Tadalafil is an oral, selective phosphodiesterase type 5 (PDE5) inhibitor. It is used for the treatment of pulmonary arterial hypertension (PAH), erectile dysfunction (ED), benign prostatic hypertrophy (BPH), or the concurrent treatment of ED and BPH. In clinical studies of PAH, tadalafil-treated patients experienced improved exercise capacity and less clinical worsening compared to placebo. In the treatment of men with ED, effectiveness extends to men with diabetes mellitus or those having undergone prostatectomy. Tadalafil also significantly improved erectile function in patients taking antidepressant therapy in one analysis. The longer duration of action of tadalafil compared to some PDE5 inhibitors is promoted as allowing for more spontaneity in sexual activity. As with other PDE5 inhibitors, tadalafil should not be used by those who take nitrates because the combination can cause a sudden drop in blood pressure that can be dangerous. PDE5 inhibitors are first-line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. A course of an alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Those refractory to PDE5 inhibitors for ED should be counseled on appropriate use, potentially modifiable factors (e.g. hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with their partner), and the risks and benefits of other therapies. Follow-up visits are necessary to determine whether therapy continues to be effective for ED or if cardiovascular health has significantly changed.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
Oral Tablets for pulmonary hypertension (e.g., Adcirca, Alyq)
-Administer the entire dose once daily; do not give in divided doses over the course of the day.
Oral Tablets for erectile dysfunction (ED) and/or benign prostatic hypertrophy (BPH) (e.g., Cialis)
-For as needed use for ED: Instruct patient to take dose at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours.
-For once daily use for ED: Inatruct patient to take at approximately the same time each day, without regard to timing of sexual activity.
-For once daily use for benign prostatic hyperplasia: Administer at approximately the same time each day.
-For once daily use for those with combined ED and BPH: Administer at approximately the same time each day, without regard to timing of sexual activity.
Oral Liquid Formulations
Oral Suspension for pulmonary arterial hypertension (e.g., Tadliq):
-Administer once daily at the same time each day.
-Shake well for 30 seconds before measuring the daily dose. To ensure accurate dosing, measure dosage with calibrated spoon, cup, or oral syringe.
Adverse reactions to tadalafil for the treatment of erectile dysfunction (ED) were evaluated based on global clinical trials of tadalafil involving over 5,700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or more, and over 1,300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with pulmonary arterial hypertension (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days, and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). Also, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients vs. 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.
During clinical trials, hypotension was reported in less than 2%, and hypertension was reported in 1% to 3% of all tadalafil recipients. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in postmarketing experience with tadalafil. Most of the affected patients had preexisting cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity. The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds, which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo concerning time to ischemia. Of note, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood pressure lowering effects of nitrates. Also, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.
The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.
During clinical trials, adverse reactions occurring in at least 2% of patients with erectile dysfunction, at least 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2% to 12%), myalgia (1% to 14%), and pain in limb/extremity (musculoskeletal pain, 1% to 11%). Adverse musculoskeletal reactions reported in less than 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs. 1.4%), extremity musculoskeletal pain (1.4% vs. 0%), and myalgia (1.2% vs. 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia led to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a few patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.
Headache occurred in 3% to 15% of patients during erectile dysfunction clinical trials and in 32% to 42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs. 2.3%) and dizziness (1% vs. 0.5%). Headache led to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Adverse reactions reported in less than 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during postmarketing use of tadalafil.
Dyspepsia occurred in 1% to 10% of patients during erectile dysfunction clinical trials and in 10% to 13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal or digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1% to 11%), viral gastroenteritis (3% to 5%), gastroesophageal reflux (1% to 3%), abdominal pain (1% to 2%), and diarrhea (1% to 2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, dyspepsia (2.4% vs. 0.2%) and diarrhea (1.4% vs. 1%) occurred more frequently in tadalafil-treated patients than in placebo-treated patients. Adverse gastrointestinal reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain led to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal GI bleeding, and xerostomia were reported in less than 2% of patients treated with tadalafil during clinical trials.
Nasal congestion occurred in 2% to 4% of patients during erectile dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, naso-pharyngitis (1% to 13%), upper and lower respiratory tract infection (3% to 13%), influenza (2% to 5%), cough (2% to 4%), and bronchitis (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.
Flushing occurred in 1% to 3% of patients during erectile dysfunction clinical trials and in 6% to 13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.
During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis (and/or conjunctival hyperemia), increased lacrimation, and ocular pain were reported in less than 2% of tadalafil recipients.
Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma concentrations. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n = 59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (less than 0.1%). Postmarketing reports have included cases of visual impairment such as retinal vein occlusion, retinal artery occlusion (retinal thrombosis), and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disc ratio. Symptoms, such as blurred vision (less than 2%) and loss of visual field in 1 or both eyes, are usually reported within 24 hours of use. Most, but not all, patients who reported this adverse event had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio ("crowded disc"), age older than 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, 2 patients had retinal detachment and 1 patient had hypoplastic optic neuropathy. An observational, case-crossover study evaluated the risk of NAION when PDE5 inhibitor use occurred immediately before NAION onset compared to PDE5 inhibitor use in a prior time period. Results suggest a 2-fold increase in the risk of NAION (risk estimate of 2.15 [95% CI 1.06, 4.34]). A similar study reported consistent results (risk estimate of 2.27 [95% CI 0.99, 5.2]). Other risk factors for NAION may have contributed to the occurrence of NAION in these studies. A causal relationship between PDE5 inhibitor use and the occurrence of NAION cannot be substantiated based on the rare postmarketing reports or these observational studies.
Adverse reactions affecting hearing or otic special senses and occurring in less than 2% of patients in controlled clinical trials of tadalafil include hearing loss and tinnitus. Also, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported during postmarketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Instruct patients to promptly contact their healthcare professional if they experience changes in hearing.
There have been rare reports of prolonged erections more than 4 hours and priapism (painful erections more than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug, while urinary tract infection was reported in 2% of patients.
During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).
During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash, and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in postmarketing experience with tadalafil.
Oligospermia has been reported with tadalafil. Of 3 studies in adult males, tadalafil decreased sperm concentrations in the study of tadalafil 10 mg for 6 months and the study of tadalafil 20 mg for 9 months; however, this effect was not seen in the study of tadalafil 20 mg taken for 6 months. There was no adverse effect of tadalafil 10 or 20 mg on mean concentrations of testosterone, luteinizing hormone, or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the 2 studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men.
Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.
The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH.
Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy or guanylate cyclase (GC) stimulators therapy, such as riociguat. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered for erectile dysfunction. When tadalafil is administered for pulmonary arterial hypertension, nitrates should not be administered within 48 hours after the last tadalafil dose. Tadalafil may potentiate the hypotensive effects of GC stimulators.
Avoid use of tadalafil for pulmonary arterial hypertension or benign prostatic hyperplasia as well as daily use in erectile dysfunction in patients with renal failure or severe renal impairment (CrCl less than 30 mL/minute), including dialysis-dependence, due to increased tadalafil exposure, limited clinical experience, and lack of ability to influence clearance by dialysis. Starting dose modifications and dosage limits may apply for patients with mild or moderate renal impairment.
Avoid use of tadalafil in patients with severe hepatic disease (Child-Pugh Class C). Tadalafil has not been studied in patients with cirrhosis. Cautious use and starting dose modifications are recommended in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).
There is a degree of cardiac risk associated with sexual activity; therefore, consider cardiovascular status of the patient before initiating tadalafil for erectile dysfunction. Do not use tadalafil in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Educate patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity, and advise any patient experiencing anginal chest pain after taking tadalafil for any indication to seek immediate medical attention. Tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Before starting tadalafil, carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to vasodilators, including PDE5 inhibitors. Tadalafil use for erectile dysfunction or benign prostatic hypertrophy is not recommended for the following patient groups due to lack of safety and efficacy data: myocardial infarction within the last 90 days; unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (less than 90/50 mmHg); uncontrolled hypertension; or a stroke within the last 6 months. Additionally, there is a lack of safety and efficacy data in the treatment of pulmonary arterial hypertension due to exclusion from clinical trials for the following patient groups: aortic and mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, significant left ventricular dysfunction, life-threatening arrhythmias, symptomatic coronary artery disease, hypotension (less than 90/50 mmHg), or uncontrolled hypertension. Further, tadalafil is not recommended for use in patients with pulmonary veno-occlusive disease (VOD) since there are no clinical data. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary VOD may experience significant worsening in cardiovascular status. If signs of pulmonary edema occur with tadalafil administration, consider the possibility of associated pulmonary VOD.
Prolonged erections more than 4 hours and priapism (painful erections more than 6 hours) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil with caution in patients with a penile structural abnormality, such as angulation, cavernosal fibrosis, or Peyronie's disease, or with conditions predisposing to priapism, such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism.
Educate patients that use of tadalafil for erectile dysfunction offers no protection against sexually transmitted disease. Counsel patients about protective measures necessary to guard against sexually transmitted diseases, including human immunodeficiency virus (HIV) infection.
Patients with sudden visual impairment, such as loss of vision in one or both eyes, should stop using tadalafil immediately and seek medical attention. Postmarketing reports of sudden vision loss, including permanent vision loss, have occurred with PDE5 inhibitors like tadalafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Most of the patients who developed NAION had underlying anatomic or vascular risk factors for the development of NAION, including, but not limited to, low cup to disc ratio ("crowded disc"), age older than 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Advise patients of the increased risk of NAION if they have already experienced NAION in 1 eye. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in clinical trials; tadalafil use is not recommended in these patients.
Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.
Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, tadalafil has not been studied in patients with bleeding disorders or significant active peptic ulcer disease. Carefully assess risk-benefit and use tadalafil with caution in patients with significant hematological disease (e.g., bleeding disorders) or significant active peptic ulceration.
Before initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consider other urological conditions that may cause similar symptoms, such as prostate cancer. Prostate cancer and BPH cause many of the same symptoms and frequently coexist.
Available data from a randomized controlled trial, observational studies, and case series with tadalafil administration during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies in rats and mice at exposures of 7 times the maximum recommended human dose (MRHD) of 40 mg/day based on AUC revealed no evidence of teratogenicity, embryotoxicity, or fetotoxicity. In a perinatal/postnatal development study involving rats, a reduction in postnatal pup survival occurred with doses of 60 mg/kg, 200 mg/kg, and 1,000 mg/kg. The no-observed-effect-level (NOEL) for development toxicity was 30 mg/kg, which was 5 times the MRHD. Maternal toxicity was observed at 200 mg/kg, which was 8 times the MRHD. Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. It is recommended that women with pulmonary arterial hypertension avoid becoming pregnant.
There are no data on the presence of tadalafil or its metabolites in human breast milk, the effects on the breastfed child, or the effects on breast-feeding. Tadalafil or some metabolite of tadalafil was excreted in rat milk. Because many drugs are excreted in human breast milk, use tadalafil with caution in breast-feeding women. The developmental and health benefits of breast-feeding should be considered along with the mother's need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or the underlying maternal condition.
Decreased sperm concentration with tadalafil therapy was observed in 2 studies involving adult males who received tadalafil 10 mg for 6 months and 20 mg for 9 months; this effect was not seen in male patients in a third study taking tadalafil 20 mg for 6 months. Tadalafil did not have an adverse effect on testosterone, luteinizing hormone, or follicle-stimulating hormone. The clinical significance of the reductions in sperm count and whether it may result in infertility are not known. No studies have evaluated the effect of tadalafil on fertility in men or women.
For the treatment of erectile dysfunction (ED):
Oral dosage (as needed therapy):
Adults: 10 mg PO as needed before anticipated sexual activity. May decrease the dose to 5 mg or increase the dose to 20 mg PO as needed before anticipated sexual activity. Max: 1 dose/day and 20 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (daily therapy):
Adults: 2.5 mg PO once daily. May increase the dose to 5 mg/day if needed. Max: 5 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH):
Oral dosage (Cialis or equivalent):
Adults: 5 mg PO once daily. When therapy for BPH is initiated concurrently with finasteride, use for up to 26 weeks. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the concurrent treatment of benign prostatic hyperplasia and erectile dysfunction:
Oral dosage (Cialis or equivalent):
Adults: 5 mg PO once daily, taken at approximately the same time every day, without regard to timing of sexual activity. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of pulmonary hypertension to improve exercise ability in persons with WHO Group I pulmonary hypertension:
Oral dosage:
Adults: 20 or 40 mg PO once daily, initially. Increase dose to 40 mg PO once daily as tolerated. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Efficacy studies primarily included people with NYHA functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).
Children* and Adolescents* 4 to 17 years: 0.5 to 1 mg/kg/dose PO once daily, initially. Increase dose as tolerated. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For altitude sickness prophylaxis*, specifically prevention of high altitude pulmonary edema*:
Oral dosage:
Adults: 10 mg PO twice daily starting the day before ascent and continuing for 5 days after reaching the target altitude or until descent is initiated as an alternative to nifedipine. Prophylactic medications should only be considered for individuals with a history of high altitude pulmonary edema.
Maximum Dosage Limits:
-Adults
40 mg/day PO for pulmonary hypertension; 5 mg/day PO for erectile dysfunction for once daily use; 20 mg/dose PO for erectile dysfunction for as needed use, not to exceed 1 dose/24 hours in most patients; 5 mg/day PO for benign prostatic hyperplasia (BPH) or combined treatment of erectile dysfunction/BPH for once daily use.
-Geriatric
40 mg/day PO for pulmonary hypertension; 5 mg/day PO for erectile dysfunction for once daily use; 20 mg/dose PO for erectile dysfunction for as needed use, not to exceed 1 dose/24 hours in most patients; 5 mg/day PO for benign prostatic hyperplasia (BPH) or combined treatment of erectile dysfunction/BPH for once daily use.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Erectile Dysfunction (ED) for use as needed
Mild to moderate impairment (Child-Pugh class A or B): Do not exceed 10 mg PO once daily.
Severe impairment (Child-Pugh class C): Tadalafil is not recommended.
Erectile Dysfunction (ED), Benign Prostatic Hypertrophy (BPH), or Erectile Dysfunction (ED) with Benign Prostatic Hypertrophy (BPH) for once daily use
Mild to moderate impairment (Child-Pugh class A or B): Use with caution; usually do not exceed 10 mg PO once daily as is recommended with "as needed" use. Use of tadalafil once daily has not been extensively evaluated in patients with hepatic impairment.
Severe impairment (Child-Pugh class C): Tadalafil is not recommended.
Pulmonary Arterial Hypertension (PAH)
Mild to moderate impairment (Child-Pugh class A or B): Consider an initial dose of 20 mg PO once daily; limited data available for use in this patient population.
Severe impairment (Child-Pugh class C): Avoid use of tadalafil.
Patients with Renal Impairment Dosing
Erectile Dysfunction (ED) for use as needed
CrCl 51 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: A starting dose of 5 mg PO not more than once per day is recommended. Max: 10 mg PO not more than once per every 48 hours.
CrCl less than 30 mL/ minute: Do not exceed 5 mg PO once every 72 hours; once daily use is not recommended.
Erectile Dysfunction (ED) for once daily use
CrCl 30 to 50 mL/minute: Dosage adjustment may be needed.
CrCl less than 30 mL/ minute: Once daily use is not recommended.
Benign Prostatic Hypertrophy (BPH) with or without Erectile Dysfunction (ED) for once daily use
CrCl 51 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: Initially, 2.5 mg PO once daily. An increase to 5 mg PO once daily may be considered based on individual response.
CrCl less than 30 mL/ minute: Tadalafil is not recommended for once daily use.
Pulmonary Arterial Hypertension (PAH)
CrCl more than 80 mL/minute: No dosage adjustment needed.
CrCl 51 to 80 mL/minute: 20 mg PO once daily, initially. Max: 40 mg PO once daily.
CrCl 30 to 50 mL/minute: 20 mg PO once daily, initially. Max: 40 mg PO once daily.
CrCl less than 30 mL/minute: Avoid use of tadalafil.
Intermittent hemodialysis
The maximum recommended dose in patients with ED receiving tadalafil for use as needed for ED is 5 mg PO given not more than once every 72 hours. Not recommended for once daily use for ED, BPH, a combination of ED and BPH, or for PAH.
*non-FDA-approved indication
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Adagrasib: (Major) Avoid coadministration of tadalafil and adagrasib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of adagrasib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as adagrasib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Alfuzosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alfuzosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of alfuzosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alfuzosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and alfuzosin.
Alpha-blockers: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Amiodarone: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with amiodarone is necessary. Tadalafil is a CYP3A4 substrate and amiodarone is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Amyl Nitrite: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Aprepitant, Fosaprepitant: (Moderate) Use caution if tadalafil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tadalafil-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tadalafil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tadalafil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Atazanavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Atazanavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Berotralstat: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Bosentan: (Moderate) Bosentan reduces tadalafil systemic exposure by 42% and Cmax by 27% with multiple-dose coadministration. Tadalafil has no significant effect on the exposure of bosentan. Bosentan is a substrate and moderate inducer of CYP3A; tadalafil is a CYP3A substrate.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Brompheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Carbamazepine: (Major) Avoid coadministration of tadalafil with carbamazepine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of carbamazepine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Carbinoxamine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Ceritinib: (Major) Avoid coadministration of tadalafil and ceritinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ceritinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as ceritinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Codeine; Phenylephrine; Promethazine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Conivaptan: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with conivaptan is necessary. Tadalafil is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Crizotinib: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Darunavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Darunavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Delavirdine: (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
Dexamethasone: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Studies have shown that concomitant administration of CYP3A4 enzyme-inducers, such as dexamethasone, will decrease plasma levels of tadalafil.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Dextromethorphan; Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Diltiazem: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with diltiazem is necessary. Tadalafil is a CYP3A4 substrate and diltiazem is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Doxazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tadalafil is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Duloxetine: (Moderate) Monitor blood pressure closely if duloxetine is coadministered with tadalafil due to the risk of additive hypotension. Orthostatic hypotension and syncope have been reported during duloxetine administration.
Dutasteride; Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
Efavirenz: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Elbasvir; Grazoprevir: (Moderate) Administering tadalafil with elbasvir; grazoprevir may result in elevated tadalafil plasma concentrations. Tadalafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Enzalutamide: (Major) Avoid coadministration of tadalafil with enzalutamide in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of enzalutamide due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Erythromycin: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with erythromycin is necessary. Tadalafil is a CYP3A4 substrate and erythromycin is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking tadalafil. Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure lowering effects may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including an increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Etravirine: (Moderate) Etravirine is an inducer of CYP3A4; coadministration may result in decreased tadalafil concentrations. Dosage adjustments may be needed based on clinical efficacy.
Fluconazole: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fluconazole is necessary. Tadalafil is a CYP3A4 substrate and fluconazole is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Fluvoxamine: (Major) Avoid coadministration of fluvoxamine and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72 hours of fluvoxamine for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as fluvoxamine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Fosamprenavir: (Major) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fosamprenavir is necessary. The prescribing information for fosamprenavir recommends to avoid coadministration of tadalafil for the treatment of pulmonary hypertension and to stop tadalafil at least 24 hours prior to starting fosamprenavir. After at least 1 week of fosamprenavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. For the treatment of erectile dysfunction, the prescribing information for fosamprenavir recommends to not exceed 10 mg tadalafil within 72 hours of fosamprenavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Fosphenytoin: (Major) Avoid coadministration of tadalafil with fosphenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of fosphenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Grapefruit juice: (Moderate) Tadalafil is metabolized via the CYP3A4 isozyme. Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Tadalafil levels may increase; it is possible that tadalafil-induced side effects could also be increased in some individuals.
Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Hydralazine; Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tadalafil, a CYP3A substrate, as tadalafil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Imatinib: (Major) Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as imatinib, STI-571, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
Indinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of indinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of indinavir therapy. Stop tadalafil at least 24 hours prior to starting indinavir. After at least 1 week of indinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and indinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tadalafil may result in increased serum concentrations of tadalafil. Tadalafil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Isosorbide Mononitrate: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Itraconazole: (Major) Avoid use of tadalafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of itraconazole for the as needed dose or 2.5 mg daily for the once-daily dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as itraconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Ketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Lenacapavir: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with lenacapavir is necessary. Tadalafil is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) An increase in the plasma concentration of tadalafil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of tadalafil for pulmonary hypertension if the patient is receiving letermovir and cyclosporine. When used for erectile dysfunction in patients receiving letermovir with cyclosporine, the as needed (PRN) dose of tadalafil should not exceed 10 mg once every 72 hours and the daily dose should not exceed 2.5 mg. Tadalafil is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, the exposure and maximum plasma concentration of tadalafil increased by up to 312% and 22%, respectively, when administered with another potent CYP3A4 inhibitor. Studies with moderate CYP3A4 inhibitors have not been conducted.
Levoketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
Lonafarnib: (Major) Avoid coadministration of tadalafil and lonafarnib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of lonafarnib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as lonafarnib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Lopinavir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Lorcaserin: (Moderate) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Mifepristone: (Major) Avoid coadministration of tadalafil and mifepristone for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of mifepristone for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as mifepristone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Mitotane: (Major) Avoid coadministration of tadalafil with mitotane in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of mitotane due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Nefazodone: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as nefazodone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Nelfinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of nelfinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of nelfinavir therapy. Stop tadalafil at least 24 hours prior to starting nelfinavir. After at least 1 week of nelfinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and nelfinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tadalafil. The plasma concentrations of tadalafil can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nevirapine: (Moderate) Monitor for reduced efficacy of tadalafil if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease tadalafil exposure. Tadalafil is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
Nilotinib: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and tadalafil, a CYP3A4 substrate, may result in increased tadalafil levels. A tadalafil dose reduction may be necessary if these drugs are used together.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Nitrates: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroglycerin: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroprusside: (Contraindicated) Concomitant use of nitroprusside and tadalafil is contraindicated due to the risk of additive hypotension. If the patient has taken tadalafil, at least 48 hours must elapse before nitroprusside administration is considered; monitor hemodynamics closely. In addition, tadalafil may potentiate the nitric oxide-mediated platelet anti-aggregatory effect of nitroprusside.
Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Oritavancin: (Minor) Concomitant use of oritavancin and tadalafil may decrease the effectiveness of tadalafil; therefore, use caution and monitor therapeutic effects of tadalafil when coadministered. Oritavancin is a weak inducer of CYP3A4 and tadalafil is a CYP3A4 substrate. Clinical studies have shown that CYP3A4 inducers may reduce tadalafil exposure. The reduced exposure of tadalafil with the coadministration of CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil for once daily use; however the magnitude of decreased efficacy is unknown. Potent CYP3A4 inducers should be avoided with tadalafil when it is used to treat pulmonary hypertension.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tadalafil, a CYP3A4 substrate, may cause an increase in systemic concentrations of tadalafil. Use caution when administering these drugs concomitantly.
Phenobarbital: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Phenoxybenzamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Phentolamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Phenytoin: (Major) Avoid coadministration of tadalafil with phenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Posaconazole: (Major) Posaconazole and tadalafil should be coadministered with caution due to an increased potential for tadalafil-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tadalafil. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose should not exceed 10 mg within a 72 hour time period and the 'once-daily' dose should not exceed 2.5 mg.
Prazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Primidone: (Major) Avoid coadministration of tadalafil with primidone in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of primidone due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Promethazine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Ranolazine: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Ribociclib: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Rifapentine: (Major) Avoid coadministration of tadalafil with rifapentine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifapentine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Riociguat: (Contraindicated) Use of riociguat and tadalafil is contraindicated due to the risk of hypotension. Do not administer riociguat 24 hours before or within 48 hours after tadalafil. When transitioning therapy, consider initiating riociguat at a starting dose of 0.5 mg PO 3 times daily in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including tadalafil, may potentiate the hypotensive effects of riociguat.
Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Saquinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of saquinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of saquinavir therapy. Stop tadalafil at least 24 hours prior to starting saquinavir. After at least 1 week of saquinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and saquinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Silodosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on silodosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of silodosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue silodosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and silodosin.
Simeprevir: (Moderate) Coadministration of tadalafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in tadalafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest tadalafil dose and increase as needed while monitoring clinically.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of tadalafil with St. John's wort in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of St. John's wort due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
Terazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Tipranavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of tipranavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of tipranavir therapy. Stop tadalafil at least 24 hours prior to starting tipranavir. After at least 1 week of tipranavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and tipranavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Trandolapril; Verapamil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Tucatinib: (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Vardenafil: (Major) Avoid coadministration of tadalafil and vardenafil. The safety and efficacy of combinations of tadalafil and other phosphodiesterase 5 (PDE5) inhibitors, such as vardenafil, has not been studied.
Vemurafenib: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tadalafil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tadalafil when coadministered with vemurafenib.
Verapamil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Vericiguat: (Contraindicated) Use of vericiguat and tadalafil is contraindicated due to the risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including tadalafil, may potentiate the hypotensive effects of vericiguat.
Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Voriconazole: (Major) Avoid coadministration of voriconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of voriconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Voxelotor: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with voxelotor is necessary. Tadalafil is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased concentrations of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. PDE5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum, and at recommended doses, does not affect in the absence of sexual stimulation. The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has also not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.
In vitro studies show that tadalafil has greater selectivity for PDE5 and is more than 10,000-fold more potent for PDE5 than for other phosphodiesterase types, including PDE3 that is found in the heart and blood vessels. Tadalafil can also inhibit PDE5 present in esophageal smooth muscle and lung tissue, which results in the relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation and makes tadalafil an effective agent in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Tadalafil has greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 versus PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.
Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues and has a volume of distribution of 63 to 77 L. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalafil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 15 to 17.5 hours in healthy subjects.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Tadalafil is a CYP3A4 substrate. Avoidance of use with potent CYP3A4 inhibitors or inducers is recommended.
-Route-Specific Pharmacokinetics
Oral Route
The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. After a single oral dose, the maximum observed plasma concentration (Cmax) occurs between 30 minutes and 8 hours (Tmax median time of 2 to 4 hours). The AUC increased proportionately over a dose range of 2.5 mg to 20 mg. In individuals with pulmonary arterial hypertension (PAH) administered 20 mg and 40 mg tadalafil, an approximately 50% greater increase in AUC was observed indicating a less than proportional increase in exposure over the dose range of 2.5 mg to 40 mg. Following daily administration of tadalafil 20 mg and 40 mg to patients with PAH, steady-state concentrations were attained within 5 days and exposure was approximately 30% higher than after a single dose. The usual onset of action is within 30 to 45 minutes, and the usual duration is up to 36 hours. In patients with pulmonary arterial hypertension, the mean oral clearance was 1.6 L/hour (versus 3.4 L/ hour in healthy individuals) and the mean terminal half-life was 35 hours. The average tadalafil exposure at steady-state following 40 mg was 26% higher in patients with PAH compared to healthy patients, suggesting reduced clearance in individuals with PAH. Food does not affect the pharmacokinetics of tadalafil; however, absolute bioavailability data are not available.
-Special Populations
Hepatic Impairment
In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the AUC following a 10 mg tadalafil dose was comparable to that of healthy subjects. There are no data available for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available on use of tadalafil in patients with severe hepatic impairment (Child-Pugh class C).
Renal Impairment
In clinical pharmacology studies of adults with mild (CrCl 51 to 80 mL/minute) or moderate renal impairment (CrCl 31 to 50 mL/minute), tadalafil AUC was doubled after single doses of 5 to 10 mg compared to those with normal renal function. In those with end-stage renal disease on hemodialysis, there was a 2-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in those with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) had negligible effects on tadalafil or metabolite clearance.
Geriatric
In a healthy volunteer study of older adult males (65 years and older) and younger adult males (19 to 45 years), the AUC of tadalafil was 25% higher in the older population with no effect on Cmax. In males with benign prostatic hyperplasia (BPH) receiving single and multiple doses of tadalafil 20 mg, there were no statistically significant differences in AUC and Cmax in older adults (70 to 85 years) compared to younger adults (60 years and younger).
Other
Diabetes mellitus
In adults with diabetes mellitus receiving a 10 mg tadalafil dose, the AUC was reduced approximately 19% and Cmax was approximately 5% lower than that observed in healthy subjects. No dosage adjustment is necessary for this subpopulation as long as organ function is normal.
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