Spedra Drug Interactions



Menarini-Von Heyden


Agencia Lei Va Hong


A. Menarini
Full Prescribing Info
Drug Interactions
Potential for pharmacodynamic interactions with avanafil: Nitrates: Avanafil was shown to augment the hypotensive effects of nitrates compared to placebo in healthy subjects. This is thought to result from the combined effects of nitrates and avanafil on the nitric oxide/cGMP pathway. Therefore, administration of avanafil to patients who are using any form of organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. In a patient who has taken avanafil within 12 hours, where nitrate administration is deemed medically necessary in a life-threatening situation, the likelihood of a significant and potentially dangerous drop in blood pressure is increased. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate haemodynamic monitoring (see Contraindications).
Medicinal products reducing systemic blood pressure: As a vasodilator, avanafil may reduce systemic blood pressure. If Spedra is used in combination with another medicinal product which reduces systemic blood pressure, the additive effects may result in symptomatic hypotension (e.g. dizziness, light-headedness, syncope or near-syncope). In phase III clinical trials no events of "hypotension" but occasional episodes of "dizziness" were observed (see Adverse Reactions). One episode of "syncope" was observed in placebo and one episode on 100 mg of avanafil in phase III clinical trials.
Patients with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators including avanafil.
Alpha-blockers: Haemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-period crossover-design trial. In patients receiving stable doxazosin treatment, the placebo-subtracted mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing were 2.5 mmHg and 6.0 mmHg, respectively. In total, 7/24 subjects experienced values or decreases from baseline that were of potential clinical significance following avanafil dosing (see Precautions).
In patients receiving stable tamsulosin treatment, the placebo-subtracted mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing were 3.6 mmHg and 3.1 mmHg, respectively and 5/24 subjects experienced blood pressure values or decreases from baseline that were of potential clinical significance following avanafil dosing (see Precautions). There were no reports of syncope or other severe adverse events associated with lowering of blood pressure on either cohort of subjects.
Antihypertensives other than alpha-blockers: A clinical study was conducted to assess the effect of avanafil on the potentiation of the blood pressure-lowering effects of selected antihypertensive medicinal products (amlodipine and enalapril). Results showed a mean maximum decrease in supine blood pressure of 2/3 mmHg compared to placebo with enalapril and 1/-1 mmHg with amlodipine when avanafil was co-administered. There was a statistically significant difference in maximum decrease from baseline in supine diastolic blood pressure with enalapril and avanafil only, which returned to baseline 4 hours after the dose of avanafil. In both cohorts, one subject experienced a decrease in blood pressure without symptoms of hypotension, which resolved within 1 hour of onset. Avanafil had no effect on the pharmacokinetics of amlodipine, but amlodipine increased the maximum and total exposure of avanafil by 28% and 60%, respectively.
Alcohol: Consumption of alcohol in combination with avanafil can increase the potential for symptomatic hypotension. 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) (see Precautions).
Other treatments for erectile dysfunction: The safety and efficacy of combinations of avanafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied (see Precautions).
Effects of other substances on avanafil: Avanafil is a substrate of and predominantly metabolised by CYP3A4. Studies have shown that medicinal products that inhibit CYP3A4 can increase avanafil exposure (see Dosage & Administration).
CYP3A4 Inhibitors: Ketoconazole (400 mg daily), a selective and highly potent inhibitor of CYP3A4, increased avanafil 50 mg single-dose Cmax and exposure (AUC) equal to 3-fold and 14-fold respectively and prolonged the half-life of avanafil to approximately 9 hours. Ritonavir (600 mg twice daily), a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours. Other strong inhibitors of CYP3A4 (e.g. itraconazole, voriconazole, clarithromycin, nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) would be expected to have similar effects. Consequently, co-administration of avanafil with potent CYP3A4 inhibitors is contraindicated (see Dosage & Administration, Contraindications and Precautions).
Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, increased avanafil 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of avanafil is 100 mg, not to exceed once every 48 hours for patients taking concomitant moderate CYP3A4 inhibitors (see Dosage & Administration).
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase avanafil exposure. Patients should be advised to avoid grapefruit juice within 24 hours prior to taking avanafil.
CYP3A4 substrate: Amlodipine (5 mg daily) increased avanafil 200 mg single-dose Cmax and AUC by approximately 28% and 60%, respectively. These exposure changes are not considered clinically significant. There was no effect of a single dose of avanafil on amlodipine plasma levels.
Although specific interactions of avanafil with rivaroxaban and apixaban (both CYP3A4 substrates) have not been studied, an interaction is not expected.
Cytochrome P450 Inducers: 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.
Effects of avanafil on other medicinal products: Cytochrome P450 Inhibition: In in vitro studies in human liver microsomes, avanafil showed a negligible potential for drug-drug interactions with CYP1A1/2, 2A6, 2B6 and 2E1. Further, the metabolites of avanafil (M4, M16 and M27), also demonstrated a minimal inhibition of CYPs 1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Based on these data avanafil is not anticipated to have a significant effect on other medicinal products metabolised by these enzymes.
Since the in vitro data identified potential avanafil interactions with CYPs 2C19, 2C8/9, 2D6 and 3A4, further clinical studies using omeprazole, rosiglitazone and desipramine did not reveal clinically relevant interactions with CYPs 2C19, 2C8/9 and 2D6.
Cytochrome P450 Induction: The potential induction of CYP1A2, CYP2B6 and CYP3A4 by avanafil evaluated in primary human hepatocytes in vitro did not reveal any potential interaction at clinically relevant concentrations.
Transporters: In vitro results showed for avanafil a modest potential for acting as P-gp substrate and P-gp inhibitor with digoxin as a substrate at concentrations lower than the calculated intestinal concentration. The potential of avanafil to interfere with the transport of other medicinal products mediated by P-gp is not known.
Based on in vitro data, at clinically relevant concentrations avanafil could be an inhibitor of BCRP.
At clinically relevant concentrations, avanafil is not an inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3 and BSEP.
The impact of avanafil on other transporters is unknown.
Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including avanafil, is contraindicated (see Contraindications).
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