Fosinopril sodium/Hydrochlorothiazide

Uses and Indications

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

Dosage and Administration

Fosinopril sodium and hydrochlorothiazide tablets are indicated for the treatment of hypertension. The recommended dosage of fosinopril is 10 to 80 mg administered once daily, while hydrochlorothiazide is effective in doses ranging from 12.5 to 50 mg per day.

In clinical trials involving the combination therapy of fosinopril and hydrochlorothiazide, fosinopril doses varied from 2.5 to 40 mg, and hydrochlorothiazide doses ranged from 5 to 37.5 mg. The antihypertensive effects of the combination therapy are enhanced with increasing doses of either component. For patients whose blood pressure is not adequately controlled with monotherapy using either fosinopril or hydrochlorothiazide, switching to the combination therapy is recommended.

Dosage adjustments should be guided by the clinical response of the patient. Notably, the addition of 12.5 mg of hydrochlorothiazide to a regimen of 10 to 20 mg of fosinopril typically results in an additional reduction in seated diastolic blood pressure at 24 hours post-dosing. The combination of 10 mg of fosinopril with 12.5 mg of hydrochlorothiazide has been shown to produce effects comparable to those achieved with monotherapy using either 40 mg of fosinopril or 37.5 mg of hydrochlorothiazide.

In patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m² or serum creatinine ≥ 3 mg/dL), the use of loop diuretics is preferred over thiazides, and therefore, fosinopril sodium and hydrochlorothiazide tablets are not recommended in this population. However, in patients with lesser degrees of renal impairment, these tablets may be used without any change in dosage.

Contraindications

Fosinopril sodium and hydrochlorothiazide tablets are contraindicated in patients who are anuric. Additionally, the use of this medication is contraindicated in individuals who are hypersensitive to fosinopril, any other ACE inhibitor, hydrochlorothiazide, 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.

Warnings and Precautions

Patients receiving fosinopril sodium and hydrochlorothiazide may experience serious adverse reactions, particularly those related to anaphylactoid responses.

Serious Warnings

• Anaphylactoid and Possibly Related Reactions: Patients may experience a variety of serious adverse reactions, including:

  • Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema occurs, treatment should be discontinued, and appropriate therapy should be instituted immediately.

  • Intestinal Angioedema: This condition has been reported in patients treated with ACE inhibitors, presenting with abdominal pain. Symptoms typically resolve after discontinuation of the ACE inhibitor.

  • Anaphylactoid Reactions During Desensitization: Life-threatening reactions have occurred in patients undergoing desensitization while receiving ACE inhibitors.

  • Anaphylactoid Reactions During Membrane Exposure: Such reactions have been reported in patients dialyzed with high-flux membranes while on ACE inhibitors.

• Hypotension: Fosinopril sodium and hydrochlorothiazide can cause symptomatic hypotension, particularly in patients who are volume- and/or salt-depleted. Close monitoring is required in patients with congestive heart failure.

• Impaired Renal Function: Caution is advised when using this medication in patients with severe renal disease. Renal function should be monitored during the first few weeks of therapy, especially in patients with renal artery stenosis.

• Neutropenia/Agranulocytosis: Monitoring of white blood cell counts is recommended for patients with collagen-vascular disease, particularly if renal function is impaired.

• Fetal Toxicity: Use during the second and third trimesters of pregnancy can adversely affect fetal renal function and increase morbidity and mortality. Discontinue as soon as pregnancy is detected.

• Impaired Hepatic Function: Discontinue treatment if jaundice or marked elevation of hepatic enzymes occurs. Use with caution in patients with impaired hepatic function.

• Systemic Lupus Erythematosus: Thiazide diuretics may exacerbate or activate systemic lupus erythematosus.

General Precautions

• Derangements of Serum Electrolytes: Initial and periodic determinations of serum electrolytes should be performed to detect possible electrolyte imbalances.

Laboratory Tests

• Therapy with fosinopril sodium and hydrochlorothiazide should be interrupted for a few days before conducting tests of parathyroid function.

• Fosinopril may cause false low measurements of serum digoxin levels when using the Digi-Tab RIA Kit.

Get Emergency Medical Help

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

Stop Taking and Call Your Doctor

Patients should discontinue the medication and seek medical attention if jaundice or marked elevation of hepatic enzymes occurs, or if hypotension is experienced, in which case the patient should be placed in a supine position and treated with intravenous infusion of physiological saline if necessary.

Side Effects

Common adverse reactions observed in patients taking Fosinopril Sodium and Hydrochlorothiazide include:

• Headache: 7%

• Cough: 5.6%

• Fatigue: 3.9%

• Dizziness: 3.2%

• Upper Respiratory Infection: 2.3%

• Musculoskeletal Pain: 2%

Other adverse reactions occurring in 0.5% to <2% of patients include:

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

• Cardiovascular: Orthostatic hypotension (1.8% in treated patients; 0.3% in placebo), edema, flushing, rhythm disturbance, syncope.

• Dermatologic: Pruritus, rash, urticaria, photosensitivity.

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

• Gastrointestinal: Nausea/vomiting, diarrhea, dyspepsia/heartburn, abdominal pain, gastritis/esophagitis, pancreatitis, hepatitis, dysphagia, abdominal distention, flatulence, appetite/weight change, dry mouth.

• Immunologic: Angioedema (see Warnings).

• Musculoskeletal: Myalgia/muscle cramps, arthralgia.

• Neurologic/Psychiatric: Somnolence, depression, numbness/paresthesia, memory disturbance, tremor, confusion, mood change, sleep disturbance.

• Respiratory: Sinus congestion, pharyngitis, rhinitis, bronchospasm, laryngitis/hoarseness, epistaxis, eosinophilia.

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

• Urogenital: Urinary tract infection, urinary frequency, dysuria, renal insufficiency.

Serious adverse reactions include:

• Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx can be fatal. Intestinal angioedema may present as abdominal pain with or without nausea or vomiting.

• Hypotension: Symptomatic hypotension can occur, particularly in volume-depleted patients.

• Neutropenia/Agranulocytosis: Monitoring of white blood cell counts is recommended in patients with collagen-vascular disease.

• Impaired Renal Function: Caution is advised in patients with severe renal disease, as this may precipitate azotemia.

Laboratory test abnormalities may include changes in serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides, calcium, and neutropenia. Elevations of BUN and creatinine, leukopenia, eosinophilia, and elevated liver function tests (transaminases, LDH, alkaline phosphatase, and serum bilirubin) have also been reported.

Additionally, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients taking large cumulative doses.

Drug Interactions

The concomitant use of fosinopril sodium and hydrochlorothiazide with certain medications may lead to significant interactions that require careful management and monitoring.

Pharmacodynamic Interactions

• Potassium Supplements and Potassium-Sparing Diuretics: The combination of fosinopril sodium and hydrochlorothiazide may result in variable effects on serum potassium levels, potentially leading to hyperkalemia. Caution is advised when using potassium-sparing diuretics (e.g., spironolactone, amiloride, triamterene) or potassium supplements, and frequent monitoring of serum potassium is recommended.

• Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been observed in patients receiving ACE inhibitors, including fosinopril, during lithium therapy. The risk of lithium toxicity may be further elevated when a thiazide diuretic is coadministered. Caution is warranted, and serum lithium levels should be monitored regularly.

• Nonsteroidal Anti-Inflammatory Agents (NSAIDs): The antihypertensive, diuretic, and natriuretic effects of thiazide diuretics may be diminished when NSAIDs are used concurrently. The specific impact of NSAIDs on the antihypertensive effect of fosinopril sodium and hydrochlorothiazide has not been thoroughly studied.

• Dual Blockade of the Renin-Angiotensin System (RAS): The use of multiple agents that affect the RAS, such as ACE inhibitors, angiotensin receptor blockers, or aliskiren, is associated with increased risks of hypotension, hyperkalemia, and renal function changes, including acute renal failure. Close monitoring of blood pressure, renal function, and electrolytes is essential. Aliskiren should not be coadministered with fosinopril and hydrochlorothiazide in patients with diabetes or renal impairment (GFR <60 mL/min).

Pharmacokinetic Interactions

• Antacids: The absorption of fosinopril may be impaired when taken with antacids containing aluminum hydroxide, magnesium hydroxide, or simethicone. If coadministration is necessary, dosing should be separated by at least 2 hours.

• Cholestyramine and Colestipol Resins: The presence of anionic exchange resins can significantly reduce the absorption of hydrochlorothiazide, with cholestyramine and colestipol resins binding hydrochlorothiazide and decreasing its gastrointestinal absorption by up to 85% and 43%, respectively.

• Warfarin: Studies have not demonstrated any clinically significant effects of fosinopril on the serum concentration or clinical effects of warfarin.

Other Interactions

• Gold: Rare nitritoid reactions, characterized by facial flushing, nausea, vomiting, and hypotension, have been reported in patients receiving injectable gold (sodium aurothiomalate) alongside fosinopril sodium and hydrochlorothiazide.

• Norepinephrine: Thiazides may reduce arterial responsiveness to norepinephrine, although this effect is not sufficient to negate the therapeutic efficacy of norepinephrine.

• Tubocurarine: The use of thiazides may enhance responsiveness to tubocurarine.

• Methenamine: Hydrochlorothiazide may decrease the effectiveness of methenamine by alkalinizing the urine.

Laboratory Test Interactions

Patients taking hydrochlorothiazide should be advised to protect their skin from sun exposure and undergo regular skin cancer screenings due to an increased risk of non-melanoma skin cancer associated with thiazide diuretics.

In summary, careful consideration and monitoring are essential when fosinopril sodium and hydrochlorothiazide are used in conjunction with other medications or in specific patient populations.

Pediatric Use

Neonates with a history of in utero exposure to fosinopril and hydrochlorothiazide may experience oliguria or hypotension. In such cases, it is crucial to support blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to reverse hypotension and/or substitute for impaired renal function. It is important to note that the removal of fosinopril and hydrochlorothiazide, which can cross the placenta, from the neonatal circulation is not significantly accelerated by these interventions.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of fosinopril sodium and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution, typically starting at the low end of the dosing range. This recommendation reflects the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population. Regular monitoring of renal function and blood pressure is advised to ensure safety and efficacy in elderly patients.

Pregnancy

Use of fosinopril sodium and hydrochlorothiazide during pregnancy is associated with significant risks, particularly during the second and third trimesters. This combination is classified as Pregnancy Category D, indicating evidence of risk to the fetus. The use of drugs that act on the renin-angiotensin system during these trimesters can lead to reduced fetal renal function, resulting in oligohydramnios, which may be associated with fetal lung hypoplasia and skeletal deformations. Potential adverse neonatal outcomes include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, it is recommended to discontinue fosinopril and hydrochlorothiazide as soon as possible. If there is no appropriate alternative therapy for managing maternal hypertension, healthcare providers should inform the patient of the potential risks to the fetus and conduct serial ultrasound examinations to monitor the intra-amniotic environment. If oligohydramnios is observed, discontinuation of the medication should be considered unless it is deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Intrauterine exposure to thiazide diuretics, such as hydrochlorothiazide, has been associated with fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. However, no teratogenic effects of fosinopril or the combination of fosinopril and hydrochlorothiazide were observed in studies involving pregnant rats and rabbits, even at doses significantly higher than the maximum recommended human dose.

Healthcare providers should closely monitor infants with a history of in utero exposure to fosinopril and hydrochlorothiazide for signs of hypotension, oliguria, and hyperkalemia. Appropriate management of maternal hypertension during pregnancy is crucial to optimize outcomes for both the mother and the fetus.

Lactation

Both fosinopril and hydrochlorothiazide are excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the use of fosinopril sodium and hydrochlorothiazide. This decision should take into account the importance of the medication to the lactating mother.

Renal Impairment

Fosinopril sodium and hydrochlorothiazide should be administered with caution in patients with severe renal impairment. The use of thiazides in this population may precipitate azotemia, and the cumulative effects of repeated dosing warrant careful consideration.

In patients with severe congestive heart failure, where renal function may be reliant on the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors, including fosinopril, can lead to oliguria, progressive azotemia, and, in rare cases, acute renal failure or death.

Monitoring of renal function is essential, particularly during the initial weeks of therapy in hypertensive patients with unilateral or bilateral renal artery stenosis, as ACE inhibitors have been associated with increases in blood urea nitrogen and serum creatinine. These increases are typically reversible upon discontinuation of the ACE inhibitor or diuretic therapy.

Additionally, some patients treated with ACE inhibitors who do not have preexisting renal vascular disease may experience minor and transient increases in blood urea nitrogen and serum creatinine, especially when combined with diuretics. In such cases, a dosage reduction of fosinopril sodium and hydrochlorothiazide may be necessary.

Routine evaluation of renal function should be included in the assessment of hypertensive patients, and monitoring of white blood cell counts is advisable in those with collagen-vascular disease, particularly if renal function is compromised.

Hepatic Impairment

Patients with hepatic impairment should use fosinopril sodium and hydrochlorothiazide with caution. The metabolism of fosinopril to its active form, fosinoprilat, is dependent on hepatic esterases; therefore, patients with impaired liver function may experience elevated plasma levels of fosinopril.

In clinical studies involving patients with alcoholic or biliary cirrhosis, the rate of hydrolysis to fosinoprilat was reduced, leading to decreased clearance of fosinoprilat. Consequently, the area under the fosinoprilat-time curve was approximately doubled in these patients.

Patients who develop jaundice or marked elevations in hepatic enzymes while on fosinopril sodium and hydrochlorothiazide should discontinue the medication and receive appropriate medical follow-up. Additionally, minor alterations in fluid and electrolyte balance in patients with impaired hepatic function or progressive liver disease may precipitate hepatic coma, necessitating careful monitoring and potential dosage adjustments.

Overdosage

In the event of an overdose of fosinopril sodium and hydrochlorothiazide, it is essential to seek immediate assistance from a certified Regional Poison Control Center, as they provide up-to-date information on overdose management. The management of overdose should consider the potential for multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics.

Currently, there is no specific information available regarding the treatment of overdose with fosinopril sodium and hydrochlorothiazide tablets; therefore, treatment should be symptomatic and supportive. It is recommended that therapy with these medications be discontinued, and the patient should be closely observed. Established procedures should be followed to address dehydration, electrolyte imbalances, and hypotension.

Animal studies indicate that single oral doses of 2600 mg/kg of fosinopril resulted in significant lethality, while most rats survived doses of up to 2750 mg/kg of hydrochlorothiazide. These doses are significantly higher than the maximum recommended daily doses for humans. In human cases, the most common manifestation of fosinopril overdose is likely to be hypotension. For hydrochlorothiazide overdose, symptoms typically include dehydration and electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Laboratory determinations of serum levels of fosinopril and its metabolites are not widely available and do not play a significant role in the management of fosinopril overdose. Furthermore, there are no established physiological maneuvers that could enhance the elimination of fosinopril and its metabolites. It is important to note that fosinoprilat is poorly removed from the body through hemodialysis or peritoneal dialysis.

While angiotensin II could theoretically act as a specific antagonist-antidote in cases of fosinopril overdose, it is largely unavailable outside of specialized research facilities. Given that the hypotensive effect of fosinopril is mediated through vasodilation and effective hypovolemia, the infusion of normal saline solution is a reasonable approach to managing fosinopril overdose.

Nonclinical Toxicology

Reproductive studies and long-term carcinogenicity studies with fosinopril sodium and hydrochlorothiazide have not been conducted. The combination of fosinopril and hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or the Chinese hamster ovary cell cytogenetic assay. Additionally, the combination was not genotoxic in a mouse micronucleus test in vivo.

No evidence of carcinogenicity was found when fosinopril was administered in the diet to rats and mice for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose was approximately 250 times the maximum human dose of 80 mg, given to a 50 kg subject. On a body surface area basis, this dose is 20 (mice) to 40 (rats) times the maximum human dose. Neither fosinopril nor the fosinoprilat moiety exhibited mutagenic properties in the aforementioned assays. 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, no increase in chromosomal aberrations was observed at lower drug concentrations without metabolic activation or at any concentration with metabolic activation.

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were approximately 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies revealed no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays using concentrations of hydrochlorothiazide ranging from 43 to 1300 mg/mL. Additionally, positive test results were noted in the Aspergillus nidulans nondisjunction assay using an unspecified concentration of hydrochlorothiazide.

There were no adverse reproductive effects observed in male and female rats treated with up to 60 mg/kg daily. At doses four times higher, slight increases in pairing time were noted. This higher dose is approximately 125 (body surface area basis) or 600 (body weight basis) times greater than the dose received by a 50 kg human receiving 20 mg a day. Furthermore, no adverse effects on fertility were observed when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day, which are from 3.2 (body surface area basis in rats) to 400 (body weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.

Storage and Handling

Fosinopril Sodium and Hydrochlorothiazide is supplied in tablet form.

Tablets should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as per USP Controlled Room Temperature guidelines.

To maintain product integrity, it is essential to protect the tablets from moisture by keeping the bottle tightly closed. Additionally, the tablets should be dispensed in a tight, light-resistant container that complies with USP standards, equipped with a child-resistant closure as required.