Approved on.
Revision Date.
Enerapril Maleate Tablets InstructionsPlease read the instructions carefully and use under the guidance of a physician
[Drug Name].
Generic name: Enalapril Maleate Tablets
Trade name: Qinkosi®
English name: Enalapril-Male-Tablets
Hanyu Pinyin: Malaisuan-Yinapuli-Pian
[Ingredients
The main ingredient of this product is Enalapril Maleate.
Chemical name: N-[(S)-1-ethoxycarbonyl-3-phenylalanyl]-L-alanyl-L-proline maleic acid salt.
Chemical structure formula.
Molecular formula: C20H28N2O5-C4H4O4
Molecular weight: 492.52
[Properties
This product is a white or off-white tablet.
[Indications]
*All stages of essential hypertension
*Renal vascular hypertension
*Heart failure at all levels
For patients with symptomatic heart failure, this product is also indicated for.
Increased survival
Delaying the progression of heart failure
Reducing hospitalization due to heart failure
*Preventing Symptomatic Heart Failure
In patients with asymptomatic left ventricular insufficiency, this product is indicated for.
Delaying the progression of symptomatic heart failure
Reducing hospitalizations due to heart failure
*Prevention of coronary ischemic events in patients with left ventricular insufficiency
This product is indicated for.
Reduces the incidence of myocardial infarction. =”font-family:Times New Roman”>
Reducing the incidence of unstable angina caused by reduce hospitalizations due to unstable angina
[Specifications
10mg
[Dosage].
The absorption of this product is not affected by food, so it can be taken before, during or after a meal.
Orthostatic hypertension
The starting dose is 10 mg to 20 mg once daily, depending on the severity of hypertension. For mild hypertension, the recommended starting dose is 10 mg daily. for other degrees of hypertension, the starting dose is 20 mg daily. the usual maintenance dose is 20 mg daily. the maximum dose may be adjusted to 40 mg daily, depending on the patient’s needs.
Renal vascular hypertension
Because the blood pressure and renal function in these patients may be particularly sensitive to angiotensin-converting enzyme inhibitors, treatment should be started at a smaller dose (eg, 5 mg or less). The dose should then be adjusted according to the patient’s needs. For most patients, 20 mg of this product once daily will provide the desired benefit. Caution is advised in patients with hypertension who have been recently treated with diuretics (see next section).
Treatment of hypertension in combination with diuretics
Symptomatic hypotension may occur after initiation of this product; this is more likely in patients recently treated with diuretics. Because these patients may have hypovolemia or salt loss, caution is advised. Diuretic therapy should be discontinued 2-3 days prior to initiation of this product. If this is not possible, the product should be started at a small dose (5 mg or less) to determine its starting effect on blood pressure. The dose should then be adjusted according to the patient’s needs.
Dosing for renal insufficiency
In general, the interval between doses of enalapril should be extended and/or its dose reduced.
Kidney conditionCreatinine clearance (mL/min)Starting dose (mg/day)Mild renal insufficiency<80 <80>30 mL/min5-10mgModerate renal insufficiency≤30>10 mL/min2.5-5mgSevere renal insufficiency
Usually these patients will be on dialysis*≤10mL/min 2.5mg
During the dialysis period***See [Caution]: Patients on hemodialysis
**Enalaprilat is dialyzable and the dose in the non-dialysis period should be adjusted based on the blood pressure response.
Heart failure/asymptomatic left ventricular insufficiency
In patients with symptomatic heart failure or asymptomatic left ventricular insufficiency, the starting dose of this product is 2.5 mg and should be taken under close medical supervision to determine its starting effect on blood pressure. This product is usually used in combination with a diuretic (and digitalis, if appropriate) for the treatment of symptomatic heart failure. After initiation of treatment of heart failure with this product, if symptomatic hypotension has not occurred or if symptomatic hypotension has been effectively managed, the dose should be gradually increased to the commonly used maintenance dose of 20 mg in one or two divided doses, as tolerated by the patient. This dose adjustment can be completed over a period of 2-4 weeks, and the dose escalation process can be accelerated if some of the signs and symptoms of heart failure are still present. In patients with symptomatic heart failure, this dosing regimen can be effective in reducing the incidence of death.
Blood pressure and renal function should be monitored closely before and after initiation of therapy with this product because hypotension and subsequent renal failure (more rare) have been reported (see [Precautions]). For patients treated with diuretics, the dose of diuretics should be reduced as much as possible before starting treatment with this product. The development of hypotension after initiation of this drug does not indicate that hypotension will recur during long-term treatment with this drug, nor does it preclude its continued use. Serum potassium should also be monitored (see [Drug Interactions]).
[Adverse Reactions
This product has been shown to be generally well tolerated. In clinical studies, the overall incidence of adverse reactions was similar to that of placebo. Most of the adverse reactions were mild and transient in nature and did not require discontinuation of therapy.
The following adverse reactions have been associated with the use of this product.
Dizziness and headache were the more commonly reported adverse reactions. 2% to 3% of patients reported feeling tired and weak. Other adverse reactions, including hypotension, upright hypotension, syncope, nausea, diarrhea, muscle cramps, rash, and cough, were reported in less than 2% of patients. Renal dysfunction, renal failure, and oliguria were rare.
Allergic/angioneurotic edema
Angioneurotic edema has been reported in the face, extremities, lips, tongue, voice and/or larynx, but is rare (see [Precautions]).
Very rare adverse reactions that have occurred in controlled clinical trials or after the drug has been introduced are.
Cardiovascular system
Myocardial infarction or cerebrovascular accident, possibly secondary to hypotension in high-risk patients (see [Precautions]).
Chest pain
Palpitations
Arrhythmias
Angina pectoris
Reynolds phenomenon
Endocrine system
Syndrome of abnormal secretion of antidiuretic hormone (SIADH)
Gastrointestinal system
Intestinal obstruction
Pancreatitis
Hepatic failure
Hepatitis – hepatocellular or bile-depleted
Jaundice
abdominal pain
Vomiting
Indigestion
Constipation
Anorexia
Stomatitis
Metabolism
Cases of hypoglycemia have been reported in diabetic patients using oral hypoglycemic agents or applying insulin (see [Drug Interactions]).
Neurological/psychiatric
Depression
Mental confusion
Sleepiness
Insomnia
Nervousness
Sensory abnormalities
Vertigo
Abnormal dreams
Respiratory
Pulmonary infiltrates
Bronchospasm/asthma
Respiratory distress
runny nose
Sore throat and hoarseness
skin
Excessive sweating
Polycythemia vera
Exfoliative dermatitis
Stevens-Johnson syndrome
Toxic epidermolysis bullosa
Pemphigus vulgaris
pruritus
Urticaria
Baldness
Other
Impotence
Flushing
Changes in taste
Tinnitus
Tongue inflammation
Blurred vision
A syndrome with some or all of the following symptoms has been reported: fever, plasmacytitis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibodies, increased sedimentation, eosinophilia, and leukocytosis. Rash, photosensitivity, and other dermatologic manifestations may also occur.
Laboratory Tests
Clinically significant changes in standard laboratory parameters are rarely associated with administration of this product. However, there are elevations in blood urea and serum creatinine, and increases in liver enzymes and/or serum bilirubin. These often recover after discontinuation of the product. Hyperkalemia and hyponatremia have also occurred.
Reductions in hemoglobin and hematocrit have also been reported.
Neutropenia, thrombocytopenia, myelosuppression, and granulocyte deficiency have been reported in a few cases since the drug was introduced, and it cannot be ruled out that these conditions are related to the use of this product.
[Contraindication].
This product is contraindicated in patients with hypersensitivity to any component of this product, or in patients with a history of angioneurotic edema from prior treatment with an angiotensin-converting enzyme inhibitor, and in patients with hereditary or idiopathic angioneurotic edema.
This product should not be used in combination with aliskiren in patients with diabetes (see [Drug Interactions]).
The combination of this product with an enkephalinase inhibitor (eg, sacubitril) is contraindicated. Whether converting from this product to the enkephalinase inhibitor sacubitril/valsartan or sacubitril/valsartan to this product, do not take this product within 36 hours of taking sacubitril/valsartan (see [PRECAUTIONS] and [DRUG INTERACTIONS]).
[Precautions
Symptomatic hypotension
Symptomatic hypotension rarely occurs in patients with uncomplicated hypertension. Hypotension is more likely to occur in hypertensive patients taking this product who have insufficient blood volume due to diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting (see [Drug Interactions] and [Adverse Reactions]). The occurrence of symptomatic hypotension has been observed in patients with heart failure with or without renal insufficiency. The likelihood of hypotension is greatest in patients with more severe heart failure (e.g., on high-dose diuretics, low blood sodium, or functional renal insufficiency). Such patients should be started on medically monitored therapy and should be closely followed whenever the dose of this product or/and diuretics is adjusted. The same management applies to patients with ischemic heart disease or cerebrovascular disease, where excessive drops in blood pressure may lead to myocardial infarction or cerebrovascular accidents.
If hypotension occurs, the patient should lie on his or her back and be given intravenous saline if necessary. Transient hypotensive reactions are not a contraindication to continued dosing and are usually administered once blood pressure rises after volume expansion. Some patients with heart failure who have normal or low blood pressure may experience a further decrease in systemic blood pressure after administration of this product. This effect is expected and usually does not require discontinuation of therapy. If hypotension becomes symptomatic, it may be necessary to reduce the dose and/or discontinue the diuretic and/or the product.
Aortic stenosis/hypertrophic cardiomyopathy
As with all vasodilators, angiotensin-converting enzyme inhibitors should be used with caution in patients with left ventricular outflow tract infarction.
Renal insufficiency
The hypotension that occurs after initiation of therapy with angiotensin-converting enzyme inhibitors can cause some further impairment of renal function in some patients. This condition has been reported to cause acute renal failure, but is usually reversible.
Patients with renal insufficiency may need to reduce the dose of this product and/or reduce the frequency of dosing (see [DOSAGE]). Some patients with bilateral renal artery stenosis or sole kidney with renal artery stenosis have experienced increased blood urea nitrogen and serum creatinine, which is usually reversible with discontinuation of therapy; this is especially true in patients with renal insufficiency.
Some patients without significant prior renal disease usually have mild and transient elevations in blood urea and serum creatinine when concomitant diuretics are used, and may require dose reduction and/or discontinuation of diuretics and/or this product.
Allergic/angioneurotic edema
Angioneurotic edema of the face, extremities, lips, tongue, voice and/or larynx has occasionally been reported in patients using angiotensin-converting enzyme inhibitors, including this product. This can occur at any time during the treatment period. At this point, the product should be discontinued immediately and appropriate monitoring should be given to ensure complete resolution of symptoms before the patient is discharged. Even if only tongue swelling occurs without dyspnea, it may be necessary to extend the patient’s observation period because antihistamine and corticosteroid therapy may be inadequate.
Very rarely, there have been reports of angioneurotic edema with laryngeal or tongue edema resulting in death. Patients with lingual, vocal or laryngeal edema are at risk for airway obstruction, especially those who have undergone airway surgery. When edema occurs in the tongue, voice box, or larynx, it may cause airway obstruction and should be treated immediately and appropriately, including such things as subcutaneous injection of 1:1000 epinephrine solution (0.3 mL-0.5 mL) and/or immediate measures to keep the airway open.
The incidence of angioneurotic edema from angiotensin-converting enzyme inhibitors has been reported to be higher in blacks compared with non-blacks.
People with a history of angioneurotic edema unrelated to angiotensin-converting enzyme inhibitor therapy may be at increased risk of angioneurotic edema with angiotensin-converting enzyme inhibitors (see [Contraindications]).
Patients taking a combination of an ACE inhibitor and an mTOR (mammalian target of rapamycin) inhibitor (eg, temsirolimus, sirolimus, everolimus) may be at increased risk of angioneurotic edema.
Patients on concomitant angiotensin-converting enzyme inhibitors and enkephalinase inhibitors may be at increased risk of angioneurotic edema (see [Contraindications] and [Drug Interactions]).
Allergic-like reactions in desensitization with venom from hymenopteran insects
Life-threatening allergic-like reactions may occur, relatively rarely, when hymenopteran venom is used to desensitize patients treated with angiotensin-converting enzyme inhibitors. This reaction can be avoided by temporarily discontinuing angiotensin-converting enzyme inhibitors before each desensitization.
Patients on hemodialysis
Patients on dialysis with a high permeability membrane (e.g., AN69®) who are also treated with an angiotensin-converting enzyme inhibitor have been reported to have anaphylactic-like reactions. Another type of dialysis membrane or a different class of antihypertensive agent should be considered for such patients.
Cough
Cough has been reported to be induced with angiotensin-converting enzyme inhibitors and is characterized by absence of sputum, persistence, and disappearance after discontinuation of the drug. The possibility of cough caused by angiotensin-converting enzyme inhibitors should be considered in the differential diagnosis of cough.
Surgery/anesthesia
In patients undergoing major surgery or anesthesia with anesthetic drugs that may cause hypotension, enalapril blocks angiotensin II production due to compensatory renin release. If hypotension occurs and is considered to be due to one of these mechanisms, it should be corrected by expansion of blood volume.
Hyperkalemia – see [Drug Interactions], Serum Potassium
Risk factors for hyperkalemia include the presence of renal insufficiency, diabetes mellitus and concomitant use of potassium-preserving diuretics (eg, ambrisentin, eplerenone, aminoglutethimide, or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase blood potassium (eg, drugs containing meperidine).
The use of potassium-repleasing preparations, potassium-preserving diuretics, potassium-containing salt substitutes (especially in patients with renal insufficiency), or other medications that may increase blood potassium can cause significant increases in serum potassium. Hyperkalemia may cause severe, even fatal, cardiac arrhythmias.
If concomitant use of enalapril maleate and any of the above agents is considered appropriate, use with caution and monitor serum potassium frequently.
Low blood glucose
Patients with diabetes mellitus treated with oral hypoglycemic agents or insulin should be advised to monitor closely for the occurrence of hypoglycemia when starting ACE inhibitors, especially during the first month of combination (see [Drug Interactions]).
[Use in Pregnant and Lactating Women
The use of this medication is not recommended during pregnancy. If pregnancy is identified, discontinue this product immediately unless it is necessary to save the life of the mother.
In a published retrospective epidemiologic study, an increased risk of congenital malformations was found in infants whose mothers had taken ACE inhibitor drugs during the first trimester of pregnancy than in infants whose mothers had not taken ACE inhibitor drugs during the first trimester of pregnancy. The number of cases in which birth defects occurred was small, and the results of this study have not been replicated.
The use of angiotensin-converting enzyme inhibitors during the middle and last trimesters of pregnancy can cause fetal and neonatal morbidity and mortality. The use of angiotensin-converting enzyme inhibitors during this period has been associated with a variety of fetal and neonatal impairments, including hypotension, renal failure, hyperkalemia, and/or cranial hypoplasia in the newborn. Maternal amniotic fluid hypohydration has occurred, which primarily reflects reduced fetal renal function and can lead to limb spasms, craniofacial anomalies, and pulmonary dysplasia. If the patient is on this product, the patient should be informed of the potential hazards to the fetus.
Exposure of the uterus to this angiotensin-converting enzyme inhibitor by administration in the first trimester does not cause the adverse reactions described above in the embryo and fetus.
Those rare cases in which angiotensin-converting enzyme inhibitors must be used during pregnancy should undergo a series of ultrasounds to evaluate the intra-amniotic condition. If low amniotic fluid is found, the product should be discontinued unless it is necessary to save the mother’s life. Both the patient and the physician should be aware that the fetus has suffered irreversible damage when hypoamniotic fluid is present.
Infants born to mothers who have used this product should be closely monitored for hypotension, oliguria, and hyperkalemia. Enalapril can cross the placenta and peritoneal dialysis can be clinically useful to remove it from the fetal circulation. In theory, it could be cleared by blood exchange.
Nursing mothers
Enalapril and enalaprilat are secreted in small amounts in human milk. Caution should be exercised when using this product in nursing mothers.
[Pediatric use
The safety and efficacy of this product was studied in pediatric hypertensive patients aged 1 month to 16 years. Use of this product in these age groups is supported by evidence from adequate and validated controlled studies in pediatric and adult patients and from the published pediatric dosing literature.
In a multidose pharmacokinetic study including 40 pediatric hypertensive patients, with neonates excluded, the product was generally well tolerated. After oral administration of enalapril in these patients, the pharmacokinetics were identical to the data recorded for adults.
In a clinical trial including 110 pediatric hypertensive patients aged 6-16 years, patients weighing <50 kg were given enalapril 0.625, 2.5, or 20 mg per day, and patients weighing ≥ 50 kg were given enalapril Once daily, enalapril has a dose-dependent effect in lowering blood pressure troughs. This dose-dependent antihypertensive efficacy was consistent across all subgroups (age, Tanner stage, sex, race). However, the lowest dose studies using 0.625 mg and 1.25 mg corresponded to a mean dose of 0.02 mg/kg per day and did not show consistent antihypertensive efficacy. The maximum dose study was 0.58 mg/kg per day (up to 40 mg). In this study, the product was generally well tolerated.
Adverse reactions in pediatric patients were similar to those observed in adult patients.
In neonates and pediatric patients with a glomerular filtration rate<30mL/min/1.73m2, this product is not recommended because there is no information available.
[Geriatric Use].
This trial was not performed.
[Drug Interactions
Antihypertensive therapy
Iterative effects can occur when this product is used concomitantly with other antihypertensive drugs, especially with concomitant diuretics.
The combination of this product with beta-blockers, methyldopa, or calcium channel blockers can enhance antihypertensive efficacy.
When ganglion blockers or adrenoceptor blockers are used in combination with this product, the patient should be carefully monitored.
Concomitant application of this product may reduce the decrease in serum potassium caused by thiazide diuretics.
Drug interactions between enalapril maleate and the following compounds are not clinically significant: hydrochlorothiazide, furosemide, digoxin, thimerosal, methyldopa, warfarin, indomethacin, and sulforaphane. The combination of propranolol with enalapril maleate decreased serum concentrations of enalaprilat, but this did not have any clinical significance. Because there were no interactions between cimetidine and enalapril maleate in animals, no drug interactions can be expected to occur in humans.
Serum potassium – see [caution], hyperkalemia
Serum potassium has generally remained within the normal range in clinical trials. After 48 weeks of treatment of hypertensive patients with this product alone, a mean increase in serum potassium of about 0.2 mEq/L was seen. In patients treated with this product plus a thiazide diuretic, the potassium-removal effect of the diuretic was often diminished by the effect of enalapril.
The use of this product together with a potassium-eliminating diuretic may reduce diuretic-induced hypokalemia.
Risk factors for hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-preserving diuretics (eg, ambrisentin, eplerenone, aminoglutethimide, or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase blood potassium (eg, drugs containing meperidine).
The use of potassium-repleasing preparations, potassium-preserving diuretics, potassium-containing salt substitutes (especially in patients with renal insufficiency), or other drugs that may increase blood potassium can cause significant increases in serum potassium.
If concomitant use of this product and the above agents is considered appropriate, use with caution and monitor serum potassium frequently.
Antidiabetic drugs
Epidemiologic studies have shown that the combination of ACE inhibitors and antidiabetic medications (insulin, oral hypoglycemic agents) may lead to enhanced hypoglycemic effects and an increased risk of hypoglycemia. This occurs mostly in the first few weeks of combined therapy and in patients with impaired renal function. In patients with diabetes treated with oral hypoglycemic agents or insulin, glycemic control should be monitored closely for hypoglycemia, especially during the first month of treatment with ACE inhibitors.
Serum lithium
As with other sodium-removal drugs, lithium clearance may be reduced. Therefore, serum lithium concentrations should be carefully monitored if lithium salts are taken.
Nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), may reduce the effectiveness of diuretics or other antihypertensive drugs. Thus, the effects of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors are also attenuated by the class of NSAIDs, including selective COX-2 inhibitors.
In some patients with renal insufficiency taking NSAIDs including selective COX-2 inhibitors (eg, elderly patients or patients with hypovolemia, including those on diuretic therapy), concomitant administration of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may lead to further decompensation of renal function, including the possibility of acute renal failure. This effect is usually reversible. Therefore, caution should be exercised when administering combination therapy to patients with renal insufficiency.
Dual blockade of the renin-angiotensin-aldosterone system
Treatment with dual blockade of the RAAS with an angiotensin receptor antagonist, ACE inhibitor, or direct renin inhibitor (eg, aliskiren) increases the risk of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared with treatment with a single blockade of the renin-angiotensin-aldosterone system (RAAS). Closely monitor blood pressure, renal function, and electrolytes in patients on combined enalapril maleate tablets and other drugs that affect RAAS. Do not combine enalapril maleate tablets and aliskiren in diabetic patients. Avoid the combination of enalapril maleate tablets and aliskiren in patients with renal impairment (GFR<60 mL/min).
Gold
There have been very few reports of nitrite reactions (symptoms including facial flushing, nausea, vomiting, and hypotension) in patients treated with injectable gold (gold thiodisodium) in combination with ACE inhibitors, including enalapril.
Mammalian target of rapamycin (mTOR) inhibitors
Patients taking this product in combination with mTOR inhibitors (eg, temsirolimus, sirolimus, everolimus) may be at increased risk of angioneurotic edema (see [Precautions]).
Enkephalinase inhibitors
Patients taking concomitant enkephalinase inhibitors (eg, sacubitril) may have an increased risk of angioneurotic edema (see [Contraindications] and [Drug Interactions]).
[Drug overdose
The information on overdose with this drug in humans is limited. By far, the most striking feature of an overdose is significant hypotension, which begins 6 hours after dosing. At the same time, the renin-angiotensin system is blocked and coma occurs. Cases have been reported in which serum enalaprilat levels were 100 and 200 times higher than the normal therapeutic dose after doses of 300 mg and 440 mg, respectively.
The recommended treatment for overdose is intravenous infusion of saline solution, and if angiotensin II is available, infusion of angiotensin II may be beneficial. If this product is newly administered, emetic administration may be possible. Enalaprilat can be removed from the body circulation by hemodialysis (see [PRECAUTIONS], Patients on Hemodialysis).
[Pharmacology and Toxicology
Pharmacological effects
Angiotensin-converting enzyme (ACE) is a peptide-based dipeptidase that converts angiotensinI into the blood pressure-raising substance angiotensinII. Enalapril is absorbed in vivo and hydrolyzed to enalaprilat, which inhibits ACE, causing a decrease in plasma concentrations of angiotensin II, causing an increase in plasma renin activity (a weakened negative feedback mechanism for renin release), and decreasing secretion of aldosterone. Enalapril produces its blood pressure-lowering effect mainly by inhibiting the renin-angiotensin-aldosterone system, which plays an important role in blood pressure regulation.
Toxicological studies
Genotoxicity:
Enalapril and Enalaprilat Ames test (with/no activation system), Rec-analysis test, mammalian cell sister chromatid exchange test, and mouse in vivo micronucleus test, all with negative results.
Reproductive toxicity:
Rats were given enalaprilta 90 mg/kg/day orally. No significant effects on female and male fertility were seen (approximately 26 times the maximum recommended daily dose of MRHDD in humans, extrapolated from body surface area). Enalapril was given orally to pregnant rats at 1200 mg/kg/day (approximately 2000 of MRHDDfold), a decrease in mean fetal litter weight and an increase in serum urea nitrogen and serum potassium levels were seen, and the above phenomena could be reduced with saline supplementation, and no significant abnormalities were seen in the100 mg/kg/day dose group. In rabbits on days 6-18 of gestation, enalapril was given orally 30 mg/kg/day (approximately MRHDDof 50times) and saline supplementation, visible maternal and fetal toxicity, 3 mg/kg/day, 10 mg/kg/day and salt supplementation, no significant toxicity to mother and fetus was observed.
Carcinogenicity:
Rats given enalapril 90 mg/kg/day orally (approximately 150fold of MRHDD), administered for 106weeks, and no carcinogenicity was seen . Enalapril was given orally to male and female mice at doses up to 90 and 180 mg/kg/day, respectively, administered 94week, no carcinogenicity was seen. Extrapolated from body surface area, the dose administered to rats and female mice was 26fold of MRHD and to males was MRHDDof 13fold.
Other toxicity:
Multiple published studies have shown that rat pups from birth to postnatal day 13day (rat renal growth and development stage), daily oral administration of enalapril was seen to be irreversibly toxic to the kidneys. However, no significant toxicity to the developing relatively mature kidney was seen when administered after day 14of birth. The kidneys of rats at birth and on postnatal day14were equivalent to fetal and infant kidney development in the middle trimester of human gestation, respectively. Extrapolating from body surface area, the toxic doses tested above are approximately 10times the highest recommended oral dose (0.58 mg/kg/day) for the treatment of hypertension in children. Lower doses were not studied. Pharmacological effects
Angiotensin-converting enzyme (ACE) is a peptide-based dipeptidase that converts angiotensin I to the elevating substance angiotensin II. Enalapril is absorbed in vivo and hydrolyzed to enalaprilat, which inhibits ACE, leading to a decrease in plasma concentrations of angiotensin II, causing an increase in plasma renin activity (a diminished negative feedback mechanism for renin release), and a decrease in aldosterone secretion. Enalapril produces its blood pressure-lowering effects primarily by inhibiting the renin-angiotensin-aldosterone system, which plays an important role in blood pressure regulation.
Toxicological studies
Genotoxicity.
Enalapril and enalaprilat Ames assay (with/without activation system), Rec-analysis assay, mammalian cell sister chromatid exchange assay, and in vivo micronucleus assay in mice, all with negative results.
Reproductive toxicity.
Oral administration of enalapril up to 90 mg/kg/day to rats did not show significant effects on female and male fertility (approximately 26 times the maximum recommended daily dose of MRHDD in humans, extrapolated from body surface area). In pregnant rats, oral administration of enalapril 1200 mg/kg/day (about 2000 times the MRHDD) showed a decrease in the mean body weight of fetuses and an increase in serum urea nitrogen and serum potassium levels, which were reduced by saline supplementation, and no significant abnormalities were observed in the 100 mg/kg/day dose group. In rabbits, maternal and fetal toxicity was seen on days 6-18 of gestation when enalapril was given orally at 30 mg/kg/day (about 50 times the MRHDD) and supplemented with saline, and no significant toxicity to the mother and fetus was seen at 3 mg/kg/day and 10 mg/kg/day with salt supplementation.
Carcinogenicity.
Rats given enalapril 90 mg/kg/day (approximately 150 times the MRHDD) orally for 106 weeks did not show carcinogenicity. No carcinogenicity was seen in male and female mice given enalapril orally at doses up to 90 and 180 mg/kg/day, respectively, for 94 weeks. Extrapolating from body surface area, rats and female mice were given 26 times the dose of MRHDD, and males were given 13 times the dose of MRHDD.
Other toxicity.
Numerous published studies have shown irreversible renal toxicity in rat pups given daily orally from birth to postnatal day 13 (the stage of renal growth and development in rats) with enalapril. However, no significant toxicity to the developing relatively mature kidneys was seen when administered after day 14 of life. The kidneys of rats at birth and on postnatal day 14 were equivalent to fetal and infant kidney development in the middle trimester of human gestation, respectively. The toxic doses tested above were approximately 10 times the highest recommended oral dose (0.58 mg/kg/day) for the treatment of hypertension in children, as extrapolated from body surface area. Lower doses were not studied.
[Pharmacokinetics
Enalapril is rapidly absorbed after oral administration and reaches peak serum concentrations within 1 hour. The degree of absorption of oral enalapril is approximately 60% based on urine recovery data.
After oral absorption, enalapril is rapidly and completely hydrolyzed to enalaprilat, a potent angiotensin-converting enzyme inhibitor, and the time to reach similar peak serum concentrations of enalaprilat is approximately 4 hours. Enalaprilat is excreted primarily from the kidneys. The major components in the urine are approximately 40% enalaprilat and the prototype enalapril. There is no evidence of significant metabolites of enalapril other than its conversion to enalaprilat. The serum concentration profile of enalaprilat shows a prolonged terminal phase that appears to be related to its binding to angiotensin-converting enzyme. In subjects with normal renal function, enalaprilat reached steady-state serum concentrations after 4 days of oral enalapril. The cumulative effective half-life of enalaprilat after multiple oral doses of enalapril was 11 hours. Its absorption after oral administration of enalapril is not affected by the presence of food in the gastrointestinal tract. The degree of absorption and hydrolysis is the same for all doses of enalapril within the recommended therapeutic range.
Studies in dogs have shown that enalapril rarely or fails to cross the blood-brain barrier; enalaprilat does not enter the brain. There was no accumulation in any tissue after oral administration of multiple doses of enalapril in rats. Radioactivity was detected in the milk of lactating rats after administration of 14C-labeled enalapril maleate. Radioactivity was able to pass through the placenta when 14C-labeled enalapril maleate was administered to pregnant hamsters.
[Storage] Store under shade and seal.
[Package]: Polyvinyl chloride solid pharmaceutical rigid tablets and pharmaceutical aluminum foil, plus polyester/aluminum/polyethylene pharmaceutical composite film and solid pharmaceutical paper bags with silica gel desiccant, 10 tablets/plate/bag/box, 16 tablets/plate/bag/box, 2×10 tablets/plate/bag/box, 14 tablets/plate/bag/box.
[Expiration date] 12 months
[Executive Standard
[Approval number] State Drug Certificate H10980305
[Marketing license holder
Name of the holder of the marketing authorization for the drug: Shiyapharm Group Ouyi Pharmaceutical Co.
Registered Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Phone number: 0311-87886158
Fax number: 0311-87039126
[Manufacturer].
Company name: Shiyao Group Ouyi Pharmaceutical Co.
Production Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Tel: 0311-87886158
Fax number: 0311-87039126
Website: http://www.ouyipharma.com