CENTER FOR DRUG EVALUATION AND RESEARCHApproval Package for:Application Number:020895Trade Name:VIAGRAGeneric Name:Sildenafil CitrateSponsor:PfizerApproval Date:March 27,1998
`
`INTELGENX 1004, pg. 1
`
`

`
`I
`
`FEB
`
`2 1998
`
`----· .....
`
`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`Joint Clinical Review
`
`NDA:
`
`20-895 (Sildenafil for male impotence).
`
`Sponsor:
`
`Pfizer Phannaceuticals, Inc.
`
`Submission:
`
`Review date:
`
`22 January 1998.
`
`Reviewers:
`
`K. Mahioob, Ph.D., HFD-710
`
`P. Martoum, Ph.D., HFD-860
`
`N. Stockbridge, M.D., Ph.D., HFD-110
`
`Concurrences:
`
`G. Chi, Ph.D., HFD-710
`
`Distribution:
`
`A. Parekh, Ph.D., HFD-860
`
`NDA20-895
`HFD-340Niswanathan
`HFD-710/Mahjoob
`HFD-71 0/Chi
`HFD-860/Malinowsky
`
`HFD-19 (FOI)
`HFD-110
`HFD-860/Marroum
`HFD-70 1/ Anello
`HFD-860/Mehta
`
`HFD-110/CSO
`HFD-11 0/Stockbridge
`
`HFD-860/Parekh
`
`INTELGENX 1004, pg. 2
`
`

`
`Center for Drug Evaluation and Research
`
`Table of Contents
`
`Viagra (Sildenafil)
`
`"Joint Clinical Review" for NDA-20-895
`
`INTELGENX 1004, pg. 3
`
`

`
`I
`
`Table of contents
`
`NDA 20-895
`Sildenafil for male impotence
`
`Table of contents
`
`Section 1. Materials utilized in review ......................................................................................................................... 1
`
`Section 1.1. Materials from NDA/IND ..................................................................................................................... 1
`
`Section 1.2. Related reviews or consults ................................................................................................................... 1
`
`Section 1.3. Other resources ...................................................................................................................................... 1
`
`Section 2. Background .................................................................................................................................................. 2
`
`Section 2.1. lndication ................................................................................................................................................ 2
`
`Section 2.2. Information from related pharmacologically related agents ............................................................. 2
`
`Section 2.3. Administrative history ........................................................................................................................... 2
`
`Section 2.4. Proposed labeling ................................................................................................................................... 2
`
`Section 2.5. Foreign marketing ................................................................................................................................. 2
`
`Section 2.6. Other background information ............................................................................................................ 2
`
`Section 3. Chemistry, manufacturing, and controls .................................................................................................. 3
`
`Section 3.1. Basis of review ........................................................................................................................................ 3
`
`Section 3.2. Structure ................................................................................................................................................. 3
`
`Section 3.3. Deficiencies ............................................................................................................................................. 3
`
`Section 4. Animal pharmacology ................................................................................................................................. 4
`
`Section 4.1. Basis of review ........................................................................................................................................ 4
`
`Section 4.2. Mechanism of action .............................................................................................................................. 4
`Section 4.2.1. Screening for other activities .......................................................................................................... 4
`
`Section 4.3. Pharmacokinetics ................................................................................................................................... 5
`
`Section 4.4. Toxicology ............................................................................................................................................... 5
`Section 4.4.1. Genetic toxicity ................................................................................................................................ .5
`Section 4.4.2. Single-dose ........................................................................................................................................ 5
`Section 4.4.3. Sub-chronic/chronic ......................................................................................................................... 5
`Section 4.4.3.1. Oral .............................................................................................................................................. 5
`Section 4.4.3.1.1. Rats ........................................................................................................................................ 5
`Section 4.4.3.1.2. Dogs ................................................................................................................... _ .................. 6
`Section 4.4.3.1.3. Mice ........................................ ; ................................................................ ~ ............ ~ ................ 6
`Section 4.4.3.2. Intravenous ................................................................................................................................. 6
`Section 4.4.3.2.1. Rats ........................................................................................................................................ 6
`Section 4.4.3.2.2. Dogs ....................................................................................................................................... 6
`Section 4.4.4. Chronic .............................................................................................................................................. 6
`Section 4.4.4.1. Rats .............................................................................................................................................. 6
`Section 4.4.4.2. Mice ............................................................................................................................................. 6
`Section 4.4.5. Special toxicity studies ..................................................................................................................... 6
`Section 4.4.6. Safety margin ................................................................................................................................... 6
`
`Section 4.5. Summary of significant findings ........................................................................................................... 7
`
`Section 5. Description of clinical data sources ..................................................... ~ ...................................................... S
`
`Section 5.1. Primary source data .............................................................................................................................. 8
`
`Joint Clinical Review
`
`- I t -
`
`22 January 1998
`
`INTELGENX 1004, pg. 4
`
`

`
`I
`
`Table of contents
`
`NDA 20-895
`Sildenafil for male impotence
`
`Section 5.1.1. Study type and design and subject enumeration .......................................................................... 8
`Section 5.1.1.1. Controlled studies ...................................................................................................................... 8
`Section 5.1.1.2. Clinical pharmacology .••..•••..••.....•••••••••••••••....•.•••...••••••••.•••.•••.•••••••.•.••••••••..•••••••..•••••.•.•..•••••..... 9
`Section 5.1.1.3. Open-label extensions •.••.•••.•.•..••••.••••••.••.....•.••••••...••••••••.•••••••••.••••••••••••••....•••••.•••••••••••.••••......• 11
`Section 5.1.1.4. Studies not reviewed in detai1 ...•.••••...••......•.•........••••....•.••..•.•••.••.•••....••••••..•....•••....•.••......•..... 12
`Section 5.1.2. Enumeration .......•..............•••••......•.•.•........••..•.•.....••••.....•.•••....••••..•.....•.•.•........•••.....••••••......•......•.. 13
`Section 5.1.3. Demographics ••....•...••.••••••....•.•.•.•.•.•••••••.•••.•.......•.•.•.....••.•..••.•.••••.••••••••••••••..•...•••••.•....•.•••....•••......• 13
`Section 5.1.4. Extent of exposure .......................................................................................................................... 14
`Section 5.1.4.1. Placebo-controlled experience ••••••••.••••.....•.•••..•...••••......•.••..•.•••••••....••••..•.••••.....••••••....•.•.....•.. 14
`Section 5.1.4.2. Open-label experience •.•.•.....••••••••.•.•...•••..•••..•.•••••.•.•.••••••••••.•••••••••••••...•••....•..•.•......••••••....••..... 15
`Section 5.1.4.3. Safety updates ....•.•.••.•••...•...•.••••.•.•.•••••••.•.••.•.••.•.•••.•.•••.•.•.••••..••••••••••.•••.•.•.•.•••.•.••..•••...••••••....•.•• 15
`
`Section 5.2. Secondary source data .••.•...••••••.••.....••••..•••.•.••••••.•••..•••••.•...••••••••..••••••.•.••••••.••••••....•••.•.......•.•.•....•.••.... 15
`Section 5.2.1. Other studies •••••.....•.•.•.•.••••.......••.•••••.....•••••••....•••••..••••••.••.••••.••.••.•••••••••.•••••..•.••••.•..•••••.•.•.••••.....•••• 15
`Section 5.2.2. Post-marketing experience .•...•.•....•••••.••.•....•.•. ~\ ....••.........•.•.....•.••.....•••••.....•.........••......•.•••......•... 15
`Section 5.2.3. Literature ••••........•.••.•.......•••.•.•......•...•.•.••......••••....•.•.•.•...•.•.•....••.•....•••.•.•....••.•..•.••.•.•.•.....••••...•...•... 15
`
`Section 5.3. Adequacy of clinical experience ....•.....••••.••.•...••••.••..••.••......••••••.....•••••...•••••••.•.••....••••••••...••.••••....•••.... 15
`
`Section 5.4. Data quality and completeness ........................................................................................................... 15
`
`Section 6. Clinical pharmacology and biopharmaceutics .•••.•.........•.•.......•.•.•....•.••••....•.•••...•.•...............•.••..........•... 16
`
`Section 6.1. Bioavailabilitylbioequivalence ...........•.•.•...•.•...••.••.....•••••.•..•.••••......•........••.•.....•••...•..••..•....•••••......•.... 16
`Section 6.1.1. Absolute bioavailability ................................................................................................................. 16
`Section 6.1.2. Food effects ..................................................................................................................................... 16
`Section 6.1.3. Bioequivalence .•..•.••........••..........••.••••.......•.•••••....••••••....••.•••...•••••....•••.......•••......••......•••••.....•.•..•.... 16
`
`Section 6.2. Pharmacokinetics .......•..........•...•.•.•........•.•.••....•.•••••...•.••••......•••••.....•••......•.••....•••••...•.••......•.........•.•.... 16
`Section 6.2.1. Single-dose pharmacokinetics .•.•........••.•.....•..••••••...•.....•....••••.....••.••..•.•••.•...•........•••.........••.........• 16
`Section 6.2.2. Multiple-dose pharmacokinetics .••.••......•••••••••....•.••••.....•••••..•••.••••.••••••••..••••.....•••••.....•.•........•••.... 17
`Section 6.2.3. ADME •....•••.••.•.......••••........•.••..••........•••••••••••..•••••.•..•••.••....••••••...•••••.....•.••......••••.....••••.••••.•.•.•....•.•. 17
`Section 6.2.4. Plasma level-dose relationship •.•••.•......••••••••......•.•.•...•.•••....•••.•••.....•••.•...•.•.....•••.......••...•...•••••.....• 18
`Section 6.2.5. Concentrations in semen •.•......•.••.•.•.•...•••••.••••....•.•.••....•.••••••.••.•.••.•.•••••••...•....•..•....•...••••.......••••.... 18
`Section 6.2.6. Protein binding .......••.....•••••...........•••••••••...•••••••...•.•••••••..•••••••.•••....•...••••...•.••••....•.••••...•.•.•••....•••.•••. 18
`
`Section 6.3. Special populations •...................••.•••.•••.••••••••••••.•..••••••••...••••••....••••....•.••••.••••••......•••..••••.•.....•.•.••.......•• 19
`Section 6.3.1. Renal impairment ••.......••.......•••.•••••••••.•••••••••....••.•••.......•.•••....•.•.....•.••..••••......••••.....••••.....•.•••..•....• 19
`Section 6.3.2. Hepatic impairment •.....••.•.........•••••••••••...•.••••••.•..•.•.•.•...•••••••••••••••.••.•.•...•••••.....•••••....••••...••.•.•.•....• 19
`Section 6.3.3. Age .•••.......••.••..........•.•.......•..••••......•••.•.•.•••...••••.••••.•.••••••••.••.••••.••••••....•••.•...•.•••..•.••••...•••••...•.••.•....... 19
`Section 6.3.4. Diabetes ....••••.••.........•.•.....•••...•.•.••••••.••••.••.•.••••.•••..•.•••••••..•••••....••••••.•••••••.•••..•...•••......••••.•..•..•.•••....• 20
`Section 6.3.5. Erectile dysfunction •......•.•........••.•.•••••••.•.••••••.••...••••••••..••••••...••.•....••••••...••••......••....••••••.•••••.•.••...•• 20
`
`Section 6.4. Drug interactions ................................................................................................................................. 20
`Section 6.4.1. Tolbutamide •.••.•.....•.••.•••....•.•••••••.....•••.••••••.....•.••.......•.•.•••...••••.•..••.•••...•••....••........••••...•••••......•..•••. 20
`Section 6.4.2. Warfarin •..•.••••...................•.••••.•.......••.•••••.•.••.•.••••.•.••••••••••••••.•..••••••.•...•••....••..•....•.••••••••••••••...•.•..•. 20
`Section 6.4.3. Ethano1 ..•••.•...........•.•.•••....••••••.•.••.•.•.•••.•••.•.•••••••••.•••••••••....•••••...•.••••••..••••••••••.••••••••....•.••••.•..•.•.••••••. 20
`Section 6.4.4. Calcium channel blockers .....•..•••.•••.....•.•••.........•••••••...••••••••.••.••.•.•••••••...••••.•...••........••••....••••.••..•• 20
`Section 6.4.5. Cimetidine ....................•.•......•.••...•.••.....•••••.•....•••••••.•....•••.•••....•.•.....••.•.......••......•......•.••..... ; •••......•• 20
`Section 6.4.6. Maalox ••.........•••.•..........••.....•.•...•.......••.••••.....•.............•.•.•.•......•••......•....•.••.........•....•.•••.......•.........• 20
`Section 6.4. 7. Erythromycin ................................................................................................................................. 20
`Section 6.4.8. CYP3A4 inducers ...........•.... : .......................................................................................................... 21
`Section 6.4.9. Diuretics .......................................................................................................................................... 21
`Section 6.4.10. P-blockers .•.....................••..........••.•.•...•.•••••.•••...••••••.....•••••••....••.....••••....••••......•••....••••..••••••••.•.....• 21
`Section 6.4.11. CYP2C9 inhibitors .....•...........•.•.•.•••••••••••.•..••••.•......•.••..•.............•••....•........••......••......••...•......•.•.• 21
`Section 6.4.12. CYP2D6 inhibitors ...•.........•............•.•••.•.......••........•.•.•.....•.••.• ,: ..•••.....••....•.•........•......•..........•.•.... 21
`Section 6.4.13. ACE inhibitors and angiotensin II antagonists •.•..•...................•.......•...................••.........•........ 21
`
`Joint Clinical Review
`
`-iii-
`
`22 January 1998
`
`INTELGENX 1004, pg. 5
`
`

`
`I
`
`Table of contents
`
`NDA 20-895
`Sildenafil for male impotence
`
`Section 6.4.14. Inhibition of CYP by slldenafil and UK-103,320 ...................................................................... 21
`
`Section 6.5. Population pharmacokinetic analysis ................................................................................................ 21
`
`Section 6.6. Pharmacokinetidpharmacodynamic relationships .......................................................................... 21
`
`Section 6.7. Formulations ........................................................................................................................................ 22
`
`Section 6.8. Dissolution ............................................................................................................................................ 22
`
`Section 6.9. Assay ..................................................................................................................................................... 24
`
`Section 6.10. Comments ........................................................................................................................................... 24
`
`Section 6.11. Recommendation ............................................................................................................ - ................ 24
`
`Section 7. Integrated review of effectiveness ............................................................................................................ 25
`
`Section 7.1. Mechanism of action .................. ; ............................................................................................ : ............ 25
`Section 7.1.1. Single-dose studies ......................................................................................................................... 25
`Section 7.1.1.1. Mixed etiology .......................................................................................................................... 25
`Section 7 .1.1.2. Psychogenic etiology ................................................................................................................ 25
`Section 7.1.1.3. Diabetes ..................................................................................................................................... 26
`Section 7.1.1.4. Spinal cord injury ......................... , .......................................................................................... 26
`Section 7.1.2. Multiple-dose studies ..................................................................................................................... 26
`Section 7.1.2.1. Psychogenic etiology ................................................................................................................ 26
`Section 7.1.3. Effects by etiology of erectile dysfunction ................................................................................... 26
`Section 7.1.4. Time course of effects after a dose ................................................................................................ 26
`Section 7.1.5. Time course of effects with repetitive dosing .............................................................................. 26
`Section 7.1.6. Relationship between dose and erectile function ........................................................................ 26
`Section 7.1.7. Relationship between plasma levels and erectile function ......................................................... 27
`
`Section 7.2. Effects on sexual performance ............................................................................................................ 27
`Section 7.2.1. Methods of assessment ................................................................................................................... 27
`Section 7.2.1.1. Primary ..................................................................................................................................... 27
`Section 7.2.1.2. Supportive ................................................................................................................................. 27
`Section 7.2.2. Dose dependence ............................................................................................................................ 27
`Section 7.2.2.1. Common characteristics of fixed-dose studies ....................................................................... 27
`Section 7.2.2.2. Fixed-dose studies assessed by liEF ....................................................................................... 28
`Section 7.2.2.2.1. Analyses of sexual performance by liEF ......................................................................... 28
`Section 7.2.2.2.2. Analyses of other liEF questions ...................................................................................... 30
`Section 7.2.2.2.3. Analyses of event logs ......................................................................................................... 31
`Section 7.2.3. Titration studies ............................................................................................................................ .32
`Section 7.2.3.1. Common characteristics of titration studies .......................................................................... 32
`_Section 7.2.3.2. Titration studies assessed by IIEF .................................. ., ...................................................... 32
`Section 7.2.3.2.1. Analyses of sexual performance by liEF ......................................................................... 33
`Section 7.2.3.2.2. Analyses of other liEF questions ...................................................................................... 34
`Section 7.2.3.2.3. Analyses of event logs ......................................................................................................... 35
`
`Section 7 .3. Summary of key effectiveness findings .............................................................................................. 36
`Section 7.3.1. Mechanism of action ...................................................................................................................... 36
`Section 7.3.2. Dose-dependent effects .................................................................................................................. 36
`Section 7 .3.3. Time course of effects .................................................................................................................... 36
`Section 7.3.3.1. Time course after a dose .......................................................................................................... 36
`Section 7 .3.3.2. Time course with repeated dosing .......................................................................................... 37
`Section 7.3.4. Effectiveness in sub-groups ........................................................................................................... 37
`Section 7.3.4.1. Non-specific organic etiology .................................................................................................. 37
`Section 7.3.4.2. Psychogenic etiology ................................................................................................................ 37
`Section 7.3.4.3. Diabetes ..................................................................................................................................... 38
`
`Joint Clinical Review
`
`-iv-
`
`22 January 1998
`
`INTELGENX 1004, pg. 6
`
`

`
`I
`
`Table of contents
`
`NDA 20-895
`Sildenafil for male impotence
`
`Section 7 .3.4.4. Spinal cord trauma •••••••••••.•••••••••••.••.•••.••••••••.••••.•••.••••••••••.••••••••••••••••••••••••.•••••••••••.••••••••.•••••••• 38
`Section 7.3.4.5. Blacks ........................................................................................................................................ 39
`Section 7.3.4.6. Elderly ....................................................................................................................................... 39
`
`Section 8. Integrated review ofsafety ........................................................................................................................ 40
`
`Section 8.1. Methodology ......................................................................................................................................... 40
`Section 8.1.1. Deaths .............................................................................................................................................. 40
`Section 8.1.2. Serious adverse events ................................................................................................................... 40
`Section 8.1.3. Withdrawals and other significant adverse events ..................................................................... 40
`Section 8.1.3.1. Overall profile ofwithdrawals ................................................................................................ 40
`Section 8.1.3.2. Adverse events associated with withdrawal ......................................................... ~ ................. 40
`Section 8.1.3.3. Other significant adverse events ............................................................................................ .40
`Section 8.1.4. Other search strategies .................................................................................................................. 40
`Section 8.1.5. Adverse event incidence ................................................................................................................ 40
`Section 8.1.5.1. Approach to eliciting adverse events in the development program .................................... 40
`Section 8.1.5.2. Appropriateness of adverse event categorization and preferred terms .............................. 40
`Section 8.1.5.3. Identifying common and drug-related adverse events ......................................................... 40
`Section 8.1.5.4. Additional analyses .................................................................................................................. 40
`Section 8.1.6. Laboratory findings ....................................................................................................................... 40
`Section 8.1.6.1. Extent of laboratory testing .................................................................................................... 40
`Section 8.1.6.2. Selection of studies and analyses for drug-control comparisons ......................................... 40
`Section 8.1.6.3. Standard analyses .................................................................................................................... 41
`Section 8.1.6.3.1. Analyses focussed on central tendency and outliers ...................................................... .41
`Section 8.1.6.3.2. Withdrawals for laboratory abnormalities ..................................................................... .41
`Section 8.1.7. Vital signs ........................................................................................................................................ 41
`Section 8.1.8. ECGs ............................................................................................................................................... 41
`Section 8.1.9. Special studies ................................................................................................................................. 41
`Section 8.1.10. Withdrawal phenomena .............................................................................................................. 41
`Section 8.1.11. Abuse potentia1 ............................................................................................................................. 41
`Section 8.1.12. Human reproduction data ........................................................................................................... 41
`Section 8.1.13. Overdose experience .................................................................................................................... 41
`
`Section 8.2. Safety results ........................................................................................................................................ 41
`Section 8.2.1. Deaths .............................................................................................................................................. 41
`Section 8.2.2. Withdrawals ................................................................................................................................... 42
`Section 8.2.2.1. Withdrawals for any cause ...................................................................................................... 42
`Section 8.2.2.1.1. Withdrawals from placebo-controlled studies ................................................................ .42
`Section 8.2.2.1.2. Withdrawals from open-label extensions ......................................................................... 43
`Section 8.2.2.2. Withdrawals for adverse events .............................................................................................. 43
`Section 8.2.2.2.1. Withdrawals from placebo-controlled studies ................................................................. 43
`Section 8.2.2.2.2. Withdrawals from open-label extensions .......................... ~ .............. -.... ~ ...... : .. :.; ...... ;.-~ .. ; ... 47
`Section 8.2.3. Common adverse events ................................................................................................................ 48
`Section 8.2.3.1. Relationship to dose ................................................................................................................. 48
`Section 8.2.3.2. Overall incidence ...................................................................................................................... 49
`Section 8.2.4. Laboratory data ....................... , ..................................................................................................... 50
`Section 8.2.4.1. Hepatic function ....................... , ............................................................................................... 50
`Section 8.2.4.2. Renal function ......................................................................................................................... ,50
`Section 8.2.4.3. Electrolytes, hematology, etc ................................................................................................ , .. 50
`Section 8.2.4.4. Vital signs .................................................................................................................................. 51
`Section 8.2.4.5. ECG ................................................................................................................. , ......................... 52
`Section 8.2.5. Pharmacologic basis for safety issues ........................................................................................... 53
`Section 8.2.5.1. Vital signs .................................................................................................................................. 54
`Section 8.2.5.2. Hemorrhage .............................................................................................................................. 55
`Section 8.2.5.3. Weakness ................................................................................................................................... 55
`
`Joint Clinical Review
`
`- v -
`
`22 January 1998
`
`INTELGENX 1004, pg. 7
`
`

`
`I
`
`Table of contents
`
`NDA 20-895
`Sildenafil for male impotence
`
`Section 8.2.5.4. Decreased gastrointestinal motility , ....................................................................................... 55
`Section 8.2.5.5. Vision abnormalities .••••••••••••.••••.•.•..•.•......•.•.•.••••..•..••...•.•••••..•...•••••..••••••......•. , •..•••••.••••••••••.•.•. 55
`
`Section 8.3. Summary of key safety findings .•. , ..................................................................................................... 55
`
`Section 9. Labeling review ....................................................................................................................................... , .. 57
`
`Section 10. Summary and recommendations ........................................................................................................... 69
`
`Section 10.1. Chemistry •...........•.••.•••••••••••••••••.•......................•••.••••.•••••........••••••.•.•.••.•••••••••••.•••...••••••••••.•••..•....•.•.•• 69
`
`Section 10.2. Pharmacology and toxicology ••••••••••••••.•••••........•••.••••••.•.••.•...••.••••••..•.••••••••••••••••••••••••••••••••••••....•.•••• 69
`
`Section 10.3. Biopharmaceutics •••.•••••••••••••••.•.•..••.•..•..•••.•••....•.•........•.•..•.•••....•..••••......•••••••••••.•.•••••••.••. : ..•••.••.••••..•. 69
`
`Section 10.4. Effectiveness ••..•••••..••.••••••••••••••••.•••.••••.........•••...•.•••••.•.•.......••••••.•.•.•.••••••••••••••••••••••••••••••••••••••••.••.•••••• 69
`
`Section 10.5. Safety ...........................................................