Dosage Details for Cialis

Adcirca, Alyq, or generic equivalent only

tadalafil (Rx)

PRN use: 10 mg PO initially before sexual activity, with or without food; may be increased to 20 mg or reduced to 5 mg on basis of efficacy and tolerability; in most patients, maximum dosing frequency is once daily

Once-daily use: 2.5 mg/day PO in single daily dose, without regard to timing of sexual activity, with or without food; may be increased to 5 mg/day on basis of efficacy and tolerability

Dosing considerations

• PRN use: Decrease dose with concomitant use of potent CYP3A4 inhibitor (eg, ritonavir, ketoconazole, itraconazole); not to exceed 10 mg/72 hr
• Once-daily use: Decrease dose with concomitant use of potent CYP3A4 inhibitor (eg, ritonavir, ketoconazole, itraconazole); not to exceed 2.5 mg/day

Benign Prostatic Hyperplasia

Indicated for treatment of signs and symptoms of benign prostatic hyperplasia (BPH); daily use also indicated for treatment of patients with both BPH and erectile dysfunction

BPH with ED: 5 mg PO once daily, taken at approximately same time each day without regard to timing of sexual activity

Coadministration with finasteride for BPH: Tadalafil 5 mg plus finasteride 5 mg PO once daily for ≤26 weeks; incremental benefit of tadalafil decreases from 4 weeks until 26 weeks, and the benefit beyond 26 weeks is unknown

Pulmonary Arterial Hypertension

Indicated for pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability; studies establishing effectiveness included predominately patients with NYHA Functional Class II – III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%)

Adcirca, Alyq, or generic equivalent only

40 mg PO once daily; dividing dose for more frequent dosing is not recommended

Patients also taking ritonavir: 20 mg PO once daily initially for ≥1 week; may be increased to 40 mg/day on basis of tolerability

Dosing considerations

• If possible, avoid coadministration with CYP3A4 inhibitors; if coadministration is essential, long-term therapy is indicated, or strong CYP3A4 inhibitors are required, modify or hold dose
• Patients already taking strong CYP3A4 inhibitor who require tadalafil: 20 mg PO once daily; may be increased to 40 mg/day on basis of tolerability
• Patients already taking tadalafil who require strong CYP3A4 inhibitor: Avoid using tadalafil while starting strong CYP3A4 inhibitor; stop tadalafil ≥24 hours before starting strong CYP3A4 inhibitor; after 1 week, resume tadalafil at 20 mg PO once daily; may be increased to 40 mg/day on basis of tolerability

Dosing Modifications

Renal impairment (ED)

Cialis (PRN use)

• Mild (CrCl ≥51 mL/min): No dosage adjustment needed
• Moderate (CrCl 30-50 mL/min): Not to exceed 5 mg PO once daily initially; maximum dosage, 10 mg PO q48hr
• Severe (CrCl Enter a drug name and tadalafil

Contraindicated

Serious – Use Alternative

Significant – Monitor Closely

Minor

Contraindicated (11)

• isosorbide dinitrate isosorbide dinitrate, tadalafil. Mechanism: additive vasodilation. Contraindicated. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• isosorbide mononitrate isosorbide mononitrate, tadalafil. Mechanism: additive vasodilation. Contraindicated. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• nitroglycerin IV nitroglycerin IV, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• nitroglycerin PO nitroglycerin PO, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• nitroglycerin rectal tadalafil increases effects of nitroglycerin rectal by additive vasodilation. Contraindicated. Use of nitroglycerin within a few days of PDE5 inhibitors is contraindicated. PDE5 inhibitors have been shown to potentiate the hypotensive effects of organic nitrates.
• nitroglycerin sublingual nitroglycerin sublingual, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• nitroglycerin topical nitroglycerin topical, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• nitroglycerin transdermal nitroglycerin transdermal, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• nitroglycerin translingual nitroglycerin translingual, tadalafil. Mechanism: additive vasodilation. Contraindicated. Potentially fatal hypotension.
• riociguat tadalafil, riociguat. Either increases effects of the other by additive vasodilation. Contraindicated. Coadministration of PDE-5 inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil) and guanylate cyclase stimulators (eg, riociguat) is contraindicated due to risk of additive hypotension; do not administer 24 hr before or within 48hr of each other.
• vericiguat tadalafil, vericiguat. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Coadministration of vericiguat with PDE-5 inhibitors may result in additive hypotensive effects.

Serious – Use Alternative (27)

• abametapir abametapir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.
• amyl nitrite amyl nitrite, tadalafil. Mechanism: additive vasodilation. Avoid or Use Alternate Drug. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• apalutamide apalutamide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
• atazanavir atazanavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• clarithromycin clarithromycin will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• cobicistat cobicistat will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Adjust tadalafil dose for PAH; if on cobicistat, start tadalafil 20 mg/day and may increase up to 40 mg/day; avoid tadalafil when starting cobicistat; for ED, may take a single dose of tadalafil not exceeding 10 mg in 72 hr.
• darunavir darunavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Adjust tadalafil dose for PAH; if on cobicistat, start tadalafil 20 mg/day and may increase up to 40 mg/day; avoid tadalafil when starting cobicistat; for ED, may take a single dose of tadalafil not exceeding 10 mg in 72 hr.
• enzalutamide enzalutamide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
• erythromycin base erythromycin base will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin ethylsuccinate erythromycin ethylsuccinate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin lactobionate erythromycin lactobionate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin stearate erythromycin stearate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• fexinidazole fexinidazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.
• fosamprenavir fosamprenavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• idelalisib idelalisib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates
• indinavir indinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• itraconazole itraconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• ketoconazole ketoconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• levoketoconazole levoketoconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• lonafarnib lonafarnib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.
• lopinavir lopinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• nelfinavir nelfinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• nicardipine nicardipine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• nirmatrelvir/ritonavir nirmatrelvir/ritonavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration if tadalafil used for pulmonary arterial hpertension. Reduce tadalafil dose if used for erectile dysfunction.
• ritonavir ritonavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• tucatinib tucatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.
• voxelotor voxelotor will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

Monitor Closely (154)

• acebutolol tadalafil increases effects of acebutolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• acetazolamide tadalafil increases effects of acetazolamide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• alfuzosin tadalafil increases effects of alfuzosin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• aliskiren tadalafil increases effects of aliskiren by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amifostine amifostine, tadalafil. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Monitor blood pressure response to phosphodiesterase type 5 (PDE5) inhibitors in patients receiving concurrent blood pressure lowering therapy.
• amiloride tadalafil increases effects of amiloride by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amiodarone amiodarone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• amlodipine tadalafil increases effects of amlodipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amobarbital amobarbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• aprepitant aprepitant will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• armodafinil armodafinil will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• artemether/lumefantrine artemether/lumefantrine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• asenapine tadalafil increases effects of asenapine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• atazanavir atazanavir increases levels of tadalafil by decreasing metabolism. Use Caution/Monitor. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• atenolol tadalafil increases effects of atenolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• azilsartan tadalafil increases effects of azilsartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• benazepril tadalafil increases effects of benazepril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• betaxolol tadalafil increases effects of betaxolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• bicalutamide bicalutamide will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• bisoprolol tadalafil increases effects of bisoprolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• bosentan bosentan will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• budesonide budesonide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• bumetanide tadalafil increases effects of bumetanide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• butabarbital butabarbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• butalbital butalbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• candesartan tadalafil increases effects of candesartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• captopril tadalafil increases effects of captopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• carbamazepine carbamazepine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• carvedilol tadalafil increases effects of carvedilol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• cenobamate cenobamate will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
• chlorthalidone tadalafil increases effects of chlorthalidone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• cimetidine cimetidine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• clevidipine tadalafil increases effects of clevidipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• clonidine tadalafil increases effects of clonidine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• clotrimazole clotrimazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• conivaptan conivaptan will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• crizotinib crizotinib increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.
• crofelemer crofelemer increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.
• cyclosporine cyclosporine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• dabrafenib dabrafenib will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.
• dasatinib dasatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• deferasirox deferasirox will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• desipramine desipramine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• dexamethasone dexamethasone will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• diltiazem diltiazem will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Risk of hypotension.
• doxazosin tadalafil increases effects of doxazosin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• dronedarone dronedarone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• duvelisib duvelisib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
• efavirenz efavirenz will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• elagolix elagolix decreases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.
• elvitegravir/cobicistat/emtricitabine/tenofovir DF elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tadalafil dose for PAH; if on Stribild, start tadalafil 20 mg/day; avoid tadalafil when starting Stribild; for ED, a single dose of tadalafil not exceeding 10 mg in 72 hr.
• enalapril tadalafil increases effects of enalapril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• encorafenib encorafenib, tadalafil. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
• eplerenone tadalafil increases effects of eplerenone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• eprosartan tadalafil increases effects of eprosartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• eslicarbazepine acetate eslicarbazepine acetate will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• esmolol tadalafil increases effects of esmolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• ethacrynic acid tadalafil increases effects of ethacrynic acid by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• ethanol ethanol, tadalafil. Either increases effects of the other by additive vasodilation. Use Caution/Monitor. Combination may increase risk of orthostatic hypotension, tachycardia, dizziness and headache.
• etravirine etravirine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fedratinib fedratinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
• felodipine tadalafil increases effects of felodipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• fluconazole fluconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fluvoxamine fluvoxamine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fosinopril tadalafil increases effects of fosinopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• fosphenytoin fosphenytoin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• furosemide tadalafil increases effects of furosemide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• grapefruit grapefruit will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• griseofulvin griseofulvin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• guanfacine tadalafil increases effects of guanfacine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• haloperidol haloperidol will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• hydralazine tadalafil increases effects of hydralazine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• hydrochlorothiazide tadalafil increases effects of hydrochlorothiazide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• iloperidone iloperidone increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.
• imatinib imatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• indapamide tadalafil increases effects of indapamide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• irbesartan tadalafil increases effects of irbesartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• isoniazid isoniazid will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• isradipine tadalafil increases effects of isradipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• istradefylline istradefylline will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.
• labetalol tadalafil increases effects of labetalol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• lapatinib lapatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• letermovir letermovir increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• lisinopril tadalafil increases effects of lisinopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• losartan tadalafil increases effects of losartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• lumefantrine lumefantrine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• maraviroc maraviroc, tadalafil. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of orthostatic hypotension.
• marijuana marijuana will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• metolazone tadalafil increases effects of metolazone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• metoprolol tadalafil increases effects of metoprolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• metronidazole metronidazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• mifepristone mifepristone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• minoxidil tadalafil increases effects of minoxidil by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• mitotane mitotane decreases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.
• nadolol tadalafil increases effects of nadolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• nafcillin nafcillin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• nebivolol tadalafil increases effects of nebivolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• nefazodone nefazodone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• nevirapine nevirapine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• nifedipine nifedipine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Risk of hypotension.

Minor (1)

• ranolazine ranolazine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as tadalafil.

• abametapir Serious – Use Alternative (1) abametapir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.
• acebutolol Monitor Closely (1) tadalafil increases effects of acebutolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• acetazolamide Monitor Closely (1) tadalafil increases effects of acetazolamide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• alfuzosin Monitor Closely (1) tadalafil increases effects of alfuzosin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• aliskiren Monitor Closely (1) tadalafil increases effects of aliskiren by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amifostine Monitor Closely (1) amifostine, tadalafil. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Monitor blood pressure response to phosphodiesterase type 5 (PDE5) inhibitors in patients receiving concurrent blood pressure lowering therapy.
• amiloride Monitor Closely (1) tadalafil increases effects of amiloride by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amiodarone Monitor Closely (1) amiodarone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• amlodipine Monitor Closely (1) tadalafil increases effects of amlodipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• amobarbital Monitor Closely (1) amobarbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• amyl nitrite Serious – Use Alternative (1) amyl nitrite, tadalafil. Mechanism: additive vasodilation. Avoid or Use Alternate Drug. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• apalutamide Serious – Use Alternative (1) apalutamide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
• aprepitant Monitor Closely (1) aprepitant will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• armodafinil Monitor Closely (1) armodafinil will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• artemether/lumefantrine Monitor Closely (1) artemether/lumefantrine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• asenapine Monitor Closely (1) tadalafil increases effects of asenapine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• atazanavir Monitor Closely (1) atazanavir increases levels of tadalafil by decreasing metabolism. Use Caution/Monitor. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability. Serious – Use Alternative (1) atazanavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• atenolol Monitor Closely (1) tadalafil increases effects of atenolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• azilsartan Monitor Closely (1) tadalafil increases effects of azilsartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• benazepril Monitor Closely (1) tadalafil increases effects of benazepril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• betaxolol Monitor Closely (1) tadalafil increases effects of betaxolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• bicalutamide Monitor Closely (1) bicalutamide will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• bisoprolol Monitor Closely (1) tadalafil increases effects of bisoprolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• bosentan Monitor Closely (1) bosentan will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• budesonide Monitor Closely (1) budesonide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• bumetanide Monitor Closely (1) tadalafil increases effects of bumetanide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• butabarbital Monitor Closely (1) butabarbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• butalbital Monitor Closely (1) butalbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• candesartan Monitor Closely (1) tadalafil increases effects of candesartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• captopril Monitor Closely (1) tadalafil increases effects of captopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• carbamazepine Monitor Closely (1) carbamazepine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• carvedilol Monitor Closely (1) tadalafil increases effects of carvedilol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• cenobamate Monitor Closely (1) cenobamate will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
• chlorthalidone Monitor Closely (1) tadalafil increases effects of chlorthalidone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• cimetidine Monitor Closely (1) cimetidine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• clarithromycin Serious – Use Alternative (1) clarithromycin will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• clevidipine Monitor Closely (1) tadalafil increases effects of clevidipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• clonidine Monitor Closely (1) tadalafil increases effects of clonidine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• clotrimazole Monitor Closely (1) clotrimazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• cobicistat Serious – Use Alternative (1) cobicistat will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Adjust tadalafil dose for PAH; if on cobicistat, start tadalafil 20 mg/day and may increase up to 40 mg/day; avoid tadalafil when starting cobicistat; for ED, may take a single dose of tadalafil not exceeding 10 mg in 72 hr.
• conivaptan Monitor Closely (1) conivaptan will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• crizotinib Monitor Closely (1) crizotinib increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.
• crofelemer Monitor Closely (1) crofelemer increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.
• cyclosporine Monitor Closely (1) cyclosporine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• dabrafenib Monitor Closely (1) dabrafenib will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.
• darunavir Serious – Use Alternative (1) darunavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Adjust tadalafil dose for PAH; if on cobicistat, start tadalafil 20 mg/day and may increase up to 40 mg/day; avoid tadalafil when starting cobicistat; for ED, may take a single dose of tadalafil not exceeding 10 mg in 72 hr.
• dasatinib Monitor Closely (1) dasatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• deferasirox Monitor Closely (1) deferasirox will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• desipramine Monitor Closely (1) desipramine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• dexamethasone Monitor Closely (1) dexamethasone will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• diltiazem Monitor Closely (1) diltiazem will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Risk of hypotension.
• doxazosin Monitor Closely (1) tadalafil increases effects of doxazosin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• dronedarone Monitor Closely (1) dronedarone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• duvelisib Monitor Closely (1) duvelisib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
• efavirenz Monitor Closely (1) efavirenz will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• elagolix Monitor Closely (1) elagolix decreases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.
• elvitegravir/cobicistat/emtricitabine/tenofovir DF Monitor Closely (1) elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tadalafil dose for PAH; if on Stribild, start tadalafil 20 mg/day; avoid tadalafil when starting Stribild; for ED, a single dose of tadalafil not exceeding 10 mg in 72 hr.
• enalapril Monitor Closely (1) tadalafil increases effects of enalapril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• encorafenib Monitor Closely (1) encorafenib, tadalafil. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
• enzalutamide Serious – Use Alternative (1) enzalutamide will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
• eplerenone Monitor Closely (1) tadalafil increases effects of eplerenone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• eprosartan Monitor Closely (1) tadalafil increases effects of eprosartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• erythromycin base Serious – Use Alternative (1) erythromycin base will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin ethylsuccinate Serious – Use Alternative (1) erythromycin ethylsuccinate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin lactobionate Serious – Use Alternative (1) erythromycin lactobionate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• erythromycin stearate Serious – Use Alternative (1) erythromycin stearate will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• eslicarbazepine acetate Monitor Closely (1) eslicarbazepine acetate will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• esmolol Monitor Closely (1) tadalafil increases effects of esmolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• ethacrynic acid Monitor Closely (1) tadalafil increases effects of ethacrynic acid by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• ethanol Monitor Closely (1) ethanol, tadalafil. Either increases effects of the other by additive vasodilation. Use Caution/Monitor. Combination may increase risk of orthostatic hypotension, tachycardia, dizziness and headache.
• etravirine Monitor Closely (1) etravirine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fedratinib Monitor Closely (1) fedratinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
• felodipine Monitor Closely (1) tadalafil increases effects of felodipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• fexinidazole Serious – Use Alternative (1) fexinidazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.
• fluconazole Monitor Closely (1) fluconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fluvoxamine Monitor Closely (1) fluvoxamine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• fosamprenavir Serious – Use Alternative (1) fosamprenavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• fosinopril Monitor Closely (1) tadalafil increases effects of fosinopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• fosphenytoin Monitor Closely (1) fosphenytoin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• furosemide Monitor Closely (1) tadalafil increases effects of furosemide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• grapefruit Monitor Closely (1) grapefruit will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• griseofulvin Monitor Closely (1) griseofulvin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• guanfacine Monitor Closely (1) tadalafil increases effects of guanfacine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• haloperidol Monitor Closely (1) haloperidol will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; increased levels may result in increased associated adverse events.
• hydralazine Monitor Closely (1) tadalafil increases effects of hydralazine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• hydrochlorothiazide Monitor Closely (1) tadalafil increases effects of hydrochlorothiazide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• idelalisib Serious – Use Alternative (1) idelalisib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates
• iloperidone Monitor Closely (1) iloperidone increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.
• imatinib Monitor Closely (1) imatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• indapamide Monitor Closely (1) tadalafil increases effects of indapamide by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• indinavir Serious – Use Alternative (1) indinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• irbesartan Monitor Closely (1) tadalafil increases effects of irbesartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• isoniazid Monitor Closely (1) isoniazid will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• isosorbide dinitrate Contraindicated (1) isosorbide dinitrate, tadalafil. Mechanism: additive vasodilation. Contraindicated. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• isosorbide mononitrate Contraindicated (1) isosorbide mononitrate, tadalafil. Mechanism: additive vasodilation. Contraindicated. Contraindicated. Potentially fatal hypotension. Allow 48h after last tadalafil dose before nitrate administration.
• isradipine Monitor Closely (1) tadalafil increases effects of isradipine by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• istradefylline Monitor Closely (1) istradefylline will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.
• itraconazole Serious – Use Alternative (1) itraconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• ketoconazole Serious – Use Alternative (1) ketoconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• labetalol Monitor Closely (1) tadalafil increases effects of labetalol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• lapatinib Monitor Closely (1) lapatinib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• letermovir Monitor Closely (1) letermovir increases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• levoketoconazole Serious – Use Alternative (1) levoketoconazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• lisinopril Monitor Closely (1) tadalafil increases effects of lisinopril by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• lonafarnib Serious – Use Alternative (1) lonafarnib will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.
• lopinavir Serious – Use Alternative (1) lopinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• losartan Monitor Closely (1) tadalafil increases effects of losartan by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• lumefantrine Monitor Closely (1) lumefantrine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• maraviroc Monitor Closely (1) maraviroc, tadalafil. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of orthostatic hypotension.
• marijuana Monitor Closely (1) marijuana will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• metolazone Monitor Closely (1) tadalafil increases effects of metolazone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• metoprolol Monitor Closely (1) tadalafil increases effects of metoprolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• metronidazole Monitor Closely (1) metronidazole will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• mifepristone Monitor Closely (1) mifepristone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• minoxidil Monitor Closely (1) tadalafil increases effects of minoxidil by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• mitotane Monitor Closely (1) mitotane decreases levels of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.
• nadolol Monitor Closely (1) tadalafil increases effects of nadolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• nafcillin Monitor Closely (1) nafcillin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
• nebivolol Monitor Closely (1) tadalafil increases effects of nebivolol by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypotension.
• nefazodone Monitor Closely (1) nefazodone will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For ED limit tadalafil to max of 2.5 mg/day (for daily use) or 10 mg dose every 72 hr (for use as needed). Avoid concurrent use of tadalafil for pulmonary HTN in patients taking strong CYP3A4 inhibitors.
• nelfinavir Serious – Use Alternative (1) nelfinavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Stop tadalafil >24 hours prior to protease inhibitor (PI) initiation, restart 7 days after PI initiation at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
• nevirapine Monitor Closely (1) nevirapine will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.
• nicardipine Serious – Use Alternative (1) nicardipine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 inhibitors may reduce tadalafil clearance increasing systemic exposure to tadalafil; significantly increased levels may result in significant adverse events including severe hypotension, syncope, visual changes, and priapism.
• nifedipine Monitor Closely (2) nifedipine will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Risk of hypotension.

Dosage Details for Cialis

If you have erectile dysfunction (ED) or benign prostatic hyperplasia (BPH), your doctor might suggest Cialis (tadalafil) as a treatment option for you.

Cialis is a prescription medication that’s used to treat ED and symptoms of BPH (such as urination problems) in adult males.* It can also be used if you have both of these conditions.

Cialis comes as a tablet that you’ll swallow whole. Cialis belongs to a group of drugs called phosphodiesterase 5 (PDE5) inhibitors. These drugs treat ED by relaxing blood vessels to increase blood flow into the penis. For BPH symptoms, they relax the bladder muscles, allowing urine to flow more easily.

This article describes the dosages of Cialis, including its form, strengths, and how to take the drug. To learn more about Cialis, see this in-depth article.

Note: This article covers typical dosages of Cialis, which are provided by the drug’s manufacturer. But when using Cialis, always take the dosage that your doctor prescribes.

* In this article, we use the term “male” to refer to someone’s sex assigned at birth. For information about the difference between sex and gender, see this article.

Get answers to common questions about the dosage of Cialis.

What form does Cialis come in?

Cialis comes as a tablet that you take by mouth.

Available strengths of Cialis (2.5 mg, 5 mg, 10 mg, 20 mg)

Cialis tablets come in four strengths: 2.5 mg, 5 mg, 10 mg, and 20 mg.

What are the typical dosages of Cialis?

Typically, your doctor will start you on a low dosage. Then they’ll adjust your dosage over time to reach the right amount for you. Your doctor will ultimately prescribe the smallest dosage that provides the desired effect.

If you have certain kidney or liver problems, your doctor may prescribe a low dosage for you. This is because the normal dosage may increase the risk of side effects with your condition.

The information below describes the usual dosage recommendations for Cialis. But be sure to take the dosage your doctor prescribes for you. Your doctor will determine the best dosage to fit your needs.

Dosage for erectile dysfunction (ED)

There are two dosage options when Cialis is used to treat ED: dosage for occasional use and for daily use.

With occasional use, you’ll take Cialis only as needed. You’ll likely take one 10-mg tablet before having sex.

Depending on how well the 10-mg dose works for your ED, your doctor may adjust your dose. It may be decreased to 5 mg or increased to 20 mg. You’ll continue to take it only as needed before sex.

You should not take Cialis more than once per day. You also should not take more than the recommended maximum dosage of Cialis, which is 20 mg per day. Taking higher dosages of Cialis than this, such as 40 mg per day, raises your risk for serious side effects. Examples of these side effects include very low blood pressure and priapism (a painful erection lasting 4 hours or longer).

With daily use, you’ll take one dose of Cialis per day. You don’t need to time your dose to be taken before having sex. You should take it around the same time each day.

For daily use of Cialis for ED, the usual starting dosage is 2.5 mg per day. If this dosage isn’t effective for you, your doctor may increase your dosage to 5 mg per day.

Dosage for benign prostatic hyperplasia (BPH)

The usual dosage of Cialis for BPH symptoms is 5 mg once daily for up to 26 weeks. You should take your dose around the same time each day.

Dosage for ED and BPH

If your doctor prescribes Cialis to treat ED along with BPH symptoms, you’ll take Cialis once daily.

For this use, the usual dosage is 5 mg per day. You should not take any additional doses of Cialis for occasional use before sex.

You don’t need to time your dose to be taken before having sex. You should take it around the same time each day.

Is Cialis used long term?

Yes, Cialis is typically used as a long-term treatment. If you and your doctor determine that it’s safe and effective for you, it’s likely that you’ll use Cialis long term.

Dosage adjustments

If you have certain kidney or liver problems, your doctor may prescribe a lower dosage of Cialis for you. This is because with your condition, the usual dosage may raise your risk for side effects from the drug.

Depending on how severe your kidney or liver problems are, your doctor may recommend occasional dosing instead of daily dosing to treat ED.

How can I get the maximum effect from Cialis?

To get the maximum effect from Cialis, take it exactly as prescribed.

If you’re using once-daily Cialis for either erectile dysfunction (ED) or benign prostatic hyperplasia (BPH), take your dose around the same time each day. This helps keep a consistent amount of the drug in your body to provide the maximum effect. If you forget to take doses, skip doses, or take doses late, the medication won’t work as well.

If you’re prescribed occasional (as needed) Cialis for ED, it’s best to take your dose at least 2 hours before having sex. This is because it takes an average of 2 hours for the drug to reach its highest level in your body.

Because this is an average, you may notice better effects if you have sex a little sooner or a little later than this 2-hour timeframe. In studies, Cialis improved erectile function as soon as 30 minutes to as long as 36 hours after a dose was taken. As long as you do not take more than the maximum daily dose, you can experiment with how long you wait to have sex after taking a dose.

If you have other questions about how to get the most from Cialis, talk with your doctor or pharmacist.

If I take 5 milligrams (mg) of Cialis daily, how long does it take the drug to work?

Cialis starts working quickly. Studies show that the drug begins to work 30 minutes to 6 hours after you take your first dose. But it may take several days for the medication to reach its full effectiveness. If you don’t notice an improvement in your BPH symptoms or ED within a week of daily use, talk with your doctor. They may need to adjust your dosage.

Could I take an 80-mg dose of Cialis?

No, it’s not safe to take an 80-mg dose of Cialis. The maximum recommended daily dosage of Cialis is 20 mg per day if you take it as needed for ED. If you take Cialis daily, the maximum dosage is 5 mg per day.

Taking doses of Cialis above the recommended limit could lead to serious side effects, such as dangerously low blood pressure or priapism (a painful erection lasting 4 hours or longer).

What’s the typical Cialis dosage for a 70-year-old?

Cialis dosage is not based on your age alone. Instead, your doctor will prescribe the dosage that’s best for your condition. Before prescribing Cialis, your doctor may send you for a blood test to check how well your kidneys and liver are working. This is because they’ll take your kidney and liver health into consideration when determining your dosage.

For many people, their kidneys may not work as well as they age. So if you’re an older adult (ages 65 years and older), it may take longer for your body to break down and clear Cialis from your system. Older adults may also be more sensitive in how they react to Cialis, which may increase their risk for side effects.

If you’re 70 years old, your doctor will likely start you on a low dosage of Cialis. If it works well for you, you’ll probably continue taking a low dosage. If it doesn’t work well for you or you develop bothersome side effects, your doctor will adjust your dosage. The goal is to find the lowest dosage that effectively treats your BPH symptoms or ED without causing bothersome side effects.

If you have questions about what your Cialis dosage should be, talk with your doctor.

How do the dosages for Cialis and Viagra compare?

As ED treatments, both Cialis and Viagra can be taken occasionally (as needed) before sexual activity. The usual dosage for occasional Cialis use is one dose 2 hours before having sex. The usual dosage for occasional Viagra use is one dose 1 hour before having sex.

Cialis is also approved for once-daily dosing for ED, but Viagra is not. This is because the effects of Cialis on ED can last much longer than Viagra’s effects. One dose of Cialis can help improve erectile function for up to 36 hours. In comparison, Viagra’s effects can last up to 4 hours. But on average, its effects start to lessen 2 to 3 hours after you take a dose.

The typical dose for once-daily Cialis for ED is 2.5 milligrams (mg) to 5 mg. When used as needed for ED, the usual Cialis dose is 10 mg (with a maximum daily dose of 20 mg). The typical dose of Viagra for ED is 50 mg.

Talk with your doctor about whether Cialis or Viagra may be a better option for you.

The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

Abstract

A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function – in particular, on ED – has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED.

Introduction

During the last decade, several preclinical and clinical studies have been initiated to investigate the links between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED).1 The reported evidence is based on single and multicenter trials from general and/or uro-/andrological populations; however, trial outcomes have been controversial.

Although the efficacy of all currently available treatments for LUTS/BPH is well defined, the negative impact of all therapies on erectile function (EF) is still under evaluation. Lifestyle modifications and phytotherapies have no or minimal impact on sexual function but these are also less effective on lower urinary tract symptoms (LUTS). In contrast, α-blockers, 5α-reductase inhibitors, and prostatic surgery, although associated with a strong improvement in LUTS, are usually associated with worsening sexual function.1

Several clinical trials have extensively reported on the efficacy and safety of chronic treatment with phosphodiesterase type 5 inhibitors (PDE5-Is) – either alone or in combination with conventional therapies – in ameliorating LUTS in men with or without ED.2

The aims of the present review were to analyze the links between LUTS/BPH and ED, examine the efficacy and safety of current treatment options for LUTS/BPH, and summarize the literature concerning the use of tadalafil for the treatment of LUTS/BPH, including randomized controlled trials (RCTs) and systematic and nonsystematic reviews of this topic.

The emerging links between LUTS and ED in aging men

Epidemiologic data

Many authors have analyzed the association between LUTS/BPH and ED in aging men.3 The strong and independent relationship between LUTS and ED has been shown in several epidemiologic trials. The positive association of LUTS severity with clinically relevant ED – independent of well-known causes of ED such as age, diabetes, medications, or coronary artery disease – has strongly suggested a common pathogenetic mechanism.

The National Health and Social Life Survey suggested that LUTS are a significant risk factor for ED, with an odds ratio (OR) of 3.13 in 1410 men aged 18–59 years.4 In the Krimpen study, which included men aged 50–78 years, the prevalence of severe ED was tenfold higher in men aged 70–78 years than in those aged 50–54 years. Logistic regression showed that, regardless of age, severe LUTS were strongly associated with ED (OR 7.5; compared with no LUTS).5 The Asian Survey of Aging Males, a study on 1155 men aged 50–80 years, demonstrated that males with severe LUTS were three times more likely to have ED than those without LUTS (OR 3.17).6 In recent times, the Boston Area Community Health Survey investigated 5506 men aged 30–80 years and suggested that the relationship between LUTS and ED is primarily due to symptoms of prostatitis, incontinence, and nocturia (OR for ED: 1.86, 1.73, and 0.76 for prostatitis, incontinence, and nocturia respectively).7 In this study, only age > 60 years, diabetes, and low socioeconomic status were more relevant than LUTS as predictive factors for ED.

In a study of 1420 men with LUTS, although age has been shown to be the most important predictor of sexual function, benign prostatic hyperplasia (BPH)-related symptoms (according to the Benign Prostatic Hyperplasia Impact Index [BII]), as well as general quality of life (QOL) were also predictive for sexual dysfunction, including ED. In contrast, uroflowmetry parameters or post-void residual (PVR) urine volume were not associated with sexual dysfunction.8 In a representative population sample of 4489 German men aged 30–80 years (Cologne Male Survey11), the overall prevalence of ED was 19.2%, ranging from 2% in men in their 40’s to 53% in men in their 80s; the prevalence of LUTS was 72.2% in men with ED, compared with 37.7% in those without ED. The Multinational Survey of the Aging Male (MSAM-7) investigated 12,815 men aged 50–80 years and demonstrated an ED prevalence of 43.0%, 65.8%, and 82.5% in men with mild, moderate, and severe LUTS, respectively; severe LUTS resulted in an OR of 7.67 for ED.9 The Epidemiology of LUTS survey of 11,834 men with a mean age of 56 years showed that men with LUTS had more severe ED; additionally, urgency with fear of urinary leakage and leakage during sexual activity were also positively associated with ED.10

In a recent comprehensive review that summarized data obtained in 20 community- and clinical-based studies of 71,322 men, a positive correlation between LUTS and ED was demonstrated, with the overall ORs ranging from 1.4 to 9.74.11

Taken together, this evidence implies that both LUTS/BPH and ED are associated with aging, but that the association between severity of LUTS/BPH and ED is independent of age. Alterations in mechanisms associated with metabolic syndrome and cardiovascular disorders are crucial to understanding the pathways and underlying links between these symptoms.

Common pathways linking LUTS/BPH and ED

The pathophysiology of LUTS/BPH and ED is complex and likely to be multifactorial involving numerous mechanisms affecting the entire lower urinary tract (LUT). The major mechanisms determining LUTS have been extensively reviewed elsewhere.12 Briefly, these are: reduced nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) mainly in the prostate, urethra, and bladder but also in the pelvic neuronal and vascular bed; increased RhoA kinase pathway activity; increased autonomic nerve activity; and pelvic hypoxygenation and ischemia.

The altered balance between relaxation (reduced NO/cGMP-signaling) and contraction (increased RhoA/Rho kinase activity) in the penile smooth muscle compartment, as well as penile hypoxygenation/ischemia, are pathogenic factors underlying ED. Essentially, in animal models of ED associated with cardiovascular diseases – including hypertension, diabetes, and metabolic syndrome or neurogenic ED15–17 – the concomitant impairment of smooth muscle relaxation and reduced oxygenation were documented.

In humans, phosphodiesterase type 5 (PDE5) is expressed in the whole of the LUT, including the urethra, prostate, and bladder – all potential targets of PDE5-Is.13–16 In all these organs, PDE5 was prominently localized in the stroma and in the vascular bed (endothelial and smooth muscle cells), suggesting a possible action of PDE5-I either on smooth muscle contraction and/or blood flow. Animal models have provided a great deal of information on the possible mechanisms of action of PDE5-Is, including the effects of tadalafil on LUT. Chronic pelvic ischemia was one of the main determinants of the functional and morphological changes observed in both bladder and prostate in the spontaneous hypertensive rat model.16,23

Chronic treatment with tadalafil or other PDE5-I in the spontaneous hypertensive rat was able to counteract all these LUT alterations, most likely through an increased blood perfusion and LUT oxygenation.15,16 A similar effect of tadalafil concerning increasing tissue perfusion and oxygenation has also been described in an animal model of severe neurogenic ED; chronic treatment with tadalafil after bilateral cavernous nerve neurotomy in the rat normalized penile oxygenation as well as smooth muscle content. One of the best described mechanisms of action of PDE5-Is with regard to inducing vasodilatation and increasing blood flow is smooth muscle cell relaxation of the LUT mediated by NO/cGMP.15,16 In addition, modulation of autonomic nervous system overactivity and bladder/prostate afferent nerve activity by PDE5-Is has also been suggested.12,19,20

Recently, it was documented that tadalafil enhances prostate and bladder neck relaxation through the inhibition of neurogenic contractions.18 Accordingly, it has been demonstrated that PDE5-Is induce a cGMP/protein kinase G-mediated inhibition of the contractile RhoA/Rho-associated protein kinase signaling in the bladder,19 which also suggests a crucial role of PDE5-Is in ameliorating the dynamic/functional component of LUTS/BPH pathogenesis. These preclinical hypotheses have been confirmed by clinical evidence with PDE5-Is in spinal cord injured men investigated by urodynamics20 and in men under sexual rehabilitation for post-prostatectomy ED.21

A specific action of tadalafil in counteracting the pathogenic factors mainly related to the static component of LUTS (ie, prostate enlargement and urethral compression) has been demonstrated as well.18 We recently reported, for the first time, a specific action of tadalafil on the prostatic chronic inflammatory process, the third recognized pathogenetic component of LUTS/BPH.22,23,28

Although primarily characterized by increased proliferation of both fibroblastic stromal and epithelial cells, intraprostatic chronic inflammation has also been documented to play a causative role in LUTS/BPH. From a pathophysiological standpoint, an autocrine/paracrine proinflammatory loop between chronically activated T cells and stromal cells seems to be the key determinant factor in BPH development and progression.24

The prostate of the adult male rabbit fed a high fat diet (HFD) developed severe histological inflammation coupled with stromal derangement and hypoxia.25–30 HFD-induced Metabolic Sydrome (MetS)-like features were associated with marked histological alterations of the prostate gland, characterized by severe inflammation coupled with stromal derangement and hypoxia. Interestingly, the HFD prostate showed also a marked increased expression of PDE5, suggesting that prostate in MetS condition could be the optimal target for PDE5-Is. PDE5 expression in the prostate was also strongly and positively associated with the expression of several inflammatory, myofibroblast activation, and hypoxia-related markers.28

Chronic use of a PDE5-I (12-week treatment with tadalafil) reduced the expression of inflammatory, pro-fibrotic, and myofibroblast activation markers in the prostate.28 Consistent with these data, it has previously been reported that tadalafil strongly attenuated tumor growth factor beta 1-induced fibroblast-to-myofibroblast trans-differentiation in primary human prostate stromal cells.31 Short-term treatment (1 week) with tadalafil was also able to significantly blunt HFD-related prostatic alterations, mainly reducing the inflammatory process. A significant reduction in interleukin 8, tumor necrosis factor alpha, and genes related to tissue remodeling was observed.28 Interleukin 8 is considered as a reliable surrogate marker of prostatic inflammatory diseases,32 linking chronic inflammation to prostatic enlargement. In particular, an increase in subtype-1 T-helper cells (Th1) is crucial in loss of self-tolerance and autoimmune-tissue remodeling with hyperplastic overgrowth. Interestingly, we found that Th1 was absent from healthy rabbit prostate but was significantly induced by an HFD.23,27

Remarkably, both acute and chronic treatment with tadalafil dramatically reduced Th1 immune response in the prostates of animal subject on HFDs, further indicating the inhibitory action of PDE5-Is on the inflammatory processes affecting the prostate during metabolic derangements. Therefore, animal models demonstrated that both chronic and acute tadalafil administration were effective in reducing the HFD-related prostatic alterations, mainly attenuating chronic inflammatory and pro-fibrotic processes.28 Other positive effects of tadalafil on LUT oxygenation have also been reported.16

In conclusion, these experimental findings in animals and studies in humans add new insights into the understanding of the mechanism of action of PDE5-Is, and in particular of tadalafil, in alleviating LUTS (even in MetS patients). Study results strongly support the multiple potentiality of this drug class.

Active treatments for LUTS/BPH and their impact on sexual function

Active treatments include phytotherapy, conventional medical therapies, and surgical procedures (minimally invasive or invasive).33 The more invasive the treatment, the greater the occurrence of adverse events (AEs). Consequently, while invasive surgery (eg, transurethral resection of the prostate [TURP]) can sufficiently and quickly decrease symptoms or signs of BPH, it is also associated with well-defined severe AEs, such as bleeding, the need for blood transfusions, transurethral resection syndrome, urinary incontinence, and ED. Therefore, it is crucial that any treatment for LUTS/BPH relieves the LUTS without producing major or troublesome AEs. Both medical and surgical treatments can have problematic side effects, including a remarkable worsening of sexual function, but these particular AEs appear in different treatment modalities with different probabilities.1

The efficacy of the various treatments and any sexual dysfunction/ED side effects they might produce have been well documented for the various treatment options of LUTS/BPH.

Phytotherapy

The evidence of phytotherapy for LUTS/BPH has strikingly increased during the last two decades. Plant extracts contain a large variety of chemical components, including phytosterols, plant oils, fatty acids, and phytoestrogens, which have various biochemical effects – including anti-inflammatory, antioxidant, and inhibitory – on 5α-reductase. In the TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare (TRIUMPH) study, Serenoa repens and Pygeum africanum, the most used phytotherapeutic agents, both produced an equally significant improvement in LUTS in 43% of patients, giving a mean change of 3 International Prostate Symptom Score (IPSS) points but were less effective than α-blockers or 5α-reductase inhibitors (5ARIs).34 However, only mild and infrequent AEs, with particular concern regarding the impact on sexual function, (decreased libido) or gastrointestinal function, have been reported. In a trial with 811 LUTS/BPH patients, the incidence of ejaculatory dysfunction was reported to be significantly lower with Serenoa repens than with tamsulosin (0.6% vs 4.2% respectively).35 In another study on 2511 men, an increase in sexual dysfunction, evaluated using the Male Sexual Function-4 questionnaire, was reported with tamsulosin (+0.3) and finasteride (+0.8), while a slight improvement with Serenoa repens (−0.2) was documented.36

Medical therapies

Medical therapies for LUTS/BPH mainly include α-blockers and 5ARIs, alone or in combination, with well-established efficacy and AE profiles.1 In the TRIUMPH study, which recorded the treatment and outcomes of 2351 newly presenting LUTS/BPH patients in six European countries over 3 years, the use of α-blockers alone resulted in the most effective monotherapy, with a mean reduction of 6.3 IPSS points. In contrast, 5ARIs reduced LUTS by only 4.1 IPSS points. However, a statistically significant advantage resulted when using the combination therapy of tamsulosin plus finasteride, which resulted in a decrease of 8.1 IPSS points.34

Despite the fact that some α-blockers (eg, alfuzosin) improved EF in some trials, ejaculatory dysfunction was usually reported in these trials, occurring in 2%–14% of patients.37 Further, several sexual AEs have been reported to result from treatment with 5ARIs, including impaired sexual desire or loss of libido in 2%–10% of patients, ED in 3%–16%, and ejaculatory dysfunction in 0%–8%.38 The Combination of Avodart and Tamsulosin (CombAT) study evaluated tamsulosin and dutasteride combination therapy in 4844 men with signs and symptoms of BPH; after 24 months, the rate of ED was 3.8% with tamsulosin, 6.0% with dutasteride, and 7.4% with combination therapy.39

Minimally invasive procedures

In recent years, a number of minimally invasive therapies for LUTS/BPH have been developed and refined, including transurethral needle ablation (TUNA), transurethral microwave thermotherapy, and interstitial laser coagulation. Although these procedures are less effective at relieving LUTS/BPH than conventional surgical treatments (eg, TURP) – with a mean 10.2 and 9.1 IPSS point reduction at 1 year for transurethral microwave thermotherapy and TUNA, respectively40 – AEs such as bleeding, ED, or ejaculatory dysfunction occur at a lower frequency. Consequently, their attractiveness for both patients and physicians is increasing. In a systematic review and meta-analysis of TUNA in symptomatic BPH patients, ED was reported in only 0.3% of men, retrograde ejaculation in 0.2%, and loss of ejaculation in 0.08% 41

Conventional and new surgical treatments

If treatment with drugs proves insufficient, the surgical gold standard for moderate to severe LUTS/BPH in patients with prostate volumes of less than 80–100 mL is TURP, which has replaced open prostatectomy (OP).42 Alternatively, for men with a prostate volume of ≤30 mL, transurethral incision of the prostate or bladder neck incision may be undertaken. A retrospective meta-analysis of 3304 men treated by conventional surgical therapies reported retrograde ejaculation in 6%–80% of patients after OP, 70% after TURP, and 39% after transurethral incision of the prostate. ED was reported in 13% of patients after TURP and in 11% after OP.43 The newest treatments for signs or symptoms of BPH are holmium laser enucleation of the prostate and photoselective vaporization of the prostate; fewer AEs (eg, bleeding or blood transfusions) have been reported for both procedures than for conventional surgery, but their impact on sexual function was almost the same.44

Although the efficacy and AE profiles of all currently available treatment options for LUTS/BPH have been well investigated and defined, outcomes are sometimes unsatisfactory for patients and partners, mainly due to the postoperative AEs – above all, those affecting sexual function. These treatment-related disadvantages have triggered the search for new treatment options for effective relief of LUTS that result in very few or no sexual or other AEs. PDE5-I treatment (eg, with tadalafil [Cialis™, Eli-Lilly, Indianapolis, IN, USA]) seems to combine the efficacy of drugs (α-blockers) and can maintain or even improve sexual function.

Clinical evidence for tadalafil for LUTS/BPH

In 2007, McVary et al45 evaluated for the first time the efficacy and safety of tadalafil for the treatment of LUTS/BPH in men with or without ED. A total of 479 patients were screened and, after a 4-week washout and 4-week placebo run-in period, 281 were randomly assigned to a 6-week treatment with once-daily placebo or tadalafil 5 mg. After 6 weeks, the remaining 261 patients were assigned to continue with placebo for another 6 weeks (a total of 12 weeks of once-daily placebo treatment) or to dose escalate tadalafil to 20 mg once daily. Of 143 placebo-assigned patients, 121 (84.6%) were sexually active, 84 (59.2%) had no ED, and 76 (53.1%) were sexually active despite ED, while, of 138 men treated with 5 or 20 mg tadalafil, 107 (77.5%) were sexually active, 99 (71.7%) had normal sexual function, and 80 (58.0%) were sexually active despite ED. Patients were evaluated for LUTS using the IPSS (including the IPSS-QOL question) and BII questionnaires. Maximum urinary flow rate (Q_max) and average urinary flow rate (Q_ave) of free uroflowmetry were recorded, post-void residual urine (PVR) was measured by ultrasound after uroflowmetry, and sexual function was studied by using the erectile function (EF) domain of the International Index of Erectile Function (IIEF) questionnaire (questions 1 to 5 and 15).

In McVary et al’s study,45 tadalafil significantly improved LUTS at week 6 (mean IPSS change from baseline for 5 mg tadalafil was −2.8 compared with −1.2 for placebo) but improvement of LUTS was even better at week 12 with dose escalated tadalafil (5/20 mg tadalafil −3.8 vs placebo −1.7). BII changes observed were −0.7 for tadalafil 5 mg versus −0.4 for placebo at week 6 and −1.3 for tadalafil versus −0.6 for placebo at week 12. No significant changes of uroflowmetry parameters were observed after week 12 between placebo and tadalafil: Q_max 2.3 mL/s versus 2.7 mL/s (P = 0.81); Q_ave 1.1 mL/s versus 0.9 mL/s (P = 0.79). Additionally, there was no change of PVR between the groups: −1.2 mL versus −2.5 mL (P = 0.57). As expected, sexual activity, as measured by the IIEF questionnaire, significantly improved only with tadalafil (+8.4) compared with placebo (+1.6; P < 0.001) after week 12. Also in this study, the authors were the first to evaluate the safety profile for PDE5-Is in patients with LUTS/BPH. The most commonly reported AEs (>2%) were dyspepsia, back pain, headache, nasopharyngitis, and upper respiratory tract infection (each AE occurred in ≤5.1%). As expected, erections improved after 12 weeks with 5/20 mg tadalafil in 5.1%. Thus, in this study, McVary et al demonstrated for the first time that tadalafil is an effective and safe treatment for LUTS/BPH; patients achieved an effective LUTS response without significant AEs but with improvement of concomitant ED.

In 2008, Roehrborn et al46 published their report on a randomized, double-blind, placebo-controlled, 12-week study performed in ten countries and 92 centers in order to evaluate the optimal dose of tadalafil for the treatment of LUTS/BPH. The authors included 1813 LUTS/BPH patients aged 45 years or older. After a 4-week washout and 4-week placebo run-in period, the study population was equally divided into five treatment arms: either (1) placebo or tadalafil (2) 2.5 mg, (3) 5 mg, (4) 10 mg, or (5) 20 mg once daily. Patients were assessed at baseline and at weeks 4, 8, and 12. At week 12, patients’ IPSS had significantly improved for all tadalafil doses compared with placebo. However, the best IPSS/QOL/AE ratios were obtained with tadalafil 5 mg. Compared with placebo (decrease of 2.3 IPSS points), improvement of IPSS was 3.9 for tadalafil 2.5 mg (P < 0.015), 4.9 for tadalafil 5 mg (P < 0.001), 5.2 for tadalafil 10 mg (P < 0.001), and 5.2 for tadalafil 20 mg (P < 0.001). In terms of safety profile, back pain, myalgia, and headache were more frequent at higher tadalafil doses. AEs reported in the placebo arm versus 2.5/5/10/20 mg tadalafil arms were: six (2.8%) versus five, six (2.8%), eleven (5.1%), and seven (3.3%) for headache; zero versus two (1.0%), ten (4.7), six (2.8%), and ten (4.8%) for dyspepsia; and one (0.5%) versus three (1.4%), two (0.9%), ten (4.6%), and twelve (5.7%) for back pain. AEs led to study discontinuation for 2.4% of placebo-treated men versus 1.9%, 5.7%, 5.1%, and 6.7%, respectively, of 2.5/5/10/20 mg tadalafil-treated males. Thus, this study determined that tadalafil 5 mg once daily is the best dosage for the treatment of LUTS/BPH, providing an effective response to LUTS, with a minimal occurrence of AEs and rate of discontinuation.

Also in 2008, Bechara et al47 considered combination therapy of tadalafil with an α-blocker for the treatment of LUTS/BPH for the first time and compared tamsulosin 0.4 mg with tamsulosin 0.4 mg plus tadalafil 20 mg once daily. They enrolled 30 men with LUTS/BPH of at least 6 months in a randomized, double-blind, crossover study. Patients were treated with monotherapy or combination therapy for 45 days and then switched to the other treatment mode for another 45 days. The authors found a significant improvement in IPSS (tamsulosin −6.7 vs tadalafil/tamsulosin −9.2; P < 0.05) and for the QOL question in the IPSS questionnaire (IPSS-QOL) (P < 0.001) with both treatment modalities compared with baseline but differences were greater with combination therapy. In terms of Q_max and PVR, there was a significant improvement from baseline with both treatment regimens (P < 0.001) but no significant differences between tamsulosin alone versus tamsulosin plus tadalafil 20 mg (P > 0.05). Improvement in IIEF score was significant with tamsulosin plus tadalafil (P < 0.001) but not with tamsulosin alone (P > 0.05). In this study, therefore, the authors demonstrated for the very first time that combination therapy is more efficacious when adding a PDE5-I (tadalafil) to standard treatment (tamsulosin) than α-blocker monotherapy.

In 2009, Liguori et al48 considered the combination of tadalafil 20 mg with alfuzosin 10 mg for the treatment of LUTS/BPH and ED. The authors enrolled 66 men who were randomized to either alfuzosin 10 mg once daily (22 patients), tadalafil 20 mg on alternate days (21 patients), or a combination of both (23 patients) and assessed treatment outcomes at baseline and at week 12. They did not find a significant IPSS improvement for tadalafil alone (−8.4%, P not significant) but demonstrated a significant reduction in IPSS for alfuzosin monotherapy (−27.2%, P < 0.003) and combination therapy (−41.6%, P < 0.001). As such, Liguori et al confirmed the improved efficacy of improving LUTS/BPH (according to IPSS) with combination therapy (α-blockers plus a PDE5-I) compared with monotherapy (α-blocker or PDE5-I). Furthermore, the authors found an increased efficacy for EF and uroflowmetry parameters when using the combination therapy: IIEF +37.6% (P < 0.001) and Q_max +29.6% (P < 0.001) versus α-blocker monotherapy (IIEF +15.0%, P = 0.026; Q_max +21.7%, P = 0.006) or tadalafil monotherapy (IIEF +36.3%, P = 0.011; Q_max +9.5%, P = 0.044). At the end of the trial, 15 AEs (55.5%) occurred in the combination therapy arm and five (18.5%) in the tamsulosin/placebo arm; headache was the most reported AE: two patients discontinued the study due to AEs. This trial confirmed the efficacy and safety of combination therapy, even when using another α-blocker (alfuzosin) compared with α-blocker monotherapy.

In 2009, Porst et al49 investigated a selected group of 581 men with comorbid LUTS/BPH and ED who reported being sexually active. Mean age was 62 years and mean body mass index (BMI) was 28.3 kg/m 2 . The majority of patients (84.5%) had had LUTS/BPH for more than 1 year, and 50.4% had a LUTS/BPH history > 3 years. After 4-week washout period for patients taking BPH and/or ED drugs and 4-week placebo run-in period, patients were assigned to once-daily placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 weeks. At baseline, the majority of patients had moderate ED (IIEF score of between 11 and 16): 60.0% in the placebo group, 57.5% in the tadalafil 2.5 mg group, 57.3% in the tadalafil 5 mg group, 48.3% in the tadalafil 10 mg group, and 57.8% in the tadalafil 20 mg group. Improvement in IPSS from baseline to study end was significantly greater for all tadalafil doses versus placebo: −2.1 for placebo, −3.6 for tadalafil 2.5 mg (P = 0.043), −4.2 for tadalafil 5 mg (P = 0.004), −4.7 for tadalafil 10 mg (P < 0.001), and −4.7 for tadalafil 20 mg (P = < 0.001). Q_max was not significantly different for any tadalafil group versus placebo. In terms of sexual function in men with an IIEF score < 26 at baseline, normal EF (IIEF ≥ 26) was dose-dependently obtained for tadalafil-treated men: 21.2% with tadalafil 2.5 mg, 34.2% with tadalafil 5 mg, 42.5% with tadalafil 10 mg, and 40% for tadalafil 20 mg versus 14% for placebo-treated men. AEs occurring in ≥2% of tadalafil-treated patients were headache, dyspepsia, back pain, and myalgia. For the 2.5, 5, 10, and 20 mg tadalafil groups, the discontinuation frequency due to AEs was 2.7%, 5.1%, 5%, and 5.2%, respectively. Thus, this dose-finding study confirmed the efficacy of tadalafil 5 mg once daily in ameliorating LUTS/BPH and corroborated the role of this daily treatment in the concomitant improvement of EF in LUTS/BPH men with or without ED.

Also in 2009, for the first time, Roehrborn et al50 specifically evaluated uroflowmetry data in LUTS/BPH patients treated with tadalafil once daily. After a 4-week placebo run-in period, they enrolled 1058 LUTS/BPH patients and randomly allocated these men to receive once-daily treatment with placebo or tadalafil (2.5, 5, 10, or 20 mg) for 12 weeks. Uroflowmetry variables were stratified by age, Q_max, LUTS severity, prostate size, previous α-blocker use, and sexual activity, including ED history. The authors demonstrated that tadalafil was able to induce a dose-dependent increase in Q_max, although not one that was significantly different from placebo (1.4 mL/s [+15%] for tadalafil 2.5 mg, 2.0 mL/s [+22%] for tadalafil 20 mg, and 1.2 mL/s [+12%] for placebo). Moreover, age, Q_max severity at baseline, ED history, sexual activity, and previous treatment with α-blockers were determinants for the change in Q_max across all tadalafil and placebo treatment groups. In tadalafil 2.5, 5, 10, or 20 mg once daily groups, there were study discontinuations due to AEs in 1.9%, 5.7%, 5,1% and 6.7%, respectively. Once again, the lack of a significant Q_max improvement was documented in this trial; this finding has since been confirmed by sub-analyses of other tadalafil trials.2

In 2010, Dmochowski et al51 conducted a multicenter, randomized, double-blind, placebo-controlled, 12-week trial comparing once-daily tadalafil 20 mg with placebo in LUTS/BPH men with or without bladder outlet obstruction. Invasive computer-urodynamic evaluation, free uroflowmetry, and IPSS were assessed in this study. However, men with severe bladder outlet obstruction were not included in this study. In 101 placebo-treated patients (mean age 59 years and BMI 29.4 kg/m 2 ), mean Q_max was 13.3 ± 7.4 mL/s and mean PVR 59.3 ± 60.9 mL, while the 99 tadalafil-treated patients (mean age 58.2 years and BMI 29.5 kg/m 2 ) had a mean Q_max of 15.4 ± 11.1 mL/s and a mean PVR of 45.7 ± 49.6 mL. The differences of Q_max and Q_ave between men treated with tadalafil 20 mg versus placebo were not statistically significant for free uroflowmetry (mean difference of change from baseline tadalafil vs placebo: Q_max −0.6 mL/s and Q_ave +1 mL/s) or pressure flow study (Q_max −0.1 mL/s and Q_ave +0.1 mL/s). The incidence of AEs was higher in the tadalafil group (55.6%) than in the placebo group (27.7%), but discontinuations due to AEs were low in both groups (tadalafil 2.0% vs placebo 1.0%). In this safety study using a high dosage of tadalafil (20 mg for 12 weeks), Dmochowski et al suggested that once-daily administration of tadalafil should not worsen urodynamic parameters in men with LUTS/BPH.

In 2011, Porst et al52 evaluated the efficacy and safety of once-daily tadalafil 5 mg for the treatment of LUTS/BPH in an international, randomized, double-blind, placebo-controlled, 12-week trial. The authors screened 442 men and, after 4-week washout period and 4-week placebo run-in period, randomized 325 patients to receive placebo or tadalafil 5 mg once daily. From baseline to endpoint, tadalafil significantly improved IPSS in comparison to placebo (−5.6 vs −3.6, P = 0.004). There was a significant reduction in IPSS already at week 4 (tadalafil 5 mg −5.3 vs placebo −3.5, P = 0.003) and after week 12. Likewise, the BII score had already sig nificantly improved at week 4 (tadalafil 5 mg −1.8 vs placebo −1.2, P = 0.029) and continued to improve until week 12 (tadalafil 5 mg −1.8 vs placebo −1.3, P = 0.057). As in other studies, Porst et al found a remarkable improvement in IIEF in sexually active men with ED who were treated with tadalafil 5 mg versus placebo (+6.7 vs +2.0, P < 0.001) at week 12. The incidence rate of at least one AE was 22% and 26.1%, and one (0.6%) and six (3.7%) patients discontinued due to AEs in the placebo and tadalafil 5 mg groups, respectively. As such, this study demonstrated that the clinical efficacy of tadalafil 5 mg once daily in treatment of LUTS/BPH is already detectable after 4 weeks.

In 2011, Donatucci et al53 evaluated the long-term efficacy and safety of tadalafil for LUTS/BPH. They enrolled 427 men who had been investigated in a 12-week, placebo-controlled, dose-finding study with once-daily tadalafil (2.5, 5, 10, or 20 mg) or placebo46 and continued treatment in the open-label extension study with tadalafil 5 mg for 52 weeks. Independent of the dosage used in the 12-week dose-finding period, at endpoint, there was an improvement of −5.0 ± 6.7 points in IPSS and of 5.9 ± 7.6 points in IIEF score. After 1 year, compared with at week 12, a further improvement in total IPSS and storage and voiding sub-scores was reported (−0.9 ± 5.7, −0.3 ± 2.6, and −0.6 ± 3.6, respectively). The most common AEs (≥2%) were dyspepsia, gastroesophageal reflux disease, back pain, headache, sinusitis, hypertension, and cough. A total of 22 men (5.2%) discontinued the study due to AEs. Thus, this long-term study showed that tadalafil 5 mg once daily is well tolerated during a treatment period of 1 year and that the drug maintains or even improves storage and voiding symptoms, but the cost-effectiveness of the long-term chronic use of tadalafil was not evaluated.

In 2012, Oelke et al54 evaluated for the first time tadalafil 5 mg and tamsulosin 0.4 mg once daily for the treatment of LUTS/BPH in an international, placebo-controlled, randomized, double-blind, 12-week trial comparing separately and independently these two drugs with placebo. Following screening and washout, if needed, and a 4-week placebo run-in, they evaluated 511 men who were randomly assigned to placebo (n = 172), tadalafil 5 mg (n = 171), or tamsulosin 0.4 mg (n = 168). Compared with placebo, there was a significant decrease in IPSS of 1.5 points after only 1 week of treatment with tadalafil or tamsulosin (P < 0.01). After 12 weeks, decrease in IPSS with tadalafil (2.1 points, P = 0.001) was even more pronounced than with tamsulosin (1.5, P = 0.023) compared with placebo. Additionally, BII score had significantly improved at week 4 with tadalafil (−0.8; P < 0.001) and tamsulosin (−0.9; P < 0.001) and at week 12 (tadalafil −0.8, P = 0.003; tamsulosin −0.6, P = 0.026) compared with placebo. QOL (IPSS-QOL), treatment satisfaction (Treatment Satisfaction Scale), and Patient or Physician Global Impression of Improvement scores only improved for tadalafil, not for placebo or tamsulosin. Improvement in IIEF score was once more documented for tadalafil (4.0, P < 0.001) but not for tamsulosin (−0.4, P = 0.699) compared with placebo. The patient discontinuation rate due to AEs was 1.2% for placebo, 1.2% for tadalafil 5 mg, and 0.6% for tamsulosin 0.4 mg. The unexpected outcome of this study was the significant improvement of uroflowmetry parameters. Q_max and Q_ave similarly increased with both tadalafil (2.4 mL/s, P = 0.009 and 1.6 mL/s, P = 0.002, respectively) and tamsulosin (2.2 mL/s, P = 0.014 and 1.3 mL/s, P = 0.023, respectively) at week 12. In this trial, therefore, Oelke et al54 demonstrated a significant and clinically meaningful improvement in LUTS/BPH with tadalafil 5 mg once daily, which was similar to that attained by tamsulosin 0.4 mg once daily after only 1 week, a further improvement in LUTS/BPH after 12 weeks, improvement of QOL and treatment satisfaction parameters only with tadalafil, and an unexpected but remarkable improvement of urinary flow rates at week 12.

Also in 2012, Regadas et al55 evaluated for the first time the effects on free uroflowmetry of treating patients with LUTS/BPH for 30 days with tamsulosin 0.4 mg with or without tadalafil 5 mg in a cohort of 40 men with bladder outlet obstruction (mean ± standard deviation: Q_max 6.2 mL/s ± 2.6 for α-blockers alone and 7.4 mL/s ± 2.6 for an α-blocker plus tadalafil). Patients were equally randomized into two treatment arms: once-daily tamsulosin 0.4 mg plus tadalafil 5 mg or tamsulosin 0.4 mg plus placebo. The study design included an urodynamic study based on the recommendations of the International Continence Society. Detrusor pressure at maximum flow was significantly reduced with tamsulosin plus tadalafil compared with tamsulosin alone (13 ± 17.0 vs −1.2 ± 14.35, P = 0.03). Moreover, Q_max increased in both treatment groups (1.0 ± 2.4 mL/s with tamsulosin + tadalafil and 1.4 ± 2.4 mL/s with tamsulosin + placebo), but differences were not significantly different (P = 0.65). Finally, LUTS/BPH decreased significantly in both the tadalafil plus tamsulosin and tamsulosin plus placebo groups (−9.75 vs −6.0 IPSS points, P = 0.01). No significant AEs led to discontinuation in the tadalafil plus tamsulosin group. This is the first trial – based on a computer-urodynamic study – to have demonstrated that tadalafil reduces detrusor pressure at maximum flow and improves LUTS/BPH without significantly changing Q_max.

Again in 2012, Yokoyama et al56 directly compared tadalafil with tamsulosin 0.2 mg in the first study to do so. The authors enrolled 612 men aged ≥ 45 years who had a history of LUTS/BPH for at least 6 months, a total IPSS ≥ 13, Q_max 4–15 mL/s, and a prostate volume > 20 mL. After a 2-week washout period and 4-week placebo lead-in period, they randomized patients into four groups and treated patients with once-daily placebo, tadalafil 2.5 mg, tadalafil 5 mg, or tamsulosin 0.2 mg for 12 weeks. From baseline to endpoint, LUTS/BPH significantly decreased by 4.8 IPSS points with tadalafil 2.5 mg (P = 0.003), 4.7 points with tadalafil 5 mg (P = 0.004), and 5.5 points with tamsulosin 0.2 mg compared with 3.0 IPSS points with placebo. They observed that a relevant decrease in total IPSS (P < 0.05) was reached after 2 weeks of once-daily tadalafil 5 mg treatment but only after 8 weeks for tadalafil 2.5 mg treatment. Q_max improvements were not significant with once-daily tadalafil or tamsulosin in this study. In terms of safety profile, the rate of discontinuation from each group due to AEs was 0.6% from the placebo group, 3.3% from the tadalafil 2.5 mg group, 4.5% from the tadalafil 5.0 mg group, and 1.3% from the tamsulosin group. In this study the authors demonstrated that tadalafil did not significantly modify prostate-specific antigen concentration during the 12-week treatment period (baseline to 12 weeks: 1.7 vs 1.8 ng/mL, P = 0.083).

Safety/tolerability and efficacy of tadalafil in systematic reviews and meta-analyses of men with LUTS/BPH

Safety

All PDE5-Is included in the systematic review authored by Liu et al57 showed a good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively). Moreover, the occurrence of serious AEs was rare for all PDE5-Is (1.1%, 1.85%, and 1.05% for the tadalafil, vardenafil, and sildenafil subgroups, respectively).

Martínez-Salamanca et al58 confirmed that tadalafil has a favorable tolerability profile, with most of the AEs being mild to moderate in severity. Moreover, discontinuation rates due to AEs were very low for tadalafil and comparable to those reported for placebo (2.0% vs 1.0%). Headache, dyspepsia, back pain, gastroesophageal reflux, sinusitis, and myalgia were the most frequently reported AEs in clinical trials (11.1%, 10.2%, 11.1%, 3.0%, 0.3%, and 5.7%, respectively; Table 1 ). These same AEs were reported in the previously published PDE5-I meta-analysis, however, the probability of an AE was higher in the latter report.2 The overall incidence of AEs reported in the present review on tadalafil versus placebo was very similar to that reported by Gacci et al2 in the systematic review of all PDE5-Is versus placebo: 16.0% versus 6.0%.

Table 1

The most common adverse events (AEs) reported for tadalafil in the different studies included in this review, n (%). Overall number of events for each drug and for each single AE are reported (%).

AE	Arm	McVary et al, 44 2007	Roehrborn et al,45 2008				Porst et al,48 2009				Dmochowski et al,50 2010	Porst et al,51 2011	Donatucci et al,52 2011	Oelke et al,53 2012	Yokoyama et al,55 2012	Overall
	Dose	10 mg	2.5 mg	5 mg	10 mg	20 mg	2.5 mg	5 mg	10 mg	20 mg	20 mg	5 mg	5 mg	5 mg	5 mg
Headache	D	4 (2.9)	5 (2.4)	6 (2.8)	11 (5.1)	7 (3.3)	4 (3.5)	4 (3.4)	6 (5.0)	2 (1.7)	3 (3.0)	6 (3.7)	0	5 (2.9)	3 (1.9)	66 (11.1)
	P	1 (0.7)	6 (2.8)	4 (3.5)	7 (7.1)	1(0.6)	3 (3.3)	2 (1.2)	1 (0.6)	25 (11.2)
Dyspepsia	D	6 (4.3)	2 (1.0)	10 (4.7)	6 (2.8)	10 (4.8)	1 (0.9)	5 (4.3)	2 (1.7)	3 (2.6)	8 (8.1)	4 (4.8)	4 (2.3)	61 (10.2)
	P	0	0	0	0	4(4.3)	0	4 (1.8)
Back pain	D	5 (3.6)	3 (1.4)	2 (0.9)	10 (4.6)	12 (5.7)	2 (1.8)	1 (0.9)	5 (4.2)	6 (5.2)	5 (5.1)	5 (3.1)	2 (2.4)	4 (2.3)	4 (2.6)	66 (11.1)
	P	2 (1.4)	1 (0.5)	1 (0.9)	3 (3.0)	4 (2.4)	4 (4.3)	1 (0.6)	1 (0.6)	17 (7.6)
G.E.Reflux	D	2 (1.0)	2 (0.9)	6 (2.8)	3 (1.4)	3 (3.0)	2 (2.4)	18 (3.0)
	P	0	0	2(2.2)	2 (0.9)
Sinusitis	D	2 (2.4)	2 (0.3)
	P	0	0
Rhinitis	D	3 (2.2)	7 (3.3)	4 (1.9)	2 (0.9)	5 (2.4)	5 (2.9)	2 (1.3)	2 (0.3)
	P	0	2 (0.9)	8 (4.7)	4 (2.6)	14 (6.3)
Hypertension	D	3 (3.6)	3 (0.5)
	P	0	0
Myalgia	D	3 (1.4)	3 (1.4)	6 (2.8)	6 (2.9)	2 (1.8)	1 (0.9)	4 (3.3)	3 (2.6)	6 (3.9)	34 (5.7)
	P	0	0	0	0
Cough	D	1 (1.2)	1 (0.2)
	P	1 (1.1)	1 (0.5)
Other	D	16 (11.2)	14	16	12	15	24	19	25	29	36	31	33	22	32	318 (53.2)
	P	3 (2.1)	5	19	18	31	36	24	24	160 (71.7)
Overall	D	28	36	43	53	58	33 (29.2)	30 (25.6)	42 (35.0)	43 (37.1)	55 (55.6)	42 (26.1)	47 (56.6)	40 (23.4)	47 (30.3)	597
	P	6	14	24 (20.9)	28 (27.7)	36 (22.0)	50 (54.3)	35 (20.3)	30 (19.5)	223

Abbreviations: D, drug; AE, adverse event; GE, gastroesophageal; P, placebo.

Efficacy

Liu et al57 included in their systematic review three studies (six RCTs) of tadalafil versus placebo, demonstrating a mean difference in IPSS change from baseline of 2.57 (95% confidence interval [CI] 3.15–1.98) and in IIEF-EF score of 5.34 (95% CI 4.11–6.57) in favor of tadalafil. In the same review, the meta-analysis of mean difference in Q_max and PVR were not statistically significant: 0.20 (95% CI 0.24–0.64, P = 0.38) and 0.47 (95% CI 5.17–6.10, P = 0.87), respectively. In this review, the authors emphasized that there is no significant correlation between LUTS/BPH improvement (change in IPSS) and recovery of sexual activity (change in IIEF-EF score) and that the efficacy of tadalafil on LUTS/BPH in men without ED demonstrates a direct activity of tadalafil on the LUT; in particular, the overall improvement of IPSS in men with ED overlapped the improvement in IPSS in men without ED (IPSS mean difference −2.57 vs −2.60, respectively).

In 2011, in a nonsystematic descriptive review including data from 1088 men treated with tadalafil compared with 444 treated with placebo, Martínez-Salamanca et al58 confirmed that tadalafil significantly improves LUTS/BPH compared with placebo (mean IPSS difference between treatments +4.2, P < 0.001). The overall decrease in IPSS was comparable with that reported in previous α-blocker studies. In the subgroup of sexually active men (55%), a significant improvement in EF was also reported (IIEF-EF domain scores +7.15 with tadalafil vs +2.38 with placebo, P = 0.001). Finally, none of the studies included in this review showed a significant effect of tadalafil on uroflowmetry variables.

The latest systematic review with meta-analysis by Gacci et al2 included four RCTs on tadalafil versus placebo (1360 vs 568 patients) and two RCTs on tadalafil plus α-blocker versus α-blocker alone (34 vs 32 patients). The overall outcomes in terms of efficacy as measured by IPSS, IIEF, and Q_max were very similar to those reported for other PDE5-Is selected for the review ( Figure 1 ). In particular, the most remarkable improvement in LUTS/BPH with tadalafil alone was obtained by Roehrborn et al’s study46 (mean difference in change from baseline compared with placebo: IPSS −3.7, CI −5.5 to −1.8), while the maximum improvement in LUTS/BPH achieved tadalafil and α-blocker combined therapy compared with α-blocker alone was reported by Bechara et al47 (IPSS −2.5, CI −5.7 to +0.7). Excellent results were obtained either with tadalafil alone or in combination with α-blockers with regard to EF (IIEF +6.8, CI 4.3–9.2 and IIEF +6.3, CI 0.9–11.7, respectively).45,47 Combination therapy with tadalafil and an α-blocker achieved a statistically significant – albeit clinically negligible – improvement of Q_max (+0.9 and +1.0 mL/s respectively).47,48 Moreover, Gacci et al’s2 meta-analysis demonstrated that younger men with lower BMI and more severe LUTS/BPH are the best candidates (target patients) for PDE5-I treatment when improvement of LUTS/BPH is intended.

Weighted mean differences (with 95% confidence interval) of International Prostate Symptom Score (IPSS) (A) and International Index of Erectile Function-Erectile Function (IIEF-EF) score (B) for the studies on tadalafil versus placebo.

Conclusion

Many preclinical and clinical studies emphasize the close link between LUTS/BPH and ED. The majority of active treatments for LUTS/BPH have a negative impact on EF.

The remarkable improvement of both LUTS/BPH and ED with tadalafil 5 mg once daily suggests a leading role for this PDE5-I treatment for men with comorbid BPH and ED. PDE5-I treatment is associated with a low rate of AEs and any AEs that do occur tend to be of low severity.

Further studies are needed to better understand the mechanisms of action of PDE5 or PDE5-Is, analyze the correct time for treatment, the cost-effectiveness of treatment, and to better define the long-term safety and efficacy of once-daily use of tadalafil 5 mg for men with LUTS/BPH with or without ED.

Footnotes

Matthias Oelke has been advisor, lecturer, or trial investigator for Eli Lilly and Company as well as for Pfizer. Mario Maggi is a scientific consultant for Bayer Pharma AG, Germany and Eli-Lilly Indianapolis, Indiana Other authors declare no conflicts of interest in this work.

References

1. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011; 60 (4):809–825. [PubMed] [Google Scholar]

2. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012; 61 (5):994–1003. [PubMed] [Google Scholar]

3. Macfarlane GJ, Botto H, Sagnier PP, Teillac P, Richard F, Boyle P. The relationship between sexual life and urinary condition in the French community. J Clin Epidemiol. 1996; 49 (10):1171–1176. [PubMed] [Google Scholar]

4. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999; 281 (6):537–544. [PubMed] [Google Scholar]

5. Blanker MH, Bohnen AM, Groeneveld FP, et al. Correlates for erectile and ejaculatory dysfunction in older Dutch men: a community-based study. J Am Geriatr Soc. 2001; 49 (4):436–442. [PubMed] [Google Scholar]

6. Li MK, Garcia LA, Rosen R. Lower urinary tract symptoms and male sexual dysfunction in Asia: a survey of ageing men from five Asian countries. BJU Int. 2005; 96 (9):1339–1354. [PubMed] [Google Scholar]

7. Brookes ST, Link CL, Donovan JL, McKinlay JB. Relationship between lower urinary tract symptoms and erectile dysfunction: results from the Boston Area Community Health Survey. J Urol. 2008; 179 (1):250–255. [PubMed] [Google Scholar]

8. Sak SC, Hussain Z, Johnston C, Eardley I. What is the relationship between male sexual function and lower urinary tract symptoms (LUTS)? Eur Urol. 2004; 46 (4):482–487. [PubMed] [Google Scholar]

9. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7) Eur Urol. 2003; 44 (6):637–649. [PubMed] [Google Scholar]

10. Wein AJ, Coyne KS, Tubaro A, Sexton CC, Kopp ZS, Aiyer LP. The impact of lower urinary tract symptoms on male sexual health: EpiLUTS. BJU Int. 2009; 103 (Suppl 3):33–41. [PubMed] [Google Scholar]

11. Bouwman II, Van Der Heide WK, Van Der Meer K, Nijman R. Correlations between lower urinary tract symptoms, erectile dysfunction, and cardiovascular diseases: are there differences between male populations from primary healthcare and urology clinics? A review of the current knowledge. Eur J Gen Pract. 2009; 15 (3):128–135. [PubMed] [Google Scholar]

12. Andersson KE, de Groat WC, McVary KT, et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol Urodyn. 2011; 30 (3):292–301. [PubMed] [Google Scholar]

13. Filippi S, Morelli A, Sandner P, et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology. 2007; 148 (3):1019–1029. [PubMed] [Google Scholar]

14. Fibbi B, Morelli A, Vignozzi L, et al. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J Sex Med. 2010; 7 (1 Pt 1):59–69. [PubMed] [Google Scholar]

15. Morelli A, Filippi S, Comeglio P, et al. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med. 2010; 7 (1 Pt 1):107–120. [PubMed] [Google Scholar]

16. Morelli A, Sarchielli E, Comeglio P, et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. J Sex Med. 2011; 8 (10):2746–2760. [PubMed] [Google Scholar]

17. Vignozzi L, Filippi S, Morelli A, et al. Cavernous neurotomy in the rat is associated with the onset of an overt condition of hypogonadism. J Sex Med. 2009; 6 (5):1270–1283. [PubMed] [Google Scholar]

18. Angulo J, Cuevas P, Fernández A, et al. Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck. J Sex Med. 2012; 9 (9):2293–2306. [PubMed] [Google Scholar]

19. Morelli A, Filippi S, Sandner P, et al. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med. 2009; 6 (6):1594–1608. [PubMed] [Google Scholar]

20. Gacci M, Del Popolo G, Macchiarella A, et al. Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study. J Urol. 2007; 178 (5):2040–2043. [PubMed] [Google Scholar]

21. Gacci M, Ierardi A, Rose AD, et al. Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: results of a randomized, double blind, placebo-controlled pilot study. J Sex Med. 2010; 7 (1 Pt 1):234–243. [PubMed] [Google Scholar]

22. Fibbi B, Penna G, Morelli A, Adorini L, Maggi M. Chronic inflammation in the pathogenesis of benign prostatic hyperplasia. Int J Androl. 2010; 33 (3):475–488. [PubMed] [Google Scholar]

23. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate Cancer Prostatic Dis. 2012 Nov 20; Epub. [PubMed] [Google Scholar]

24. Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol. 2007; 51 (5):1202–1216. [PubMed] [Google Scholar]

25. Filippi S, Vignozzi L, Morelli A, et al. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J Sex Med. 2009; 6 (12):3274–3288. [PubMed] [Google Scholar]

26. Vignozzi L, Morelli A, Filippi S, et al. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med. 2011; 8 (1):57–77. [PubMed] [Google Scholar]

27. Vignozzi L, Morelli A, Sarchielli E, et al. Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J Endocrinol. 2012; 212 (1):71–84. [PubMed] [Google Scholar]

28. Morelli A, Comeglio P, Filippi S, et al. Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: an experimental study in the rabbit. Prostate. 2012; 73 (4):428–441. [PubMed] [Google Scholar]

29. Morelli A, Comeglio P, Filippi S, et al. Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J Steroid Biochem Mol Biol. 2012; 132 (1–2):80–92. [PubMed] [Google Scholar]

30. Maneschi E, Morelli A, Filippi S, et al. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J Endocrinol. 2012; 215 (3):347–362. [PubMed] [Google Scholar]

31. Zenzmaier C, Sampson N, Pernkopf D, Plas E, Untergasser G, Berger P. Attenuated proliferation and trans-differentiation of prostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia. Endocrinology. 2010; 151 (8):3975–3984. [PubMed] [Google Scholar]

32. Penna G, Mondaini N, Amuchastegui S, et al. Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia. Eur Urol. 2007; 51 (2):524–533. [PubMed] [Google Scholar]

33. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011; 185 (5):1793–1803. [PubMed] [Google Scholar]

34. Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries. Eur Urol. 2007; 51 (1):207–215. discussion 215–216. [PubMed] [Google Scholar]

35. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol. 2002; 41 (5):497–506. [PubMed] [Google Scholar]

36. Zlotta AR, Teillac P, Raynaud JP, Schulman CC. Evaluation of male sexual function in patients with Lower Urinary Tract Symptoms (LUTS) associated with Benign Prostatic Hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon), Tamsulosin or Finasteride. Eur Urol. 2005; 48 (2):269–276. [PubMed] [Google Scholar]

37. Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernández Fernández E, European Silodosin Study Group Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011; 59 (3):342–352. [PubMed] [Google Scholar]

38. Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ. 1996; 155 (9):1251–1259. [PMC free article] [PubMed] [Google Scholar]

39. Roehrborn CG, Siami P, Barkin J, et al.CombAT Study Group The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010; 57 (1):123–131. [PubMed] [Google Scholar]

40. McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association Guideline: Management of BPH. Baltimore, MD; American Urological Association Education and Research; 2003. Guideline on the management of benign prostatic hyperplasia (BPH) [Google Scholar]

41. Bouza C, López T, Magro A, Navalpotro L, Amate JM. Systematic review and meta-analysis of Transurethral Needle Ablation in symptomatic Benign Prostatic Hyperplasia. BMC Urol. 2006; 6 :14. [PMC free article] [PubMed] [Google Scholar]

42. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms, including benign prostatic obstruction. Eur Urol. 2013 [Epub ahead of print. March 2013] [PubMed] [Google Scholar]

43. Roehrborn CG. Standard surgical interventions: TURP/TUIP/OPSU. In: Kirby RS, McConnell JD, Fitzpatrick JM, Roehrborn CG, Boyle P, editors. Textbook of Benign Prostatic Hyperplasia. Oxford; ISIS Medical Media; 1996. pp. 341–378. [Google Scholar]

44. Briganti A, Naspro R, Gallina A, et al. Impact on sexual function of holmium laser enucleation versus transurethral resection of the prostate: results of a prospective, 2-center, randomized trial. J Urol. 2006; 175 (5):1817–1821. [PubMed] [Google Scholar]

45. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007; 177 (4):1401–1407. [PubMed] [Google Scholar]

46. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008; 180 (4):1228–1234. [PubMed] [Google Scholar]

47. Bechara A, Romano S, Casabé A, et al. Comparative efficacy assessment of tamsulosin vs tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med. 2008; 5 (9):2170–2178. [PubMed] [Google Scholar]

48. Liguori G, Trombetta C, De Giorgi G, et al. Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med. 2009; 6 (2):544–552. [PubMed] [Google Scholar]

49. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009; 56 (4):727–735. [PubMed] [Google Scholar]

50. Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int. 2010; 105 (4):502–507. [PubMed] [Google Scholar]

51. Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, Kraus S. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J Urol. 2010; 183 (3):1092–1097. [PubMed] [Google Scholar]

52. Porst H, Kim ED, Casabé AR, et al.LVHJ study team Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011; 60 (5):1105–1113. [PubMed] [Google Scholar]

53. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011; 107 (7):1110–1116. [PubMed] [Google Scholar]

54. Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012; 61 (5):917–925. [PubMed] [Google Scholar]

55. Regadas RP, Reges R, Cerqueira JB, et al. Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial. Int Urol Nephrol. 2012; 45 (1):39–43. [PubMed] [Google Scholar]

56. Yokoyama O, Yoshida M, Kim SC, et al. Int J Urol. 2012. Sep 7, 2012. Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosin-controlled 12-week study in Asian men. Epub. [PubMed] [Google Scholar]

57. Liu L, Zheng S, Han P, Wei Q. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review and meta-analysis. Urology. 2011; 77 (1):123–129. [PubMed] [Google Scholar]

58. Martínez-Salamanca JI, Carballido J, Eardley I, et al. Phosphodiesterase type 5 inhibitors in the management of non-neurogenic male lower urinary tract symptoms: critical analysis of current evidence. Eur Urol. 2011; 60 (3):527–535. [PubMed] [Google Scholar]

Tadalafil Tablets (Erectile Dysfunction, BPH)

TADALAFIL (tah DA la fil) treats erectile dysfunction (ED). It works by increasing blood flow to the penis, which helps to maintain an erection. It may also be used to treat symptoms of an enlarged prostate (benign prostatic hyperplasia).

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

COMMON BRAND NAME(S): Adcirca, ALYQ, Cialis

What should I tell my care team before I take this medication?

They need to know if you have any of these conditions:

How should I use this medication?

Take this medication by mouth with a glass of water. Follow the directions on the prescription label. You may take this medication with or without meals. When this medication is used for erection problems, your care team may prescribe it to be taken once daily or as needed. If you are taking the medication as needed, you may be able to have sexual activity 30 minutes after taking it and for up to 36 hours after taking it. Whether you are taking the medication as needed or once daily, you should not take more than one dose per day. If you are taking this medication for symptoms of benign prostatic hyperplasia (BPH) or to treat both BPH and an erection problem, take the dose once daily at about the same time each day. Do not take your medication more often than directed.

Talk to your care team about the use of this medication in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.

NOTE: This medicine is only for you. Do not share this medicine with others.

What if I miss a dose?

If you are taking this medication as needed for erection problems, this does not apply. If you miss a dose while taking this medication once daily for an erection problem, benign prostatic hyperplasia, or both, take it as soon as you remember, but do not take more than one dose per day.

What may interact with this medication?

Do not take this medication with any of the following:

This medication may also interact with the following:

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medication?

If you notice any changes in your vision while taking this medication, call your care team as soon as possible. Stop using this medication and call your care team right away if you have a loss of sight in one or both eyes.

Contact your care team right away if the erection lasts longer than 4 hours or if it becomes painful. This may be a sign of serious problem and must be treated right away to prevent permanent damage.

If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medication, you should refrain from further activity and call your care team as soon as possible.

Do not drink alcohol to excess (examples, 5 glasses of wine or 5 shots of whiskey) when taking this medication. When taken in excess, alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure.

Using this medication does not protect you or your partner against HIV infection (the virus that causes AIDS) or other sexually transmitted diseases.

What side effects may I notice from receiving this medication?

Side effects that you should report to your care team as soon as possible:

Side effects that usually do not require medical attention (report to your care team if they continue or are bothersome):

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medication?

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medication after the expiration date.

NOTE: This sheet is a summary. It may not cover all possible information. If you have questions about this medicine, talk to your doctor, pharmacist, or health care provider.