Brand names: Cialis, Adcirca
Drug class: Phosphodiesterase Type 5 Inhibitors
VA class: GU900
Chemical name: (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione
Molecular formula: C₂₂H₁₉N₃O₄
CAS number: 171596-29-5

Medically reviewed by Drugs.com on Mar 29, 2023. Written by ASHP.

Introduction

Vasodilator; a selective phosphodiesterase (PDE) type 5 inhibitor.

Uses for Tadalafil

Erectile Dysfunction

To facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence).

May be used as needed (on demand) or on a daily basis (without regard to timing of sexual activity).

Some experts recommend a selective PDE type 5 inhibitor as first-line therapy for ED unless contraindicated. Evidence currently insufficient to support superiority of one selective PDE type 5 inhibitor over another.

Benign Prostatic Hyperplasia

Symptomatic management (e.g., to improve lower urinary tract symptoms) of benign prostatic hyperplasia (BPH, benign prostatic hypertrophy).

Not recommended for use in combination with an α-adrenergic blocking agent (e.g., doxazosin, terazosin); inadequate data and potential for additive hypotensive effects. (See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions.)

Concomitant ED and BPH

Treatment of both ED and symptomatic BPH in men with such coexisting conditions.

Pulmonary Arterial Hypertension (PAH)

Symptomatic management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity.

Efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic, heritable, or associated with connective tissue diseases).

Recommended as one of several treatment options for 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 failed. Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid or endothelin-receptor antagonist (added sequentially). By targeting different pathophysiologic pathways of the disease, such combination therapy may provide additive and/or synergistic benefits.

Tadalafil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.

May be administered as-needed (just prior to [e.g., ≥0.5 hours before] anticipated sexual activity) or on a daily basis (at approximately the same time every day) for treatment of ED; take entire dose and do not split tablets. Because of prolonged duration of action (up to 36 hours), timing of administration relative to anticipated sexual activity is less important than with relatively short-acting drugs for ED.

Administer as a once-daily dose at approximately the same time every day in patients with BPH with or without coexisting ED.

When used for the treatment of PAH, administer as a once-daily dosage. Take entire dose at one time and not as divided doses throughout the day.

Dosage

Adults

ED

Oral

As-needed therapy: Usual initial dosage is 10 mg just prior to anticipated sexual activity. (See Oral Administration under Dosage and Administration.) Depending on effectiveness and tolerance, may increase dose to 20 mg or decrease to 5 mg. Concomitant use with HIV protease inhibitors or with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) requires dosage adjustment. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Maximum recommended dosing frequency is once daily for most patients.

Once-daily therapy: Initially, 2.5 mg once daily. Depending on effectiveness and tolerance, may increase dosage to 5 mg once daily.

Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) requires dosage adjustment. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

BPH

Oral

5 mg once daily.

Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) requires dosage adjustment. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Concomitant ED and BPH

Oral

5 mg once daily.

Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) requires dosage adjustment. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

PAH

Oral

40 mg once daily.

Concomitant use with ritonavir or other HIV protease inhibitors that are potent inhibitors of CYP3A requires dosage adjustment. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Special Populations

Hepatic Impairment

As-needed use for ED: In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), maximum dosage is 10 mg once daily.

Once-daily use for BPH and/or ED: Use with caution in patients with mild or moderate hepatic impairment.

Treatment of PAH: Consider a reduced initial dosage of 20 mg once daily in patients with mild or moderate hepatic cirrhosis (Child-Pugh class A or B).

Use not recommended in any patient with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Cautions.)

Renal Impairment

As-needed use for ED: For patients with Cl_cr 30–50 mL/minute, reduce initial dosage to 5 mg administered no more frequently than once daily; maximum dosage 10 mg no more frequently than once every 48 hours. For patients with Cl_cr<30 mL/minute or those undergoing hemodialysis, maximum dosage 5 mg no more frequently than once every 72 hours.

Once-daily use for ED: Dosage adjustments not necessary in patients with Cl_cr ≥30 mL/minute. Use not recommended in patients with Cl_cr <30 mL/minute or those on hemodialysis.

Once-daily use for BPH with or without ED: For Cl_cr 30–50 mL/minute, initial dosage of 2.5 mg once daily recommended; may increase to 5 mg once daily based on patient response and tolerance. Use not recommended in patients with Cl_cr <30 mL/minute or those on hemodialysis.

Treatment of PAH: Reduce initial dosage to 20 mg once daily in patients with mild (Cl_cr 51–80 mL/minute) or moderate (Cl_cr 31–50 mL/minute) renal impairment; may increase to 40 mg once daily based on patient response and tolerance. Avoid use in severe renal impairment (Cl_cr <30 mL/minute and those on hemodialysis).

Geriatric Patients

No dosage adjustments necessary based solely on age.

Cautions for Tadalafil

Contraindications

• Known hypersensitivity to tadalafil or any ingredient in the formulation.

• Concomitant use of any form of organic nitrates (e.g., nitrates, nitrites, or nitric oxide donors). Concomitant use of riociguat. (See Specific Drugs and Foods under Interactions.)

Warnings/Precautions

Patient Assessment

Thorough medical history and physical examination is recommended to determine potential underlying causes and identify appropriate treatment options for ED and/or BPH. Prior to initiating therapy in patients with BPH, consider possibility of other urologic conditions, including prostate cancer, that may cause similar symptoms.

Cardiovascular Effects

Serious, potentially fatal cardiovascular events reported. Most, but not all, of these events occurred in individuals with preexisting cardiovascular risk factors.

Safety and efficacy for treatment of ED not established and use not recommended in patients with a recent MI (within 90 days) or stroke (within 6 months); uncontrolled arrhythmias, hypotension (<90/50 mm Hg systolic/diastolic BP) or uncontrolled hypertension; heart failure (>NYHA class II) in the previous 6 months; or those with unstable angina or angina occurring during sexual intercourse. Also not evaluated in patients with 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 (BP <90/50 mm Hg), or uncontrolled hypertension.

Possible hypotension, particularly in patients with left-ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and in patients with severely impaired autonomic control of blood pressure. Additive BP-lowering effects may occur when used concomitantly with other vasodilating agents (e.g., α-adrenergic blocking agents or other antihypertensive drugs, alcohol, riociguat). (See Specific Drugs and Foods under Interactions.)

Potentiation of hypotensive effect with organic nitrates, which may result in life-threatening hypotension and/or hemodynamic compromise; concomitant use contraindicated. (See Specific Drugs and Foods under Interactions.)

Consider whether patients with underlying cardiovascular disease could be adversely affected by tadalafil’s vasodilatory activity, especially in combination with sexual activity.

Use not recommended in patients with pulmonary veno-occlusive disease (PVOD). Current lack of data on use of tadalafil in such patients. If pulmonary edema occurs, consider possibility of PVOD.

Ocular Effects

Nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, reported rarely during postmarketing experience in temporal association with use of all PDE type 5 inhibitors. Potential increased risk of NAION in the second eye in patients who have already experienced NAION in one eye.

Possible visual disturbances (e.g., blurred vision, changes in color vision, conjunctivitis, eye pain, increased lacrimation, periorbital edema).

Use not recommended in patients with hereditary degenerative retinal disorders, including retinitis pigmentosa.

Otic Effects

Sudden decrease or loss of hearing reported rarely during postmarketing experience with all PDE type 5 inhibitors. Adverse otic effects (e.g., vertigo, tinnitus) also observed in a few patients in controlled clinical trials of tadalafil. In at least 1 case, permanent, bilateral sensorineural deafness occurred.

Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g., patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed.

Priapism

Possible prolonged erections (>4 hours) and priapism (painful erection >6 hours).

May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately. Use with caution in patients with conditions that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia) and in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).

Hematologic Effects

Tadalafil inhibits PDE type 5, which is found in platelets. Although increase in bleeding time not observed in healthy individuals, manufacturer recommends caution in patients with bleeding disorders or substantial, active peptic ulcers; carefully weigh risks versus benefits of therapy.

Concomitant Use with Other PDE Type 5 Inhibitors or ED Therapies

Safety and efficacy not established for use in combination with other PDE type 5 inhibitors or other treatments for ED; do not use concomitantly with other PDE type 5 inhibitors.

Concomitant Administration with α-Adrenergic Blocking Agents

Use with caution in patients receiving α-adrenergic blocking agents; possible potentiation of hypotensive effects due to additive vasodilatory action. In some cases, dosage adjustments are necessary, while in other cases, concomitant administration not recommended. (See Specific Drugs and Foods under Interactions.) Safety of concomitant therapy also may be affected by intravascular volume depletion and use of additional antihypertensive agents.

Concomitant Administration with Potent CYP3A4 Inhibitors or Inducers

Consider potential for increased or decreased tadalafil concentrations when used concomitantly with potent inhibitors or inducers of CYP3A4; in some cases, dosage adjustments may be necessary, while in other cases, concomitant administration not recommended. (See Specific Drugs and Foods under Interactions.)

Specific Populations

Pregnancy

Category B. Tadalafil (Cialis) not indicated for use in women.

Lactation

Excreted into milk in rats. Not known if tadalafil is excreted into milk in humans. Tadalafil (Cialis) not indicated for use in women. Use caution if tadalafil (Adcirca) is used in nursing women.

Pediatric Use

Safety and efficacy for the treatment of BPH or ED not established in patients <18 years of age and not indicated for such use in children or neonates.

Manufacturer states that safety and efficacy for treatment of PAH not established in pediatric patients; however, PDE type 5 inhibitors have been used in a limited number of children with PAH.

Geriatric Use

Safety and efficacy in those >65 years of age is similar to that in younger patients. Possibility exists of greater sensitivity to the drug in some geriatric individuals. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Insufficient experience in patients with severe hepatic impairment (Child-Pugh C); use not recommended.

Data limited in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) receiving once-daily tadalafil for ED, BPH, or for both conditions; caution advised in such patients. Dosage adjustments recommended in patients with mild or moderate hepatic impairment receiving as-needed therapy for ED or once-daily therapy for PAH. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use of once-daily tadalafil not recommended in any patient with severe renal impairment.

Dosage adjustments recommended in patients with mild or moderate renal impairment receiving once-daily tadalafil for PAH. Dosage adjustments also recommended in patients with moderate to severe renal impairment receiving as-needed tadalafil for ED. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

ED and/or BPH: Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, limb pain.

PAH: Headache, myalgia, nasopharyngitis, flushing, upper/lower respiratory tract infection, pain in extremity, nausea, back pain, dyspepsia, nasal/sinus congestion.

Interactions for Tadalafil

Metabolized principally by CYP3A4. Does not appear to induce or inhibit the clearance of other drugs metabolized by CYP isoforms 1A2, 3A4, 2C9, 2C19, 2D6, or 2E1.

Drugs Affecting Hepatic or Metabolized by Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased tadalafil exposure) and increased risk of PDE type 5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, priapism). When used concomitantly in patients with BPH and/or ED, do not exceed tadalafil dosage of 2.5 mg once daily; avoid concomitant use of tadalafil (Adcirca) with potent CYP3A inhibitors (with exception of ritonavir). (See Specific Drugs and Foods under Interactions.)

Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased tadalafil exposure) and possible decreased efficacy of tadalafil. No dosage adjustment warranted in patients with BPH and/or ED; avoid concomitant use of tadalafil (Adcirca) with potent CYP3A inducers.

Specific Drugs and Foods

Tadalafil Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations usually attained within 0.5–6 hours.

Onset

Following a single oral dose, effects were obtained within 30 minutes.

Duration

Improved erection up to 36 hours.

Food

Food does not appear to affect absorption.

Distribution

Extent

Distributed into tissues.

Plasma Protein Binding

Approximately 94%.

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4, to inactive metabolites.

Elimination Route

Excreted principally as metabolites in the feces (61%) and urine (36%). Not appreciably removed by hemodialysis.

Half-life

17.5 hours.

Special Populations

Clearance reduced in patients ≥65 years of age compared with younger adults.

In patients with mild (Cl_cr 51-80 mL/minute) or moderate (Cl_cr 31-50 mL/minute) renal impairment, clearance was reduced, resulting in a twofold increase in AUC compared to healthy adults. In patients with end-stage renal disease on hemodialysis, clearance was reduced, resulting in a twofold to fourfold increase in AUC compared to healthy adults.

In patients with diabetes mellitus, AUC and peak plasma concentrations are decreased compared with healthy individuals.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

• Selective inhibitor of phosphodiesterases (PDEs), with the greatest selectivity for PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis.

• PDE type 5 also found in smooth muscle of the prostate and bladder, as well as in vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.

• Enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP, resulting in vascular relaxation.

• Potentiates accumulation of cGMP only when cGMP production in the penis is increased by sexual arousal. No effect on erectile function in the absence of sexual stimulation.

• Exact mechanism of action in reducing symptoms of BPH not established, but may be related to smooth muscle relaxation and increased vascular perfusion of the lower urinary tract (i.e., bladder, prostate).

• Modest peripheral vasodilation at usual dosages.

• Although pharmacologically related to other PDE type 5 inhibitors (e.g., sildenafil, vardenafil), tadalafil has a longer elimination half-life and longer duration of action. Also exhibits less affinity for PDE type 6 receptor involved in phototransduction in the retina. No effects on intraocular pressure or pupillometry; changes in color vision reported rarely.

Advice to Patients

• Importance of providing a copy of the manufacturer’s patient information.

• Provide instructions regarding proper administration for optimal use. Importance of taking the drug exactly as prescribed and not exceeding recommended doses or frequency of use.

• Importance of informing clinician of the presence of risk factors for cardiovascular disease prior to initiating any treatment for ED.

• Possibility of visual disturbances (e.g., bluish tinge to objects, difficulty distinguishing between blue and green, visual field changes). Potential for sudden vision loss or decreased vision, which may be a sign of NAION. Advise patients to discontinue tadalafil or other PDE type 5 inhibitors and seek immediate medical attention if sudden vision loss or decreased vision occurs in one or both eyes.

• Risk of sudden hearing impairment; advise patients to discontinue tadalafil or other PDE type 5 inhibitors and seek immediate medical attention if sudden hearing loss or decreased hearing occurs.

• Importance of informing patients of the potential for life-threatening hypotension and/or hemodynamic compromise with concurrent use of organic nitrates and nitrites in any form, including the recreational use of inhaled nitrites (“poppers”). Importance of contacting a clinician if anginal pain occurs after using tadalafil.

• Importance of using caution during concurrent use of α-adrenergic blocking agents (or other antihypertensive drugs) because of the potential for hypotension, dizziness, or fainting.

• Importance of informing patients of potential for interactions with concurrent drugs (e.g., nitrates, α-adrenergic blocking agents, antihypertensive agents, potent inhibitors of CYP3A4 [e.g., ritonavir, ketoconazole]) or alcohol.

• Importance of not using other PDE type 5 inhibitors during tadalafil therapy.

• Importance of refraining from further activity and contacting a clinician if cardiovascular symptoms (e.g., anginal pain, dizziness) occur upon initiation of sexual activity.

• Importance of seeking immediate medical attention if an erection persists >4 hours or is painful.

• Potential for transmission of sexually transmitted diseases (e.g., HIV) and the need to use protective measures to guard against such transmission.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption, as well as any concomitant illnesses. Importance of limiting intake of alcohol-containing beverages or products.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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