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| |genericName=generic name
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| |drugClass=Adrenergic receptor agonist
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| |indication=a list of indications, separated by commas.
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| |hasBlackBoxWarning=Yes
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| |adverseReactions=a list of adverse reactions, separated by commas.
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| |blackBoxWarningTitle=Warning Title
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
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| |fdaLIADAdult======Condition 1=====
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| |contraindications====Ramipril===
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| :* 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).
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| :* Do not co-administer [[aliskiren]] with Altace in patients with [[diabetes]]
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| ====Hydrochlorothiazide====
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| *Hydrochlorothiazide is contraindicated in [[anuria]]. It is also contraindicated in patients who have previously demonstrated [[hypersensitivity]] to hydrochlorothiazide or other sulfonamide-derived drugs.
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| |warnings====Ramipril===
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| ====Anaphylactoid and Possibly Related Reactions====
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| Presumably because drugs that act directly on the [[renin-angiotensin-aldosterone system]] (e.g., [[ACE inhibitors]]) affect the metabolism of [[eicosanoids]] and polypeptides, including endogenous [[bradykinin]], patients receiving these drugs (including Altace) may be subject to a variety of adverse reactions, some of them serious.
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| ====Angioedema====
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| =====Head and Neck Angioedema=====
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| Patients with a history of [[angioedema]] unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
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| Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal [[stridor]] or [[angioedema]] of the face, tongue, or glottis occurs, discontinue treatment with Altace and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous [[epinephrine]] solution 1:1000 [0.3 mL to 0.5 mL]) promptly.
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| In considering the use of Altace, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
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| In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically.
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| Patients taking concomitant [[mTOR inhibitor]] (e.g. [[temsirolimus]]) therapy may be at increased risk for angioedema
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| =====Intestinal Angioedema=====
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| Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with [[abdominal pain]] (with or without [[nausea]] or [[vomiting]]); in some cases there was no prior history of [[facial angioedema]] and [[C-1 esterase]] levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
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| ====Anaphylactoid Reactions During Desensitization====
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| Two patients undergoing desensitizing treatment with [[hymenoptera venom]] while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
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| ====Anaphylactoid Reactions During Membrane Exposure====
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| Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing [[low-density lipoprotein]] apheresis with dextran sulfate absorption.
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| ====Hepatic Failure and Impaired Liver Function====
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| Rarely, ACE inhibitors, including Altace, have been associated with a syndrome that starts with [[cholestatic jaundice]] and progresses to [[fulminant hepatic necrosis]] and sometimes death. The mechanism of this syndrome is not understood. Discontinue Altace if patient develops jaundice or marked elevations of hepatic enzymes.
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| As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.
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| ====Renal Impairment====
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| As a consequence of inhibiting the [[renin-angiotensin-aldosterone system]], changes in renal function may be anticipated in susceptible individuals. In patients with severe [[congestive heart failure]] whose renal function may depend on the activity of the [[renin-angiotensin-aldosterone system]], treatment with ACE inhibitors, including Altace, may be associated with oliguria or progressive [[azotemia]] and rarely with [[acute renal failure]] or death.
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| In hypertensive patients with unilateral or bilateral [[renal artery stenosis]], increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of Altace and/or [[diuretic therapy]]. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in [[blood urea nitrogen]] and [[serum creatinine]], usually minor and transient, especially when Altace has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Altace and/or discontinuation of the diuretic may be required.
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| ====Neutropenia and Agranulocytosis====
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| In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, [[agranulocytosis]], [[pancytopenia]], and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., [[systemic lupus erythematosus]], [[scleroderma]]) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
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| ====Hypotension====
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| ===General Considerations===
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| Altace can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Altace, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, [[dialysis]], [[diarrhea]], or vomiting. Correct volume- and salt-depletion before initiating therapy with Altace.
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| If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Altace treatment usually can be continued following restoration of blood pressure and volume.
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| ====Heart Failure Post-Myocardial Infarction====
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| In patients with heart failure post-myocardial infarction who are currently being treated with a [[diuretic]], symptomatic [[hypotension]] occasionally can occur following the initial dose of Altace. If the initial dose of 2.5 mg Altace cannot be tolerated, use an initial dose of 1.25 mg Altace to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.
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| ====Congestive Heart Failure====
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| In patients with [[congestive heart failure]], with or without associated [[renal insufficiency]], ACE inhibitor therapy may cause excessive [[hypotension]], which may be associated with [[oliguria]] or [[azotemia]] and rarely, with [[acute renal failure]] and death. In such patients, initiate Altace therapy under close medical supervision and follow patients closely for the first 2 weeks of treatment and whenever the dose of Altace or diuretic is increased.
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| ====Surgery and Anesthesia ====
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| In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block [[angiotensin II]] formation that would otherwise occur secondary to compensatory [[renin]] release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
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| ====Fetal Toxicity====
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| ====Pregnancy Category D====
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| 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 Altace as soon as possible.
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| ====Dual Blockade of the Renin-Angiotensin-Aldosterone System====
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| 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. Closely monitor blood pressure, renal function and electrolytes in patients on Altace and other agents that affect the RAS.
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| ====Telmisartan====
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| The ONTARGET trial enrolled 25,620 patients >55 years old with [[atherosclerotic disease]] or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, [[MI]], [[stroke]] and [[heart failure]] hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of [[serum creatinine]], or [[dialysis]]) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.
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| ====Aliskiren====
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| 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) [see Drug Interactions (7.6)].
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| ====Hyperkalemia====
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| In clinical trials with Altace, [[hyperkalemia]] (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include [[renal insufficiency]], [[diabetes mellitus]], and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace.
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| ====Cough====
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| Presumably caused by inhibition of the degradation of endogenous [[bradykinin]], persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
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| ===Hydrochlorothiazide===
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| *Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
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| *Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
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| *[[Sensitivity]] reactions may occur in patients with or without a history of allergy or bronchial asthma.
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| *The possibility of exacerbation or activation of [[systemic lupus erythematosus]] has been reported.
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| *In general, lithium should not be given with diuretics
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| |clinicalTrials====Ramipril===
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| 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.
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| ====Hypertension====
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| 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%).
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| 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).
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| 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.
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| ====Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes====
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| =====HOPE Study=====
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| 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.
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| ====Heart Failure Post-Myocardial Infarction====
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| =====AIRE Study=====
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| 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.
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| ====Other Adverse Reactions====
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| 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):
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| ====Body as a whole====
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| ====Cardiovascular====
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| Symptomatic [[hypotension]] (reported in 0.5% of patients in U.S. trials) [[syncope]], and [[palpitations]].
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| ====Hematologic====
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| Pancytopenia, hemolytic anemia, and thrombocytopenia.
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| 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]].
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| ====Renal====
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| [[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.
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| ====Angioneurotic edema====
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| [[Angioneurotic edema]] has been reported in 0.3% of patients in U.S. clinical trials of Altace.
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| ====Gastrointestinal====
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| [[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.
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| ====Dermatologic====
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| 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]].
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| ====Neurologic and Psychiatric====
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| [[Anxiety]], [[amnesia]], [[convulsions]], [[depression]], [[hearing loss]], [[insomnia]], [[nervousness]], [[neuralgia]], [[neuropathy]], [[paresthesia]], [[somnolence]], [[tinnitus]], [[tremor]], [[vertigo]], and vision disturbances.
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| ====Miscellaneous====
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| 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.
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| =====Diuretics====
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| 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.
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| 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.
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| ====Other Antihypertensive Agents====
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| 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]].
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| The combination of ramipril and [[propranolol]] showed no adverse effects on dynamic parameters (blood pressure and heart rate).
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| 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.
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| ====Lithium====
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| 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.
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| ====Gold====
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| 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.
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| ====Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)====
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| 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.
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| The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by [[NSAIDs]].
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| ====Aliskiren====
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| 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).
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| ====mTOR Inhibitors====
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| Patients taking concomitant [[mTOR inhibitor]] (e.g. [[temsirolimus]]) therapy may be at increased risk for angioedema.
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| ====Carcinogenesis, Mutagenesis, Impairment of Fertility====
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| 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.
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| 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.
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| ====Other====
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| 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.
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| ===Hydrochlorothiazide===
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| =====General=====
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| * [[Chest pain]], weakness, fever, viral infection.
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| =====Cardiovascular=====
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| * [[Orthostatic hypotension]] (seen in 1.8% of fosinopril sodium and hydrochlorothiazide patients and 0.3% of placebo patients; no patients discontinued therapy due to orthostatic hypotension), edema, flushing, rhythm disturbance, syncope.
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| =====Dermatologic=====
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| * [[Pruritus]], [[rash]].
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| =====Endocrine/Metabolic=====
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| * Sexual dysfunction, change in libido, breast mass.
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| =====Gastrointestinal=====
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| * Nausea/vomiting, [[diarrhea]], [[dyspepsia]]/heartburn, abdominal pain, [[gastritis]]/ esophagitis.
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| =====Immunologic=====
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| * [[Angioedema]] (see WARNINGS: Head and Neck [[Angioedema]] and Intestinal Angioedema).
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| =====Musculoskeletal=====
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| *[[Myalgia]]/muscle cramps.
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| =====Neurologic/Psychiatric=====
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| * [[Somnolence]], [[depression]], numbness/paresthesia.
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| =====Respiratory=====
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| * Sinus congestion, [[pharyngitis]], [[rhinitis]].
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| =====Special Senses=====
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| * [[Tinnitus]].
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| =====Urogenital=====
| |
| * Urinary tract infection, urinary frequency, dysuria.
| |
|
| |
| =====Laboratory Test Abnormalities=====
| |
| * Serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides, and calcium (see PRECAUTIONS). [[Neutropenia]].
| |
|
| |
| * Antihypertensive monotherapy with fosinopril has been evaluated for safety in more than 1500 patients, of whom approximately 450 patients were treated for a year or more. The observed adverse events included events similar to those seen with fosinopril sodium and hydrochlorothiazide; in addition, the following others have also been reported with fosinopril:
| |
|
| |
| =====Cardiovascular=====
| |
| * [[Angina]], myocardial infarction, cerebrovascular accident, [[hypertensive crisis]], [[hypotension]], claudication.
| |
|
| |
| =====Dermatologic=====
| |
| * [[Urticaria]], [[photosensitivity]].
| |
|
| |
| =====Endocrine/Metabolic=====
| |
| * [[Gout]].
| |
|
| |
| =====Gastrointestinal=====
| |
| * [[Pancreatitis]], [[hepatitis]], [[dysphagia]], abdominal distention, flatulence, appetite/weight change, dry mouth.
| |
|
| |
| =====Hematologic=====
| |
| * Lymphadenopathy.
| |
|
| |
| =====Musculoskeletal=====
| |
| * [[Arthralgia]].
| |
|
| |
| =====Neurologic/Psychiatric=====
| |
| * Memory disturbance, [[tremor]], confusion, mood change, sleep disturbance.
| |
|
| |
| =====Respiratory=====
| |
| * Bronchospasm, laryngitis/hoarseness, [[epistaxis]], and (in two patients) a symptom-complex of cough, bronchospasm, and eosinophilia.
| |
|
| |
| =====Special Senses=====
| |
| * Vision disturbance, taste disturbance, eye irritation.
| |
|
| |
| =====Urogenital=====
| |
| * Renal insufficiency.
| |
|
| |
| =====Laboratory Test Abnormalities=====
| |
| * Elevations (usually transient and minor) of BUN and creatinine have been observed, but these have not been more frequent than in parallel patients treated with placebo. The hemoglobin in fosinopril-treated patients generally decreases by an average of 0.1 g/dL, but this nonprogressive change has never been symptomatic. Leukopenia and eosinophilia have also been reported.
| |
|
| |
| * Serum levels of liver function tests (transaminases, LDH, alkaline phosphatase and serum bilirubin) have occasionally been found to be elevated, and these elevations have lead to discontinuation of therapy in 0.7% of patients. Other risk factors for liver dysfunction have often been present in these cases; in any event the elevations generally have resolved after discontinuation of therapy with fosinopril.
| |
| Other Adverse Events Reported with ACE Inhibitors
| |
| Other adverse effects reported with ACE inhibitors include cardiac arrest; pancytopenia, hemolytic anemia; aplastic anemia; thrombocytopenia; bullous pemphigus, exfoliative dermatitis; and a syndrome that may include one or more of arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermopathy, positive ANA titer, leukocytosis, eosinophilia, and elevated ESR.
| |
| Hydrochlorothiazide has now been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency.
| |
|
| |
| =====Cardiovascular=====
| |
| * [[Orthostatic hypotension]] (may be potentiated by alcohol, barbiturates, or narcotics).
| |
|
| |
| =====Gastrointestinal=====
| |
| * [[Pancreatitis]], [[jaundice]] (intrahepatic cholestatic), [[sialadenitis]], [[vomiting]], [[diarrhea]], cramping, [[nausea]], gastric irritation, constipation, and anorexia.
| |
|
| |
| =====Hematologic=====
| |
| * Aplastic [[anemia]], [[agranulocytosis]], [[leukopenia]], [[thrombocytopenia]], and [[hemolytic anemia]].
| |
|
| |
| =====Immunologic=====
| |
| * Necrotizing angiitis, [[Stevens-Johnson syndrome]], respiratory distress (including [[pneumonitis]] and pulmonary edema), anaphylactic reactions, [[purpura]],[[urticaria]], [[rash]], and [[photosensitivity]].
| |
|
| |
| =====Metabolic=====
| |
| * [[Hyperglycemia]], glycosuria, and hyperuricemia.
| |
|
| |
| =====Musculoskeletal=====
| |
| * Muscle spasm.
| |
|
| |
| =====Neurologic=====
| |
| * [[Vertigo]], lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.
| |
| |postmarketing=(Description)
| |
| |drugInteractions====Ramipril===
| |
|
| |
| ====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.
| |
|
| |
| ===Hydrochlorothiazide===
| |
|
| |
| * Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.
| |
|
| |
| * Thiazides may increase the responsiveness to tubocurarine.
| |
|
| |
| * The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents; the effects (if any) of these agents on the antihypertensive effect of fosinopril sodium and hydrochlorothiazide have not been studied.
| |
|
| |
| * By alkalinizing the urine,[[hydrochlorothiazide]] may decrease the effectiveness of methenamine.
| |
|
| |
| * [[Cholestyramine]] and [[Colestipol]] Resins:Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
| |
|
| |
| * Hydrochlorothiazide: Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
| |
|
| |
| * Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.
| |
|
| |
| * No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.
| |
| |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=====
| |
|
| |
| (Description regarding monitoring, from ''Warnings'' section)
| |
|
| |
| =====Condition 2=====
| |
|
| |
| (Description regarding monitoring, from ''Warnings'' section)
| |
|
| |
| =====Condition 3=====
| |
|
| |
| (Description regarding monitoring, from ''Warnings'' section)
| |
| |IVCompat====Solution===
| |
|
| |
| ====Compatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Not Tested====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Variable====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Incompatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ===Y-Site===
| |
|
| |
| ====Compatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Not Tested====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Variable====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Incompatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ===Admixture===
| |
|
| |
| ====Compatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Not Tested====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Variable====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Incompatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ===Syringe===
| |
|
| |
| ====Compatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Not Tested====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Variable====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Incompatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ===TPN/TNA===
| |
|
| |
| ====Compatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Not Tested====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Variable====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
|
| |
| ====Incompatible====
| |
|
| |
| * Solution 1
| |
| * Solution 2
| |
| * Solution 3
| |
| |overdose====Acute Overdose===
| |
|
| |
| ====Signs and Symptoms====
| |
|
| |
| (Description)
| |
|
| |
| ====Management====
| |
|
| |
| (Description)
| |
|
| |
| ===Chronic Overdose===
| |
|
| |
| ====Signs and Symptoms====
| |
|
| |
| (Description)
| |
|
| |
| ====Management====
| |
|
| |
| (Description)
| |
| |drugBox={{Drugbox2
| |
| | verifiedrevid =
| |
| | IUPAC_name =
| |
| | image =
| |
| | drug_name =
| |
|
| |
| <!--Clinical data-->
| |
| | tradename =
| |
| | MedlinePlus =
| |
| | licence_US =
| |
| | pregnancy_AU =
| |
| | pregnancy_US =
| |
| | legal_status =
| |
| | routes_of_administration =
| |
|
| |
| <!--Pharmacokinetic data-->
| |
| | bioavailability =
| |
| | metabolism =
| |
| | elimination_half-life =
| |
| | excretion =
| |
|
| |
| <!--Identifiers-->
| |
| | CAS_number_Ref =
| |
| | CAS_number =
| |
| | ATC_prefix =
| |
| | ATC_suffix =
| |
| | PubChem =
| |
| | IUPHAR_ligand =
| |
| | DrugBank_Ref =
| |
| | DrugBank =
| |
| | ChemSpiderID_Ref =
| |
| | ChemSpiderID =
| |
| | UNII_Ref =
| |
| | UNII =
| |
| | KEGG_Ref =
| |
| | KEGG =
| |
| | ChEBI_Ref =
| |
| | ChEBI =
| |
| | ChEMBL_Ref =
| |
| | ChEMBL =
| |
|
| |
| <!--Chemical data-->
| |
| | C= | H= | N= | O=
| |
| | molecular_weight =
| |
| | smiles =
| |
| | InChI =
| |
| | InChIKey =
| |
| | StdInChI_Ref =
| |
| | StdInChI =
| |
| | StdInChIKey_Ref =
| |
| | StdInChIKey =
| |
| | melting_point =
| |
| }}
| |
| |mechAction======Ramipril=====
| |
|
| |
| =====Hydrochlorothiazide=====
| |
|
| |
| * Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.
| |
| |structure=(Description with picture)
| |
| |PD=(Description)
| |
| |PK=(Description)
| |
| |nonClinToxic======Ramipril=====
| |
|
| |
| =====Hydrochlorothiazide=====
| |
|
| |
| * Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
| |
|
| |
| * Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.
| |
|
| |
| * No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.
| |
| |clinicalStudies======Condition 1=====
| |
|
| |
| (Description)
| |
|
| |
| =====Condition 2=====
| |
|
| |
| (Description)
| |
|
| |
| =====Condition 3=====
| |
|
| |
| (Description)
| |
| |howSupplied=(Description)
| |
| |fdaPatientInfo=(Patient Counseling Information)
| |
| |nlmPatientInfo=(Link to patient information page)
| |
| |lookAlike=* (Paired Confused Name 1a) — (Paired Confused Name 1b)
| |
| * (Paired Confused Name 2a) — (Paired Confused Name 2b)
| |
| * (Paired Confused Name 3a) — (Paired Confused Name 3b)
| |
| |drugShortage=Drug Shortage
| |
| }}
| |