Approved on.
Revision Date.
Elanapril Maleate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name].
Generic Name: Enalapril Maleate Tablets
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 (5mg) or light red (10mg) tablet.
[Indications
This product is used for the treatment of.
*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
Preventing coronary ischemic events in patients with left ventricular insufficiency
This product is indicated for.
Reducing the incidence of myocardial infarction
Reduced 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 a meal.
Orthostatic hypertension
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 can be adjusted to 40 mg daily depending on the patient’s needs.
Renal vascular hypertension
Because 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 (e.g., 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 who have been recently treated with diuretics. Caution is advised because these patients may have hypovolemia or salt loss. 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>30 mL/min5-10 mgModerate renal insufficiency≤30>10 mL/min2.5-5 mg Severe renal insufficiency
Usually these patients will be on dialysis*≤10 mL/min2.5 mg
during the dialysis period** =”font-size:10pt”>*See [Caution]: 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 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 usual 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.
Because hypotension and subsequent renal failure (more rare) have been reported, blood pressure and renal function should be monitored closely both before and after initiation of therapy with this product (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 occurrence 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
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 with 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 commonly reported adverse reactions. 2%-3% of patients reported feeling fatigued and weak. Other adverse reactions were reported in less than 2% of patients and included hypotension, upright hypotension, syncope, nausea, diarrhea, muscle cramps, rash, and cough. 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 occurred in controlled clinical trials or after the drug was introduced are.
Cardiovascular System
Myocardial infarction or cerebrovascular accident, possibly secondary to hypotension in high-risk patients (see [Precautions]).
Chest pain
Heart palpitations
Cardiac arrhythmia
Angina pectoris
Raynaud’s phenomenon
Endocrine system
Syndrome of abnormal secretion of antidiuretic hormone (SIADH)
Gastrointestinal 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]).
Neurologic/psychiatric
Depression
Mental confusion
Drowsiness
Insomnia
Nervousness
Sensory abnormalities
Vertigo
Abnormal dreams
Respiratory
Pulmonary infiltrates
Bronchospasm/asthma
Difficulty in breathing
Runny
Sore throat and hoarseness
skin
Excessive sweating
Polycythemia vera
Exfoliative dermatitis
Stevens-Johnson syndrome
Toxic epidermal necrolysis loosening syndrome
Pemphigus vulgaris
Itching
Hives
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, plagiocephaly, vasculitis, myalgia/myalgias, 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 the administration of enalapril maleate tablets. However, there are elevated blood urea and serum creatinine, and increased liver enzymes and/or 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 excluded that these conditions are associated with the use of enalapril maleate tablets.
[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 one of the angiotensin-converting enzyme inhibitors, and in patients with hereditary or idiopathic angioneurotic edema.
This product should not be used in combination with aliskiren in patients with diabetes mellitus (see [Drug Interactions]).
The combination of this product with enkephalinase inhibitors (e.g., 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 medication and are usually administered once blood pressure rises after expansion of blood volume. 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
Low blood pressure 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 require a reduction in the dose of this product and/or a reduction in the frequency of dosing (see [DOSAGE]). Some patients with bilateral renal artery stenosis or solitary kidney with renal artery stenosis have experienced 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 without previous 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.
Allergic/angioneurotic edema
Angioneurotic edema of the face, extremities, lips, tongue, vocal cords, and/or larynx has been reported occasionally in patients using angiotensin-converting enzyme inhibitors, including this product. This can occur at any time during the treatment period. This is when 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, angioneurotic edema with laryngeal or lingual edema has been reported to cause 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 with appropriate therapy, including such things as subcutaneous 1:1000 epinephrine solution (0.3 mL-0.5 mL) and/or immediate measures to keep the airway open.
A higher incidence of angioneurotic edema has been reported in blacks on angiotensin-converting enzyme inhibitors 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 Hymenoptera
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 high permeability membranes (e.g. AN69®) who are also treated with angiotensin-converting enzyme inhibitors 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 that angiotensin-converting enzyme inhibitors cause cough should be taken into account 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 the above mechanism, 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, eplerenone, aminoglutethimide, or amiloride), potassium supplementation, potassium-containing salt substitutes, or other medications that may increase blood potassium (e.g., meperidine containing drugs).
The use of potassium supplements, 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 tablets 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 drug is not recommended during pregnancy. If pregnancy is identified, discontinue this product immediately unless it is necessary to save the mother’s life.
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 cephalic 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.
Uterine exposure to this angiotensin-converting enzyme inhibitor by administration in the first trimester of pregnancy does not cause the adverse effects 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
The safety and efficacy of enalapril maleate tablets were studied in pediatric hypertensive patients between the ages of 1 month and 16 years. 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 published pediatric dosing literature.
In a multi-dose pharmacokinetic study including 40 pediatric hypertensive patients, with neonates excluded, enalapril maleate tablets were 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 1.25, 5, or 40 mg per day. 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 did not show consistent antihypertensive efficacy relative to the mean daily dose of 0.02 mg/kg. The maximum dose study was 0.58 mg/kg per day (up to 40 mg). In this study, generic enalapril maleate tablets were well tolerated.
Adverse reactions seen in pediatric patients were similar to those observed in adult patients.
In neonates and pediatric patients with glomerular filtration rates 2, enalapril maleate tablets are not recommended because no information is 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 in combination with beta-blockers, methyldopa, or calcium channel blockers can enhance antihypertensive efficacy.
Cautiously observe patients when combining ganglion blockers or adrenoceptor blockers with enalapril maleate tablets.
Concomitant application of enalapril maleate tablets 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, timolol, 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 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. In patients with hypertension treated with enalapril maleate tablets alone for 48 weeks, a mean increase in serum potassium of about 0.2 mEq/L was seen. In patients treated with enalapril maleate tablets plus a thiazide diuretic, the potassium-removal effect of the diuretic was often attenuated by the effect of enalapril.
The use of enalapril maleate tablets together with a potassium-eliminating diuretic may reduce diuretic-induced hypokalemia.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and concomitant use of potassium-preserving diuretics (e.g., ambrisentin, eplerenone, aminoglutethimide, or amiloride), potassium supplementation, potassium-containing salt substitutes, or other medications that may increase blood potassium (e.g., meperidine containing drugs).
The use of potassium supplements, 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 agents
Epidemiologic studies have shown that the combination of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic agents) may lead to enhanced hypoglycemic effects and an increased risk of hypoglycemia. This occurs mostly in the first 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
Nonsteroidal 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 being treated with diuretics), 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
Compared with treatment with a single blockade of the renin-angiotensin-aldosterone system (RAAS), treatment with dual blockade of the RAAS with an angiotensin receptor antagonist, an ACE inhibitor, or a direct renin inhibitor (e.g., aliskiren) increases hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function, and electrolytes in patients on combination 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 enalapril maleate tablets 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 (e.g., sacubitril) may be at increased risk of angioneurotic edema (see [Contraindications] and [Drug Interactions]).
[Drug Overdose
Information on human overdose with this drug 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 drug overdose is intravenous infusion of saline solution, and if angiotensin II is available, infusion of angiotensin II may be beneficial. 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 angiotensin I to the blood pressure-raising substance angiotensin II. Enalapril is absorbed in vivo and hydrolyzed to enalaprilat, which inhibits ACE, resulting in angiotensin A decrease in plasma concentrations of angiotensin II causes 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 test (with/without activation system), Rec-analysis test, mammalian cell sister chromatid exchange test, and in vivo micronucleus test in mice, all with negative results.
Reproductive toxicity.
Rats given enalapril up to 90 mg/kg/day orally 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) was associated with a decrease in mean fetal weight 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 30 mg/kg/day (approximately 50 times the MRHDD) was given orally with saline supplementation, and no significant maternal or fetal toxicity was seen at 3 mg/kg/day and 10 mg/kg/day with salt supplementation.
Carcinogenicity.
Rats were given enalapril 90 mg/kg/day (approximately 150 times the MRHDD) orally for 106 weeks, and no carcinogenicity was observed. Male and female mice were given enalapril orally at doses up to 90 and 180 mg/kg/day for 94 weeks, respectively, and no carcinogenicity was observed. 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 the level of 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 10 times the highest recommended oral dose for the treatment of hypertension in children (0.58 mg/kg/day). 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 in pregnant hamsters given 14C-labeled enalapril maleate.
[Storage]Sealed below 25°C. .
[Package]Packaged in aluminum blister, 10 tablets/plate x 1 plate/box.
[Expiration date]24 months
[Execution Standard
[Approval number]5mg: State Drug Registration H14023577
10mg：国药准字H14023578
[Drug Listing Permit Holder
Name:Yabao Pharmaceutical Group Co.
Registered Address: No. 43, Fumin Road, Rucheng County, Yuncheng City, Shanxi Province
[Manufacturer
Company Name: Yabao Pharmaceutical Group Co.
Manufacturing Address: No.1, Industrial Avenue, Fenglingdu Economic Development Zone, Shanxi Province
Postal Code: 044602
Tel: 0359-3388011
Fax Number: 0359-3388012
Website: http://www.yabao.com.cn