Lisinopril (Page 5 of 8)

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 lisinopril.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.

Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m2 , respectively.

*Calculations assume a human weight of 50 kg and human body surface area of 1.62 m2.

Nursing Mothers

Milk of lactating rats contains radioactivity following administration of 14 C lisinopril. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision should be made whether to discontinue nursing or discontinue lisinopril, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to lisinopril

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

Antihypertensive effects of lisinopril have been established in hypertensive pediatric patients aged 6 to 16 years.

There are no data on the effect of lisinopril on blood pressure in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and DOSAGE AND ADMINISTRATION .)

Geriatic Use

Clinical studies of lisinopril in patients with hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience in this population has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In the ATLAS trial of lisinopril in patients with congestive heart failure, 1,596 (50%) were 65 and over, while 437 (14%) were 75 and over. In a clinical study of lisinopril in patients with myocardial infarctions 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In these studies, no overall differences in safety or effectiveness were observed between elderly and younger patients, and other reported clinical experiences has not identified differences in responses between the elderly and younger patients (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Heart Failure and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Acute Myocardial Infarction ).

Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ).

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of patients with hypertension, congestive heart failure, or myocardial infarction should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

Lisinopril has been found to be generally well tolerated in controlled clinical trials involving 1969 patients with hypertension or heart failure. For the most part, adverse experiences were mild and transient.

Hypertension

In clinical trials in patients with hypertension treated with lisinopril, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range.

For adverse experiences occurring in greater than 1% of patients with hypertension treated with lisinopril or lisinopril plus hydrochlorothiazide in controlled clinical trials, and more frequently with lisinopril and/or lisinopril plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:

PERCENT OF PATIENTS IN CONTROLLED STUDIES
Lisinopril ( n = 1349 ) Incidence ( discontinuation ) Lisinopril / Hydrochlorothiazide ( n = 629 ) Incidence ( discontinuation ) Placebo ( n = 207 ) Incidence ( discontinuation )
Body as a Whole
Fatigue 2.5 (0.3) 4.0 (0.5) 1.0 (0.0)
Asthenia 1.3 (0.5) 2.1 (0.2) 1.0 (0.0)
Orthostatic Effects 1.2 (0.0) 3.5 (0.2) 1.0 (0.0)
Cardiovascular
Hypotension 1.2 (0.5) 1.6 (0.5) 0.5 (0.5)
Digestive
Diarrhea 2.7 (0.2) 2.7 (0.3) 2.4 (0.0)
Nausea 2.0 (0.4) 2.5 (0.2) 2.4 (0.0)
Vomiting 1.1 (0.2) 1.4 (0.1) 0.5 (0.0)
Dyspepsia 0.9 (0.0) 1.9 (0.0) 0.0 (0.0)
Musculoskeletal
Muscle Cramps 0.5 (0.0) 2.9 (0.8) 0.5 (0.0)
Nervous / Psychiatric
Headache 5.7 (0.2) 4.5 (0.5) 1.9 (0.0)
Dizziness 5.4 (0.4) 9.2 (1.0) 1.9 (0.0)
Paresthesia 0.8 (0.1) 2.1 (0.2) 0.0 (0.0)
Decreased Libido 0.4 (0.1) 1.3 (0.1) 0.0 (0.0)
Vertigo 0.2 (0.1) 1.1 (0.2) 0.0 (0.0)
Respiratory
Cough 3.5 (0.7) 4.6 (0.8) 1.0 (0.0)
Upper Respiratory Infection 2.1 (0.1) 2.7 (0.1) 0.0 (0.0)
Common Cold 1.1 (0.1) 1.3 (0.1) 0.0 (0.0)
Nasal Congestion 0.4 (0.1) 1.3 (0.1) 0.0 (0.0)
Influenza 0.3 (0.1) 1.1 (0.1) 0.0 (0.0)
Skin
Rash 1.3 (0.4) 1.6 (0.2) 0.5 (0.5)
Urogenital
Impotence 1.0 (0.4) 1.6 (0.5) 0.0 (0.0)

Chest pain and back pain were also seen, but were more common on placebo than lisinopril.

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