Hypertension Altace has been evaluated for safety in more than 4,000 patients with hypertension, including 1,230 patients were studied in US trials, and 1,107 were studied abroad controlled trials. Nearly 700 of these patients were treated for at least one year. The overall incidence of side effects was similar for Altace and placebo. The most common side effects clinical (possibly or probably related to the study drug) reported by patients receiving US Altace in placebo-controlled trials were: headache (5.4%), "Vertigo" (2 , 2%) and fatigue or asthenia (2.0%), but only the latter was more common in patients Altace that in patients who received placebo. Generally, the side effects were mild and transient, and there was no comparison with the total dose in the range of 1.25 to 20 mg. Discontinuation of treatment due to side effects was needed in about 3% of patients treated with USA Altace. The most frequent reasons for the judgment were cough (1.0%), "Vertigo" (0.5%), and impotence (0.4%). Observed side effects considered possibly or probably related to the study drug, which took place in US placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% versus 1%). US patients in the placebo-controlled studies Altace (N = 651) Placebo (N = 286) N% N% Asthenia (Fatigue) 13 2 2 1 In placebo-controlled trials, there was also an excess of upper respiratory tract infection and flu syndrome in the ramipril group, and not attributed at the time to ramipril. As these studies were carried out before the report of the cough of ACE inhibitors has been recognized, some of these events may represent ramipril induced cough. In a 1-year study, increased cough has been observed in approximately 12% of patients ramipril, with about 4% of these patients requiring discontinuation of therapy. Heart failure after myocardial infarction Adverse (with the exception of laboratory abnormalities) discussed possibly / probably related to the study drug, which took place in more than one percent of patients and more frequently on ramipril are listed below . The frequency represent the experiences of the study AIRE. The follow-up time between 6 and 46 months for the study. The percentage of patients with adverse events possibly / probably related to the study drug Other adverse events reported in controlled clinical trials (less than 1% of the patients ramipril), or more rare, seen in the post-marketing events, including (in some, a causal link with the use of drugs is uncertain ): As Whole body: anaphylaxis. (See WARNINGS.) Cardiovascular: symptomatic hypotension (reported in 0.5% of patients in the American trial) (See WARNINGS and PRECAUTIONS), syncope and palpitations. Hematologic: pancytopenia, thrombocytopenia and hemolytic anemia. Rein: Some hypertensive patients without apparent pre-existing renal disease have developed minor, usually trnsient, increased blood urea nitrogen and serum creatinine when taking Altace, especially when Altace was given in combination with a diuretic . (See WARNINGS.) Acute renal insufficiency. Angioneurotic edema: angioneurotic edema was reported in 0.3% of patients in clinical trials US. (See WARNINGS.) Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with the enzyme suggesting changes pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis , increased salivation and taste disturbance. Dermatological: Apparent hypersensitivity reactions (shown by pruritus, and rash, with or without fever), photosensitivity, purpura onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome. Neurological and Psychiatric: anxiety, amnesia, seizures, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, dizziness, and blurred vision. Various: As with other ACE inhibitors, a symptom complex has been reported that may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia / arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity rash Skin and other dermatologic manifestations. In addition, like other ACE inhibitors, eosinophilic pneumonia has been reported. Fœtale / neonatal mortality and morbidity. See WARNINGS: Fetal / mortality and neonatal morbidity. Others: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. Post-Marketing Experience: In addition to the reported side effects in clinical trials, there have been rare cases reported during hypoglycemia Altace therapy when administered to patients simultaneously taking oral hypoglycemic agents or insulin. The causal link is unknown. Laboratory test clinical findings: Creatinine and blood urea nitrogen: creatinine increase 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 only Altace and 3% of patients with a diuretic Altace. None of these increases required discontinuation of therapy. 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, should be particularly likely to occur in patients with stenosis of the renal artery. (See WARNINGS and PRECAUTIONS.) Since ramipril decreases the secretion of aldosterone, the elevation of serum potassium may occur. Extras potassium and potassium-sparing diuretics should be given with caution, and the patient serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS). Hematocrit and hemoglobin: A decrease in hemoglobin and 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 at 1, 5% of patients receiving a diuretic More Altace. No US patients treatment because of the decline of hemoglobin or hematocrit. Other (relationship unknown cause): clinically significant changes in the standard laboratory tests were rarely associated with the administration Altace. Elevation of liver enzymes, uric acid serum bilirubin, and blood glucose were reported, as well as cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In the United States trials, less than 0.2% of patients discontinued the treatment of laboratory abnormalities, and all these cases were proteinuria or abnormal-tests of liver function. Drug Interactions With nonsteroidal anti-inflammatory drugs: Rarely, treatment with ACE inhibitors and nonsteroidal anti-inflammatory drugs have been associated with worsening kidney failure and an increase in serum potassium. With diuretics: Patients on diuretics, particularly those in which little diuretic, may experience an excessive reduction in blood pressure after starting treatment with Altace. The possibility of Altace with hypotensive effects can be minimized by either abandoning diuretic or increasing the salt before starting treatment with Altace. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.) With supplements potassium and potassium-sparing diuretics: Altace can mitigate the loss of potassium caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if the concurrent use of these agents is indicated, it should be given with caution, and the patient serum potassium should be monitored frequently. With lithium: Increased serum lithium levels and the symptoms of lithium toxicity has been reported in patients receiving ACE inhibitors during treatment with lithium. These medications must be co-administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Others: Neither Altace nor its metabolites were found to interact with digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. Combining Altace and propranolol showed no adverse effects on the dynamic parameters (blood pressure and heart rate). Co-administration of warfarin Altace and did not adversely affect the anticoagulant effects of this drug. In addition, the administration of Altace with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects' status of the fight against coagulation. Anaphylactoïdes and possibly linked reactions Presumably because of angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and endogenous peptide which bradykinin, patients receiving ACE inhibitors (including Altace) can be subject to a variety of adverse effects, some of which are serious. Head and neck angioedema Patients with a history of angioedema unrelated to IEC to an increased risk of angioedema while receiving an ACE inhibitor. (See CONTRAINDICATIONS.) Angio-oedèmes of the face, extremities, lips, tongue, glottis and larynx has been reported in patients treated with inhibitors of angiotensin converting enzyme. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, glottis or occurs, Altace treatment should be discontinued immediately and the establishment of an appropriate therapy. Where there is the tongue, glottis or larynx, which can lead to airway obstruction, therapy, eg, subcutaneous epinephrine solution 1:1,000 (0.3 mL to 0.5 mL) should be administered promptly. (See REACTIONS.) Intestinaux Angioedema Intestinal angioedema have 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 history of angioedema face and the C-1 esterase levels were normal. Angioedema has been diagnosed by the procedures, including abdominal computed tomography or ultrasound, or at surgery, and the symptoms disappeared after discontinuation of the ACE inhibitor. Angioedema intestinal should be included in the differential diagnosis of patients with ACE inhibitors with abdominal pain. In a large US study post, angioedema (defined as the reports of CT angio, face, larynx, tongue, or throat swelling) was reported in 3 / 1523 (0.20%) black patients and in 8 / 8680 (0 .09%) patients white. These rates are not statistically different. Anaphylactoïdes during desensitisation: Two patients treated with desensitization hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily, but they have reappeared after rechallenge involuntary. Anaphylactoïdes during membrane exposure: Anaphylactoïdes have been reported in patients on dialysis with high f1ux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoïdes have also been reported in patients undergoing low-density lipoprotein apheresis with the absorption of dextran sulfate. Hypotension Altace can cause symptomatic hypotension or after the initial dose or at a dose when the dose was increased. Ramipril has only rarely been associated with hypotension singles hypertensive. Symptomatic hypotension is the most likely to occur in patients who were the volume and / or salt-depleted as a result of long diuretic therapy, dietary salt restriction, diarrhea or vomiting. Volume and / or salt depletion should be corrected before starting therapy with Altace. In patients with heart failure, with or without kidney failure, excessive IEC can cause hypotension, which may be associated with azotemia and oliguria or, rarely, acute renal failure and death. In these patients, Altace therapy should be initiated under close medical supervision, they should be closely monitored during the first 2 weeks of treatment and whenever the dose of ramipril or diuretic is increased. If hypotension, the patient should be placed in a supine position and, if necessary, treated by intravenous infusion of saline solution. Altace treatment can usually be prosecuted following restoration of blood pressure and volume. Liver Failure Rarely, IEC, including Altace, were associated with a syndrome that starts with cholestatic jaundice and the fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations in liver enzymes should discontinue the IEC and appropriate medical monitoring. Neutropenia / Agranulocytosis Like other ACE inhibitors, rarely, a slight in isolated cases severe reduction in red blood cells and hemoglobin content, white blood cells or platelets can develop. In isolated cases, agranulocytosis, pancytopenia, and the bone marrow may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen vascular diseases (eg systemic lupus erythematosus, scleroderma), and renal. Monitoring of white blood cells should be considered in patients with collagen vascular diseases, especially if the disease is linked to renal failure. Fœtale / morbidity and neonatal mortality ACE inhibitors may cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or renal failure irreversible, and death. Oligoamnios have also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this has been associated with contractions, fetal limb, craniofacial deformation, and hypoplastic lung. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, but it was unclear if these problems were caused by exposure to ACE inhibitor. These adverse effects do not appear to have resulted from intrauterine exposure ACE inhibitor, which was limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors during the first quarter alone should be so informed. Nonetheless, when patients become pregnant, physicians should do everything possible to end the use of Altace as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the risks to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, Altace should be discontinued unless it is deemed vital for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants who have a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required for hypotension and / or substituting for disordered renal function. Altace, which cross the placenta can be removed from the neonatal circulation by these means, but little experience has not shown that the elimination is essential for the treatment of these children. No teratogenic effects Altace (ramipril) were observed in studies of pregnant rats, rabbits and cynomolgus monkeys. On a body surface area basis, the doses used were up to nearly 400 times (in rats and monkeys) and 2 times (rabbit) the recommended human dose. PRECAUTIONS Renal failure: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function can be expected in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with inhibitors of angiotensin converting enzyme, including Altace, may be associated with oliguria and / or progressive azotemia and (rarely) with acute renal failure L'and / or death. In hypertensive patients with unilateral or bilateral stenosis of the renal artery, increased blood urea nitrogen and serum creatinine may occur. Experience with another inhibitor of angiotensin converting enzyme suggests that these increases are usually reversible after discontinuation of Altace and / or diuretic therapy. In these patients renal function should be monitored during the first weeks of treatment. Some hypertensive patients without apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace were administered in combination with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Altace reduced dosage and / or discontinuation of the diuretic may be necessary. Evaluation of hypertension patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.) Hyperkalemia: In clinical trials, hyperkalemia (serum potassium level to 5.7 mEq / L) was observed in approximately 1% of hypertensive patients receiving Altace. In most cases, it was iso1ated values that despite continued therapy. None of these patients has been interrupted since the trial because of hyperkalemia. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and / or containing potassium salt substitutes, which should be used with caution, if any, with Altace. (See Drug Interactions.) Cough: Presumably due to the inhibition of the degradation of bradykinin endogenous, the persistence of nonproductive cough has been reported with all ACE inhibitors, always resolve after cessation of treatment. Cough induced by the IEC should be considered in the differential diagnosis of cough. Hepatic: Since ramipril is mainly metabolized by the liver esterases to its active moiety, ramiprilat, patients with hepatic could develop significantly elevated plasma levels of ramipril. No pharmacokinetic studies were performed in hypertensive patients with hepatic impairment. However, given that the renin-angiotensin system can be activated in patients with severe cirrhosis and / or ascites, particular caution should be exercised in the treatment of these patients. Surgery / Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril could block the formation of angiotensin II, which would otherwise occur secondary to the release of renin. Hypotension occurs as a result of this mechanism can be corrected by an extension. 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 up to 500 mg / kg / day or mouse period until 18 months at doses up to 1000 mg / kg Day. (For both species, these doses are approximately 200 times the maximum recommended human dose when compared on the basis of the body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus assay in the mouse, not in a DNA synthesis human cell line, or a gene from the front-test mutation 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 doses as high as 500 mg / kg / day produced no adverse effects on fertility. Pregnancy Pregnancy Categories C (first quarter) and D (second and third trimesters). See WARNINGS: Fetal / mortality and neonatal morbidity. Breastfeeding Ingestion single 10 mg oral dose of Altace led undetectable quantities of ramipril and its metabolites in human milk. However, because of multiple doses can produce low concentrations of milk which are not foreseeable single doses, women receiving Altace should not breastfeed. Elderly Of the total number of patients who received ramipril in US clinical studies Altace 11.0% were 65 and over, while 0.2% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and others reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older people can not be excluded. A pharmacokinetic study conducted at the hospital indicated that elderly patients edge ramiprilat levels and the area under the plasma concentration curve (AUC) for ramiprilat are higher in elderly patients. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in young rats given a single dose of ramipril Single oral dose in rats and mice 10-11 g / kg resulted in significant lethality. In dogs, oral doses as high as 1 g / kg, induces mild gastrointestinal disorders. The limited data on overdose are available. Clinical manifestations are the most likely symptoms attributable to hypotension. Laboratory determinations of serum ramipril and its metabolites are not widely available, and these decisions shall, in any event, no role in the management of ramipril overdose. There is no data to suggest maneuvers physiological (eg, maneuvers to change urine pH), which could accelerate the elimination of ramipril and its metabolites. Similarly, we do not know which, if any, of these substances may be usefully removed from the body by hemodialysis. Angiotensin II is likely to serve as an antagonist - antidote to the fixation of ramipril overdose, but angiotensin II is essentially outside the unavailability of dispersed research facilities. Because the hypotensive effect of ramipril vasodilatation is performed by hypovolemia and effective, it is reasonable to treat ramipril overdose injection of normal saline.Thursday, November 8, 2007
Side Effects & Drug Interactionsfont sizeAAA
Hypertension Altace has been evaluated for safety in more than 4,000 patients with hypertension, including 1,230 patients were studied in US trials, and 1,107 were studied abroad controlled trials. Nearly 700 of these patients were treated for at least one year. The overall incidence of side effects was similar for Altace and placebo. The most common side effects clinical (possibly or probably related to the study drug) reported by patients receiving US Altace in placebo-controlled trials were: headache (5.4%), "Vertigo" (2 , 2%) and fatigue or asthenia (2.0%), but only the latter was more common in patients Altace that in patients who received placebo. Generally, the side effects were mild and transient, and there was no comparison with the total dose in the range of 1.25 to 20 mg. Discontinuation of treatment due to side effects was needed in about 3% of patients treated with USA Altace. The most frequent reasons for the judgment were cough (1.0%), "Vertigo" (0.5%), and impotence (0.4%). Observed side effects considered possibly or probably related to the study drug, which took place in US placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% versus 1%). US patients in the placebo-controlled studies Altace (N = 651) Placebo (N = 286) N% N% Asthenia (Fatigue) 13 2 2 1 In placebo-controlled trials, there was also an excess of upper respiratory tract infection and flu syndrome in the ramipril group, and not attributed at the time to ramipril. As these studies were carried out before the report of the cough of ACE inhibitors has been recognized, some of these events may represent ramipril induced cough. In a 1-year study, increased cough has been observed in approximately 12% of patients ramipril, with about 4% of these patients requiring discontinuation of therapy. Heart failure after myocardial infarction Adverse (with the exception of laboratory abnormalities) discussed possibly / probably related to the study drug, which took place in more than one percent of patients and more frequently on ramipril are listed below . The frequency represent the experiences of the study AIRE. The follow-up time between 6 and 46 months for the study. The percentage of patients with adverse events possibly / probably related to the study drug Other adverse events reported in controlled clinical trials (less than 1% of the patients ramipril), or more rare, seen in the post-marketing events, including (in some, a causal link with the use of drugs is uncertain ): As Whole body: anaphylaxis. (See WARNINGS.) Cardiovascular: symptomatic hypotension (reported in 0.5% of patients in the American trial) (See WARNINGS and PRECAUTIONS), syncope and palpitations. Hematologic: pancytopenia, thrombocytopenia and hemolytic anemia. Rein: Some hypertensive patients without apparent pre-existing renal disease have developed minor, usually trnsient, increased blood urea nitrogen and serum creatinine when taking Altace, especially when Altace was given in combination with a diuretic . (See WARNINGS.) Acute renal insufficiency. Angioneurotic edema: angioneurotic edema was reported in 0.3% of patients in clinical trials US. (See WARNINGS.) Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with the enzyme suggesting changes pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis , increased salivation and taste disturbance. Dermatological: Apparent hypersensitivity reactions (shown by pruritus, and rash, with or without fever), photosensitivity, purpura onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome. Neurological and Psychiatric: anxiety, amnesia, seizures, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, dizziness, and blurred vision. Various: As with other ACE inhibitors, a symptom complex has been reported that may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia / arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity rash Skin and other dermatologic manifestations. In addition, like other ACE inhibitors, eosinophilic pneumonia has been reported. Fœtale / neonatal mortality and morbidity. See WARNINGS: Fetal / mortality and neonatal morbidity. Others: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. Post-Marketing Experience: In addition to the reported side effects in clinical trials, there have been rare cases reported during hypoglycemia Altace therapy when administered to patients simultaneously taking oral hypoglycemic agents or insulin. The causal link is unknown. Laboratory test clinical findings: Creatinine and blood urea nitrogen: creatinine increase 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 only Altace and 3% of patients with a diuretic Altace. None of these increases required discontinuation of therapy. 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, should be particularly likely to occur in patients with stenosis of the renal artery. (See WARNINGS and PRECAUTIONS.) Since ramipril decreases the secretion of aldosterone, the elevation of serum potassium may occur. Extras potassium and potassium-sparing diuretics should be given with caution, and the patient serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS). Hematocrit and hemoglobin: A decrease in hemoglobin and 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 at 1, 5% of patients receiving a diuretic More Altace. No US patients treatment because of the decline of hemoglobin or hematocrit. Other (relationship unknown cause): clinically significant changes in the standard laboratory tests were rarely associated with the administration Altace. Elevation of liver enzymes, uric acid serum bilirubin, and blood glucose were reported, as well as cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In the United States trials, less than 0.2% of patients discontinued the treatment of laboratory abnormalities, and all these cases were proteinuria or abnormal-tests of liver function. Drug Interactions With nonsteroidal anti-inflammatory drugs: Rarely, treatment with ACE inhibitors and nonsteroidal anti-inflammatory drugs have been associated with worsening kidney failure and an increase in serum potassium. With diuretics: Patients on diuretics, particularly those in which little diuretic, may experience an excessive reduction in blood pressure after starting treatment with Altace. The possibility of Altace with hypotensive effects can be minimized by either abandoning diuretic or increasing the salt before starting treatment with Altace. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.) With supplements potassium and potassium-sparing diuretics: Altace can mitigate the loss of potassium caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if the concurrent use of these agents is indicated, it should be given with caution, and the patient serum potassium should be monitored frequently. With lithium: Increased serum lithium levels and the symptoms of lithium toxicity has been reported in patients receiving ACE inhibitors during treatment with lithium. These medications must be co-administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Others: Neither Altace nor its metabolites were found to interact with digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. Combining Altace and propranolol showed no adverse effects on the dynamic parameters (blood pressure and heart rate). Co-administration of warfarin Altace and did not adversely affect the anticoagulant effects of this drug. In addition, the administration of Altace with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects' status of the fight against coagulation. Anaphylactoïdes and possibly linked reactions Presumably because of angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and endogenous peptide which bradykinin, patients receiving ACE inhibitors (including Altace) can be subject to a variety of adverse effects, some of which are serious. Head and neck angioedema Patients with a history of angioedema unrelated to IEC to an increased risk of angioedema while receiving an ACE inhibitor. (See CONTRAINDICATIONS.) Angio-oedèmes of the face, extremities, lips, tongue, glottis and larynx has been reported in patients treated with inhibitors of angiotensin converting enzyme. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, glottis or occurs, Altace treatment should be discontinued immediately and the establishment of an appropriate therapy. Where there is the tongue, glottis or larynx, which can lead to airway obstruction, therapy, eg, subcutaneous epinephrine solution 1:1,000 (0.3 mL to 0.5 mL) should be administered promptly. (See REACTIONS.) Intestinaux Angioedema Intestinal angioedema have 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 history of angioedema face and the C-1 esterase levels were normal. Angioedema has been diagnosed by the procedures, including abdominal computed tomography or ultrasound, or at surgery, and the symptoms disappeared after discontinuation of the ACE inhibitor. Angioedema intestinal should be included in the differential diagnosis of patients with ACE inhibitors with abdominal pain. In a large US study post, angioedema (defined as the reports of CT angio, face, larynx, tongue, or throat swelling) was reported in 3 / 1523 (0.20%) black patients and in 8 / 8680 (0 .09%) patients white. These rates are not statistically different. Anaphylactoïdes during desensitisation: Two patients treated with desensitization hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily, but they have reappeared after rechallenge involuntary. Anaphylactoïdes during membrane exposure: Anaphylactoïdes have been reported in patients on dialysis with high f1ux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoïdes have also been reported in patients undergoing low-density lipoprotein apheresis with the absorption of dextran sulfate. Hypotension Altace can cause symptomatic hypotension or after the initial dose or at a dose when the dose was increased. Ramipril has only rarely been associated with hypotension singles hypertensive. Symptomatic hypotension is the most likely to occur in patients who were the volume and / or salt-depleted as a result of long diuretic therapy, dietary salt restriction, diarrhea or vomiting. Volume and / or salt depletion should be corrected before starting therapy with Altace. In patients with heart failure, with or without kidney failure, excessive IEC can cause hypotension, which may be associated with azotemia and oliguria or, rarely, acute renal failure and death. In these patients, Altace therapy should be initiated under close medical supervision, they should be closely monitored during the first 2 weeks of treatment and whenever the dose of ramipril or diuretic is increased. If hypotension, the patient should be placed in a supine position and, if necessary, treated by intravenous infusion of saline solution. Altace treatment can usually be prosecuted following restoration of blood pressure and volume. Liver Failure Rarely, IEC, including Altace, were associated with a syndrome that starts with cholestatic jaundice and the fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations in liver enzymes should discontinue the IEC and appropriate medical monitoring. Neutropenia / Agranulocytosis Like other ACE inhibitors, rarely, a slight in isolated cases severe reduction in red blood cells and hemoglobin content, white blood cells or platelets can develop. In isolated cases, agranulocytosis, pancytopenia, and the bone marrow may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen vascular diseases (eg systemic lupus erythematosus, scleroderma), and renal. Monitoring of white blood cells should be considered in patients with collagen vascular diseases, especially if the disease is linked to renal failure. Fœtale / morbidity and neonatal mortality ACE inhibitors may cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or renal failure irreversible, and death. Oligoamnios have also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this has been associated with contractions, fetal limb, craniofacial deformation, and hypoplastic lung. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, but it was unclear if these problems were caused by exposure to ACE inhibitor. These adverse effects do not appear to have resulted from intrauterine exposure ACE inhibitor, which was limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors during the first quarter alone should be so informed. Nonetheless, when patients become pregnant, physicians should do everything possible to end the use of Altace as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the risks to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, Altace should be discontinued unless it is deemed vital for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants who have a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required for hypotension and / or substituting for disordered renal function. Altace, which cross the placenta can be removed from the neonatal circulation by these means, but little experience has not shown that the elimination is essential for the treatment of these children. No teratogenic effects Altace (ramipril) were observed in studies of pregnant rats, rabbits and cynomolgus monkeys. On a body surface area basis, the doses used were up to nearly 400 times (in rats and monkeys) and 2 times (rabbit) the recommended human dose. PRECAUTIONS Renal failure: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function can be expected in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with inhibitors of angiotensin converting enzyme, including Altace, may be associated with oliguria and / or progressive azotemia and (rarely) with acute renal failure L'and / or death. In hypertensive patients with unilateral or bilateral stenosis of the renal artery, increased blood urea nitrogen and serum creatinine may occur. Experience with another inhibitor of angiotensin converting enzyme suggests that these increases are usually reversible after discontinuation of Altace and / or diuretic therapy. In these patients renal function should be monitored during the first weeks of treatment. Some hypertensive patients without apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace were administered in combination with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Altace reduced dosage and / or discontinuation of the diuretic may be necessary. Evaluation of hypertension patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.) Hyperkalemia: In clinical trials, hyperkalemia (serum potassium level to 5.7 mEq / L) was observed in approximately 1% of hypertensive patients receiving Altace. In most cases, it was iso1ated values that despite continued therapy. None of these patients has been interrupted since the trial because of hyperkalemia. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and / or containing potassium salt substitutes, which should be used with caution, if any, with Altace. (See Drug Interactions.) Cough: Presumably due to the inhibition of the degradation of bradykinin endogenous, the persistence of nonproductive cough has been reported with all ACE inhibitors, always resolve after cessation of treatment. Cough induced by the IEC should be considered in the differential diagnosis of cough. Hepatic: Since ramipril is mainly metabolized by the liver esterases to its active moiety, ramiprilat, patients with hepatic could develop significantly elevated plasma levels of ramipril. No pharmacokinetic studies were performed in hypertensive patients with hepatic impairment. However, given that the renin-angiotensin system can be activated in patients with severe cirrhosis and / or ascites, particular caution should be exercised in the treatment of these patients. Surgery / Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril could block the formation of angiotensin II, which would otherwise occur secondary to the release of renin. Hypotension occurs as a result of this mechanism can be corrected by an extension. 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 up to 500 mg / kg / day or mouse period until 18 months at doses up to 1000 mg / kg Day. (For both species, these doses are approximately 200 times the maximum recommended human dose when compared on the basis of the body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus assay in the mouse, not in a DNA synthesis human cell line, or a gene from the front-test mutation 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 doses as high as 500 mg / kg / day produced no adverse effects on fertility. Pregnancy Pregnancy Categories C (first quarter) and D (second and third trimesters). See WARNINGS: Fetal / mortality and neonatal morbidity. Breastfeeding Ingestion single 10 mg oral dose of Altace led undetectable quantities of ramipril and its metabolites in human milk. However, because of multiple doses can produce low concentrations of milk which are not foreseeable single doses, women receiving Altace should not breastfeed. Elderly Of the total number of patients who received ramipril in US clinical studies Altace 11.0% were 65 and over, while 0.2% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and others reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older people can not be excluded. A pharmacokinetic study conducted at the hospital indicated that elderly patients edge ramiprilat levels and the area under the plasma concentration curve (AUC) for ramiprilat are higher in elderly patients. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in young rats given a single dose of ramipril Single oral dose in rats and mice 10-11 g / kg resulted in significant lethality. In dogs, oral doses as high as 1 g / kg, induces mild gastrointestinal disorders. The limited data on overdose are available. Clinical manifestations are the most likely symptoms attributable to hypotension. Laboratory determinations of serum ramipril and its metabolites are not widely available, and these decisions shall, in any event, no role in the management of ramipril overdose. There is no data to suggest maneuvers physiological (eg, maneuvers to change urine pH), which could accelerate the elimination of ramipril and its metabolites. Similarly, we do not know which, if any, of these substances may be usefully removed from the body by hemodialysis. Angiotensin II is likely to serve as an antagonist - antidote to the fixation of ramipril overdose, but angiotensin II is essentially outside the unavailability of dispersed research facilities. Because the hypotensive effect of ramipril vasodilatation is performed by hypovolemia and effective, it is reasonable to treat ramipril overdose injection of normal saline.
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