Tadalafil

Registered South African indications: 

• Erectile dysfunction (2.5mg, 5mg, 10mg, 20mg)
• Signs and symptoms of benign prostatic hyperplasia in adult males (5mg)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration in patients who are using any form of organic nitrate
• Patients with severe hepatic insufficiency (Child-Pugh Class C)
• Loss of vision in one or both eyes because on non-arteritic anterior ischaemic optic neuropathy (NAION) regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure
• Previous experience of unilateral or bilateral decrease or loss of hearing with or without associated vesicular symptoms
• Patients with myocardial infarction within the last 90 days
• Patients with unstable angina or angina occurring during sexual intercourse
• Patients with New York Heart Association Class 2 or greater heart failure in the last 6 months
• Patients with uncontrolled dysrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled hypertension
• Patients with a stroke within the last 6 months
• Concomitant therapy with guanylate cyclase stimulators, such as riociguat due to the possibility of symptomatic hypotension

• Pregnancy
• Breastfeeding
• Renal impairment (eGFR ≥11-49ml/min/1.73m²) (when used for erectile dysfunction)
• Renal impairment (eGFR ≥30-89 ml/min/1.73m²) (when used for pulmonary arterial hypertension)
• Mild to moderate renal impairment (when used for benign prostatic hyperplasia)
• Mild to moderate hepatic impairment (Child-Pugh Class A & B) (when used for erectile dysfunction or pulmonary arterial hypertension)
• Hepatic impairment (when used for benign prostatic hyperplasia)
• Porphyria
• Patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy (when used for erectile dysfunction and/or benign prostatic hyperplasia)
• Carcinoma of the prostate (when used for benign prostatic hyperplasia)
• Pre-existing cardiovascular risk factors (when used for erectile dysfunction and/or benign prostatic hyperplasia)
• Cardiovascular disease:
  - Clinically significant aortic and mitral valve disease (when used for pulmonary arterial hypertension)
  - Pericardial constriction (when used for pulmonary arterial hypertension)
  - Restrictive or congestive cardiomyopathy (when used for pulmonary arterial hypertension)
  - Significant left ventricular dysfunction (when used for pulmonary arterial hypertension)
  - Life-threatening arrhythmias (when used for pulmonary arterial hypertension)
  - Symptomatic coronary artery disease (when used for pulmonary arterial hypertension)
  - Uncontrolled hypertension (when used for pulmonary arterial hypertension)
• Pulmonary veno-occlusive disease (PVOD) (when used for pulmonary arterial hypertension)
• Severe left ventricular outflow obstruction (when used for pulmonary arterial hypertension)
• Fluid depletion (when used for pulmonary arterial hypertension)
• Autonomic hypotension (when used for pulmonary arterial hypertension)
• Resting hypotension (when used for pulmonary arterial hypertension)
• Known hereditary degenerative retinal disorders, including retinitis pigmentosa (when used for pulmonary arterial hypertension)
• Risk factors for decreased or sudden loss of hearing:
  - Age
  - Diabetes mellitus
  - Hypertension
  - Previous hearing loss history
  - Associated connective tissue diseases
• Patients who experience erections lasting 4 hours or longer
• Anatomical deformation of the penis
  - Angulation
  - Cavernosal fibrosis
  - Peyronie's disease
• Conditions that may predispose patients to priapism
  - Sickle cell anaemia
  - Multiple myeloma
  - Leukaemia
• Coadministration with alpha1-blockers, such as doxazosin
• Coadministration with antihypertensive medicinal products
• Coadministration with potent CYP3A4 inhibitors or inducers
• Coadministration with other phosphodiesterase-5 inhibitors or other treatments for erectile dysfunction
• Coadministration with CYP1A2 substrates (e.g. theophylline)
• Coadministration with 5-alpha reductase inhibitors (5-ARIs)(when used for erectile dysfunction and/or benign prostatic hyperplasia)
• Coadministration with prostacyclin or its analogues (when used for pulmonary arterial hypertension)
• Coadministration withbosentan therapy and other endothelin-1 receptor antagonists (when used for pulmonary arterial hypertension)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Erectile dysfunction

• Oral (fct, tab): 2.5-5mg, dly, at approx. the same time each day with or without food

OR

• Oral (fct, tab): Max: 20mg, taken prior to anticipated sexual activity and without regard to food; Max frequency: Once per day

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Tadalafil can be taken up to 36 hours and as early as 16 minutes prior to sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness

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Signs and symptoms of benign prostatic hyperplasia in adult males

• Oral (fct, tab): 5mg, dly, at approx. the same time each day with or without food

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Not indicated for use by women

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For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5mg taken at approximately the same time every day

Not established for use in children

Pregnancy

• Caution; not recommended
• There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of tadalafil during pregnancy

Breastfeeding

• Caution; not recommended
• Available pharmacodynamic/ toxicological data in animals have shown excretion of tadalafil in milk. A risk to the breastfeeding child cannot be excluded. Tadalafil should not be used during breastfeeding

Fertility

• Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men

Renal Impairment

Erectile dysfunction

• eGFR ≥50-89 ml/min/1.73m²: No dose adjustment recommended
• eGFR ≥11-49ml/min/1.73m²: Caution; dose adjustment recommended
• eGFR ≤10ml/min/1.73m²: Contraindicated

eGFR (ml/min/1.73m2)	Dose
≥50-89	No dose adjustment recommended
≥30-49	Initial: 2.5mg; titrate slowly; Max: 10mg/48hrs
≥11-29	Initial: 2.5mg; titrate slowly; Max: 5mg/72hrs
≤10/ESRD	Contraindicated

Pulmonary arterial hypertension

• eGFR ≥30-89 ml/min/1.73m²: Caution; dose adjustment recommended
  Initial: 20mg; titrate slowly; Max: 40mg/24hrs
  Closely monitor renal function
• eGFR ≤29mL/min/1.73m² or ESRD: Contraindicated

Benign prostatic hyperplasia

• Caution; no dose adjustment recommended

Renal impairment	Dose
Mild to moderate	No dose adjustment recommended
Severe	Not recommended for use

Hepatic Impairment

Erectile dysfunction

• Mild to moderate (Child-Pugh Class A & B): Caution; dose adjustment recommended
• Severe (Child-Pugh Class C): Contraindicated

Hepatic impairment	Dose
Mild (Child-Pugh Class A)	Max/24hrs: 10mg as a single dose
Moderate (Child-Pugh Class B)	Max/24hrs: 5mg as a single dose
Severe (Child-Pugh Class C)	Contraindicated

Pulmonary arterial hypertension

• Mild to moderate (Child-Pugh Class A & B): Caution; dose adjustment recommended
• Severe (Child-Pugh Class C): Contraindicated

Hepatic impairment	Dose
Mild (Child-Pugh Class A)	Max/24hrs: 20mg as a single dose
Moderate (Child-Pugh Class B)	Max/24hrs: 20mg as a single dose
Severe (Child-Pugh Class C)	Contraindicated

Benign prostatic hyperplasia

• Caution; no information available
  Once-a-day dosing for the treatment of benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Stroke
  - Haemorrhagic events
• Syncope
• Transient ischaemic attacks
• Migraine
• Seizures
• Transient amnesia
• Fatigue

Cardiovascular Disorders

• Tachycardia
• Palpitations
• Myocardial infarction
• Unstable angina pectoris
• Ventricular arrhythmia
• Flushing
• Hypotension
• Hypertension
• Sudden cardiac death
• ECG abnormalities
• Primarily sinus bradycardia

Respiratory Disorders

• Nasal congestion
• Dyspnoea
• Epistaxis
• Chest pain

Gastrointestinal Disorders

• Dyspepsia
• Abdominal pain
  - Upper abdominal pain
  - Lower abdominal pain
• Abdominal discomfort
  - Stomach discomfort
• Nausea and vomiting
• Gastro-oesophageal reflux
• Diarrhoea

Genitourinary Disorders

• Haematuria
• Increased uterine bleeding
• Abnormal/excessive menstrual bleeding
  - Menorrhagia
  - Metrorrhagia
  - Menometrorrhagia
  - Vaginal haemorrhage
• Priapism
• Penile haemorrhage
• Haematospermia
• Prolonged erections

Musculoskeletal Disorders

• Back pain
• Myalgia
• Pain in extremity
  - Limb discomfort

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Stevens-Johnson syndrome
• Exfoliative dermatitis
• Hyperhydrosis (sweating)

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Angioedema
• Peripheral oedema
• Facial oedema

Sensory Disorders

• Blurred vision
• Eye pain
• Visual field defects
• Swelling of eyelids
• Conjunctival hyperaemia
• Non-arteritic anterior ischaemic optic neuropathy
• Retinal vascular occlusion
• Tinnitus
• Sudden hearing loss

• Nitrates
• Nitroglycerin
• Guanylate cyclase stimulators
• Riociguat
• CYP3A4 inhibitors
• Ketoconazole
• Ritonavir
• CYP3A4 inducers
• Rifampicin
• Phenobarbital
• Phenytoin
• Carbamazepine
• Protease inhibitors
• Saquinavir
• Erythromycin
• Clarithromycin
• Itraconazole
• Antihypertensive agents
• Doxazosin
• Angiotensin II receptor blockers and amlodipine (in combination)
• Alpha-1 blockers
• Ethinylestradiol
• Terbutaline
• Prostacyclin or its analogues (when used for pulmonary arterial hypertension)
• Endothelin-1 receptor antagonists (when used for pulmonary arterial hypertension)
• Bosentan (when used for pulmonary arterial hypertension)

Other interactions

• Grapefruit juice

• Blood pressure
• Urine flow

Specific cases may require

• Prostate specific antigen

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.

Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations within the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of the pulmonary vascular smooth muscle cell and vasodilation of the pulmonary vascular bed.

Tablet 2.5mg

• Cialis oad (Eli Lilly) originator

Tablet 5mg

• Cialis oad (Eli Lilly) originator
• Ciavor 5 (Eli Lilly)
• Cyfil (Accord) 
• Talvior 5 (Forrester Pharma)

Tablet 20mg

• Adafill 20 (Forrester Pharma)
• Cialis (Eli Lilly) originator
• Ciavor (Eli Lilly) originator
• Cyfil (Accord) 
• Talvior 20 (Forrester Pharma)