| SECTION 2
The following has been added:
(as hemifumarate)
SECTION 4.2
The following has been added:
Grapefruit juice should not be taken together with Rasilez
SECTION 4.3
The following has been added:
The concomitant use of aliskiren with ciclosporin, a highly potent P-gp inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).
SECTION 4.4
The following has been added:
Moderate P-gp inhibitors
Co-administration of aliskiren 300 mg with ketoconazole 200 mg resulted in a 76% increase in aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations more than plasma concentrations. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole (see section 4.5).
SECTION 4.5
The following has been added:
Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see P-glycoprotein interactions below).
P-glycoprotein interactions
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of Rasilez. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.
P-gp substrates or weak inhibitors
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%.
Moderate P-gp inhibitors
Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and Cmax). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of ketoconazole is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. Yet, P-gp inhibitors are expected to increase tissue concentrations more than plasma concentrations. Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate pgp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).
P-gp potent inhibitors
A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).
Potassium and potassium-sparing diuretics
Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. If co-medication is considered necessary, caution is advisable.
Grapefruit juice
Due to the lack of data a potential interaction between grapefruit juice and aliskiren cannot be excluded. Grapefruit juice should not be taken together with Rasilez.
The following has been deleted:
Ketoconazole
Co-administration of ketoconazole 200 mg twice daily with Rasilez resulted in a 1.8-fold increase in plasma levels of Rasilez (AUC and Cmax). The change in plasma levels in the presence of ketoconazole is expected to be within the range that would be achieved if the dose were doubled; Rasilez doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be safe in well-controlled clinical trials. Preclinical studies indicate that Rasilez and ketoconazole co-administration enhances Rasilez gastrointestinal absorption and decreases biliary excretion.
SECTION 10
The date of revision has been changed from 09 Jul 2008 to 28 Aug 2008
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