Perindopril

Diuretics: Excessive drop in blood pressure. (7.1) Potassium-Sparing Diuretics/Potassium Supplements: Hyperkalemia. (7.2) Lithium: Increase serum lithium levels, symptoms of lithium toxicity. (7.3) Injectable Gold: Nitritoid reactions (facial flushing, nausea, vomiting, and hypotension). (7.4) NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect. (7.7) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7.8 ) Neprilysin Inhibitor: risk of angioedema ( 7 ).

7.1 Diuretics Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of perindopril erbumine therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of perindopril erbumine, for at least two hours and until blood pressure has stabilized for another hour [see Warnings and Precautions (5.2) ] .

The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

7.2 Potassium Supplements and Potassium-Sparing Diuretics Perindopril erbumine may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

7.3 Lithium Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

7.4 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including perindopril erbumine.

7.5 Digoxin A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with perindopril erbumine, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.

7.6 Gentamicin Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.

7.7 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.8 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on perindopril erbumine and other agents that affect the RAS. Do not co-administer aliskiren with perindopril erbumine in patients with diabetes.

Avoid use of aliskiren with perindopril erbumine in patients with renal impairment (GFR <60 mL/min). 7.9 mTOR Inhibitors Patients taking concomitant mTOR (mammalian target of rapamycin) inhibitor therapy may be at increased risk for angioedema [see Warnings and Precautions (5.1) ].

7.10 Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. [see Warnings and Precautions (5.1) ]

8.1 Pregnancy Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4) ] . Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue perindopril erbumine as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue perindopril erbumine, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to perindopril erbumine for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ] . Radioactivity was detectable in fetuses after administration of 14 C-perindopril to pregnant rats.

8.3 Nursing Mothers Milk of lactating rats contained radioactivity following administration of 14 C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when perindopril erbumine is given to nursing mothers.