 24-hour infusions, mean (SD) val­ues for cumulative urinary recovery of unchanged drug ranged from 1.3% (0.5%) to 12.6% (16.2%) of the dose, indi­cating extensive non-renal clearance. TAXOL has been dem­onstrated to be metabolized in the liver in animals and there is evidence suggesting hepatic metabolism in humans. High paclitaxel concentrations have been reported in the bile of patients treated with T AXOL. The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated. Possible interactions of paclitaxel with concomitantly ad­ministered medications have not been formally investigated. CLINICAL STUDIES: Ovarian Carcinoma: Data from five Phase 1 and 2 clinical studies (189 patients), a multicenter, randomized Phase 3 study (407 patients I, as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use ofTAXOL in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies 192 patients) utilized an initial doi;e of 135 to 170 mg/ m2 in most patients ( > 90%1 administered ~"er 24 hours by continuous infusion. Response rates in these t.wo studies were 22% (95% Cl= 11-37%) and 30% (95% Cl = 16--46%) with a total of six complete and 18 partial responses iIHl2 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2

------175/24 135/3 135/24 (n=106) (n=99) (n=108)

21.7 15.2 13.2 (14.5-31.0) (9.0-24.U (7.7-21.5)

4.2 3.4 2.8 (3.5-5.1) (2.8-4.2) 11.9-4.0)

11.8 13.1 10.7 (8.9-14.6) (9.1-14.6) (8.1-13.6)

months (range: 3.5 -15.8 months) and 7.5 months (range: 5.3 - 17.4 months), respectively. The median survival was 8.1 months (range: 0.2 - 36. 7 months) and 15.9 months (range! 1.8 - 34.5+ months). The Phase 3 study had a bifactorial design and compared the efficacy and· safety ofTAXOL, administered at two different doses (135 or 175 mg/m2) and schedules (3- or 24-hour infu­sion). The overall response rate for the 407 patients was 16.2% (95% Cl = 12.8--20.2%), with 6 complete and 60 par­tial responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2-21.6 months). Median time to progression was 3. 7 months (range: 0.1 +-25.1 +months). Median survival was 11.5 months (range: 0.2 - 26.3+ months). Response rates, median survival and median time to progres­sion for the 4 arms are given in the following table. The arms are listed by doses and schedule (mg.m2/hours). Comparisons between study arms should be done with caution in view of the bifactorial study design and small sample sizes per arm. [See second table above.} Analyses were performed as planned by the study protocol, by comparing the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules irre­spective of dose. Patients receiving the 175 mg/m2 dose achieved a higher response rate than those receiving the 135 mg/m2 dose: 18% vs. 14% (p=0.28). No difference in response rate was de­tected when comparing the 3-hour with the 24-hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose of TAXOL (paclitaxel) for Injection Concentrate had a longer time to progression than those receiving the 135 mg/ m2 dose: median 4.2 v's. 3.1 months (p=0.03). Time to pro­gression was longer for patients receiving the 3-hour vs. the 24-hour infusion: 4.0 months vs. 3.7 months (p=0.08). No difference in survival according to dose or schedule was ob­served. T AXOL remained active in patients who had developed re­sistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapsed within 6 months from completion of, platinum containing regimens) with response rates of 14% in the Phase 3 study and 31 % in the Phase 1 & 2 clinical studies. The adverse event profile in the Phase 3 study was consistent with that seen for a pooled analysis performed on 812 pa· tients treated in ten clinical studies (see, "ADVERSE REAC­TIONS" section). For the 403 patients who received TAXOL in the Phase 3 study, the following table shows the incidence of some key adverse events by treatment arm. The arms are listed by dose and schedule (mg/m2/hours). [See first table on top of next page.] Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions <HSRs) was rare; 1 % of the patients and 0.2% of the courses overall. There was no ap­parent dose or schedule effect seen for the HSRs. Addition· ally, peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence. The results of the randomized stu? support the use of TAXOL at doses of 135 or 175 mg/m , administered by a 3-hour infusion. The same doses administered by 24-hour infu· sion were more toxic; the bifactorial study design and small sample size per arm preclude definitive conclusions regard· ing relative efficacy between the 4 arms of the study. Breast Carcinoma: Data from 83 patients accrued in three p~ 2 open label studies and from 471 patients enrolled in

Information will be superseded by supplements and subsequent editions

5 of 8 Celltrion, Inc., Exhibit 1012

base 3 randomized study were available to support the use 8 f f/J{OL in patients with metastatic breast carcinoma. phJJS" 2 open label studies: Two studies were conducted in 53

tients previously treated with a maximum of one prior

P~emotherapeutic regimen. TAXOL was administered in

~ese 2 trials as a 24-hour infusion at initial doses of 250 mg/

• 2 (with G.CSF support) or 200 mg/ m2. The response rates

"'ere 57% (95% Cl: 37-75%) and 52% (95% Cl: 32-72%), re­"'pectively. The third phase 2 study evaluated quality of life 8 Jiallges and was conducted in extensively pretreated pa­tients who had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of metastatic disease. The dose ofTAXOL was 200 mg/mz as a 24-hour infusion with G.CSF support. Nine of the 30 patients analyzed achieved a partial response, for a re­sponse rate of 30% (95% Cl: 15-50%). p/iaSe 3 randomized study: This multicenter trial was con­ducted in patients previously treated with one or two regi­mens of chemotherapy. Patients were randomized to re­'ceived TAXOL at a dose of either 175 mg/m2 or 135 mg/m2

given as a 3-hour infusion. In the 471 patients enrolled, 60% bad symptomatic disease with impaired performance status al study entry, and 73% had visceral metastases. These pa­tients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31 %). Sixty-seven percent of the patients had been previously ex­posed to anthracyclines and 23% of them had disease consid­ered resistant to this class of agents. Tbe overall response rate for the 454 evaluable patients was 26% (95% Cl: 22-30%), with 17 complete and 99 partial re­sponses. The median duration of response, measured from the flJ!lt day of treatment, was 8.1 months (range: 3.4-18.1 + months). Overall for the 471 patients, the me­dian time to progression was 3.5 months (range: 0.03-17.l months). Median survival was 11.7 months (range: 0-18.9

months). Response rates, median survival and median time to progres­sion for the 2 arms are given in the following table. The arms are listed by dose and schedule (mgem2/hours). [See second table at right.] For the 458 patients who received TAXOL (paclitaxoll for Injection Concentrate in the Phase 3 study, the following table shows the incidence of some key adverse events by treatment arm (each arm was administered by a 3-hour infu­sion). [See third table at right.] Myelosuppresaion and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.

INDICATIONS TAXOL is indicated, after failure of first-line or subsequent chemotherapy for the treatment of metastatic carcinoma of the ovary. TAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unlesa clini­cally contraindicated.

CONTRAINDICATIONS T AXOL is contraindicated in patients who have a history of hypersensitivity reactions to TAXOL or other drugs formu­lated in Cremophor@ EL (polyoxyethylated castor oil). TAXOL should not be used in patients with baseline neutropenia of < 1,500 cells/mm3.

WARNINGS Patients should be pretreated with corticosteroids (such as dexamethasone), diphenhydramine and H2 antagonists (such as cimetidine or ranitidine) before receiving T AXOL. (See "DOSAGE AND ADMINISTRATION" section.) Severe hypersensitivity reactions characterized by dyspnea and

~ypotension requiring treatment, angioedema, and general­ized urticaria have occurred in 2% of patients receiving TAXOL. These reactions are probably histamine-mediated. One of these reactions was fatal in a patient with pulmonary

metastases who was a participant in a Phase I trial. This patient received no premedication; the first course of TAXOL, which was uneventful, was administered at 190 mg/m2 infused over three hours. Within a few minutes from the beginning of a second course of TAXOL, the patient de­

veloped severe hypotension and died. Patients who experi­

ence severe hypersensitivity reactions to TAXOL should not

be rechallenged with the drug. Bone marrow suppresaion (primarily neutropenia) is dose­

dependent and is the dose-limiting toxicity. Neutrophil na­

dirs occurred at a median of 11 days. TAXOL should not be

administered in patients with baseline neutrophil counts of

less than 1,500 cells/mm3. Frequent monitoring of blood

counts should be instituted during TAXOL treatment. Pa­

tients should not be re-treated with subsequent cycles of

TAXOL until neutrophils recover to a level > 1,500 celiB/

mm3 and platelets recover to a level > 100,000 cells/mm3.

Severe conduction abnormalities have been documented in

< 1 % of patients during TAXOL therapy and in some C!'Be8

PRcoucT INF=oRMATION/683

Frequency of Key Adverse Events in the Phase 3 Ovarian Carcinorna study ~~~~~~~~

175/3 Percent of patients

175/24 135/3 135/24 (11 = 95) (n= 105) (n=9Bl (n=105l

• Bone Marrow - Neutropenia <2,000/mm2 78 98 78 98

<500/mm2 'l:I 67 75 14

- Thrombocytopenia < 100,000/ mm2 4 18 8 6 < 50,000/mm2 1 7 2 1

- Anemia < 11 g/dL 84 -90 68 88 <8 g/ dL 11 12 6 10

- Infections 26 29 20 18

• Hypersensitivity Reaction•

- All 41 45 38 45

- Severe 2 0 2 1

• Peripheral Neuropathy - Any symptoms 63 60 55 42

- Severe symptoms 1 2 0 0

• Mucosltis Any symptoms 17 35 21 25

- Severe symptoms 0 3 0 2 . All patumf.s received premedication

Key Efficacy Parameters in the Phase 3 Breast Carcinoma Study

• Response -rate (percent) -95% Confidence Interval

• Time to Progression -median (months) -95% Confidence Interval

• Survival -median (months) -95% Confidence Interval

175/3 (n=235)

28 (22-34)

4.2 (3.2-4.6)

11.7 (10.0-13.8)

135/3 . tn=23&1

22 !17-'l:/)

3.0 (2.5-3.8)

10.5 (9.0-12.8)

Fre~uency of Key Adverse Events in the Phase 3 Breast Carcinoma Study

Percent of Patients 175 mg/rri2 135 mg/m2

(n=229) (n=229)

Bone Marrow -Neutropenia* <2,000/mm3 90 81

<500/mm2 28 19

Thrombocytopenia • < 100,000/mm2 11 7 < 50,000/mm2 3 2

-Anemia' <11 g/dL <8 g/dL

-Infections -Febrile Neutropenia

Hypersensitivity Reaction•• -All -Severe

Peripheral Neuropathy -Any symptoms -Severe symptoms

Mucositis -Any symptoms -Severe symptoms

Bosed on worst course analysis .. All patienf.s received premedication

requiring pacemaker placement. 1f patients develop signifi­cant conduction abnormalities during T AXOL infusion, ap­propriate therapy should be administered and continuous.

cardiac monitoring should be performed during subsequent therapy with TAXOL. TAXOL may cause fetal harm when administered to a preg­nant woman. TAXOL baa been shown to be embryo- and feto­

toxic in rats and rabbits and to decrease fertility in rats. In these studies, TAXOL was shown to result in abortions, de­

creased corpora lutes, a decrease in implantations and live fetuses, and increased resorptions and embryo-fetal deaths. No gross external, sqft tissue or skeletal alterations oc­curred. There are no studies in pregnant women. lfTAXOL

is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of

the potential hazard. Women of childbearing potential

should be advised to avoid becoming pregnant during therapy with TAXOL.

PRECAUTIONS Contact of the undiluted concentrate with plasticized polyvi­

nyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to mini­

mize patient exposure to the plasticizer DEHP [di-{~tbylex­

yllphthalate, which may be leached from PVC infusion bags

or sets, diluted TAXOL solutions should preferably be stored

in bottles (glass, polypropylene) or plastic bags (polypropyl-

55 47 4 2

23 15 2 2

36 31 0 <l

70 46 7 3

23 17 3 <1

ene, polyolefin) and administered through polyethylene­

lined administration sets. TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22 mi­crons. Use of filter devices such as IVEX-2@ filters which

incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP. Drug Interaction: In a Phase I trial 1 using escalating doses of TAXOL (110-200 mg/m2) and cisplatin (50 or 75 mg/m2)

given as sequential infusions, myelosuppresaion was more

profound when TAXOL was given after cisplatin than with

the alternate sequence (i.e., TAXOL before cisplatin). Pbar­

macokinetic data from these patients demonstrated a de-

. crease in paclitaxel clearance of approximately 33% when TAXOL was administered following cisplatin. Based on in vitro data, there is the posaibility of an inhibition ofTAXOL metabolism in patients treated with ketoconazole.

As a result, caution should be exercised when treating pa­

tients with T AXOL when they are receiving ketoconazole as

concomitant therapy. Hematology: T AXOL therapy should not be administered

to patients with baseline neutrophil counts of less than 1,500 cells/mm3• In order to monitor the occurrence ofmyelotoxic­

ity, it is recommended that frequent peripheral blood cell

Continued on next page

Consult 1995 supplements and future editions for revilliona

6 of 8 Celltrion, Inc., Exhibit 1012

684/PHYSICIANS' DESK REFERENCE®

Bris~ol-Myers Squibb-Cont.

. counts be performed-on all patients-receiving TAXOL. Pa­tients should not 'be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level > 1,500 cells/ mm3 and platelets recover to a level > 100,000 cells/mm3. In the case of severe neutropenia ( < 500 cells/mm3 for seven days or morel during a course ofTAXOL therapy, a 20% re­ducti(m in dose for subsequent courses of therapy is recom­mended. · Hypersensitivity Reactions: Patients with a history of se­vere hypersensitivity reactions to products containing Cremophor® EL (e.g.; cyclosporin for injection concentrate· and teniposide for- injection concentrate) should not be treated- with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactiol\ll, all patients treated with TAXOLshould be premedicated withcorticosteroids(such as dexamethasonel, diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension or tachycar­dja do not require interrµption of therapy. However, severe reactions, such as .hypotension requiring treatment, dyspnea ·requiring bronchodilators, angiodema or generalized urtica­ria require immediate discontinuation of TAXOL and ag­gressive syll)ptomatic therapy. Patients who have developed sevlire nypersensitivity'reactions sho,uld not be rechallenged with TAXOL. . Cardiovascular: Hypotension and bradycardia h<1ve been observed .during ad-ministration ofTAXOL, but generally do not require treatment. Frequent vital sign monitoring, par­ticularly during the first hour ofTAXOL fnfusion, is recom­mended. Continuous cardiac monitoring is not required ex­cept for patients with serious conduction abnormalities. <See "WARNINGS" section.) Nervous System: Although, the occurrence of peripheral neuropathy is frequent, the development of severe symptom­atology is unusual and requires a dose reduction of 20% for all subsequent courses of TAXOL. Hepatic: There is no evidence that the toxicity ofTAXOL is enhanced in patients with elevated liver enzymes, but no . data are available for patients with severe baseline cholesta­sis. However, evidence suggests that the. liver·plays an im­portant role in the metabolism of T AXOL. As a result, since there are no data available from patients with severe liver disease, caution should be exercised when administering TAXOL to patients with severe hepatic impairment. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of T AXOL has not been studied. T AXOL has been shown to be mutagenic in vitro (chromo­some aberrations in human lymphocytes) and in vivo (micro­nucleus test in mice) mammalian test systems, however, it did not induce mutagenicity in the Ames test or the CHO/ HGPRT gene mutation assay. TAXOL at an I.V. dose of 1 mg/kg 16 mg/m2) produced low fertility and fetal toxicity in rats. TAXOL has also been shown to be maternal and em­bryo-fetal toxic in rabbits receiving the drug at an LY. dose of 3 mg/kg (33 mg/m2l during organogenesis. !See "WARN­INGS" section.I Pregnancy: Pregnancy "Category D." <See "WARNINGS" section.I Nursing Mothers: It is not known whether the drug is ex­creted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving TAXOL therapy. Pediatric Use: The safety and effectiveness of TAXOL in children have not been established.

ADVERSE REACTIONS Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma! enrolled in 10 studies. Two hundred and seventy-five patients were treated in 8 Phase 2 studies with TAXOL doses ranging from 135 to 300 mg/m2 administered over 24 hours lin 4 of these studies, G-CSF was administered as hematopoletic support!. Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared two doses 1135 or 175 mg/m21 and two schedules 13 or 24 hours) ofTAXOL. Two hundred and thirty· six patients with breast carcinoma received TAXOL (135 or 175 mg/m21 administered over 3 hours in a controlled study. [See table above.] The following data relate to the overall safety database of 812 patients treated in clinical studies. In addition, rare events have been reported from the postmarketing experi­ence or from other clinical studies. The frequency and sever­ity of adverse events are generally similar between patients receiving TAXOL for the treatment of ovarian or breast car­cinoma. The frequency and severity of key adverse events for the Phase 3 ovarian and breast carcinoma studies are pres­ented in tabular form by treatment arm in "CLINICAL PHARMACOLOGY", "Clinical Studies" section. Hematologic: Bone marrow suppression was the major dose-limiting toxicity ofTAXOL. Neutropenia, the most im-

Summary of Adverse Events in 812 Patients Receiving TAXOL

• Bone Marrow -Neutropenia < 2,000/mm3 ·

< 500/mm3 -Leukopenia <4,000/mm3

<l,000/mm3 -Thrombocytopenia < 100,000/mm3

< 50,000/mm3 -Anemia < 11 g/dL

< 8 g/dL -Infections -Bleeding -Red Cell Transfusions -Platelet Transfusions

• Hypersensitivity Reaction• -All -Severe·

• Cardiovascular -Vital Sign Changes" -Bradycardia (N = 537) -Hypotension (N=532) -Significant cardiovascular events

• Abnormal ECG -All Pts -Pts with normal baseline (N -559)

• Peripheral Neuropathy -Any symptoms -Severe symptoms

• Myalgia/ Arthralgia -Any symptoms -Severe symptoms

• Gastrointestinal -Nausea and vomiting -Diarrhea -Mucositis

• Alopecia • Hepatic (Pts with normal baseline and on study data)

-Bilirubin elevations (N =765) -Alkaline phosphatase elevations <N = 575) -AST (SGOTl elevations (N = 591)

• lnjectmn Site Reaction

All patients received premedication •• During the first 3-hours of infU1lion

% Incidenc<! .

90 52 90 17 20 7

78 16 30 ,,. 14 25 2·

41 2 .....

3 12 1

23 14

60 3

60 8

52' 38 31 87

·7 .22 19 13

None of the observed toxicities were clearly influenced by age.

portant hematologic toxicity, was dose and schedule depen­dent and was generally rapidly reversible. Among patients treated in Phase 3 ovarian study with a 3-hour infusion, neu­trophil counts decline below 500 cells/mm3 in 13% of the patients treated with a dose of 135mg/m2 compared to 27% at a dose of 175 mg/m2<p=0.05). In the same study, severe neutropenia ( < 500 cells/mm3) was more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutl'ope­nia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for pa­tients previously treated with radiation therapy. Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all pati~nts and 9% of all courses; these episodes were fatal in 1 % of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 ovarian study, infectious episodes were rerorted in 19% of the patients given either 135 or 175 mg/ m doS'e by a 3 hour infusion. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. Thrombocytopenia was uncommon, and almost never severe ( < 50,000 cells/mm3J. Twenty percent of the patients experi­enced a drop in their platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had a platelet count < 50,000 cells/mm3 at the time of their worst nadir. Among the 812 patients, bleeding episodes were reported in 4% of all courses and by 14% of all patients but most of the hemor­hagic episodes were localized and the frequency of these events was unrelated to .the TAXOL dose and schedule. In the Phase 3 ovarian study, bleeding episodes were reported in 10% of the patients receiving either the 135 or 175 mg/m2 dose given by a 3-hour infusion; no patients treated with the 3-hour infusion received platelet transfusions. Anemia (Hb < 11 g/dLJ was observed in 78% of all patients and was severe <Hb < 8g/ dL) in 16% of the cases. No consis­tent relationship between dose or schedule and the fre­quency of anemia was observed. Among all patients with normal baseline hemoglobin, 69% become anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with nor­mal baseline hemoglobin levels.

Hypersensitivity Reactions (HSRs): All patients received premedication prior to TAXOL !See "WARNINGS" and "PRECAUTIONS, Hypersensitivity Reactions" sections). The frequency and severity of HSRs were not affected by the dose

or schedule of T AXOL administration. In the Phase 3 ovar­ian study the 3-hour infusion was not associated with a greater increase in HSRs when compared to the 24-hour in­fusion. Hypersensitivity reactions were observed in 20% of all courses and in 41 % of all patients. These reactions were severe in less than 2% of the patients and 1 % of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of TAXOL (paclitaxel) for injection Concentrate infusion. The most frequent symptoms observed during these severe reac­tions were dyspnea, flusl\ing, chest pain and tachycardia. The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%) and hypertension (1 %). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.

Cardiovascular: Hypotension, during the first 3-hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3-hours of infusion, occurred in 3% of all patients and 1 % of all courses. In Phase 3 ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycar­dia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discon­tinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy. Significant cardiovascular events possibly related to TAXOL occurred in approximately 1 % of all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the patients with syncope treated with TAXOL at 175 mg/m2 over 24-hours had progressive hypotension and died. The arrhythmias included asymptom­atic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement . . Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnor• ma! tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnor­malities, sinus bradycardia, sinus tachycardia and prema­ture beats. Among patients with normal ECG at baseline, Information will be superseded by supplements and subsequent editions

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i i therapy with anthracyclines did not influence the fre­pr 00cy of ECG abnormalities. 9~101ogic: The frequency and severity of neurologic mani· ~· 19-tions were dose-dependent, but were not influenced by !'tuSion duration. Peripheral neuropathy was observed in ;.y, of all patients (3% severe) and in 52% (2% severe) of the

tients without pre-existing neuropathy. K!e frequency of peripheral neuropathy increased with cu-1ru]ative dose. Neurologic symptoms were observed in 27% ~tj!e patients after the first course of treatment and 34-51 % 0(0!ll course 2 to 10. C r\pheral neuropathy was the cause oT TAXOL discon· fi:uation in 1 % of all patients. Sensory symptoms hav.e usu­ally improved or resolved within several months ofTAXOL d\seontinuation. The incidence of neurologic symptoms did oi increase in the subset of patients previously treated with

~~platin. Pre-existing neuropathies resulting from prior tJierapies are not a contraindication for TAXOL therapy. (Jther than peripheral neuropathy, serious neurologic events following TAXOL administration have been rare 1" 1%) and have included grand ma! seizures, syncope, ataxia and neuroencephalopathy. J!l!re reports of autonomic neuropathy resulting in paralytic 1;eus have been received as part of the continuing surveil­lance of T AXOL safety. Arthralgia/Myalgia: There was no consistent relatipnship between dose or schedule of TAXOL and the frequency or severity of arthralgia/mya\gia. Sixty percent of all patients trJated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after TAXOL administration, and reSolved within a few days. The frequency and severity of uiusculoskeletal symptoms remained unchanged throughout the treatment period .. Hepatic: No relationship was observed between liver func­tion abnormalities and eithet dose or schedule of TAXOL administration. Among patients with normal baseline liver function 7%, 22% and 19% had elevations in billrubin, alka· line phosphatase and AST (SGOT), respectively. Prolong exposure to TAXOL was not associated with cumulative he­patic toxicity. Tuire reports of hepatic necrosis and hepatic encephalopath)' leading to death have.been received as part of the continuing surveillance of TAXOL safety. Gastrointestinal IGI): Nausea/vomiting, diarrhea and mus­cOSitis were reported by 52%, 38% and 31 % of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred inore frequently with the 24-hour than with the 3-hour infu

,. , ~_ion. Rare reports of intestinal obstruction, intestinal perforation ahd ischemic colitis have been received as part of the con· tinuing surveillance of T AXOL safety. Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been ob­served more frequently with 24-hour infusion than with 3-hour infusion. A specific treatment for extravasation reac­tions is unknown at this time. Rare reports of more severe events such as phlebitis and cel­lulitis have been received as part of the continuing surveil­lance of TAXOL safety. Other Clinical Events: Alopecia wali observed in almost all (87%) of the patients. Transient skin changes due to TAXOL related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with TAXOL administration. Nail changes (changes in pigmenta­tion or discoloration of nail bed) were uncommon (2%). Edema was reported in 21 % of all patients (17% of those without baseline edema); only 1 % had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study. Rare reports of skin abnormalities related to radiation recall have been received as part of the continuing surveillance of TAXOL safety.

OVERDOSAGE There is no known antidote for TAXOL overdosage. The pri­mary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

DOSAGE AND ADMINISTRATION Note: Contact of the undiluted concentrate with plasticized PVC.equipment or devices used to prepare solutions for infu­sion is not recommended. In order to minimize patient expo­sure to the plasticizer DEHP[di-(2-ethylhexyi)phthalate], Which may be leached from PVC infusion bags or sets, di­luted TAXOL solutions should be stored in bottles (glass, Polypropylene) or plastic bags (polypropylene, polyolefin) a.nd administered through polyethylene-lined administra­tion sets.

All patients should be premedicated prior to T AXOL admin­istration in order to prevent severe hypersensitivity reac­tions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before TAXOL, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to TAXOL, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before TAXOL. In patients with carcinoma of the ovary, TAXOL has been used at several doses and schedules; however, the optional regimen is not yet clear (see "CLINICAL PHARMACOL­OGY" section). In patients previously treated with chemo­therapy for ovarian cancer, the recommended regimen is TAXOL 135 mg/m2 or 175 mg/m2 administered intrave­nously over three hours every three weeks. For patients with carcinoma of the breast, TAXOL at a dose of 175 mg/m2 administered intravenously over 3 hours every three weeks has been shown to be effective after failure of chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, Courses of TAXOL should not be repeated until the neutro­phil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3• Patients who experience se­vere neutropenia (neutrophil < 500 c~lls/mm3 for a week or longer) or severe peripheral neuropathy during TAXOL therapy should have dosage reduced by 20% for subsequent courses of TAXOL. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Preparation and Administration Precautions: TAXOL is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling TAXOL. The use of gloves is recommended. If TAXOL solution con­tacts the skin, wash the skin immediately and thoroughly with soap and water. IfTAXOL contact mucous membranes, the membranes should be flushed thoroughly with water.

Preparation for Intravenous Administration: TAXOL for Injection Concentrate must be diluted prior to infusion. TAXOL should be diluted in 0.9% Sodium Chloride Injec­tion, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/ mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25'C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and dis­coloration prior to administration whenever solution and container permit . . Upon preparation, solutions may show hazinetls, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an in-line (0.22 micron) filter. Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. T AXOL solutions should be prepared and stored in glass, polypropylene or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene­lined, should be used. T AXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22 mi· crons. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC.Coated tubing has not resulted in sigl)ificant leaching of DEHP.

Stability: Unopened vials of TAXOL (paclitaxel) for injec­tion Concentrate are stable until the date indicated on the package when stored under refrigeration. 2' -8' C (36' -46' F), in the original package. Freezing does not adversely affect the product. Upon refrigeration components in the TAXOL vial may precipitate, but will redissolve upon reaching room temperature wilth little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommendE:d are stable at ambient temperature (approxi­mately 25' CJ and lighting conditions for up to 27 hours.

HOW SUPPLIED NDC 0015-3456-20 30 mg/5mL single-dose vial individu­ally packaged in a carton. NDC 0015-3456-99 30 mg/5 mL single-dose vial individu­ally cartoned, shelf packs of 10 cartons. Storage: Store the vials in original cartons under refrigera· tion, 2' -.!!'C (36'-46'F). Retain in the original package to protect from light. Handling and Di1poa1I: Procedures for proper handling and disposal of anticancer drugs should be considered. Sev­eral guidelines on this subject have been published.2-s. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropri­ate.

PRODUCT INFORMATION/685

REFERENCES 1. Rowinsky EK, et al: Sequences of Taxol and Cisplatin: A

Phase I and Pharmacologic Study. J Clin Oncol 1991; 9(9):1692-1703.

2. Recommendations for the safe handling of parenteral an­tineoplastic drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

3. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 1985; 253(11):1590-1592.

4. National Study Commission on Cytotoxic Exposure­Recommendations for handling cytotoxic agents. Avail­able from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts Col, lege of Pharmacy and Allied Health Sciences. 179 Long­wood Avenue, Boston, Massachusetts, 02115.

5. Clinical Oncological Socienty of Australia. Guidelines and recommendations for safe handling of antineoHlastic agents. Med J Australia 1983; 1:426-428;

6. Jones RB, et al: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Can­cer Journal for Clinicians 1983; Sept./Oct. 25S-263.

7. American Society of Hospital Pharmacists Technical As­sistance Bulletin on Handling cyrotoxic and Hazardous Drugs. Am J Hosp Phar 1990; 47:1033-1049.

8. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986;, 43:1193-1204.

3456DIM--07 Slwwn in Product Identificatwn Guide, page 306

TESLAC • [tez 'lak l Testolactone Tablets

This product does NOT meet USP requirements. Testolac­tone exceeds USP Organic Volatile Impurities (OVU Limit for Methylene Chloride. The USP limit for Methylene Chlo­ride is 100 ppm. Testolactone normally contains 1,000 ppm.

DESCRIPTION Teslac (Testolactone Tablets) is available for oral admlni!h tration as tablets providing 50 mg testolactone per tablet. Testolactoneis a synthetic antineoplastic agent that is struc­turally distinct from the androgen steroid nucleus in possess­ing a six-membered lactone ring in place of the usual five, membered carbocyclic D-ring. Testolactone is chemically designated as 13-hydraxy-3-0xo-13,17 -secoandrosta-l,4-dien-17-oic acid -lactone. Graphic formula:

~o C19H2403 MW 300.40 CAS-968-93-4

Inactive ingredients: calcium stearate, cornstarch,, gelatin, and lactose. Testolactone is a white, odorless, crystalline solid, solubll! in· ethanol and slightly soluble in water.

CLINICAL PHARMACOLOGY Although the precise mechanism. by which testolactone pro­duces_ its clinical antineoplastic effects has not been estab­lished; its principal action is reported to be ii\hlbition of ste­roid aromatase activity and consequent reductiOn in estrone synthesis from adrenal androstenedione, the major source of estrogen In postmenopausal women. !3ased on in vitro stud­ies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persis· tence oftestolactone's effect on estrogen synthesis after drllg withdrawal. .. Despite some similarity to testosterone, testolactone bas no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving tes­tolactone. In one study, testolactone administered orally (1000 mg/day) was reported to increase renal tubular reab, sorption of calcium but to have no effect on serum calci\im concentration. The mechanism of the hypocalciuric effect is unknown. No clinical effects in humans of testolactone oir adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/ day orally. Testolactone is well absorbed from the gastrointestinal tract. It is metabolized to several derivatives .in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine. Additional pharmacokinetic data in humans are un• available. For information concerning carcinogenesis, mutagenesis, pregnancy, and lactation, see the corresponding PRECAU­TIONS s.Ctions.

Continued on next page

Consult 1995 supplements and future editions for revisions

8 of 8 Celltrion, Inc., Exhibit 1012