There have been no drug interaction studies for DUODART. The following statements reflect the information available on the individual components.
Dutasteride: In vitro drug metabolism studies show that dutasteride is metabolised by human cytochrome P450 isoenzyme CYP3A4. Therefore blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4.
Phase II data showed a decrease in clearance of dutasteride when co-administered with the CYP3A4 inhibitors verapamil (37%) and diltiazem (44%). In contrast no decrease in clearance was seen when amlodipine, another calcium channel antagonist, was co-administered with dutasteride. A decrease in clearance and subsequent increase in exposure to dutasteride, in the presence of CYP3A4 inhibitors, is unlikely to be clinically significant due to the wide margin of safety (up to 10-times the recommended dose has been given to patients for up to six months), therefore no dose adjustment is necessary.
In vitro, dutasteride is not metabolised by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.
Dutasteride neither inhibits human cytochrome P450 drug-metabolising enzymes in vitro nor induces cytochrome P450 isoenzymes CYP1A, CYP2B, and CYP3A in rats and dogs in vivo.
In vitro studies demonstrate that dutasteride does not displace warfarin, acenocoumorol, phenprocoumon, diazepam, or phenytoin from plasma protein, nor do these model compounds displace dutasteride. Compounds that have been tested for drug interactions in man include tamsulosin, terazosin, warfarin, digoxin, and cholestyramine, and no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.
Although specific interaction studies were not performed with other compounds, approximately 90% of the subjects in large Phase III studies receiving dutasteride were taking other medications concomitantly. No clinically significant adverse interactions were observed in clinical trials when dutasteride was co-administered with anti-hyperlipidemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.
Tamsulosin: There is a theoretical risk of enhanced hypotensive effects when tamsulosin hydrochloride is co-administered with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha-1 adrenergic blockers. DUODART should not be used in combination with other alpha-1 adrenergic blockers.
Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 2.2 and 2.8 respectively. Concomitant administration of tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 1.3 and 1.6 respectively. A similar increase in exposure is expected in CYP2D6 poor metabolisers as compared to extensive metabolisers when co-administered with a strong CYP3A4 inhibitor. The effects of co-administration of both CYP3A4 and CYP2D6 inhibitors with tamsulosin hydrochloride have not been evaluated clinically, however there is a potential for significant increase in tamsulosin exposure. (see Precautions).
Concomitant administration of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of tamsulosin hydrochloride. Caution should be used when DUODART is used in combination with cimetidine.
A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive.
Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride.
In three studies, no interactions were seen when tamsulosin (0.4 mg for seven days followed by 0.8 mg for seven days) was given concomitantly with atenolol, enalapril or nifedipine for three months; therefore no dose adjustments are necessary when these drugs are co-administered with DUODART.
Concomitant administration of tamsulosin hydrochloride (0.4 mg/day for two days, followed by 0.8 mg/day for five to eight days) and a single intravenous dose of theophylline (5 mg/kg) resulted in no change in the pharmacokinetics of theophylline; therefore no dose adjustment is necessary.
Concomitant administration of tamsulosin hydrochloride (0.8 mg/day) and a single intravenous dose of furosemide (20 mg) produced an 11% to 12 % reduction in the Cmax and AUC of tamsulosin hydrochloride, however these changes are expected to be clinically insignificant and no dose adjustment is necessary.