Alyq (tadalafil)

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Tadalafil is metabolized principally via cytochrome P-450 (CYP) isoenzyme 3A4. Inhibitors and inducers of this isoenzyme may increase or decrease tadalafil exposure, respectively.

Tadalafil does not appear to induce or inhibit the clearance of other drugs metabolized by P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP), or CYP isoforms.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cgmp Specific Pde Type-5 Inhibitors/Nitrates

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nitrates activate guanyl cyclase, an enzyme that increases levels of cyclic guanosine monophosphate (cGMP). cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit phosphodiesterase type 5 (PDE5), which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates.

CLINICAL EFFECTS: The concurrent use of CGMP specific PDE type-5 inhibitors and nitrates potentiates the hypotensive effects of nitrates(1-7) which may result in dizziness, syncope, heart attack, or stroke.(4) The concurrent use of sildenafil and sodium nitroprusside may potentiate the antiaggregatory effect of sodium nitroprusside in addition to increased hypotensive effects.(2)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitor may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The administration of avanafil to patients receiving organic nitrates, either regularly and/or intermittently, is contraindicated. In a patient who has taken avanafil, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered and it should only be administered under close medical supervision with appropriate hemodynamic monitoring.(1) The administration of sildenafil to patients receiving organic nitrates, either regularly and/or intermittently, in any form is contraindicated.(2) The administration of tadalafil to patients receiving any form of organic nitrate, either regularly and/or intermittently, is contraindicated.(3,4) Patients should be instructed to seek immediate medical attention if they experience anginal chest pain following tadalafil. In such cases where nitrate administration is considered medically necessary, at least 48 hours should elapse after tadalafil administration before nitrate administration is considered. In such cases, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(4) The administration of vardenafil to patients receiving nitrates or nitric oxide donors is contraindicated.(5-7) In patients prescribed vardenafil in whom nitrate administration is deemed medically necessary in a life-threatening situation, the Canadian manufacturer of vardenafil states that at least 24 hours should have elapsed after the last dose of vardenafil before the nitrate administration is considered. Nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(7) The concomitant use of nicorandil(8) or subinguinal nitroglycerin(9) and PDE type-5 inhibitors is contraindicated. Treat hypotension resulting from concurrent use as a nitrate overdose, with elevation of the extremities and central volume expansion.(10)

DISCUSSION: Nitrates activate guanylate cyclase, an enzyme that increases levels of cGMP. cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit PDE5, which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates. It is unknown when nitrates, if necessary, can be safely administered to patients who have taken CGMP specific PDE type-5 inhibitors. Following a single 100 mg oral dose of sildenafil, peak plasma levels are approximately 440 ng/mL and levels 24 hours post dose are approximately 2 ng/ml. Sildenafil plasma levels at 24 hours post dose are three to eight times higher in the following patients: those age greater than 65, those with hepatic impairment, those with severe renal impairment (creatinine clearance less than 30 ml/min), and those with concomitant use of potent CYP P-450-3A4 inhibitors (erythromycin). Although plasma levels of sildenafil are lower at 24 hours post dose, the manufacturer of sildenafil states that it is still unknown whether nitrates can safely be coadministered at that time.(2) In vitro studies with human platelets have shown that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside.(2) In a study of 150 subjects who received tadalafil (20 mg) daily for 7 days, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, and 96 hours after tadalafil. A significant interaction between tadalafil and nitroglycerin was observed up to and including 24 hours post-tadalafil. At 48 hours, the interaction was not observed by most hemodynamic measures. After 48 hours, the interaction was not detectable.(4) In a population-based cohort study of 61,487 men who received nitrates, 5,710 (9%) concurrently received PDE Type-5 inhibitors (PDE5i). Crude hazard ratios found a significant and inverse association between combination use of nitrates and PDE5i and all cause, cardiovascular, and non-cardiovascular mortality. All-cause mortality incidence rates were 2.69 cases per 100 person-years for the nitrate and PDE5i group vs 3.83 cases per 100 person-years in the nitrate-only group. Concurrent use of nitrates and PDE5i found a multivariate adjusted HR for all-cause mortality of 1.39 (95% CI: 1.28-1.51). Concurrent use of nitrates and PDE5i found an adjusted HR for cardiovascular death, non-cardiovascular death, myocardial infarction, heart failure, revascularization, and major adverse cardiovascular event (MACE) in patients treated with both nitrates and PDE5i was 1.34 (95% CI: 1.11-1.62), 1.40 (95% CI: 1.27-1.54), 1.72 (95% CI: 1.55-1.90), 1.67 (95% CI: 1.48-1.90), 1.95 (95% CI: 1.78-2.13), and 1.70 (95% CI: 1.58-1.83), respectively, compared with patients with nitrates only.(11)

Pde Inhibitors/Riociguat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1)

CLINICAL EFFECTS: The concurrent use of PDE inhibitors and riociguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The administration of riociguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil (5), sildenafil (2), tadalafil (3,6), or vardenafil (4)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is contraindicated.(1) If transitioning from sildenafil to riociguat, discontinue sildenafil at least 24 hours prior to administering riociguat.(1) If transitioning from tadalafil to riociguat, discontinue tadalafil at least 48 hours prior to administering riociguat. Consider starting riociguat at 0.5 mg in patients at risk for hypotension.(1) If transitioning from riociguat to a PDE inhibitor, discontinue riociguat at least 24 hours prior to administering a PDE inhibitor.(1)

DISCUSSION: In a study of 7 PAH patients maintained on sildenafil (20 mg TID), single doses of riociguat (0.5 mg and 1 mg, sequentially) showed additive hemodynamic effects.(1) In clinical trials, there was a high rate of discontinuation for hypotension among patients receiving sildenafil (20 mg TID) and riociguat (1 mg to 2.5 mg TID) and one death.(1)

Sildenafil; Tadalafil (For Pah)/Boceprevir;Telaprevir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The metabolism of sildenafil and tadalafil by CYP3A4 may be inhibited by boceprevir(1) and telaprevir.(2)

CLINICAL EFFECTS: The concurrent administration of boceprevir(1) or telaprevir(2) may result in elevated levels of sildenafil or tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of boceprevir(1) and telaprevir(2) state that concurrent use of sildenafil or tadalafil when used for the treatment of pulmonary arterial hypertension (PAH) is contraindicated.

DISCUSSION: Boceprevir has been shown to be a strong inhibitor of CYP3A4.(1) Telaprevir has also been shown to inhibit CYP3A4.(1) Therefore, concurrent use of boceprevir(1) or telaprevir(2) with agents that are highly dependent on CYP3A4 for clearance and for which elevated plasma levels are associated with serious and/or life-threatening events is contraindicated.

Tadalafil (Pah)/Nirmatrelvir-Ritonavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The nirmatrelvir-ritonavir may inhibit the metabolism of tadalafil by CYP3A4.(1-2)

CLINICAL EFFECTS: The concurrent administration of nirmatrelvir-ritonavir may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of nirmatrelvir-ritonavir states the concurrent use of tadalafil for pulmonary arterial hypertension (PAH) should be avoided.(2) The US manufacturers of the protease inhibitors state that in patients who have received a protease inhibitor for at least one week, the initial dosage of tadalafil for the treatment of primary pulmonary hypertension should be 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(3-11) The US manufacturers of the protease inhibitors state that in patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be discontinued for 24 hours before beginning protease inhibitor therapy other than nelfinavir without concurrent ritonavir. After one week, tadalafil may be resumed at a dosage of 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(3-11) In patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily prior to beginning therapy with nelfinavir without concurrent ritonavir. The dosage may be increased to 40 mg daily based upon tolerability.(5) The US manufacturer of tadalafil states that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concurrent strong CYP3A4 inhibitors.(1) The US manufacturer of tadalafil states that the recommended dose of daily tadalafil for the treatment of erectile dysfunction in patients taking strong CYP3A4 inhibitors is 2.5 mg.(1) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician.

DISCUSSION: Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (500 mg or 600 mg twice daily) increased tadalafil area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum (Cmax) by 30%. Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily for 17 doses) had no significant effects on the AUC of a single dose of tadalafil (10 mg). Tadalafil Cmax decreased 30%. Tipranavir Cmax, AUC, and concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively. Administration of a single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold. Tadalafil Cmax decreased 22%. Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Pde Inhibitors/Vericiguat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vericiguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1-6)

CLINICAL EFFECTS: The concurrent use of PDE inhibitors and vericiguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, or with severe renal impairment. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The manufacturer of vericiguat states that administration of vericiguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil,(2) sildenafil,(3) tadalafil,(4,5) or vardenafil(6)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is not recommended.(1) The manufacturers of the PDE-5 inhibitors state that concurrent use of guanylate cyclase stimulators is contraindicated.(2-6)

DISCUSSION: Concomitant use of vericiguat 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of vericiguat alone.(1)

Sildenafil(Pah);Tadalafil(Bph,Pah)/Slt Strong 3A4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of sildenafil(1) and tadalafil.(2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of sildenafil(1) and tadalafil.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sildenafil states that the concurrent use of strong CYP3A4 inhibitors with sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(5) The US manufacturer of tadalafil states that the concurrent use of strong CYP3A4 inhibitors with tadalafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(6) The US manufacturer of itraconazole states that the concurrent use of sildenafil or tadalafil is not recommended during and for 2 weeks after treatment with itraconazole, when sildenafil or tadalafil is used for the treatment of PAH.(7) The US manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil for erectile dysfunction in patients receiving concomitant therapy with strong CYP3A4 inhibitors.(1) The US manufacturer of tadalafil states that the maximum recommended dose of as needed tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 10 mg every 72 hours.(2) The maximum recommended dose of daily tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 2.5 mg.(3)

DISCUSSION: Concurrent administration of a single 100 mg dose of sildenafil with erythromycin (500 mg twice daily for five days) resulted in an increase of sildenafil area-under-curve (AUC) by 182%. Therefore, the manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil in patients receiving concomitant therapy with other strong CYP3A4 inhibitors such as itraconazole or ketoconazole.(1) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2) Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin, ensitrelvir, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, nefazodone, posaconazole, ribociclib, telithromycin, and voriconazole.(1-4)

Tadalafil (Pah)/Lenacapavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lenacapavir may inhibit the metabolism of tadalafil by CYP3A4.(1-4)

CLINICAL EFFECTS: The concurrent administration of lenacapavir may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lenacapavir states the concurrent use of tadalafil for pulmonary arterial hypertension (PAH) is not recommended.(2-4) The US manufacturer of tadalafil and the UK and Canadian manufacturers of lenacapavir state that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concomitant therapy.(1,3-4) The US manufacturer of tadalafil and the UK and Canadian manufacturers of lenacapavir state that the recommended dose of daily tadalafil is 2.5 mg for the treatment of erectile dysfunction in patients receiving concomitant therapy.(1,3-4) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician.

DISCUSSION: Concurrent administration of lenacapavir 600 mg with a single 2.5 mg dose of midazolam (a CYP3A4 substrate) increased midazolam maximum concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold, respectively.(2-4) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(1)

Tadalafil (Pah)/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may accelerate the metabolism of tadalafil.(1-3)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of tadalafil.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inducers with tadalafil is not recommended. If concurrent use is necessary, closely monitor for treatment response.(1-3)

DISCUSSION: Rifampin (600 mg daily), a strong CYP3A4 inducer, reduced tadalafil 10 mg single-dose exposure AUC by 88% and Cmax by 46%, respectively, compared to tadalafil alone.(1-3) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(4,5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Cgmp Specific Pde Type-5 Inhibitors/Alpha-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14) and an alpha-blocker may result in additive or synergistic effects on blood pressure.

CLINICAL EFFECTS: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14)) and an alpha-blocker may result in symptomatic hypotension.

PREDISPOSING FACTORS: Patients who have a history of hemodynamic instability on alpha-blocker therapy prior to initiating avanafil, sildenafil, tadalafil, or vardenafil may be at an increased risk of symptomatic hypotension during concurrent therapy.

PATIENT MANAGEMENT: The US manufacturer of avanafil states that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning avanafil therapy. Avanafil should be initiated at the 50 mg dosage. In patients stabilized on avanafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(1) The US, Australian, Canadian, and UK manufacturers of sildenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning sildenafil therapy. Sildenafil should be initiated at the lowest possible dosage. In patients stabilized on sildenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(2-5) The US manufacturer of tadalafil states that patients taking tadalafil for erectile dysfunction (ED) and alpha-blockers should be stabilized on their alpha-blocker prior to beginning tadalafil therapy. Tadalafil should be initiated at the lowest possible dosage. In patients stabilized on tadalafil therapy, alpha-blocker therapy should be initiated at the lowest possible dose. The combination of tadalafil and an alpha-blocker for treatment of benign prostatic hyperplasia (BPH) is not recommended. Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil for once daily use for the treatment of BPH.(6) The Australian manufacturer of tadalafil states that tadalafil should be used with caution in patients taking alpha-blockers.(7) The Canadian manufacturer of tadalafil states that it may be used with tamsulosin and should be used with caution with other alpha-blockers.(8) The UK manufacturer of tadalafil states that concurrent use with alpha-blockers is not recommended.(9) The US, Canadian, and UK manufacturers of vardenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning vardenafil therapy. Vardenafil should be initiated at the lowest possible dosage. In patients stabilized on vardenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(10-12) The UK manufacturer of vardenafil states that vardenafil may be give at any time in relation to tamsulosin; however, a dose separation period of 6 hour should be considered for other alpha-blockers.(12) The Australian manufacturer of vardenafil states that concurrent use with alpha-blockers is not recommended.(13) The US manufacturers of doxazosin,(14) prazosin(15) and terazosin(16) state that PDE-5 inhibitor therapy should be initiated at the lowest dose.

DISCUSSION: In a study in 24 subjects, concurrent use of avanafil (200 mg) with doxazosin (1 mg on Day 1, titrated to 8 mg for Days 8-18) resulted in 7 subjects experiencing potentially clinically significant changes in blood pressure.(1) In a study in 24 subjects, concurrent use of avanafil (200 mg) with tamsulosin (0.4 mg Days 1-11) resulted in 5 subjects experiencing potentially clinically significant changes in blood pressure.(1) Simultaneous administration of sildenafil (25 mg) and doxazosin (4 mg) resulted in mean additional reductions of supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic. When doxazosin (4 mg) was simultaneously administered with higher doses of sildenafil, there were reports of symptomatic postural hypotension within one to four hours.(2) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving alfuzosin (10 mg daily) resulted in mean maximum decreases in standing and supine systolic blood pressure by 2.2 mmHg and 4.4 mmHg, respectively. There were no subjects with a decrease from baseline standing systolic blood pressure greater than 30 mmHg.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to 18 healthy subjects receiving doxazosin (8 mg daily) resulted in significant augmentation of the blood-pressure lowering effects of doxazosin (by 9.8 mmHg). The number of subjects with a standing blood pressure of less than 85 mmHg was greater after concurrent doxazosin and tadalafil than when compared to doxazosin with placebo (28% versus 6%). One subject reported vertigo and another reported dizziness. No syncope was reported.(5,14) In a second study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving doxazosin (4-8 mg daily) also resulted in augmentation of the blood-pressure lowering affects of doxazosin. One subject reported symptomatic hypotension and another reported dizziness with concurrent therapy.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no significant decreases in blood pressure.(6,17) Hypotension has been reported with concurrent use of terazosin and phosphodiesterase-5 inhibitors.(16) With simultaneous administration of vardenafil (10 mg) and terazosin (10 mg), 6 of 8 healthy subjects experienced a standing systolic blood pressure of less than 85 mmHg. With simultaneous vardenafil (20 mg) and terazosin (10 mg), 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered 6 hours apart from terazosin (10 mg), 7 of 28 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) With simultaneous administration of vardenafil (10 mg) and tamsulosin (0.4 mg), two of 16 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered six hours apart from tamsulosin (0.4 mg), one of 24 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) In a study in subjects with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy, simultaneous vardenafil (5 mg) and tamsulosin resulted in no effects on blood pressure. Simultaneous vardenafil (5 mg) with terazosin resulted in hypotension in some subjects. This effect did not occur when vardenafil and terazosin were separated by 6 hours.(12) In a placebo controlled, crossover study in 22 subjects with benign prostatic hyperplasia receiving tamsulosin, subjects received single doses of vardenafil (10 mg and 20 mg). No patients exhibited symptomatic hypotension. Three patients receiving 20 mg of vardenafil reported dizziness, but none had a systolic blood pressure of less than 95 mmHg.(18) In a placebo-controlled study in 24 health male subjects, administration of sildenafil (100 mg) or tadalafil (20 mg) with silodosin resulted in an increase in positive orthostatic tests in the 12 hours after concurrent administration when compared with the administration of silodosin alone. There were no reports of symptomatic orthostasis or dizziness.(19)

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Tadalafil (Pah)/Select Protease Inhibitors; Cobicistat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of tadalafil.(1-10)

CLINICAL EFFECTS: The concurrent administration of a protease inhibitor may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-10)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of the protease inhibitors state that in patients who have received a protease inhibitor for at least one week, the initial dosage of tadalafil for the treatment of primary pulmonary hypertension should be 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(2-10) The US manufacturers of the protease inhibitors state that in patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be discontinued for 24 hours before beginning protease inhibitor therapy other than nelfinavir without concurrent ritonavir. After one week, tadalafil may be resumed at a dosage of 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(2-10) In patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily prior to beginning therapy with nelfinavir without concurrent ritonavir. The dosage may be increased to 40 mg daily based upon tolerability.(7) In patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, maintain tadalafil dose when switching from darunavir/ritonavir to darunavir/cobicistat.(11) The US manufacturers of tadalafil(1) and the protease inhibitors(2-10) state that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concurrent therapy. The US manufacturer of tadalafil states that the recommended dose of daily tadalafil for the treatment of erectile dysfunction in patients taking potent inhibitors of CYP3A4 is 2.5 mg.(1) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician.

DISCUSSION: Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (500 mg or 600 mg twice daily) increased tadalafil area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum (Cmax) by 30%. Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily for 17 doses) had no significant effects on the AUC of a single dose of tadalafil (10 mg). Tadalafil Cmax decreased 30%. Tipranavir Cmax, AUC, and concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively. Administration of a single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold. Tadalafil Cmax decreased 22%. Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.

*Concomitant use of organic nitrates or nitrites, either regularly or intermittently. Do not use nitrates within 48 hours of the last tadalafil dose.

*Concomitant use of guanylate cyclase stimulators (e.g., riociguat).

*Hypersensitivity to tadalafil or any ingredient in the formulation; Stevens-Johnson syndrome and exfoliative dermatitis have been reported.

• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min

• Alcohol intoxication
• Anterior ischemic optic neuropathy
• Aortic valve stenosis
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Fibrosis of corpus cavernosum
• Hypertrophic cardiomyopathy
• Hypotension
• Life-threatening cardiac arrhythmias
• Penile angulation
• Peptic ulcer
• Peyronie's disease
• Pigmentary retinopathy
• Restrictive cardiomyopathy
• Unstable angina pectoris

• Cerebrovascular accident
• Hearing loss
• Increased risk of bleeding
• Increased risk of bleeding due to coagulation disorder
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Leukemia
• Multiple myeloma
• Seizure disorder
• Severe uncontrolled hypertension
• Sickle cell disease

The most common adverse effect of tadalafil is headache.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Angina
• Anterior ischemic optic neuropathy
• Blurred vision
• Cerebrovascular accident
• Chest pain
• Conjunctivitis
• Dysphagia
• Dyspnea
• Esophagitis
• Exfoliative dermatitis
• Facial edema
• Hearing loss
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Orthostatic hypotension
• Palpitations
• Priapism
• Rectal bleeding
• Retinal vascular occlusion
• Seizure disorder
• Stevens-johnson syndrome
• Syncope
• Tachycardia
• Vision impairment
• Visual field defect

More Frequent

• Headache disorder

Less Frequent

• Acute abdominal pain
• Anemia
• Back pain
• Cough
• Diarrhea
• Dyspepsia
• Flushing
• Gastroesophageal reflux disease
• Myalgia
• Nasal congestion
• Nausea
• Pain in extremities
• Pharyngitis
• Upper respiratory infection

Rare or Very Rare

• Acquired chromatopsia
• Arthralgia
• Conjunctival hyperemia
• Dizziness
• Drowsy
• Epistaxis
• Eye tearing
• Eyelid edema
• Fatigue
• Frequent erections
• Gastritis
• General weakness
• Hyperhidrosis
• Hypoesthesia
• Insomnia
• Loose stools
• Migraine
• Neck pain
• Ocular pain
• Pain
• Paresthesia
• Peripheral edema
• Pruritus of skin
• Skin rash
• Tinnitus
• Transient global amnesia
• Urticaria
• Vertigo
• Visual changes
• Vomiting
• Xerostomia

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The manufacturer states that safety and efficacy of tadalafil have not been established in pediatric patients with PAH.

Limited published data from a randomized controlled trial, observational studies, and case series of tadalafil use in pregnant females have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with untreated PAH are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Experts recommend that patients with PAH avoid pregnancy.

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 7 times the maximum recommended human dose (MRHD) of 40 mg/day based on AUC.

There are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. The manufacturer states when a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tadalafil and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Tadalafil dosage adjustment based solely on age is not necessary in geriatric patients.

Safety of tadalafil in geriatric patients (>65 and >=75 years of age) is similar to that in younger patients. The manufacturers state that modification of tadalafil dosage is not needed in geriatric patients solely on the basis of age; however, the possibility of greater sensitivity in some geriatric individuals should be considered.

Compared to healthy subjects 19-45 years of age, clearance was lower, AUC increased 25%, and no effect on peak plasma concentration was observed in elderly (>=65 years of age) males given a 10 mg dose of tadalafil.