SILDENAFIL CITRATE (sildenafil citrate)

There are 4 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
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)	AMYL NITRITE, BIDIL, GONITRO, ISORDIL, ISORDIL TITRADOSE, ISOSORBIDE, ISOSORBIDE DINIT-HYDRALAZINE, ISOSORBIDE DINITRATE, ISOSORBIDE MONONITRATE, ISOSORBIDE MONONITRATE ER, NIPRIDE RTU, NITHIODOTE, NITRO-BID, NITRO-DUR, NITRO-TIME, NITROGLYCERIN, NITROGLYCERIN IN D5W, NITROGLYCERIN PATCH, NITROLINGUAL, NITROMIST, NITROSTAT, RECTIV, SODIUM NITRITE, SODIUM NITROPRUSSIDE, SODIUM NITROPRUSSIDE-0.9% NACL
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)	APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, KALETRA, LOPINAVIR-RITONAVIR, PAXLOVID, PREZCOBIX, PREZISTA, REYATAZ, STRIBILD, SYMTUZA, VIRACEPT
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.	KORLYM, MIFEPREX, MIFEPRISTONE
Riociguat/PDE Inhibitors 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)	ADEMPAS

Drug contraindication overview.

*Concomitant use of organic nitrates (e.g., nitroglycerin) 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.

*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.

Adverse reaction overview.

The most common adverse effects (>=2%) of sildenafil used for the treatment of ED include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. 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.

Sildenafil for ED (e.g., Viagra(R)) is not indicated for use in pediatric patients. The manufacturer states that safety and efficacy of sildenafil in children have not been established. 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.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None