Sildenafil/Tadalafil

Sildenafil citrate is an oral and intravenous phosphodiesterase type 5 (PDE5) inhibitor. FDA-approved products include Viagra (sildenafil citrate) tablets and Revatio (sildenafil) tablets, oral suspension and injection, with generic equivalents. Doses in FDA labeling are expressed as sildenafil base. Compounded forms include oral capsules, rapid dissolve tablets and topical creams; topical use has no FDA labeling.

• Viagra (oral): treatment of erectile dysfunction in men.
• Revatio (oral and intravenous): treatment of pulmonary arterial hypertension (WHO Group I) in adults, and in pediatric patients 1 to 17 years old.
• Prescribers also use compounded sildenafil preparations for erectile dysfunction when a commercial strength or dosage form does not fit, and topically in women, which is off-label; Viagra labeling states it is not indicated for use in women.

During sexual stimulation, nitric oxide released in the corpus cavernosum activates guanylate cyclase and raises cyclic guanosine monophosphate (cGMP), relaxing smooth muscle and increasing inflow of blood. Sildenafil inhibits PDE5, the enzyme that degrades cGMP, enhancing the effect of nitric oxide; it has no effect without sexual stimulation. PDE5 inhibition in the pulmonary vascular smooth muscle causes pulmonary vasodilation. Weaker inhibition of retinal PDE6 accounts for color-vision changes at higher exposures.

Oral sildenafil is rapidly absorbed (bioavailability about 41%), peaking at a median of 60 minutes fasting; a high-fat meal delays the peak by about 60 minutes and lowers it by about 29%. Protein binding is about 96%.

Sildenafil is cleared mainly by CYP3A4 (major) and CYP2C9 (minor); the N-desmethyl metabolite has about half the parent's PDE5 potency. Terminal half-life is about 4 hours, and metabolites are excreted mostly in feces. Exposure is higher in adults over 65 (free AUC about 40% higher), with hepatic cirrhosis (AUC about 84% higher) and with creatinine clearance below 30 mL/min (AUC about doubled).

• Concomitant use of organic nitrates or nitric oxide donors in any form, regularly or intermittently, including nitroglycerin, isosorbide mononitrate and dinitrate, and amyl or butyl nitrite; sildenafil potentiates their hypotensive effect.
• Concomitant use of guanylate cyclase stimulators such as riociguat, because of the risk of hypotension.
• Known hypersensitivity to sildenafil or any component of the product.

• Cardiovascular: evaluate cardiovascular status before treating erectile dysfunction, since sexual activity carries cardiac risk. Left ventricular outflow obstruction and severely impaired autonomic control of blood pressure increase sensitivity to vasodilators. Recent myocardial infarction, stroke or life-threatening arrhythmia, resting hypotension, uncontrolled hypertension and unstable angina were not studied. ACC/AHA guidance advises at least 24 hours after the last sildenafil dose before an emergency nitrate.
• Priapism: erections lasting more than 4 hours need emergency treatment. Use caution with penile anatomic deformity or conditions predisposing to priapism such as sickle cell anemia, multiple myeloma or leukemia.
• Vision and hearing: sudden vision loss from non-arteritic anterior ischemic optic neuropathy (NAION) and sudden hearing loss have been reported; stop the drug and evaluate promptly. Prior NAION raises recurrence risk. Retinitis pigmentosa has not been studied; use with caution.
• Hypotension with alpha-blockers and other antihypertensives (see Drug Interactions). Combination with other PDE5 inhibitors, including Viagra with Revatio, or with other erectile dysfunction treatments has not been studied and is not recommended.
• Safety in bleeding disorders or active peptic ulcer disease is not known. PAH (Revatio labeling): pulmonary edema may signal pulmonary veno-occlusive disease, where vasodilators are not recommended; vaso-occlusive crises were more frequent in pulmonary hypertension from sickle cell disease; in a long-term pediatric trial, mortality rose with increasing dose.

• Nitrates, nitric oxide donors and riociguat: contraindicated (see Contraindications).
• Alpha-blockers: symptomatic hypotension has occurred; patients should be stable on the alpha-blocker before sildenafil is started at the lowest dose. Other antihypertensives and heavy alcohol use add to blood-pressure lowering.
• CYP3A4 inhibitors: ritonavir raised sildenafil AUC about 11-fold; with ritonavir, Viagra labeling gives 25 mg before sexual activity and a maximum of 25 mg in 48 hours, and Revatio labeling does not recommend strong CYP3A inhibitors. Saquinavir and erythromycin raised AUC about 3-fold, and ketoconazole or itraconazole are expected to raise it more; a 25 mg starting dose is considered. Cimetidine raised concentrations about 56%.
• CYP3A4 inducers such as bosentan, rifampin, carbamazepine and phenytoin lower sildenafil concentrations.

• Erectile dysfunction trials (Viagra): headache and flushing were most common, followed by dyspepsia, abnormal vision (color tinge, light sensitivity, blurring), nasal congestion, back pain, myalgia, nausea, dizziness and rash.
• Pulmonary arterial hypertension trials (Revatio): epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and rhinitis.
• Postmarketing: serious cardiovascular events (myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage), NAION, sudden hearing loss, priapism, seizure and transient global amnesia; many patients had pre-existing risk factors.

Viagra is not indicated for use in women. Revatio labeling notes that limited data in pregnancy have not shown a clear drug-associated risk of major birth defects or miscarriage, and that untreated pulmonary arterial hypertension in pregnancy carries serious maternal and fetal risk. Limited data show sildenafil and its active metabolite in breast milk at low levels.

Cardiovascular status before treatment; blood pressure and orthostatic symptoms, especially with alpha-blockers; visual or hearing changes; prolonged erection. Review medications for nitrates, riociguat, other PDE5 inhibitors and CYP3A4 inhibitors or inducers. Consider age and hepatic and renal function when selecting a dose.

• Viagra (sildenafil citrate) Tablets Prescribing Information, Viatris Specialty LLC.
• Revatio (sildenafil) Tablets, Oral Suspension and Injection Prescribing Information, Viatris Specialty LLC.
• Cheitlin MD, et al. ACC/AHA Expert Consensus Document: Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology and American Heart Association, 1999.

Tadalafil is an oral phosphodiesterase type 5 (PDE5) inhibitor. FDA-approved products include Cialis tablets and generics for erectile dysfunction (ED) and benign prostatic hyperplasia (BPH), and Adcirca and Alyq tablets and Tadliq oral suspension for pulmonary arterial hypertension (PAH). Lake Hills Pharmacy compounds tadalafil as a 503A pharmacy, pursuant to patient-specific prescriptions, in oral capsules, rapid dissolve tablets and combination preparations. Tadalafil is not a controlled substance.

• Cialis (oral): ED; the signs and symptoms of BPH; and ED with BPH. When used with finasteride to start BPH treatment, labeling covers up to 26 weeks.
• Adcirca (oral): PAH (WHO Group 1) to improve exercise ability.
• Prescribers use compounded tadalafil when a strength or dosage form not available commercially is needed, including in combination with other actives.

Sexual stimulation releases nitric oxide in the corpus cavernosum, activating guanylate cyclase and raising cGMP, which relaxes smooth muscle and increases blood inflow. Tadalafil selectively inhibits PDE5, which degrades cGMP, so it enhances this response but has no effect without stimulation. PDE5 inhibition also relaxes prostate, bladder neck and pulmonary vascular smooth muscle. Tadalafil has some PDE11 activity of unknown significance and little PDE6 activity.

After oral dosing, peak plasma concentration is reached at a median of 2 hours (range 0.5 to 6 hours). Absorption is not affected by food. Volume of distribution is about 63 L and protein binding is about 94%. Tadalafil is metabolized mainly by CYP3A4 to an inactive catechol metabolite and excreted as metabolites, about 61% in feces and 36% in urine. Mean half-life is about 17.5 hours in healthy adults, which underlies labeled efficacy for up to 36 hours after a dose. Exposure rises in renal impairment and with strong CYP3A4 inhibitors.

• Use of nitrates or nitric oxide donors in any form, regularly or intermittently, because of potentiated hypotension. If a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last tadalafil dose, with hemodynamic monitoring.
• Concomitant riociguat or other guanylate cyclase stimulators, because of hypotension.
• Known serious hypersensitivity to tadalafil, including Stevens-Johnson syndrome and exfoliative dermatitis.

• Cardiovascular: assess cardiac status before use, as sexual activity carries cardiac risk. Not recommended after myocardial infarction within 90 days, with unstable angina or angina during intercourse, NYHA class II or greater heart failure within 6 months, uncontrolled arrhythmias, hypotension (<90/50 mmHg), uncontrolled hypertension or stroke within 6 months. Left ventricular outflow obstruction (aortic stenosis, idiopathic hypertrophic subaortic stenosis) increases sensitivity to vasodilators.
• Prolonged erection and priapism: an erection lasting more than 4 hours needs immediate care. Use caution with anatomic penile deformity or conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia).
• Sudden vision loss from non-arteritic anterior ischemic optic neuropathy (NAION) has been reported; stop and seek care. Use is not recommended in hereditary degenerative retinal disorders such as retinitis pigmentosa. Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported.
• Renal impairment: on-demand use no more than 10 mg once per 48 hours for creatinine clearance 30 to 50 mL/min and no more than 5 mg once per 72 hours below 30 mL/min or on hemodialysis; once-daily use is not recommended below 30 mL/min. Hepatic impairment: Child-Pugh A or B, on-demand no more than 10 mg once daily; Child-Pugh C not recommended.
• Alcohol: substantial intake (for example, 5 or more units) with tadalafil increases orthostatic signs, dizziness and headache. Use with other PDE5 inhibitors or other ED therapies has not been studied and is not recommended. Use caution with bleeding disorders or active peptic ulceration. Evaluate for prostate cancer and other urologic conditions before treating BPH.

• Nitrates and nitric oxide donors, and riociguat: contraindicated.
• Alpha-blockers: additive blood-pressure lowering. For ED, patients should be stable on alpha-blocker therapy before starting tadalafil, at the lowest dose; tadalafil with an alpha-blocker is not recommended for BPH. Other antihypertensives and alcohol: additive lowering of blood pressure.
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir and other HIV protease inhibitors, clarithromycin) raise exposure: on-demand use no more than 10 mg once per 72 hours, and once-daily use no more than 2.5 mg. Adcirca labeling gives separate guidance for ritonavir in PAH.
• CYP3A4 inducers (rifampin, and bosentan, which induces CYP3A4) lower tadalafil exposure and may reduce its effect.

The most common adverse reactions are headache, dyspepsia, back pain, myalgia, nasal congestion, flushing and pain in the limbs. Back pain and myalgia typically begin 12 to 24 hours after a dose. Less common or serious reactions include hypotension, syncope, chest pain, myocardial infarction, priapism, NAION, sudden hearing loss, visual disturbance and hypersensitivity reactions, including Stevens-Johnson syndrome and exfoliative dermatitis.

Cialis is not indicated for use in women. Adcirca labeling notes no adverse developmental effects in animal studies and limited human data in pregnancy. It is not known whether tadalafil is present in human milk; it is present in rat milk. The prescriber weighs benefits and risks for any use during pregnancy or breastfeeding.

Assess cardiovascular status and blood pressure before starting and when other blood-pressure-lowering drugs are added. Review renal and hepatic function and current CYP3A4 inhibitors or inducers to apply labeled dose limits. Ask about visual or hearing changes, prolonged erections and orthostatic symptoms. For BPH, evaluate for prostate cancer before treatment.

• Cialis (tadalafil) tablets Prescribing Information, Eli Lilly and Company.
• Adcirca (tadalafil) tablets Prescribing Information, Eli Lilly and Company.
• USP General Chapter <795> Pharmaceutical Compounding, Nonsterile Preparations.