No clinically significant pharmacokinetic interactions have been reported when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide/glibenclamide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was reported to be more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies report that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely due to low extent of metabolism.
Transporters: The results from an in vitro study with human liver tissue indicated that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (e.g. rifampin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors), Acetylsalicylic Acid >3 g/day, and Non-selective NSAIDs: In elderly patients, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may reportedly result in deterioration of renal function, including possible acute renal failure and an increase in serum potassium. These effects are reported to be reversible. Therefore, monitoring of renal function at the beginning of the treatment and periodically as well as adequate hydration of the patient is recommended in patients receiving valsartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is reportedly associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Close monitoring of blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS is advised.
Do not co-administer aliskiren with valsartan in patients with diabetes (see CONTRAINDICATIONS). Avoid use of aliskiren with valsartan in patients with renal impairment (GFR <60 ml/min).
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including valsartan. Monitoring of serum lithium levels during concomitant use is recommended.
Pediatric population: In hypertension in children and adolescents, where underlying renal abnormalities are common, caution is recommended with the concomitant use of valsartan and other substances that inhibit the renin angiotensin aldosterone system which may increase serum potassium. Renal function and serum potassium should be closely monitored.
Clinical Laboratory Test Findings: In reported controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.
Creatinine: In reported controlled clinical trials of hypertensive patients, minor elevations in creatinine have been reported to occur in a smaller percentage of patients taking valsartan. In reported heart failure trials, ≥ 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was reported in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were reported in 0.4% and 0.8%, respectively, of valsartan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient reportedly discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (≥150%) of liver chemistries reported in valsartan-treated patients.
Neutropenia: Neutropenia has been reported in patients treated with valsartan.
Serum Potassium: In hypertensive patients, >20% increases in serum potassium have been reported in 4.4% of valsartan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium have been reported in 10.0% of valsartan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In reported heart failure trials, greater than 50% increases in BUN have been reported in 16.6% of valsartan-treated patients as compared to 6.3% of placebo-treated patients.