Drug class: Phosphodiesterase type 5 inhibitors

Introduction

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

Uses for Tadalafil (Pulmonary Hypertension)

Pulmonary Arterial Hypertension (PAH)

Symptomatic management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening in adults.

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

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with PAH-targeted medications. PDE type 5 inhibitors such as tadalafil are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Tadalafil (Pulmonary Hypertension) Dosage and Administration

Administration

Commercially available as tablets or oral suspension.

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.

Tablets

Administer orally once daily without regard to meals.

Oral Suspension

Administer orally once daily without regard to meals.

Shake the suspension well for 30 seconds prior to use.

Dosage

Adults

PAH

Oral

40 mg (two 20-mg tablets or 10 mL of the oral suspension) once daily.

Concomitant use with ritonavir or other HIV protease inhibitors that are potent inhibitors of CYP3A requires dosage adjustment.

Patients currently receiving ritonavir (or another HIV protease inhibitor) for ≥1 week: Initiate tadalafil 20 mg once daily; increase to 40 mg once daily based on patient response and tolerance.

Patients currently receiving tadalafil: Discontinue tadalafil ≥24 hours prior to initiating ritonavir or HIV protease inhibitor; after ≥1 week, resume tadalafil 20 mg once daily and increase to 40 mg once daily based on patient response and tolerance.

Special Populations

Hepatic Impairment

Consider 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 patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

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.

Related/similar drugs

tamsulosin, finasteride, sildenafil, tadalafil, Flomax, prazosin, Cialis

Cautions for Tadalafil (Pulmonary Hypertension)

Contraindications

• Concomitant use of organic nitrates or nitrites, either regularly or intermittently. Do not use nitrates within 48 hours of the last tadalafil dose.

• Concomitant use of guanylate cyclase stimulators (e.g., riociguat).

• Hypersensitivity to tadalafil or any ingredient in the formulation; Stevens-Johnson syndrome and exfoliative dermatitis have been reported.

Warnings/Precautions

Hypotension

Transient BP decreases reported.

Consider whether patients with underlying cardiovascular disease could be adversely affected by tadalafil’s vasodilatory activity.

Patients with preexisting hypotension, left-ventricular outflow obstruction, or autonomic dysfunction may be particularly sensitive to vasodilators.

Worsening Pulmonary Vascular Occlusive Disease

Use not recommended in patients with pulmonary veno-occlusive disease (PVOD). If pulmonary edema occurs, consider possibility of PVOD.

Vision Loss

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, reported rarely during postmarketing in temporal association with use of PDE type 5 inhibitors. Risk is increased in patients who have already experienced NAION in one eye.

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

Hearing Loss

Sudden decrease or loss of hearing, with or without tinnitus or dizziness, reported.

Unclear whether such effects are directly related to PDE type 5 inhibitors or to other factors.

Concomitant Use with Other PDE Type 5 Inhibitors

Safety and efficacy not established for use in combination with other PDE type 5 inhibitors; do not use concomitantly with Cialis, Alyq, Tadliq, or other PDE type 5 inhibitors.

Prolonged Erection

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).

Specific Populations

Pregnancy

Limited data in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

No adverse developmental effects observed in animal studies.

Pregnant women with untreated PAH at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Experts recommend avoiding pregnancy in patients with PAH.

Lactation

Excreted into milk in rats. Not known whether drug is distributed into milk in humans, affects the breastfed child, or affects milk production.

Consider the benefits of breastfeeding along with the mother's clinical need for tadalafil and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

Decreased spermatogenesis observed in dogs and humans. No studies evaluating effect on fertility in men or women.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Safety in patients >65 and ≥75 years of age is similar to that in younger patients. Possibility exists of greater sensitivity to the drug in some geriatric individuals.

Hepatic Impairment

Insufficient experience in patients with severe hepatic impairment (Child-Pugh class C); avoid use.

Data limited in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); consider a starting dosage of tadalafil 20 mg once daily.

Renal Impairment

Avoid use in patients with severe renal impairment (Cl_cr ≤30 mL/minute) and those on hemodialysis.

Mild or moderate renal impairment (Cl_cr 31-80 mL/minute): Initial dosage 20 mg once daily; may increase to 40 mg once daily based on patient response and tolerance.

Common Adverse Effects

Headache.

Drug Interactions

Metabolized principally by CYP3A4. Does not appear to induce or inhibit clearance of other drugs metabolized by P-glycoprotein (P-gp), organic anion transport protein (OATP), or CYP isoforms.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased tadalafil exposure). Avoid concomitant use of tadalafil with potent CYP3A4 inhibitors (with exception of ritonavir).

Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased tadalafil exposure) and possible decreased efficacy of tadalafil. Avoid concomitant use of tadalafil with potent CYP3A inducers.

Drugs Affecting or Affected by Transport Systems

Substrates of P-gp: No clinically meaningful effects on steady-state pharmacokinetics of the P-gp substrate have been observed.

Specific Drugs and Foods

Tadalafil (Pulmonary Hypertension) Pharmacokinetics

Absorption

Bioavailability

Absorbed following oral administration; absolute bioavailability unknown.

Peak plasma concentrations usually attained within 2–8 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

15 hours in healthy subjects; 35 hours in patients with PAH not receiving concomitant bosentan.

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_cr31-50 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 mild or moderate hepatic impairment (Child-Pugh class A or class B), AUC was comparable to healthy subjects. Insufficient data are available for those with severe hepatic impairment (Child-Pugh class C).

In male patients with diabetes mellitus, AUC and peak plasma concentration reduced.

No clinically relevant differences in exposure to tadalafil between males or females or among different ethnic groups.

Stability

Storage

Oral

Tablets

20-25°C (excursions permitted to 15–30°C).

Oral Suspension

20–25°C (excursions permitted to 15–30°C); dispense in a tight container.

Actions

• Selective inhibitor of PDEs, with greatest selectivity for PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the vascular smooth muscle, smooth muscle of the pulmonary vasculature, prostate, bladder, and corpora cavernosa of the penis.

• Enhances effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP, resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Advice to Patients

• Advise patients to read the manufacturer's patient information.

• Instruct patients to avoid contraindicated medications such as regular and/or intermittent use of organic nitrates, organic nitrites (e.g., “poppers”), and guanylate cyclase stimulators (e.g., riociguat).

• Inform patients that tadalafil is marketed for erectile dysfunction (Cialis and generic equivalents), benign prostatic hyperplasia (Cialis and generic equivalents, Entadfi), and PAH (Adcirca and generic equivalents, Alyq, Tadliq); advise patients not to take a combination of these agents or other PDE type 5 inhibitors.

• 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. Such an event may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision.

• Risk of sudden hearing impairment; advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking tadalafil. These events may be accompanied by tinnitus and dizziness.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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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