Indications: Tadalifil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability.
Mechanism: Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and therefore lower cGMP concentrations in the pulmonary vascular smooth muscle. Inhibition of PDE5 by tadalafil increases concentrations of cGMP, resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vasculature.
Dosing: 40 mg once daily (2 x 20 mg tabs), with or without food. Dividing the dose (40 mg) over the course of the day is not recommended.
Efficacy: A randomized, double-blind, 16 week placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension. The primary efficacy endpoint was the change from baseline at week
16 in 6-MWD (Figure 1). In the tadalifil 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD was 33 meters (95% C.I. 15-50 meters; p=0.0004). The improvement in 6-MWD was apparent at
8 weeks of treatment and then maintained at week 12 and week 16.
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There was less clinical worsening (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE5 inhibitor], or worsening WHO functional class) in the tadalifil
40 mg group compared to the placebo group and the groups that used lower doses of tadalifil (Figure 2).
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Adverse Events: The most common adverse reaction is headache. Other serious reactions include hypotension, vision loss, hearing loss, and priapism; these are discussed further under Warnings.
Warnings:
- Cardiovascular effects: patients with certain underlying conditions (e.g., cardiovascular disease, impaired autonomic control of blood pressure, aortic stenosis) could be adversely affected by vasodilatory effects of tadalifil. Not recommended in patients with pulmonary veno-occlusive disease.
- Concomitant alpha-blockers or alcohol: Note additive blood pressure-lowering effects.
- Drug interactions with ritonavir/CYP3A4 mofifiers, see Drug Interactions
- Effects on the eye: Patients should seek immediate medical attention if sudden loss of vision occurs, which could be a sign of non-arteritic ischemic optic neuropathy (NAION).
- Hearing impairment: Advise patients to seek immediate medical attention if sudden decrease or loss of hearing occurs.
- Concomitant PDE5 inhibitors: Avoid use with CIALIS or other PDE5 inhibitors.
- Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours.
Contraindications:
- Concomitant organic nitrates
- History of known serious hypersensitivity reaction to tadalifil (ADCIRCA or CIALIS)
Metabolism/Drug interactions: Tadalifil is predominantly metabolized by CYP3A.
- Co-administration of tadalifil in patients on ritonavir: In patients receiving ritonavir for at least one week, start tadalifil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of tadalifil during the initiation of ritonavir.
- Co-administration of ritonavir in patients on tadalifil: Stop tadalifil at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume tadalifil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
- Other concomitant potent CYP3A inhibitors: Avoid use with tadalifil.
- Potent inducers of CYP3A: Avoid use of tadalifil in patients chronically taking potent inducers of CYP3A (e.g., rifampin).
- Nitrates: Do not use tadalifil in patients who are using any form of organic nitrate; tadalifil may potentiate the hypotensive effect of nitrates. If nitrate administration is deemed medically necessary in a life- threatening situation to a patient who has received tadalifil, at least 48 hours should elapse after the last dose of tadalifil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
- Alpha-Blockers: PDE5 inhibitors (including tadalifil) and alpha-adrenergic blocking agents are both vasodilators which lower blood pressure. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.
- Antihypertensives: PDE5 inhibitors (including tadalifil) are mild systemic vasodilators. Tadalifil may potentiate the blood pressure-lowering effects of selected antihypertensive medications (i.e. amlodipine, angiotensin II receptor blockers, enalapril, and metoprolol).
- Alcohol: Both alcohol and tadalifil, a PDE5 inhibitor, act as mild vasodilators. When taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalifil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
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