Ramipril

7 DRUG INTERACTIONS Diuretics: Possibility of excessive hypotension ( 7.1 ). Lithium: Use with caution (7.4). Gold: Nitritoid reactions have been reported (7.5). NSAIDS use may lead to increased risk of renal impairment and loss of antihypertensive effect (7.6). mTOR inhibitor or neprilysin inhibitor use may increase angioedema risk (7.7). 7.1 Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, reduce the starting dose [ see Dosage and Administration ( 2 ) ]. 7.2 Agents Increasing Serum Potassium Coadministration of ramipril with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. 7.3 Other Agents Affecting RAS In general, avoid combined use of RAS inhibitors. [see Warnings and Precautions (5.7) ] . Do not co-administer aliskiren with Ramipril in patients with diabetes [see Contraindications (4) ] . 7.4 Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. 7.5 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 ramipril. 7.6 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 ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs. 7.7 mTOR Inhibitors or Other Drugs Known to Cause Angioedema Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. [see Warnings and Precautions (5.1) ]

Ramipril capsules are indicated for: - Hypertension, to lower blood pressure and reduce the risk of fatal and nonfatal cardiovascular events - Reduction of risk of myocardial infarction, stroke, and death from cardiovascular causes in patients at high risk - Heart failure post-myocardial infarction, in stable patients who show signs of congestive heart failure within a few days after an acute MI.

2 DOSAGE AND ADMINISTRATIO Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage according to blood pressure response after 2 to 4 weeks of treatment. The usual maintenance dose following titration is 2.5 mg to 20 mg daily as a single dose or equally divided doses ( 2.1 ). Reduction in the risk of myocardial infarction, stroke, or death from cardiovascular causes: 2.5 mg once daily for 1 week, 5 mg once daily for 3 weeks, and increased as tolerated to a maintenance dose of 10 mg once daily (2.2). Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice daily. If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg twice daily. Increase dose as tolerated toward a target dose of 5 mg twice daily, with dosage increases about 3 weeks apart (2.3). Dosage adjustment: See respective sections pertaining to dosage adjustment in special situations ( 2.5 ). 2.1 Hypertension The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ramipril capsules alone, a diuretic can be added. 2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, ramipril capsules can also be given as a divided dose. 2.3 Heart Failure Post-Myocardial Infarction For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of ramipril capsules is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart. After the initial dose of ramipril capsules, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ramipril capsules does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see Warnings and Precautions (5.5) , Drug Interactions (7.1) ]. 2.4 General Dosing Information Generally, swallow ramipril capsules whole. The ramipril capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration. Concomitant administration of ramipril capsules with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium [see Warnings and Precautions (5.8) ]. 2.5 Dosage Adjustment Renal I mpairment Establish baseline renal function in patients initiating ramipril capsules. Usual regimens of therapy with ramipril capsules may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific Populations (8.6) ] . Hypertension For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ramipril capsules once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg. Heart Failure Post-Myocardial Infarction For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ramipril capsules once daily. The dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability. Volume Depletion or Renal Artery Stenosis Blood pressure decreases associated with any dose of ramipril capsules depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.

In hypertension trials, most common were "headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%)." In post-MI heart failure studies, hypotension (11%), increased cough (8%), and dizziness (4%) were notable. Rare but serious reactions include angioedema, hepatic failure, and agranulocytosis.