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Basic Drug Info
Drug Name:Fosinopril Sodium and Hydrochlorothiazide
Manufacturer:Genpharm L.P.
Other Info:GENPHARM INC.Etobicoke, ON, CanadaM8Z 2S6012-668-01July 2007



Clinical Trials:


Indications and Usage

Fosinopril Sodium and Hydrochlorothiazide tablets are indicated for the treatment of hypertension.These fixed dose combinations are not indicated for initial therapy.

(See DOSAGE AND ADMINISTRATION.)In using Fosinopril Sodium and Hydrochlorothiazide, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.

Available data are insufficient to show that fosinopril does not have a similar risk (see WARNINGS: Neutropenia/ Agranulocytosis).ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema).
Hypertensive disease -- Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.

Agranulocytosis -- A decrease in the number of GRANULOCYTES; (BASOPHILS; EOSINOPHILS; and NEUTROPHILS).

COLLAGEN VASCULAR DISEASE --

Angioedema -- Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.

Contraindications

Fosinopril Sodium and Hydrochlorothiazide tablets are contraindicated in patients who are anuric.

Fosinopril Sodium and Hydrochlorothiazide is also contraindicated in patients who are hypersensitive to fosinopril, to any other ACE inhibitor, to hydrochlorothiazide, or other sulfonamide-derived drugs, or any other ingredient or component in the formulation.

Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Anuria -- Absence of urine formation. It is usually associated with complete bilateral ureteral (URETER) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present.

Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Immediate hypersensitivity -- Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigen-antibody reaction and causes smooth muscle contraction and increased vascular permeability.

Asthma -- A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL).

Warnings

Anaphylactoid and Possibly Related ReactionsPresumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Fosinopril Sodium and Hydrochlorothiazide) may be subject to a variety of adverse reactions, some of them serious.Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors.

Angioedema associated with laryngeal edema can be fatal.

If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Fosinopril Sodium and Hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately.

When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3-0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS).Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained lifethreatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.Anaphylactoid Reactions During Membrane Exposure:Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.HypotensionFosinopril Sodium and Hydrochlorothiazide can cause symptomatic hypotension.

Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients.

Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume and/or salt depletion should be corrected before initiating therapy with Fosinopril Sodium and Hydrochlorothiazide.Fosinopril Sodium and Hydrochlorothiazide tablets should be used cautiously in patients receiving concomitant therapy with other antihypertensives.

The thiazide component of Fosinopril Sodium and Hydrochlorothiazide may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs.

The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patient.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death.

In such patients, Fosinopril Sodium and Hydrochlorothiazide therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased.If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline.

Fosinopril Sodium and Hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.Impaired Renal FunctionFosinopril Sodium and Hydrochlorothiazide should be used with caution in patients with severe renal disease.

Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative.When the renin-angiotensin-aldosterone system is inhibited by ACE inhibitors, changes in renal function may be anticipated in susceptible individuals.

In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including fosinopril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.In some studies of hypertensive patients with unilateral or bilateral renal artery stenosis, treatment with ACE inhibitors has been associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ACE inhibitor therapy, concomitant diuretic therapy, or both.

When such patients are treated with Fosinopril Sodium and Hydrochlorothiazide, renal function should be monitored during the first few weeks of therapy.

Some ACE-inhibitor-treated hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when the ACE inhibitor has been given concomitantly with a diuretic.

Dosage reduction of Fosinopril Sodium and Hydrochlorothiazide may be required.

Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).Neutropenia/AgranulocytosisAnother angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence probably less than once per 10,000 exposures), but more frequently (incidence possibly as great as once per 1,000 exposures) in patients with renal impairment, especially those who also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.

Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates.

Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially it the disease is associated with impaired renal function.Neutropenia/agranulocytosis has also been associated with thiazide diuretics.Fetal/Neonatal Morbidity and MortalityACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women.

Several dozen cases have been reported in the world literature.

When pregnancy is detected, Fosinopril Sodium and Hydrochlorothiazide should be discontinued as soon as possible.The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed.

Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of fosinopril as soon as possible.Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found.

In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.If oligohydramnios is observed, fosinopril should be discontinued unless it is considered life-saving for the mother.

Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia.

If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.Exchange transfusion or peritoneal dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Fosinopril is poorly dialyzed from the circulation of adults, and indeed there is no experience with any procedure for removing fosinopril from the neonatal circulation, but limited experience with other ACE inhibitors has not shown that such removal is central to the treatment of these infants.

When fosinopril is given to pregnant rats at doses about 80 to 250 times (on a mg/kg basis) the maximum recommended human dose, three similar orofacial malformations and one fetus with situs inversus were observed among the offspring.

In pregnant rabbits, no teratogenic effects of fosinopril were seen in studies at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose.Impaired Hepatic FunctionRarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

The mechanism of this syndrome is not understood.

A patient receiving Fosinopril Sodium and Hydrochlorothiazide who develops jaundice or marked elevation of hepatic enzymes should discontinue Fosinopril Sodium and Hydrochlorothiazide tablets and receive appropriate medical follow-up.

Fosinopril Sodium and Hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Also, since the metabolism of fosinopril to fosinoprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop elevated plasma levels of fosinopril.

In a study of patients with alcoholic or biliary cirrhosis the rate (but not the extent) of hydrolysis to fosinoprilat was reduced.

In these patients the clearance of fosinoprilat was reduced, and the area under the fosinoprilat-time curve was approximately doubled.Systemic Lupus ErythematosusThiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

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