Fosinopril Sodium and Hydrochlorothiazide (Page 5 of 6)

Pregnancy

Pregnancy Categories C (first trimester) and D(second and third trimesters). See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Nursing mothers

Both fosinopril and hydrochlorothiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue fosinopril sodium and hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Clinical studies of fosinopril sodium-hydrochlorothiazide 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 responses between 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.

ADVERSE REACTIONS

Fosinopril sodium and hydrochlorothiazide tablets have been evaluated for safety in over 660 patients with hypertension; approximately 137 of these patients were treated for more than one year. The observed adverse events were generally mild, transient, and similar to those seen with fosinopril and hydrochlorothiazide taken separately. There was no relationship between the incidence of side effects and age.

In placebo-controlled clinical trials of fosinopril sodium and hydrochlorothiazide tablets, the usual duration of therapy was two months. Adverse clinical or laboratory events led to discontinuation of therapy by 4.3% of 368 placebo-treated patients and by 3.5% of 660 fosinopril sodium and hydrochlorothiazide tablet-treated patients.

The most common reasons for discontinuation of therapy with fosinopril sodium and hydrochlorothiazide tablets in U.S. studies were headache (0.3%), cough (0.3%; see PRECAUTIONS), and fatigue (0.2%).

The side effects considered probably or possibly related to study drug that occurred in placebo-controlled trials in more than 2% of patients treated with fosinopril sodium and hydrochlorothiazide tablets are shown in the table below.

Drug-Related Incidences Table
(click image for full-size original)

Reactions Possibly or Probably Drug-Related Incidence in Placebo-Controlled Studies

Other side effects considered possibly or probably related to study drug that occurred in controlled trials in 0.5% to < 2.0% of patients treated with fosinopril sodium and hydrochlorothiazide tablets, and rarer but clinically significant events regardless of causal relationship were:

General: Chest pain, weakness, fever, viral infection.

Cardiovascular: Orthostatic hypotension (seen in 1.8% of fosinopril sodium hydrochlorothiazide tablet patients and 0.3% of placebo patients; no patients discontinued therapy due to orthostatic hypotension), edema, flushing, rhythm disturbance, syncope.

Dermatologic: Pruritus, rash.

Endocrine/Metabolic: Sexual dysfunction, change in libido, breast mass.

Gastrointestinal: Nausea/vomiting, diarrhea, dyspepsia/heartburn, abdominal pain, gastritis/esophagitis.

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

Musculoskeletal: Myalgia/muscle cramps.

Neurologic/Psychiatric: Somnolence, depression, numbness/paresthesia.

Respiratory: Sinus congestion, pharyngitis, rhinitis.

Special Senses: Tinnitus.

Urogenital: Urinary tract infection, urinary frequency, dysuria.

Laboratory Test Abnormalities: Serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides, and calcium (see PRECAUTIONS). Neutropenia.

Fetal/Neonatal Morbidity and Mortality

See WARNINGS: Fetal/Neonatal Morbidity and Mortality

Antihypertensive monotherapy with fosinopril has been evaluated for safety in more than 1500 patients, of whom approximately 450 patients were treated for a year or more. The observed adverse events included events similar to those seen with fosinopril sodium and hydrochlorothiazide tablets; in addition, the following others have also been reported with fosinopril:

Cardiovascular: Angina, myocardial infarction, cerebrovascular accident, hypertensive crisis, hypotension, claudication.

Dermatologic: Urticaria, photosensitivity.

Endocrine/Metabolic: Gout.

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

Hematologic: Lymphadenopathy.

Musculoskeletal: Arthralgia.

Neurologic/Psychiatric: Memory disturbance, tremor, confusion, mood change, sleep disturbance.

Respiratory: Bronchospasm, laryngitis/hoarseness, epistaxis, and (in two patients) a symptom-complex of cough, bronchospasm, and eosinophilia.

Special Senses: Vision disturbance, taste disturbance, eye irritation.

Urogenital: Renal insufficiency.

Laboratory Test Abnormalities: Elevations (usually transient and minor) of BUN and creatinine have been observed, but these have not been more frequent than in parallel patients treated with placebo. The hemoglobin in fosinopril-treated patients generally decreases by an average of 0.1 g/dL, but this nonprogressive change has never been symptomatic. Leukopenia and eosinophilia have also been reported.

Serum levels of liver function tests (transaminases, LDH, alkaline phosphatase and serum bilirubin) have occasionally been found to be elevated, and these elevations have lead to discontinuation of therapy in 0.7% of patients. Other risk factors for liver dysfunction have often been present in these cases; in any event the elevations generally have resolved after discontinuation of therapy with fosinopril.

Other Adverse Events Reported with ACE Inhibitors

Other adverse effects reported with ACE inhibitors include cardiac arrest; pancytopenia, hemolytic anemia; aplastic anemia; thrombocytopenia; bullous pemphigus, exfoliative dermatitis; and a syndrome that may include one or more of arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermopathy, positive ANA titer, leukocytosis, eosinophilia, and elevated ESR.

Hydrochlorothiazide has now been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency.

Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).

Gastrointestinal: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia.

Immunologic: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), anaphylactic reactions, purpura, urticaria, rash, and photosensitivity.

Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal: Muscle spasm.

Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.

OVERDOSAGE

To obtain up-to-date information about the treatment of overdose, a good resource is a certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

No specific information is available on the treatment of overdosage with fosinopril sodium and hydrochlorothiazide tablets; treatment should be symptomatic and supportive. Therapy with fosinopril sodium and hydrochlorothiazide tablets should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures.

In rats, single oral doses of 2600 mg/kg of fosinopril were associated with significant lethality. In single-dose studies of hydrochlorothiazide, most rats survived doses of up to 2750 mg/kg. Both doses are more than 6000 times (on a mg/kg basis) the maximum recommended daily dose of either fosinopril or hydrochlorothiazide in fosinopril sodium and hydrochlorothiazide tablets.

Data from human overdoses of fosinopril are scanty, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

Laboratory determinations of serum levels of fosinopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites. Fosinoprilat is poorly removed from the body by hemodialysis or peritoneal dialysis.

Angiotensin II could presumably serve as aspecific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution.

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