Approval Date:
Date of revision:
Enerapril Maleate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
Generic Name: Enalapril Maleate Tablets
Trade Name: Enalapril®
English Name:Enalapril Maleate Tablets
Hanyu Pinyin:Malaisuan Yinapuli Pian
[Ingredients]
The main ingredient of this product is: enalapril maleate.
The chemical name is:N -[(S)-1-(Ethoxycarbonyl)-3-phenylalanyl]-L-alanyl-L-proline (Z )-2-Butenedioate.
The chemical structure formula is:
Molecular Formula:C20H28N2O5-C4H4O4
Molecular weight:492.52
[Properties]
This product is a white or off-white tablet.
[Indications]
This product is used to treat:
*All stages of essential hypertension
*Renovascular hypertension
*Heart failure at all levels =”font-family:Arial”>
For patients with symptomatic heart failure, this product is also indicated:
Increasing survival
Delay the progression of heart failure
Reducing hospitalization due to heart failure
*Preventing Symptomatic Heart Failure
For patients with asymptomatic left ventricular insufficiency, this product is indicated for:
Delaying the progression of symptomatic heart failure
Reducing hospitalization due to heart failure
*Preventing left ventricular insufficiency in patients with Coronary ischemic events
This product is indicated for:
Reduces the incidence of myocardial infarction
Reducing hospitalizations due to unstable angina
[Specifications]
(1)5mg(2)10mg
[dosage]
The absorption of this product is not affected by food, so it can be taken before, during or after meals.
Orthostatic hypertension =”font-family:Arial”>
Depending on the severity of hypertension, the starting dose is 10mgto20mg daily1time. For mild hypertension, the recommended starting dose is10 mg daily. For the treatment of other degrees of hypertension, the starting dose is20 mg daily. The usual maintenance dose is 20mg daily. The maximum dose may be adjusted to a maximum of 40mg daily depending on the patient’s needs.
Renovascular hypertension
Because the blood pressure and renal function of such patients may be particularly sensitive to angiotensin-converting enzyme inhibitors, they should be started at smaller doses (e.g.) style=”font-family:Arial”>5 mgor less). The dose is then adjusted according to the patient’s needs. For most patients, the expected efficacy can be received with this product20 mg once daily. Caution is recommended for patients with hypertension 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. Caution is advised because these patients may have hypovolemia or salt loss. Before starting this product2-3days,
diuretic therapy should be discontinued. 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 is then adjusted according to the patient’s needs.
Dosing for renal insufficiency
In general, the dosing interval of enalapril should be extended and/or reduce its dose.
Kidney conditionCreatinine clearance(mL/min)Starting dose( mg/day)Mild renal insufficiency<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 Note: Patients on hemodialysis
** Enalaprilat is dialyzable and the dose in the non-dialysis period should be adjusted according to 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 is2.5 mg and should be taken under close medical supervision to determine its onset 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 does not occur or if symptomatic hypotension has been effectively managed, the dose should be gradually increased to the usual 20 mg as tolerated by the patient family:equine”> maintenance dose in one or two divided doses. This dose adjustment can be completed over a period of 2-4weeks, 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 is effective in reducing the incidence of death.
For a history of hypotension and subsequent renal failure(more rarely), blood pressure and renal function should be closely monitored before and after initiation of this treatment. Renal function(see [Precautions]). In patients treated with diuretics, the dose of diuretics should be reduced as much as possible before starting treatment with this product. The presence of hypotension after initiation of this product does not indicate that further hypotension will occur during long-term treatment with this product and does not preclude continued use of this drug. Serum potassium should also be monitored (see [Drug Interactions]) .
[Adverse Reactions]
Enalapril maleate tablets have been shown to be generally well tolerated. In clinical studies, the overall incidence of adverse reactions with enalapril maleate tablets 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 enalapril maleate tablets:
Dizziness and headache were the more frequently reported adverse reactions. 2%-3%of patients report feeling tired and weak. Less than2% of patients reported other adverse reactions, including hypotension, upright hypotension, syncope, nausea, diarrhea, muscle cramps, rash, and cough. Renal dysfunction, renal failure, and oliguria were rare.
Allergy/Angioneurotic edema
Has been reported in the face, extremities, lips, tongue, vocal cords and / or larynx with angioneurotic edema, but it is rare (see [Caution]).
Very rare adverse reactions that occurred in controlled clinical trials or after the drug was introduced are:
Cardiovascular System “font-family:Arial”>
Myocardial infarction or cerebrovascular accident, possibly secondary to hypotension in high-risk patients (see [Caution]).
Chest pain
Heart palpitations
Arrhythmia
Angina pectoris
Reynolds phenomenon
Endocrine System “font-family:Arial”>
Abnormal antidiuretic hormone secretion syndrome( SIADH)
Gastrointestinal SystemGastrointestinal System
Intestinal obstruction
Pancreatitis
Hepatic failure
Hepatitis–hepatocellular or biliary depression
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]).
Nervous system/Mental
Depression
Mental confusion
Drowsiness
Insomnia
Nervousness
Sensory abnormalities
Vertigo
Abnormal dreams
Respiratory
Lung infiltrates
Bronchospasm//Bronchospasm “font-family:equine”>asthma
Hypopnea
runny
Sore throat and hoarseness
Skin
Sweaty
Polycythemia vera
Exfoliative dermatitis
Stevens-JohnsonSyndrome
Toxic epidermal necrolysis loosening syndrome
Pemphigus
Itching
Hives
Baldness
Other
Impotence
Flushing
Altered taste
Tinnitus
Tongue infection
Blurred vision
A syndrome with some or all of the following symptoms has been reported: fever, plagiocephaly, vasculitis, myalgia/myalgia, arthralgia/ arthritis, positive antinuclear antibodies, increased sedimentation, eosinophilia and leukocytosis. Rash, photosensitivity and other manifestations of skin disease may also occur.
Laboratory tests. “font-family:Arial”>
Clinically significant changes in standard laboratory parameters are rarely associated with the administration of enalapril maleate tablets. However, there are elevations in blood urea and serum creatinine, liver enzymes and/ or elevated serum bilirubin. These often recover after discontinuation of enalapril maleate tablets. Hyperkalemia and hyponatremia have also occurred.
Decreased hemoglobin and hematocrit have also been reported.
Neutropenia, thrombocytopenia, myelosuppression, and granulocyte deficiency have been reported in a few cases since the introduction of enalapril maleate tablets, and it cannot be ruled out that these conditions are related to the use of enalapril maleate tablets. Enalapril tablets were used.
[Contraindicated]
Patients who are hypersensitive to any of the components of this product, or who have a history of angioneurotic edema from previous treatment with an angiotensin-converting enzyme inhibitor, and patients with hereditary or idiopathic angioneurotic edema, this product is contraindicated.
The combination of this product with aliskiren should not be used in patients with diabetes mellitus (see [Drug Interactions]).
The combination of this product with an enkephalinase inhibitor (e.g., sacubitril) is contraindicated. Either conversion from this product to the enkephalinase inhibitor sacubitril/valsartan, or sacubitrilValsartan converted to this product after taking Sacubitril/Valsartan family:equivocal”>Valsartan within 36 hours of administration (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. More severe heart failure(e.g., with high-dose diuretics, hyponatremia, or functional renal insufficiency)patients with high dose diuretics, low blood sodium, or functional renal insufficiency are most likely to develop hypotension. Such patients should be started on medically monitored treatment, and whenever this product is adjusted or/ and diuretic doses, they should be closely followed up and observed. The same treatment applies to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive drop in blood pressure may lead to myocardial infarction or cerebrovascular accident.
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 medication 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 to be 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 use of diuretics and/or this product.
Aortic stenosis. =”font-family:Arial”>/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. “font-family:Arial”>
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 number of doses (see [Dosage]). Some patients with bilateral renal artery stenosis or solitary kidney with renal artery stenosis have had increased blood urea nitrogen and serum creatinine, which is usually reversed with discontinuation of therapy; this is especially true for patients with renal insufficiency.
Some patients with no prior significant renal disease usually have mild and transient elevations of blood urea and serum creatinine when concomitant diuretics are used, and may require dose reduction and/or discontinuation of diuretics and/or this product.
Allergenic/Angioneurotic edema
Facial, extremity, lip, tongue, vocal cord, and angioneurotic edema has been reported occasionally in patients using angiotensin-converting enzyme inhibitors, including this product span style=”font-family:Arial”>/ or angioneurotic edema of the larynx. 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 respiratory distress, 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 lingual 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, vocal cords, or larynx, it may cause airway obstruction and should be treated immediately with appropriate therapy, including, for example, subcutaneous injections of1:1000Epinephrine solution(0.3mL-0.5mL)and/or take immediate measures to keep the airway open.
A higher incidence of angioneurotic edema has been reported in blacks taking angiotensin-converting enzyme inhibitors compared to 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 increased (see [Contraindications]).
Coadministration of ACE inhibitors and span>mTOR(mammalian target of rapamycin protein)inhibitors (e.g.temsirolimus, sirolimus (everolimus) patients, the risk of angioneurotic edema may be increased.
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 when desensitizing patients treated with angiotensin-converting enzyme inhibitors with hymenopteran insect venom, which is relatively rare. This reaction can be avoided by temporarily discontinuing angiotensin-converting enzyme inhibitors before each desensitization.
Patients on hemodialysis
with high permeability membranes (e.g.AN69®) ) on dialysis in conjunction with treatment with angiotensin-converting enzyme inhibitors, the occurrence of classical allergic reactions has been reported. 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 that angiotensin-converting enzyme inhibitors cause cough 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 due to compensatory renin release II production. 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 the development of hyperkalemia include the presence of renal insufficiency, diabetes mellitus, and concomitant use of potassium-preserving diuretics (e.g., ambrisentin, eplidone, amiloride or amiloride), potassium supplementation preparations, potassium-containing salt substitutes, or other medications that may increase blood potassium (e.g., 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 elevations in serum potassium. Hyperkalemia may cause severe, even fatal, cardiac arrhythmias.
If concomitant administration of enalapril maleate and any of the above agents is considered appropriate, use with caution and monitor serum potassium frequently.
Low blood sugar
Diabetic patients treated with oral hypoglycemic agents or insulin started withACEinhibitors should be advised to monitor closely for the occurrence of hypoglycemia, especially during the first month of combination (see [Drug Interactions]).
[For pregnant and lactating women]
The use of this drug is not advocated during pregnancy. If pregnancy is identified, this product should be discontinued immediately unless it is necessary to save the life of the mother.
In a published retrospective epidemiologic study, mothers were found to have taken in the first trimester of pregnancy family:Arial”>ACEinhibitor drugs in the first trimester than in infants whose mothers had not taken ACEinfants who had taken inhibitor drugs were at increased risk for congenital malformations. 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 neonatal cephalic (underdevelopment) is related. Maternal hypohydramnios have 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.
Uterine exposure to this angiotensin-converting enzyme inhibitor by administration in the first trimester of pregnancy 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 patient and physician should be aware that when hypoamniotic fluid is present, the fetus has suffered irreversible damage.
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]
In116years. study. The use of enalapril maleate tablets 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 multi-dose pharmacokinetic study including40patients with pediatric hypertension, with neonates excluded, who generally tolerated enalapril maleate tablets well. The pharmacokinetics after oral administration of enalapril in these patients were identical to the data recorded for adults.
In a study including1106-16year-old pediatric hypertensive patients weighing 50kg per day in patients with hypertension taking
Enalapril0.625, 2.5or20mg and weight ≥50 kg per day for patients taking enalapril1.25, 5 or40mg. Taken once daily, enalapril has a dose-dependent effect in lowering blood pressure troughs. This dose-dependent antihypertensive efficacy was observed in all subgroups(age, Tanner stage, gender, race) are consistent. However, using 0.625mg and 1.25mg the lowest dose study with a mean daily dose of 0.02 mg/Kgcorrespondingly, no consistent antihypertensive efficacy emerged. The maximum dose studied was 0.58 mg/kg per day ( up to 40mg). In this study, generic enalapril maleate tablets were well tolerated.
Adverse reactions in pediatric patients were similar to those observed in adult patients.
in neonates and glomerular filtration rate 30mL/min/ 1.73m2in pediatric patients, enalapril maleate tablets are not recommended because there is no information available.
[Geriatric use]
This trial was not conducted.
[Drug Interactions]
Antihypertensive therapy
Iterative effects can occur when enalapril maleate tablets are used concomitantly with other antihypertensive drugs, especially when diuretics are applied concomitantly.
Enalapril maleate tablets withβreceptor blockers, methyldopa, or calcium channel blockers can enhance antihypertensive efficacy.
Ganglion blockers or adrenoceptor blockers should be carefully monitored in patients when combined with enalapril maleate tablets.
Concurrent application of enalapril maleate tablets may attenuate 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, thiamethoxene, methyldopa, warfarin, indomethacin, and sulindac. The combination of propranolol with enalapril maleate decreased serum concentrations of enalaprilat, but this did not have any clinical significance. Because there was no interaction between cimetidine and enalapril maleate in animals, all drug interactions that could be expected to occur in humans did not occur.
Serum potassium- See [caution], Hyperkalemia
Serum potassium has generally remained within the normal range in clinical trials. In patients with hypertension treated with enalapril maleate tablets alone for 48weeks, a mean increase in serum potassium was seen of approximately family:Arial”>0.2 mEq/L. In patients treated with enalapril maleate tablets plus a thiazide diuretic, the potassium excretory effect of the diuretic is often attenuated by the effect of enalapril.
Enalapril maleate tablets used with potassium-removing diuretics may reduce diuretic-induced hypokalemia.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-retaining diuretics (e.g., ambien,
Ipridone, amphetamine or amiloride), potassium-replete preparations Potassium-containing salt substitutes or other medications that may increase blood potassium (e.g., medications containing methotrexate).
The use of potassium-supplementing 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.
If concomitant use of enalapril maleate tablets and the above agents is considered appropriate, use with caution and monitor serum potassium frequently.
Antidiabetic drugs =”font-family:Arial”>
Epidemiological studies have shown that co-administration ofACEinhibitors and antidiabetic drugs(insulin, oral hypoglycemic drugs) span>)may lead to enhanced hypoglycemic effects and increased risk of hypoglycemia. This occurs most often 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.
Serolithium
As with other sodium-removal drugs, lithium clearance may be reduced. Therefore, serum lithium concentrations should be carefully monitored if lithium salts are administered.
Including selective cyclooxygenase-2inhibitors of nonsteroidal anti-inflammatory drugs
including selective cyclooxygenase-2inhibitors(COX-2inhibitors)Non-steroidal anti-inflammatory drugs(NSAIDs)may reduce the effectiveness of diuretics or other antihypertensive drugs. Thus, the effects of angiotensinIIreceptor antagonists or angiotensin-converting enzyme inhibitors would also be included in selectiveCOX-2inhibitors, including selectiveNSAIDsclass of drugs diminished.
In some cases taking drugs including selectiveCOX-2in patients with renal insufficiency including nonsteroidal anti-inflammatory drugsinhibitors
(e.g., elderly patients or patients with hypovolemia, including those being treated with diuretics) while taking angiotensinIIreceptor 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.
Renin-angiotensin-Dual blockade of the aldosterone system
with single blockade of renin-angiotensin-aldosterone system (RAAS) compared with treatment with angiotensin receptor antagonists, ACEinhibitors or direct renin inhibitors (e.g., aliskiren) dual blockadeRAAStreatment would increase the risk of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure. Closely monitor blood pressure, renal function, and electrolytes in patients on combined enalapril maleate tablets and other medications affecting RAAS. Do not combine enalapril maleate tablets and aliskiren in diabetic patients. Patients with renal impairment (GFR 60 mL/ min)Avoid the combination of enalapril maleate tablets and aliskiren.
Gold
Very little information is available on the use of injectable gold (gold thiodisodium) in combination with gold including enalapril family:Arial”>ACEinhibitors have been reported in patients treated with nitrite reactions (symptoms include facial flushing, nausea, vomiting, and hypotension).
Mammalian rapamycin target protein(mTOR)Inhibitor
Coadministration of enalapril maleate tablets withmTOR inhibitors(for example temsirolimus, sirolimus, everolimus) may be at increased risk of angioneurotic edema (see [Precautions]).
Enkephalinase inhibitors
Patients taking concomitant enkephalinase inhibitors (e.g., sacubitril) may be at increased risk of angioneurotic edema (see [Contraindications] and [Drug interactions]).
[Drug overdose]
The information on human overdose with this drug is limited. By far, the most striking feature of an overdose is marked hypotension, which begins 6hours after dosing. At the same time, the renin-angiotensin system is blocked and coma occurs. There have been reports of doses of 300 mg and 440 mgdose, serum enalaprilat levels were higher than the normal therapeutic dose by 100fold and 200fold cases.
The recommended treatment for drug overdose is intravenous infusion of saline solution and, if angiotensinIIis available, infusion of angiotensinII may be beneficial. If this product is newly administered, it may be administered to induce vomiting. 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 peptidyl dipeptidase that converts angiotensinI into the blood pressure-raising substance angiotensinII. Enalapril is absorbed in vivo and hydrolyzed to enalaprilat, which inhibitsACE, leading to a decrease in plasma concentrations of angiotensin II, causing an increase in plasma renin activity (renin release negative feedback mechanism is diminished), and decreases aldosterone secretion. Enalapril works mainly by inhibiting renin-angiotensin, which plays an important role in blood pressure regulation. family:Arial”>-aldosterone system and produce blood pressure lowering effect.
Toxicological studies
Genotoxicity:
Enalapril and EnalaprilatAmestests (with/no activation system),Rec-analysis assay, mammalian cell sister chromatid exchange assay, and mouse in vivo micronucleus assay, which were all negative.
Reproductive toxicity:
Rats given enalaprilta90 mg/kg/day, no significant effects on female and male fertility were seen (extrapolated from body surface area to approximately the maximum recommended human daily doseof MRHDDof26fold). Enalapril was given orally to pregnant rats1200 mg/kg/day (approximatelyMRHDD of 2000 times), as seen The average weight of fetuses decreased, and the serum urea nitrogen and serum potassium levels increased, which could be reduced by saline supplementation, 100mg/kg/day dose group did not show significant abnormalities . In rabbits on day 6-18 of gestation, enalapril was given orally 30 mg/kg/day (about the MRHDD of) span>50 times) and saline supplementation, visible maternal and fetal toxicity,3mg/kg/day,10mg/kg/day and salt supplementation No significant toxicity to mothers and fetuses was seen at the time of the study.
Carcinogenicity:
Rats given enalapril90 mg/kg/day (about MRHDDof150fold), administered for 106weeks, did not show carcinogenicity. Enalapril was given orally to male and female mice at doses up to 90 and 180 mg/kg/day, administered for 94 weeks, no carcinogenicity was seen. The doses administered to rats and female mice, extrapolated from body surface area, weretheMRHD of26 times the dose administered to male mice atMRHDDof13times.
Other toxicity:
Multiple published studies have shown that rat pups from birth to postnatal day13day (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 day 14were 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 of the highest recommended oral dose for the treatment of hypertension in children (0.58 mg/kg/day) 10times. Lower doses were not studied.
[Pharmacokinetics]
Enalapril is rapidly absorbed after oral administration,1hour to reach peak serum concentration. 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 for enalaprilat to reach similar peak serum concentrations is approximately. family:Arial”>4 hours. Enalaprilat is excreted primarily from the kidneys. The major component in the urine is approximately40% of enalaprilat and the prototype enalapril. There is no evidence of other significant metabolites of enalapril other than conversion to enalaprilat. The serum concentration profile of enalaprilat showed a prolonged terminal phase that appeared to be related to its binding to angiotensin-converting enzyme. In subjects with normal renal function, enalapril reached steady-state serum concentrations after 4days of oral enalapril. The cumulative effective half-life of enalaprilat after multiple oral doses of enalapril is 11hours. 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 never crosses 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 14Clabeled enalapril maleate. Radioactivity was able to pass through the placenta in pregnant hamsters given14Clabeled enalapril maleate.
[Storage]
Shelter from light,25C or below for sealed storage.
[Package][Package]
(1)5mg(2)10mg
1.1. =”font-family:isoline”>Double foil pack,8pieces/plate×1board/box
2.2. =”font-family:isoline”>Double foil pack,8pieces/plate×2board/box
3.3. =”font-family:isoline”>Double foil pack,6pieces/plate×2board/box
[Expiration date]
18months
[Executive Standard]
[approval number]
(1)5mg:国药准字H10930062
((2)10mg:国药准字H10930061
[Marketing Authorization Holder]
Changzhou Pharmaceutical Factory Co. font-family:Times New Roman”>
Address: Labor East Road, Changzhou, Jiangsu 518No.
[Manufacturer]
Company Name: Changzhou Pharmaceutical Factory Co. style=”font-family:Times New Roman”>
Production Address: Changzhou City, Jiangsu Province, Labor Road East518No.
Postal Code:213018
Phone Number:0519-88813251
Fax Number:0519-88828412
Net
Address:www.czzyc.com