VARDENAFIL Drug Interactions: What You Need to Know

INTERACTIONS V ardenafil hydrochloride tablets can potentiate the hypotensive effects of nitrates, alpha-blockers, and antihypertensives. (7.1)

7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Tablets Nitrates: Concomitant use of vardenafil hydrochloride tablets and nitrates and nitric oxide donors is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of vardenafil hydrochloride tablets in healthy middle-aged subjects. These effects were not observed when vardenafil hydrochloride tablets 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil hydrochloride tablets and nitrates is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4.1 ) and Clinical Pharmacology ( 12.2 ) . Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil hydrochloride tablets and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin. [See Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( 12.2 ).]</span> Antihypertensives: Vardenafil hydrochloride tablets may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Alcohol: Vardenafil hydrochloride tablets (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

7.2 Effect of Other Drugs on Vardenafil In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 )]</span> . In vivo studies Strong CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil hydrochloride tablets (5 mg) in healthy volunteers. A 5-mg vardenafil hydrochloride tablets dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C max and AUC, a single 2.5 mg dose of vardenafil hydrochloride tablets should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily. [See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Indinavir (800 mg t.i.d.) co-administered with vardenafil hydrochloride tablets 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg vardenafil hydrochloride tablets dose in a 24-hour period when used in combination with indinavir. [See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 ).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil hydrochloride tablets 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C max . The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg vardenafil hydrochloride tablets dose in a 72-hour period when used in combination with ritonavir. [See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 ).] . Cobicistat with vardenafil hydrochloride tablets can result in increased plasma concentrations, therefore it is recommended that a single 2.5 mg dose of vardenafil hydrochloride tablets should not be exceeded in a 72-hour period. [ See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C max when coadministered with vardenafil hydrochloride tablets 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of vardenafil hydrochloride tablets in a 24-hour period when used in combination with erythromycin. [See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.

Other Drug

Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters. Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C max ) of vardenafil when co-administered with 20 mg vardenafil hydrochloride tablets in healthy volunteers.

7.3 Effects of Vardenafil on Other Drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki &gt;100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values after an 80 mg vardenafil dose. In vitro data suggest that vardenafil has the potential to inhibit P-glycoprotein (P-gp) at therapeutic doses. While concomitant use of vardenafil hydrochloride tablets did not significantly increase plasma concentrations of digoxin, a P-gp substrate, the effect on plasma concentrations of P-gp substrates that are more sensitive than digoxin (e.g. dabigatran) is not known. In vivo studies Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or C max of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil hydrochloride tablets when taken in combination. In these patients whose hypertension was controlled with nifedipine, vardenafil hydrochloride tablets 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo. Ritonavir and Indinavir: Upon concomitant administration of 5 mg of vardenafil hydrochloride tablets with 600 mg BID ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil hydrochloride tablets with 800 mg TID indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively. Aspirin: vardenafil hydrochloride tablets (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other interactions: Vardenafil hydrochloride tablets had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

Administration with nitrates and nitric oxide donors ( 2.4 , 4.1 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 2.4 , 4.2 )

4.1 Nitrates Administration of vardenafil hydrochloride orally disintegrating tablets with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> . Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, may potentiate the hypotensive effects of nitrates. A suitable time interval following vardenafil hydrochloride orally disintegrating tablets dosing for the safe administration of nitrates or nitric oxide donors has not been determined.

4.2 Guanylate Cyclase (GC) Stimulators Do not use vardenafil hydrochloride orally disintegrating tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets may potentiate the hypotensive effects of GC stimulators.

AND PRECAUTIONS The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment. Before prescribing vardenafil hydrochloride orally disintegrating tablets, it is important to note the following:

• Cardiovascular Effects: Patients should not use vardenafil hydrochloride orally disintegrating tablets if sex is inadvisable due to cardiovascular status. ( 5.1 )
• Strong and Moderate CYP3A4 Inhibitors: Do not use vardenafil hydrochloride orally disintegrating tablets in patients taking strong or moderate CYP3A4 inhibitors. ( 5.2 , 7.2 )
• Risk of Priapism: In the event that an erection lasts more than 4 hours, the patient should seek immediate medical assistance. ( 5.3 )
• Effects on the Eye: Patients should stop use of vardenafil hydrochloride orally disintegrating tablets and seek medical attention in the event of sudden loss of vision in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). Vardenafil hydrochloride orally disintegrating tablets should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION. ( 5.4 , 6.2 )
• Sudden Hearing Loss: Patients should stop vardenafil hydrochloride orally disintegrating tablets and seek medical attention in the event of sudden decrease or loss in hearing. ( 5.5 , 6.2 )
• Alpha-Blockers: Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). In patients taking alpha-blockers, do not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. ( 2.4 , 5.6 )
• QT Prolongation: Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using vardenafil hydrochloride orally disintegrating tablets. ( 5.7 , 12.2 )
• Phenylketonurics: Each vardenafil hydrochloride orally disintegrating tablet contain 1.403 mg phenylalanine per tablet, which could be harmful for patients with phenylketonuria. ( 5.12 )

5.1 Cardiovascular Effects General Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including vardenafil hydrochloride orally disintegrating tablets, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status. There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of &lt;90 mmHg); uncontrolled hypertension (&gt;170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.

Left Ventricular Outflow Obstruction

Patients with left ventricular outflow obstruction (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.

Blood Pressure Effects

Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic) [see Clinical Pharmacology (12.2)] . While this normally would be expected to be of little consequence in most patients, prior to prescribing vardenafil hydrochloride orally disintegrating tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

5.2 Potential for Drug Interactions with Strong or Moderate CYP3A4 Inhibitors Concomitant administration with strong CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole and cobicistat) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Do not use vardenafil hydrochloride orally disintegrating tablets in patients taking strong or moderate CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Drug Interactions (7.2) and Patient Counseling Information (17).]</span>

5.3 Risk of Priapism There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. Vardenafil hydrochloride orally disintegrating tablets should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

5.4 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including vardenafil hydrochloride orally disintegrating tablets, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.2). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, for this uncommon condition. Vardenafil hydrochloride orally disintegrating tablets have not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.

5.5 Sudden Hearing Loss Physicians should advise patients to stop taking all PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>.

5.6 Alpha-Blockers In patients taking alpha-blockers, do not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be changed to vardenafil hydrochloride orally disintegrating tablets at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology (12.2)]</span> leading to symptomatic hypotension (for example, fainting). Consideration should be given to the following: · Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. · In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose. In patients taking alpha-blockers, do not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients <span class="opacity-50 text-xs">[see Dosage and Administration (2.4)]</span> . · In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

5.7 Congenital or Acquired QT Prolongation In a study of the effect of vardenafil on QT interval in 59 healthy males <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> , therapeutic (10 mg film-coated tablets) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> . These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval. Patients taking Class 1A (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using vardenafil hydrochloride orally disintegrating tablets.

5.8 Hepatic Impairment Do not use vardenafil hydrochloride orally disintegrating tablets in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)

Clinical

Pharmacology (12.3)] and Use in Specific Populations (8.6)] .

5.9 Renal Impairment Do not use vardenafil hydrochloride orally disintegrating tablets in patients on renal dialysis, as vardenafil has not been evaluated in this population <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Use in Specific Populations (8.7)]</span>.

5.10 Combination with Other Erectile Dysfunction Therapies The safety and efficacy of vardenafil hydrochloride orally disintegrating tablets used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

5.11 Effects on Bleeding In humans, vardenafil film-coated tablet alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Vardenafil hydrochloride orally disintegrating tablets have not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore vardenafil hydrochloride orally disintegrating tablets should be administered to these patients after careful benefit-risk assessment.

5.12 Phenylketonurics Vardenafil hydrochloride orally disintegrating tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria. Phenylketonurics: Each vardenafil hydrochloride orally disintegrating tablet contains 1.403 mg phenylalanine per tablet.

5.14 Sexually Transmitted Disease Use of vardenafil hydrochloride orally disintegrating tablets offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.