Avanafil

The potential effect of CYP inducers, especially inducers of CYP3A4 (e.g. bosentan, carbamazepine, efavirenz, phenobarbital and rifampicin) on the pharmacokinetics and efficacy of avanafil has not been evaluated. The concomitant use of avanafil and a CYP inducer is not recommended as it may decrease the efficacy of avanafil.

The concomitant use of alpha-blockers and avanafil may lead to symptomatic hypotension in some patients due to additive vasodilatory effects.

Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating avanafil. Patients who demonstrate haemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of avanafil.
• In those patients who are stable on alpha-blocker therapy, avanafil should be initiated at the lowest dose of 50 mg.
• In those patients already taking an optimised dose of avanafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking avanafil.
• The safety of combined use of avanafil and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive medicinal products.

Consumption of alcohol in combination with avanafil can increase the potential for symptomatic hypotension. Patients should be advised that concurrent use of avanafil and alcohol may increase the likelihood of hypotension, dizziness, or syncope. Physicians should also advise patients on what to do in the event of postural hypotensive symptoms.

In a single-dose three-way crossover design study evaluating healthy subjects, the mean maximum reduction in diastolic blood pressure was significantly greater following avanafil administered in combination with alcohol than following avanafil alone (3.2 mmHg) or alcohol alone (5.0 mmHg).

In patients receiving concomitant treatment with moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil should not exceed 100 mg, with an interval of at least 48 hours between doses.

Patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/min but <80 mL/min) who were enrolled in phase 3 studies showed decreased efficacy compared to those with normal renal function.

Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) should initiate treatment with the minimum efficacious dose and adjust posology based on tolerance.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients since there is a degree of cardiac risk associated with sexual activity. Avanafil has vasodilator properties, resulting in mild and transient decreases in blood pressure, and as such potentiates the hypotensive effect of nitrates. Patients with left ventricular outflow obstruction, e.g. aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators, including PDE5 inhibitors.

Avanafil 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).

Patients who experience erections lasting 4 hours or more (priapism) should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Priapism has been reported in a small number of post-marketing and clinical trial cases with other PDE5 inhibitors. No cases were reported during clinical trials of avanafil.

Avanafil is not indicated for use in women.

There are no data from the use of avanafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development.

There are no data on the use of avanafil during breast-feeding.

Fertility

There was no effect on sperm motility or morphology after single 200 mg oral doses of avanafil in healthy volunteers.

In a clinical trial performed in healthy volunteers and adult males with mild erectile dysfunction, the daily administration of avanafil 100 mg oral doses over a period of 26 weeks was not associated with any untoward effects on sperm concentration, count, motility, or morphology.

Avanafil has minor influence on the ability to drive and use machines. As dizziness and altered vision were reported in clinical trials with avanafil, patients should be aware of how they react to Spedra before driving or using machines.

Summary of the safety profile

The safety profile of avanafil is based on 2,566 subjects exposed to avanafil during the clinical development program. The most common adverse reactions reported in clinical studies were headache, flushing, nasal and sinus congestion and back pain. Overall adverse events and adverse reactions for avanafil-treated subjects were more frequent in subjects with a Body Mass Index (BMI) <25 (normal BMI subjects).

In the long term clinical study, the percentage of patients who experienced adverse reactions decreased with increasing length of exposure.

Tabulated list of adverse reactions

The table below lists the adverse reactions observed in placebo-controlled clinical trials according to the MedDRA frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions observed with other PDE5 inhibitors

Non-arteritic anterior ischaemic optic neuropathy (NAION) and sudden loss of hearing have been reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors. No cases were reported during clinical trials of avanafil.

Priapism has been reported in a small number of post-marketing and clinical trial cases with other PDE5 inhibitors. No cases were reported during clinical trials of avanafil.

Haematuria, haematospermia and penile haemorrhage has been reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors.

Hypotension has been reported post marketing with other PDE5 inhibitors, and dizziness, a symptom commonly caused by lowered blood pressure, has been reported in clinical trials with avanafil.