Date of approval.
Date of revision.
Perindopril tert-butylamine tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Perindopril tert-butylamine Tablets
English name: Perindopril tert-Butylamine Tablets
Hanyu Pinyin: Peiduopuli Shuding’an Pian
Ingredients
Main active ingredient: Perindopril tert-butylamine Chemical name: (2S,3aS,7aS)-1-[(S)-N-[(S)-1-ethoxycarbonylbutyl]alanyl]octahydro-2-indolecarboxylic acid tert-butylamine salt
Structural formula
Molecular formula: C19H32N2O5-C4H11N
Molecular weight: 441.61
Properties
This product is a white or off-white shaped tablet with indentation in the middle.
Indications
Hypertension and congestive heart failure.
Specification
4mg
Dosage and Administration
Dosage
The dose can be individualized according to the patient’s specific situation (see [Precautions]) and blood pressure response.
Hypertension.
This product may be used as monotherapy or in combination with other classes of antihypertensive drugs (see [Contraindications], [Precautions], [Drug Interactions] and [Pharmacology and Toxicology]).
The recommended starting dose is 4 mg once daily in the early morning.
After one month of treatment, the dose can be increased to 8 mg once daily.
In patients with excessive activation of the renin-angiotensin-aldosterone system (especially: renal vascular hypertension, sodium and/or volume loss, cardiac decompensation or severe hypertension), an excessive drop in blood pressure may be induced after the starting dose. For such patients, it is recommended to start the application at a dose of 2 mg. Initiation of therapy should be done under medical observation.
Symptomatic hypotension may occur after initiation of therapy with this product. This is more likely to occur in patients treated with combination diuretics, as such patients may have volume and/or sodium reductions and should be treated with caution.
If necessary, diuretics should be discontinued 2-3 days prior to initiating treatment with this product (see [Precautions]).
For hypertensive patients who cannot discontinue diuretics, this product should be started at 2 mg and renal function and serum potassium concentrations should be monitored.
Subsequent doses of this product should be adjusted according to blood pressure response. Diuretic therapy may be resumed if needed.
In the elderly, it should be started at 2 mg and gradually increased to 4 mg after one month. if necessary, it may be increased to 8 mg depending on renal function (see table below).
Congestive Heart Failure.
When used in combination with a non-potassium preserving diuretic and/or digoxin and/or beta-blocker, it is recommended that this product be taken early in the morning at a starting dose of 2 mg under careful medical observation. If tolerated by the patient, the dose may be increased to 4 mg once daily after 2 weeks. dose adjustment should be based on the patient’s individual clinical response.
In patients with severe heart failure and those considered at high risk (patients with renal impairment and susceptibility to electrolyte disturbances, patients treated concomitantly with diuretics and/or vasodilators), treatment should be initiated under cautious observation (see [Precautions]).
Patients who are highly susceptible to symptomatic hypotension, such as patients with salt loss (with or without hyponatremia), patients with reduced blood volume, or patients being treated with potent diuretics, should have these conditions corrected prior to treatment with this product. Patients should be closely monitored for blood pressure, renal function, and serum potassium both before and during treatment (see [Precautions]).
Special Populations
Patients with renal impairment.
The dose for patients with renal impairment should be based on creatinine clearance
as listed in Table 1 below.
Table 1: Dose adjustment in renal impairment
Creatinine clearance (ml/min) Recommended dose Creatinine clearance ≥ 60 4mg per day 30 < Creatinine clearance < 60 2mg per day 15 < Creatinine clearance < 30 2mg every other day Patients on hemodialysis * Creatinine clearance < 15 2mg on the day of dialysis * Dialysis clearance for perindoprilat is 70 ml/min. For patients on hemodialysis, the drug should be taken after dialysis.
Patients with hepatic impairment.
No dose adjustment is required in patients with concomitant hepatic impairment (see [Precautions] and [Pharmacokinetics]).
Method of administration
Oral.
Recommended to be taken once daily in the morning before meals.
[Adverse Reactions].
a. Summary of safety profile
The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.
The most commonly reported adverse events in clinical trials and with perindopril include: dizziness, headache, abnormal sensation, vertigo, visual disturbance, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbance, dyspepsia, nausea, vomiting, pruritus, rash, muscle cramps, and malaise.
b. List of Adverse Reaction Tables
The following adverse reactions were observed in clinical trials and/or post-marketing use of perindopril, graded by the following frequency criteria.
Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); rare (<1/10,000); unknown (cannot be estimated from available data).
MedDRA
System Organ Classification Adverse Reaction Frequency Blood and lymphatic system disorders Eosinophilia uncommon* Granulocyte deficiency or allogeneic hematocrit rare Hemoglobinopenia and hematocrit reduction rare Leukopenia/neutropenia rare Hemolytic anemia (see [Caution]) rare in patients with congenital G-6PDH deficiency Thrombocytopenia rare Metabolic and nutritional Disorders hypoglycemia (see [Precautions] and [Drug Interactions]) uncommon * hyperkalemia, reversible after discontinuation (see [Precautions]) uncommon * hyponatremia uncommon * psychiatric disorders mood disorders uncommon sleep disorders uncommon neurological disorders dizziness common headache common sensory abnormalities common vertigo common drowsiness uncommon * syncope uncommon * confusion rare eye disorders visual disturbances common ear and vagal disorders Tinnitus common Cardiac disorders Palpitations uncommon * Tachycardia uncommon * Angina pectoris (see [Precautions]) rare Arrhythmias rare Myocardial infarction, possibly secondary to excessive lowering of blood pressure in high-risk patients (see [Precautions]) rare Vascular disorders Hypotension (and reactions related to hypotension) common Vasculitis uncommon * Stroke, possibly secondary to excessive lowering of blood pressure in high-risk patients (see [Precautions]) rare See [Precautions]) Rare Respiratory, thoracic, and mediastinal disorders Cough common Dyspnea common Bronchospasm uncommon Eosinophilic pneumonia rare Rhinitis rare Gastrointestinal disorders Abdominal pain common Constipation common Diarrhea common Taste disturbances common Dyspepsia common Nausea common Vomiting common Dry mouth uncommon Pancreatitis rare Hepatobiliary disorders Cytolytic or cholestatic hepatitis (see [Precautions]) Rare Skin and subcutaneous tissue disorders Pruritus common Rash common Urticaria (see [Precautions]) uncommon Angioedema of face, extremities, lips, mucous membranes, tongue, voice and/or larynx (see [Precautions]) uncommon Photosensitivity reactions uncommon * Pemphigoid uncommon * Hyperhidrosis uncommon Psoriasis worsening rare * Erythema multiforme uncommon Musculoskeletal and connective tissue disorders Muscle spasms common Arthralgia uncommon common* myalgia uncommon* renal and urinary disorders renal insufficiency uncommon acute renal failure rare genital and breast disorders erectile dysfunction uncommon systemic diseases and administration site conditions malaise common chest pain uncommon* discomfort uncommon* peripheral edema uncommon* fever uncommon* increased blood urea on examination uncommon* increased blood creatinine uncommon* increased blood bilirubin uncommon increased liver enzymes uncommon Injury, toxicity and operational complications Falls uncommon **For adverse events monitored in spontaneous reports, frequency calculated from clinical trial data
Cases of SIADH have been reported during the use of ACE inhibitors. SIADH is considered a possible (including perindopril) and very rare complication during ACE inhibitor therapy.
Suspicious Adverse Reaction Reports
It is important to report suspected adverse reactions after approval of a drug for marketing so that the benefit/risk of the drug can be continuously monitored. All suspected adverse reactions should be reported by medical personnel through the national reporting system.
Contraindications
● Hypersensitivity to the active ingredient, any of the excipients, or other angiotensin-converting enzyme inhibitors.
● History of angioedema associated with the use of angiotensin-converting enzyme inhibitors (see [Precautions]).
● Genetic or idiopathic angioedema.
● during pregnancy (see [Precautions] and [Use in Pregnant and Lactating Women]).
● Concomitant use of perindopril and aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see [Drug Interactions] and [Pharmacology and Toxicology]).
● Concomitant use with sakubatril/valsartan (see [Precautions] and [Drug Interactions]).
● In vitro treatment resulting in blood contact with negatively charged surfaces (see [Drug Interactions]).
● Significant bilateral renal artery stenosis or arterial stenosis in a single functioning kidney (see [Precautions]).
[Precautions].
Stable coronary artery disease.
If an episode of unstable angina (major or non-major) occurs during the first month of perindopril, the risk/benefit ratio should be carefully evaluated before continuing treatment.
Hypotension.
Angiotensin-converting enzyme inhibitors can cause a decrease in blood pressure. Symptomatic hypotension is rare in patients with simple hypertension and is more likely to occur in patients with reduced blood volume, such as those treated with diuretics, salt-restricted diets, dialysis, diarrhea, or vomiting, or in patients with severe renin-dependent hypertension (see [Drug Interactions] and [Adverse Reactions]).
Symptomatic hypotension has been observed in symptomatic heart failure, with or without renal insufficiency. This is more likely to occur in patients with severe degrees of heart failure (patients on high-dose tab diuretics, hyponatremia, or renal impairment).
In patients at higher risk for symptomatic hypotension, close monitoring should be performed when starting treatment and adjusting doses (see [DOSAGE AND ADMINISTRATION] and [ADVERSE REACTIONS]). This should also be done in patients with ischemic heart disease and cerebrovascular disease, where excessive drops in blood pressure can lead to myocardial infarction or cerebrovascular events.
Patients experiencing hypotension should be placed in the supine position and saline should be administered intravenously if necessary. A transient hypotensive response is not a contraindication to continued dosing and may be continued after the blood pressure has been raised by volume expansion.
In some patients with congestive heart failure who have normal or low blood pressure, this product may further lower systemic blood pressure. This reaction is to be expected and there is usually no need to discontinue therapy. If a patient develops symptoms of hypotension, the dose may be reduced or the product may be discontinued.
Aortic or mitral valve stenosis/hypertrophic cardiomyopathy.
As with other angiotensin-converting enzyme inhibitors, this product should be used with caution in patients with mitral stenosis and left ventricular outflow tract obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.
Renal Impairment.
In the setting of renal impairment (creatinine clearance <60 ml/min), the starting dose of perindopril should be adjusted according to the patient’s creatinine clearance (see [DOSAGE]) and as the patient’s response to therapy. In these patients, potassium and creatinine should be included as part of the routine screening program (see [Adverse Reactions]).
In patients with symptomatic heart failure, hypotension after initiation of treatment with angiotensin-converting enzyme inhibitors may lead to further impairment of renal function. Acute renal failure in this setting has been reported, and this acute renal failure is usually reversible.
Some patients with bilateral renal artery stenosis or single renal artery stenosis who have been treated with angiotensin-converting enzyme inhibitors may see an increase in blood urea and serum creatinine that is reversible after cessation of therapy. This is more likely to occur in patients with renal insufficiency. The risk of severe hypotension and renal insufficiency is increased in the presence of coexisting renal vascular hypertension. In these patients, treatment should be started at small doses under close medical observation, with careful dose adjustment. Because treatment with diuretics may be associated with these conditions, these patients should discontinue diuretics and have their renal function monitored during the first few weeks of treatment with this product.
Elevations in blood urea and serum creatinine, usually mild and transient, may occur in some patients with hypertension without significant prior renal vascular disease, particularly when this product is combined with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of diuretics and/or discontinuation of this product may be required.
Hemodialysis Patients.
Anaphylactoid reactions have been reported in patients treated with high-flow membrane dialysis in combination with angiotensin-converting enzyme inhibitors. A different type of dialysis membrane or a different type of antihypertensive drug should be considered.
Renal transplantation.
There is no experience with the use of this product in patients with recent renal transplantation.
Renal vascular hypertension.
Treatment with ACE inhibitors in patients with bilateral renal artery stenosis or arterial stenosis on one side of a single functioning kidney may increase the risk of hypotension and renal insufficiency (see [Contraindications]). Diuretic therapy may be an influencing factor. In patients with unilateral renal artery stenosis, even small changes in blood creatinine may result in loss of renal function.
Hypersensitivity reactions/angiogenic edema.
Angioedema of the face, extremities, lips, mucous membranes, tongue, vocal cords, and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme inhibitors, including this product (see [Adverse Reactions]). It can occur at any time during treatment. Once it occurs, the product should be discontinued immediately and monitored appropriately until complete resolution of symptoms. In patients with edema confined to the face and lips, antihistamines may relieve symptoms but usually resolve without treatment.
Angioedema associated with laryngeal edema may be fatal. Edema in this area may involve the tongue, vocal cords, or larynx, may cause airway obstruction, and must be treated immediately and urgently. Emergency treatment may include the use of epinephrine and/or continuous airway opening. These patients should be under careful medical observation until complete and sustained relief of symptoms is achieved.
Patients with a history of angioedema unrelated to angiotensin-converting enzyme inhibitors may be at increased risk of angioedema when treated with angiotensin-converting enzyme inhibitors (see [Contraindications]).
There are rare reports of angiotensin-converting enzyme inhibitors causing intestinal angioedema in patients. These patients usually present with abdominal pain (with or without nausea and vomiting); usually, these patients do not progress to facial angioedema and the patient has normal C-1 esterase levels. The diagnosis can be confirmed by abdominal CT scan, ultrasound or surgery, and the symptoms disappear after discontinuation of angiotensin-converting enzyme inhibitors. In patients on angiotensin-converting enzyme inhibitors who present with abdominal pain, intestinal angioedema should be considered in the differential diagnosis.
The combination of perindopril and sakubatril/valsartan is contraindicated due to the elevated risk of angioedema (see [Contraindications]). Saccubatril/valsartan should not be initiated within 36 hours of the last dose of perindopril administration. If treatment with sacubitril/valsartan is discontinued, perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan has been administered (see [Contraindications] and [Drug Interactions]). Concomitant use of other NEP inhibitors (e.g., abscisicadotril) and ACE inhibitors may also increase the risk of angioedema (see [Drug Interactions]). Therefore, the risk of benefit needs to be carefully assessed before starting treatment with NEP inhibitors (e.g., abscisicadotril) in patients receiving perindopril.
Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus).
Patients treated concomitantly with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may be at increased risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment) (see [Drug Interactions]).
Allergic-like reactions during LDL clearance.
Life-threatening allergic-like reactions can occur, rarely, in patients treated with angiotensin-converting enzyme inhibitors during LDL clearance with dextran sulfate. These reactions can be avoided by temporarily discontinuing angiotensin-converting enzyme inhibitor therapy prior to each LDL clearance.
Allergic-like reactions during desensitization.
Allergic-like reactions have occurred in patients undergoing desensitization to hymenopteran venom with angiotensin-converting enzyme inhibitors. In such patients, temporary discontinuation of angiotensin-converting enzyme inhibitor therapy may avoid these reactions. These reactions reappear when angiotensin-converting enzyme inhibitors are not reapplied with care.
Liver Failure.
Rarely, angiotensin-converting enzyme inhibitors are associated with cholestatic jaundice and can progress to sudden hepatic necrosis and (sometimes) death; the mechanism by which this condition occurs is not known. Patients receiving angiotensin-converting enzyme inhibitors who develop jaundice or significant elevation of liver enzymes should discontinue angiotensin-converting enzyme inhibitors and receive appropriate medical follow-up (see [Adverse Reactions]).
Neutropenia/granulocyte deficiency/thrombocytopenia/anemia.
Neutropenia/granulocyte deficiency, thrombocytopenia, and anemia have been reported in patients treated with angiotensin-converting enzyme inhibitors. In patients with normal renal function and no other risk factors, neutropenia rarely occurs. Perindopril should be used with caution in patients with collagen vascular disease, immunosuppressive therapy, allopurinol or procainamide therapy, or in the presence of both of these conditions, especially in patients with prior renal impairment.
Severe infections can occur in some of the above patients, and some infections do not respond to intensive antibiotic therapy. If perindopril is used in these patients, regular monitoring of white blood cell counts and instructing patients to report any signs of infection (e.g., sore throat, fever) is recommended.
Ethnicity.
Angiotensin-converting enzyme inhibitors have a higher incidence of angioedema in black than in non-black individuals. As with other angiotensin-converting enzyme inhibitors, perindopril is less effective in lowering blood pressure in blacks than in non-blacks, probably because the incidence of hyporenal states is higher in the black hypertensive population.
Cough.
Cough caused by the administration of angiotensin-converting enzyme inhibitors has been reported. This cough is characterized by a persistent dry cough that resolves with cessation of treatment. The possibility of cough due to angiotensin-converting enzyme inhibitors should be considered in the differential diagnosis of cough.
Surgery/anesthesia.
When undergoing major surgery or anesthesia with drugs that can cause hypotension, this product may block angiotensin II formation secondary to renin release in patients. This product should be discontinued one day prior to surgery. If hypotension occurs and is thought to be due to this mechanism, it can be corrected by volume expansion.
Hyperkalemia.
Elevated serum potassium has been found in some patients treated with angiotensin-converting enzyme inhibitors, including perindopril. Risk factors predisposing to hyperkalemia include renal insufficiency, worsening renal function, age (>70 years), diabetes mellitus with dehydration, acute cardiac failure, metabolic acidosis, combination of potassium-preserving diuretics (e.g., spironolactone, eplerenone, aminoglutethimide, amiloride), potassium-replete preparations or potassium-containing salt substitutes, or patients taking other medications with elevated potassium (e.g., heparin, compounded Synthroid also known as methotrexate/sulfamethoxazole). The use of potassium-protective diuretics, potassium supplements or potassium substitutes, especially in patients with altered renal function, can cause a significant increase in potassium. Hyperkalemia can trigger severe arrhythmias, sometimes fatal. If it is considered appropriate for a patient to combine the drugs mentioned above, they should be used with caution and frequent monitoring of serum potassium (see [Drug Interactions]).
Diabetic patients.
Patients with diabetes mellitus treated with oral hypoglycemic agents or insulin should be closely monitored for glycemic control during the first month of treatment with angiotensin-converting enzyme inhibitors (see [Drug Interactions]).
Lithium.
Lithium is not recommended in combination with perindopril (see [Drug Interactions]).
Potassium-preserving drugs, potassium-replenishing preparations, or potassium-containing salt substitutes.
Perindopril is not recommended in combination with potassium-preserving drugs, potassium-replenishing preparations, or potassium-containing alternatives (see [Drug Interactions]).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that concomitant treatment with angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of RAAS with angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see [Drug Interactions] and [Pharmacology and Toxicology]).
If dual blockade therapy is deemed necessary, it should be done under specialist supervision with frequent and close monitoring of renal function, electrolytes and blood pressure.
Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists should not be administered concomitantly in patients with diabetic nephropathy.
Primary aldosteronism.
Patients with primary aldosteronism do not usually respond to antihypertensive drugs that act by inhibiting the renin-angiotensin system. Therefore, the use of this product is not recommended.
Pregnancy.
Angiotensin-converting enzyme inhibitor therapy should not be initiated during pregnancy. Unless continued angiotensin-converting enzyme inhibitor therapy is deemed necessary, patients planning pregnancy should be switched to other antihypertensive therapy with a clear safety profile during pregnancy. If pregnancy is confirmed, angiotensin-converting enzyme inhibitors should be discontinued immediately and, if necessary, other treatment should be switched (see [Contraindications] and [Use in Pregnant and Lactating Women]).
Excipients
Because the drug contains lactose, it should not be used in patients with rare congenital galactose intolerance, impaired glucose and galactose absorption syndrome, or lactase deficiency.
Effects on the ability to drive a motor vehicle and operate machinery
This product does not directly affect the ability to drive a motor vehicle and operate machinery, but some patients may experience individual reactions related to a decrease in blood pressure, especially at the beginning of treatment or in combination with other antihypertensive drugs. As a result, the ability to drive and operate machinery may be diminished.
[For Pregnant and Lactating Women].
Pregnancy.
The available epidemiological data do not conclude that there is a teratogenic risk of angiotensin-converting enzyme inhibitor exposure during the first trimester of pregnancy. However, a slight increase in this risk cannot be excluded. In patients planning pregnancy, treatment with other antihypertensive agents with an established safety profile during pregnancy should be recommended unless continuous use of angiotensin-converting enzyme inhibitors is necessary. If pregnancy is confirmed, angiotensin-converting enzyme inhibitors should be discontinued immediately and, if necessary, treatment should be switched to other therapy.
Exposure to angiotensin-converting enzyme inhibitors in the 4th to 9th trimester of pregnancy is known to cause human fetal toxicity (decreased renal function, hypohydramnios, delayed cranial bone development) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see [Pharmacologic Toxicology]). If angiotensin-converting enzyme inhibitors have been used in the 4th-6th months of pregnancy, ultrasonography of renal function and cranial bone is recommended. If maternal angiotensin-converting enzyme inhibitors are used, they should be closely monitored for hypotension (see [Contraindications] and [Precautions]).
Lactation.
Because no information is available regarding the use of this product during lactation, it is not recommended for use in women who are breastfeeding, and other treatments with a known better safety profile are recommended during lactation, especially when caring for a newborn or premature infant.
Fertility
There is no effect on reproductive performance or fertility.
[Pediatric Use].
The efficacy and safety of perindopril in children and adolescents under 18 years of age have not been established. Therefore, it is not recommended for use in children and adolescents.
Geriatric use
The elderly should start with 2 mg once daily and gradually increase to 4 mg once daily after one month. If necessary, the dose may be increased to 8 mg once daily depending on renal function (see [Dosage] for details).
Drug Interactions]
Clinical trial data indicate that dual blockade of the RAAS with ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the frequency of adverse events such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared to the use of a single agent acting on the renin-angiotensin-aldosterone system (see [Contraindications], [Precautions], and [Pharmacologic Toxicology]). and [Pharmacologic Toxicology]).
Drugs that cause hyperkalemia
Several drugs or therapeutic classes may increase the incidence of hyperkalemia: aliskiren, potassium salts, potassium-preserving diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, heparin, immunosuppressants (e.g., cyclosporine or tacrolimus), and methotrexate. The combination of these drugs increases the risk of hyperkalemia.
Combinations are contraindicated (see [Contraindications])
Aliskiren
In patients with diabetes or renal impairment, there is an increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality.
In vitro treatment
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-throughput membranes (e.g., polyacrylonitrile membranes) and LDL separation using dextran sulfate, can cause an increased risk of severe class of allergic reactions (see [Contraindications]). If such treatment is required, a different type of dialysis membrane or a different class of antihypertensive agent should be considered.
Sacubitril/valsartan
Concomitant inhibition of neutral peptide chain endonuclease and ACE may increase the risk of angioedema
The concomitant use of perindopril and sacubitril/valsartan is therefore prohibited. Saccubatril/valsartan should not be started within 36 hours of the last dose of perindopril.
Perindopril therapy should not be started within 36 hours of the last dose of sacubitril/valsartan administration (see [Contraindications] and [Precautions]).
Not recommended in combination (see [Precautions])
Aliskiren
Increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality in patients without diabetes mellitus and renal impairment.
Combination ACE inhibitor and angiotensin receptor blocker therapy
In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concurrent treatment with ACE inhibitors and angiotensin receptor blockers is reported in the literature to increase the frequency of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with drugs that act solely on the renin-angiotensin-aldosterone system. Dual blockade (e.g., by combining an ACE inhibitor and an angiotensin II receptor antagonist) should be limited to specific cases with close monitoring of renal function, potassium levels, and blood pressure.
Estramustine.
Increased risk of adverse reactions such as angioneurotic edema (angioedema).
Cotrimoxazole (meprobamate/sulfamethoxazole)
Increased risk of hyperkalemia in patients taking concomitant cotrimoxazole (methotrexate/sulfamethoxazole) (see [Precautions]).
Potassium-preserving diuretics (e.g., aminopterin, amiloride, etc.), potassium salts.
May cause hyperkalemia (potentially fatal), especially in patients with concomitant renal impairment (additional potassium-increasing effect). The combination of perindopril with the above mentioned drugs is not recommended (see [Precautions]). If concomitant use is indicated, it should be used with caution and frequent monitoring of blood potassium. The use of spironolactone in patients with heart failure is described below.
Lithium
Reversible increases in serum lithium concentrations and lithium toxicity have been reported with the combination of angiotensin-converting enzyme inhibitors and lithium. Although the combination of perindopril with lithium is not recommended, serum lithium levels must be monitored closely if the combination proves necessary (see [Precautions]).
Combinations that require special attention
Anti-diabetic drugs (insulin, oral hypoglycemic agents)
Epidemiological studies suggest that the concomitant use of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic agents) may increase the hypoglycemic effect and risk the occurrence of hypoglycemia. The probability of this phenomenon is higher in the first weeks of combination therapy and in patients with renal impairment.
Baclofen
Increases the hypotensive effect. If necessary, monitor blood pressure and adjust the dose of antihypertensive medication.
Non-potassium-preserving diuretics
Excessive drop in blood pressure may occur after initiation of ACE inhibitor therapy with diuretics, especially in patients with volume and/or salt reduction. Perindopril should be started in small doses and gradually increased. Diuretics should be discontinued prior to initiation of therapy, and supplemental volume or salt intake may reduce the likelihood of hypotension.
In patients with arterial hypertension, diuretics must be discontinued prior to initiation of ACE inhibitors if previous diuretic therapy may have resulted in a decrease in salt/volume, in which case a non-potassium preserving diuretic can be reinstituted later, or ACE inhibitor therapy must be started at a low dose and gradually increased.
In patients with congestive heart failure treated with diuretics, ACE inhibitor therapy should be started at a very low dose and may need to be preceded by a reduction in the dose of the associated non-potassium-preserving diuretic.
In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.
Potassium-preserving diuretics (eplerenone, spironolactone)
12.5-50 mg eplerenone or spironolactone daily and low-dose ACE inhibitors.
In patients with class II-IV heart failure (NYHA) with an ejection fraction <40% and prior treatment with ACE inhibitors and tab diuretics, there is a risk of hyperkalemia, potentially fatal, especially in patients who do not comply with prescribing recommendations at the time of this combination therapy.
Confirm the absence of hyperkalemia and renal impairment prior to initiating combination therapy.
Close monitoring of potassium and creatine levels is recommended weekly at the beginning of the first month of treatment and monthly thereafter.
Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin ≥3 g/day.
The use of NSAIDs (e.g., acetylsalicylic acid used as an anti-inflammatory agent, COX-2 inhibitors, and nonselective NSAIDs) diminishes the antihypertensive effect of angiotensin-converting enzyme inhibitors. Furthermore, the combination of NSAIDs with angiotensin-converting enzyme inhibitors may increase the risk of worsening renal function, including acute renal failure and elevated potassium, especially in patients with pre-existing renal function changes. The combination of these two drugs needs to be used with caution, especially in elderly patients. Patients should be given appropriate rehydration and subsequent tests to monitor renal function levels at the start of therapy and periodically thereafter.
Decadron
Angiotensin-converting enzyme inhibitors (e.g., perindopril) are known to cause angioedema, and this risk may be increased when used in conjunction with abscisicadotril, a drug used to treat acute diarrhea.
mTORmTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
The risk of angioedema may be increased in patients taking concomitant mTOR inhibitor therapy (see [Precautions]).
Combination medications to be aware of
Antihypertensive drugs and vasodilators.
Concomitant use of these drugs may increase the hypotensive effects of perindopril. Combining with nitroglycerin, other nitrates, or other vasodilators can lower blood pressure even more.
Liptin (liragliptin, saxagliptin, sitagliptin, vildagliptin):
Because of the reduction in dipeptidyl peptidase IV (DPP-IV) activity by liptin drugs, there is an increased risk of angioedema in patients receiving concomitant ACE inhibitor therapy.
Tricyclic antidepressants/antipsychotics/anaesthetics.
The combination of certain narcotics, tricyclic antidepressants and antipsychotics with angiotensin-converting enzyme inhibitors can lead to a further decrease in blood pressure (see [Precautions]).
Sympathomimetic drugs.
Sympathomimetic drugs can attenuate the antihypertensive effects of angiotensin-converting enzyme inhibitors.
Gold:
There have been rare reports of nitrite-like reactions (including symptoms such as facial flushing, nausea, vomiting, and hypotension) in patients who have been coadministered gold injections (e.g., gold sodium thiomalate) and angiotensin-converting enzyme inhibitors (e.g., perindopril).
[Drug overdose].
There is less information on drug overdose in humans. Symptoms associated with angiotensin-converting enzyme inhibitor overdose include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
The recommended treatment for overdose is an intravenous infusion of 0.9% saline. If hypotension occurs, the patient should remain in the shock position. If possible, angiotensin II infusion and/or intravenous infusion of catecholamines may be considered for treatment. Perindopril can be eliminated from the body circulation by hemodialysis (see [Precautions]). Patients with treatment-naïve bradycardia require pacemaker therapy. Vital signs, serum electrolytes, and creatinine concentrations should be monitored continuously.
Pharmacology and Toxicology
Pharmacological effects
Perindopril is an angiotensin-converting enzyme inhibitor. Angiotensin-converting enzyme converts angiotensin I into angiotensin II, which has a vasoconstrictive effect, and stimulates aldosterone secretion from the renal cortex. Perindopril acts through its active metabolite perindoprilat.
Toxicological studies
Genotoxicity: The Ames test, chromosomal aberration test, mouse lymphoma test, and in vivo mouse micronucleus test for perindopril were negative.
Reproductive toxicity.
Rats were administered up to 10 mg/kg/d orally for 80 days prior to mating and continued after mating until execution; females were administered 14 days prior to mating until day 7 or 20 after pregnancy or delivery. All female rats were executed 24 hours before delivery. Results: maternal body weight gain was reduced in all rats, with kidney abnormalities in the maternal animals in the 4 mg/kg group; delayed skeletal development of fetuses, increased mortality and slow weight gain in the F1 offspring.
In rats, 16 mg/kg/d was administered orally from day 6 to 17 of gestation, and the rats were executed on day 20; in rabbits, 5 mg/kg/d was administered orally from day 6 to day 18 of gestation.
In rats, oral administration of 16 mg/kg/d was administered from day 17 of gestation to day 21 after delivery, resulting in reduced maternal animal intake and body weight, reduced body weight in pregnant rats, reduced pup weight and increased postnatal mortality, delayed behavioral development, reduced fertility, polyuria, and renal damage, but no significant effects on F2 generation growth and development were observed.
Carcinogenicity.
In the 104-week carcinogenicity test in rats and mice, the administered dose reached 7.5 mg/kg/d, and no carcinogenicity was observed.
Pharmacokinetics
Absorption
After oral administration, perindopril is rapidly absorbed and reaches peak concentration within 1 hour. The plasma half-life of perindopril is 1 hour.
Perindopril is a precursor drug. 27% of orally administered perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to the active metabolite perindoprilat, perindopril produces five metabolites, all of which are inactive. Perindoprilat reaches peak concentrations in plasma in 3-4 hours.
Ingestion of food reduces the conversion, i.e. bioavailability, of perindoprilat, and perindopril should be taken once daily before the morning meal.
A linear relationship between the dose of perindopril and its plasma exposure has been demonstrated.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 l/Kg, and binding to plasma proteins is very slight at 20% (mainly to angiotensin-converting enzyme), but is concentration-dependent.
Elimination
Perindoprilat is cleared by urine and the elimination half-life of the free fraction is approximately 17 hours, with steady state achieved within 4 days.
Special Populations
Elimination of perindoprilat is reduced in the elderly and in patients with heart failure or renal failure. The dose in patients with renal insufficiency needs to be adjusted according to the degree of renal impairment (creatinine clearance).
The dialysis clearance of perindoprilat is 70 ml/min.
Perindopril kinetics are altered in patients with cirrhosis: the hepatic clearance of the parent molecule is reduced by half. However, the amount of perindoprilat formed is not reduced and therefore no dose adjustment is required (see [Dosage and Administration] and [Precautions]).
Storage】Store under 30℃ in a sealed container.
Package】Aluminum-plastic package, 30 tablets/plate/bag/box.
Expiration date】24 months
Execution Standard
Approval number】
[Drug Marketing Licensee
Name: Ningbo Menohuatiankang Pharmaceutical Co.
Registered Address: No. 85, Binhai West Road, Daxie Development Zone, Ningbo, China
Postal Code: 315812
Contact：(0574)87918610
Fax
Fax: (0574)86778700
Web
Address: http://www.menovotkpharm.com
Manufacturer
Company name: Ningbo Menohuatiankang Pharmaceutical Co.
Address: No. 85, Binhai West Road, Daxie Development Zone, Ningbo, China
Postal Code: 315812
Contact：(0574)87918610
Fax
Fax: (0574)86778700
Web
Address: http://www.menovotkpharm.com