Sandboxtry

{{DrugProjectFormSinglePage |genericName=generic name |aOrAn=a |drugClass=Adrenergic receptor agonist |indication=a list of indications, separated by commas. |hasBlackBoxWarning=Yes |adverseReactions=a list of adverse reactions, separated by commas. |blackBoxWarningTitle=Warning Title |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult======Condition 1=====

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|contraindications=:* Altace 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).

• Do not co-administer aliskiren with Altace in patients with diabetes

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(Description) |clinicalTrials=====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

Altace 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 Altace and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace 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 Altace 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 Altace. 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 Altace, only asthenia (fatigue) was more common on Altace 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 in the Altace 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 Altace patients, with about 4% of patients requiring discontinuation of treatment.

Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

HOPE Study

Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials.

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 Altace are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.

Other Adverse Reactions

Other adverse reactions reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):

Cardiovascular

Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) 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 Altace alone and in 1.5% of patients receiving Altace plus a diuretic.

Renal

Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking Altace, particularly when Altace was given concomitantly with a diuretic.

Angioneurotic edema

Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of Altace.

Gastrointestinal

Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance.

Dermatologic

Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

Neurologic and Psychiatric

Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

Miscellaneous

As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.

Other

Arthralgia, arthritis, dyspnea, edema, [[epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during Altace therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.

Clinical Laboratory Test Findings

Creatinine and Blood Urea Nitrogen

Increases in creatinine levels occurred in 1.2% of patients receiving Altace alone, and in 1.5% of patients receiving Altace and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving Altace alone and in 3% of patients receiving Altace with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently.

Hemoglobin and Hematocrit

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 Altace alone and in 1.5% of patients receiving Altace plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (causal relationships unknown)

Clinically important changes in standard laboratory tests were rarely associated with Altace administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests. |postmarketing=(Description) |drugInteractions=====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 Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.

Altace 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.

Other Antihypertensive Agents

Limited experience in controlled and uncontrolled trials combining Altace 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.

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.

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 Altace.

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.

Aliskiren

Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2).

mTOR Inhibitors

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Other

Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation. |useInPregnancyFDA=(Description) |useInPregnancyAUS=(Description) |useInLaborDelivery=(Description) |useInNursing=(Description) |useInPed=(Description) |useInGeri=(Description) |useInGender=(Description) |useInRace=(Description) |useInRenalImpair=(Description) |useInHepaticImpair=(Description) |useInReproPotential=(Description) |useInImmunocomp=(Description) |othersTitle=Others |useInOthers=(Description) |administration=(Oral/Intravenous/etc) |monitoring======Condition 1=====

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(Description regarding monitoring, from Warnings section) |IVCompat====Solution===

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|overdose=:* Single oral doses of ramipril in rats and mice of 10 g/kg–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.

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Sandboxtry
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