Uperio Drug Interactions

Anticipated interactions resulting in a contraindication: ACE inhibitors: The concomitant use of UPERIO with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE inhibitor therapy may increase the risk of angioedema. UPERIO must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of UPERIO (see Contraindications, and Dosage & Administration).
Aliskiren: The concomitant use of UPERIO with aliskiren is contraindicated in patients with Type 2 diabetes or in patients with renal impairment (eGFR <60 ml/min/1.73 m²) (see Contraindications).
The combination of UPERIO with direct renin inhibitors such as aliskiren is not recommended (see Precautions). Combination of UPERIO with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension hyperkalaemia and decreased renal function (including acute renal failure) (see Contraindications and Precautions).
Anticipated interactions resulting in concomitant use not being recommended: UPERIO should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of UPERIO (see Precautions).
Observed interactions to be considered: Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters. UPERIO may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of UPERIO increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised upon co-administration of UPERIO with statins. No clinically relevant drug-drug interaction was observed when simvastatin and Uperio were co-administered.
Sildenafil: Addition of a single dose of sildenafil to UPERIO at steady state in patients with hypertension was associated with greater BP reduction compared to administration of UPERIO alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with UPERIO.
Anticipated interactions to be considered: Potassium: Concomitant use of potassium-sparing diuretics (e.g, triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if UPERIO is co-administered with these agents (see Precautions).
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors): In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of UPERIO and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on UPERIO who are taking NSAIDs concomitantly.
Lithium: The potential for a drug interaction between UPERIO and lithium has not been investigated. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended during concomitant use with UPERIO. If a diuretic is also used, the risk of lithium toxicity may be increased further.
Furosemide: Co-administration of UPERIO and furosemide had no effect on the pharmacokinetics of UPERIO but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with UPERIO.
Nitrates, e.g. nitroglycerine: There was no drug-drug interaction between UPERIO and intravenously administered nitroglycerin with regard to blood pressure reduction. Coadministration of nitroglycerin and UPERIO was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone. A similar effect on the heart rate may occur when UPERIO is co-administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.
OATP and MRP2 Transporters: The active metabolite of sacubitril (sacubitrilat) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of UPERIO with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporine), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure to sacubitrilat or valsartan, respectively. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
Metformin: Co-administration of UPERIO with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with UPERIO in patients receiving metformin, the clinical status of the patient should be evaluated.
No significant interactions: No clinically meaningful drug-drug interaction was observed upon co-administration of UPERIO and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol. No interaction is expected with atenolol, indomethacin, glyburide, or cimetidine.
CYP 450 Interactions: In vitro metabolism studies indicate that the potential for CYP 450 - based drug interactions is low since there is limited metabolism of UPERIO via the CYP450 enzymes. UPERIO does not induce or inhibit CYP450 enzymes.