Torfil 2.5/Torfil 5/Torfil 10/Torfil 20 Drug Interactions

Torfil 2.5: Cytochrome P450 Inhibitors: Tadalafil is predominantly metabolized in the liver by CYP3A4. CYP 3A4 inhibitors (e.g., Ketoconazole, erythromycin, itraconazole, and grapefruit juice) increases tadalafil exposure.
Cytochrome P450 Inducers: Co-administration with CYP3A4 inducers (e.g., Rifampicin, carbamazepine, phenytoin and phenobarbital) reduces tadalafil exposure.
Antacids: Concomitant use of antacids (e.g., Magnesium hydroxide and/or Aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without modifying tadalafil exposure.
H2 Antagonists: Use of H2 antagonist has no significant effect on the pharmacokinetics of tadalafil; Co-administration of Tadalafil and Nizatidine reduces the gastric pH.
Nitrates: Administration of Tadalafil is contraindicated in patients who are taking any form of organic nitrates as it is known to increase the hypotensive effects of the nitrate. In a patient whose taken tadalafil, where administration of nitrate is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil before nitrate administration is considered.
Warfarin: There is no significant effect on the exposure to warfarin nor did tadalafil affect changes in the prothrombin time induced by warfarin.
HIV Protease Inhibitors: Ritonavir, an inhibitor of CYP 3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil exposure. Other HIV protease inhibitors would likely increase tadalafil exposure.
Aspirin: Tadalafil did not potentiate the increase in bleeding time caused by aspirin.
Alpha-blockers: Caution is advised on co-administration of alpha-blockers (e.g., doxazosin, tamsulosin, and alfuzosin) and PDE5 inhibitors as they are both vasodilators. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.
Antihypertensives: PDE5 inhibitors, including tadalafil, are mild vasodilators. Tadalafil potentiates the blood pressure-lowering effects of selected antihypertensive agents (e.g., amlodipine, angiotensin II receptor blockers, enalapril, and metoprolol) and small reduction in blood pressure occurred.
Alcohol: When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentration and alcohol did not affect tadalafil plasma concentrations.
Theophylline: Tadalafil has no significant effect on the pharmacokinetics and pharmacodynamics of theophylline.
Midazolam and Lovastatin: Tadalafil had no significant effect on exposure to midazolam and lovastatin.
P-glycoprotein (e.g., Digoxin): Tadalafil had no significant effect on the pharmacokinetics of digoxin.
Torfil 5: Potential for Pharmacodynamic Interactions with Tadalafil: Nitrate: Administration of tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil tablets before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including tadalafil, 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 coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin.
Antihypertensives: PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo.
Alcohol: Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure- lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Potential for Other Drugs to Affect Tadalafil: Antacids: Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
H2 Antagonists (e.g. Nizatidine): An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.
Cytochrome P450 Inhibitors: Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.
CYP3A4 (e.g., Ketoconazole): Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.
HIV Protease inhibitor: Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.
Cytochrome P450 Inducers: Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.
CYP3A4 (e.g., Rifampin): Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil tablets for once daily use; the magnitude of decreased efficacy is unknown.
Potential for Tadalafil to Affect Other Drugs: Aspirin: Tadalafil did not potentiate the increase in bleeding time caused by aspirin.
Cytochrome P450 Substrates: Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
CYP1A2 (e.g. Theophylline): Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.
CYP2C9 (e.g. Warfarin): Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.
CYP3A4 (e.g. Midazolam or Lovastatin): Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.
P-glycoprotein (e.g. Digoxin): Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.
Torfil 10/Torfil 20: CYP3A4 Inhibitors: Co-administration with CYP3A4 inhibitors such as ketoconazole, ritonavir, saquinavir, erythromycin, and itraconazole increases tadalafil exposure.
HIV protease Inhibitor: HIV protease inhibitors such as saquinavir, erythromycin, and itraconazole would likely decrease tadalafil exposure.
CYP3A4 Inducers: Co-administration with CYP3A4 inducers (e.g. Rifampicin) reduces tadalafil exposure.
Antacids: Concomitant use of antacids (e.g. Magnesium hydroxide and/or Aluminum hydroxide and tadalafil reduces the rate of absorption of tadalafil without modifying tadalafil exposure.
H2 antagonists: Use of H2 antagonist has no significant effect on the pharmacokinetics of tadalafil. Co-administration of Tadalafil and Nizatidine reduces the gastric pH.
Nitrates: Concomitant use of tadalafil with any other organic nitrates is contraindicated as it may augment hypotensive effects of nitrates.
Warfarin: There is no significant effect on the exposure to warfarin nor did tadalafil affect changes in the prothrombin time induced by warfarin.
Acetylsalicylic Acid: Tadalafil did not potentiate the increase in bleeding time caused by ASA.
Antihypertensive Agents: Co-administration of tadalafil with alpha-adrenergic receptor blockers may augment blood pressure lowering effects of anti-hypertensive agents (e.g. doxazosin) which may lead to systemic hypotension.
Alcohol: Tadalafil has no effect in the alcohol concentration and vice versa. Postural dizziness and orthostatic hypotension were observed but can be prevented by reducing dose of alcohol.
Theophylline: Tadalafil has no significant effect on the pharmacokinetics and pharmacodynamics of theophylline.