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From Medscape Medical News

FDA Approvals: Rapaflo and Akten
News Author: Yael Waknine
CME Author: Yael Waknine

October 16, 2008 — The US Food and Drug Administration (FDA) has approved
silodosin capsules for the treatment of benign prostatic hyperplasia and lidocaine HCl
3.5% ophthalmic gel for analgesic use in ophthalmic procedures.

Silodosin Capsules (Rapaflo) Approved for the Treatment of Benign Prostatic

Hyperplasia

On October 8, the FDA approved silodosin capsules (Rapaflo; Watson Laboratories, Inc)
for the treatment of signs and symptoms of benign prostatic hyperplasia (BPH).

Silodosin is a selective α1-adrenergic blocker with a high affinity for α-receptors

concentrated in the prostate. Their binding causes smooth muscles in these tissues to relax,
thereby improving urine flow and reducing BPH symptoms.

Its affinity for α1β-receptors is significantly lower, yielding a reduced potential for drug
interactions and adverse cardiovascular events; no meaningful prolongation of the QT
interval has been observed in clinical trials.

The approval of silodosin was based on data from two phase 3, 12-week, randomized,
double-blind, placebo- controlled, multicenter studies as well as a 40-week open-label
safety study.

A pooled analysis of results from the phase 3 studies (n = 923; mean age, 64.6 years)
showed that use of 8-mg silodosin yielded significant and rapid relief of BPH symptoms
relative to placebo, as measured by the change in points on the International Prostate
Symptom Score (IPSS mean Δ, –6.4 vs –3.5; P < .0001). IPSS subanalysis revealed
reduction of irritative (frequency, urgency, and nocturia) and obstructive (hesitancy,
incomplete emptying, intermittency, and weak stream) symptoms (mean Δ, –2.3 vs –1.4
and –4.0 vs –2.1; P < .0001 for both).

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On secondary endpoints, silodosin was shown to significantly improve maximal urine flow
rate (Qmax score) both at 2 to 6 hours after the first dose (mean Δ, 2.8 mL/second vs 1.5
mL/second; P < .0001) and after 12 weeks (mean Δ, 2.6 mL/second vs 1.5 mL/second; P
= .0007).

Data from the 9-month, open-label extension trial of patients who had successfully
completed the phase 3 studies (n = 661) showed that although 65.2% of all patients
reported at least 1 adverse event, less than one third of these events (28.4%) were drug
related. Retrograde ejaculation was the most commonly reported treatment- emergent
adverse event, followed by dizziness.

Efficacy endpoints for the evaluable population (n = 429) showed that IPSS decreased by
a mean of 3.1 points between weeks 0 and 40. Although the decrease was greater in
patients who were previously randomly assigned to placebo therapy, those continuing to
receive silodosin also experienced amelioration of symptoms (mean Δ, –4.4 vs –1.6).
Decreases in irritative and obstructive symptoms were likewise represented (mean Δ, –1.7
vs –0.6 and –2.7 vs –1.0, respectively).

Results from a fourth study (n = 22) revealed that concomitant use of silodosin and
maximal doses of sildenafil or tadalafil in healthy men yielded no changes in blood
pressure, heart rate, or orthostatic symptoms. The number of positive orthostatic tests
(decrease in systolic/diastolic pressure by > 30/20 mm Hg, > 20-bpm increase in heart
rate, or orthostatic symptoms on change of position) was similar for all treatments, both in
patients younger than65 years (sildenafil [n = 28] and tadalafil [n = 27] vs placebo [n =
29]) and patients older than 65 years (sildenafil [n = 6] and tadalafil [n = 8] vs vs placebo
[n = 5]).

"These data provide important new evidence about this potential treatment option for BPH.
Considering that many men with BPH also have other co-morbid conditions, including
erectile dysfunction, heart failure, hypertension and coronary artery disease, it's important
to find complementary treatments that can be used with other medications without
deleterious cardiovascular interactions, including the prolongation of the QTc interval and

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do not complicate patient care," said Norman Lepor, MD, in a company news release.

Dr. Lepor is a cardiologist and associate clinical professor of medicine at the University of
California, Los Angeles and an attending cardiologist at the Heart Institute at Cedars-Sinai
Medical Center.

According to the news release, silodosin capsules are expected to be available in strengths
of 4 and 8 mg during early 2009.

Lidocaine HCl Gel (Akten) Approved for Ophthalmic Topical Anesthesia

On October 7, the FDA approved lidocaine HCl 3.5% ophthalmic gel (Akten; Akorn, Inc)
for ocular surface anesthesia during ophthalmic procedures.

The unit-dose, preservative-free lidocaine gel product is expected to be launched this month.

Its approval was based on data from a multicenter, randomized controlled, double-blind
phase 3 clinical trial (n = 209), showing that use of lidocaine 3.5% gel achieved anesthesia
within 5 minutes for 92% of patients.

Time to onset of anesthesia ranged from 20 seconds to 5 minutes (mean, 60 seconds;

median, 40 seconds). Of the patients who achieved anesthesia within 5 minutes,
approximately 90% had done so within 1 minute of dose application.

Duration of anesthesia generally ranged from approximately 5 to 30 minutes (mean, 15

minutes). Nearly 84% of subjects experienced anesthesia for at least 5 minutes, 55%
experienced it for 10 minutes or longer, and 27% experienced anesthesia for 15 minutes or
longer.

"The robust data from the multi-center clinical trial with respect to rapid onset and
extended duration of anesthesia will be ideally suited for many ophthalmic procedures in
both hospital and office based surgical setting," Abu Alam, PhD, Akorn's senior vice
president of new business development, said in a company news release.

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The recommended dose of the local analgesic is 2 drops applied to the area of the planned
procedure. Although the anesthetic effect of additional applications has not been
evaluated, the gel may be reapplied as needed.

Rapaflo Prescribing Information

Lidocaine HCl 3.5% Ophthalmic Gel Prescribing Information

Pearls for Practice

The FDA has approved silodosin for the symptomatic treatment of benign prostatic
hyperplasia. In clinical trials, use of silodosin 8 mg/day significantly decreased irritative
and obstructive disease symptoms and improved the maximal flow rate without causing
cardiovascular adverse events or drug interactions with sildenafil or tadalafil.

Lidocaine HCl 3.5% ophthalmic gel has been approved for ocular surface anesthesia
during ophthalmic procedures. The recommended dose is 2 drops to the procedural area;
92% of patients achieve anesthesia within 5 minutes (90% of patients in the first 60
seconds). Duration of anesthesia is 5 to 30
minutes (mean, 15 minutes).

Medscape Medical News © 2008

The material presented here does not necessarily reflect the views of Medscape or
companies that support educational programming on www.medscape.com. These materials
may discuss therapeutic products that have not been approved by the US Food and Drug
Administration and off-label uses of approved products. A qualified healthcare professional
should be consulted before using any therapeutic product discussed. Readers should verify
all information and data before treating patients or employing any therapies described in this
educational activity.

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