PHOSPHODIESTERASE 5 INHIBITOR

INTERACTION BETWEEN THE PHOSPHODIESTERASE 5 INHIBITOR, TADALAFIL AND 2 α-BLOCKERS, DOXAZOSIN AND TAMSULOSIN IN HEALTHY NORMOTENSIVE MEN

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Tadalafil, a phosphodiesterase type 5 inhibitor, is effective therapy for erectile dysfunction (ED). Men with ED have a high incidence of comorbid conditions including cardiovascular disease, diabetes mellitus and benign prostatic hyperplasia. Although phosphodiesterase type 5 inhibitors are safe when administered with most medications, sildenafil given with doxazosin and vardenafil given with terazosin evoke orthostatic hypotension in some patients.

Tadalafil augmented the hypotensive effects of doxazosin but had little hemodynamic interaction with tamsulosin. In patients taking tadalafil for ED, tamsulosin 0.4 mg may be given for the treatment of benign prostatic hyperplasia.
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It is in a class of drugs called phosphodiesterase inhibitors. The most common side effects of Cialis are facial flushing (reddening), headaches, stomach upset, diarrhea, flu-like symptoms, and nausea. Cialis also may cause low blood pressure, blurred vision and changes in color vision, abnormal ejaculation, and priapism.

The breakdown and elimination of Cialis from the body may be decreased by erythromycin, ketoconazole (Nizoral), itraconazole (Sporanox), indinavir (Crixivan) and ritonavir (Norvir). Therefore, these drugs may increase the levels of Cialis in the blood. Cialis exaggerates the increases in heart rate and lowering of blood pressure caused by nitrates (for example, nitroglycerin, isosorbide dinitrate (Isordil), isosorbide mononitrate (Imdur)
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Tadalafil is used to treat male sexual function problems (impotence or erectile dysfunction) by blocking a certain enzyme (phosphodiesterase-PDE5) in the body. In combination with sexual stimulation, tadalafil helps blood flow into the penis to achieve and maintain an erection.
Use of this drug does not protect against sexually transmitted diseases (e.g., HIV, hepatitis B, gonorrhea, syphilis). Practice "safe sex" such as using latex condoms. Consult your doctor or pharmacist for more details.
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Trade Names
Adcirca
- Tablets 20 mg

Cialis
- Tablets 2.5 mg
- Tablets 5 mg
- Tablets 10 mg
- Tablets 20 mg

Pharmacology
Adcirca
Inhibition of phosphodiesterase type 5 (PDE5) by tadalafil increases the concentrations of cyclic guanosine monophosphate (cGMP), resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Cialis
Enhances the effect of nitric oxide at the nerve ending and endothelial cells in the corpus cavernosum by inhibiting PDE5 in the corpus cavernosum of the penis. This results in vasodilation, increased inflow of blood into the corporus cavernosum, and ensuing penile erection upon sexual stimulation.

Pharmacokinetics
Absorption

Bioavailability undetermined. T max is 2 to 8 h (median, 4 h) ( Adcirca ) and 30 min to 6 h (median, 2 h) ( Cialis ). Food does not influence rate and extent of absorption of tadalafil.

Distribution

Vd of tadalafil is approximately 77 L ( Adcirca ) and 63 L ( Cialis ). Tadalafil is 94% protein bound.

Metabolism

Predominantly metabolized by CYP3A4 to a catechol metabolite, which undergoes further metabolism to the major circulating metabolite, a methylcatechol glucuronide.

Elimination

Mean oral Cl is 3.4 L/h ( Adcirca ) and 2.5 L/h ( Cialis ). The mean half-life is 15 h ( Adcirca ) and 17.5 h ( Cialis ). Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61%) and to a lesser degree in the urine (about 36%).

Special Populations

Renal Function Impairment
Tadalafil exposure (AUC) doubled in subjects with CrCl 31 to 80 mL/min. In patients with ESRD on hemodialysis, there was a 2-fold increase in C max and 2.7- to 4.1-fold increase in AUC. Dosage adjustments are required.

Hepatic Function Impairment
Tadalafil exposure (AUC) after a 10 mg dose in patients with mild or moderate hepatic impairment was comparable with exposure in healthy subjects. There are insufficient data for subjects with severe hepatic impairment.

Elderly
Subjects older than 65 yr of age have a 25% higher exposure compared with subjects 19 to 45 yr of age; however, no dosage adjustment is warranted based on age alone.

Children
Tadalafil has not been evaluated in children.

Gender
No clinically relevant differences in AUC and C max have been observed.

Race
No differences in the typical exposure to tadalafil have been identified among different ethnic groups.

Indications and Usage
Treatment of pulmonary arterial hypertension (WHO group I) ( Adcirca ); treatment of erectile dysfunction ( Cialis )

Unlabeled Uses

Raynaud phenomenon

Contraindications
Administration with nitrates; hypersensitivity to any component.

Dosage and Administration
Pulmonary Arterial Hypertension ( Adcirca )
Adults
PO 40 mg taken once daily with or without food.

Erectile Dysfunction ( Cialis )
Adults
PO

For use as needed
10 mg prior to anticipated sexual activity. The dose may be titrated to 5 or 20 mg based on efficacy and tolerability. The max recommended frequency is once per day for most patients.

Once-daily use
Start with 2.5 mg once daily, taken at approximately the same time each day, without regard to timing of sexual activity. The dosage may be increased to 5 mg daily based on individual efficacy and tolerability.

Hepatic Function Impairment
Adults
PO

Adcirca Mild or moderate hepatic impairment (Child-Pugh class A or B)
Consider a starting dosage of 20 mg/day.

Severe hepatic impairment (Child-Pugh class C)
Use is not recommended.

Cialis For use as needed Mild or moderate hepatic impairment:
Use with caution. Dosage should not exceed 10 mg/day.

Severe hepatic impairment:
Use is not recommended.

For once-daily use Mild or moderate hepatic impairment:
Not extensively evaluated; use with caution.

Severe hepatic impairment:
Use is not recommended.

Renal Function Impairment
Adults
PO

Adcirca Mild or moderate renal impairment (CrCl 31 to 80 mL/min)
Start dosing at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Severe renal impairment (CrCl less than 30 mL/min)
Use not recommended.

Cialis For use as needed Mild renal impairment:
No dosage adjustment is required.

Moderate renal impairment (CrCl 31 to 50 mL/min)
Start with 5 mg not more than once a day (max, 10 mg every 48 h).

Severe renal impairment (CrCl less than 30 mL/min and on hemodialysis)
Max recommended dosage is 5 mg not more than once every 72 h.

For once-daily use Mild or moderate renal impairment (CrCl 31 to 80 mL/min)
No dosage adjustment is required.

Severe renal impairment (CrCl less than 30 mL/min and on hemodialysis)
Once-daily use is not recommended.

Concurrent Medications
Adults
PO

Alpha blockers
Patients should be stable on alpha-blocker therapy prior to starting tadalafil. Tadalafil should be started at the lowest recommended dose.

Potent CYP3A4 inhibitors (eg, ketoconazole, ritonavir) Adcirca
Avoid use during the initiation of ritonavir; stop Adcirca at least 24 h before staring ritonavir. After at least 1 wk of ritonavir, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Cialis For use as needed:
Max recommended dose is 10 mg, not to exceed once every 72 h.

For once-daily use:
Max dose should not exceed 2.5 mg.

General Advice

May be taken without regard to food.
Storage/Stability
Store at 59° to 86°F.