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Ramipril

FDA Drug Information • Also known as: Ramipril, Vostally

Brand Names
Ramipril, Vostally
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning

  • When pregnancy is detected, discontinue ramipril as soon as possible ( 5.6 ).
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus ( 5.6 ). WARNING: FETAL TOXICITY
  • When pregnancy is detected, discontinue ramipril as soon as possible ( 5.6 ).
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus ( 5.6 ).

    • Description

    11. DESCRIPTION Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°-112°C. The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [ b ]pyrrole-2-carboxylic acid, 1-ethyl ester. Ramipril capsules USP are supplied as hard gelatin capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril. The inactive ingredients present are gelatin, meglumine, pregelatinized starch, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1. The structural formula for ramipril is: Its empirical formula is C 23 H 32 N 2 O 5 and its molecular weight is 416.5. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. structural formula for ramipril

    What Is Ramipril Used For?

    1. INDICATIONS AND USAGE

  • Ramipril capsules USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. ( 1.1 ).
  • Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure post-myocardial infarction ( 1.3 ). 1.1 Hypertension Ramipril capsules USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. 1.3 Heart Failure Post-Myocardial Infarction Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of ramipril to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure [see CLINICAL STUDIES ( 14.3 ) ].

    • Dosage and Administration

    2. DOSAGE AND ADMINISTRATION

  • Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage according to blood pressure response after 2–4 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 ).
  • 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 alone, a diuretic can be added. 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 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, 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 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 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 Impairment Establish...

    • Side Effects (Adverse Reactions)

    6. ADVERSE REACTIONS The most common adverse reactions in patients with hypertension included headache, dizziness, fatigue, and cough ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypertension Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in ramipril patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%). Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% [n=13/651] vs. 1% [n=2/286], respectively). In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome i n the Ramipril group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of patients requiring discontinuation of treatment. Heart Failure Post-Myocardial Infarction AIRE Study: Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on ramipril are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study. Table 1. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality Study Adverse Event Placebo (N=982) Ramipril (N=1004) Hypotension 5% 11% Cough increased 4% 8% Dizziness 3% 4% Angina pectoris 2% 3% Nausea 1% 2% Postural hypotension 1% 2% Syncope 1% 2% Vomiting 0.5% 2% Vertigo 0.7% 2% Abnormal kidney function 0.5% 1% Diarrhea 0.4% 1% Other Adverse Reactions Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain): Body as a whole: Anaphylactoid reactions [see WARNINGS AND PRECAUTIONS ( 5.1 ) ]. Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see WARNINGS AND PRECAUTIONS ( 5.5 ) ] , syncope, and palpitations. Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia. Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. Renal: Acute renal failure. Some hypertensive patients with no...

    Drug Interactions

    7. DRUG INTERACTIONS

  • Diuretics: Possibility of excessive hypotension ( 7.1 ).
  • Lithium: Use with caution ( 7.3 ).
  • Gold: Nitritoid reactions have been reported ( 7.4 ).
  • NSAIDS use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.5 ). 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 ) ]. Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently. 7.2 Other Antihypertensive Agents Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual Blockade of the Renin-Angiotensin-Aldosterone System ( 5.7 ) ]. 7.3 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. 7.4 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 ramipril. 7.5 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...

    • Contraindications

    4. CONTRAINDICATIONS Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema.( 4 ). Ramipril is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

    Pregnancy and Breastfeeding

    8.1 Pregnancy Pregnancy Category D 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 ramipril 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 ramipril unless it is considered life-saving 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 ramipril for hypotension, oliguria, and hyperkalemia [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ]. 17.4 Pregnancy Female patients of childbearing age should be told about the consequences of exposure to ramipril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as...

    8.3 Nursing Mothers Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use ramipril in nursing mothers.

    Overdosage

    10. OVERDOSAGE Single oral doses of ramipril in rats and mice of 10 g/kg to 11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

    How Supplied

    16. HOW SUPPLIED/STORAGE AND HANDLING Ramipril Capsules, USP are available in 5 mg and 10 mg hard gelatin capsules. Descriptions of Ramipril Capsules USP are summarized below. Ramipril Capsules USP, 5 mg are: Size "4" capsules with red cap, imprinted with 'LUPIN' in black ink and red body imprinted with 'RAMIPRIL 5 mg' in black ink, containing white to off-white powder. NDC 63187-073-30 bottles of 30 NDC 63187-073-60 bottles of 60 NDC 63187-073-90 bottles of 90 Ramipril Capsules USP, 10 mg are: Size "4" capsules with light blue cap, imprinted with 'LUPIN' in black ink and light blue body imprinted with 'RAMIPRIL 10 mg' in black ink, containing white to off-white powder. NDC 63187-277-30 bottles of 30 NDC 63187-277-60 bottles of 60 NDC 63187-277-90 bottles of 90 Dispense in light-resistant, tight container with child-resistant closure. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.