Amtrel Special Precautions

General: Patients with Renal Dysfunction: Patients with severe renal diseases should take Amtrel with caution. Patients with high susceptibility can expect that, when the renin-angiotensin-aldosterone system is suppressed by benazepril, corresponding changes in renal function can occur. Patients with severe congestive heart failure rely on operation of the renin-angiotensin-aldosterone system, so using ACE inihibitors (including benazepril) for treatment can cause oliguria, azotemia and acute renal failure or death. In a few reports studying patients with unilateral or bilateral renal stenosis, the results indicated that benazepril therapy increased blood urea nitrogen (BUN) and serum creatinine concentration. However, if benazepril was stopped or combined with diuretics, BUN and serum creatinine concentration can be restored to normal. If patients in this category were to receive treatment with Amtrel, intensive monitoring of renal function should be performed a few weeks before treatment starts. Hypertensive patients without significant symptoms of renal vascular disease can experience increased BUN and serum creatinine concentration after receiving benazepril therapy, but the symptoms are mild and temporary, and this is especially true when benazepril is given along with diuretics. Assessments of hypertensive patients should include renal function assessment (see Dosage & Administration).
Hyperkalemia: In a placebo-controlled clinical study performed in the United States, it was found that about 1.5% of patients that received a similar combination formula experienced hyperkalemia, but the increased potassium ion concentration in the serum can be reversed. Risk factors for developing hyperkalemia include: Renal dysfunction, diabetes and concurrent use of potassium-preserving diuretics, potassium supplements or salts containing potassium ion.
Congestive Heart Failure (CHF): Hemodynamic and clinical studies performed in the United States on New York Heart Association (NYHA) class II-III, CHF patients all indicated that amlodipine did not cause clinical worsening as measured by exercise tolerance tests, left ventricular rejection or symptomatic changes clinically. Overall, patients with CHF should take all calcium-ion blockers with caution.
Liver Failure: In patients with liver dysfunction as a result of liver cirrhosis, benazeprilat concentration in the body will not change. However, amlodipine is metabolized by the liver and its plasma half-life is as long as 56 hrs in patients with liver dysfunction. Therefore, extreme caution should be taken when patients with severe liver damage use Amtrel (see Warnings).
Cough: ACE inhibitors use can cause breakdown of intrinsic bradykinins, so persistent dry coughs can result. After amtrel is discontinued, however, the condition may be reversed. During the diagnostic process, the physician should distinguish between coughs stimulated by ACE inhibitors and general coughs.
Surgery/Anesthesia: When a patient uses agents that cause hypotension during surgery or under anesthesia, benazepril will block the synthesis of angiotensin II, causing compensatory release of renins. Hypotension caused by this mechanism may be recovered by supplementing body fluids.
Amtrel should not be used in the initial treatment of hypertension (see Dosage & Administration) and use only with a physician's prescription.
When using Amtrel, it should be noted that ACE inhibitors may cause agranulocytosis, especially in patients with renal dysfunction or collagen vascular diseas. Also, there is insuffivient evidence to demonstrate that similar risks will not occur with benazepril use (see Neutrophil/Agranulocyte under Warnings).
Carcinogenesis, Mutagenesis, Impairment of Fertility: In Study with Benazepril: No carcinogenicity was found when giving rats and mice benazepril 150 mg/kg/day for 104 weeks. With weight as the basis of calculation, this dosage exceeds 100 times the maximum recommended dosage for humans. When calculated with surface area of the body as the basis, this dosage is 9-18 times the maximum recommended dosage for humans. The bacterial Ames test, mutagenicity test of in vitro mammalian cell culture and tests of abnormal cell nucleus all showed no mutations. Within the dosage of 50-500 mg/kg/day (with weight as the basis of calculation, it is 38-375 times the maximum recommended dosage for humans; using surface area as the basis of calculation, it is 6-61 times the maximum recommended dosage for humans), benazepril does not cause adverse effects in male and female mice.
In Study with Amlodipine: Using the dosage of 0.5, 1.25 and 2.5 mg/kg/day, amlodipine was given to rodents daily for 2 years. Results revealed no risk of carcinogenicity. For mice (not applicable to rats), the maximum dosage is similar to the maximally tolerated dosage. Using surface area as the basis of calculation (mg/m²), the dosage given to mice is close to the maximum clinically recommended dosage. The same dosage given to rats is similar to twice the maximum recommended dosage clinically. Mutagenicity studies of amlodipine have indicated no drug-related effects in both the gene and chromosome level. When amlodipine 10 mg/kg/day is given to mice [calculated with surface area as the basis (mg/m²)], it is similar to 8 times the maximum recommended dosage for a 50 kg human), fertility is unaffected (the drug is given 64 days in male mice before mating and 14 days in female mice before mating).
When benazepril:amlodipine are given concurrently with the dosage of 15:7.5 mg/kg/day, no adverse effects are found in male and female mice before mating and during pregnancy.
Use in pregnancy: Pregnancy Category C (1st Trimester) and D (2nd and 3rd Trimesters): See Fetus/Newborn Disease Incidence and Death Rate under Warnings.
Use in lactation: Only minute amounts of benazepril and benazeprilat are secreted in the breast milk of breastfeeding women. Therefore, if the newborn consumes breast milk, <0.1% of the dosage received by the mother will be absorbed by the newborn.
It is currently unclear whether amlodipine may be found in the breast milk. Thus, it is recommended that when taking Amtrel for treatment, breastfeeding should stop.
Use in children: Safety and efficacy of Amtrel in children have yet to be established.
Use in the elderly: In clinical studies published in the United States, 19% were patients ≥65 years and 2% were patients ≥75 years; no differences have been reported in terms of safety and efficacy of Amtrel between young and elderly patients.