FDA Approvals: Tadalafil for Benign Prostatic Hyperplasia
Clinical Context
Tadalafil is a phosphodiesterase-5 (PDE5)
inhibitor that was approved by the US Food and Drug Administration (FDA)
in 2003 to treat erectile dysfunction (ED). The FDA has now expanded
the approved indications to include benign prostatic hyperplasia (BPH),
either alone or in combination with ED.
The inhibition of PDE5 by tadalafil improves
erectile function by increasing the amount of cyclic guanosine
monophosphate in the smooth muscle of the corpus cavernosa. This action
increases penile blood flow, resulting in penile erection during sexual
stimulation. PDE5 inhibition also affects concentration of cyclic
guanosine monophosphate in the smooth muscle of the prostate, the
bladder, and their vascular supply, but the precise mechanism for
reducing BPH symptoms has not been determined.
Study Synopsis and Perspective
The FDA approved tadalafil (Cialis, Eli
Lilly) a PE5 inhibitor to also treat the signs and symptoms of BPH as
well as a combination of BPH and ED when the conditions coincide.
Men with BPH often experience sudden urges to urinate, difficulty in
starting urination, a weak urine stream, and more frequent urination,
including at night. In 2 clinical trials, men with BPH who took 5 mg of
tadalafil daily experienced a significant improvement in these symptoms
compared with men receiving a placebo. A third study showed that men who
experienced both ED and BPH and who took 5 mg of tadalafil daily had
improvement in both conditions compared with a placebo group.
Scott Monroe, MD, director of the Division of Reproductive and
Urologic Products in the FDA's Center for Drug Evaluation and Research,
said in a press release that both BPH and ED are common disorders among
older men. "Cialis offers these men another treatment option," Dr.
Monroe said.
For men with BPH or ED and BPH, dosage of tadalafil is 5 mg, taken at
approximately the same time every day, with or without food.
Tadalafil joins a long list of other FDA-approved drugs for BPH symptoms: finasteride (Proscar); dutasteride (Avodart); dusasteride plus tamsulosin (Jalyn); and alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo).
The agency approved tadalafil for treating ED in 2003.
The FDA advises clinicians that they should not prescribe tadalafil
for men taking nitrates such as nitroglycerin because the combination
may trigger an unsafe drop in blood pressure. Also, the agency does not
recommend combining tadalafil with alpha-blockers for the treatment of
BPH because the combination therapy has not been adequately studied, and
it comes with a risk of lowering blood pressure.
Warnings and Precautions
Men with limited cardiovascular function precluding sexual activity should not use tadalafil.
Concomitant use of tadalafil with alpha-blockers, antihypertensive drugs, or 5 or more units of alcohol may cause hypotension.
The dose of tadalafil should be adjusted for men taking potent
inhibitors of cytochrome P450 3A4 (CYP3A4) such as ketoconazole or
ritonavir, which increase exposure to tadalafil. For once-daily use, the
dose of tadalafil should not exceed 2.5 mg, and for use as needed for
ED, the cumulative dose should not exceed 10 mg every 72 hours.
CYP3A4 inducers such as rifampin reduce exposure to tadalafil.
In men with a history of priapism, tadalafil should be used with
caution. If an erection lasts for more than 4 hours, men taking
tadalafil should seek emergency treatment.
A sudden loss of vision in 1 or both eyes in men taking tadalafil may
be a sign of nonarteritic ischemic optic neuropathy (NAION). These
patients should stop the drug and seek medical attention. Patients with a
history of NAION should be counseled regarding the increased risk for
NAION with use of tadalafil.
Men who experience sudden decrease or loss of hearing while taking tadalafil should stop the drug and seek prompt medical care.
Before prescribing tadalafil for treatment of BPH, clinicians should rule out other urologic conditions with similar symptoms.
The most often reported adverse reactions, occurring in 2% or more of
patients taking tadalafil, include headache, dyspepsia, back pain,
muscle pain, nasal stuffing, flushing, and limb pain.
Use in Specific Populations
Use of tadalafil is not recommended in patients with severe hepatic
impairment, and dosage adjustment may be needed in patients with mild or
moderate hepatic impairment.
Once-daily use of tadalafil is not recommended in patients with renal
impairment requiring hemodialysis or in patients with a creatinine
clearance of less than 30 mL/minute. For use in these patients as needed
for ED, the dose should not exceed 5 mg every 72 hours. Dosage
adjustment may be needed in patients with a creatinine clearance of 30
to 50 mL/minute.
Clinical Implications
- The FDA has now approved daily use of tadalafil to treat urinary signs and symptoms in men with BPH. The drug may also be used to treat both BPH and ED when these conditions coexist. For daily use in BPH or BPH/ED, the dosage of tadalafil is 5 mg, taken at approximately the same time every day, with or without food.
- Use of tadalafil with nitrates, alpha-blockers, antihypertensive drugs, or 5 or more units of alcohol may cause hypotension. Men in whom cardiovascular function is too limited to engage in sexual activity should not be given tadalafil. Potent inhibitors of CYP3A4 increase exposure to tadalafil, whereas CYP3A4 inducers such as rifampin reduce exposure to tadalafil. Before prescribing tadalafil for treatment of BPH, clinicians should rule out other urologic conditions causing similar symptoms.
- Patients with severe hepatic impairment should not be prescribed tadalafil. Patients with mild or moderate hepatic impairment may require dosage adjustment. Patients with renal impairment requiring hemodialysis, or patients with a creatinine clearance of less than 30 mL/minute, should not use tadalafil once daily. For as-needed use, the dose should not exceed 5 mg every 72 hours. Patients with a creatinine clearance of 30 to 50 mL/minute may require dosage adjustment.
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