Introduction
Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor used primarily for the treatment of erectile dysfunction and benign prostatic hyperplasia. First approved by the FDA in 2003, it has become a widely prescribed medication due to its prolonged duration of action compared to other PDE5 inhibitors. Tadalafil represents a significant advancement in the management of sexual dysfunction and lower urinary tract symptoms.
Mechanism of Action
Tadalafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme that degrades cyclic guanosine monophosphate (cGMP). During sexual stimulation, nitric oxide release increases cGMP levels, causing smooth muscle relaxation in the corpus cavernosum and subsequent penile erection. By inhibiting PDE5, tadalafil enhances the effect of nitric oxide, increasing cGMP levels and facilitating erection. For benign prostatic hyperplasia, tadalafil relaxes smooth muscle in the prostate and bladder through a similar mechanism, improving urinary flow.
Indications
- Erectile dysfunction (ED)
- Benign prostatic hyperplasia (BPH) with associated lower urinary tract symptoms
- Pulmonary arterial hypertension (PAH) (under the brand name Adcirca®)
- Combination therapy for both ED and BPH when both conditions coexist
Dosage and Administration
Erectile Dysfunction:- As-needed dosing: 10 mg taken at least 30 minutes before sexual activity (may be increased to 20 mg or decreased to 5 mg based on efficacy/tolerability)
- Once-daily dosing: 2.5 mg or 5 mg taken at approximately the same time each day
- 5 mg once daily taken at approximately the same time each day
- Renal impairment: Maximum dose 10 mg for as-needed ED dosing (CrCl 30-50 mL/min); not recommended for CrCl <30 mL/min or hemodialysis
- Hepatic impairment: Maximum dose 10 mg for as-needed ED dosing (Child-Pugh A or B); not recommended for Child-Pugh C
- Elderly: Consider lower starting doses due to potential increased exposure
- Concomitant medications: Dose adjustments required with certain CYP3A4 inhibitors
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 2 hours (range 0.5-6 hours); bioavailability approximately 36% Distribution: Mean apparent volume of distribution 63 L; extensively bound to plasma proteins (94%) Metabolism: Primarily metabolized by CYP3A4 to catechol metabolites; metabolites undergo extensive glucuronidation Elimination: Mean elimination half-life 17.5 hours; primarily excreted in feces (61%) and urine (36%)Contraindications
- Concomitant use of organic nitrates or nitric oxide donors
- History of serious hypersensitivity reaction to tadalafil
- Concomitant use with guanylate cyclase stimulators (riociguat)
- Patients with cardiac conditions where sexual activity is inadvisable
Warnings and Precautions
Cardiovascular Effects:- May cause decreases in blood pressure; use with caution in patients with underlying cardiovascular disease
- Evaluate cardiovascular status before prescribing for sexual activity
- Priapism (erection lasting >4 hours) reported; requires immediate medical attention
- Sudden decrease or loss of hearing reported; discontinue use if occurring
- Non-arteritic anterior ischemic optic neuropathy (NAION) reported
- Patients with anatomic risk factors should be cautioned
- Adcirca® formulation should not be used interchangeably with ED/BPH formulations
Drug Interactions
Contraindicated Combinations:- Nitrates: Profound hypotension may occur
- Riociguat: Additive hypotensive effects
- Strong CYP3A4 inhibitors (ketoconazole, ritonavir): Increase tadalafil exposure; limit maximum dose to 10 mg
- Alpha-adrenergic blockers: Additive blood pressure lowering effects; initiate at lowest doses
- Antihypertensics: Potential additive blood pressure effects
- Alcohol: May increase blood pressure lowering effects and orthostatic symptoms
Adverse Effects
Common (≥2%):- Headache (15%)
- Dyspepsia (13%)
- Back pain (6%)
- Myalgia (5%)
- Nasal congestion (4%)
- Flushing (3%)
- Limb pain (3%)
- Cardiovascular events (myocardial infarction, stroke)
- Sudden hearing loss
- Vision loss (NAION)
- Priapism
- Severe hypersensitivity reactions
Monitoring Parameters
- Blood pressure and heart rate (baseline and periodically)
- Vision and hearing changes
- Cardiovascular status assessment
- Renal and hepatic function (periodically in long-term use)
- Efficacy assessment for intended indication
- Adverse effect profile
Patient Education
- Take as prescribed; do not exceed recommended dosage
- For as-needed dosing: take at least 30 minutes before sexual activity
- For daily dosing: take at approximately the same time each day
- Seek immediate medical attention for erection lasting >4 hours
- Report sudden vision or hearing changes, chest pain, or dizziness
- Avoid concurrent use with nitrates or recreational drugs containing nitrates
- Limit alcohol consumption while taking tadalafil
- Inform all healthcare providers about tadalafil use
- Store at room temperature away from moisture and heat
References
1. FDA Prescribing Information: Cialis® (tadalafil) 2. Hatzimouratidis K, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57(5):804-814 3. Porst H, et al. Efficacy and safety of tadalafil 5 mg once daily for the treatment of erectile dysfunction. J Sex Med. 2013;10(2):342-352 4. Roehrborn CG, et al. Tadalafil administered once daily for lower urinary tract symptoms. J Urol. 2014;192(1):160-166 5. Kloner RA, et al. Cardiovascular safety of tadalafil. Postgrad Med. 2014;126(2):7-17 6. McVary KT, et al. Tadalafil relieves lower urinary tract symptoms. J Urol. 2007;177(4):1401-1407 7. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2023