PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Benign Prostatic Hypertrophy (BPH) Products
    Erectile Dysfunction Products
    Pulmonary Hypertension Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral selective phosphodiesterase-5 (PDE5) inhibitor
    Approved for treating pulmonary arterial hypertension, male erectile dysfunction (ED), and benign prostatic hyperplasia (BPH)
    Duration of action (up to 36 hours) for the treatment of ED is longer than sildenafil, allowing for spontaneity in sexual activity

    COMMON BRAND NAMES

    Adcirca, Cialis

    HOW SUPPLIED

    Adcirca/Cialis Oral Tab: 2.5mg, 5mg, 10mg, 20mg

    DOSAGE & INDICATIONS

    For the treatment of erectile dysfunction (ED), including ED patients with diabetes mellitus or following radical prostatectomy.
    For use as needed for ED.
    Oral dosage
    Adult males

    The recommended starting dose in most patients is 10 mg PO, taken prior to anticipated sexual activity. The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The usual onset of action is within 30 to 45 minutes and the usual duration is up to 36 hours. Tadalafil improved ED compared to placebo up to 36 hours following dosing; therefore, when advising patients on optimal use, this should be taken into consideration. Phase III data report that doses of 20 mg PO improved sexual function in 64% of diabetics with ED. In one clinical study, positive responses were noted at doses of 2, 5, 10, and 25 mg. Doses 5 mg or more were superior to placebo in inducing and maintaining erections adequate for penetration.
       -PDE5 inhibitors are first line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. A course of an alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Patients refractory to PDE5 inhibitors should be counseled on appropriate use, potentially modifiable factors (e.g. hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with his partner), and the risks and benefits of other therapies. Second-line treatment options include intracavernous injection and intra-urethral therapy. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.

    For use once daily for ED without regard to timing of sexual activity.
    Oral dosage
    Adult males

    2.5 mg PO once daily at about the same time each day. May increase to 5 mg PO once daily depending on efficacy and tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the concurrent treatment of erectile dysfunction and benign prostatic hypertrophy.
    Oral dosage
    Adults

    5 mg PO once daily, taken at approximately the same time every day, without regard to timing of sexual activity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For improvement in exercise ability in patients with WHO Group I pulmonary hypertension.
    Oral dosage
    Adults

    40 mg PO (two 20 mg tablets) once daily with or without food. Dividing the dose over the course of the day is not recommended by the manufacturer. Studies establishing effectiveness were comprised predominately of patients with NYHA Functional Class II to III symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (PAH) (61%) or PAH associated with connective tissue diseases (23%). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
    For the concurrent treatment of benign prostatic hyperplasia and erectile dysfunction.
    Oral dosage
    Adults

    5 mg PO once daily, taken at approximately the same time every day, without regard to timing of sexual activity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Oral dosage
    Adults

    5 mg PO once daily, taken at approximately the same time every day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of sexual dysfunction† in males receiving antidepressant therapy.
    Oral dosage
    Adult males

    A retrospective, pooled-analysis of 19 double-blind, placebo-controlled studies evaluated the efficacy of tadalafil (10 or 20 mg PO prior to anticipated sexual activity) in improving sexual dysfunction in men on antidepressant therapy (i.e., SSRIs, TCAs, MAOIs, serotonin and norepinephrine reuptake inhibitors, and others). Tadalafil at both doses significantly improved erectile function in these patients compared to patients receiving placebo. Although tadalafil was effective, it was not known it the etiology of sexual dysfunction in these patients was specifically due to antidepressant therapy or secondary to other factors (e.g., cardiovascular or neurological disorder, depressive disorder).

    For altitude sickness prophylaxis, specifically prevention of high altitude pulmonary edema.
    Oral dosage
    Adults

    10 mg PO twice daily is recommended in clinical practice guidelines. Slow ascent is the primary recommended method for prevention of high altitude pulmonary edema (HAPE). Pharmacologic prophylaxis should only be considered for individuals with a prior history of HAPE, and nifedipine is preferred. Start prophylaxis the day prior to ascent. Continue prophylaxis for 5 days after reaching target altitude or until descent is initiated.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO for pulmonary hypertension; 5 mg/day PO for erectile dysfunction for once daily use; 20 mg/dose PO for erectile dysfunction for as needed use, not to exceed 1 dose/24 hours in most patients; 5 mg/day PO for benign prostatic hyperplasia (BPH) or combined treatment of erectile dysfunction/BPH for once daily use.

    Geriatric

    40 mg/day PO for pulmonary hypertension; 5 mg/day PO for erectile dysfunction for once daily use; 20 mg/dose PO for erectile dysfunction for as needed use, not to exceed 1 dose/24 hours in most patients; 5 mg/day PO for benign prostatic hyperplasia (BPH) or combined treatment of erectile dysfunction/BPH for once daily use.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate impairment (Child-Pugh class A or B): Do not exceed 10 mg PO once daily when used as needed for erectile dysfunction (ED). The use of tadalafil once daily has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised in this patient population. Consider a starting dose of 20 mg/day PO when used for pulmonary hypertension.
    Severe impairment (Child-Pugh class C): Tadalafil is not recommended.

    Renal Impairment

    CrCl greater than 80 mL/minute: No dosage adjustment needed.
    CrCl 51 to 80 mL/minute: For as needed or daily use for erectile dysfunction, for once daily use for benign prostatic hyperplasia (BPH), or daily use for a combination of erectile dysfunction and BPH, no dosage adjustment needed. For pulmonary arterial hypertension (PAH), starting dose of 20 mg PO once daily is recommended; increase to 40 mg PO once daily as tolerated.
    CrCl 30 to 50 mL/minute: For as needed use for erectile dysfunction, starting dose of 5 mg PO not more than once daily is recommended; maximum dose should be limited to 10 mg not more than once every 48 hours. For once daily use for erectile dysfunction, no dosage adjustment is needed. For once daily use in benign prostatic hyperplasia (BPH) or erectile dysfunction and BPH, a starting dose of 2.5 mg is recommended; an increase to 5 mg may be considered based upon individual response and tolerability. For pulmonary arterial hypertension (PAH), a starting dose of 20 mg PO once daily is recommended; increase to 40 mg PO once daily as tolerated.
    CrCl less than 30 mL/minute: For as needed use (e.g., PRN) for erectile dysfunction, the maximum recommended dose is 5 mg PO given not more than once every 72 hours. Once daily use for erectile dysfunction, for pulmonary arterial hypertension (PAH), benign prostatic hyperplasia (BPH), or a combination of erectile dysfunction and BPH is not recommended.
     
    Intermittent hemodialysis
    The maximum recommended dose in patients with erectile dysfunction receiving tadalafil for use as needed (e.g., PRN) is 5 mg PO given not more than once every 72 hours. Not recommended for once daily use for erectile dysfunction, benign prostatic hyperplasia (BPH), a combination of erectile dysfunction and BPH, or pulmonary arterial hypertension.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.
    For pulmonary hypertension: Administer the entire dose once daily; do not give in divided doses over the course of the day.
    For as needed use for erectile dysfunction: May be taken between 30 minutes and 36 hours of anticipated sexual activity.
    For once daily use for erectile dysfunction: Take at approximately the same time each day, without regard to timing of sexual activity.
    For once daily use for benign prostatic hyperplasia: Take at approximately the same time each day.
    For once daily use for those with combined benign prostatic hyperplasia and erectile dysfunction: Take at approximately the same time each day, without regard to timing of sexual activity.

    STORAGE

    Adcirca:
    - 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

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.
     
    The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
     
    Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).

    Nitrate/nitrite therapy

    Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. 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.

    Dialysis, renal failure, renal impairment

    Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for erectile dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.

    Hepatic disease

    Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions).

    Angina, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypertension, hypotension, hypovolemia, myocardial infarction, stroke

    There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (< 90/50 mmHg); uncontrolled hypertension (> 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered.

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

    Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) 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 greater than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil, and other agents for the treatment of erectile dysfunction, with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).

    Human immunodeficiency virus (HIV) infection

    Educate patients that tadalafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances.

    Non-arteritic anterior ischemic optic neuropathy, retinitis pigmentosa, visual disturbance

    Use tadalafil cautiously in patients with pre-existing visual disturbance. Postmarketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. 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 over 50, 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.

    Geriatric

    Geriatric patients (>= 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of erectile dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

    Prostate cancer

    Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.

    Pregnancy

    Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed ; Cialis is not indicated for use in women.

    Gastroesophageal reflux disease (GERD), hiatal hernia, peptic ulcer disease

    Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility. Additionally, 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, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.

    Breast-feeding

    It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women ; Cialis is not indicated for use in women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hematological disease

    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, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.

    Children, infants, neonates

    According to the manufacturer, the safety and efficacy of tadalafil in neonates, infants, children, and adolescents have not been established.

    ADVERSE REACTIONS

    Severe

    myocardial infarction / Delayed / 0-2.0
    hearing loss / Delayed / 0-2.0
    stroke / Early / Incidence not known
    seizures / 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

    Moderate

    hypertension / Early / 1.0-3.0
    angina / Early / 0-2.0
    palpitations / Early / 0-2.0
    hypotension / Rapid / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    orthostatic hypotension / Delayed / 0-2.0
    esophagitis / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    gastritis / Delayed / 0-2.0
    dysphagia / 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
    migraine / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    priapism / Early / Incidence not known

    Mild

    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
    nausea / Early / 0-11.0
    nasal congestion / Early / 2.0-9.0
    influenza / Delayed / 2.0-5.0
    cough / Delayed / 2.0-4.0
    musculoskeletal pain / Early / 1.4-3.0
    gastroesophageal reflux / Delayed / 0-3.0
    syncope / Early / 0-2.0
    arthralgia / Delayed / 0-2.0
    paresthesias / Delayed / 0-2.0
    vertigo / Early / 0-2.0
    insomnia / Early / 0-2.0
    drowsiness / Early / 0-2.0
    hypoesthesia / Delayed / 0-2.0
    dizziness / Early / 1.0-2.0
    vomiting / Early / 0-2.0
    diarrhea / Early / 1.0-2.0
    abdominal pain / Early / 0-2.0
    xerostomia / Early / 0-2.0
    epistaxis / Delayed / 0-2.0
    lacrimation / Early / 0-2.0
    blepharedema / Early / 0-2.0
    ocular pain / Early / 0-2.0
    tinnitus / Delayed / 0-2.0
    fatigue / Early / 0-2.0
    asthenia / Delayed / 0-2.0
    hyperhidrosis / Delayed / 0-2.0
    rash (unspecified) / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Alpha-blockers: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    Amiodarone: (Moderate) Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Amiodarone is an inhibitor of CYP3A4 and may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Amoxicillin; Clarithromycin; Lansoprazole: (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.
    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.
    Amprenavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of amprenavir 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 amprenavir therapy. Stop tadalafil at least 24 hours prior to starting amprenavir. After at least 1 week of amprenavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and amprenavir 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.
    Amyl Nitrite: (Severe) 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.
    Atropine; Hyoscyamine; Phenobarbital; 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%.
    Belladonna Alkaloids; Ergotamine; 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%.
    Boceprevir: (Major) Tadalafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with boceprevir. Coadministration of boceprevir with phosphodiesterase type 5 (PDE5) inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Boceprevir can be used with tadalafil for erectile dysfunction; use tadalafil at reduced doses of 10 mg every 72 hours with increased monitoring for adverse reactions.
    Bosentan: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Concomitant administration of CYP3A4 enzyme-inducers, such as bosentan, will decrease plasma levels of tadalafil.
    Brigatinib: (Moderate) Monitor for decreased efficacy of tadalafil if coadministration with brigatinib is necessary. Tadalafil is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer decreased the AUC and Cmax of tadalafil by 88% and 46%, respectively; brigatinib may also decrease tadalafil exposure.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    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: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    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 ceritinib with tadalafil due to increased tadalafil exposure. If coadministration is unavoidable, monitor for tadalafil-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and tadalafil is primarily metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC of single-dose tadalafil by 107% to 312% and the Cmax by 15% to 22%; although other specific interactions have not been studied, other CYP3A4 inhibitors would also likely increase tadalafil exposure.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Cimetidine: (Major) Phosphodiesterase inhibitors are metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take phosphodiesterase inhibitors
    Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
    Cobicistat; Elvitegravir; 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
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
    Codeine; Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Conivaptan: (Major) Avoid coadministration of conivaptan and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within72 hours of conivaptan 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 conivaptan, 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.
    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 CYP3A4 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Dasatinib: (Moderate) Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme like tadalafil are administered concurrently with dasatinib as increased adverse reactions may occur.
    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: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    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) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as diltiazem, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Doxazosin: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    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) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Major) Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
    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: (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.
    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: (Major) Avoid coadministration of erythromycin 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 erythromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as ketoconazole, may reduce tadalafil clearance. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as erythromycin, 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.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin 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 erythromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as ketoconazole, may reduce tadalafil clearance. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as erythromycin, 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.
    Ethanol: (Moderate) Patients should limit the intake of alcohol while taking tadalafil, and not ingest alcohol to excess. 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 tadalfail 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) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as fluconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Fluoxetine: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as fluoxetine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Fluoxetine; Olanzapine: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as fluoxetine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    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) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of fosamprenavir 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 fosamprenavir therapy. 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. Tadalafil is metabolized by CYP3A4, and fosamprenavir 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.
    Fosphenytoin: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Concomitant administration of CYP3A4 enzyme-inducers, such as fosphenytoin, may decrease plasma levels of tadalafil.
    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: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Severe) 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.
    Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    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: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as isoniazid, INH, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    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%. (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as isoniazid, INH, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    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%. (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as isoniazid, INH, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Isosorbide Dinitrate, ISDN: (Severe) 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: (Severe) 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.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and tadalafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as tadalafil, can increase tadalafil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole 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 ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as ketoconazole, may reduce tadalafil clearance. Ketoconazole 400 mg daily increased tadalafil (20 mg single dose) AUC by 312% and Cmax by 22%, relative to the values for tadalafil (20 mg single dose) alone. Ketoconazole 200 mg daily increased tadalafil (10 mg single dose) AUC by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, 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.
    Lopinavir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of lopinavir 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 lopinavir; ritonavir therapy. Stop tadalafil at least 24 hours prior to starting amprenavir. After at least 1 week of lopinavir; ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and lopinavir; ritonavir 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. (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: (Major) 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%. (Moderate) Use caution when administering ivacaftor and tadalafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as tadalafil, can increase tadalafil exposure leading to increased or prolonged therapeutic effects and adverse events.
    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, RU-486: (Moderate) Mifepristone, RU-486 inhibits CYP3A4. Coadministration of mifepristone may lead to an increase in serum levels of drugs metabolized via CYP3A4, such as tadalafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    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; 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: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Studies have shown that concomitant administration of CYP3A4 enzyme-inducers, such as nevirapine, will decrease plasma levels of tadalafil.
    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.
    Nitrates: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroglycerin: (Severe) 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: (Moderate) The hypotensive effects of nitroprusside may be augmented by phosphodiesterase inhibitors. Monitor blood pressure when co-administering phosphodiesterase inhibitors and blood pressure lowering medications, like nitroprusside. Phosphodiesterase inhibitors have vasodilatory properties, and nitroprusside is a potent vasodilator. In addition, phosphodiesterase type-5 (PDE5) is found in platelets, and PDE5 inhibitors may potentiate the nitric oxide-mediated platelet anti-aggregatory activity 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%.
    Phenoxybenzamine: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    Phentolamine: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    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: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    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%.
    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: (Moderate) Use caution if ribociclib is coadministered with tadalafil, as the systemic exposure of tadalafil may be increased resulting in adverse events such as hypotension, syncope, visual changes, and prolonged erection. Ribociclib is a moderate CYP3A4 inhibitor, and tadalafil is a CYP3A4 substrate. Administration with a strong CYP3A4 inhibitor increased the AUC and Cmax after a single dose of tadalafil 10 mg by 107% and 15%, respectively; the AUC and Cmax after a 20 mg dose of tadalafil increased by 312% and 22%, respectively. Moderate CYP3A4 inhibitors may also increase tadalafil exposure.
    Ribociclib; Letrozole: (Moderate) Use caution if ribociclib is coadministered with tadalafil, as the systemic exposure of tadalafil may be increased resulting in adverse events such as hypotension, syncope, visual changes, and prolonged erection. Ribociclib is a moderate CYP3A4 inhibitor, and tadalafil is a CYP3A4 substrate. Administration with a strong CYP3A4 inhibitor increased the AUC and Cmax after a single dose of tadalafil 10 mg by 107% and 15%, respectively; the AUC and Cmax after a 20 mg dose of tadalafil increased by 312% and 22%, respectively. Moderate CYP3A4 inhibitors may also increase tadalafil exposure.
    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%.
    Riociguat: (Severe) 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 recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Silodosin: (Major) Symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) may occur during treatment with alpha-blockers such as silodosin. Enhanced hypotensive effects are possible when alpha-blockers are coadministered with vasodilatory agents such as tadalafil. Patients should be stabilized on alpha blocker therapy prior to starting tadalafil, or if already receiving an optimum dose of tadalafil, alpha blocker therapy should be started at the lowest possible dose.
    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: (Major) Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
    Telaprevir: (Severe) Tadalafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with telaprevir. Coadministration of telaprevir with phosphodiesterase type 5 (PDE5) inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Telaprevir can be used cautiously with tadalafil for erectile dysfunction; use tadalafil at a reduced dose of 10 mg no more frequently than every 72 hours with increased monitoring for adverse reactions.
    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.
    Telotristat Ethyl: (Major) Avoid coadministration of telotristat ethyl and tadalafil (Adcira) for the use of pulmonary arterial hypertension (PAH), as the systemic exposure of tadalafil may be decreased resulting in reduced efficacy. Use caution if coadministration of telotristat ethyl and tadalafil (Cialis) is necessary, and monitor patients for suboptimal efficacy of tadalafil. Tadalafil is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terazosin: (Major) Concurrent use of tadalafil and alpha-blockers may lead to symptomatic hypotension in some patients. The manufacturer of tadalafil states that patients should be stabilized on alpha blocker therapy prior to starting tadalafil at the lowest recommended dose. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant tadalafil therapy. Likewise, for patients currently receiving an optimized dose of tadalafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha blocker dose may be associated with further hypotension when taking tadalafil. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. 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 other medications such as alpha-blockers
    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) Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Inhibitors of CYP3A4 may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Vardenafil: (Major) The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as vardenafil, has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors.
    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) Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Inhibitors of CYP3A4 may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    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.
    Voriconazole: (Major) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include voriconazole. 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.
    Zafirlukast: (Minor) Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Inhibitors of CYP3A4, such as tadalafil, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Zileuton: (Minor) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 CYP3A4 isoenzyme. Zileuton is an Inhibitor of CYP3A4 and may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.

    PREGNANCY AND LACTATION

    Pregnancy

    Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed ; Cialis is not indicated for use in women.

    It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women ; Cialis is not indicated for use in women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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 levels 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. Phosphodiesterase type 5 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, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is >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 >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 versus 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 versus 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 >9000-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 in 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.
     
    Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.
     
    Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). 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. 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 tadalfil 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 17.5 hours in healthy subjects.

    Oral Route

    The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. After a single oral dose, the maximum observed plasma concentration (Cmax) occurs between 30 minutes and 6 hours (Tmax median time of 2 hours). The usual onset of action is within 30 to 45 minutes and the usual duration is up to 36 hours. Food has no effect on the pharmacokinetics of tadalafil, however, absolute bioavailability data are not available.