DRUGS & SUPPLEMENTS
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Fovas sodium, USP is designated chemically as:L-proline,4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-, sodium salt, trans-. Fovas sodium,USP is a white to off-white crystalline powder. It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane. Its structural formula is:
Its empirical formula is C30H45NNaO7P, and its molecular weight is 585.65.
Fovas Sodium, USP is available for oral administrations as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients include: crospovidone, lactose, microcrystalline cellulose, magnesium stearate, and povidone.
ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
In 647 hypertensive patients treated with Fovas alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with Fovas, including those receiving concomitant diuretic therapy. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Fovas sodium remains to be elucidated.
While the mechanism through which Fovas sodium lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Fovas sodium has an antihypertensive effect even in patients with low-renin hypertension. Although Fovas sodium was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.
In patients with heart failure, the beneficial effects of Fovas sodium are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin-converting enzyme produces decreases in both preload and afterload.
Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, are as under plasma concentration-time curves (AUCs) and peak concentrations (Cmaxs) are directly proportional to the dose of Fovas. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.
After an oral dose of radiolabeled Fovas, 75% of radioactivity in plasma was present as active fosinoprilat, 20% to 30% as a glucuronide conjugate of fosinoprilat, and 1% to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, Fovas, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.
After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled Fovas, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min.
In healthy subjects, the terminal elimination half-life (t1/2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of Fovas, the effective t1/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1/2 was 14 hours.
In patients with mild-to-severe renal insufficiency (creatinine clearance 10 to 80 mL/min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with end-stage renal disease (creatinine clearance <10 mL/min/1.73m2), the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function. (See DOSAGE AND ADMINISTRATION.)
Fovas is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of hydrolysis of Fovas is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one half of that in patients with normal hepatic function.
In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20 to 35 years old).
In pediatric patients, (N=20) age 6 to 16 years, with glomerular filtration rate ≥25 mL/min, given a single dose of Fovas (0.3 mg/kg given as solution), the mean AUC and Cmax values of fosinoprilat (the active form of Fovas) were similar to those seen in healthy adults receiving 20 mg (about 0.3 mg/kg for a 70 kg adult) of Fovas as a solution. The terminal elimination half-life of fosinoprilat in pediatric patients was 11 to 13 hours, also similar to that observed in adults.
Fosinoprilat was found to cross the placenta of pregnant animals.
Studies in animals indicate that Fovas and fosinoprilat do not cross the blood-brain barrier.
Administration of Fovas sodium tablets to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt-and/or volume-depleted. Use of Fovas sodium in combination with thiazide diuretics gives a blood pressure-lowering effect greater than that seen with either agent alone.
Following oral administration of single doses of 10 mg to 40 mg, Fovas sodium lowered blood pressure within one hour, with peak reduction achieved 2 to 6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Following four weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 20 to 80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8 to 9/6 to 7 mmHg more than placebo. The trough effect was about 50% to 60% of the peak diastolic response and about 80% of the peak systolic response.
In most trials, the antihypertensive effect of Fovas sodium increased during the first several weeks of repeated measurements. The antihypertensive effect of Fovas sodium has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of Fovas sodium has not resulted in a rapid increase in blood pressure.
Limited experience in controlled and uncontrolled trials combining Fovas with a calcium channel blocker or a loop diuretic has indicated no usual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system
ACE inhibitors are generally less effective in blacks than in non-blacks. The effectiveness of Fovas sodium was not influenced by age, sex, or weight.
In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that Fovas sodium does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flows were unchanged compared to baseline, as was glomerular filtration rate.
Reduction of blood pressure with low (0.1 mg/kg), medium (0.3 mg/kg) and high (0.6 mg/kg) target doses of once-daily Fovas was evaluated in a randomized, double-blind study of 252 pediatric patients 6 to 16 years of age with hypertension or high-normal blood pressure. Fovas doses in the medium and high dose groups were titrated to target doses after one week and the total duration of treatment was four weeks. The maximum dose studied was 40 mg once daily. At the end of four weeks of treatment, the mean reductions from baseline in trough systolic blood pressure were similar in all three dose groups. Withdrawal of Fovas treatment resulted in an increase in blood pressure towards baseline over a two week period. Fovas was generally well tolerated.
Fovas sodium was studied in 3 double-blind, placebo controlled, 12 to 24 week trials including a total of 734 patients with heart failure, with Fovas sodium doses from 10 mg to 40 mg daily. Concomitant therapy in 2 of these 3 trials included diuretics and digitalis; in the third trial patients were receiving only diuretics. All 3 trials showed statistically significant benefits of Fovas sodium therapy, compared to placebo, in one or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). Favorable effects were maintained for up to two years. Effects of Fovas sodium on long-term mortality in heart failure have not been evaluated. The once daily dosage for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses.
Fovas sodium tablets are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis (see DOSAGE AND ADMINISTRATION ).
In using Fovas sodium, 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 Fovas sodium does not have a similar risk (see WARNINGS ).
In considering use of Fovas sodium, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, 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 ).
Do not co-administer Fovas sodium tablets with aliskiren in patients with diabetes.
Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. If laryngeal stridor or angioedema of the face, lips, mucous membranes, tongue, glottis or extremities occurs, treatment with Fovas sodium should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS). Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
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 life-threatening 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.
In patients with heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Fovas sodium 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 Fovas or diuretic is increased. Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Fovas sodium treatment usually can be continued following restoration of blood pressure and volume.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue Fovas as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Fovas, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Fovas for hypotension, oliguria, and hyperkalemia.[see Precautions, Pediatric Use].
No teratogenic effects of Fovas were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times and one time (in rabbits) the maximum recommended human dose.
When Fovas was 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 hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Fovas sodium has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Fovas sodium and/or discontinuation of the diuretic may be required.
Evaluation of patients with hypertension or heart failure should always include assessment of renal function.
Impaired renal function decreases total clearance of fosinoprilat and approximately doubles AUC. In general, no adjustment of dosing is needed. However, patients with heart failure and severely reduced renal function may be more sensitive to the hemodynamic effects (e.g., hypotension) of ACE inhibition (see CLINICAL PHARMACOLOGY ).
Hyperkalemia: In clinical trials, hyperkalemia (serum potassium greater than 10% above the upper limit of normal) has occurred in approximately 2.6% of hypertensive patients receiving Fovas sodium. In most cases, these were isolated values which resolved despite continued therapy. In clinical trials, 0.1% of patients (two patients) were discontinued from therapy due to an elevated serum potassium. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Fovas sodium (see PRECAUTIONS: Drug Interactions ).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Impaired Liver Function: Since Fovas is primarily metabolized by hepatic and gut wall esterases to its active moiety, fosinoprilat, patients with impaired liver function could develop elevated plasma levels of unchanged Fovas. In a study in patients with alcoholic or biliary cirrhosis, the extent of hydrolysis was unaffected, although the rate was slowed. In these patients, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled.
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Fovas will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients receiving ACE inhibitors as medication. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. (See WARNINGS: Anaphylactoid reactions during membrane exposure.)
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to a physician. Patients should be told that if syncope occurs, Fovas sodium should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Fovas during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
With potassium supplements and potassium-sparing diuretics: Fovas sodium can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.
With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be co administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
With antacids: In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with Fovas reduced serum levels and urinary excretion of fosinoprilat as compared with Fovas administrated alone, suggesting that antacids may impair absorption of Fovas. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours.
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 Fovas sodium.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors):In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Fovas, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including Fovas may be attenuated by NSAIDs.
Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
Dual Blockade of the Renin-Angiotensin System (RAS):Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Fovas and other agents that affect the RAS.
Do not co-administer aliskiren with Fovas in patients with diabetes. Avoid use of aliskiren with Fovas in patients with renal impairment (GFR <60 ml/min).
Other: Neither Fovas sodium nor its metabolites have been found to interact with food. In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of Fovas with any one of these drugs. In a study with concomitant administration of aspirin and Fovas sodium, the bioavailability of unbound fosinoprilat was not altered.
In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding, and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed.
Neither Fovas nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fovas 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, Fovas 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 rats 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 time the maximum recommended human dose.
Fovas sodium should not be administered to nursing mothers.
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 Fovas, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means
The antihypertensive effects of Fovas 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 Fovas have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL
Pharmacology: Pharmacokinetics and Metabolism ). Fovas was generally well tolerated and adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients ).
During clinical trials with any Fovas 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 Fovas sodium alone and at least as frequent on Fovas sodium as on placebo in placebo-controlled clinical trials are shown in the table below.
The following events were also seen at >1% on Fovas 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 Fovas 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 Fovas 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.
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 Fovas.
Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation.
Urogenital: Renal insufficiency, urinary frequency.
Clinical adverse events probably or possibly relate or of uncertain relationship to therapy, occurring in at least 1% of patients treated with Fovas sodium and at least as common as the placebo group, in placebo-controlled trials are shown in the table below.
The following events also occurred at a rate of 1% or more on Fovas 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 Fovas 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 cardiorespiratory arrest, shock (0.2%), atrial rhythm disturbance, cardiac rhythm disturbances, non anginal chest pain, edema lower extremity, hypertension, syncope, conduction disorder, bradycardia, tachycardia.
Orthostatic hypotension occurred in 1.4% of patients treated with Fovas 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, 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.
BUN/Serum Creatinine: Elevations, usually transient and minor, of BUN or serum creatinine have been observed. In placebo-controlled clinical trials, there were no significant differences in the number of patients experiencing increases in serum creatinine (outside the normal range or 1.33 times the pre-treatment value) between the Fovas and placebo treatment groups. Rapid reduction of longstanding or markedly elevated blood pressure by any antihypertensive therapy can result in decrease in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. (See PRECAUTIONS: General.)
Hematology: In controlled trials, a mean hemoglobin decrease of 0.1 g/dL was observed in Fovas treated patients. In individual patients decreases in hemoglobin or hematocrit were usually transient, small, and not associated with symptoms. No patient was discontinued from therapy due to the development of anemia. Other: Neutropenia (see WARNINGS ), leukopenia and eosinophilia.
Liver Function Tests: Elevations of transaminases, LDH, alkaline phosphatase and serum bilirubin have been reported. Fovas therapy was discontinued because of serum transaminase elevations in 0.7% of patients. In the majority of cases, the abnormalities were either present at baseline or were associated with other etiologic factors. In those cases which were possibly related to Fovas therapy, the elevations were generally mild and transient and resolved after discontinuation of therapy.
Laboratory determination of serum levels of fosinoprilat and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Fovas overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Fovas and its metabolites. Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of Fovas overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Fovas is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Fovas overdose by infusion of normal saline solution.
No adverse clinical events were reported in 23 pediatric patients, age 6 months to 6 years, given a single 0.3 mg/kg oral dose of Fovas.
There is a published report of a 20 month-old female, weighing 12 kg, who ingested approximately 200 mg Fovas sodium. After receiving gastric lavage and activated charcoal within one hour of the ingestion, she made an uneventful recovery.
The recommended initial dose of Fovas sodium tablets is 10 mg once a day, both as monotherapy and when the drug is added to a diuretic. Dosage should then be adjusted according to blood pressure response at peak (2 to 6 hours) and trough (about 24 hours after dosing) blood levels. The usual dosage range needed to maintain a response at trough is 20 to 40 mg but some patients appear to have a further response to 80 mg. In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate, dividing the daily dose should be considered. If blood pressure is not adequately controlled with Fovas sodium alone, a diuretic may be added.
Concomitant administration of Fovas sodium with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS ).
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Fovas sodium tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Fovas sodium tablets (see WARNINGS ). Then, if blood pressure is not controlled with Fovas sodium tablets alone diuretic therapy should be resumed. If diuretic therapy cannot be discontinued, an initial dose of 10 mg of Fovas sodium tablets should be used with careful medical supervision for several hours and until blood pressure has stabilized. (See WARNINGS and PRECAUTIONS: Information for Patients and Drug Interactions ).
Since concomitant administration of Fovas sodium tablets with potassium supplements, or potassium containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS ).
In children, doses of Fovas sodium tablets between 0.1 and 0.6 mg/kg have been studied and shown to reduce blood pressure to a similar extent (see CLINICAL PHARMACOLOGY Pharmacodynamics and Clinical Effects ). Based on this, the recommended dose of Fovas sodium tablets USP in children weighing more than 50 kg is 5 to 10 mg once per day as monotherapy. An appropriate dosage strength is not available for children weighing less than 50 kg.
Digitalis is not required for Fovas sodium tablets to manifest improvements in exercise tolerance and symptoms. Most placebo-controlled clinical trial experience has been with both digitalis and diuretics presents as background therapy.
The usual starting dose of Fovas sodium tablets should be 10 mg once daily. Following the initial dose of Fovas sodium tablets, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostasis and, if present, until blood pressure stabilizes. An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed.
Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily. The usual effective dosage range is 20 mg to 40 mg once daily.
The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic.
For Hypertensive or Heart Failure Patients with Renal Impairment: In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the totally body clearance for fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances <80 mL/min/1.73m2), including end stage renal failure (creatinine clearance <10 mL/min/1.73m2) This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment. (See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis .)
NDC: 63629-7293-1 30 TABLET in a BOTTLE
NDC: 63629-7293-2 90 TABLET in a BOTTLE
NDC: 63629-7293-3 28 TABLET in a BOTTLE
Depending on the reaction of the Fovas after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Fovas not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Fovas addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology