CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: Application Number : 020458 Trade Name : GALZIN CAPSULES Generic Name: Zinc Acetate Capsules Sponsor : Lemon Company Approval Date: January 28, 1997 NDA 20-458 Lemmon Company JAN 28 IW? Attention: Deborah Jaskot 650 CathillRoad ScIIersville, PA 18960 Dear Ms. Jaskot: Please refer to your Jue 21, 1994 new dmg application submitied under section 505(b) of the Federal FOOL Drug, ad Cosmetic Act for Galzk (Zinc Acetate) Capsules, 25 and 50 mg. We acknowledge receipt of your amendments dated September 6 and October 31, 1995, January 3 and 29, March 27, April 8, August 7, September 13 and 24, october 8 and 14, 1996. - This new drug apphcation provides for Galzin at a dose of 25-50 mg three times daily as maintenance treatment for patients with Wilson’s disease initially treated with a chelating agent. We have completed the review of this application and have concluded that adequate information has been presented t.odemonstrate that the drug is safe and effective for use as recommended in the fwl printed labeling submitted cm October 8, 1996. Accordingly, the application is approved effective on the date of this letter. We remind you of your Phase 4 commitments specified in your submission dated August 29, 1995 and confirmed in our letter of January 27, 1997. These commitments, along with any completion dates agreed upon, are listed below. protocols, dab, and final repoflsshould be submitted to your IND for this product and a COPY of the cover l~er sent to this NDA. Should an IND not be required to meet your Phase 4 co[~tments, please submit pr~ioco], data, and final reports to this NDA as correspondences. h addit:~n, we requestunder 21 CFR 314.81(b)(2)(vii) that you include in your annual report to 1~5 app]ica~ion, a sta~s sumar~ of ~ac~ co~i~ent. The SUNUS su~~ should include the number of patients entered in each s~dy, expectedcompletion and submissionda~s, and any changes ~ plans since the ‘lastannual report. For administrative purposes, all — MA 20-458 Page 2 submissions, including labeling supplements, relating to these Phase 4 commitments must be clearly desigm~d “Phse 4 Commitments.” A( we next printing of the package insert, please make the revisions specified below and notify the Agency in the next annual report: 1. Overall: a. The trademarksymbol, ( m ) should be added to each instance of the word Galzin. b. The top of the insert should be revised from “GALZIN ‘“ (Zinc Acetate)” to “GALZIN ‘“ (Zinc Ace[ate) Capsules. ” 2. CLINICAL TRIALS section: The statement at the end of the table should be revised from “Some patients had more than one balance studies... ” to “Some patients had more than one balance study... ” 3. DOSAGE AND ADMINISTRATION section: a. The first sentence should be revised from “The recommended adult dose is 50 mg of elemental zinc... ” to “The recommended adult dose is 50 mg as zinc... ” Further, the following revisions should be made to the DESCRIPTION section to ensure continuity of the package insert: b. The f~st sentence should be revised from “Zinc Acetate as the dihydrate is a salt of metallic zinc used to inhibit... ” to “Zinc Acetate as the dihydrate is a salt of zinc used to itilbit...” c. The first sentence of the third paragraph should be revised from “GALZIN (Zinc Acetate) Capsules contain the equivalent of 25 or 50 mg of elemental .. zinc... ” to “GALZJW (Zinc Acetate) Capsules contain the equivalent of 25 or 50 mg of zinc... ” In addition, please submit ~ee copiesof the introductory promotional material that you Propose to use for this product. AHproposed materials should be submitted in draft or mock- Up fen, not ~na] print please ~ubmit one COpyto thisDivision and two copies of boti the NDA 20458 page 3 promotional material and the package insert directly to: Food and Drug Administration Division of Drug Marketing, Advertising and Communications, HFTWIO 5600 Fishers Lane Roclcville, Maryland 208S7 Validation bf the regulatory methods has not been completed. At the present time, it is the policy of the Center not to withhold approval because the methods are being validated. Ncvmtheless, we expect your continued coopmation to resolve my problems that maY be identified. We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR 314.80 and 314.81. If you have any questions, please contact Melodi McNeil, Consumer Safety Officer, at (301) 443-0483. cc: Original NDA 20-458 Sincerely yours, HFD-180/Div. files HFD-180/CSO/M .McNeil HFD-180/Duf& HFD-180/Chen Stephen B. Fredd, M.D. HFD-180/Choudwy Director HFD-720/Huque Division of Gastrointestinal and Coagulation HFD-820/C)~DC Division Director Drug Products DIs~CT OFFICE Office of Drug Evaluation III HF-2/Medwatch (with labeling) Center for Drug Evaluation and Research HFD-92/DDM-DIAB (with labeling) HFD.40/DDMAC (with labeling) . HFD-61310GD (with labeling) HFD-735/DPE (with labeling) - for all NDAs and supplements for adverse reaction changes, 14F]-20/press office (withlabeling) HFD.021/Acs (with labeling) drafied: mm/December 12, 1996ic:\wpFdes\cso\20458612.ap r/d Ini(ia]s: Wohnson 1/22/97 SFtedd 1/27/97 w yVj?if? final: January 28, 1997 APPROVAL(AP) [with Phase 4 Commitments] NDA20-458 GALZIN~ (ZINCACETATE) 25 mgand50 mg PACKAGEINSERTLABELING R 247 12445 1111I # GAIZIW (Zinc Acetate) 0ESCRIP710N Zmc AIMate as the Oihydrafe IS a $sii of meldhc 2itSCused to inhibd On Xnc@ion al copper in pafimfs sshhW!lson’s dwse Its chemmdl Iormula IS C,tiJf4Zn.2Hz0, M W 21951 Z!nc Acetate occurs as whd.$ crystals or granules, Ireeti soluble in waler and m bollmg alcohol an6 Wghtly soluble m alcohol GALZIN (Zinc Acetate) Capsules contain the eqwvaknt of 25 or 50 mg of elemental zinc, m addfllon to com starch and magrwslum Slearale m gelatln capsules The 25 mg capsule shells contain btamum dtonde a“d Ihe 50 mg cap. sule shelis contan Idanwm d!oxlde methyl paraben and Propyl paraben The 25 mg capsule shellscontain FD&C Blue #1, the 50 mg capsule shells contm FD6C Red #40 D&C Red t28, and O&C Yellow #10 CLINICAL PHARMACOLOtlY Introduction Wdsons Disease (hepatolenhcular degenerahon) 4San aulosomal recesswe metabolfc defecl m Mp.mc exc,etlon of copper !n the bile resulllng m accumulation of excess copper m The Ihver,and subsequently m othel organs mclud. mg the bmm k,dneys eym bone and muscles (n lh!s dnease heDalOcytes store excess cODDer bul when tklr capacwy IS exceedeo copp?r IS leleased mto the blood and IS taken up In efl”rahepatm sales, such as the brain result. mg !n molol disorders (atax!a tremors speech dithcultes) and psychlatrm man$fesfabons (mdabdoy depressmn, deterloral,on of work performance] Redmt!lbullon of excess copper m hepatocyfes leads to hepatocellular mjufy, mllammatlon necros[s and eventual clrrhosls Patients may present ckmcally with predomman fly hepahc neurc- logac or psychtalc!c sympwms The dnease has been trealed by restricting coppet m the d!el. and the use of chelatlng aWnts to bmd free copper to reduce Its foxtclfy and Iaclldate its excretion The purpose of mltlal treatment of symplomahc pabents wilh a chebl. mg a9er0 IS 10 deloxty copper Once the patlenls symptoms havs stabtlued climcally maintenance treatment begins Cltmcalmeasures are used to determme whether the patC?ntremams stable @.?ePRECAUTIONS Monitoring Pafienlsl The achve mooety m Z!nc Acetate IS mm cation Regardless of the hgand, zinc blrxk$ the mtestmal absorphon of cop pw Irom the diet and Ihe reabsorpmm 01 endogenously Secrelsd copwr such as ihat from the sahva, gastric juice and btk Zmc reduces the!pmductton of metallottwmem m ths eNerOCfl’? a protein that binds cDppeI thereby pre- venhnq !ts serosal transfer mlo the blood The bound copper IS then lost m the stool following desquamatlon of ths mlestmal cells Pharmacohinelic.s Because the proposed sde of ac(vm at zmc IS an effect on copper up!ake at ths level of the mh?slmal cell, pharma. Cokmet,c eva!ual)ons na$ed on blood levels 01zmc do no! prov,de useful mformahon on zinc b!oavaltabdm at the We Ot acllon Determmallons cdZinc content m the Ihve!anti the plasma Zmc Concemratmn afler the oral adiyn,strat,on Ot Zmc Acelale have qteldcd mcons,slenl results However foods and beverages have been shown to decrease the uQ!ake of ZIIICfhereby decreasw the levels of zmc III the Plasma of healthy volunteers For liws reason, the oral Oose of zmc should be separated from food and beverages, other than water by at Isast ons f!our Pharmacodynamies in pharmaccdynamlc studies, the methods used included net copper balance and radtolabekd copper uptake m Wdson’s disease uabents These Sludles showed that a reolmen of SD ma t., d of Zmc Acetate was eftecuve m lmduc. mg a negatwe mean copper balance (-O 44 mgiday) and ai adequate mean ‘Cu uptake (0 82% at the admmmtered aosel A regimen of 25 mu t l.d of Ztnc Acetate was also pf!drmacodynammally acove but fewer paberds have been treated wdh this regimen than 50 mg t I d CLINICAL 7RIALS In the single center Ltmted States tr!al 6U pahents wtth WIkOns titsease (31 mate. 29 female) who had ads@MSe detoxdlcatlon 01 copper after mdlal Chelatlon therapy WEre enlered mto a coppel balance study of varmus doss rer- nmens of Zinc Acetate Paoents were hospitallzsd 10 csrefully control iocd and Ihquldintake Food, urine and feces were analyzed ior copper c,mlent, and copper balance was dehned as the ddfererue between coppet lmfaksand cop w ehmmat!on{excretlon over a 10-day period A pabent was considered m adequate copper balance II the result wss less than +025 mg copperlday Resuhs for the groups m each dose regimen tested and for adequacy al mdwtdus[ resMts are prov!ded m the Iollowing table Number of Patients Dose Regimen Mean Coppsr Inadequately (mg zmc x numbw of Balance ControledIlOfal number da!ly dOSeSl N’ (m#day) of pahenls sfuded 50X3 70 -036 6/70 50X2 5 -016 0/5 25x4 5 -0 2f 0i3 25x3 fl -0.18 Illf 375x2 4 -0.02 f/4 75X1 8 016 2A 25x2 4 015 1/4 25x1 10 .0.37 2/1 o 25x6 12 005 4/12 50X1 f 01 0/1 50X5 11 -0.3 ill 1 o 6 052 — “N.