PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

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

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, selective phosphodiesterase type 5 (PDE5) inhibitor
    Used for pulmonary arterial hypertension (PAH), male erectile dysfunction (ED), and benign prostatic hyperplasia (BPH)
    Longer duration of action allowing for more spontaneity in sexual activity in treating ED

    COMMON BRAND NAMES

    Adcirca, ALYQ, Cialis

    HOW SUPPLIED

    Adcirca/ALYQ/Cialis/Tadalafil 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 once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[40259]

    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. 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.[56782] [56794] Slow ascent is the primary recommended method for prevention of high altitude pulmonary edema (HAPE). Consider pharmacologic prophylaxis for individuals with a prior history of HAPE; nifedipine is preferred. Start prophylaxis the day prior to ascent. Continue prophylaxis for 5 days after reaching target altitude or until descent is initiated.[56782]

    †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 arterial 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 (ED), for once daily use for benign prostatic hyperplasia (BPH), or daily use for a combination of ED and BPH, no dosage adjustment needed.[28220] 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.[40259]
    CrCl 30 to 50 mL/minute: For as needed use for ED, 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 ED, no dosage adjustment is needed. For once daily use in BPH or ED 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.[28220] For PAH, a starting dose of 20 mg PO once daily is recommended; increase to 40 mg PO once daily as tolerated.[40259]
    CrCl less than 30 mL/minute: For as needed use for ED, the maximum recommended dose is 5 mg PO given not more than once every 72 hours. Once daily use for ED, for PAH, BPH, or a combination of ED and BPH is not recommended.[28220] [40259]
     
    Intermittent hemodialysis
    The maximum recommended dose in patients with ED receiving tadalafil for use as needed is 5 mg PO given not more than once every 72 hours. Not recommended for once daily use for ED, BPH, a combination of ED and BPH, or PAH.

    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
    ALYQ:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Cialis:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.[40259] [28220]
     
    The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.[28220]
     
    Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH.[28220]

    Nitrate/nitrite therapy

    Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy or guanylate cyclase (GC) stimulators therapy, such as riociguat. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered for erectile dysfunction. When tadalafil is administered for pulmonary arterial hypertension, nitrates should not be administered within 48 hours after the last tadalafil dose. Tadalafil may potentiate the hypotensive effects of GC stimulators.[28220] [40259]

    Dialysis, renal failure, renal impairment

    Avoid use of tadalafil for pulmonary arterial hypertension or benign prostatic hyperplasia as well as daily use in erectile dysfunction in patients with renal failure or severe renal impairment (CrCl less than 30 mL/minute), including dialysis-dependence, due to increased tadalafil exposure, limited clinical experience, and lack of ability to influence clearance by dialysis. Starting dose modifications and dosage limits may apply for patients with mild or moderate renal impairment.[28220] [40259]

    Hepatic disease

    Avoid use of tadalafil in patients with severe hepatic disease (Child-Pugh Class C). Tadalafil has not been studied in patients with cirrhosis. Cautious use and starting dose modifications are recommended in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).[28220] [40259]

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

    There is a degree of cardiac risk associated with sexual activity; therefore, consider cardiovascular status of the patient before initiating tadalafil for erectile dysfunction. Do not use tadalafil in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Educate patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity, and advise any patient experiencing anginal chest pain after taking tadalafil for any indication to seek immediate medical attention. Tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Before starting tadalafil, carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to vasodilators, including PDE5 inhibitors. Tadalafil use for erectile dysfunction or benign prostatic hypertrophy is not recommended for the following patient groups due to lack of safety and efficacy data: myocardial infarction within the last 90 days; unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (less than 90/50 mmHg); uncontrolled hypertension; or a stroke within the last 6 months. Additionally, there is a lack of safety and efficacy data in the treatment of pulmonary arterial hypertension due to exclusion from clinical trials for the following patient groups: aortic and mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, significant left ventricular dysfunction, life-threatening arrhythmias, symptomatic coronary artery disease, hypotension (less than 90/50 mmHg), or uncontrolled hypertension. Further, tadalafil is not recommended for use in patients with pulmonary veno-occlusive disease (VOD) since there are no clinical data. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary VOD may experience significant worsening in cardiovascular status. If signs of pulmonary edema occur with tadalafil administration, consider the possibility of associated pulmonary VOD.[28220] [40259]

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

    Prolonged erections more than 4 hours and priapism (painful erections more than 6 hours) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil with caution in patients with a penile structural abnormality, such as angulation, cavernosal fibrosis, or Peyronie's disease, or with conditions predisposing to priapism, such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism.[28220] [40131]

    Sexually transmitted disease

    Educate patients that use of tadalafil for erectile dysfunction offers no protection against sexually transmitted disease. Counsel patients about protective measures necessary to guard against sexually transmitted diseases, including human immunodeficiency virus (HIV) infection.[28220]

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

    Patients with sudden visual impairment, such as loss of vision in one or both eyes, should stop using tadalafil immediately and seek medical attention. Postmarketing reports of sudden vision loss, including permanent vision loss, have occurred with PDE5 inhibitors like tadalafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Most of the patients who developed NAION had underlying anatomic or vascular risk factors for the development of NAION, including, but not limited to, low cup to disc ratio ("crowded disc"), age older than 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Advise patients of the increased risk of NAION if they have already experienced NAION in 1 eye. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in clinical trials; tadalafil use is not recommended in these patients.[28220] [40259]

    Gastroesophageal reflux disease (GERD), hiatal hernia

    Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.[26879]

    Hematological disease, peptic ulcer 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, tadalafil has not been studied in patients with bleeding disorders or significant active peptic ulcer disease. Carefully assess risk-benefit and use tadalafil with caution in patients with significant hematological disease (e.g., bleeding disorders) or significant active peptic ulceration.[28220]

    Prostate cancer

    Before initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consider other urological conditions that may cause similar symptoms, such as prostate cancer. Prostate cancer and BPH cause many of the same symptoms and frequently coexist.[28220]

    Pregnancy

    Limited data from case series with tadalafil administration during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies in rats and mice at exposures of 7 times the maximum recommended human dose (MRHD) of 40 mg/day based on AUC revealed no evidence of teratogenicity, embryotoxicity, or fetotoxicity. In a perinatal/postnatal development study involving rats, a reduction in postnatal pup survival occurred with doses of 60 mg/kg, 200 mg/kg, and 1,000 mg/kg. Maternal toxicity was observed at 200 mg/kg, which was 8 times the MRHD. It is recommended that women with pulmonary arterial hypertension avoid becoming pregnant.[40259]

    Breast-feeding

    There are no data on the presence of tadalafil in human breast milk, the effects on the breastfed child, or the effects on breast-feeding. Tadalafil or some metabolite of tadalafil was excreted in rat milk. Because many drugs are excreted in human breast milk, use tadalafil with caution in breast-feeding women. The developmental and health benefits of breast-feeding should be considered along with the mother's need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or the underlying maternal condition.[40259]

    Infertility

    Decreased sperm concentration with tadalafil therapy was observed in 2 studies involving adult males who received tadalafil 10 mg for 6 months and 20 mg for 9 months; this effect was not seen in male patients in a third study taking tadalafil 20 mg for 6 months. Tadalafil did not have an adverse effect on testosterone, luteinizing hormone, or follicle-stimulating hormone. The clinical significance of the reductions in sperm count and whether it may result in infertility are not known. No studies have evaluated the effect of tadalafil on fertility in men or women.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    hypertension / Early / 1.0-3.0
    hypotension / Rapid / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    palpitations / Early / 0-2.0
    orthostatic hypotension / Delayed / 0-2.0
    angina / Early / 0-2.0
    esophagitis / Delayed / 0-2.0
    dysphagia / Delayed / 0-2.0
    gastritis / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    dyspnea / Early / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    blurred vision / Early / 0-2.0
    edema / Delayed / 0-2.0
    QT prolongation / Rapid / Incidence not known
    amnesia / Delayed / Incidence not known
    migraine / Early / Incidence not known
    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
    drowsiness / Early / 0-2.0
    dizziness / Early / 1.0-2.0
    insomnia / Early / 0-2.0
    hypoesthesia / Delayed / 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
    blepharedema / Early / 0-2.0
    lacrimation / 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 / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    urticaria / Rapid / Incidence not known
    oligospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Alfuzosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alfuzosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of alfuzosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alfuzosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and alfuzosin.
    Alpha-blockers: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Amiodarone: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with amiodarone is necessary. Tadalafil is a CYP3A4 substrate and amiodarone is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    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: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if tadalafil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tadalafil-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tadalafil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tadalafil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Atazanavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    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%.
    Berotralstat: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    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: (Moderate) Bosentan reduces tadalafil systemic exposure by 42% and Cmax by 27% with multiple-dose coadministration. Tadalafil has no significant effect on the exposure of bosentan. Bosentan is a substrate and moderate inducer of CYP3A; tadalafil is a CYP3A substrate.
    Brompheniramine; Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Brompheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbamazepine: (Major) Avoid coadministration of tadalafil with carbamazepine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of carbamazepine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Phenylephrine; Pyrilamine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbinoxamine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Ceritinib: (Major) Avoid coadministration of tadalafil and ceritinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ceritinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as ceritinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Chlophedianol; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
    Codeine; Phenylephrine; Promethazine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Conivaptan: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with conivaptan is necessary. Tadalafil is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
    Crizotinib: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Darunavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Darunavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Delavirdine: (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
    Dexamethasone: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Studies have shown that concomitant administration of CYP3A4 enzyme-inducers, such as dexamethasone, will decrease plasma levels of tadalafil.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Dextromethorphan; Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Diltiazem: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with diltiazem is necessary. Tadalafil is a CYP3A4 substrate and diltiazem is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Doxazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tadalafil is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Moderate) Monitor blood pressure closely if duloxetine is coadministered with tadalafil due to the risk of additive hypotension. Orthostatic hypotension and syncope have been reported during duloxetine administration.
    Dutasteride; Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
    Efavirenz: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
    Elbasvir; Grazoprevir: (Moderate) Administering tadalafil with elbasvir; grazoprevir may result in elevated tadalafil plasma concentrations. Tadalafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
    Enzalutamide: (Major) Avoid coadministration of tadalafil with enzalutamide in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of enzalutamide due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Erythromycin: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with erythromycin is necessary. Tadalafil is a CYP3A4 substrate and erythromycin is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with erythromycin is necessary. Tadalafil is a CYP3A4 substrate and erythromycin is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Ethanol: (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) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fluconazole is necessary. Tadalafil is a CYP3A4 substrate and fluconazole is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    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.
    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: (Major) Avoid coadministration of tadalafil with fosphenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of fosphenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Grapefruit juice: (Moderate) Tadalafil is metabolized via the CYP3A4 isozyme. Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Tadalafil levels may increase; it is possible that tadalafil-induced side effects could also be increased in some individuals.
    Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Hydralazine; Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tadalafil, a CYP3A substrate, as tadalafil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Major) Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as imatinib, STI-571, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
    Indinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of indinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of indinavir therapy. Stop tadalafil at least 24 hours prior to starting indinavir. After at least 1 week of indinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and indinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tadalafil may result in increased serum concentrations of tadalafil. Tadalafil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
    Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Isosorbide Mononitrate: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Itraconazole: (Major) Avoid use of tadalafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of itraconazole for the as needed dose or 2.5 mg daily for the once-daily dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as itraconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Ketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) An increase in the plasma concentration of tadalafil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of tadalafil for pulmonary hypertension if the patient is receiving letermovir and cyclosporine. When used for erectile dysfunction in patients receiving letermovir with cyclosporine, the as needed (PRN) dose of tadalafil should not exceed 10 mg once every 72 hours and the daily dose should not exceed 2.5 mg. Tadalafil is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, the exposure and maximum plasma concentration of tadalafil increased by up to 312% and 22%, respectively, when administered with another potent CYP3A4 inhibitor. Studies with moderate CYP3A4 inhibitors have not been conducted.
    Levoketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
    Lonafarnib: (Major) Avoid coadministration of tadalafil and lonafarnib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of lonafarnib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as lonafarnib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Lopinavir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Lorcaserin: (Moderate) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Mifepristone: (Major) Avoid coadministration of tadalafil and mifepristone for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of mifepristone for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as mifepristone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Mitotane: (Major) Avoid coadministration of tadalafil with mitotane in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of mitotane due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Nefazodone: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as nefazodone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Nelfinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of nelfinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of nelfinavir therapy. Stop tadalafil at least 24 hours prior to starting nelfinavir. After at least 1 week of nelfinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and nelfinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tadalafil. The plasma concentrations of tadalafil can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nevirapine: (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.
    Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Nitrates: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroglycerin: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroprusside: (Contraindicated) Concomitant use of nitroprusside and tadalafil is contraindicated due to the risk of additive hypotension. If the patient has taken tadalafil, at least 48 hours must elapse before nitroprusside administration is considered; monitor hemodynamics closely. In addition, tadalafil may potentiate the nitric oxide-mediated platelet anti-aggregatory effect of nitroprusside.
    Olanzapine; 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Oritavancin: (Minor) Concomitant use of oritavancin and tadalafil may decrease the effectiveness of tadalafil; therefore, use caution and monitor therapeutic effects of tadalafil when coadministered. Oritavancin is a weak inducer of CYP3A4 and tadalafil is a CYP3A4 substrate. Clinical studies have shown that CYP3A4 inducers may reduce tadalafil exposure. The reduced exposure of tadalafil with the coadministration of CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil for once daily use; however the magnitude of decreased efficacy is unknown. Potent CYP3A4 inducers should be avoided with tadalafil when it is used to treat pulmonary hypertension.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tadalafil, a CYP3A4 substrate, may cause an increase in systemic concentrations of tadalafil. Use caution when administering these drugs concomitantly.
    Phenobarbital: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Phenoxybenzamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Phentolamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Phenytoin: (Major) Avoid coadministration of tadalafil with phenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Posaconazole: (Major) Posaconazole and tadalafil should be coadministered with caution due to an increased potential for tadalafil-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tadalafil. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose should not exceed 10 mg within a 72 hour time period and the 'once-daily' dose should not exceed 2.5 mg.
    Prazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Primidone: (Major) Avoid coadministration of tadalafil with primidone in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of primidone due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Promethazine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Ranolazine: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Ribociclib: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
    Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
    Rifapentine: (Major) Avoid coadministration of tadalafil with rifapentine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifapentine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Riociguat: (Contraindicated) Coadministration of riociguat and tadalafil is contraindicated due to the risk of hypotension. Do not administer riociguat 24 hours before or within 48 hours after tadalafil. Consider initiating riociguat at a starting dose of 0.5 mg in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy.
    Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
    Saquinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of saquinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of saquinavir therapy. Stop tadalafil at least 24 hours prior to starting saquinavir. After at least 1 week of saquinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and saquinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Silodosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on silodosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of silodosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue silodosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and silodosin.
    Simeprevir: (Moderate) Coadministration of tadalafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in tadalafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest tadalafil dose and increase as needed while monitoring clinically.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of tadalafil with St. John's Wort in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of St. John's Wort due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
    Telaprevir: (Contraindicated) 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.
    Terazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
    Tipranavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of tipranavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of tipranavir therapy. Stop tadalafil at least 24 hours prior to starting tipranavir. After at least 1 week of tipranavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and tipranavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Trandolapril; Verapamil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Tucatinib: (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Vardenafil: (Major) 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) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Vericiguat: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
    Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Voriconazole: (Major) Avoid coadministration of voriconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of voriconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
    Voxelotor: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with voxelotor is necessary. Tadalafil is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.

    PREGNANCY AND LACTATION

    Pregnancy

    Limited data from case series with tadalafil administration during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies in rats and mice at exposures of 7 times the maximum recommended human dose (MRHD) of 40 mg/day based on AUC revealed no evidence of teratogenicity, embryotoxicity, or fetotoxicity. In a perinatal/postnatal development study involving rats, a reduction in postnatal pup survival occurred with doses of 60 mg/kg, 200 mg/kg, and 1,000 mg/kg. Maternal toxicity was observed at 200 mg/kg, which was 8 times the MRHD. It is recommended that women with pulmonary arterial hypertension avoid becoming pregnant.[40259]

    There are no data on the presence of tadalafil in human breast milk, the effects on the breastfed child, or the effects on breast-feeding. Tadalafil or some metabolite of tadalafil was excreted in rat milk. Because many drugs are excreted in human breast milk, use tadalafil with caution in breast-feeding women. The developmental and health benefits of breast-feeding should be considered along with the mother's need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or the underlying maternal condition.[40259]

    MECHANISM OF ACTION

    Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased concentrations of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. PDE5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum, and at recommended doses, does not affect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is more than 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is more than 10,000-fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 vs. PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 vs. PDE6. This lower selectivity of sildenafil for PDE5 vs. PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is more than 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.
     
    The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.[28220]
     
    Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in the relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.[40259]
     
    Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

    PHARMACOKINETICS

    Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalafil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 17.5 hours in healthy subjects.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Tadalafil is a CYP3A4 substrate.

    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 does not affect the pharmacokinetics of tadalafil; however, absolute bioavailability data are not available.