What are the main uses of fosinopril. How does fosinopril work in the body. What is the recommended dosage and administration of fosinopril. What are the potential side effects of taking fosinopril. How does fosinopril compare to other ACE inhibitors.

Understanding Fosinopril: An ACE Inhibitor for Cardiovascular Health

Fosinopril is a potent angiotensin-converting enzyme (ACE) inhibitor that has been in use for nearly three decades. This medication plays a crucial role in managing various cardiovascular conditions, primarily hypertension and heart failure. Its unique properties set it apart from other ACE inhibitors, making it an valuable option in the treatment arsenal for healthcare providers.

Key Features of Fosinopril

• Long half-life
• Hydrophilic nature
• Not metabolized by the liver

These characteristics contribute to fosinopril’s effectiveness and safety profile, allowing for once-daily dosing and potentially fewer drug interactions compared to some other ACE inhibitors.

Primary Indications for Fosinopril Therapy

Healthcare providers prescribe fosinopril for several cardiovascular conditions. The primary indications include:

1. Hypertension management
2. Heart failure treatment
3. Prevention of left ventricular remodeling after myocardial infarction
4. Diabetic nephropathy

Can fosinopril be used for other conditions? In some cases, fosinopril may be prescribed off-label for conditions such as HIV-associated nephropathy (HIVAN). However, its use in such situations should be carefully evaluated by a healthcare professional.

Mechanism of Action: How Fosinopril Works in the Body

Fosinopril’s mechanism of action involves the renin-angiotensin-aldosterone system (RAAS), a key regulator of blood pressure and fluid balance in the body. Here’s how it works:

1. Fosinopril is a prodrug that gets hydrolyzed in the liver to its active form, fosinoprilat.
2. Fosinoprilat competitively inhibits the angiotensin-converting enzyme (ACE).
3. This inhibition prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
4. As a result, there’s a decrease in angiotensin II formation and reduced aldosterone concentrations.
5. These effects lead to decreased systemic vasoconstriction and increased sodium excretion.

Why is this mechanism beneficial for cardiovascular health? By modulating the RAAS, fosinopril helps to relax blood vessels, reduce blood pressure, and decrease the workload on the heart. In heart failure patients, it also helps protect the myocardium from the remodeling effects of angiotensin II.

Dosage and Administration Guidelines for Fosinopril

Fosinopril is available in oral tablet form in strengths of 10, 20, or 40 mg. The dosing strategy typically follows a gradual approach:

• Initial dose: Usually starts at 10 mg once daily
• Dose adjustment: Based on patient response and tolerance
• Maximum dose: Generally 80 mg for average hypertensive patients
• Special populations: Reduced initial dose (5 mg) for patients with sodium/water depletion or renal failure

How should fosinopril be administered in different scenarios? Let’s break it down:

For Hypertension

Monotherapy: Begin with 10 mg once daily. Adjust the dose based on blood pressure readings at peak (2-6 hours) and trough (24 hours) levels. Most patients achieve optimal control with 20-40 mg daily.

Co-administration with diuretics: If blood pressure control is inadequate with fosinopril alone, a diuretic can be added. However, caution is needed when combining fosinopril with potassium-sparing diuretics or potassium supplements, as this can increase serum potassium levels.

For Heart Failure

Fosinopril is often prescribed as an adjunctive treatment alongside conventional therapy, which may include diuretics with or without digitalis. The dosing strategy in heart failure patients may require more careful monitoring and adjustment.

Comparing Fosinopril to Other ACE Inhibitors

While fosinopril belongs to the ACE inhibitor class, it has some unique properties that differentiate it from other members of this group. How does fosinopril compare to other commonly prescribed ACE inhibitors?

• Long half-life: Allows for once-daily dosing, potentially improving patient adherence
• Hydrophilic nature: May result in different tissue distribution compared to lipophilic ACE inhibitors
• Dual elimination pathway: Excreted by both hepatic and renal routes, which can be beneficial for patients with either liver or kidney impairment

Other ACE inhibitors approved in the US include captopril, enalapril, lisinopril, benazepril, quinapril, ramipril, moexipril, and trandolapril. Each has its own pharmacokinetic and pharmacodynamic profile, which may influence prescribing decisions based on individual patient characteristics.

Effectiveness of Fosinopril in Clinical Trials

Several clinical trials have demonstrated the efficacy of fosinopril in various cardiovascular conditions. Some notable studies include:

Fosinopril Efficacy/Safety Trial (FEST) Study Group

This study showed that fosinopril improves exercise tolerance and attenuates clinical deterioration in patients with heart failure. What were the specific findings?

• Improved exercise capacity
• Reduced symptoms of heart failure
• Decreased rate of clinical deterioration

Fosinopril Acute Myocardial Infarction Study (FAMIS)

This trial demonstrated the benefits of early fosinopril treatment in patients with acute myocardial infarction. Key outcomes included:

• Prevention of left ventricular remodeling
• Improved cardiac function
• Potential reduction in post-infarction complications

Diabetic Nephropathy Trial

A randomized clinical trial examined the effects of fosinopril combined with losartan in patients with diabetic nephropathy. The results showed:

• Reduced 24-hour total urine protein excretion
• Decreased serum creatinine levels
• Lowered blood urea nitrogen (BUN) levels

These findings suggest that fosinopril, especially when combined with an angiotensin receptor blocker like losartan, can provide significant renoprotective effects in diabetic patients.

Potential Side Effects and Precautions with Fosinopril Use

While fosinopril is generally well-tolerated, like all medications, it can cause side effects in some patients. What are the most common adverse effects associated with fosinopril?

• Dizziness
• Headache
• Fatigue
• Cough (a class effect of ACE inhibitors)
• Nausea
• Hyperkalemia (elevated potassium levels)

In rare cases, more serious side effects may occur. These can include:

• Angioedema (swelling of the face, lips, tongue, or throat)
• Severe hypotension
• Acute kidney injury
• Liver function abnormalities

Are there any specific precautions or contraindications for fosinopril use? Healthcare providers should exercise caution when prescribing fosinopril in the following situations:

• Pregnancy: ACE inhibitors are contraindicated during pregnancy due to the risk of fetal harm
• Bilateral renal artery stenosis
• History of angioedema with ACE inhibitors
• Severe renal impairment
• Concomitant use with aliskiren in patients with diabetes

Regular monitoring of blood pressure, renal function, and serum potassium levels is essential for patients taking fosinopril, especially during the initial period of treatment and after any dose adjustments.

The Role of Interprofessional Care in Fosinopril Therapy

Effective management of patients on fosinopril therapy often requires a collaborative approach involving various healthcare professionals. How can an interprofessional team optimize outcomes for patients taking fosinopril?

• Physicians: Responsible for diagnosis, prescribing, and overall management of the patient’s condition
• Pharmacists: Can provide medication counseling, monitor for drug interactions, and assist with dosage adjustments
• Nurses: Play a crucial role in patient education, monitoring of vital signs, and identifying potential side effects
• Dietitians: Can advise on dietary modifications, especially regarding potassium intake
• Cardiologists: May be involved in complex cases or patients with multiple cardiovascular issues
• Nephrologists: Often consulted for patients with renal impairment or diabetic nephropathy

Regular communication among team members is essential to ensure that all aspects of the patient’s care are coordinated and that any issues are promptly addressed. This collaborative approach can lead to improved patient outcomes, better medication adherence, and reduced risk of adverse events.

In conclusion, fosinopril is a versatile ACE inhibitor with a range of applications in cardiovascular medicine. Its unique pharmacological properties, combined with a well-established efficacy and safety profile, make it a valuable option for managing hypertension, heart failure, and related conditions. As with any medication, the key to successful therapy lies in appropriate patient selection, careful monitoring, and a collaborative approach to care. By understanding the nuances of fosinopril therapy and leveraging the expertise of an interprofessional team, healthcare providers can optimize treatment outcomes and improve the quality of life for patients with cardiovascular diseases.

Fosinopril – StatPearls – NCBI Bookshelf

Continuing Education Activity

Fosinopril is classified as an angiotensin-converting enzyme inhibitor and has been available for nearly three decades. Fosinopril has some key features that make it different from enalapril and captopril; 1) it has a long half-life, 2) it is hydrophilic, and 3) it is not broken down by the liver. Fosinopril is a competitive inhibitor of angiotensin-converting enzyme (ACE) and prevents the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. This activity covers fosinopril, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of hypertension with fosinopril.

Objectives:

• Summarize the mechanism of action of fosinopril.

• Identify the various indications for initiating fosinopril therapy.

• Review the adverse event profile of fosinopril.

• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with fosinopril.

Access free multiple choice questions on this topic.

Indications

Fosinopril is an angiotensin-converting enzyme (ACE) inhibitor that aims to decrease systemic blood pressure in hypertensive patients. Fosinopril is most often prescribed for patients suffering from hypertension (<140/90 mmHg for non-complicated patients and <130/80 mmHg for patients with either diabetes or chronic kidney disease).[1] Other ACE inhibitors approved in the US are captopril, enalapril, lisinopril, benazepril, quinapril, ramipril, moexipril, and trandolapril.[2]

Fosinopril is also prescribed as an adjunctive treatment of heart failure (HF) along with conventional therapy that includes diuretics with or without digitalis. Once-daily fosinopril treatment has been shown to improve HF signs and symptoms and reduce hospitalizations for worsening HF. [3] In a fosinopril Efficacy/Safety Trial (FEST) Study Group, fosinopril improves exercise tolerance and attenuates clinical deterioration in patients with heart failure.[4] 

Also, in the Fosinopril Acute Myocardial Infarction Study (FAMIS), early treatment with fosinopril has shown to benefit patients with acute myocardial infarction in addition to a prevention of left ventricular (LV) remodeling.[5]

Fosinopril also works as a preventative therapy for patients with diabetic nephropathy. In a randomized clinical trial of patients with diabetic nephropathy, fosinopril combined treatment with losartan resulted in reduced 24-hour total urine protein excretion, serum creatinine, and BUN.[6]

Off-label use of fosinopril also includes the treatment of HIV-associated nephropathy (HIVAN).[7]

Mechanism of Action

Fosinopril is an ester prodrug that hydrolyzes in the liver to fosinoprilat, the active metabolite form. Fosinoprilat then uses competitive inhibition to bind to ACE resulting in decreased formation of angiotensin II, reduced aldosterone concentrations, and diminished systemic vasoconstriction. By interacting with the renin-angiotensin-aldosterone system (RAAS) components, fosinopril can reduce the tendency of vasoconstriction and promote sodium excretion. It helps in heart failure by protecting the myocardium from the angiotensin II remodeling effects.

Administration

Fosinopril received official approval for use in 1991 and is available for administration in 10, 20, or 40 mg oral tablets. It is traditional to prescribe the drug at a low dose and increase the dosage as needed while evaluating the patient’s response and tolerance. The maximum dose is typically 80 mg for the average patient with hypertension. In patients with sodium or water depletion or renal failure, the initial dosing is reduced to 5 mg. It’s not uncommon to co-administer hydrochlorothiazide with fosinopril to regulate fluid volume and counteract high blood pressure.[8]

Hypertension

• Monotherapy: The recommended initial adult dose of fosinopril is 10 mg once daily, both as monotherapy and when the drug is added to diuretic treatment. The dose can then be adjusted according to the patient’s blood pressure at peak (in 2 to 6 hours) and trough ( at 24 hours) blood levels. Most patients gain optimum blood pressure control with 20 to 40 mg daily, and only some need 80 mg. However, if blood pressure control response is not adequate around the end of the dosing interval, dividing the daily dose may give better control.

• Co-administration with Diuretics: A diuretic can be added if blood pressure is inadequately controlled with fosinopril alone. Co-administration of fosinopril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can increase serum potassium.

• In patients currently treated with a diuretic, symptomatic hypotension can result following the initial dose of fosinopril. To reduce the chances of hypotension, the diuretic should, if possible, be discontinued two to three days before beginning therapy with fosinopril. Then, if blood pressure is not adequately controlled, the diuretic should be resumed. If diuretic treatment cannot be stopped, start fosinopril at 10 mg with close medical supervision for several hours and until the patient’s blood pressure is stabilized.

• Pediatrics: Monotherapy- In children weighing more than 50 kg, the recommended dose of fosinopril is 5-10 mg once daily.

Heart Failure

• Fosinopril should be started at 10 mg once daily and observe patients under medical supervision for at least 2 hours for any hypotension and/or orthostasis, and if any present, until blood pressure stabilizes.

• A starting dose of 5 mg is recommended in patients with heart failure and moderate to severe renal failure. Then, the dose should be increased over several weeks to be tolerated but not more than 40 mg daily. The usual effective dose range is 20-40 mg per day.

Hypertension/Heart Failure with Renal Impairment

In patients with renal impairment, the total clearance of fosinoprilat slows by 50 %. However, hepatobiliary elimination partially compensates for diminished renal elimination. Hence, the total body clearance of fosinoprilat stays normal with all degrees of renal impairments (CrCl < 80 mL/min/1.73 m2), including end-stage renal diseases.

Pregnant Women

Fosinopril is contraindicated during pregnancy due to its ability to cross the placenta. As a result, it may increase the risk of fetal malformations and cause congenital disabilities or death to the developing fetus. Therefore, if the patient reports pregnancy at any time during treatment, fosinopril therapy should stop immediately. In general, all ACE inhibitors should be avoided when treating hypertension in pregnancy.

Breastfeeding Patients

The manufacturer recommends against breastfeeding while using fosinopril as it is secreted in breast milk.[9]

Adverse Effects

A few common symptoms reported with fosinopril include fatigue, dizziness, gastrointestinal disturbances, dry cough, and a skin rash. [8] 

Long-term usage of fosinopril can produce a dry cough due to ACE inhibition and the resulting accumulation of bradykinin. A less common side effect of which to be aware is angioedema.

Other rarely reported adverse reactions are elevated serum aminotransferase concentrations and acute liver damage. Less than two percent of patients using fosinopril have reported increased serum aminotransferase levels without explanation. Since acute liver damage is an extremely rare reaction, only a handful of clinical reports have been documented and analyzed. Unfortunately, the few reports are insufficient to determine a consistent mechanism of injury, so the path of liver damage remains unknown in these patients. The metabolite reaction in the liver is proposed to cause the idiosyncratic adverse effect and remains under investigation.[8] Other ACE inhibitors that have shown similar liver damage are enalapril, lisinopril, and lisinopril.[2]

Contraindications

The incidence of angioedema occurring as an adverse effect is 0. 1 to 0.7% due to vasodilation and plasma extravasation.[10] If patients have a history of ACE inhibitor-induced angioedema, they should avoid using fosinopril or any other agent within that class.

In cases of hepatic failure, it is crucial to avoid prescribing any ACE inhibitors. In addition, patients experiencing the adverse effect of acute liver injury from fosinopril should refrain from using other ACE inhibitors to prevent further damage.

In patients with diabetes, fosinopril should not be co-administered with aliskiren, as aliskiren may enhance the hypotensive, hyperkaliemia, and nephrotoxic effects of fosinopril.

One needs to be careful while using fosinopril with other drugs due to drug-drug interaction.

• Potassium (K+) sparing diuretics: Fosinopril may cause hyperkalemia due to the attenuation of potassium loss caused by thiazide diuretics.

• Lithium: Fosinopril causes serious lithium drug interaction. It may slow the elimination of lithium from the body, resulting in increased lithium levels.

• Antacids: Antacids may alter the absorption of fosinopril, resulting in reduced serum levels. It can further reduce the urinary excretion of fosinoprilat.

• Nonsteroidal anti-inflammatory agents: in elderly patients, co-administration of fosinopril may result in deterioration of renal function, possibly resulting in acute renal failure.

Monitoring

While on fosinopril, the patient requires monitoring for hypotension, potassium levels, renal function, and angioedema. To decrease the possibility of hypotension as an adverse effect among ACE inhibitors, the recommendation is to prescribe fosinopril at a low dose initially. During weeks 2 to 3 of usage, clinicians should note serum creatine and potassium levels and blood pressure to gauge the patient’s tolerance. For instance, a patient with a history of hyperkalemia or a high potassium diet should be closely monitored to avoid exacerbating any preexisting conditions.[11]

Toxicity

If the patient is experiencing fosinopril toxicity, they will require general supportive care and should discontinue fosinopril immediately. The following case study describes a situation in which a patient suffered from the adverse effects of fosinopril.

The first documented case of a person experiencing uncommon adverse reactions due to fosinopril was a 61-year-old man who reported symptoms beginning during weeks 2 through 12 of treatment.[8] The patient reported no prior hepatobiliary disease and consuming 3 to 4 alcoholic beverages daily.[12] During the course of treatment with 20 mg fosinopril daily, he was also taking 50 mg of metoprolol twice a day and 5 mg of diazepam daily.[8] After just three weeks of using fosinopril, the patient presented with asthenia, jaundice, and pruritis. All medications were stopped once admitted to the hospital, and treatment was initiated. He received ursodiol, colestipol, and hydroxyzine to treat pruritis and cholestasis. Further examination also revealed him to have an elevated concentration of bilirubin, serum aminotransferase enzymes, and alkaline phosphatase.[8] However, other levels, such as immunoglobulins and eosinophilia, were reportedly within normal limits. During hospitalization, the patient faced complications such as renal failure, which required dialysis, duodenal ulcer bleeding, and septicemia.

Upon evaluation, the patient tested negative for hepatitis A, B, and C in addition to other autoantibody tests. Furthermore, the patient showed no signs of biliary obstruction or gallstones from an abdominal ultrasound or tomography imaging. Also, there were no other contributions to intrahepatic cholestasis. Any other medications were determined to be improbable causes of the acute liver injury he presented. A liver biopsy showed positive results for cholestasis and bile duct destruction.[12]

The patient was hospitalized for two months but continued to experience symptoms for up to 18 months after the incident. He reported having jaundice for four months, pruritis for six months, and anicteric cholestasis for 18 months. The overall recovery period lasted from 6 to 18 months, and the severity rating was 4+.[8] The risk of developing this acute liver injury due to fosinopril was categorized as a likelihood score of D. Other ACE inhibitors have shown similar risks for acute liver damage.

Enhancing Healthcare Team Outcomes

Even though fosinopril is a relatively safe and common means to treat hypertension, monitoring the treatment and reporting any adverse reactions under an interprofessional healthcare team is essential. Clinicians that tend to prescribe this class of ACE inhibitors include but are not limited to primary care clinicians, internal medicine specialists, and cardiologists. Before using fosinopril, the patient should be aware of all the possible side effects and receive instructions to avoid high potassium diets. To ensure the patient is maximizing their benefits from fosinopril, clinicians should schedule regular follow-ups and document the patient’s response. A pharmacist should have involvement at the outset of therapy, verifying appropriate dosing and dose titration, checking for potential interactions, and counseling the patient on possible adverse effects. Nursing will follow up with the patient, monitor therapy progress, and answer patient questions, alerting the prescriber to any concerns. With these interprofessional strategies, fosinopril’s use can achieve better patient outcomes with fewer adverse effects. [Level 5]

Review Questions

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• Comment on this article.

References

1.

Elliott WJ. Systemic hypertension. Curr Probl Cardiol. 2007 Apr;32(4):201-59. [PubMed: 17398315]

2.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Feb 11, 2018. Angiotensin-Converting Enzyme Inhibitors. [PubMed: 31644219]

3.

Shettigar U, Hare T, Gelperin K, Ilgenfritz JP, Deitchman D, Blumenthal M. Effects of fosinopril on exercise tolerance, symptoms, and clinical outcomes in patients with decompensated heart failure. Congest Heart Fail. 1999 Jan-Feb;5(1):27-34. [PubMed: 12189330]

4.

Erhardt L, MacLean A, Ilgenfritz J, Gelperin K, Blumenthal M. Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy/Safety Trial (FEST) Study Group. Eur Heart J. 1995 Dec;16(12):1892-9. [PubMed: 8682023]

5.

Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E. Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. FAMIS Working Party. Am Heart J. 1998 Aug;136(2):213-25. [PubMed: 9704681]

6.

Huang YH, Wang HT, Zhu QZ, Zhang H, Shen W, Wang Y. [Combination therapy with losartan and fosinopril for early diabetic nephropathy]. Di Yi Jun Yi Da Xue Xue Bao. 2003 Sep;23(9):963-5. [PubMed: 13129736]

7.

Wei A, Burns GC, Williams BA, Mohammed NB, Visintainer P, Sivak SL. Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition. Kidney Int. 2003 Oct;64(4):1462-71. [PubMed: 12969167]

8.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Feb 6, 2018. Fosinopril. [PubMed: 31644120]

9.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 28, 2019. Fosinopril. [PubMed: 29999858]

10.

Kostis WJ, Shetty M, Chowdhury YS, Kostis JB. ACE Inhibitor-Induced Angioedema: a Review. Curr Hypertens Rep. 2018 Jun 08;20(7):55. [PubMed: 29884969]

11.

Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71(6):e13-e115. [PubMed: 29133356]

12.

Nunes AC, Amaro P, Maç as F, Cipriano A, Martins I, Rosa A, Pimenta I, Donato A, Freitas D. Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report. Eur J Gastroenterol Hepatol. 2001 Mar;13(3):279-82. [PubMed: 11293449]

13.

Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, Wong F, Kim WR. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug;74(2):1014-1048. [PubMed: 33942342]

Disclosure: Kaitlyn Alessi declares no relevant financial relationships with ineligible companies.

Disclosure: Mayur Parmar declares no relevant financial relationships with ineligible companies.

Monopril (Fosinopril Sodium) Drug / Medicine Information

NOTICE: This Consumer Medicine Information (CMI) is intended for persons living in Australia.

Fosinopril Sodium (FOS-in-O-pril)

Consumer Medicine Information

What is in this leaflet

Read this leaflet carefully before taking MONOPRIL.*

This leaflet answers some common questions about MONOPRIL. It does not contain all
the available information. Some of the information it contains may not apply to you.
It does not take the place of talking to your doctor or pharmacist.

Keep this leaflet.

You may need to refer to it again later.

If you have any concerns about taking MONOPRIL, ask your doctor or pharmacist.

What is MONOPRIL used for

MONOPRIL is used for treating high blood pressure (hypertension) or heart failure.
Both of these are long term (chronic) diseases so it is important that you continue
to take your MONOPRIL every day.

High blood pressure (hypertension):

Everyone has blood pressure. This pressure helps get your blood all around your body.
Your blood pressure may be different at different times of the day, depending on how
busy or worried you are. If you have hypertension (high blood pressure), this means
that your blood pressure stays higher than is needed, even when you are relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have
hypertension is to have your blood pressure checked on a regular basis. If high blood
pressure is not treated it can lead to serious health problems, including stroke,
heart disease and kidney failure.

Heart Failure:

Heart failure means that the heart muscle cannot pump blood strongly enough to supply
all the blood needed throughout the body. Heart failure is not the same as heart
attack and does not mean that the heart stops. Heart failure may start off with no
symptoms, but as the condition progresses, patients feel short of breath or may get
tired easily after light physical activity such as walking. Some patients may wake
up short of breath at night. Fluid may collect in different parts of the body, often
first noticed as swollen ankles and feet.

How MONOPRIL works

MONOPRIL contains fosinopril sodium. Fosinopril sodium belongs to a class of medicines
known as ACE inhibitors. It works by widening your blood vessels, reducing the pressure
in the vessels (reducing ‘blood pressure’) and by making it easier for your heart
to pump blood around your body. This helps your heart to work better by increasing
the supply of oxygen to your heart.

Your doctor may have prescribed MONOPRIL for another reason.

Ask your doctor if you have any questions about why MONOPRIL has been prescribed for
you.

MONOPRIL is not addictive.

MONOPRIL is available only with a doctor’s prescription.

The safety and effectiveness of MONOPRIL in children has not been established.

Before you take MONOPRIL

When you must not take it

Do not take MONOPRIL if:

you have an allergy to fosinopril sodium (the active ingredient in MONOPRIL), or to
any of the inactive ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to MONOPRIL may include skin rash, itchiness, shortness
of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint
pain.

you have taken any other ‘ACE inhibitor’ medicine before, which caused your face,
lips, tongue, throat, hands or feet to swell up or made it hard for you to breathe.

If you have had an allergic reaction to an ACE inhibitor medicine before, you may
be allergic to MONOPRIL.

you have a history of angioedema or angioneurotic oedema, which is swelling of the
face, lips, tongue, throat (which may cause difficulty in swallowing or breathing),
hands or feet, for no apparent reason.

Do not take MONOPRIL if you are pregnant or are trying to become pregnant.

MONOPRIL may cause serious injury to your developing baby if you take it during pregnancy.

Do not take MONOPRIL if you are breastfeeding or intend to breastfeed.

Do not take MONOPRIL after the expiry date printed on the pack.

Do not take MONOPRIL if the packaging is torn or shows signs of tampering.

If it has expired or is damaged return it to your pharmacist for disposal.

Do not take MONOPRIL if the tablets change in appearance, colour or taste.

If you are not sure whether you should start taking MONOPRIL, talk to your doctor.

Before you start to take MONOPRIL

Tell your doctor if you have allergies to:

any other medicine

any other substances, such as foods, preservatives or dyes

Tell your doctor if you have a family history of swelling of the face, lips, tongue,
throat that may cause difficulty in swallowing or breathing.

Tell your doctor if you have any medical conditions, especially the following:

diabetes

take any other medicines or drugs including any immunosuppressant medicine or trimethoprim
containing medicines

kidney problems, or have had kidney problems in the past, or are having dialysis

liver problems, or have had liver problems in the past

low blood pressure, which you may notice as dizziness or lightheadedness

are going to have surgery (including dental surgery) involving a general anaesthetic,
even if it is minor

Tell your doctor if you are pregnant or plan to become pregnant or breastfeed.

If you have not told your doctor about any of the above, tell them before you start
taking MONOPRIL.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any
that you buy without a prescription from your pharmacy, supermarket or health food
shop.

Some medicines can affect the way MONOPRIL works. It is especially important that
you tell your doctor if you are taking any of the following:

water tablets or diuretics (for example Lasix^®, Urex^®, Natrilix^®, Moduretic^®)

lithium or lithium-containing preparations (for example Lithicarb^®, Priadel^®)

potassium tablets (for example SPAN-K^®, SLOW-K^®or MAG-K^®)

potassium-containing salt substitutes (for example PRESSOR-K^®)

antacids

if you are taking MONOPRIL for high blood pressure do not take any medicine (including
ones bought without prescription) for appetite control, asthma, colds, coughs, hayfever
or sinus problems unless you have discussed the medicine with your doctor or pharmacist.

aspirin

anti-inflammatory medicines (these are used to relieve pain, swelling and other symptoms
of inflammation, including arthritis) and include nonsteroidal anti-inflammatory agents
– NSAIDs (for example Voltaren, Indocid) and COX-2 inhibitors (for example Celebrex). Taking
a combination of Monopril with a thiazide diuretic (fluid tablet) and an anti-inflammatory
medicine may damage your kidneys.

medicines that lower your immune system, such as medicines used to prevent rejection
of transplant organs.

trimethoprim containing medicines (for example Bactrim, Septrim, Alprim) used to treat
certain types of infections

Your doctor will decide whether your treatment needs to be altered or whether you
should have check ups or blood tests more frequently

How to take MONOPRIL

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information in this leaflet. Your doctor or pharmacist will
tell you how many tablets you will need to take each day.

If you do not understand the instructions on the label on the box, ask your doctor
or pharmacist for help.

How much to take

MONOPRIL is usually taken at a dose of 10mg to 40mg once a day. Your doctor may have
prescribed a different dose for you.

When to take it

Take MONOPRIL at about the same time each day.

Taking your tablet at about the same time each day will help you to remember when
to take it. It does not matter if you take MONOPRIL before or after food.

If you need to take an antacid, take it at least 2 hours before or two hours after
your dose of MONOPRIL.

How long to take it

MONOPRIL helps to control your condition but does not cure it. Therefore you must
take MONOPRIL every day. Continue taking it for as long as your doctor tells you.

If you forget to take MONOPRIL

If you forget to take one or more doses of MONOPRIL, if it is almost time for your
next dose, skip the dose you missed and take your next dose at the normal time and
in the normal amount.

Otherwise take it as soon as you remember, and then go back to taking it as you would
normally.

Do not take a double dose to make up for the dose that you missed. Do not take any
more than your doctor prescribed for you.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble
remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much MONOPRIL

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26),
or go to the Accident and Emergency Department at your nearest hospital, if you think
that you or anyone else may have taken too much MONOPRIL. Do this even if there are
no signs of discomfort or poisoning.

You may need urgent medical attention.

Things you must do

Tell any other doctors, dentists and pharmacists who are treating you that you are
taking MONOPRIL.

If you are about to be started on a new medicine, tell your doctor, dentist or pharmacist
that you are taking MONOPRIL. Tell your doctor if you have excessive vomiting or diarrhoea
or experience any of the following symptoms:

light-headed or dizzy

dry mouth or thirst

weakness, tiredness or drowsiness

muscle pain or cramps

fast heart beat

passing less urine than normal

If you experience these symptoms, you may be dehydrated because you are losing too
much water.

This is more likely to occur when you begin to take MONOPRIL or if your dose is increased.

Make sure you drink enough water during exercise and hot weather when you are taking
MONOPRIL, especially if you sweat a lot.

If you do not drink enough water while taking MONOPRIL, your blood pressure may drop
suddenly and you may dehydrate. If you experience any of the above symptoms, tell
your doctor.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or
dentist that you are taking MONOPRIL.

Having a general anesthetic while taking MONOPRIL may also cause your blood pressure
to drop suddenly.

If you become pregnant while taking MONOPRIL, tell your doctor immediately.

If you are about to have blood tests, tell your doctor that you are taking MONOPRIL.

MONOPRIL may interfere with the results of some tests.

Have your blood pressure checked when your doctor says, to make sure MONOPRIL is working.

Go to your doctor regularly for a check-up.

Your doctor may like to do blood tests to see how MONOPRIL is affecting you.

Things you must not do

Do not give MONOPRIL to anyone else, even if they have the same condition as you.

Do not take MONOPRIL to treat any other complaints unless your doctor or pharmacist
tells you to.

Do not stop taking MONOPRIL, or lower the dosage, without checking with your doctor.

Things to be careful of

As with other ACE inhibitor medicines, you may feel light-headed or dizzy when you
begin to take MONOPRIL or after your dose is increased. This is because your blood
pressure is dropping suddenly.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get
up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your
body get used to the change in position and blood pressure. Be careful the first time
you take MONOPRIL, especially if you are elderly.

Be careful driving or operating machinery until you know how MONOPRIL affects you.

As with other ACE inhibitor medicines, MONOPRIL may cause dizziness, or light-headedness
in some people. Make sure you know how you react to MONOPRIL before you drive a car,
operate machinery, or do anything else that could be dangerous if you are dizzy or
light-headed. If this occurs do not drive

If you drink alcohol, dizziness or light-headedness may be worse.

Things that would be helpful for your blood pressure

Some self help measures suggested below may help your condition. Talk to your doctor
or pharmacist about these measures and for more information.

Alcohol –

your doctor may advise you to limit your alcohol intake.

Weight –

your doctor may suggest losing some weight to help lower your blood pressure and help
lessen the amount of work your heart has to do. Some people may need a dietician’s
help to lose weight.

Diet –

eat a healthy low-fat diet which includes plenty of fresh vegetables, fruit, bread,
cereals and fish. Also eat less fat and sugar.

Salt –

your doctor may advise you to watch the amount of salt in your diet. To reduce your
salt intake you should avoid using salt in cooking or at the table.

Exercise –

regular exercise helps to reduce blood pressure and helps to get the heart fitter,
but it is important not to overdo it. Walking is good exercise, but try to find a
route that is reasonably flat. Before starting any exercise, ask your doctor about
the best kind of programme for you.

Smoking –

your doctor may advise you to stop smoking or at least cut down.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you
are taking MONOPRIL.

MONOPRIL helps most people with high blood pressure, but it may have unwanted side
effects in a few people. All medicines can have side effects. Sometimes they are
serious, most of the time they are not. You may need medical treatment if you get
some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Following is a list of possible side effects. Do not be alarmed by this list. You
may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

feeling lightheaded, dizzy or faint

headache

tiredness, fatigue or weakness

dry cough

feeling sick (nausea) or vomiting

upset stomach (dyspepsia) or heartburn

diarrhoea

stomach pains

muscle cramps or pains

These are the more common side effects of MONOPRIL. (Mostly these are mild and short
lived).

Tell your doctor as soon as possible if you notice any of the following:

changes to your heart rhythm

infections of your urinary tract or upper respiratory tract (URTI, or cold or flu
symptoms)

severe dizziness (vertigo)

impotence (inability to get or maintain an erection)

mild rash or itching

gout (painful, swollen joints)

diabetes (symptoms include – excessive thirst, greatly increased amount of urine,
increase of appetite with a loss of weight, feeling tired, drowsy, weak, depressed,
irritable and generally unwell)

sore throat and fever

hepatitis (symptoms include – nausea, vomiting, loss of appetite, feeling generally
unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine)

confusion; irregular heartbeat; nervousness; numbness or tingling of the hands, feet
or lips; shortness of breath or difficulty breathing; weakness or heaviness of legs.
(You may experience these symptoms if too much potassium builds up in your body.)

These are serious side effects. You may need medical attention. Serious side effects
are rare.

If any of the following happen, tell your doctor immediately or go to Accident and
Emergency at your nearest hospital.

Swollen face, swollen lips, swollen mouth, swollen throat, swollen hands or feet

if you faint or if your skin turns yellow

sore throat and fever

chest pain

difficulty breathing

itchy skin and/or rash

not urinating (passing water) as much as usual

stomach pain with or without nausea

These are very serious side effects. You may need urgent medical attention or hospitalisation

Other side effects not listed above may occur in some patients. Tell your doctor
or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects.

You may not experience any of them

After using MONOPRIL

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the pack they will not keep well.

Keep MONOPRIL tablets in a cool dry place, in the dark, where the temperature stays
below 25°C.

Do not store MONOPRIL or any other medicine in the bathroom or near a sink. Do not
leave it in the car on hot days or on window sills.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place
to store medicines.

Disposal

If your doctor tells you to stop taking MONOPRIL or the tablets have passed their
expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like:-

MONOPRIL 10mg tablets –

White biconvex, diamond shaped tablet and marked on one side and with a star design
and on the other side ‘158’ (AUST R 46475). Each carton contains 30 tablets.

Ingredients

Active ingredient

MONOPRIL 10mg tablets – 10mg fosinopril sodium per tablet

Other ingredients

MONOPRIL tablets also contain lactose, microcrystalline cellulose, crospovidone, povidone
and sodium stearyl fumarate.

Sponsored by

Bristol-Myers Squibb Australia Pty Ltd,

4 Nexus Court, Mulgrave,

Victoria 3170, Australia

Date of Preparation: September 2019

* Monopril is a registered trademark of Bristol-Myers Squibb

AU_CMI_Monopril_V19.0_6 September 2019

Use of ACE inhibitors in a polymorbid patient: focus on fosinopril | Fomin I.V.

Introduction

All over the world, there is a trend towards an aging population. In the middle of the XX century. There were about 600 million elderly people. In accordance with the dynamics of population aging in the middle of the XXI century. the number of people over 60 will reach 2 billion. This poses new challenges for society, science and medicine – in particular, the task of developing measures aimed at treating and preventing disability and early death among elderly patients [1]. It is known that the risk of developing certain diseases increases with age, which radically changes the strategic and tactical objectives of the treatment, control and rehabilitation of elderly patients.

The problem of polymorbidity from a medical point of view includes three main areas of activity: the creation of a coherent system to deal with the main risk factors, the formation of an environment for the patient with the highest priorities of mental and physical well-being, and the determination of the most effective and safe medical support [2-4]. Even 30 years ago, in real clinical practice, we identified the underlying disease and tried to change its course as much as possible in order to improve the prognosis. Today, the very concept of treatment effectiveness has changed, as a polymorbid patient has more complex medical needs, which include the treatment of multiple diseases and complex treatment regimens [4].

In order to maintain the safety of treatment, the doctor tries to prescribe drugs in minimal doses without active titration, which subsequently becomes a huge problem in terms of achieving the target indicators of therapy for any condition. The main reasons are the fear of side effects with increasing doses of drugs, a lack of understanding of the capabilities of the drug in terms of action on various target organs, and the lack of deep knowledge on the issue of drug interactions of the drug used.

This article is devoted to the use of drugs of the pharmacological group of angiotensin-converting enzyme inhibitors (ACE inhibitors), which is most often prescribed to patients with cardiovascular diseases (CVD).

At an outpatient clinic, polymorbid patients are most often encountered. The presence of 3 or more diseases is diagnosed in 13–95% of patients, the severity of polymorbidity depends on age and the presence of the first underlying disease that triggers the cardiovascular continuum [5, 6]. The combination of arterial hypertension (AH), diabetes mellitus (DM), atrial fibrillation (AF), coronary heart disease (CHD) is most common in the Russian population. Chronic kidney disease (CKD), pathology of the lungs or gastrointestinal tract can join these diseases, and at the age of over 60-65 years, the risk of developing chronic heart failure (CHF) sharply increases in patients. Over the past 10 years, oncological diseases have become increasingly common in the structure of polymorbidity
[12, 13]. Since 2020, complications after a coronavirus infection have been detected in polymorbid patients [7–11]. Thus, most often in real clinical practice there is a polymorbid patient with a high risk of exacerbation of any disease, an increase in the severity of side effects with an increase in the dose of the drug, and the presence of drug interactions.

ACE inhibitors in patients with CVD and CKD

The PIFAGOR IV [14] and EPOCHA-AG [15] studies found that in Russia, for the treatment of major CVDs, ACE inhibitors are used as first-line drugs of choice, which account for 25–35% of the pharmaceutical market of all cardiovascular drugs. In patients with hypertension, the frequency of prescribing ACE inhibitors reaches 65%. What ACE inhibitor is the safest and most studied in the Russian population?

The main question for the practitioner is: how dangerous is the drug and its metabolites at high concentrations for the body and its target organs at the elimination stage? The answer suggests itself: when a drug has several elimination routes, it is the safest possible. The most studied drug among all ACE inhibitors, which has a double excretion route (50% – with bile through the liver, 50% – through the kidneys), regardless of age, gender, is fosinopril and its metabolite fosinoprilat. Comparative studies [16–19] among young patients and elderly patients showed the same rate of excretion of metabolites in both groups. Its half-life is about 11.5 hours, and among polymorbid patients this figure reaches 14 hours [16]. At the same time, a decrease in elimination in the presence of a lesion in one of the systems increases the activity of elimination through the second system [19].

A study [17] in the most severe polymorbid patients with CHF II-IV functional class (FC) and CKD with creatinine clearance (CrCl) <30 ml/min showed that increasing the dose of fosinopril was safer in terms of area under the curve (AUC ) and the cumulation index compared to those on the background of taking enalaprilat and lisinopril. A greater accumulation of enalaprilat and lisinopril in patients with CHF and CKD, associated with higher values ​​of the cumulation index, may indicate the need for dose adjustment in polymorbid patients with one predominant elimination route. The double elimination of fosinoprilat, as evidenced by the low values ​​of the accumulation index of the drug, avoids the need for dose adjustment even in the most severe patients. This ACE inhibitor titration tactic is reflected in the 2019 recommendationson the management of patients in outpatient practice [18] (Table 1): only one ACE inhibitor, fosinopril, did not require a reduction in therapeutic dose even in stage V CKD.

In 2021, new KDIGO recommendations [20] were issued for the treatment of hypertension in CKD stages II-IV, the presence of proteinuria A2-III degree, which provide for a decrease in blood pressure (BP) below 120/80 mm Hg for this category of patients. Art. In order to reduce polypharmacy, it is proposed to increase the dose of drugs to the maximum tolerated in accordance with the level of safety (Table 2). In the KDIGO 2021 recommendations, the dose of fosinopril has been increased to 80 mg / day (changed data on the maximum allowable daily dose have not yet been included in the drug instructions) without dose adjustment at any level of CrCl reduction. After the adoption of the text of the recommendations by the Nephrological Societies of the United States and European countries, the recommended dose will be prescribed to patients with stage V CKD. In the Russian Federation, today the instructions for the drug fosinopril have not been changed, so it is possible to prescribe only a dose of 40 mg / day as the maximum. The practitioner should understand that the safety of the drug is so high that a dose of 40 mg can be prescribed for stage IV-V CKD.

Thus, the experts came to the conclusion that fosinopril is the safest among the drugs of the ACE inhibitor group, which can be used in polymorbid patients with a decrease in GFR of any degree.

Indications and safety of fosinopril

Modern antihypertensive drugs should confirm their effectiveness in lowering blood pressure, organ protection and prevention of cardiovascular complications.

The main indications for the use of fosinopril are hypertension and CHF. International studies on the safety of the drug were conducted among patients with hypertension (FLIGHT) [21], including the elderly (FOPS) [22], or with the presence of micro- and macroproteinuria (PREVENT-IT) [23]; patients with diabetes (FASET) [24] or with kidney damage (ESPIRAL) [25]. The drug was also studied in combination with statins in the prevention of atherosclerosis (PHYLLIS) [26], in acute myocardial infarction (FAMIS) [27] and CHF (FHF study) [28] and (FEST) [29]. The results obtained showed a high safety of the drug, especially among elderly patients, with a very low incidence of clinical and laboratory adverse events [30–32]. An important advantage of fosinopril was the fact of a rarer frequency of cough compared with that while taking other drugs of the ACE inhibitor group. When the previously taken ACE inhibitor was changed to fosinopril, the frequency of cough was significantly lower [33, 34].

Numerous studies [23–25, 35–38] have confirmed the organoprotection of fosinopril in patients with AH, DM, and proteinuria. The use of this ACE inhibitor made it possible to slow down the progression of the disease in patients with stage III–IV CKD. With emerging microalbuminuria (MAU) in patients of working age with high normal blood pressure and a minimal risk of cardiovascular complications or diabetes (no more than 3.0%), the PREVENT-IT study [23] confirmed the hypothesis of fosinopril nephroprotection. In patients with severe MAU >50 mg/day, long-term therapy (at least 3 months) with fosinopril led to a 45% reduction in the risk of developing cardiovascular complications (p = 0. 04), as well as a significant prevention of the progression of proteinuria during the entire observation period [37, 38]. It should be noted that in patients with MAU <50 mg/day, no significant organ protection was found either after 4 years or after 10 years of follow-up [38].

The ESPIRAL study [25] demonstrated organoprotection during fosinopril therapy in the most severe patients with renal pathology (primary glomerulonephritis, nephrosclerosis, and polycystic kidney disease) without DM. In another study [39], the administration of fosinopril led to a significant decrease in the 2-fold increase in serum creatinine and the need for dialysis by 21% (p=0.01), which was associated with a decrease in proteinuria by 53% (p=0.002 ).

In a study [40], devoted to the safety of ACE inhibitors in hemodialysis, 2 groups of ACE inhibitors were compared depending on dialysability: group 1 – drugs with low dialysability (fosinopril and ramipril), group 2 – with high dialysability (enalapril, lisinopril and perindopril). Fosinopril was comparable in terms of mortality from all causes and cardiovascular complications during 1 year of hemodialysis with high-dialysable ACE inhibitors (p=0.6), and no effect of accumulation of the drug in the blood was found during the observation period.

Experimental studies [41, 42] on animals with DM caused by streptozotocin showed that the use of fosinopril reduced the concentrations of creatinine in the blood, urea nitrogen, protein in daily urine, chemerin, and vascular epithelial growth factor protein (VEGF). Researchers [41] demonstrated that fosinopril can protect kidney tissue in DM by suppressing the expression of chemerin and VEGF protein. A preventive effect on the development of tactile allodynia in rats with DM was also found, which suggests that fosinopril may reduce the risk of diabetic neuropathic pain [42].

In the PHYLLIS study [26], fosinopril enhanced the effects of statins in terms of slowing the progression of atherosclerosis based on changes in the thickness of the intima-media complex. Slowing down of atherosclerosis was found in groups using fosinopril, pravastatin and their combination. Metabolic neutrality of fosinopril was also revealed with a tendency to reduce the levels of total cholesterol and low-density lipoprotein cholesterol. With the combined use of a statin and fosinopril, the decrease in lipidogram parameters was significantly more pronounced than in the statin monotherapy group.

In a recent study [43], fosinopril showed a more significant potentiating effect in the prevention of convulsions with some antiepileptic drugs, especially carbamazepine, felbamate, lamotrigine, topiramate and valproate, compared with enalapril, zofenopril, lisinopril. The experts concluded that it is possible to use ACE inhibitors, especially fosinopril, in order to increase the therapeutic efficacy of combined antiepileptic drugs.

Use of fosinopril in CHF

The largest number of studies [27-29, 44-50] to study the effectiveness of fosinopril were conducted among patients with CHF. A positive hemodynamic effect of the drug was revealed in the FAMIS study [27] in acute heart failure secondary to acute myocardial infarction (AMI). Patients were included in the study 9 hours after the onset of AMI, regardless of the level of systemic blood pressure. Fosinopril dose titration began with 2.5 mg 2 r / day in case of diagnosed hypotension, subsequently stabilization of the underlying pathological process made it possible to increase the dose of fosinopril to 40 mg / day. This tactic led to an improvement in hemodynamic parameters, an increase in physical activity and an increase in rehabilitation potential within 2 years. The use of high doses of fosinopril after AMI led to a decrease in the risk of developing CHF III-IV FC within 2 years by 34.1% (p = 0.05) and a combined point (mortality or any CHF) by 29.1% (p=0.04). The preservation of the configuration and volume of myocardial cavities during therapy was established, which is associated with an improvement in prognosis [45].

According to the recommendations of specialists in heart failure [46, 47], in stable patients with CHF and normal or high blood pressure, the initial dose of fosinopril is 10 mg / day. When taking diuretics at the same time, the initial dose should not exceed 5 mg / day. Also, experts recommend monitoring hemodynamic parameters for 2-6 hours after the first dose of the drug. In the absence of an intensive decrease in blood pressure, fosinopril dose titration should be started, if hypotension is noted, maintain the initial dose until blood pressure stabilizes. The next step is to reduce the dose of the diuretic in order to minimize the risk of hypotension.

In CHF patients with low ejection fraction (EF) (25±7%), fosinopril significantly reduced clinical symptoms, increased EF and exercise tolerance [48, 49]. The FEST randomized trial [29] included stable patients with CHF and low EF (26.5±6.9%) who were treated within 12 weeks. cycling was done. The exclusion criterion is the ability to perform a workout on an exercise bike for more than 10 minutes. Against the background of fosinopril therapy after 12 weeks. the training time on the exercise bike increased significantly — by more than 38 s (p=0.01). Clinical symptoms (shortness of breath, fatigue, weakness) significantly decreased, and the risks of CHF progression and the need to increase the dose of diuretics significantly decreased compared to placebo (p = 0.001). A direct correlation was found between a decrease in the risk of CHF progression and an increase in the dose of fosinopril to 40 mg/day. A similar pattern was found among patients with CHF and low EF who did not take digitalis [48].

Fosinopril has also been studied in heart transplant patients. The results obtained showed the safety of the combination of fosinopril with immunosuppressive drugs, good antihypertensive efficacy with daily control of blood pressure, and an increase in the effect of statins in terms of achieving the target level of total cholesterol and LDL cholesterol. In the postoperative period, the use of fosinopril significantly faster led to stabilization of renal function compared to placebo [50].

Evidence base for the effectiveness of fosinopril in the Russian population

In Russia, fosinopril was studied in the TRI-F program [51]: in patients with uncomplicated AH (FLAG [52]), with complicated AH (FAGOT [53]) and with CHF (FASON [54, 55]). If the FLAG study [52] included patients with varying degrees of increased blood pressure and did not analyze polymorbidity, then the FAGOT study [53] included patients with AH and DM, CHF, MAU, CKD, and chronic obstructive pulmonary disease. The studies [52, 53] were multicenter and were conducted in 20 different regions of the country. The total number of patients was 4334. The intensity of the decrease in blood pressure depended on the dose of fosinopril, the degree of hypertension, the presence of risk factors and concomitant diseases. Target BP was achieved in 62.1% of patients on low-dose therapy with fosinopril (10 mg/day). In the group of patients who took fosinopril at a dose of 20–30 mg/day, the achievement of target blood pressure was 86. 4%. On average, the level of decrease in SBP was 28.7 mm Hg. Art., DBP – 16.2 mm Hg. Art. The use of fosinopril in combination with a thiazide diuretic turned out to be more cost-effective compared to any other combination of antihypertensive drugs.

The FASON study [54], which was devoted to determining the efficacy and safety of fosinopril titration up to 20 mg/day, included patients with CHF and EF <40%. A follow-up pharmacoeconomic evaluation of the treatment was carried out. The dynamics of clinical symptoms, changes in EF and CHF class were similar to those of the FEST studies [29] and FHF study [28]. The total cost of treating patients with CHF decreased by 54% due to a decrease in the number of hospitalizations, emergency calls, and the number of drugs taken [55].

The TRI-F program [51], which included 5779 patients, answered a very important question: which patients should be given fosinopril in the first place? These are patients with risk factors and hypertension, which corresponds to the initial stage of CVD; patients with complicated hypertension with past AMI, with diabetes, CKD, CHF; patients with CHF with various hemodynamic parameters. Thus, patients with CVD of all stages with various lesions of target organs were studied. The results obtained confirmed the high degree of organoprotection of fosinopril, the predictable dynamics of blood pressure reduction, improvement in the quality of life, and the low incidence of side effects (cough while taking ACE inhibitors, hypotension with rapid dose titration).

Conclusion

Modern recommendations [56, 57] provide for the use of drugs with multidirectional pharmacological action. The fight against polypharmacy is becoming a priority of the modern strategy for the treatment of elderly patients with a combination of various diseases. Preference is given to drugs with a good evidence base in various categories of patients, which have minimal side effects and a high level of safety when used simultaneously in various combinations.

Numerous domestic and foreign studies have shown that fosinopril exhibits organoprotection regardless of the level of blood pressure reduction in comorbid patients with diabetes, CKD, asymptomatic atherosclerosis, chronic heart failure and after AMI, which was associated with a reduced risk of stroke and cardiovascular complications.

Information about the author:

Fomin Igor Vladimirovich — MD, Associate Professor, Head of the Department of Hospital Therapy and General Medical Practice named after V.G. Vogralik FGBOU VO “PIMU” of the Ministry of Health of Russia; 603005, Russia, Nizhny Novgorod, pl. Minin and Pozharsky, 10/1; ORCID ID 0000-0003-0258-5279.

Contact information: Fomin Igor Vladimirovich, e-mail: [email protected].

Financial transparency: the author has no financial interest in the submitted materials or methods.

No conflict of interest.

Article received on 01/11/2022.

Received after review on February 3, 2022.

Accepted for publication 03/01/2022.

About the author:

Igor V. Fomin – Dr. Sc. (Med.), Head of V.G. Vogralik Department of Hospital Therapy & General Medical Care, Privolzhsky Research Medical University; 10/1, Minin and Pozharsky sq. , Nizhny Novgorod, 603950, Russian Federation; ORCID ID 0000-0003-0258-5279.

Contact information: Igor V. Fomin, e-mail: [email protected].

Financial Disclosure: the author has no a financial or property interest in any material or method mentioned.

There is no conflict of interest.

Received 01/11/2022.

Revised 02/03/2022.

Accepted 03/01/2022.

Use of fosinopril and hydrochlorothiazide fixed combination in the treatment of arterial hypertension :: DIFFICULT PATIENT

N.V. Sturov

Department of General and Clinical Pharmacology, Peoples’ Friendship University of Russia, Moscow

The rationality of combining different groups of antihypertensive drugs is pathophysiologically justified by the need for parallel correction of various pathological links leading to an increase in blood pressure (BP), and has been proven in many clinical trials [1], with the most often, to achieve the target level of blood pressure, they resort to adding a diuretic, usually hydrochlorothiazide, to the prescribed drugs.
The need for widespread use of rational combinations of antihypertensive drugs is dictated by a higher degree of blood pressure control against the background of their appointment. It should be remembered that the achievement of the target level of blood pressure is the main criterion for the quality of treatment of arterial hypertension (AH). However, even in the United States, out of 65 million Americans receiving antihypertensive therapy, only 31% achieve the target BP level [2], and in a significant number of cases the reason is non-compliance with the prescribed drugs. That is why attention is paid to the study of ways to increase adherence to treatment. One of the simple and effective methods of improving compliance is the use of fixed combinations of drugs.
Combinations of angiotensin converting enzyme inhibitors (ACE inhibitors) with thiazide diuretics, such as fosinopril with hydrochlorothiazide, are the most popular.
It is known that with an isolated appointment in monotherapy, the antihypertensive activity of fosinopril gradually increases in the first few weeks of treatment, blood pressure reaches target levels without the manifestation of elements of compensatory cardiac arrhythmias, and drug withdrawal does not lead to a rapid rise in blood pressure. The action of fosinopril, as a rule, does not depend on the age and sex characteristics and body weight of patients [3].
In addition to the actual antihypertensive effect, fosinopril is effective in preventing and reversing left ventricular (LV) hypertrophy in AH, i.e. not only reduces blood pressure, but promotes regression of structural remodeling of the heart chambers. Within 9 months, the mass of the LV myocardium in persons with severe hypertrophy decreases (up to 5 g reduction), and in the comparison group it increases. This observation is very important, since LV wall hypertrophy is one of the key predictors of cardiovascular events [4].
The drug has a positive effect on the course of atherosclerosis of the carotid arteries. It has been shown that the thickness of the intima-media complex in this area of ​​the vascular bed after 36 weeks of regular use of the drug decreases by 0.0278 ± 0.03 mm, while this indicator only increases without taking fosinopril [4].
The results of the double-blind, placebo-controlled study PHYLLIS (The Plaque Hypertension Lipid-Lowering Italian Study) demonstrated an inhibitory effect of fosinopril therapy on the progression of carotid atherosclerosis. The study involved 508 patients with hypertension with asymptomatic atherosclerotic lesions of the carotid basin. The patients were divided into groups depending on the therapy: 127 patients received hydrochlorothiazide at a dose of 25 mg/day, 127 – fosinopril at a dose of 20 mg/day, 126 – 25 mg of hydrochlorothiazide and an additional 40 mg of pravastatin, 128 – 20 mg of fosinopril and 40 mg of pravastatin. The mean follow-up period was 2.6 years. The thickness of the intima-media complex (mainly in the area of ​​bifurcation of the common carotid artery) significantly increased in the group of patients treated with hydrochlorothiazide alone. In patients treated with fosinopril, pravastatin, or both, a significant decrease in the thickness of the atherosclerotic lesion was observed. Thus, it has been shown that fosinopril has an antiatherogenic effect in hypertensive patients [5].
The combination of ACE inhibitors and thiazides is very effective for the treatment of hypertension and is one of the most common and rational. In order to verify this statement, the antihypertensive efficacy and safety of fosinopril and its combination with hydrochlorothiazide were evaluated in a placebo-controlled study. After 4-5 weeks of placebo, 67 patients with mild or moderate hypertension (DBP ranged from 95-110 mmHg) were randomized into 4 parallel groups: fosinopril 20 mg + hydrochlorothiazide 12.5 mg, fosinopril 20 mg, 12 .5 mg hydrochlorothiazide, placebo control. Evaluation of the results was made after 8 weeks of admission. The combination of fosinopril and hydrochlorothiazide appeared to be most effective when compared with these agents alone (p A large, double-blind, placebo-controlled, parallel-group study examined the efficacy of an ACE inhibitor/thiazide diuretic combination in 17 different dosing regimens of fosinopril and hydrochlorothiazide in 550 patients with mild to moderate Hypertension was analyzed using a quadratic response surface model (QRSM), which predicted the required doses during the trial.The combination of fosinopril 10 mg + hydrochlorothiazide 12. 5 mg was found to reduce DBP by 6.3 over 8 weeks mm Hg, and the combination of fosinopril 20 mg + hydrochlorothiazide 12.5 mg – by 9.1 mmHg Art. Both combinations demonstrated a good mutually potentiating effect of the two antihypertensive components [7].
In a double-blind study (following a four- or six-week placebo period in all patients), 418 subjects with grade I-II hypertension were randomized to receive fosinopril 5, 10, 20, or 40 mg once daily by mouth for 4 weeks . After 4 weeks, patients who did not sufficiently respond to the prescribed therapy, the dose of the drug was doubled, and they took fosinopril at a new dosage for the next 4 weeks. If necessary, hydrochlorothiazide was added to therapy in the last 4 weeks. A significant and smooth antihypertensive response (when measuring blood pressure in the sitting and standing position) was demonstrated after 4 weeks of taking 20 or 40 mg of fosinopril, while both dosing regimens gave a similar result. Further analysis showed that in mild to moderate hypertension, the dose of fosinopril can be successfully titrated in the range of 5 to 40 mg once a day with the parallel addition of hydrochlorothiazide. Treatment was interrupted in 3% of patients in the fosinopril group and 1% in the placebo group due to side effects. No abnormalities were noted in laboratory tests throughout the study. Fosinoprilat (the active metabolite of fosinopril) was eliminated in two ways – renal and hepatic [8].
The efficacy and safety of fosinopril in various age categories, including in combination with hydrochlorothiazide, has been proven in clinical trials. So, in the FOPS study (Fosinopril in Old Patients Study), 757 patients over 60 years old with hypertension took part, the follow-up period was 12 weeks. Target BP was achieved in 80% of patients. The effect of the drug did not depend on the degree of renal dysfunction. In the case of an unsatisfactory result in terms of achieving the indicated therapeutic result, a better effect was observed when 12.5 mg of hydrochlorothiazide was added to the treatment regimen than when the dose of the drug was doubled [9].
The FLAG study (Fosinopril in the Treatment of Arterial Hypertension) assessed the likelihood of reaching blood pressure targets in patients with mild to moderate hypertension on an outpatient basis when treated with fosinopril (10-20 mg/day) or in combination with hydrochlorothiazide. 2,557 patients were included, of which 26.7% were over 60 years of age. Target BP was achieved in 62.1% of patients. Side effects were noted in 8.3% of patients, and only 5.2% required discontinuation of drugs [10].
2,59 patients were included in the FAGOT study (Pharmacoeconomic evaluation of the use of fosinopril ACE inhibitors in the outpatient treatment of patients with Complicated Arterial Hypertension).6 patients with mild to moderate hypertension and the presence of two risk factors for cardiovascular complications. The effectiveness of fosinopril monotherapy or in combination with hydrochlorothiazide was compared with conventional conventional therapy (diuretics, b-blockers, calcium antagonists) in patients of different ages. Target blood pressure when taking fosinopril and hydrochlorothiazide was achieved in 67.8% of patients. It has been shown that the speed and clinical efficacy of BP normalization under the influence of fosinopril does not differ in elderly and young patients and exceeds the traditional treatment regimen. Compared with other drugs, fosinopril was favorably distinguished by ease of administration and final cost-effectiveness [11].
Of interest is a multicenter (n = 11) and multinational (Denmark, Finland, Iceland, Norway, Sweden), double-blind, randomized study comparing fosinopril in parallel groups with enalapril, one of the most popular ACE inhibitors. The trial involved 195 patients with mild or moderate hypertension (DBP – 95-110 mm Hg. Art.). The study lasted 24 weeks. After discontinuation of all previous antihypertensive drugs, patients received placebo for 4-6 weeks. Subjects were then given fosinopril 20 mg, with a possible increase after 8 weeks to 40 mg (average dose was 25.6 mg) or enalapril at a starting dose of 10 mg, with a possible increase to 20 mg after the same period (average dose turned out to be 12.9mg). Hydrochlorothiazide (12.5 mg) could be added after 16 weeks; this was required in 27% of patients in the fosinopril group and 30% in the enalapril group. All drugs were administered once a day. As a result, in the fosinopril group, SBP decreased from 157 to 143 mm Hg. Art. (p The most important distinguishing feature of fosinopril is a balanced dual route of elimination from the body – renal excretion with urine and hepatic excretion with bile through the gastrointestinal tract [13]. Due to this excretion mechanism, the pharmacokinetics of fosinopril depends little on the state of the liver and kidneys, and the risk of cumulation of the drug practically disappears with rational use [14,15].0015 According to the results of the study of the pharmacokinetics of fosinopril in combination with hydrochlorothiazide, the joint administration of these drugs is possible even in patients with impaired renal function (mean creatinine clearance 55.7 ± 15.6 ml / min × 1.73 m2). The pharmacokinetics of fosinoprilat in patients with impaired and intact renal function on the first day were: the maximum concentration in the blood 387 ± 0.19 and 324 ± 0.25 ng / ml (p = 0.07), the time to reach the maximum concentration of 3. 5 and 3.0 h (p = 0.58), area under the concentration-time curve 3510 ± 0.29and 2701 ± 0.35 ng × h/ml (p = 0.072), cumulative renal excretion 5.08 ± 2.70 and 7.40 ± 2.56% (p = 0.009), respectively. By the fifth day of therapy, only the time to reach the maximum concentration in the blood increased statistically significantly [16].
In addition, fosinoprilat is known to have the lowest accumulation index (1.21) in patients with chronic renal failure with creatinine clearance less than 30 ml / min (this criterion reflects the increase in the area under the concentration-time curve during treatment). This feature is due to the presence of two interchangeable routes of elimination of the drug (hepatic and renal) and is very important in violation of the excretory function of the kidneys. For comparison, the same indicator for the same pathology for enalaprilat is 1.96, for lisinopril – 2.76 [17]. Fosinoprilat is also distinguished by a high degree of lipophilicity (class IIB according to Opie), which ensures sufficient penetration of the drug into tissues, especially the myocardium, which is associated with a pronounced cardioprotective effect, and blockade of the renin-angiotensin-aldosterone system both in the systemic circulation and in individual organs ( heart, kidneys) [18].
The data presented demonstrate the high antihypertensive efficacy of fosinopril and the possibility of achieving the target level of blood pressure in patients who have not sufficiently responded to the prescribed treatment by adding hydrochlorothiazide. The presence of a fixed combination of these drugs (Fozicard N) significantly simplifies patient compliance with the therapy regimen and is one of the ways to improve the quality of antihypertensive therapy.

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14.