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Benign Prostatic Hypertrophy (BPH) Agents
Phosphodiesterase Inhibitors for ED
Phosphodiesterase Inhibitors for PAH

DEA Class

Description

Oral, selective phosphodiesterase type 5 (PDE5) inhibitor with longer duration of action
Used for pulmonary arterial hypertension (PAH), erectile dysfunction (ED), benign prostatic hyperplasia (BPH), or a combination of ED and BPH
As with other PDE5 inhibitors, contraindicated for use with nitrates because the combination can cause a sudden drop in blood pressure

Common Brand Names

How Supplied

Adcirca/ALYQ/Cialis/Tadalafil Oral Tab: 2.5mg, 5mg, 10mg, 20mg
Tadliq Oral Susp: 1mL, 4mg

Dosage & Indications

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.

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.

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.

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 treatment of pulmonary hypertension to improve exercise ability in persons with WHO Group I pulmonary hypertension.

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%).[40259]

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.

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.[56782] Prophylactic medications should only be considered for individuals with a history of high altitude pulmonary edema.[56782]

Maximum Dosage

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.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Dosing Considerations

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.

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.

Administration

May be administered without regard to meals.

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 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.

Storage

Adcirca:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
ALYQ:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Cialis:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Tadliq:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

Contraindications / Precautions

Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.[40259] [28220]

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.[28220]

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.[28220]

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.[28220] [40259]

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.[28220] [40259]

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).[28220] [40259]

Angina, cardiac arrhythmias, coronary artery disease, heart failure, hypertension, hypotension, myocardial infarction, stroke, veno-occlusive disease (VOD)

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.[28220] [40259]

Leukemia, multiple myeloma, penile structural abnormality, Peyronie’s disease, polycythemia, priapism, sickle cell disease

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.[28220] [40131]

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.[28220]

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.[28220] [40259]

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.[26879]

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.[28220]

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.[28220]

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.[40259]

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.[40259]

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.

Adverse Reactions

myocardial infarction / Delayed / 0-2.0
GI bleeding / Delayed / 0-2.0
hearing loss / Delayed / 0-2.0
stroke / Early / Incidence not known
seizures / Delayed / Incidence not known
retinal thrombosis / Delayed / Incidence not known
visual impairment / Early / Incidence not known
non-arteritic anterior ischemic optic neuropathy / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known

hypertension / Early / 1.0-3.0
palpitations / Early / 0-2.0
orthostatic hypotension / Delayed / 0-2.0
hypotension / Rapid / 0-2.0
angina / Early / 0-2.0
chest pain (unspecified) / Early / 0-2.0
sinus tachycardia / Rapid / 0-2.0
dysphagia / Delayed / 0-2.0
esophagitis / Delayed / 0-2.0
gastritis / Delayed / 0-2.0
elevated hepatic enzymes / Delayed / 0-2.0
dyspnea / Early / 0-2.0
conjunctivitis / Delayed / 0-2.0
blurred vision / Early / 0-2.0
edema / Delayed / 0-2.0
QT prolongation / Rapid / Incidence not known
amnesia / Delayed / Incidence not known
migraine / Early / Incidence not known
conjunctival hyperemia / Early / Incidence not known
priapism / Early / Incidence not known

headache / Early / 3.0-42.0
myalgia / Early / 1.0-14.0
dyspepsia / Early / 1.0-13.0
pharyngitis / Delayed / 1.0-13.0
infection / Delayed / 2.0-13.0
flushing / Rapid / 1.0-13.0
back pain / Delayed / 2.0-12.0
musculoskeletal pain / Early / 1.4-11.0
nausea / Early / 0-11.0
nasal congestion / Early / 2.0-9.0
influenza / Delayed / 2.0-5.0
cough / Delayed / 2.0-4.0
gastroesophageal reflux / Delayed / 0-3.0
syncope / Early / 0-2.0
arthralgia / Delayed / 0-2.0
insomnia / Early / 0-2.0
vertigo / Early / 0-2.0
dizziness / Early / 1.0-2.0
hypoesthesia / Delayed / 0-2.0
paresthesias / Delayed / 0-2.0
drowsiness / Early / 0-2.0
xerostomia / Early / 0-2.0
vomiting / Early / 0-2.0
abdominal pain / Early / 0-2.0
diarrhea / Early / 1.0-2.0
epistaxis / Delayed / 0-2.0
ocular pain / Early / 0-2.0
blepharedema / Early / 0-2.0
lacrimation / Early / 0-2.0
tinnitus / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
fatigue / Early / 0-2.0
pruritus / Rapid / 0-2.0
hyperhidrosis / Delayed / 0-2.0
rash / Early / 0-2.0
urticaria / Rapid / Incidence not known
oligospermia / Delayed / Incidence not known

Drug Interactions

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,
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; Carbetapentane; 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; 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%.
Carbetapentane; 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,
Carbetapentane; 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,
Carbetapentane; 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,
Carbetapentane; 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,
Carbetapentane; Phenylephrine; Pyrilamine: (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,
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.
Chlophedianol; 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,
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 clear
ance. 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 n
oted 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, resum
e 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.
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) Coadm
inistration 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) Coadministration 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. Consider initiating riociguat at a starting dose of 0.5 mg in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy.
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 recomme
nds 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.
Telithromycin: (Major) Avoid coadministration of telithromycin 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 telithromycin 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 telithromycin 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.
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: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. The manufacturer of avanafil contraindicates this combination. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
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 in
hibitors 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.

Pregnancy and Lactation

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.[40259]

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.[40259]

Mechanism of Action

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. In vitro studies show that tadalafil is selective for PDE5 and is more than 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is more than 10,000-fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 vs. PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 vs. PDE6. This lower selectivity of sildenafil for PDE5 vs. PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is more than 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has 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.[28220]

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in the relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.[40259]

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). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

Pharmacokinetics

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.

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.

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If you are wondering whether Cialis is better than Viagra, it may be — depending on your goals and how you respond to the medicine. There are many reasons why a doctor may prescribe Cialis over Viagra, and vice-versa. Additionally, there are reasons you may prefer Cialis over Viagra. Below we discuss what might make you a better candidate for Cialis.

Cialis vs Viagra – Side effects compared

One reason many people chose Cialis over Viagra is based on side-effects. While not everyone will experience side-effects, those who do with Viagra may consider Cialis a better option. Cialis generally has fewer side-effects than Viagra, as illustrated in the table below.

Side effect	Viagra	Cialis
Stuffy or runny nose	x	x
Headache	x	x
Dizziness	x
Upset stomach	x	x
Nausea	x
Indigestion	x
Vision changes	x
Rash	x
Flushing	x	x
Back pain	x	x
Pain in the limbs	x
Muscle aches	x	x

If you have taken Viagra and have experienced unpleasant side-effects such as dizziness, nausea, vision changes or rashes, consider taking Cialis as it does not have these same common side-effects. Likewise, if you are experiencing pain in the limbs or indigestion when taking Cialis, Viagra actually may be a better option for you.

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As with Viagra and sildenafil, Cialis is the branded name of tadalafil. Both tadalafil and Cialis are exactly the same product, one with a brand attached and the other is generic. You can save money in the purchase of Cialis if you buy the generic version, known as tadalafil.

Prescription requirement

Currently in the UK, you cannot buy Cialis (or generic Tadalafil) unless you have a prescription. You can, however, buy Viagra without a prescription in the form of Viagra Connect. If you really do not want to bother with a prescription, getting 50mg tablets of Viagra Connect may be a good solution for you. Keep in mind that we have an online doctor’s service and can help you get a prescription for either Viagra or Cialis online from the convenience of your home. It is cheaper to get regular Viagra as generic sildenafil (with a prescription) instead of Viagra Connect which doesn’t require one.

Cialis vs Viagra – how long they last

Depending on your circumstance, Cialis may be the better choice over Viagra because it can remain active in your system for up to 36 hours, whereas Viagra begins to lose its effectiveness after six hours. If you know exactly when you intend to have sex and are able to take a tablet 60 minutes prior, neither pill gives much of an advantage. However, if you aren’t certain exactly when sex will happen, Cialis gives a definite advantage as it lasts for 36 hours. Cialis is often called the “weekend pill” because you can take it Friday evening and it will last through Sunday afternoon.

For both ED pills, they will only have their desired effect if you are sexually stimulated. Normally, you should only obtain an erection when sexual stimulation is available to you. You wouldn’t get an erection if you aren’t attempting to engage in sex. For Viagra, the timeframe to be able to experience an erection with sexual stimulation is at most a 12-hour window, whereas with Cialis it is a 36-hour window.

Try them all

The best way to know which ED pill is best for you is to try each one. Everyone has their own unique experience and you may find you prefer one pill over another. There are three main erectile dysfunction pills for sale here at UK Meds; Viagra, Cialis and Levitra. If you have taken one type of ED pill safely, there’s no reason you couldn’t try the others to see which is best for you. Each has its own set of advantages and potential side effects. By experimenting with all three, you are certain to find the best pill.

You should always ensure to follow the proper dosage instructions and only take any medication as advised by the prescriber. Do not take more than one ED tablet in a 24 hour period (even if it’s not the same ED tablet).

Read Viagra reviews

It’s always helpful to read other people’s experience with a medication you intend to take. There are many Viagra reviews on drugs.com. Found within the reviews are people’s actual experiences, side effects experienced, their rating of the medicine and whether they considered it the best ed medicine.

Read Cialis reviews

As with Viagra, there are many Cialis reviews found on drugs.com. Browse through them to see what other men are experiencing with Cialis. You’ll see many men comparing the experience with Cialis vs Viagra.

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The breakdown of reviews of Viagra on drugs.com is an 8.3 average rating (out of 10). That is from 178 Viagra reviews as of the time this is being written. Cialis has an average 8.7 average rating with 390 user reviews. Browse and read user reviews of both Viagra and Cialis to get a better understanding of how these ed medications differ from each other.

Summary

In summary, there are many different factors to consider when selecting whether Cialis is better than Viagra, or vice-versa. You should take into consideration the side effects, cost, timing (6 hour Viagra vs 36 hour Cialis), and reviews that share the experiences of other men taking both ED medications.

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This is the middle cabin of the fishing boat, covered with shiny best curve enhancement pills decking, with a folded quilt beside it.It seems that at night the cabin is the bedroom.I stretched out my hand to Qi Yuhong and said, give me the book.Qi Yuhong handed me her hand.I opened the book, and there were dense words on it, not the concise formulas I imagined, and those dense words could not be read clearly under the dim oil lamp.What is written on it I asked, frowning.Don t you understand Qi Yuhong asked me.It s not that I can t read it, it s that I can t read it clearly.The characters are too small, and the light is too dim.I hope she can turn on the light.But she said the lamp was not using rapeseed or soybean oil, not diesel or alcohol, but a type of clam oil.I ask what oil is clam oil She said a shellfish.Shellfish can also extract oil to light lamps, which is the first time I heard about it when I was so old.

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There was Daily Cialis Vs 36 Hour a commotion ahead.No, something happened again I exclaimed.With a wave of testovital enhancement his hand, the security guards rushed forward with their baton in hand.But I have experience, don t rush forward at this time, just stay where you are and wait for the rabbit.Sure enough, when the security guard next to me rushed forward and left me alone, one person jumped from the front.Chapter Two Hundred and Twenty Scary Giant Spider This man jumped up almost like a kangaroo, directly over the heads of the security guards, and rushed to me.He stood before me.I saw that he was holding a wolf sprout stick in his hand.He had already waved wildly at the people on the street, and he didn t know how many people he had injured.I immediately recognized him as Professor Shu.Enemies are very jealous when they meet each other.

He thinks he has a plan, and he is very proud of it.I wanted to pour a bowl of cold water on them and said with a faint smile, It s a pity that your abacus is wrong.Do you think I can t continue to practice after making such a fuss The way I practice is beyond your imagination.Sure enough, Tang Shaoyuan He seemed very interested, cared about what I said, and asked, What method do you practice You guys think that I must be a hundred times quieter when I practice, and there shouldn t be any disturbance around me, and I have to be completely still and calm to be lucky, right , I m practicing while talking to you now.But you won t believe it, I said.What, what You can still practice qigong like this Of course, qigong practice is like smoking.You ve heard that whoever smokes must hide in a place where no one is disturbed You can walk while chatting with people while smoking.

I sent Zhang Jiayu to the door of the girls dormitory area, and then went herbs for male fertility and sperm health back to my dormitory.As soon as we arrived downstairs in our dormitory, we ran into March.As soon as he saw me, he asked, Where have asexual panic you been I thought you were going to disappear just like Jian Tong.Why, Jian Tong is still missing I asked.There is no news at all.Ma Qi was very worried.You said, will he have any accident I am also worried.If Jane Tong did have an accident, what aspect and nature would it be But I can t tell Ma Qi what Zhang Jiali said.After all, Zhang Jiali also mentioned gnc male enhancement any good Ma Qi.I can t help but be aware that the three of them have already colluded secretly and formed an alliance.Otherwise, why would Zhang best site for sex Jiali know that Ma Qi and Jian Tong will change Rather, I myself need to guard against them.I said perfunctorily Maybe he went home and something urgent happened at home, so he just said goodbye.

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She wondered if there was an explosion on Hu Lili s grave, but thought it was unlikely., Some corpses are buried in coffins.For a period of time, due to decay and inflation, there will be a belly explosion.If someone outside can hear that kind of popping sound, but usually the sound is not so loud, just a little dull.At that time, exercise for sexually long time the third aunt did not enter the mountain in the middle of the night, and because of something at home, he went into the mountain for two days to check.When he saw it, he was shocked.s pit.With Fan Yan s keenness, the third aunt realized that something was coming out of it.As for where the tombstone flew to, and where the coffin rushed out and settled first, it was not something that the third aunt could see.But what I m wondering is why the third aunt asked me to tell me about this, and also deliberately asked me if I had met Hu Lili before.

Hey, where s my brother she asked.Going to his headquarters, I said.Headquarters Where is it He belongs to the front line anxiety relief pills walmart commander, and of course he is on the front line.Where is the front line The Outer Ring Road.Then let s go to the Outer Ring Road to find him.said to go.I stopped her and persuaded her You can t find his headquarters, it s actually a mobile headquarters, besides him, there should be a few small bosses, but he s the only one, not his deputy.Man.How can you go to him But he became the commander of the zombie army, isn t that unusual How can I watch him command the zombies to attack the city Zhang Jiayu was so anxious that she burst into tears.The problem is not your brother s problem now.It should be mine, I said.What s your problem She looked at me puzzled, What s your problem I explained that although Homeopathic Remedies For Penis Enlargement Daily Cialis Vs 36 Hour the army of zombies was numerous and filled the outer ring road around the city like ants, they were driven by magic after all.

There is nothing left to let nyagra for women the boat drift on its own.But I also know that I don t have to worry about it, she will naturally manipulate it.Sure enough, after we sat up, she said, Get up The boat left the shore and went into the middle of the stream.But unexpectedly, the boat did not float down the current, but rushed up against the current.It s amazing that a boat without horsepower is not carried down by the strong current, but marches against the direction of the current.I suspect that the boat did not touch the water, but was flying in the air.However, the boat was Male Enhancement & Vitality? Daily Cialis Vs 36 Hour obviously ups and downs, bumping up and down or left and right, swaying erratically, much like running in a rapids.Gu Daqin was sitting in the stern, I was sitting in the bow, looking back and looking forward, I saw the rapids rushing towards you, splashing everywhere, and the boat was like a stubborn beast kicking the spray and running wildly.

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Because it was a girl s voice.Chapter 6 Strange Girl and Mysterious Light At auctus pills dawn, before dawn, there was a girl knocking on the door of our boys dormitory, and her sensitivity is self evident.I really don t know how she managed to escape the eyes of the manager s Daily Cialis Vs 36 Hour aunt and slip up.I believe that the three of Daily Cialis Vs 36 Hour us are in the same mood, eager to find out what kind of girl it is face, body, skin, clothes Our three pairs of eyes are staring at the door, expecting that angel s gorgeous render.However, Zhang Jiali clearly understood our respective psychology, and seemed to deliberately prevent us from succeeding.He did not open the door very wide, but only opened it a little, just to stick his head out.From our point of view, we cannot see what is going on outside.This guy is such a ghost, a girl came to him, and he was not willing to let us have a feast for the eyes.

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Mu Guiying s legs suddenly became weak and she knelt down in front of me.Xiao Mu, you must give us a way to survive.Now only you can save us.I was shocked by her action, but I didn t dare to help her.Said How can I give you a way to survive You have to explain clearly and see if I can help you, but how will I know if you don t explain clearly Mu Guiying pointed to the accomplices in the pool and called them All come ashore.So the female ghosts climbed up from the water one by one, each of them soaking wet, like chickens in soup.But they all had serious expressions, as if they had been trained, and lined up in front of me.Everyone was silent, no one spoke, and even the sound of breathing was vigrx plus vs extenze controlled.It s like this, Xiao Mu, we have encountered such a thing Mu Guiying was about to describe in detail when a wind suddenly blew from nowhere, causing her body to shrink abruptly.

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Tu Zeng He explained, My teacher is over 100 years old, and I have does lube make you last longer long since retired from the rivers and lakes to spend the Daily Cialis Vs 36 Hour rest of my life in peace.What kind of devil or ghost We disciples come to visit, and he may not meet, so it is more likely to thank you behind closed doors.We were again seriously disappointed.The two sighed at each other.It was hard to visit the real Shanmu Daoist, but his old man is what is a girl penis no longer the high road of the past, but a comfortable old man who lives in seclusion and cares for his years.We will be disturbing to find him again.Seeing our dejection, Tu Zeng laughed and asked, Why are you so stupid, when you hear that my master is out of the mountains, you are so depressed Yeah, if Daoist Shanmu doesn t do what he does, what will we do What to do Who else are you going to find those female ghosts Zhang Jiayu said helplessly.

What I need is divine power.Then do you know, will I get spells in the future This is the question I am most concerned about.Su Yuexi said with certainty Of course there will be.Your ability will be great in the future.Otherwise, how can you defeat the chaste woman and the devil I asked her how she knew so clearly She blinked her eyes and was also very puzzled.After a endowinex male enhancement while, she said that this was her instinctive premonition, plus Mu Guiying s hint, and even the death of the star officer, to come to this conclusion.It is not easy to come to an absolutely correct conclusion now.Anyway, Su Yuexi came to me and said she wanted to follow me, wouldn t that sound like Weng Xiafei However, their goals are quite different.Weng Xiafei wants to be a ruler with me.This dream is too big, it s just whimsical, and Su Yuexi hopes to rely on my ability to avenge her, which seems to be more realistic.

But as soon as we entered the town, we heard a loud noise and saw a lot of people gathered in a square by the lake.I initially judged what kind of assembly was being held here, and when I got closer, I saw that there seemed to be a temple here.But this is not a serious temple.It is a place for burning incense and worshiping the gods.The temple is just four tiled houses side by side, obviously newly built.There is a plaque above the gate with the four characters Anle Lake Immortal.At this time, colorful flags were fluttering around the temple, and banners were pulled up between the erected poles, which were nothing more than blessings, blessings, and good luck.There is no altar on the square, but there is a large incense burner, and people line up to burn incense and light candles, which is very lively.

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I just said that Ai Enli and the others had already told me that Mu Guiying and Su Yuexi would definitely die.As for how they died, and how the devils executed them, I don t know.Zhang Jiayu sighed deeply It s sad, my brother, a living person, can t What’s Daily Cialis Vs 36 Hour? compare to these female undead.They are loyal.Zhang Jiayu is concerned about whether I remember those spells This is the centerpiece.All the adventures and sacrifices are for the spell.I said with certainty Bring it back, bring it all back, and remember it clearly.Then you must be careful, don t fall for Wu Meiniang s trickery again, and their male self stimulation techniques memory will be erased by them.She warned worriedly.I.I told him to be at ease.Now that I have learned to be good, I won t trust anyone easily anymore.Last time it was Gu Daqin pretending to be Gu Xiaoqin, why didn t you recognize it Zhang Jiayu asked.

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Classmate, don t go in.It was a policeman who was holding the door.I knew he was a special police officer just by looking at his clothes.I was herbal male enhancement pills that work invited by Squadron He.I said quickly.Who are you Student of this school, the case that happened here last time was reported by me, so Squadron He specially invited me to participate in this investigation today.The SWAT is still skeptical.At this time, my aunt was running into the stairwell.She looked back and saw that I was being stopped, so she stopped and waved to us.When the SWAT saw this was true, they let me in.My aunt took me up the stairs when a special police officer came running from the corridor on the first floor and reported to her He Squadron, the situation here is also a bit strange.Those doors are automatically opened.I know that all of them have walkie talkies.

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Tadalafil in the treatment of erectile dysfunction; an overview of the clinical evidence

Correspondence: Flavio Pozzi, Chair of Endocrinology, Dept of Internal Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy, Tel +39 06 7259 6522, Fax +39 06 7259 6522, Email ti.orebil@izzopoivalf

Abstract

Prevalence and severity of erectile dysfunction (ED) increase with aging and are often associated with illnesses, like diabetes mellitus, heart disease, and hypertension, pathologically characterized by endothelial dysfunction and whose prevalence increases with age. The assumption that ED is mainly a neurovascular disease is supported by the evidence that specific phosphodiesterase type 5 (PDE5) inhibition produces an efficient erection in a wide range of ages and conditions. The availability of specific PDE5 inhibitors has enabled the development of effective treatment strategies, in this contest, tadalafil may be considered as the least “typical” PDE5 inhibitor. In clinical trials, tadalafil significantly enhanced, in patients of different ages, all efficacy outcomes across disease etiologies and severities. With an effectiveness lasting up to 36h, tadalafil allows patients to choose when to have sexual activities without the need to time it, showing positive feedback in terms of quality of life related to the treatment. Headache and dyspepsia were the most frequent side-effects of tadalafil, followed by back pain, nasal congestion, myalgia, and flushing, but the impact that long time action could have on effectiveness and safety is not yet entirely defined. The aim of this article is to critically review the available evidence from the tadalafil clinical research program and give the physician a rational approach for intervention in the treatment of ED and related diseases.

Introduction

Epidemiological studies suggest that ED is a common disorder in men, affecting up to 52% of men between the age of 40 and 70 years ( Feldman et al 1994 ). Consistent with increasing life expectancies, the prevalence and the severity of ED increases in the elderly because of the aging process and related organic, iatrogenic and social problems ( Feldman et al 1994 ; Parazzini et al 2000 ; Derby et al 2001 ; Kubin et al 2003 ). Meanwhile, a decline of testosterone (T) level is observed with age ( Harman et al 2001 ), even though this phenomenon may be largely dependent on interindividual variability ( Mazur 1998 ; Morley 2001 ). It is noteworthy that basal and dynamic peak cavernosal velocity at Penile Doppler Ultrasonography (PDU) examination is reduced in older patients ( Corona et al 2004 ), and the pathophysiology of erectile dysfunction in this patient group mainly includes chronic ischemia, which triggers the deterioration of cavernous smooth muscle and the development of corporeal fibrosis. Generally, ED is associated with illnesses with a common basis of endothelial dysfunction, like diabetes mellitus, heart disease, and hypertension, whose prevalence increases with age ( Virag et al 1985 ; Feldman et al 1994 ; Aversa et al 2002 ). The neural and endothelium-dependent mechanisms that would normally cause relaxation in corporal smooth muscle are impaired in tissue collected from men with diabetes and ED ( Saenz De Tejada et al 1989 ). This body of knowledge leads to the assumption that ED is mainly a neurovascular disease ( Virag et al 1985 ; Sullivan et al 2001 ), and is strongly supported by the evidence that specific PDE5 inhibition enhances vasodilatation in the corpus cavernosum ( Ballard et al 1998 ) producing an efficient erection in a wide range of ages and conditions ( Frajese and Pozzi 2003 ). Since the introduction of sildenafil, remarkable progress has been made in the treatment of erectile dysfunction. At present, inhibition of PDE5 with oral agents appears to be the treatment of choice ( Kubin et al 2003 ). The critical role of PDE5 in penile erection and the availability of the new specific and potent inhibitors, tadalafil and vardenafil, have enabled the development of effective treatment strategies. PDE5 inhibitors are a safe and efficacious option for most elderly patients, and now represent first-line therapy also for their socio-economic impact ( Anastasiadis et al 2002 ). An efficacious erectogenic effect by drugs is defined as an erection adequate for vaginal penetration and leading to successful intercourse. Nevertheless, considering the frequent association of sexual and medical problems in the aged, a holistic approach toward the treatment of ED should include counseling, adjustment of lifestyle, and modification of risk factors, such as medication, overweight, smoking, alcohol consumption, and lack of exercise ( Meuleman 2002 ).

Due to its peculiar chemical and pharmacokinetics properties (essentially half-life), tadalafil may be considered as the least “typical” among the current generation of PDE5 inhibitors ( Montorsi et al 2004 ). Providing more flexibility in dosing and more continuity in pharmacological action, tadalafil may ameliorate both sexual behavior and physiological processes leading to penile erection. This can be reflected on both efficacy and safety issues of the therapy of ED, in short as well as in long-term treatment. While the discovery of sildenafil opened a new era, mainly defeating the “impotence” of physicians in treating ED, the availability of tadalafil seems to give new perspectives as far as the treatment strategy and cure of ED is concerned.

A clinical pharmacological approach to the effective and safe use of tadalafil

The mechanism of action leading to penile erection involves inhibition of PDE5, the major cyclic guanosine monophospate (cGMP) hydrolyzing enzyme located in the vascular smooth muscle cells of corpus cavernosum. Sexual stimulation triggers the release of the endothelium dependent relaxing factor nitric oxide (NO) ( Saenz De Tejada 1989 ), stimulating through the protein kinase G the release of guanylyl cyclase with an increase of intracellular cGMP, thus causing a decrease in intracellular calcium and, ultimately, the relaxation of trabecular erectile tissues and the dilatation of the helicine artery of the penis ( Burnett et al 1992 ). The increase in blood flow causes the engorgement of the sinusoidal spaces of the corpora cavernosa, the tunica albuginea compresses the subtunical venules that drain the corpora and reduces the venous outflow increasing penile blood pressure and causing erection ( NIH 1992 ). This mechanism acts primarily to maintain the tumescence phase, whereas neuronal-derived NO is mainly active in the induction of erectile function ( Moreland et al 2001 ). Inhibiting PDE5 prolongs the effects of nerve stimulation. Tadalafil, like the PDE5 inhibitors sildenafil and vardenafil, competitively blocks the cGMP hydrolysis by PDE5, thereby fostering cGMP accumulation and the relaxation of vascular smooth muscle. Increased concentrations of cGMP produce higher PDE5 promoter activities ( Lin et al 2002 ). cGMP accumulation stimulates cGMP degradation, but the pharmacological PDE5 inhibition blocks this negative feedback process. Thus, with PDE5 inhibitors, erection develops in a physiologic manner and only with sexual stimulation.

Chronic PDE inhibition, via the persistent activation of PDE5 promoters, may up-regulate PDE expression and, therefore, be associated with the development of drug tachyphylaxis ( Moreland et al 1999 ). It has been shown that in the trabecular smooth muscle of the rat penis, sildenafil moderately down-regulated PDE5 ( Ferrini et al 2004 ). The clinical long–term consequences of chronic PDE5 inhibition are still unknown. It has been reported that 20% of long-term sildenafil responders required increased dosages, while 17% discontinued because of loss of efficacy ( El Galley et al 2001 ). It is also possible that the positive erectile response obtained with chronic administration may be related to functional tissue modifications involving up-regulation of either muscarinic receptors, or the transduction mechanism leading to the activation of endothelial NO synthase ( Behr Roussel et al 2004 ). As PDEs are expressed in different tissues, selectivity is a prerequisite for therapeutic application of PDE inhibitors. Tadalafil is selective for PDE5 and minimally inhibits PDE6 ( Angulo et al 2001 ), which works for visual transduction in the retina. With respect to PDE5, a 780-fold greater concentration of tadalafil is needed to inhibit PDE6, and a 14-fold greater concentration to inhibit PDE11, an enzyme with unknown physiological function. Tadalafil’s nonselectivity with respect to PDE1 (expressed in the brain, myocardium, and vascular smooth muscle cells), may result in vasodilatation and tachycardia ( Bischoff 2004 ).

Tadalafil is rapidly absorbed with the maximum plasma concentration occurring at 2.0 h, the extended terminal half life being 17.5 h ( Patterson et al 2001 ; Rosen et al 2001 ). The rate and extent of absorption of tadalafil is not altered by food ingestion, age, diabetes, or mild to moderate hepatic insufficiency ( Patterson et al 2001 ). The earliest significant time from dosing to erectogenic effect, objectively determined by a stopwatch in a placebo-controlled design, is 16 minutes with tadalafil 20 mg, and 30 minutes with the dose of 10 mg ( Rosen et al 2004 ). This demonstrates that effective plasma level is achieved before reaching the maximum plasma concentration. Nevertheless, most men would require more time for tadalafil to be optimally effective; in particular, patients with severe ED or older patients should be encouraged to optimize the period of sexual stimulation.

In healthy subjects, over a range of 2.5–20 mg, tadalafil’s systemic exposure increases proportionally with the dose. Steady state plasma concentrations are attained within 5 days of once-daily dosing, with an exposure that is approximately 1.6-fold greater than after a single dose ( Eli Lilly 2006 ).

The clinical evidence: efficacy of tadalafil in ED

The most important outcome for an ED therapy is the patient’s perception of success ( Hanson-Divers et al 1998 ). When patients with ED experience a successful intercourse after treatment, they feel cured of their problem. Furthermore, they express the desire of unplanned, unpremeditated or spontaneous sexual intercourse. In this sense, one possible use of the self-administered questionnaire International Index of Erectile Function – Erectile Function domain (IIEF-EF) score is to ascertain whether patients return to normal erectile function after treatment, with scores of 26–30 representing the normal ranges ( Rosen et al 1999 ; Mulhall 2003 ). Integrated analysis of data from phase III trials demonstrated that tadalafil, at doses from 5 mg to 20 mg versus placebo, significantly improved erectile function (EF) by all measures. In particular, 50%–65% of patients, regardless of ED severity at baseline, returned to normal erectile function with almost 60%–90% of success rate at intercourse attempts during active treatment.

In the community-based Massachusetts Male Aging Study (MMAS) ( Feldman et al 1994 ), 52% of 1290 men aged 40 to 70 years were found to have some degree of ED. The probability was 9.6% in the whole sample, and higher in men aged 60–69 years (40%) and in those treated for heart diseases (39%), diabetes (28%), or hypertension (15%). This indicates that ED is often a symptom present in cardiovascular disease and diabetes. Analogously, in the majority of the studies reported in this review the population selected is similar, as far as age and causes of ED are concerned, to that of MMAS.

With the purpose of assessing efficacy and safety of tadalafil in the treatment of ED, an integrated analysis of five randomized double-blind placebo controlled parallel group trials was conducted ( Brock et al 2002 ). An update of this analysis has been made with six newest tadalafil studies including an additional group of 1215 men with ED ( Carson et al 2004 ). The final analysis included eleven studies with 2102 patients (mean age 56 years, age range 22–88 years) who had a minimum 3-month history of mild (36%), moderate (27%), or severe (33%) ED, of organic (58%), psychogenic (12%), or mixed etiology (31%). Hypertension, diabetes mellitus, and hyperlipidemia were the most common comorbidities.

The subjects were randomly allocated to a 12-week treatment with placebo (n=638) or tadalafil at fixed daily doses of 2.5 mg (n=74), 5mg (n=151), 10 mg (n=321), and 20 mg (n=1143). The doses of 2.5 mg and 5 mg were included only in the “five studies analysis”. Treatment was self administered as needed before sexual intercourse with no restrictions on food or alcohol intake or timing of sexual activity. Exclusion criteria were impotence due to radical prostatectomy, pelvic surgery, penile deformities, or recent history of stroke or spinal cord trauma, severe cardiovascular diseases and/or clinically significant renal or hepatic insufficiency. Men treated with nitrates, antiandrogens or cancer chemotherapy agents were also excluded from study participation. The international index of erectile function (IIEF) ( Rosen et al 1999 ), that includes the domains of EF, intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction, was used to globally evaluate EF. In particular, ED severity in the EF domain is scored mild (22–25), moderate (11–21), and severe (≤10) ( Cappelleri et al 1999 ). The diary Sexual Encountered Profile (SEP) that consists of 6 and 4 yes/no questions to be answered by the patient and the partner respectively, and Global Assessment Question (GAQ) related to improvement of erections and ability to engage in sexual activity, were also administered at baseline and following treatment to evaluate the effect of therapy on successful completion of intercourse and satisfaction. Compared with placebo, tadalafil significantly enhanced, in a dose-dependent manner, in patients of different ages, all efficacy outcomes across disease etiologies and severities. The primary efficacy outcome measure was the EF domain that consists of 6 questions with possible score range from 1 (worse function) to 30 (normal function). The score increase was

Early treatment success may be important in enhancing self-confidence to continue successful treatment. An integrated post-hoc analysis of the “five double-blind studies” ( Brock et al 2002 ) examined the first dose success, the cumulative success by dose and the maintenance of success among men taking tadalafil ( Shulman et al 2004 ). The SEP diary questions assessed these three perspectives. With the first dose, significantly greater proportions of men taking tadalafil 10 mg and 20 mg versus placebo achieved successful erection (SEP-Q1: 85% and 90% vs 66% respectively), successful penetration (SEP-Q2: 74% and 79% vs 47% respectively), successful intercourse (SEP-Q3: 56% and 67% vs 31 % respectively), and were satisfied overall with their sexual experience (SEP-Q5: 36% and 47% vs 15%, respectively; all p<0.001). Regardless of the ED severity or patient age, continued dosing increased the proportion of men achieving first success, reaching a plateau between dose 4th and 8th at approximately 95% (SEP-Q2), 90% (SEP-Q3), and 81% (SEP-Q5). After first-dose success, success rate in a 12-week period was significantly greater for men taking tadalafil versus placebo (SEP-Q2: 85% and 91% vs 75%; SEP-Q3: 81 and 88% vs 64%, respectively; p<0.001). Note the high proportion of patients attaining initially a successful erection while on placebo. This success was not maintained under the measures of successful penetration, intercourse, and satisfaction.

Regardless of the degree of ED, tadalafil 20 mg every other day for one month has been shown to improve endothelial function in patients with increased cardiovascular risk ( Rosano et al 2004 ), since endothelial damage is a common marker of diseases of the cardiovascular system. The benefit was sustained two weeks after treatment discontinuation and was associated with an increase in nitrite/nitrate levels and a decrease in endothelin-1. Age itself is an important risk factor for vascular disease and ED, and thereby endothelial dysfunction. In elderly patients (60–70 years) affected by ED, with slight or no signs of carotid disease, resumption of spontaneous erections was obtained with chronic tadalafil 20 mg administered for three months on alternate days. One month after withdrawal from dosing, spontaneous improvement in sexual function was reported in 55%–65% of patients unaffected from carotid disease and in 16% of those with increase of carotid intimal thickness ( Caretta et al 2005 ). Nocturnal penile tumescence rigidity monitoring and PDU parameters were inversely related to different degrees of carotid wall alteration and showed a significant improvement in those patients with atherosclerotic plaques, probably due to the amelioration of endothelial function during treatment.

Tadalafil 20 mg was effectively administered in the treatment of 303 men suffering from ED following bilateral nerve sparing radical retropubic prostatectomy ( Montorsi, Padma-Nathan, et al 2004 ). Compared with placebo, a greater improvement on all the evaluated end-points was reported. IIEF–EF domain score increased by 5.3 (p

In a randomized blind cross-over trial for the treatment of ED in 30 male spinal cord-injured patients (mean age 34.6, range 21–60 years) tadalafil 10 mg was compared with sildenafil 50 mg ( Del Popolo et al 2004 ). In these patients, either psychogenic erections or reflexive spinally elicited erections or both are necessary for PDE5 inhibitor response. Tadalafil and sildenafil allowed patients to achieve erections whit a mean total score on IIEF of 17.82 and 15.75 (increase from baseline of 58.41% and 40%) respectively. No significant differences were observed up to 12 h, while, as expected, normal sexual functioning and improved overall sex satisfaction up to 24 h post-dosing was better for tadalafil compared with sildenafil (p<0.01).

The clinical evidence: safety of tadalafil in ED

Most of the side effects reported in the clinical trials are dose-dependent and consistent with the vasodilatatory effect of PDE-5 inhibition. When tadalafil was administered on an on-demand basis headache and dyspepsia were the most frequent symptoms, followed by back pain, nasal congestion, myalgia, and flushing. Subgroup analyses have revealed no differences between incidences of adverse events in tadalafil-treated men over 65 years compared with the younger group. No relevant differences in the frequency and pattern of side-effects have been reported when tadalafil was schedully administered (eg, three times per week, or daily). The daily administration of tadalafil was well tolerated with headache, dyspepsia, facial flushing, nasal congestion, and backache as the most frequently reported adverse events ( McMahon 2004 ). In the “eleven trials analysis” ( Carson et al 2004 ), adverse events leading to study discontinuation account for 3.2% of patients taking tadalafil 20 mg, 1.6% of patients taking tadalafil 10 mg and 1.3% of patients on placebo. Respectively, 51%, 58%, and 39% of the subjects experienced at least one or more unwanted symptoms. Side-effects were generally mild to moderate and decreased in frequency during continued treatment. While no significant laboratory or electrocardiographic changes were assessed, the most common treatment-emergent adverse events were headache (15%, 12%, 5% respectively), dyspepsia (8%, 7%, 1% respectively), back pain/myalgia (8%, 11%, 3% respectively), nasopharyngitis and nasal congestion (4%, 11%, 5% respectively), flushing (3%, 3%, 1% respectively), pain in limb (3%, 3%, 1% respectively).

In a comprehensive review on the cardiovascular effects of tadalafil, a safety assessment of more than 4000 subjects who received the drug during clinical studies was performed ( Kloner et al 2003 ). When tadalafil 10 mg and 20 mg was administered to healthy subjects, minimal, but statistically significant differences over placebo in standing systolic (SBP) and diastolic blood pressure (DBP) were observed. Tadalafil 20mg administered daily for 26 weeks in healthy volunteers or in subjects with mild ED (age ≥45 years) did not result in significant changes in sitting SBP or DBP. A small decrease in standing SBP and DBP has been reported in patients with chronic stable angina treated with different doses of tadalafil (5 mg and 10 mg), however, these changes were greater and statistically significant with respect to placebo in the so called “outlier patients”, in whom a decrease of >30 mm Hg in SBP or >20 mm Hg in DBP from baseline was recorded.

An update on thirty-five placebo-controlled and eight open clinical trials of tadalafil demonstrated no increased risk of cardiovascular adverse events such as myocardial infarction, cerebrovascular events or cardiac mortality ( Jackson et al 2004 ).

The evidence that duration of action for tadalafil is well beyond the elimination half-life, advises for a careful monitoring of its long-term effect. However, the duration of side-effects has not been measured in the majority of the studies. Due to the potential for a clinically significant decrease in blood pressure, the major contraindications of the PDE5 inhibitors are concomitant use with nitrates or molsidomine-containing medications, because of the increased sensitivity to nitroglycerin ( Dishy et al 2001 ). Interaction between grapefruit juice and sildenafil, tadalafil, or vardenafil may cause serious systemic vasodilatation ( Bailey and Dresser 2004 ), and we do suggest such a possibility with alcohol as well ( Frajese and Pozzi 2005 ). Since men with ED have high incidence of cardiovascular disease, diabetes mellitus and BPH, they are likely to be taking medications that affect blood pressure like the alpha-blockers terazosin and doxazosin ( Simonsen 2002 ). Tadalafil augmented the hypotensive effects of doxazosin, but had little hemodynamic interaction with tamsulosin, a drug prescribed for BPH ( Kloner et al 2004 ). The long-term safety and tolerability of tadalafil 10–20 mg in the treatment of erectile dysfunction has been assessed, evaluating in a 18–24 month open extension trial in 1173 subjects (mean age 57, range 23–83 years) ( Montorsi, Verheyden, et al 2004 ). Notably, 74% of patients were taking concomitant medication for comorbid conditions, including diabetes mellitus (30.5%) and hypertension (29.5%). After three months, 72% of patients had chosen the 20mg dose. 173 (14.7%) of men discontinued because of perceived lack of efficacy over 18–24 months of treatment. 234 (20%) and 493 subjects (42%) completed 18 and 24 months of treatment respectively. The total tadalafil exposure was 1676 patient-years. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%) and back pain (8.2%) were the most common treatment emergent side-effects. Consistent with the low affinity of tadalafil for PDE6, only 1 patient complained of cyanopsia (blue vision). The rate of discontinuation due to adverse events was 6.3%. No clinically significant laboratory, or electrocardiographic findings, or changes in vital signs, or serious adverse events (8.6%), or major safety concerns were causally associated with tadalafil administration.

Back pain or myalgia or both appearing as a consequence of PDE5 inhibition was experienced by 8.3%–9.4% of men taking tadalafil 10–20 mg. The potential mechanism of this side effect remains unknown. The underlying symptoms include diffuse bilateral lower lumbar gluteal, thigh, or thoracolumbar muscular discomfort, exacerbated by recumbency. The integrated analysis of ten placebo-controlled tadalafil studies, including 1846 patients ( Seftel et al 2005 ), showed that laboratory markers of inflammation or muscle damage and renal plasma flow were unchanged with respect to baseline, and no lumbar or gluteal myositis was evidenced by positron emission tomography scan or magnetic resonance imaging.

Across tadalafil clinical trials no impairment of blue-green color discrimination was detected, and color vision alterations were rare (0.1%) ( Eli Lilly 2006 ). Chronic tadalafil administration has no detrimental effect on human spermatogenesis or reproductive hormones ( Ellstrom et al 2003 ).

Treatment strategies and effect on sexual behavior

Although efficacy and safety are two important characteristics when choosing a pharmacological treatment for ED, the ideal therapy should be reliable during maintenance. Furthermore, beyond erection and penetration, intercourse success and overall satisfaction needs have to be considered. The primary goal in the treatment of ED should be the restoration of sexual life rather than merely the achievement of a penile erection.

An important characteristic of tadalafil is its prolonged period of responsiveness. In prescribing a therapy for ED, the long lasting effect of the drug may not be the most important issue. Tadalafil is unique to the PDE5 inhibitors available because of its efficacy up to 36 h after dosing. This should release from the need to plan sexual activities and therefore favor spontaneity.

In a study designed to assess whether tadalafil 20 mg was associated with a treatment effect discriminated from placebo ( Porst et al 2003 ), a greater proportion of successful intercourse attempts up to 36 hours post-tadalafil dose compared with placebo at 24 h and 36 h was reported. Fifty-three percent versus 29% (p<0.001) of successful intercourse attempts according to SEP-Q3 was undertaken up to 24 h, and 59% versus 28% (p<0.001) within 36 h after dosing.

In a randomized prospective placebo-controlled trial, the chronological distribution of sexual intercourse was evaluated ( De Rose et al 2005 ). Tadalafil 20 mg administered twice a week resulted in a significant change of sexual attitude with the highest percentages of successful intercourse after 6–12 h (35%), and 12–24 h (28%) from dosing. It should be mentioned that 5% and 2% of intercourse were recorded up to 48 h and 60 h, while none of the placebo patients has reported sexual intercourse over 16 h. Recovery of spontaneous night, awakening, and day long erections at the rate of 78% was also reported. Besides the quality of sexual intercourse, these results showed an improvement of sexuality in the broadest sense. Unfortunately, due to the low mean age of patients enrolled (46 years), it is difficult to extrapolate this data to elderly patients.

When taken on demand, tadalafil 20 mg versus placebo allows a range of 62%–74% (vs 0%–33%) of successful intercourse attempt rate up to 36 h (p

Patients on tadalafil changed their sexual behavior significantly when on an alternate dose regimen (3 times/week) and had sexual attempts distributed over a wide period of time post dosing ( Mirone et al. 2005 ). The on-demand regimen versus scheduled use was evaluated in 4262 patients in a cross-over open-label study conducted to assess patient’s choice of treatment regimens. Overall, both regimen were effectives with a normal IIEF–EF domain score (≥26) achieved by 60.2% and 62.3% of patients, and a 72.6% and 74.4% mean per patient intercourse success rate. A preference for the on-demand administration was expressed by 57.8% of patients. An analysis of preferences based on comorbidities associated with ED ( Moncada et al 2005 ) showed that the on demand regimen was preferred in each subgroup except for the depressed patients, in which 53% expressed preference for the 3 times/week treatment. It was concluded that the patient’s choice of treatment regimens is not exclusively determined by demographics or clinical features, but is possibly related to individual cultural and psychosocial factors. Forty seven percent of the attempts on the on-demand regimen and 71% on the 3 times/week treatment were performed by patients more than 4h post-dosing. The efficacy of tadalafil 20 mg was more than 70% (mean-per-patient) success rate regardless of the time interval post-dosing. Since age is a potential influencing factor on sexual habits, a subgroup analysis of age was performed. On three cohorts of patients aged 65 years, overall 52%–56% of attempts were performed within 4h post-dosing with on-demand regimen and 68%–71% of attempts beyond 4h post-dosing with the 3 times/week interval. In all the three groups the evening was the preferred time for sexual activity, but with increasing age fewer weekend attempts (about 51%, 48%, and 45% respectively) and more morning attempts were observed on the 3 times/week regimen (about 13%, 22% and 28% for patients aged >65 years). Moncada and collegues (2005) commented that this behavior may be a general response to a less pronounced perception of a deadline to engage in sexual activity and to the major availability of time for sexual activity in the older patients and their partners.

Similar results emerged from the post-hoc analyses ( Shabsigh et al 2005 ) assessing the time from dosing to sexual intercourse attempts of the “eleven double-blind trials” ( Carson et al 2004 ) and of the double-blind studies conducted in eastern Europe ( Hatzichristou et al 2005 ). Regardless of age, ED severity or previous experience with sildenafil, most patients attempted sexual intercourse 12–36 h after one dose of tadalafil and did not adhere to a fixed schedule of intimacy.

The efficacy of PDE5 inhibitors is probably related to the extent and severity of ED. In patients suffering from ED with diabetes, or severe vasculogenic disease, or post-radical prostatectomy, a significantly reduced efficacy of these drugs was demonstrated in several experiences ( Goldstein et al 1998 ; Emmick et al 2002 ; Saenz De Tejada et al 2002 ). Different salvage strategies have been applied in such cases ( McMahon 2002 ; Atiemo et al 2003 ). In a clinical trial ( McMahon 2004 ) involving subjects with ED of predominantly vasculogenic etiology, (mean age of 63; range 21–79 years), previously unresponsive to on-demand tadalafil, daily administration of tadalafil, at the flexible dose of 10–20 mg significantly enhanced all efficacy outcome variables. Improved erections at end-point were reported by 69% of men compared with 42% of men with on-demand tadalafil. A significant improvement in the IIEF–EF domain of 12.8 versus pre-treatment (p<0.001), and of 8.2 from on-demand tadalafil baseline (p<0.001) was reported. Sexual intercourse was successfully completed on 58% of attempts with daily tadalafil 10 mg compared with 21% at baseline, and 28% with on-demand tadalafil 20 mg (p<0.001). However, McMahon (2004) hypothesized that although the potential for tachyphylaxis ( Moreland et al 1999 ) is probably low for on-demand use of PDE5 inhibitors, the long lasting duration of tadalafil’s effect and its chronic use may facilitate the loss of treatment efficacy.

Conclusions

With an effectiveness that lasts up to 36 h, tadalafil could provide nearly continuous coverage when taken on a regular basis, allowing patients and their partners to choose freely when to have sexual activities without the need of timing it. This property of tadalafil explains why patients suffering from ED showed positive feedback in terms of quality of life related to the treatment. Although various studies reported the superior pharmacokinetic properties of tadalafil compared with the other PDE5 inhibitors, this should be cautiously interpreted, especially in the elderly, because up to now it has not been entirely defined the impact that such a long lasting effect could have both on clinical effectiveness and safety, especially in the presence of comorbid conditions or other drugs. Nevertheless, the efficacy of tadalafil was demonstrated in patients of all ages across disease severities and etiologies with a broad range of outcomes, including improved erections, hardness, ability to penetrate the partner’s vagina, maintenance of erection, intercourse satisfaction, and overall satisfaction. The treatment choices that are possible with tadalafil allow patients to take the drug on a regular basis and to regain satisfaction with sex life.