Tadalafil

Indications and Dosage

Oral

Erectile dysfunction

Adult: As needed dosing: Initially, 10 mg as a single dose, taken at least 30 minutes before sexual activity; may be increased to 20 mg, or decreased to 5 mg depending on patient response and tolerability. Max dosing frequency: Once daily. In patients anticipating frequent use (e.g. at least twice weekly), a regular once-daily regimen with the lowest dose may be considered suitable. Regular daily dosing: 5 mg once daily, taken at the same time each day; may be decreased to 2.5 mg once daily depending on patient response and tolerability. Alternatively, start with 2.5 mg once daily, taken at the same time each day; may be increased to 5 mg once daily according to efficacy and tolerability. Periodically reassess the appropriateness of continued use of the daily regimen. Dosage recommendations may vary among individual products and between countries (refer to detailed product guideline).

Oral

Benign prostatic hyperplasia

Adult: 5 mg once daily, taken at the same time each day. For men being treated for both benign prostatic hyperplasia (BPH) and erectile dysfunction (ED): 5 mg once daily, taken at the same time each day; without regard to the timing of sexual activity.

Oral

Pulmonary arterial hypertension

Adult: To improve exercise ability: 40 mg once daily.

Special Patient Group

Erectile dysfunction:

Patients taking potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir): For as-needed dosing: Max: 10 mg once every 72 hours. For regular daily dosing: Max: 2.5 mg once daily.

Patients taking α-blockers: Initiate at the lowest recommended dose. Patient must be stable on α-blocker therapy before starting treatment.

Benign prostatic hyperplasia (with or without concomitant erectile dysfunction):

Patients taking potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir): Max: 2.5 mg once daily.

Pulmonary arterial hypertension:

Patients taking ritonavir for at least 1 week: Initially, 20 mg once daily, increased to 40 mg once daily as tolerated.

For concurrent use of ritonavir in patients taking tadalafil: Avoid use during ritonavir initiation; stop tadalafil treatment at least 24 hours before starting ritonavir. After at least 1 week of starting ritonavir, resume tadalafil at 20 mg once daily, increased to 20 mg once daily as tolerated.

Administration

May be taken with or without food.

Contraindications

MI within the last 90 days, hypotension (<90/50 mmHg); vision loss in 1 eye due to non-arteritic anterior ischaemic optic neuropathy (NAION). When used for ED or BPH: Cardiac disease wherein sexual activity is inadvisable; unstable angina or angina during sexual activity, NYHA class ≥II heart failure in the last 6 months; uncontrolled arrhythmias, uncontrolled hypertension, stroke within the last 6 months. Concurrent use with any form of organic nitrate (regularly or intermittently), and guanylate cyclase stimulators (e.g. riociguat).

Special Precautions

Patient with pre-existing CV disease or risk factors, left ventricular outflow obstruction (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy); anatomical penis deformation (e.g. angulation, cavernosal fibrosis, Peyronie’s disease); conditions which may be predisposed to priapism (e.g. sickle cell anaemia, multiple myeloma, leukaemia); risk factors of NAION (e.g. history of NAION, low cup-to-disc ratio [“crowded disc”], coronary artery disease, diabetes, hypertension, hyperlipidaemia, smoking, >50 years); peptic ulcer disease, bleeding disorders. Not recommended in patients with hereditary degenerative retinal disorders, including retinitis pigmentosa. When used for pulmonary arterial hypertension (PAH): Not recommended in patients with pulmonary veno-occlusive disease (PVOD), significant aortic or mitral valve disease, life-threatening arrhythmias, restrictive or congestive cardiomyopathy, coronary artery disease, significant left ventricular dysfunction, and pericardial constriction. Not indicated for use in women (when used for ED and BPH). Therapy in patients with severe renal impairment (CrCl <30 mL/min), including haemodialysis is avoided when used for PAH, and not recommended for BPH and ED (regular daily dosing). Not recommended in patients with severe hepatic impairment (Child-Pugh class C). Patients taking potent CYP3A4 inhibitors, or α-blockers (when used for ED). Concomitant use with α-blockers is not recommended when used for BPH. Renal and mild to moderate hepatic impairment. Pregnancy and lactation (when used for PAH).

Adverse Reactions

Significant: Anginal chest pain, palpitations, tachycardia; impairment of colour discrimination (dose-related), hypotension; may worsen CV status of patients with PVOD. Rarely, sudden hearing loss (may be accompanied by dizziness and tinnitus), priapism or prolonged erections (>4 hours), sudden vision loss or NAION.

Eye disorders: Blurred vision.

General disorders and administration site conditions: Facial oedema.

Gastrointestinal disorders: Dyspepsia, nausea, vomiting, abdominal pain, GERD.

Immune system disorders: Hypersensitivity reactions.

Musculoskeletal and connective tissue disorders: Back pain, pain in extremity, myalgia.

Nervous system disorders: Headache, migraine, syncope.

Reproductive system and breast disorders: Increased uterine bleeding.

Respiratory, thoracic and mediastinal disorders: Nasal congestion, epistaxis, dyspnoea, nasopharyngitis, respiratory tract infection.

Skin and subcutaneous tissue disorders: Rash, exfoliative dermatitis, Stevens-Johnson syndrome.

Vascular disorders: Flushing.

Potentially Fatal:

Serious CV events (e.g. MI, stroke, TIA, sudden cardiac death, ventricular arrhythmia, unstable angina pectoris).

Pregnancy Category (US FDA)

PO: B

Patient Counseling Information

This drug may cause dizziness, if affected, do not drive or operate machinery.

Monitoring Parameters

Evaluate CV status of the patient, and possible underlying causes of ED or BPH (to rule out the presence of prostate cancer) before starting therapy. Monitor blood pressure, urine flow, prostate-specific antigen; signs of postural hypotension.

Drug Interactions

May enhance the hypotensive effects of α-blockers and other antihypertensive drugs. Increased serum concentration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, ritonavir, saquinavir, erythromycin, clarithromycin). Decreased plasma concentration with CYP3A4 inducers (e.g. rifampicin, phenobarbital, phenytoin, carbamazepine). May cause a slight increase in heart rate with theophylline. May increase the oral bioavailability of ethinylestradiol and terbutaline. Bosentan may reduce serum levels of tadalafil.

Potentially Fatal:

Enhanced hypotensive effects of organic nitrates (any form), and guanylate cyclase stimulators (e.g. riociguat).

Food Interaction

May increase serum concentration with grapefruit juice. May increase the risk of orthostatic hypotension with alcohol.

Action

Description:

Mechanism of Action: 

Tadalafil is a potent and selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the metabolism of cyclic guanosine monophosphate (cGMP). For ED, sexual stimulation causes the local release of nitric oxide in the corpus cavernosum then PDE-5 inhibition leads to increased cGMP levels. This effect causes smooth muscle relaxation and increased blood flow into the corpus cavernosum of the penile tissues, thereby producing an erection. For BPH, effects of PDE-5 inhibition results in decreased bladder nerve activity, and increased smooth muscle relaxation and blood perfusion of the bladder and prostate. For PAH, PDE-5 inhibition elevates cGMP concentrations leading to relaxation of pulmonary smooth muscle and vasodilation of the pulmonary vascular bed.

Onset: Within 1 hour.

Duration: Erectile dysfunction: Up to 36 hours.

Pharmacokinetics:

Absorption: Readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 2 hours (range: 0.5-6 hours).

Distribution: Widely distributed in the tissues. Detected in semen (small amounts). Volume of distribution: 63-77 L. Plasma protein binding: Approx 94%.

Metabolism: Metabolised in the liver primarily by CYP3A4 isoenzyme into methylcatechol glucuronide (major inactive metabolite).

Excretion: Via faeces (approx 61%, mainly as metabolites); urine (approx 36%, primarily as metabolites). Elimination half-life: 15-17.5 hours.

Chemical Structure

Tadalafil

Source: National Center for Biotechnology Information. PubChem Database. Tadalafil, CID=110635, https://pubchem.ncbi.nlm.nih.gov/compound/Tadalafil (accessed on Jan. 23, 2020)

Storage

Store between 15-30°C. Protect from moisture.

MIMS Class

Drugs for Bladder & Prostate Disorders / Drugs for Erectile Dysfunction & Ejaculatory Disorders / Other Antihypertensives

ATC Classification

G04BE08 - tadalafil ; Belongs to the class of drugs used in erectile dysfunction.