CENTER FOR DRUG EVALUATION AND RESEARCH APPROVAL PACKAGE for: APPLICATION NUMBER: 020579 TRADE NAME: Flomax 0.4 mg capsules GENERIC NAME: Tamsulosin hydrochloride SPONSOR: Boehringer Ingelheim Pharmaceuticals, Inc. APPROVAL DATE: 04/15/97 NO. 286 Q02 c34/’l5/97 17:31 ODE–II + 74575 ,S9V,CQ, ../ \ DEPARTMENTOF HEALTH& HUMAN SERVICES PublicHealfiservjc~ - f < ‘%+.. 4 o FoodandDrugAdministration RockvdleMD 20857 NDA 20-579 , — 130ehringer Ingetheim Pharnmceutictds, Inc. ,’ Attgnticm: Mr. Peter P. Femandes, M.Pharrn. API? t 5 1997 Associate Director. Drug Regulatory Affairs P.O. BOX368 Ridgefield, CT 06877 J3;ar Mr. Fernancles: Please refer to your new drug application dated ApriJ 1S, 1996, received April 15.1996. submitted under section 505(b) of the Federal Food, Dreg, and Cosmetic Act for FIomaxw (tamsu!oshr hydrochloride) Capsu!cs, 0.4 mg. We acknowledge receipt of your submissions dated May 21, June 28, July 11. August 6 and 16, and December 13 and 18, 1996; and January 10 tmd April 1, 10, 14 (2) and 15 (3). 1997. The User Fee goal date for this application is April 15, i 997. This new drug application provides for the use of Flomax for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). We have completed the review of this application, as amended, and have concluded tlmt adequate information has been presented to demonstrate that the drug product is safe and effective for use as recommended in the draft labeling dated April 15, 1997. Accordingly, the application is approved effective on the date of this letter. The final printed labeling (FPL) must be identical to the draft physician and patie;t labeling dated April 15, 1997, andthe dr~ft carton and container labeling dated October 7, 1996. Marketing the product.with FPL that is not identictd to this draft labeling may render the product misbranded and an unapproved new drug. Please submit 20 copies of the FPL as soon m il is available, in no case more than 30 days after it is printed. Please individually mount ten of the copies On heavy-weight paper or similar material. For administrative pm-poses, this submission should be designated “’FINAL PRJNTED LABELING” for approved NDA 20-579. Approval of this submission by FDA is not required before the labeling is used. Should additional information relating to the safety and effectiveness of the drug become available, revision of that labeling may be required. / We remindy& of yourPhase 4 commitmentsspecified in your submission dated April 10, 1997. These commitments, along with any completion dates agreed upon, are listed below NO. 2E16 Q03 04/15/97 17:31 ODE-11 + ‘74576 NDA20-S?9 Page 2 — Please submit protocols, data, tmd final reports to this NDA as correspondences. h addition, we request under 21 CFR 314.81 (b)(2)(vii) that you include in your annual report to this application a status summary of your commitments. The status summary should include expected completion and submission dates and any changes in plans since the last annual report. For administrative purposes. all submissions, including labeling supplements, relating to these Phase 4 commitments should be clearly designated “Phase 4 Conunirments, ” in addition, please submit three copies of the introductory promotional material that you propose to use for this product. All proposed materials should be submitted in draft or mock-up form, not final print. Please submit one copy to the Division of Reproductive and Urologic Drug Products and two copies of both the promotional material and the package insert directly to: a Food and Drug Administration Division of Drug Marketing. Advertising, and Communications . ~--- HPD-40 5600 Fishers Lane Rockville, Maryland 20857 Validation of the regulatorymethodsh not been completed. At the present time, it is the policy O.f the Center not to withhold approval becwse the methods are being validated. Nevertheless, we expect your continued cooperation to resolve any problems that may be identified. Please submit one market package of the drug product when it is available. We remind you thatyou mustcomply ~ith the requirements for an approved NDA set forth under 21 CFR 314.80 and3!4.81. NO. 286 D04 @4/15/97 17:31 ODE–II + 7457’6 N13A20-579 Page 3 If you have any questions, please contact Terri F. Rumble, B.S. N., Regula~ory Health Project Manager, at (301) 827-4260. Sincerely, . a--’---~ames Biistad, M.D. Director Office of Drug Evaluation II Center for Drug Evaluation and R&&arch * ... ---- ,, ‘) DIVISION DIRECTOR MEMO TO FILE ~~{ Date: April 14, 1997 NDA : 20-579 — Product: Flomax (tamsulosin hydrochloride) Sponsor: Boehringer Ingelheim Pharmaceuticals, Inc. *************** *************** *************** *************** ***** This new drug application was submitted April 15, 1996 for Flomax (tamsulosin hydrochloride) as indicated for treatment of the signs and symptoms of benign prostatic hy-pertrophy (BPH~. Y concur with Dr. Jolson, Deputy Director, as well as the NDA review team that this application is approvable. Several issues raised in the review process and described in the action package require clarification. Issues related to appropriate dosing, description of selectivity ) for specific alpha receptors, adequate information regarding the risk of orthostatic hypotension and elimination of references to statistical testing at time points other than those intended per protocol have been discussed with the review team and with the sponsor. Appropriate labeling, which addresses these concerns, is now included in the action package. In terms of Phase IV commitments recommended by the review team: I agree with the proposal to allow the submission of information related to in vitro dissolution and metabolic testing to be post-approval. The sponsor has performed this study and we anticipate submission of results within the next six months. The biopharmaceutics review also raises the issue of a possible drug interaction study between tamsulosin and other alpha-adrenergic blocking agents. On discussion with the biopharmaceutics review team it seems that this was a misunderstanding of the M~ reviewer’s concern for possible drug interactio-ns of tamsulosin with a 5-alpha reductase inhibitor. A drug interaction study between tamsulosin and other alpha-adrenergic blocking agents is not recommended as this product is specifically labeled (in the Drug-Drug Interactions. section of the prescribing information) NOT to be used in combination with alpha-adrenergic blocking agents. The possible requirement for—a drug interaction study of the combination of tamsulosin with a 5-alpha reductase inhibitor is discussed below. The MO review raises two issues for possible post-approval consideration: I agree with Dr. Jolson that the first issue--further quantifying the incidence of retrograde ejaculation--is not a required commitment for approval. The ‘“ - information regarding the observation of a dose- dependent effect on retrograde ejaculation is included in the current label. Unless the sponsor intends to make claims regarding the combined safety and effectiveness of tamsulosin in combination with a 5-alpha reductase inhibitor, I ) collude that this sponsor should not be required to undertake such a study. We look forward to the results of an NIH sponsored study which is evaluating the efficacy of other approved alpha adrenergic blocking agents in combination with finasteride (a 5-alpha reductase inhibitor) for this indication. Recoxmnendation I concur with the review team to recommend approval for this application and have forwarded the action package to Dr. Bilstad, Dir toz, ODE .11, for review and final recommendation. ,, :’_7/3 [V1.i.c’h Y-17-77 L;sa Rarick, MD Director Division of Reproductive,and Urologic Drug Products HFD-580 cc : NDA 20-538 . HFD-580 ) JFourcroy/HJolson/LRarick/TRumble\\wpfiles\20579 .d APR -91997 Group Leader Memorandum .. ) NDA: 20-579 Drug and indication: Flomaxm (tamsulosin hydrochloride) for treatmeti of the signs and symptoms of benign prostatic hypertrophy (BPH) Dose: 0.4 mg orally once daily (two 0.4 mg capsules once daily for men who fail to respond to the 0.4 mg dose) Applicant: Boehringer Ingelheim Pharmaceuticals, Inc. Submission received: Apfi 15, 1996 —- Date of MO review: April 4, 1997 Date of Memorandum: April 5, 1997; revised April 8, 1997 In this application, the sponsor requests approval for a selective adrenergic receptor antagonist for the treatment of the signs and symptoms of benign prostatic hypertrophy (BPH). The sponsor claims that this ~-antagonist is more selective for the la receptors of the prostatic smooth muscle than for receptors at other sites. In support of the request for approval, the .) sponsor has submitted the results of five controlled studies of which two studies (US92-03A and US93-O 1) provide the primary evidence of safety and efficacy. Together, these two studies randomized 1486 men with the signs and symptoms of BPH to receive either tarnsulosin 0.4 mg or 0.8 mg, or placebo for 13 weeks of treatment. Primary efficacy parameters included: 1) changes from baseline in total American Urological Association (AUA) Symptom Score, and 2) changes from baseline in peak urine flow rate. I concur with Dr. Fourcroy, the primary medical reviewer, that this application is approvable and that the efficacy of this product based on the previously noted efficacy parameters is comparable to other products in its class. Tolerability with this product during the conduct of the clinical trials was generally acceptable, however notable adverse experience with dosing. includes: orthostasis and associated symptoms (as with other products in this class) and retrograde ejaculation. Issues of note at the time of this regulatory action include: 1. Dosing The sponsor has requested that the label provide a recommendation for dose escalation to 0.8 mg for men who fail to respond to the 0.4 mg dose. Unfortunate y, in the clinical trials, men were randomized to the lower and higher dose, rather tha~ a~lowing for titration-to-effect. Not surprising, these trial detected no significant differences in NDA 20-579 GrouD Leader Memorandum PaPe 2 ) efficacy between the 0.4 and 0.8 mg doses.