CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE: CARDIOVASCULAR AND RENAL DRUGS
ADVISORY COMMITTEE
DATE OF MEETING: 06/26/97
SLIDES
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Fenoldopam History”
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Discovered and developed by SKF Extensive preclinical and clinical programs SKF discontinued fenoldopam development of oral
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SKF continued development of IV fenoldopam Broad experience in severe hypertension
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S,KF Severe Hypertension Trials”t’
Overview of SKF Trials in Severe Hypertension*
Trial Number B-74/FEN (us) B-74/sNP (us) B-85 (US) B-63 (US) B-67 (Germany) B-69 (So. Africa) D-1101/FEN (US) D-1101/SNP (US) B-89 (Asia) A-52 (Italy) B-1101 (Germany) A-14 (Spain)
-
/V=27
N=26
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N=34 N=51 N=42 N=28 N=90 N=93 N=16 N=22 N=12 N=26
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I I I I I I I r -40 -35 -30 -25 -20 -15 -10 Mean Reduction in Diastolic Blood Pressure (mmHg)
* 95°/0confidence intervals
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IUeurex Licensed Fenoldopam .
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; ,
1988: SKF filed NDA 1991: Nonapprovable letter issued
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- Dosing regimen not defined - Malignant hypertension studied
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population not
Neurex licensed rights to fenoldoparri in 1994
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IWwrex Trials
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Pharmacokinetic/pharmacodynamic Malignant hypertension trial Renal function trial
trial
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,*
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Fenoldopam Profile
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Well-behaved Dose-response
pharmacokinetics curve well-defined
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Predictable hypotensive effects Good safety profi Ie Well tolerated renal blood flow
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o Maintains/improves
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Label Indications
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Short-term treatment of hypertension when oral j therapy is not feasible or possible Treatment of severe hypertension with or without acute end-organ damage
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Fenoldopam Clinical Pharrnacobgy
Pharmacokinetics
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and Pharmacodynamics - focus M
Dopamine receptor pharmacology fenoldopam PK/PD in previous clinical trials: Unanswered questions
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Blinded fixed-dose, constant 48 hour infusion PK/PD trial
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Fenoldopam Interaction with; ~ ~ , . Catecholamine Receptors !$~
U vasodilation (corortary, mesenteric, renal), natriuresis, GI motility decreased norepinephrine
#D-1 like receptors DI B DIA E@ #D-2 like receptors
Al
release
Hwadrenergic E ~-adrenergic /
receptors receptors
Al vasoconstriction #1 chronotropy
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Pharmacokinetics and Pharmacodynatiics Unanswered Questions
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PK Questions: - PK during prolonged infusions? + Time to C~~ + Dose proportionality of c~~ + Time-dependent A in cSs - !?K after stopping infusion? q Plasma 412 + Clearance
NE UREX
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Pharmacokinetics and Pharmacodyna’h’ics Unanswered Questions
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PD Questions: - PD during fixed-dose infusion different from PD during titration-to-effect? - PK/PD relationship during fixed-dose infusions? - Onset, offset, tolerance, rebound?
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Pha~macokinetics and Pharmacodyna~ics Study Objectives
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+ PK - Plasma fenoldopam (racemate + enantiomers) concentrations during and after 48 hour infusion - Time to C~~ - PK parameters after 48 hour infusion 9
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Pharmacokinetics and Pharmacodynamics I $ “ Study Objectives
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PD + - Time to peak effect?
- Maximum tolerable infusion rate? - Persistent hemodynamic effect during prolonged infusion (tolerance)? - Hemodynamic response to drug withdrawal after prolonged infusion?
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Pharmacokinetics and Pharmacodynamic,s I Study Design
Day O Admission H&P Day 1 Vehicle infusion Day 2 Fenoldopam infusion (O, Day 3 Fenoldopam infusion (O, 0.04,0.1,0.4, 0.8 ~g/kg/min) Day 4 $ Vetiicle infusion
0.04,0.1,0.4,
0.8 pg/kg/min) Entry DBP 95-119 mmHg Safety lab BP&HRq 15 min
QuaL DBP >90
mmHg BP& HRq15 min Fenoldopam PK . BP& HRq15 min Fenoldopam PK
Safety lab
BP& HRq15 min Fenoldopam PK
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6/18/97 12:37 PM
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Pharmacokinetics and Pharmacodynami&~ 94-005 Patient Demographics
N Mean Age Black Caucasian Hispanic/Asian Male Female Mean DBP Screening 32 50.5 24.3% 60.0% 15.7% 81 .7% 18.2% 98.8 *
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6/18/97
12:38 PM
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Pharmacokinetics and Pharmacodynamics ‘ Results: Pharmacokinetics ; ‘
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pg/kg/min Dose 0.04 pg/kg/min Dose 0.1 pglkgl~n Dose 0.4 pglkglmin
Dose 0.00 Dose
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Pharmacokinetics and Pharmacodynamic~ Re$ults: Onset and Offset Pharmacokineti&
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Pharmacokinetics and Pharmaco’dynamics $ I f’ Conclusions
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PD + - Predictable hemodynamic
effect
- Rapid onset of effect - Dose proportionality PD response
(SBP, DBP)
- Gradual tolerance with maintenance of effect - No rebound
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Study Design I
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Hypertensive
Emergency Trial
Confirmation of pharmacokinetic/pharmacodynamic study findings End-organ damage and DBP >120 rnmHg Double-blind, constant infusion, 4 rates -0.01, 0.03, 0.1, 0.3 pg/kg/min 24-hour infusion, transition to PO after 18 hours No target BP specified Reduction in DBP at 4 hours primary endpoint Statistical comparison vs. 0.01 dose group
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Patient Population
Balanced for demographic Age: 45 * ‘lom4 Gender:
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Race: 78°/0 African American
Q Baseline BP: 208A 22 / 134 k 15 mmHg
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Protqcol-specified
End-Organ Damage $
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Q Percent of all randomized patients - 65% neurological criteria cardiovascular - 39!!X0 renal criteria - 35!!X0 criteria criteria
ophthalmological - 25!!40
‘ 990/001 treated patients >1 criteria
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Q 49!!/ooff antihypertensives
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20°/0 had history of drug or alcohol abuse
. 820/0had LVH on baseline ECG
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17°/0 history of heart failure
Q 17% old Ml on ECG
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20°/0 had discontinued clonidine in past week
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Patient Disposition (cont.)
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89 patients treated up to at least 4 hours -15 patients did not complete 24 hours + 2 discontinued due to adverse events + 11 discontinued due to controlled blood pressure + 1 required proscribed medications + 1 treatment failure
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74 patients treated for 24 hours
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Trial Conduct w
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“ Only one patient unblinded before 4 hours Q 71!!/io blinded throughout trial “ 76% maintained initial dose for 4 hours - 64% in 0.01 group+ 87% in 0.3 group “ 47% maintained initial dose for 24 hours - 35%i0 0.01 group+ in
59?40 0.3 group in
Q 5 patients transferred to nitroprusside
-2 -3 discontinued discontinued prior to 4 hours after 4 hours ~ $ U~EX
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Efficacy Endpoint
Mean Diastolic Blood Pressure
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0.01 pg/kg/min; comparator
0.03 pg/kg/min; p = 0.06*
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Pharmacodynamic Effects in Renal ~ ko icA = 1 Insufficiency mp’f
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Blood pressure effects (mean z SEM) in patients ~ receiving fenoldopam
Fenoldopam -
PatientGroup %@red renal function Blood pressure (mm/Hg) Heart rate (beatslmin) Nonimpairedrenal function Blood pressure (mmHg) Heart rate (beats/rein)
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Maintenance
Dose (~g/kg/min)
214 t 8/139*6 86*6 < 11
208 A 6/130*2
176 k 81107&3* 86*6
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p <0.001 for systolic and diastolic blood prassures compamd with baseline
From: Shusternwn, et al., Amm”can Journal of Mediche 1993,95:161-168 @ -7(
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Conclusions
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Over 500 patients studied in 11 trials Wide range of patients studied Effects of fenoldopam are consistent Rapid onset Dose-dependent lowering rate and magnitude of BP
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Predictable effects
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Renal Function
Vandana Mathur, M.D. Neurex Corporation w ,.. , “/”
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Renal Function
Introduction
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Q Summary of SKF hypertension studies addressing renal function - Blood pressure - Glomerular filtration - Renal blood flow “ Review of Neurex renal function study “ Review of independent renal function study by i O’Connell, et al. NEu
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Renal Function
SKF Hypertension Studies
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5 studies including 77 patients with various degrees of hypertension were studied on fenoldopam 2 2
“ Placebo-controlled:
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Positive-control Uncontrolled: 1
(sodium nitroprusside):
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SKF Hypertension 1200
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Placebo
L42 FEN (N = 13) L42 SNP (N = 13)
600 -~+ 400 Fenoldopa Nitropruss
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Neurex Study: Introduction
Objective To study the relationship Subjects: 14 normal males of renal plasma flow to fenoldopam w dose
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Design: Randomized, placebo-controlled, alternative sodium diet
double-blinded
trial. Crossover to
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Doses: 0.03, 0.1, and 0.3 pglkglmin fixed infusions Renal hemodynamics: Renal plasma flow (PAH) Glomerular filtration rate (inulin) Electrolyte excretion Hormone levels
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HTN(N=ll)
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Hypertension.
1997;29: 1 5-122
NE’UREX ,.,
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Renal Function
Conclusions
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Fenoldopam increases or maintains renal plasma flow and maintains glomerular filtration while lowering systemic blood pressure Strongly suggests that the drug is unlikely to compromise renal function when used for blood pressure control Maintenance of renal perfusion and function during blood pressure lowering is an important pharmacologic and safety feature of this DA, receptor agonist
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IV Experience
Disease State Hypertensive emergency Severe hypertension Mild-to-moderate hypertension Postoperative HT CHF Renal failure Hepatic disease Transplant Other Total patients Healthy subjects Total Experience No. of Studies 1
No. of PatientslSubjects w 94 348 127 89 167 75 48 2“1
10
7 3 6 4 4 2 3
40 1,009 258
1,267
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Adverse Events*
Clinical Events (N= 1,009) Headache Flushing Nausea Hypotension Decreased serum potassium ECG abnormalities Tachycardia Vomiting Dizziness Extrasystoles Dyspnea Patients No. 116 53 52 48 36 29 29 29 27 23 16
SKF and Neurex Fenoldopam
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Serious Adverse Events
23 non-fatal serious adverse events Related or possibly related to study drug Resolved with treatment 18 related to cardiovascular system
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Serious Adverse Events
Related or Possibly Related
Hypotension T-wave inversion Extrasystoles Tachycardia Heart failure Chest pain Projectile vomiting Severe abdominal pain Postoperative bleeding Creatinine increase !lVlentalstatus impairment
6 5 2 2 2
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Deaths
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19 deaths in total from 1,267 patients/normal subjects exposed to IV fenoldopam - No deaths in Neurex studies -2 deaths in hypertension studies -17 deaths in other diseases
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Deaths
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17 deaths in other diseases studied
-14
deaths occurred post-therapy
-3 deaths occurred on-therapy + 1 death in CHF patient, possibly related to study drug (ventricular fibrillation)
+ 2 deaths in transplant rejection patients, unrelated to study drug
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Wide variety of drugs used Generally successful transfer to oral drugs
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Frequency of Prescribed Oral Antihypertensive Medications
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QTc Intervals ~
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Uncontrolled severe hyperterfsion trials suggested 1-2Y0 prolongation Three trials reviewed by central reader - SKF: - Neurex: - Neurex: Severe hypertension (D1 101) Mild to moderate hypertension (94-005) Hypertensive emergencies (94-006)
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Mild to Moderate Hypertension
Dose
Placebo
N
-94-005
# Pts. With 6hr AQTc ~ 50 msec # Pts. With 6 hr. A QTc ~ 10%
0.04 0.1 0.4 0.8
7 7 7 4 6
Baseline QTc msec 413 430 402 402 404
Change at 6 hours msec -6.0 -2.3 1.7 -3.3 6.3
# Pts. With 6hr QTc2 500 msec .
0
0
0 0 0 0
0 0 0 0
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Hypertensive
0.01 0.03 0.1 0.3 18 23 16 19 449 448 445 437
Emergencies
5.4 3.7 -9.1 7.4 2 2 0 1
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Severe Hypertension
Fenoldopam Nitroprusside 50 58 441 435 4.1 8.4
- DI 101
1 3 2 1 4 2
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QTc Summary
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No dose-related increase in number of patients * with:
- QTc z 500 msec - A QTc >50 msec
- A QTc > 10% increase Q No fatal events among 561 high risk severe hypertension patients
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Good Safety Profile Q Well-tolerated
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Adverse
effects
- Mostly exaggerated pharmacologic effects *
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No evidence of fenoldopam-induced compromise No unexpected
end-organ
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laboratory abnormalities
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QTc interval changes - No dose related - Without clinical sequelae
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Good Safety Characteristics
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No intra-arterial line required Short half-life - Fast offset and onset allows safe transition to oral therapy
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Summary
Robert R. Luther, M.D. Neurex Corporation
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Efficacy:
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Dosing Recommendation
Usual starting dose = 0.1 ~glkglmin - Rapid and substantial hypotensive effect - Little or no increase in heart rate Dosing increments at intervals not <30 minutes
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c Higher starting doses recommended when greater rate andlor magnitude of effect is desired
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Label Considerations
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Indications - Short-term treatment of hypertension when oral therapy is not feasible or possible - Treatment of severe hypertension with or without acute end-organ damage Renal pharmacology
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Fenoldopam Benefits u
Ease of use Rapid, predictable, dose dependent blood pressure lowering without overshoot
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Short tl/2, rapid attainment Ofc~~, ease of titration Well-behaved, linear pharmacokinetics No cytochrome P450interactions Starting dose and dose-response curves well defined No dosing adjustment for pre-existing renal or hepatic disease Good safety profile with no evidence of end-organ compromise
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