"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is warning of several treatment-related serious adverse events in association with implantable left ventricular assist devices (LVADs) in heart-failure patients.
In a "...
Whether given orally or by continuous or intermittent intravenous infusion, PRIMACOR has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with PRIMACOR was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that PRIMACOR given by long-term continuous or intermittent infusion does not carry a similar risk.
The use of PRIMACOR both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving PRIMACOR should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.
PRIMACOR should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of PRIMACOR and oral PRIMACOR have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving PRIMACOR should be closely monitored during infusion.
PRIMACOR produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.
If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, PRIMACOR should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.
There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (see ADVERSE REACTIONS). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.
Use in Acute Myocardial Infarction
No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, PRIMACOR is not recommended in these patients.
Fluid and Electrolytes: Fluid and electrolyte changes and renal function should be carefully monitored during therapy with PRIMACOR. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of PRIMACOR.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Twenty-four months of oral administration of PRIMACOR to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when PRIMACOR was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, PRIMACOR had no effect on male or female fertility at oral doses up to 32 mg/kg/day.
Oral and intravenous administration of toxic dosages of PRIMACOR to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.
Pregnancy Category C
Oral administration of PRIMACOR to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. PRIMACOR did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. PRIMACOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Caution should be exercised when PRIMACOR is administered to nursing women, since it is not known whether it is excreted in human milk.
Safety and effectiveness in pediatric patients have not been established.
Use in Elderly Patients
There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered PRIMACOR in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of PRIMACOR.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/2/2008
Additional Primacor IV Information
Report Problems to the Food and Drug Administration
Get the latest treatment options.