Fosinopril Sodium (Page 4 of 6)

Drug/Laboratory Test Interaction

Fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab“ RIA Kit, for Digoxin. Other Kits, such as the Coat-A-Counts” RIA Kit, may be used.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level and a slightly higher incidence of mesentery/omentum lipomas. Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo.

In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation.

There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rates until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing times was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose.

Pregnancy Categories C (first trimester) and D (second and third trimesters)

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

Ingestion of 20 mg daily for three days resulted in detectable levels of fosinoprilat in breast milk. Fosinopril sodium should not be administered to nursing mothers.

Geriatric Use

Clinical studies of fosinopril sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for and 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.

Pediatric Use

Neonates with a history of in utero exposure to fosinopril sodium tablets:

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. Removal of fosinopril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.The antihypertensive effects of fosinopril have been evaluated in a double-blind study in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension). The pharmacokinetics of fosinopril have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). Fosinopril was generally well tolerated and adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients).

ADVERSE REACTIONS

Fosinopril sodium has been evaluated for safety in more than 2100 individuals in hypertension and heart failure trials, including approximately 530 patients treated for a year or more. Generally adverse events were mild and transient, and their frequency was not prominently related to dose within the recommended daily dosage range.

Hypertension

In placebo-controlled clinical trials (688 fosinopril sodium -treated patients), the usual duration of therapy was two to three months. Discontinuation due to any clinical or laboratory adverse event were 4.1% and 1.1% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reasons (0.4 to 0.9%) were headache, elevated transaminases, fatigue, cough (see PRECAUTIONS: General Cough), diarrhea, and nausea and vomiting.

During clinical trials with any fosinopril sodium regimen, the incidence of adverse events in the elderly (>65 years old) was similar to that seen in younger patients.

Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium alone and at least as frequent on fosinopril sodium as on placebo in placebo-controlled clinical trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trials (Hypertension)
Fosinopril Sodium(N=688)Incidence(Discontinuation) Placebo(N=184)Incidence(Discontinuation)
Cough 2.2 (0.4) 0.0 (0.0)
Dizziness 1.6 (0.0) 0.0 (0.0)
Nausea/Vomiting 1.2 (0.4) 0.5 (0.0)

The following events were also seen at >1% on fosinopril sodium but occurred in the placebo group at a greater rate: headache, diarrhea, fatigue, and sexual dysfunction. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.2 to 1.0% of patients (excepted as noted) treated with fosinopril sodium in controlled or uncontrolled clinical trials (N=1479) and less frequent, clinically significant events include (listed by body system):

General: Chest pain, edema, weakness, excessive sweating.

Cardiovascular: Angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, rhythm disturbances, palpitations, hypotension, syncope, flushing, claudication.

Orthostatic: hypotension occurred in 1.4% of patients treated with fosinopril monotherapy. Hypotension or orthostatic hypotension was a cause for discontinuation of therapy in 0.1% of patients.

Dermatologic: Urticaria, rash, photosensitivity, pruritus.

Endocrine/Metabolic: Gout, decreased libido.

Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, abdominal pain, flatulence, constipation, heartburn, appetite/weight change, dry mouth.

Hematologic: Lymphadenopathy.

Immunologic: Angioedema. (See WARNINGS: Head and Neck Angioedema and Intestinal Angioedema.)

Musculoskeletal: Arthralgia, musculoskeletal pain, myalgia/muscle cramp.

Nervous/Psychiatric: Memory disturbance, tremor, confusion, mood change, paresthesia, sleep disturbance, drowsiness, vertigo.

Respiratory: Bronchospasm, pharyngitis, sinusitis/rhinitis, laryngitis/hoarseness, epistaxis. A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril.

Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation.

Urogenital: Renal insufficiency, urinary frequency.

Heart Failure

In placebo-controlled clinical trials (361 fosinopril sodium -treated patients), the usual duration of therapy was 3-6 months. Discontinuations due to any clinical or laboratory adverse events, except for heart failure, were 8.0% and 7.5% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of fosinopril sodium was angina pectoris (1.1%). Significant hypotension after the first dose of fosinopril sodium occurred in 14/590 (2.4%) of patients; 5/590 (0.8%) patients discontinued due to first dose hypotension.

Clinical adverse events probably or possibly relate or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium and at least as common as the placebo group, in placebo-controlled trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trials (Heart Failure)
Fosinopril Sodium(N=361)Incidence(Discontinuation) Placebo(N=373)Incidence(Discontinuation)
Dizziness 11.9 (0.6) 5.4 (0.3)
Cough 9.7 (0.8) 5.1 (0.0)
Hypotension 4.4 (0.8) 0.8 (0.0)
Musculoskeletal Pain 3.3 (0.0) 2.7 (0.0)
Nausea/Vomiting 2.2 (0.6) 1.6 (0.3)
Diarrhea 2.2 (0.0) 1.3 (0.0)
Chest Pain (non-cardiac) 2.2 (0.0) 1.6 (0.0)
Upper Respiratory Infection 2.2 (0.0) 1.3 (0.0)
Orthostatic Hypotension 1.9 (0.0) 0.8 (0.0)
Subjective Cardiac Rhythm Disturbances 1.4 (0.6) 0.8 (0.3)
Weakness 1.4 (0.3) 0.5 (0.0)

The following events also occurred at a rate of 1% or more on fosinopril sodium, but occurred on placebo more often: fatigue, dyspnea, headache, rash, abdominal pain, muscle cramp, angina pectoris, edema, and insomnia.

The incidence of adverse events in the elderly (>65 years old) was similar to that seen in younger patients.

Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.4 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled clinical trials (N=516) and less frequent, clinically significant events include (listed by body system):

General: Fever, influenza, weight gain, hyperhidrosis, sensation of cold, fall, pain.

Cardiovascular: Sudden death cardio respiratory arrest, shock (0.2%), atrial rhythm disturbance, cardiac rhythm disturbances, non anginal chest pain, edema lower extremity death, syncope, conduction disorder, bradycardia, tachycardia.

Dermatologic: Pruritus.

Endocrine/Metabolic: Gout, sexual dysfunction.

Gastrointestinal: Hepatomegaly, abdominal distension, decreased appetite, dry mouth, constipation, flatulence.

Immunologic: Angioedema (0.2%).

Musculoskeletal: Muscle ache, swelling of an extremity, weakness of an extremity.

Nervous/Psychiatric: Cerebral infarction, TIA, depression, numbness, paresthesia, vertigo, behavior change, tremor.

Respiratory: Abnormal vocalization, rhinitis, sinus abnormality, tracheobronchitis, abnormal breathing, pleuritic chest pain.

Special Senses: Vision disturbance, taste disturbance.

Urogenital: Abnormal urination, kidney pain.

Potential Adverse Effects Reported with ACE Inhibitors

Body as a whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS: Hemodialysis).

Other medically important adverse effects reported with ACE inhibitors include: Cardiac arrest; eosinophilic pneumonitis; neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia; acute renal failure; hepatic failure, jaundice (hepatocellular or cholestatic); symptomatic hyponatremia; bullous pemphigus, exfoliative dermatitis; a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia, or an elevated ESR.

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