11 DESCRIPTION

Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. 7 DRUG INTERACTIONS The drug interaction studies described below were conducted using vardenafil film-coated tablets.7.1 Potential for Pharmacodynamic Interactions with vardenafil orally disintegrating tabletNitrates: Concomitant use of vardenafil orally disintegrating tablet and nitrates 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 in healthy middle-aged subjects.

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These effects were not observed when vardenafil 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 orally disintegrating tablet and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)].Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with vardenafil orally disintegrating tablet. Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to vardenafil orally disintegrating tablet at the advice of their healthcare provider.

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indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.Aspirin: Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).Other Interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters). The drug interaction studies described below were conducted using vardenafil film-coated tablets. Nitrates: Concomitant use of vardenafil orally disintegrating tablet and nitrates is contraindicated. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil orally disintegrating tablet and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)]. Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with vardenafil orally disintegrating tablet.

Preparations of standard and sample solutions

[See Dosage and Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2).] Antihypertensives: Vardenafil orally disintegrating tablet may add to the blood pressure lowering effect of antihypertensive agents. Alcohol: Vardenafil 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. 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 [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. PDE5 inhibitors, including vardenafil orally disintegrating tablet and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. 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). ]Antihypertensives: Vardenafil orally disintegrating tablet may add to the blood pressure lowering effect of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil 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. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.Alcohol: Vardenafil 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 VardenafilIn vitro studiesStudies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9.

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Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].In vivo studiesDo not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration (2.4)].Strong CYP3A4 inhibitorsKetoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with vardenafil 5 mg in healthy volunteers.

Adverse Effects

Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. 7 DRUG INTERACTIONS The drug interaction studies described below were conducted using vardenafil film-coated tablets.7.1 Potential for Pharmacodynamic Interactions with vardenafil orally disintegrating tabletNitrates: Concomitant use of vardenafil orally disintegrating tablet and nitrates 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 in healthy middle-aged subjects. These effects were not observed when vardenafil 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 orally disintegrating tablet and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)].Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with vardenafil orally disintegrating tablet.

Determination of phosphodiesterase type V inhibitors in wastewater by direct injection followed by liquid chromatography coupled to tandem mass spectrometry

Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to vardenafil orally disintegrating tablet at the advice of their healthcare provider. PDE5 inhibitors, including vardenafil orally disintegrating tablet and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. 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). ]Antihypertensives: Vardenafil orally disintegrating tablet may add to the blood pressure lowering effect of antihypertensive agents. [See Dosage and Administration (2.4) and Warnings and Precautions (5). ]Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. ]Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking levitra pastillas hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2). ]Cobicistat with vardenafil can result in increased plasma concentrations.

Penile Injection Therapy

vardenafil should not be used with cobicistat.Moderate CYP3A4 inhibitorsErythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil Cmax when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration (2) and Warnings and Precautions (5)].Other Drug InteractionsNo 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 AUC and Cmax of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.7.3 Effects of Vardenafil on Other DrugsIn vitro studiesVardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >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 Cmax 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 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 studiesNifedipine: Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil when taken in combination. Vardenafil orally disintegrating tablet, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily bayer levitra buy in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo.Ritonavir and Indinavir: Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d.

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ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d. indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.Aspirin: Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).Other Interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters). The drug interaction studies described below were conducted using vardenafil film-coated tablets. Nitrates: Concomitant use of vardenafil orally disintegrating tablet and nitrates is contraindicated.

• Proper disposal of expired or unused medication is vital.
• Do not share medication with others.
• Always consult your healthcare provider before starting.

Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil orally disintegrating tablet and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)]. Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with vardenafil orally disintegrating tablet.

Precaution/Contraindication	Explanation	Alternatives or Actions
Use with nitrate medications	Can cause severe hypotension	Consult doctor before use
Heart conditions	Risk of cardiovascular events	Medical evaluation recommended
Liver or kidney impairment	Affects drug metabolism	Dose adjustment needed
Allergies to ingredients	Risk of allergic reactions	Check ingredient list

[See Dosage and Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2).] Antihypertensives: Vardenafil orally disintegrating tablet may add to the blood pressure lowering effect of antihypertensive agents.

Other uses for this medicine

Do not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration (2.4)]. Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with vardenafil 5 mg in healthy volunteers. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Alcohol: Vardenafil 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.

Upcoming Events

In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil 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. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.Alcohol: Vardenafil 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 VardenafilIn vitro studiesStudies 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 [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].In vivo studiesDo not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration (2.4)].Strong CYP3A4 inhibitorsKetoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with vardenafil 5 mg in healthy volunteers. [See Dosage and Administration (2.4) and Warnings and Precautions (5).

Mechanisms of penile erection

]Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. ]Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking levitra pastillas hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2). ]Cobicistat with vardenafil can result in increased plasma concentrations. 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 [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. Do not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration (2.4)].

Overdose/Missed Dose

vardenafil should not be used with cobicistat.Moderate CYP3A4 inhibitorsErythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil Cmax when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration (2) and Warnings and Precautions (5)].Other Drug InteractionsNo 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 AUC and Cmax of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.7.3 Effects of Vardenafil on Other DrugsIn vitro studiesVardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >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 Cmax 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 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.

What should I tell my healthcare provider before taking vardenafil?

dabigatran) is not known.In vivo studiesNifedipine: Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil when taken in combination. Vardenafil orally disintegrating tablet, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily bayer levitra buy in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo.Ritonavir and Indinavir: Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d. ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d. Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with vardenafil 5 mg in healthy volunteers. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax.

Dosage	Frequency	Onset Time	Duration of Effect	Notes
10 mL (200 mg)	Once 30 minutes before	30-60 min	Up to 4 hours	Maximum recommended dose
5 mL (100 mg)	As needed	30 min	3-4 hours	Consult doctor for tailored dose
15 mL (300 mg)	24 hours apart	30-60 min	Up to 4 hours	Do not exceed recommended dose