Sildenafil (Pulm.Hypertension) (sildenafil citrate)

No dosing information is available for this tab.

Sildenafil is administered orally (as tablets or oral suspension) for the treatment of pulmonary arterial hypertension (PAH); the drug is also available in a parenteral formulation that is administered by IV injection for the continued treatment of patients with PAH who are currently prescribed oral sildenafil and who are temporarily unable to take oral medications.

Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route). Inhibitors and inducers of these isoenzymes may reduce or increase sildenafil clearance, respectively.

Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less following IV administration than those observed after oral administration.

In vitro studies indicate that sildenafil is a weak inhibitor of the CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.

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)

Selected Cyp3a4 Substrates/Mifepristone

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: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1)

CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.

Sildenafil (For Pah)/Hiv Protease Inhibitors; Cobicistat

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 by CYP3A4 may be inhibited by the protease inhibitors and cobicistat.

CLINICAL EFFECTS: The concurrent administration of sildenafil with a protease inhibitor or cobicistat may result in elevated levels of sildenafil, which may result in increased adverse effects such as hypotension, syncope, visual changes, and priapism.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of atazanavir,(1) darunavir,(2) fosamprenavir,(3) indinavir,(4) lopinavir/ritonavir,(5) nelfinavir,(6) nirmatrelvir/ritonavir,(7) saquinavir,(9) tipranavir,(10) cobicistat(11), and ombitasvir-paritaprevir-ritonavir-dasabuvir(15) state that the concurrent use of sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) is contraindicated. The US manufacturer of Revatio states that concurrent use is not recommended.(12)

DISCUSSION: In a study in 16 subjects, administration of darunavir/ritonavir (400/100 mg twice daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of sildenafil (25 mg) by 38% and 3%, respectively, when compared to the administration of a 100 mg single dose of sildenafil given without darunavir.(3) In a study in 6 HIV-infected males, indinavir (800 mg every 8 hours) increased the AUC and Cmax of indinavir by 11% and 48%, respectively. Sildenafil AUC increased by 340%.(4) The concurrent administration of ritonavir (400 mg twice daily) at steady state with sildenafil (100 mg single dose) resulted in increases in the sildenafil Cmax and AUC by 300% (4-fold) and 1000% (11-fold), respectively.(7,12-14) After 24 hours, plasma levels of sildenafil were still approximately 200 ng/ml (normally 5 ng/ml 24 hours post-dose).(14) In a study in 27 healthy volunteers, the concurrent use of saquinavir (1200 mg 3 times daily for 8 days) increased the AUC and Cmax of a single dose of sildenafil (100 mg) by 210% and 140%, respectively.(9) Because a safe and effective dosage regimen for the use of sildenafil for PAH with concurrent protease inhibitor therapy has not been determined, the US manufacturer of the protease inhibitors state that concurrent use is contraindicated.(1-10,15)

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.

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)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

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

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Selected Sensitive Cyp3a4 Substrates/Voxelotor

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

MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)

DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)

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)

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)

Selected Sensitive Cyp3a4 Substrates/Schisandra

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

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Sildenafil (Pah)/Strong And Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Sildenafil is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of sildenafil.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in substantially decreased levels and effectiveness of sildenafil.(1)

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

PATIENT MANAGEMENT: Concomitant use of sildenafil with strong or moderate CYP3A4 inducers should be monitored closely. An increased dosage of sildenafil may be needed. Reduce sildenafil dose to 20 mg three times daily when discontinuing treatment with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: Population pharmacokinetic analysis of data from patients in clinical trials found that sildenafil clearance increased about 3-fold when coadministered with mild CYP3A4 inducers.(1) A randomized, double-blind, placebo-controlled, parallel-group study of 55 healthy volunteers found that 10 days of bosentan (125 mg twice daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of sildenafil by 55.4% and 62.6%, respectively. Sildenafil increased bosentan Cmax and AUC by 42% and 49.8%, respectively. The combination was well tolerated without serious adverse events.(2) In a study of 15 HIV-negative subjects, etravirine (800 mg twice daily for 14 days), a moderate CYP3A4 inducer, decreased the Cmax and AUC of sildenafil by 45% and 57%, respectively.(3) The authors of a review article on drug interactions in pulmonary arterial hypertension therapy state that phenytoin and rifampin (strong CYP3A4 inducers) are not recommended with sildenafil due to an expected near-complete clearance of sildenafil.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6)

Sildenafil/Ciprofloxacin

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

MECHANISM OF ACTION: Ciprofloxacin may increase the absorption and bioavailability of sildenafil.(1,2)

CLINICAL EFFECTS: The concurrent use of ciprofloxacin may increase sildenafil levels and effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of sildenafil may need to be adjusted during concurrent therapy with ciprofloxacin.(2)

DISCUSSION: In a bioavailability study of 12 male volunteers, concurrent use of sildenafil and ciprofloxacin resulted in an increase in the area-under-curve (AUC) of 112% and maximum concentration (Cmax) by 117%. Sildenafil half-life was prolonged 37.6%.(1)

Sildenafil/Delavirdine

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

MECHANISM OF ACTION: Delavirdine may inhibit the metabolism of sildenafil at CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of delavirdine and sildenafil may result in elevated levels of sildenafil and an increased risk for sildenafil adverse effects, including hypotension, visual changes, and prolonged erections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of delavirdine states that if delavirdine and sildenafil are used concurrently, a maximum dosage of 25 mg of sildenafil in a 48 hour period should not be exceeded.(1) Patients should be counseled that they are at an increased risk of sildenafil adverse effects, including hypotension, visual changes, and priapism.(1)

DISCUSSION: Delavirdine has been shown to be a potent inhibitor of CYP3A4. Sildenafil is metabolized by this isoenzyme. Because ritonavir, which also inhibits this isoenzyme, was shown to inhibit the metabolism of sildenafil, the manufacturer of delavirdine recommends that the sildenafil dosage recommended by the manufacturer of sildenafil for concurrent administration with ritonavir be observed for use with delavirdine.(1)

Sildenafil/Mibefradil

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

MECHANISM OF ACTION: Mibefradil may inhibit the metabolism of sildenafil at CYP3A4.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil in patients receiving concomitant therapy with strong CYP3A4 inhibitors such as mibefradil.(1)

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 mibefradil.(1)

*Concomitant use of organic nitrates (e.g., sodium nitroprusside) in any form (e.g., orally, sublingually, transmucosally, parenterally), either regularly or intermittently.

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

*Hypersensitivity to sildenafil.

• Pulmonary veno-occlusive disease

• Acute myocardial infarction
• Anterior ischemic optic neuropathy
• Esophageal dysmotility
• Hypertrophic cardiomyopathy
• Life-threatening cardiac arrhythmias

• Aortic valve stenosis
• Cerebrovascular accident
• Chronic heart failure
• Fibrosis of corpus cavernosum
• Hearing loss
• Hereditary retinal dystrophy
• Hypotension
• Leukemia
• Multiple myeloma
• Penile angulation
• Peyronie's disease
• Pigmentary retinopathy
• Severe autonomic insufficiency
• Severe uncontrolled hypertension
• Sickle cell disease
• Unstable angina pectoris

The most common adverse effects reported in adults receiving sildenafil for PAH include headache, dyspepsia, flushing, pain in limb, myalgia, back pain, and diarrhea.

The most common adverse effect reported in children receiving sildenafil for PAH include priapism.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Anemia
• Angina
• Anterior ischemic optic neuropathy
• Atrioventricular block
• Cardiac arrest
• Cardiomyopathy
• Cataracts
• Cerebral thrombosis
• Chest pain
• Chronic heart failure
• Cystitis
• Esophagitis
• Exfoliative dermatitis
• Hearing loss
• Hyperglycemia
• Hypernatremia
• Hypertension
• Hypertonia
• Hyperuricemia
• Hypoglycemic disorder
• Hypotension
• Intracerebral hemorrhage
• Leukopenia
• Myocardial ischemia
• Ocular hemorrhage
• Ocular hypertension
• Orthostatic hypotension
• Peripheral edema
• Priapism
• Pulmonary hemorrhage
• Rectal bleeding
• Retinal edema
• Retinal hemorrhage
• Seizure disorder
• Shock
• Syncope
• Tachycardia
• Tendon rupture
• Transient cerebral ischemia
• Uncontrolled diabetes mellitus
• Urinary incontinence
• Ventricular arrhythmias
• Vision impairment
• Vitreous detachment

More Frequent

• Back pain
• Dizziness
• Dyspepsia
• Edema
• Epistaxis
• Flushing
• Headache disorder
• Nasal congestion
• Nausea

Less Frequent

• Diarrhea
• Dyspnea
• Erythema
• Fever
• Flu-like symptoms
• Insomnia
• Rhinitis
• Sinusitis
• Skin rash
• Upper respiratory infection
• Urinary tract infection
• Visual changes

Rare or Very Rare

• Abnormal sexual function
• Acute abdominal pain
• Arthritis
• Asthma
• Ataxia
• Bone pain
• Bronchitis
• Chills
• Colitis
• Conjunctivitis
• Contact dermatitis
• Cough
• Depression
• Disorder of ejaculation
• Dream disorder
• Drowsy
• Dry eye
• Dysphagia
• Earache
• Edema of male genital organs
• Facial edema
• Gastritis
• Gastroenteritis
• General weakness
• Gingivitis
• Glossitis
• Gout
• Gynecomastia
• Hematuria
• Hyperhidrosis
• Hypoesthesia
• Hyporeflexia
• Increased sputum
• Increased urinary frequency
• Laryngitis
• Migraine
• Muscle weakness
• Myalgia
• Mydriasis
• Neuralgia
• Nocturia
• Ocular pain
• Orgasm disorder
• Pain
• Palpitations
• Paresthesia
• Peripheral sensory neuropathy
• Pharyngitis
• Photophobia
• Polydipsia
• Pruritus of skin
• Skin photosensitivity
• Skin ulcer
• Stomatitis
• Symptoms of anxiety
• Synovitis
• Tenosynovitis
• Testicular swelling
• Tinnitus
• Transient global amnesia
• Tremor
• Urticaria
• Vertigo
• Vomiting
• Xerostomia

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The manufacturer states that safety and efficacy of sildenafil have been established in pediatric patients 1 to 17 years of age children for the treatment of PAH (WHO functional class I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise.

Use of sildenafil for this indication is also supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients >=1 year of age.

The manufacturer states that safety and efficacy of sildenafil have not been established in pediatric patients < 1 year of age.

In the dose-ranging study (STARTS-1) in children and adolescents, patients 1-17 years of age with PAH (idiopathic, familial, or PAH associated with connective tissue or congenital heart disease) received placebo or sildenafil at a low, medium, or high dosage for 16 weeks. During the 16 week portion of the trial, there was no statistically significant improvement in exercise capacity in sildenafil-treated patients; no patients died during this time.

After completion of the placebo-controlled portion of the study, patients were enrolled in an ongoing extension phase (STARTS-2) during which all patients received sildenafil therapy; placebo patients were randomized to low-, medium-, or high-dose sildenafil. Although clinical improvements (e.g., exercise capacity, hemodynamic parameters, WHO functional class) were observed compared with placebo, an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively.

The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). The manufacturer states that given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg 3 times a day.

Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. Pregnant women with untreated pulmonary arterial hypertension (PAH) are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Experts recommend avoiding pregnancy in patients with PAH.

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in rats and rabbits receiving up to 200 mg/kg daily of sildenafil during organogenesis. These doses represent, respectively, about 32- and 68 times the maximum recommended human dose (MRHD) of 20 mg 3 times a day. No adverse effects were observed in a prenatal and postnatal development study in rats receiving 30 mg/kg daily, equivalent to 5 times the MRHD on a mg/m2 basis.

Limited data indicate that sildenafil and its active metabolite are present in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production; this precludes a clear determination of the risk to an infant during lactation.

The manufacturer recommends cautious dosage selection in geriatric patients, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease or drug therapy.

Clinical studies of sildenafil for PAH did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger adults. Other reported clinical experience has not identified differences in response between geriatric and younger patients with PAH. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered in dosage selection for the treatment of PAH.

Plasma concentrations of sildenafil are increased in geriatric patients and in patients with hepatic or severe renal impairment. AUCs for total sildenafil and its N-demethylated metabolite in geriatric individuals are approximately 84 and 107% higher, respectively, than those observed in healthy younger adults (i.e., 18-45 years of age). Free plasma sildenafil concentrations are increased by about 45% in healthy geriatric individuals (i.e., older than 65 years of age) compared with younger adults as a result of age-related differences in plasma protein binding; plasma concentrations of the N-demethylated metabolite also are increased 57%.