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Ability to drive and use machines:
As dizziness and abnormal vision have been reported in clinical trials with vardenafil, patients should be aware of how they react to LEVITRAŽ before driving or operating machinery
Interaction with other medicaments and other forms of interaction CYP inhibitors:
Vardenafil is metabolized predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce Vardenafil clearance
Cimetidine (400 mg b.i.d.), a non-specific cytochrome P450 inhibitor, had no effect on Vardenafil bioavailibility (AUC) and maximal concentration (Cm) when coadministered with Vardenafil (20 mg) to healthy volunteers
Erythromycin (500 mg t.i.d.), a CYP3A4 inhibitor, caused a 4-fold increase in Vardenafil AUC and a 3-fold (200 %) increase in Cmax when co-administered with Vardenafil (5 mg) to healthy volunteers.
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold (900 %) increase in Vardenafil AUC and a 4-fold (300 %) increase in Cmax when co-administered with Vardenafil (5 mg) to healthy volunteers.
Co-administration of Vardenafil (10 mg) with the HIV protease inhibitor Indinavir (800 mg t.i.d.) resulted in a 16-fold (1500 % ) increase in Vardenafil AUC and a 7-fold (600 %) increase in Vardenafil C,. At 24 hours after co-administration, the plasma levels of Vardenafil were approximately 4% of the maximum Vardenafil plasma level
(Cmax).
Ritonavir (600 mg b.i.d.) resulted in a 13-fold increase in vardenafil Cm and a 49-fold increase in vardenafil AUC0_24 when co-administered with vardenafil 5 mg The interaction is a consequence of blocking hepatic metabolism of LEVITRA by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of LEVITRA to 25.7 hours.
Concomitant use of the potent cytochrome P450 3A4 (CYP 3A4) inhibitors ketoconazole, itraconazole, indinavir, or ritonavir can be expected to produce an increase in Vardenafil AUC by 10-16 fold. A maximum dose of 5 mg should not be exceeded when used in combination with erythromycin (increased vardenafil AUC by 4 fold).
A maximum dose of 5 mg should not be exceeded if used in combination with ketoconazole and itraconazole. Vardenafil must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see Posology and Method of Administration). Concomitant use with indinavir or ritonavir, which are highly potent inhibitors of CYP3A4 is contraindicated.
Although specific interaction studies have not been conducted, the concomitant use of other potent CYP3A4 inhibitors (such as itraconazole or ritonavir) can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole and indinavir.
Nitrates, Nitric Oxide Donors
No potentiation of the blood pressure lowering effect of sublingual Nitroglycerin (0.4 mg) was observed when Vardenafil (10 mg) was given at varying time intervals (24 h to down to 1 h) prior to the Nitroglycerin dose in a study in 18 healthy male subjects.
The blood pressure lowering effect of sublingual Nitroglycerin (0.4 mg) taken 1 and 4 hours after Vardenafil administration were potentiated by a 20 mg dose of Vardenafil healthy middle-aged subjects. These effects were not observed when Vardenafil 20 mg was taken 24 hours before the Nitroglycerin.
However, there is no information on the potential hypotensive effects of Vardenafil when given in combination with Nitrates in patients, and concomitant use is contraindicated.
Others
Vardenafil (20 mg), when co-administered
with Glibenclamide (Glyburide, 3.5 mg), did not affect the relative bioavailability of
Glibenclamide (no effect on AUC and Cmax of Glibenclamide). There was no
evidence that Vardenafil pharmacokinetics were altered by co-administration of Glibenclamide.
No pharmacokinetic and pharmacodynamic
(prothrombin time and clotting factor II, VII and X) interaction was shown when
Warfarin (25 mg) was co-administered with Vardenafil (20 mg).
Vardenafil pharmacokinetics was not affected by co-administration of Warfarin.
No relevant pharmacokinetic interaction
was shown when Vardenafil (20 mg), was co-administered with
Nifedipine (30 or 60 mg). The combined treatment of Vardenafil and Nifedipine
did not lead to pharmacodynamic interaction (as compared to placebo, Vardenafil produced
mean additional blood pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure, respectively).
Since alpha-blocker monotherapy can cause
marked lowering of blood pressure, especially postural hypotension and syncope,
interaction studies were conducted with vardenafil. Following short-term alpha blockade with
terazosin 10 mg or tamsulosin 0.4 mg daily in normotensive volunteers,
the addition of vardenafil 10 mg and 20 mg dosed with the alpha-blocker to achieve
simultaneous Cmax with both drugs, resulted in a number of cases of
standing systolic BP <85 mmHg, reduction in standing systolic BP
≥ 30 mmHg and cases of symptomatic postural hypotension. When dosed to produce
a 6 hour separation in Cmax there were fewer cases with a reduction in
standing systolic BP and of systolic standing BP < 85 mmHg, particularly with tamsulosin.
Mean maximum reductions of up to 8 mmHg for standing systolic BP and up to 7 mmHg for
standing diastolic BP were observed for tamsulosin regardless of the dosing interval.
A further study of vardenafil 5 mg on the background of stable chronic alpha-blocker
therapy (tamsulosin 0.4 mg or terazosin 5 mg and 10 mg) in patients with benign
prostatic hypertrophy (BPH) was performed. Dosing of the alpha-blocker and vardenafil
5 mg was simultaneous or separated by 6 hours. Mean maximum reductions of up to 6 mmHg
for standing systolic BP and up to 3mmHg for standing diastolic BP were observed regardless
of the dosing interval or the alpha-blocker. Three tamsulosintreated subjects had
transient standing systolic BP < 85 mmHg following vardenafil treatment on at least one occasion,
however none of these subjects had symptoms of hypotension. For the terazosin-treated
subjects dosed simultaneously with vardenafil 5 mg, 5 had a reduction in standing systolic BP of
≥ 30 mmHg (compared to 2 on
placebo) and one subject exhibited standing systolic BP < 85 mmHg with dizziness.
A 6 hours separation of terazosin and vardenafil 5 mg did not result in any reductions in standing systolic BP of
≥ 30 mmHg or any cases of standing systolic BP < 85 mmHg or of symptoms of hypotension.
Lack of pharmacokinetic interaction was shown when
Digoxin (0.375 mg) in steadystate was co-administered with Vardenafil (20 mg)
over 14 days every other day. There was no evidence that Vardenafil pharmacokinetics were altered by co-administration of Digoxin.
Bioavailability of Vardenafil was not affected by co-administration of the H2-antagonists
Ranitidine (150 mg bid.) and Cimetidine (400 mg b.i.d.).
Single doses of Maalox (antacid; magnesium
hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of Vardenafil.
Vardenafil (10 mg) did not influence
the bleeding time when taken alone or in combination with low dose
Acetylsalicylic Acid (2 x 81 mg tablets)
Vardenafil (20 mg) did not potentiate the hypotensive effects of
Alcohol (0.5 g /kg bw). The pharmacokinetics of Vardenafil where not altered.
Population pharmacokinetic investigations
of phase III data revealed no significant effect of Acetysalicylic Acid, ACE-inhibitors,
beta-blockers, weak CYP 3A4-inhibitors, diuretics and medications for the treatment
of diabetes (sulfonylureas and metFormin) on the pharmacokinetics of Vardenafil.
Food and dietary products: when
Vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is
reduced with an increase in the median time of maximal plasma concentration of 60 minutes
and a mean reduction in peak plasma concentration of 20% . Vardenafil bioavailability was not affected.
After a normal meal (containing 30% fat) Vardenafil pharmacokinetic parameter were not affected at all.
Based on these results Vardenafil can be taken with or without food.
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