Voici le rapport de la FDA !!!!
Auj. à 11:43
Tiré du rapport ''FDA’s Joint Meeting of the Arthritis Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Briefing Document for 12 May 2010 Meeting'' qui fait 162 pages.
Lisez ces extraits, ils sont absolument éclairants !!!!!
NicOx is seeking the approval of naproxcinod for the relief of the signs and symptoms of OA (OA = arthrose).
Naproxcinod represents an additional treatment option for physicians and OA patients,
combining the proven efficacy and safety of naproxen with an NO-donating moiety that
mitigates some of the known side effects of NSAIDs. Naproxcinod is less likely to increase BP
than NSAIDs, which may be of particular importance to OA patients with pre-existing
hypertension. The overall benefit/risk profile of naproxcinod 750 mg bid and 375 mg bid is
positive and supports its use for the relief of the signs and symptoms of OA .
In conclusion, the nonclinical program conducted with naproxcinod has defined the
pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), metabolism, and
toxicology profile of the compound in several species. Naproxcinod did not present any
additional risk beyond those already reported for naproxen. Results were predictive of the
efficacy and adverse effects observed in humans. There were no nonclinical findings that would
preclude its safe administration to humans.
In contrast to the effect on BP (BP = blood pressure / pression artérielle) commonly observed with other NSAIDs vs. placebo, naproxcinod
750 mg bid did not show an increase in BP in the overall safety population.
The naproxcinod SBP profile was similar to placebo. The effects of naproxcinod on BP were a central focus of all phases of the naproxcinod
development program. Particular attention was taken to assure standardized, accepted
methodologies to measure BP, including both cuff BP measurements during office visits as well
as extensive use of ABPM studies (3 trials involving 548 participants, with data collected at
various time points up to 13 weeks of treatment) to evaluate BP over an entire 24-hour period
(two dosing cycles).
The results of these studies consistently demonstrated a difference in the BP response to
naproxcinod compared to naproxen. The ABPM studies documented that when comparing
equimolar doses of these two agents, there was a lower (1 to 5 mmHg) BP response with
naproxcinod, and this conclusion was further supported by PK/PD analysis in a subset of
patients. OBPM similarly demonstrated a small but consistent difference in BP between
naproxcinod and naproxen, with the distribution of BP changes in the naproxcinod-treated
patients being similar to that of placebo while naproxen resulted in a shift of this distribution to
higher BP values, with a greater incidence of BP destabilization. Based on these highly
consistent data, naproxcinod mitigates the BP increase seen with naproxen in the overall
population, in particular in these hypertensive OA patients receiving RAB therapy.
Specific attention throughout all phases of the development program was also directed toward
potential hypotensive effects of naproxcinod therapy. No evidence of clinically important side
effects attributed to hypotension was observed, other than a slightly increased incidence of
dizziness in patients on naproxcinod. There was no evidence of an increased incidence of
discontinuation due to potential hypotension-related adverse effects.
Across all the Phase 1, Phase 2 and Phase 3 studies, orthostatic challenge with the proposed
therapeutic doses of naproxcinod failed to elicit an increased incidence of prespecified decreases
in BP after naproxcinod therapy when compared to either active comparators or placebo.
Additional data related to orthostatic hypotension-related events are displayed in the following
section.
Use of Medication Guide
In order for patients to understand naproxcinod’s risks and use appropriately, the naproxcinod
REMS will educate patients using a Medication Guide. A Medication Guide is a current FDA
requirement for all NSAIDs, and the naproxcinod version is built around the “class” Medication
Guide. A copy of the proposed Medication Guide for Tradename™ is attached. A Medication
Guide will be dispensed with each Tradename™ prescription.
The US FDA requires that any drug with a Medication Guide has a Risk Evaluation and
Mitigation Strategy (REMS) to ensure that patients are aware of important safety information
associated with administration of Tradename™ (naproxcinod) Capsules. The primary goal of the
naproxcinod REMS is to communicate to patients the key safety information on Tradename™
(naproxcinod) Capsules including the risks serious GI and CV events.
Pursuant to 21 CFR 208.24, the Medication Guide will be made available in sufficient numbers
to distributors of Tradename™. Distributors will provide the Medication Guide with every
pharmacy shelf container of Tradename™ to ensure its availability for dispensing to patients
who are prescribed Tradename™. The label of each container or package of Tradename™ will
include a prominent instruction to authorized dispensers to provide a Medication Guide to each
patient to whom the drug is dispensed. In addition, the Medication Guide will be included with
all samples and trade packages intended for direct distribution to patients. The Medication
Guide will comply with 21 CFR §208 and the current FDA recommendations for risk
information for the class of NSAIDs.
A patient package insert is not being proposed due to the availability of a Medication Guide.
The goal of the Tradename™ REMS is to educate patients on the risks of administration of
naproxcinod and, therefore, no specific communication plan for healthcare providers is being
proposed as part of the REMS.
Naproxcinod represents a new treatment option for the relief of the signs and symptoms of OA and has been shown to be safe and effective. Naproxcinod has been designed to release naproxen and a NO-donating moiety. Naproxcinod shares the NSAID class related risks of naproxen together with the class warning. The clinical development program showed that naproxcinod has an improved safety profile with respect to BP.
These benefits were achieved without observing a clinically relevant risk due to hypotension or orthostatic hypotension.
Overall, the efficacy and safety data from the clinical studies support a positive benefit risk for naproxcinod in the treatment of patients with OA. The results achieved with naproxcinod clearly demonstrate that naproxcinod provides clinically meaningful benefit for patients, and is less likely to increase BP, without any added GI or CV risks.
