Excelvior 5 & 20 5 mg, 20 mg FC Tablet

EXCELVIOR is indicated for the treatment of erectile dysfunction. In order for EXCELVIOR to be effective, sexual stimulation is required.

Posology

In adult men:

• EXCELVIOR 5: The recommended dose is 5 mg taken once a day at approximately the same time of day.
• EXCELVIOR 20: The recommended maximum dose of EXCELVIOR 20 is 20 mg taken prior to anticipated sexual activity and without regard to food. It 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. The maximum recommended dosing frequency is once per day.

Special Populations

In men with impaired renal function

Dosage adjustments are not required in patients with mild or moderate renal impairment. Once-a-day dosing of EXCELVIOR is not recommended in patients with severe renal impairment.

Method of administration

Oral route.

EXCELVIOR is contraindicated in:

• Patients with hypersensitivity to tadalafil or to any of the excipients (see section 6.1);
• Patients who are using any form of organic nitrate (see section 4.6);
• Patients with severe hepatic insufficiency (Child-Pugh Class C) (see section 4.4);
• Patients with previous experience of partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes (see section 4.4). EXCELVIOR is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION) regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).
• Patients with previous experience of unilateral or bilateral decrease or loss of hearing with or without associated vestibular symptoms (see section 4.4).

Prior to initiating any treatment for erectile dysfunction, medical practitioners should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their medical practitioner.

Tadalafil has vasodilatory properties resulting in mild and transient decreases in blood pressure. Patients with underlying cardiovascular disease may be adversely affected by such vasodilatory effects. For patients with pre-existing cardiovascular disease sexual activity carries a potential cardiac risk. EXCELVIOR should not be used in patients with cardiac disease for whom sexual activity is not advised.

The use of EXCELVIOR in the following group of patients with cardiovascular disease is not recommended:

• Patients with myocardial infarction within the last 90 days
• Patients with unstable angina pectoris 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 who experienced a stroke within the last 6 months.

Simultaneous administration of EXCELVIOR in patients who are taking alpha-[1] blockers, such as doxazosin (4-8 mg daily), should be done with caution as this may lead to symptomatic hypotension in some patients. No symptomatic hypotension is observed with simultaneous administration of tamsulosin, an -[1A] blocker, with a single dose of tadalafil.

EXCELVIOR, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia). Priapism has been reported with tadalafil. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Visual defects and cases of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) have been reported in connection with the intake of EXCELVIOR and other PDE5 inhibitors. It is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, to stop taking EXCELVIOR and consult a medical practitioner immediately. Medical practitioners should also discuss with patients that individuals who have already experienced NAION are at increased risk of NAION and should not use EXCELVIOR or other PDE5 inhibitors again.

Cases of sudden hearing loss, which may be accompanied by tinnitus and dizziness, have been reported after the use of tadalafil. Although other risk factors were present in some cases (such as age, diabetes, hypertension and previous hearing loss history) patients should be advised to stop taking EXCELVIOR and seek prompt medical attention in the event of sudden decrease or loss of hearing.

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take EXCELVIOR in such combinations.

Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of EXCELVIOR is not recommended in patients with severe renal impairment. The taking of EXCELVIOR in patients with moderate renal failure (creatinine clearance = 31 to 50 mL/min) is safe, however less well tolerated in terms of back pain than in patients with mild renal failure (creatinine clearance = 51 to 80 mL/min) and healthy patients.

EXCELVIOR is contraindicated in patients with severe hepatic insufficiency (Child-Pugh Class C) (see section 4.3). Safety and efficacy of once-a-day administration in patients with hepatic insufficiency have not been established.

Caution should be exercised when prescribing EXCELVIOR to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin), as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined.

Paediatric population

There is no relevant use of EXCELVIOR in the paediatric population with regard to the treatment of erectile dysfunction.

Excipients

EXCELVIOR contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Cytochrome P450 CYP450 isoforms, including CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 is not inhibited or induced by EXCELVIOR. EXCELVIOR is principally metabolised by CYP3A4. Ketoconazole (400 mg daily), a selective inhibitor of CYP3A4 increased tadalafil 20 mg exposure (AUC) by 312 % and C max by 22 %. EXCELVIOR 10 mg exposure (AUC) is increased by ketoconazole (200 mg daily) by 107 % and C max by 15 % relative to the AUC and C max values for tadalafil alone. Ritonavir (200 mg twice daily) an inhibitor of CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased tadalafil exposure (AUC) by 124 % with no change in C max. Other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors such as erythromycin, clarithromycin, and itraconazole and grapefruit juice, would likely increase tadalafil plasma concentrations. A selective CYP3A4 inducer, rifampicin (rifampicin, 600 mg daily), reduced tadalafil AUC by 88 % and C max by 46 %, relative to the AUC and C max values for tadalafil alone. It can be expected that concomitant administration of other CYP3A4 inducers will also decrease plasma concentrations of tadalafil. The reduced exposure of tadalafil with the co-administration of rifampicin can be anticipated to decrease the efficacy of once-a-day-dosed EXCELVIOR.

Nitrates

Tadalafil may increase the hypotensive effects of nitrates. The use of EXCELVIOR in patients who are also taking any form of organic nitrate is contra-indicated.

Anti-hypertensives and alpha-adrenergic blockers

The co-administration of alpha-[1]-adrenergic blocker doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect in a significant manner. This effect can last at least twelve hours and some patients may experience dizziness. Although EXCELVIOR may not have an effect on blood pressure changes due to tamsulosin, caution should be exercised when using tadalafil in patients treated with tamsulosin or any alpha-blockers.

EXCELVIOR may increase the blood pressure lowering effects of antihypertensive medicines. In patients whose hypertension is not well controlled taking multiple antihypertensive medicines may cause greater reductions in blood pressure.

CYP1A2 substrates (e.g., theophylline)

Tadalafil had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a non-selective phosphodiesterase inhibitor.

Ethinylestradiol and terbutaline

Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline.

Antacids

Administration of tadalafil with antacids (magnesium hydroxide/aluminium hydroxide) reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

Alcohol

Tadalafil does not affect alcohol concentrations and alcohol does not affect tadalafil concentrations.

H2-antagonists:

An increase in gastric pH resulting from administration of nizatidine, an H2-antagonist, had no significant effect on tadalafil pharmacokinetics.

CYP2C9 substrates (e.g., warfarin)

Tadalafil does not affect changes in prothrombin time induced by warfarin. Tadalafil has no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate).

Aspirin

Tadalafil does not potentiate the increase in bleeding time caused by acetylsalicylic acid.

EXCELVIOR is not indicated for use by women.

Pregnancy

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 EXCELVIOR during pregnancy.

Breastfeeding

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. EXCELVIOR should not be used during breast feeding.

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 (see sections 5.1).

EXCELVIOR may have effects on the ability to drive and use machines. Undesirable effects may occur (e.g., allergic reaction, dizziness or blurred vision), which may influence the ability to drive and use machines (see section 4.8).

a. Tabulated summary of adverse reactions

b. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Multiple daily doses up to 100 mg and single doses of up to 500 mg have been given to healthy subjects. Adverse events are similar to those seen at lower doses.

Treatment

In cases of overdose, treatment is symptomatic and supportive as required. Haemodialysis contributes negligibly to tadalafil elimination.