Side Effects of Altace (ramipril)

Altace (ramipril) is an angiotensin converting enzyme (ACE) inhibitor used to treat high blood pressure (hypertension) and heart failure and to prevent kidney failure due to high blood pressure and diabetes.

ACE is important because it is an enzyme responsible for producing the chemical, angiotensin II. Angiotensin II causes muscles in most arteries, including the arteries of the heart, to contract, thereby narrowing the arteries and elevating blood pressure.

ACE inhibitors such as Altace lower blood pressure by reducing the production of angiotensin II, thereby relaxing arterial muscle and enlarging arteries. When the blood pressure is lower, the heart does not have to work as hard to pump blood.

The arteries supplying the heart with blood also enlarge during treatment with ACE inhibitors. This increases the flow of blood and oxygen to the heart, further improving the ability of the heart to pump blood.

The effects of ACE inhibitors are particularly beneficial to people with congestive heart failure. In the kidneys, the narrowing of the arteries by angiotensin II decreases blood flow. ACE inhibitors enlarge and reduce blood pressure in the arteries that supply blood to the kidneys. This reduces damage to the kidneys resulting from high blood pressure. 

Common side effects of Altace include

• dry and persistent cough (that goes away after discontinuing the drug),
• increased potassium in the blood (hyperkalemia),
• abdominal pain,
• constipation,
• diarrhea,
• rash,
• dizziness,
• fatigue,
• headache,
• loss of taste,
• loss of appetite,
• nausea,
• vomiting,
• fainting and numbness or
• tingling in the hands or feet.

Serious side effects of Altace include

• fainting,
• symptoms of a high potassium blood level (such as muscle weakness, slow or irregular heartbeat),
• signs of infection (such as fever, chills, persistent sore throat), and
• changes in the amount of urine.

Drug interactions of Altace include diuretics (water pills), lithium, potassium supplements, salt substitutes containing potassium, and aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen.

ACE inhibitors, including Altace, are harmful to a fetus and should not be used during pregnancy. Altace should not be administered to women who are breastfeeding.

Ramipril generally is well-tolerated, and side effects usually are mild and transient.

Common side effects include a dry, persistent cough and increased potassium in the blood (hyperkalemia). Coughing resolves after discontinuing the drug.

Other important side effects include:

• abdominal pain,
• constipation,
• diarrhea,
• rash,
• dizziness,
• fatigue,
• headache,
• loss of taste,
• loss of appetite,
• nausea,
• vomiting,
• fainting
• and numbness or
• tingling in the hands or feet.

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.

Table 1:Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study

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.

Table 2: Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality 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):

Body as a whole: Anaphylactoid reactions.

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.

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.

Agents Increasing Serum Potassium

Coadministration of Altace with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Other Agents Affecting RAS

In general, avoid combined use of RAS inhibitors. Do not co-administer aliskiren with Altace in patients with diabetes.

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.

mTOR Inhibitors

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