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tadalafil 5 mg tablet generic cialis

Out of Stock Manufacturer PRASCO LABS 66993070130
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Uses

Erectile Dysfunction

Tadalafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). Tadalafil may be used as needed (on demand) or on a daily basis (without regard to timing of sexual activity).

Assessment of the clinical need for ED therapy, including the use of tadalafil, should take into account the psychologic effect on the man and his partner. With the availability of orally active and convenient vasoactive (erectogenic) therapies (e.g., selective phosphodiesterase [PDE] type 5 inhibitors such as sildenafil, tadalafil, and vardenafil), most experts (e.g., the American Urological Association [AUA]) now consider these drugs to be first-line therapies for a broad range of patients with ED unless contraindicated. Although differences in the pharmacokinetics and certain adverse effects (e.g., potential visual effects, back pain, QT prolongation) exist, data currently are insufficient to support the superiority of one selective PDE type 5 inhibitor over another. However, tadalafil generally has a slower onset but substantially longer duration compared with sildenafil or vardenafil.

The safety and efficacy of as-needed therapy with tadalafil in men with ED of various etiologies are based principally on the results of 7 randomized, double-blind, placebo-controlled trials of 12 weeks' duration. In these and other trials of up to 24 weeks' duration in patients with ED, including trials in individuals with diabetes mellitus or those who had undergone bilateral nerve-sparing radical prostatectomy, tadalafil (2.5-20 mg, generally 5, 10, or 20 mg) produced clinically important improvement in erectile function that did not diminish over time. In these clinical trials, patients generally were allowed to choose the interval between drug administration and sexual activity. In 2 clinical trials specifically evaluating efficacy of tadalafil 20 mg at 24 hours (range: 22-26 hours) and 36 hours (range: 33-39 hours) after administration, the proportion of patients reporting at least 1 successful intercourse at each of these time points was higher with tadalafil (61 or 64% at 24 or 36 hours, respectively) than with placebo (37% of patients at each time point).

The safety and efficacy of once-daily therapy with tadalafil are based principally on the results of 3 multicenter, double-blind, placebo-controlled trials of 12- or 24-weeks' duration in men with ED of various etiologies. In 2 of these trials in patients with ED, including in those with complications from diabetes mellitus, hypertension, hyperlipidemia, or prostatic disease, tadalafil (2.5, 5, or 10 mg once daily) produced clinically important improvements in erectile function. The mean per-patient rate of maintenance of erection to successful completion of intercourse was 50 or 57% with 2.5 or 5 mg of tadalafil, respectively, in the 24-week trial compared with 31% with placebo; the per-patient rate for this efficacy measure in the 12-week trial was 67 or 37% for tadalafil 5 mg or placebo, respectively. In the 24-week clinical trial, these effects did not diminish over time. In another randomized, double-blind, placebo-controlled trial in patients with ED and diabetes mellitus, the mean per-patient rates of maintenance of erection to successful completion of intercourse were 46 or 41% with 2.5 or 5 mg of tadalafil, respectively, compared with 28% with placebo.

Like sildenafil and vardenafil, tadalafil is effective only in the presence of adequate sexual stimulation.

Benign Prostatic Hyperplasia

Tadalafil is used for the symptomatic management of patients with benign prostatic hyperplasia (BPH, benign prostatic hypertrophy). In clinical studies, tadalafil improved lower urinary tract symptoms associated with BPH (e.g., urinary frequency, urgency, nocturia, straining, incomplete emptying, weak urinary stream) but generally did not affect peak urinary flow rate or postvoid residual volume.

Efficacy and safety of once-daily tadalafil therapy for the symptomatic management of BPH are based principally on the results of 3 multinational, double-blind, placebo-controlled studies of 12 weeks' duration. Two of these studies included men with BPH alone; the third study included men with both BPH and ED. In the 2 studies evaluating the effects of tadalafil in men with BPH alone (i.e., without ED), treatment with tadalafil 5 mg once daily substantially improved the scores for severity of irritative (e.g., frequency, urgency, nocturia) and obstructive (e.g., incomplete bladder emptying, stopping and starting urination, weak stream, pushing or straining on urination) symptoms of BPH as measured by a 4-week recall questionnaire (International Prostate Symptom Score [IPSS]). A reduction in symptoms was observed at 4 weeks and continued throughout the remainder of the study periods. Tadalafil therapy also was associated with an improvement in quality of life (e.g., as measured by the Benign Prostatic Hyperplasia Impact Index [BII]); however, changes in peak urinary flow rate and postvoid residual volume with tadalafil were not substantially different from those with placebo. Results of an open-label extension study in patients with symptomatic BPH indicate that improvements in lower urinary tract symptoms are maintained during long-term (e.g., 1 year) tadalafil therapy.

The combination of tadalafil and an α-adrenergic blocking agent (e.g., doxazosin, terazosin) currently is not recommended for the treatment of BPH because of inadequate data and the potential for additive vasodilatory and hypotensive effects.(See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions: Warnings/Precautions.)

Concomitant Erectile Dysfunction and Benign Prostatic Hyperplasia

Tadalafil also is used in the management of coexisting ED and symptomatic BPH. In a randomized, placebo-controlled study, tadalafil 5 mg once daily improved ED (as measured principally by the International Index of Erectile Function-Erectile Function [IIEF-EF] domain score) and symptoms of BPH (as measured principally by the total IPSS score) in men with both conditions; a dosage of 2.5 mg once daily improved IIEF-EF but not IPSS. Tadalafil 5 mg once daily resulted in substantial improvement in maintenance of erection to successful intercourse. In addition, a reduction in the IPSS score was observed at 2 weeks and remained decreased throughout the remainder of the 12-week study. Although peak urinary flow rates were increased from baseline with tadalafil in this study, these changes were not substantially different from those with placebo.

Pulmonary Arterial Hypertension

Tadalafil is used for the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) to improve exercise capacity. Clinical studies establishing efficacy of tadalafil for the treatment of PAH were conducted principally in patients with New York Heart Association (NYHA)/WHO functional class II-III symptoms and a diagnosis of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

In addition to general treatment measures and supportive therapy (e.g., warfarin anticoagulation, diuretics, supplemental oxygen, digoxin), experts recommend PDE type 5 inhibitors (e.g., sildenafil, tadalafil) as one of several treatment options for the initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed; alternative therapies include endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan), soluble guanylate cyclase stimulators (e.g., riociguat), or prostanoids (e.g., IV epoprostenol; inhaled iloprost; inhaled, IV, or subcutaneous treprostinil. Current guidelines for the management of PAH state that an oral agent such as a PDE type 5 inhibitor generally is preferred for initial therapy in patients with NYHA/WHO functional class II symptoms, while those with more advanced NYHA/WHO functional class III disease may be treated with any currently approved PAH therapy; IV epoprostenol generally is recommended as the treatment of choice for patients with NYHA/WHO class IV PAH because of its demonstrated survival benefit. In general, choice of PAH therapy should be individualized, taking into account factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.

Efficacy of tadalafil for the treatment of PAH has been established in a 16-week randomized, double-blind, placebo-controlled study in patients 12 years of age or older with PAH (i.e., resting mean pulmonary artery pressure of 25 mm Hg or more with a pulmonary capillary wedge pressure of 15 mm Hg or less and pulmonary vascular resistance of 3 Wood units or more). The study population consisted principally of patients with idiopathic or familial pulmonary hypertension or PAH associated with connective tissue disease, with the majority having NYHA functional class II or III symptoms at baseline. Patients who were receiving stable dosages of bosentan prior to study entry (approximately 53%) were allowed to continue such therapy; however, other PAH-specific therapies such as prostacyclin or prostacyclin analogs were not permitted. Tadalafil was administered at a dosage of 2.5, 10, 20, or 40 mg once daily in this study. Treatment with tadalafil 40 mg once daily resulted in substantial improvements in exercise capacity, as measured by the change from baseline to 16 weeks in 6-minute walking distance (placebo-corrected mean increase of 33 m at 16 weeks); the improvement was apparent after 8 weeks of therapy and maintained throughout the duration of the study. Patients who were receiving tadalafil without concomitant bosentan therapy had greater improvements in walking distance than those receiving both drugs (44 versus 23 m, respectively). Although dose-related increases in walking distance were observed with other tadalafil dosages evaluated in this study, the improvements were not statistically significant. Time to clinical worsening (defined as death, lung or heart-lung transplantation, atrial septostomy, hospitalization for worsening PAH, initiation of new PAH therapy, or worsening functional WHO class) was substantially improved in patients receiving tadalafil 40 mg once daily; however, tadalafil did not affect WHO functional class.

Preliminary results of a long-term, uncontrolled extension of the placebo-controlled study suggest that improvements in exercise capacity are maintained with tadalafil for at least 10 months; a survival rate of 96.5 per 100 patient-years was reported in this extension study.

Current expert consensus guidelines recommend combination therapy in patients who have an inadequate response to initial monotherapy with a PAH-specific agent. Combination therapy with drugs that target the different pathophysiologic pathways in PAH may provide additive and/or synergistic benefits. These experts state that combined use of a PDE type 5 inhibitor with a prostanoid or an endothelin-receptor antagonist (added sequentially) may be considered; however, concomitant use of PDE type 5 inhibitors and riociguat is contraindicated because of the risk of hypotension.(See Drug Interactions: Riociguat.)

Dosage and Administration

Administration

Tadalafil is administered orally without regard to meals.

For the treatment of erectile dysfunction (ED), tadalafil may be administered as needed (just prior to sexual activity) or on a daily basis (at approximately the same time every day); the manufacturer of Cialis states that the entire dose should be taken and that tablets should not be split. In patients receiving as-needed therapy with tadalafil, sexual activity may be attempted at 0.5-36 hours after tadalafil administration. Because of the prolonged duration of action (up to 36 hours) of tadalafil, timing of administration relative to anticipated sexual activity is less important than with shorter-acting drugs for ED. In patients receiving once-daily tadalafil therapy for ED, sexual activity may be attempted at any time between doses.

When used for the treatment of benign prostatic hyperplasia (BPH) with or without coexisting ED, tadalafil is administered once daily at approximately the same time every day.

When used for the treatment of pulmonary arterial hypertension (PAH), tadalafil is administered once daily. The manufacturer of Adcirca recommends that the entire daily dosage be taken at one time and not as divided doses throughout the day.

Dosage

Erectile Dysfunction

As-Needed Therapy

For as-needed use in patients with erectile dysfunction, the usual initial oral dose of tadalafil is 10 mg taken just prior to (e.g., at least 0.5 hours before) anticipated sexual activity; optimal use should consider that improvement in erectile function may be maintained for up to 36 hours following a dose. Depending on effectiveness and tolerance, the dose subsequently may be increased to 20 mg or decreased to 5 mg. The maximum recommended dosing frequency is once daily for most patients.

In patients receiving concomitant therapy with human immunodeficiency virus (HIV) protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, lopinavir/ritonavir, ritonavir, saquinavir, tipranavir), an initial tadalafil dose of 5 mg is recommended; dosage should not exceed 10 mg once every 72 hours. In patients receiving concomitant therapy with potent inhibitors of cytochrome P-450 (CYP) 3A4 (e.g., ketoconazole, ritonavir), dosage of tadalafil should not exceed 10 mg once every 72 hours. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

If tadalafil is used concomitantly with an α-adrenergic blocking agent, the patient should be receiving a stable dosage of the α-blocking agent prior to initiating tadalafil, and tadalafil should be administered at the lowest recommended dosage.

Once-Daily Therapy

For once-daily use in patients with erectile dysfunction, the usual initial oral dosage of tadalafil is 2.5 mg once daily taken at approximately the same time every day without regard to timing of sexual activity. Depending on effectiveness and tolerance, dosage may be increased to 5 mg once daily.

In patients receiving concomitant therapy with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir), dosage of once-daily tadalafil should not exceed 2.5 mg once daily. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

If tadalafil is used concomitantly with an α-adrenergic blocking agent, the patient should be receiving a stable dosage of the α-blocking agent prior to initiating tadalafil, and tadalafil should be administered at the lowest recommended dosage.

Benign Prostatic Hyperplasia

The usual dosage of tadalafil in patients with BPH is 5 mg once daily taken at approximately the same time every day.

In patients receiving concomitant therapy with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir), dosage of tadalafil should not exceed 2.5 mg once daily. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Tadalafil should not be used in combination with an α-adrenergic blocking agent; in patients already receiving an α-adrenergic blocking agent, the α-blocker should be discontinued at least 1 day prior to initiating treatment with tadalafil.

Concomitant Benign Prostatic Hyperplasia and Erectile Dysfunction

When used for the treatment of both ED and BPH, the recommended dosage of tadalafil is 5 mg once daily at approximately the same time every day, without regard to timing of sexual activity.

In patients receiving concomitant therapy with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir), dosage of tadalafil should not exceed 2.5 mg once daily. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Tadalafil should not be used in combination with an α-adrenergic blocking agent; in patients already receiving an α-adrenergic blocking agent, the α-blocker should be discontinued at least 1 day prior to initiating treatment with tadalafil.

Pulmonary Arterial Hypertension

The recommended dosage of tadalafil for the treatment of PAH is 40 mg once daily.

Dosage adjustments are required when tadalafil is used in conjunction with ritonavir or other HIV protease inhibitors that are potent inhibitors of CYP3A. In patients who have been receiving ritonavir (or another HIV protease inhibitor) for at least 1 week, tadalafil should be initiated at a dosage of 20 mg once daily; dosage may then be increased to 40 mg once daily based on patient response and tolerance. In patients currently receiving tadalafil, the drug should be discontinued at least 24 hours prior to initiating therapy with an HIV protease inhibitor; after at least 1 week of therapy with the protease inhibitor, tadalafil can be resumed at a dosage of 20 mg once daily and then increased to 40 mg once daily based on patient response and tolerance. Use of tadalafil for the treatment of PAH should be avoided in patients receiving other potent inhibitors of CYP3A (e.g., itraconazole, ketoconazole).

Special Populations

Hepatic Impairment

Erectile Dysfunction

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B) receiving as-needed therapy for ED, the maximum dosage of tadalafil should not exceed 10 mg once daily. The manufacturer recommends that once-daily tadalafil therapy for ED be used with caution in patients with mild or moderate hepatic impairment because such therapy has not been extensively evaluated in this population.

The manufacturer states that use of tadalafil is not recommended in patients with severe hepatic impairment (Child-Pugh class C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Benign Prostatic Hyperplasia With or Without Erectile Dysfunction

The manufacturer recommends that once-daily tadalafil therapy be used with caution in patients with BPH (with or without ED) and mild or moderate hepatic impairment (Child-Pugh class A or B) because such therapy has not been extensively evaluated in such patients.

The manufacturer states that use of tadalafil is not recommended in patients with severe hepatic impairment (Child-Pugh class C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Pulmonary Arterial Hypertension

Because of limited clinical experience with tadalafil in patients with PAH and mild or moderate hepatic cirrhosis (Child-Pugh class A or B), the manufacturer recommends that a reduced initial dosage of 20 mg once daily be considered in such patients. The manufacturer states that use of tadalafil should be avoided in patients with severe hepatic cirrhosis (Child-Pugh class C).

Renal Impairment

Erectile Dysfunction

In patients with creatinine clearance of 30-50 mL/minute receiving as-needed therapy for ED, the recommended initial tadalafil dose is 5 mg administered no more frequently than once daily, and the maximum recommended dosage is 10 mg administered no more frequently than once every 48 hours. In patients with creatinine clearance of less than 30 mL/minute or those on hemodialysis receiving as-needed therapy for ED, the maximum recommended dosage of tadalafil is 5 mg administered no more frequently than once every 72 hours.

Once-daily tadalafil therapy is not recommended in patients with ED who have a creatinine clearance less than 30 mL/minute or in those on hemodialysis.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Benign Prostatic Hyperplasia With or Without Erectile Dysfunction

In patients with creatinine clearance of 30-50 mL/minute receiving once-daily tadalafil therapy for BPH alone or with coexisting ED, an initial tadalafil dosage of 2.5 mg once daily is recommended; dosage may be increased to 5 mg once daily based on patient response and tolerance. Once-daily tadalafil therapy is not recommended in patients with creatinine clearance less than 30 mL/minute or those on hemodialysis.

Pulmonary Arterial Hypertension

In patients with mild (creatinine clearance of 51-80 mL/minute) or moderate (creatinine clearance of 31-50 mL/minute) renal impairment, tadalafil should be initiated at a dosage of 20 mg once daily for the treatment of PAH; dosage may be increased to 40 mg once daily based on patient response and tolerance. The manufacturer states that use of tadalafil should be avoided in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and those on hemodialysis because of increased tadalafil exposure, limited clinical experience, and inability to influence clearance by dialysis.

Geriatric Patients

Tadalafil dosage adjustment based solely on age is not necessary in geriatric patients.

Cautions

Contraindications

Concomitant use of organic nitrates or nitrites, either regularly and/or intermittently. ( and see Cardiovascular Effects under Cautions: Warnings/Precautions.)

Concomitant use of riociguat. Known hypersensitivity to tadalafil or any ingredient in the formulation.

Warnings/Precautions

Patient Assessment

Prior to initiating tadalafil for the treatment of erectile dysfunction (ED) or benign prostatic hyperplasia (BPH), a thorough medical history and physical examination should be undertaken to determine potential underlying causes of the conditions and identify appropriate treatment options. In patients with BPH, clinicians should consider the possibility of other urologic conditions, including prostate cancer, that may cause similar symptoms to BPH.

Cardiovascular Effects

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported in temporal association with tadalafil during postmarketing experience. Most, but not all, of these events occurred in individuals with preexisting cardiovascular risk factors, and many occurred during or shortly after sexual activity. Since sexual activity is associated with a degree of cardiac risk, clinicians should assess the cardiovascular status of their patients prior to initiating tadalafil for the treatment of ED. Therapies for ED, including tadalafil, are not recommended for use in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

Tadalafil induces mild vasodilation, which generally results in only transient modest reductions in systolic and diastolic blood pressure; such blood pressure reductions usually are not clinically important when the drug is taken alone. However, additive blood pressure-lowering effects, possibly leading to symptomatic hypotension, may occur when tadalafil is used concomitantly with other vasodilating agents (e.g., α-adrenergic blocking agents or other antihypertensive drugs, alcohol, riociguat). (See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions: Warnings/Precautions and also see Drug Interactions: Antihypertensive Agents and see Drug Interactions: Alcohol.) Clinicians should consider whether patients with underlying cardiovascular disease could be adversely affected by tadalafil's vasodilatory activity. The risk of an undesired hypotensive or vasodilatory response is of particular concern in patients with left-ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure.

Tadalafil may potentiate the hypotensive effects of organic nitrates or nitric oxide donors, and concomitant use with these drugs is contraindicated.(See Cautions: Contraindications and also see Drug Interactions: Organic Nitrates and Nitric Oxide Donors.) If nitrate administration is deemed medically necessary for a life-threatening condition, at least 48 hours should have elapsed between tadalafil administration and nitrate use. In such circumstances nitrates should be administered only under close medical supervision with appropriate hemodynamic monitoring.

Patients who experience anginal chest pain following tadalafil administration should seek immediate medical attention. If chest pain occurs within 48 hours of taking tadalafil, use of non-nitrate antianginal agents (e.g., β-adrenergic blocking agents, calcium-channel blocking agents) should be considered.

Pulmonary vasodilators may worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Because clinical data on the use of tadalafil in patients with veno-occlusive disease currently are lacking, the manufacturer states that use of the drug in such patients is not recommended. The possibility of underlying PVOD should be considered in any patient exhibiting manifestations of pulmonary edema during tadalafil therapy.

Because of a lack of controlled clinical data establishing the safety and efficacy of tadalafil in the following subpopulations of patients with ED, the manufacturer does not recommend use of the drug in patients with a recent (within 90 days) myocardial infarction or stroke (within 6 months); those with uncontrolled arrhythmias, hypotension (systolic/diastolic blood pressure less than 90/50 mm Hg) or uncontrolled hypertension; those with heart failure (New York Heart Association [NYHA] class III or IV) in the previous 6 months; or those with unstable angina or angina occurring during sexual intercourse.

Tadalafil has not been systematically evaluated in clinical trials in patients with pulmonary arterial hypertension (PAH) who have clinically important mitral and/or aortic valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, substantial left ventricular dysfunction, life-threatening arrhythmias, symptomatic coronary artery disease, hypotension (blood pressure less than 90/50 mm Hg), or uncontrolled hypertension.

Ocular Effects

Nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely during postmarketing experience in temporal association with the use of all phosphodiesterase (PDE) type 5 inhibitors. Most, but not all, of these events occurred in individuals with preexisting vascular risk factors (e.g., age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, smoking) or anatomic abnormalities (e.g., low cup to disc ratio [''crowded disc'']). Observational data suggest that recent (within 1-4 days) use of a PDE type 5 inhibitor is associated with an approximate twofold increased risk of NAION; a causal relationship has not been established. The risk of NAION is greater in the second eye in patients who have already experienced NAION in one eye. ()

Use of tadalafil currently is not recommended in patients with hereditary degenerative retinal disorders, including retinitis pigmentosa; these patients were not studied in clinical trials.

Otic Effects

Sudden decrease or loss of hearing has been reported rarely during postmarketing experience with all PDE type 5 inhibitors, including tadalafil. At least 29 cases of such hearing impairment have occurred with or without concomitant vestibular manifestations (e.g., tinnitus, vertigo). Reported hearing loss was unilateral in most cases, and temporary in about one-third of the cases. Such otic effects were observed in a few patients during premarket testing of these drugs; deafness and tinnitus were reported in less than 2% of patients receiving tadalafil in controlled clinical trials. In one case, a 44-year-old man experienced permanent, bilateral sensorineural deafness 15 days after initiating therapy with another PDE type 5 inhibitor (sildenafil 50 mg daily); the patient did not have any prior or current risk factors for ototoxicity.

It is unclear whether these otic effects are directly related to PDE type 5 inhibitors or attributed to other factors (e.g., patient's underlying medical condition, concomitant use of other ototoxic drugs); however, a strong temporal relationship has been observed between the use of PDE type 5 inhibitors and the onset of hearing impairment in the reported cases.

Clinicians should advise patients about the possibility of hearing loss with tadalafil therapy and instruct patients to discontinue tadalafil and any other PDE type 5 inhibitor and seek medical attention immediately if sudden hearing loss or decreased hearing occurs.

Genitourinary Effects

Prolonged erections (exceeding 4 hours in duration) and priapism (painful erection exceeding 6 hours) have been observed with PDE type 5 inhibitors.

Priapism may result in penile tissue damage and permanent loss of potency if not treated immediately.(See Advice to Patients.) Tadalafil should be used with caution in patients with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease) and in those with conditions that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).

Concomitant Administration with Potent CYP3A4 Inhibitors or Inducers

Tadalafil is metabolized principally by cytochrome P-450 (CYP) 3A4; therefore, the potential for drug interactions with potent inhibitors or inducers of CYP3A4 should be considered. In some cases, dosage adjustments of tadalafil may be necessary, while in other cases, concomitant administration of tadalafil and a CYP3A4 inhibitor or inducer is not recommended. For additional details, see Dosage and Administration: Dosage and also see Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.

Concomitant Administration with α-Adrenergic Blocking Agents

Potentiation of hypotensive effects may occur in patients receiving concomitant therapy with α-adrenergic blocking agents due to additive vasodilatory effects. Patients who demonstrate hemodynamic instability during therapy with an α-adrenergic blocking agent alone are at increased risk for symptomatic hypotension (e.g., fainting) with concomitant use of a PDE type 5 inhibitor. Safety of such concomitant therapy also may be affected by intravascular volume depletion and use of additional antihypertensive agents.

Caution is advised when PDE type 5 inhibitors and α-adrenergic blocking agents are used concomitantly; in some cases, dosage adjustments are necessary, while in other cases, concomitant administration is not recommended.(See Drug Interactions: Antihypertensive Agents.)

Concomitant Use with other PDE Type 5 Inhibitors or ED Therapies

Data are lacking regarding the combined use of tadalafil and other PDE type 5 inhibitors or other therapies for ED; the manufacturer recommends that tadalafil not be used concomitantly with other PDE type 5 inhibitors.

Hematologic Effects

Tadalafil inhibits PDE type 5, which is found in platelets. Although tadalafil has not been shown to increase bleeding times in healthy individuals, data are lacking in patients with bleeding disorders or substantial, active peptic ulcer disease; the manufacturer recommends that tadalafil be used with caution in such patients after carefully weighing the risks versus benefits of therapy.

Specific Populations

Pregnancy

Category B. The manufacturer of Cialis states that the drug is not indicated for use in women.

Lactation

Tadalafil is excreted into milk in rats. It is not known if tadalafil is excreted into milk in humans. The manufacturer of Cialis states that the drug is not indicated for use in women. The manufacturer of Adcirca advises caution if the drug is used in nursing women.

Pediatric Use

Use of tadalafil has not been evaluated for the treatment of BPH or ED in individuals younger than 18 years of age, and the drug is not indicated for such use in children or neonates.

The manufacturer states that safety and efficacy of tadalafil have not been established in pediatric patients with PAH; however, PDE type 5 inhibitors have been used in a limited number of pediatric patients with PAH and are recommended by some experts as a potential treatment option for children with severe PAH.

Geriatric Use

Safety and efficacy of tadalafil in geriatric patients (older than 65 years of age) are similar to those in younger patients. Substantial age-related differences in pharmacokinetics of tadalafil were not observed between patients 65 years of age or older and younger individuals; therefore, the manufacturer states that modification of tadalafil dosage is not needed in geriatric patients solely on the basis of age. However, the possibility of greater sensitivity in some geriatric individuals should be considered.

Hepatic Impairment

Insufficient data are available in patients with severe hepatic impairment (Child-Pugh class C), and use of tadalafil once daily or on an as-needed basis for any indication in such patients currently is not recommended by the manufacturer. Although exposure to tadalafil (10 mg) was not appreciably altered by mild or moderate hepatic impairment in a study of individuals with stable liver cirrhosis, the manufacturer states that data are limited in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) receiving once-daily therapy with the drug for ED, BPH, or for both conditions; caution is advised in such patients. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment receiving as-needed tadalafil therapy for ED and in patients with mild to moderate hepatic impairment receiving tadalafil for the treatment of PAH.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

Renal Impairment

Increased systemic exposure to tadalafil is observed in patients with mild to moderate (creatinine clearance of 30-80 mL/minute) and severe (creatinine clearance of less than 30 mL/minute and on hemodialysis) renal insufficiency, resulting in increased adverse effects (e.g., back pain). Use of once-daily tadalafil therapy is not recommended for any indication in patients with severe renal impairment. Dosage adjustments are recommended in patients with mild or moderate renal impairment receiving once-daily tadalafil therapy for the treatment of PAH. Dosage adjustments also are recommended in patients with moderate to severe renal impairment receiving as-needed tadalafil therapy for ED. (See Renal Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

Common adverse effects reported in at least 2% of patients receiving tadalafil for the treatment of ED and/or BPH include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and limb pain.

Common adverse effects reported in at least 9% of patients receiving tadalafil 40 mg daily for the treatment of PAH (and at least 2% more frequently than with placebo) are headache, myalgia, nasopharyngitis, flushing, respiratory tract infection (upper and lower), pain in extremity, nausea, back pain, dyspepsia, and nasal congestion (including sinus congestion).

Drug Interactions

Antihypertensive Agents

A pharmacodynamic interaction (potentiation of hypotensive effect) has been observed with concurrent use of tadalafil and certain antihypertensive agents (i.e., α-adrenergic blocking agents, amlodipine, angiotensin II receptor antagonists, bendroflumethiazide, enalapril, metoprolol). Following concurrent administration of metoprolol, enalapril, amlodipine, or bendroflumethiazide, tadalafil reduced blood pressure marginally compared with placebo. Studies suggest that a clinically important decrease in blood pressure is more likely to occur with concurrent use of tadalafil and an α-adrenergic blocking agent. When used for the treatment of erectile dysfunction (ED), tadalafil should be initiated at the lowest recommended dosage in patients receiving an α-adrenergic blocking agent; conversely, in patients already receiving an optimized dosage of tadalafil for ED, therapy with an α-adrenergic blocking agent should be initiated at the lowest dosage of that drug. A stepwise increase in dosage of the α-adrenergic blocking agent may be associated with further lowering of blood pressure in patients receiving a phosphodiesterase (PDE) type 5 inhibitor (e.g., tadalafil).(See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions: Warnings/Precautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions are likely with drugs that are potent inhibitors (e.g., ketoconazole, ritonavir) or inducers (e.g., rifampin) of cytochrome P-450 (CYP) 3A4, and may increase the risk of PDE type 5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, priapism). In some cases, the manufacturer recommends dosage adjustments during concomitant therapy, while in other cases, concomitant use is not recommended.(See Dosage and Administration: Dosage.)

Pharmacokinetic interaction (increased tadalafil area under the plasma concentration-time curve [AUC]) has been observed with certain potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). Although specific drug interaction studies have not been conducted, there is a potential for similar pharmacokinetic interactions when tadalafil is given with other CYP3A inhibitors such as erythromycin, itraconazole, grapefruit juice, or human immunodeficiency virus (HIV) protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, lopinavir/ritonavir, ritonavir, saquinavir, tipranavir).

Pharmacokinetic interaction (decreased tadalafil exposure) has been observed following concomitant administration of tadalafil and certain CYP3A4 inducers (e.g., bosentan, rifampin). Although not specifically studied, decreased tadalafil exposure also is likely during concurrent therapy with other CYP3A4 inducers, such as carbamazepine, phenytoin, or phenobarbital. Such reduced drug exposure can be anticipated to decrease the effectiveness of once-daily tadalafil therapy; however, the magnitude of such decreased effectiveness with concurrent CYP3A4 inducers is unknown.

Although tadalafil is a substrate for and is metabolized by CYP3A4, tadalafil does not appear to induce or inhibit the clearance of other drugs metabolized by CYP isoforms 1A2 (e.g., theophylline), 3A4 (e.g., midazolam, lovastatin), 2C9 (e.g., S- or R-warfarin), 2C19, 2D6, or 2E1.

Endothelin Receptor Antagonists

No clinically important pharmacokinetic interactions were observed in a study of healthy adults receiving tadalafil and ambrisentan concomitantly; no dosage adjustments are necessary.

Concomitant use of tadalafil and bosentan, a moderate inducer of CYP3A, decreased systemic exposure and peak plasma concentrations of tadalafil by 42 and 27%, respectively; the effects of tadalafil on bosentan pharmacokinetics were not considered to be clinically important.

Organic Nitrates and Nitric Oxide Donors

Potential pharmacodynamic interaction (increased hypotensive effect) when tadalafil is used with organic nitrates, including with recreational use of inhaled nitrites (amyl nitrite, ''poppers''); concomitant use is contraindicated.(See Cautions: Contraindications.) If nitrate administration is deemed medically necessary for a life-threatening condition, at least 48 hours should have elapsed between tadalafil administration and nitrate use; in such situations, nitrates should be administered with caution, close medical supervision, and hemodynamic monitoring.(See Cardiovascular Effects under Cautions: Warnings/Precautions.) Additive hemodynamic effects have been observed when sublingual nitroglycerin was administered 2, 4, 8, and 24 hours following a tadalafil dose, with most hemodynamic effects no longer detectable after 48 hours.

Alcohol

Alcohol and PDE type 5 inhibitors are both mild systemic vasodilators. Pharmacodynamic effects (orthostatic hypotension manifested by increased heart rate, decreased standing blood pressure, dizziness, headache) have been observed when tadalafil was administered with alcohol (0.7 g/kg, the equivalent to 180 mL of 80-proof vodka in an 80-kg man) ingested over less than 10 minutes. Such effects were not observed, or occurred with similar frequency to ingestion of alcohol alone, when tadalafil was given concurrently with a lower dose of alcohol (0.6 g/kg, or the equivalent of 118 mL of 80-proof vodka ingested over less than 10 minutes).

Alcohol should not be consumed excessively (e.g., 5 glasses of wine or 5 shots of whiskey) when taking tadalafil.

No clinically meaningful effects on the pharmacokinetics (effects on plasma drug or alcohol concentrations) of either tadalafil or alcohol have been observed.

Antacids

Concomitant administration of tadalafil and an antacid containing magnesium hydroxide and aluminum hydroxide reduced the rate, but not extent, of tadalafil absorption.

Aspirin

Tadalafil does not increase bleeding time in healthy individuals, and concomitant administration of tadalafil and aspirin did not prolong bleeding time relative to aspirin administration alone.

Digoxin

No clinically meaningful effects on steady-state pharmacokinetics of digoxin have been observed with concomitant administration of tadalafil.

Etravirine

Decreased tadalafil concentrations are possible when used concomitantly with etravirine; tadalafil dosage increase may be necessary depending on clinical effect.

Ketoconazole

Systemic exposure and peak plasma concentrations of tadalafil were increased by 107-312% and 15-22%, respectively, with concomitant administration of ketoconazole (a potent inhibitor of CYP3A). The manufacturer states that tadalafil (Adcirca)should be avoided in patients receiving potent inhibitors of CYP3A such as ketoconazole. If ketoconazole is used in a patient receiving tadalafil for ED and/or BPH, tadalafil dosage adjustments are necessary. (See Dosage: Erectile Dysfunction and see Dosage: Benign Prostatic Hyperplasia under Dosage and Administration.)

Lovastatin

Systemic exposure of lovastatin was not substantially affected by concomitant use of tadalafil.

Midazolam

Systemic exposure of midazolam was not substantially affected by concomitant use of tadalafil.

Nizatidine

No clinically meaningful effects on the pharmacokinetics of tadalafil have been observed with concomitant administration of nizatidine.

Oral Contraceptives

Concomitant use of tadalafil and an oral contraceptive resulted in increased systemic exposure and peak plasma concentrations of the ethinyl estradiol component by 26 and 70%, respectively; however, no substantial effects on the pharmacokinetics of levonorgestrel were observed.

Rifampin

Coadministration of rifampin, a CYP3A inducer, decreased systemic exposure and peak plasma concentrations of tadalafil by 88 and 46%, respectively. The manufacturer states that use of tadalafil (Adcirca) should be avoided in patients taking potent inducers of CYP3A (e.g., rifampin) chronically.

Riociguat

Additive hypotensive effects can occur if PDE type 5 inhibitors are used concomitantly with riociguat. Concomitant use of tadalafil and riociguat is contraindicated.

Ritonavir

Ritonavir has an initial inhibitory effect on CYP3A, followed by a late inducing effect on the isoenzyme. Concomitant use of tadalafil and ritonavir (200 mg twice daily) increased systemic exposure of tadalafil by more than twofold after the first concurrent dose; however, no change in tadalafil exposure was observed at steady-state concentrations of ritonavir. Tadalafil had no substantial effect on the pharmacokinetics of ritonavir. Tadalafil dosage reduction is required when used concomitantly with ritonavir.(See Dosage and Administration: Dosage.)

Theophylline

Pharmacodynamic interaction (small augmentation of theophylline-induced increase in heart rate) has been observed with concurrent use of tadalafil and theophylline; however, tadalafil had no substantial effect on the pharmacokinetics of theophylline.

Warfarin

No clinically meaningful effects on pharmacokinetics (systemic exposure) and pharmacodynamics (i.e., changes in prothrombin time) of warfarin have been observed with concomitant tadalafil administration.

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