Xiaobendiping Kongshi Pian
Xiao Ben Di Ping Kong Shi Pian
Baixintong
BAI XIN TONG
Nifedipine Controlled-release Tablets
FUNCTION and INDICATIONS
For hypertension, coronary heart disease, and chronic stable angina pectoris (worked angina).
INGREDIENTS
Round, biconvex, hard rose-red film-coated tablet.
DESCPRIPTION
The main ingredient of this product is nifedipine. Chemical name: Dimethyl 2,6-dimethyl-4(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate. Molecular formula: C17H18N2O6. Molecular weight: 346.34.
SPECIFICATION AND PACKAGE
30mg*7 tablets/box.
USAGE AND DOSAGE
1.The medication should be used according to individual conditions as much as possible during treatment. According to the patient's clinical condition, different basic drug dosages are given.
2.Unless ordered by a special doctor, the following dosages are recommended for adults:
(1) Hypertension: 30mg or 60mg once, once a day.
(2)Coronary heart disease: chronic stable angina pectoris (worked angina), 30mg or 60mg once, once a day
(3) The initial dose of usual treatment is 30 mg per day.
3.Course of treatment: The time of medication should be determined by the doctor.
4.Medication method: Usually the whole tablet is swallowed with a small amount of liquid, and the medication time is not limited by the meal time. Avoid eating grapefruit juice (see [Drug Interactions]).
5.When combined with CYP3A4 inhibitors or CYP3A4 inducers, it may be necessary to adjust the dose of nifedipine or not to use nifedipine (see [Drug Interactions]).
6.Special groups:
Patients with liver damage: Patients with mild, moderate or severe liver damage based on the ChildPugh score should be carefully monitored and dose reductions may be required. The pharmacokinetics of nifedipine has not been studied in patients with severe hepatic impairment (see [Precautions] and [Pharmacokinetics])..
Clinical application and guidelines
1.Zhu Ye's study explored the clinical efficacy of nifedipine controlled-release tablets combined with enalapril in the treatment of elderly coronary heart disease with refractory hypertension, and concluded that the elderly with coronary heart disease combined with refractory hypertension use Bexintong combined with enalapril Advantageous treatment can effectively control blood pressure levels, reduce ischemic events, and improve clinical efficacy. (Northern Pharmacy, 2019(04):124-125.)
2.Yang Yuanming studied and analyzed the clinical efficacy of valsartan combined with nifedipine controlled-release tablets in the treatment of essential hypertension, and concluded that the clinical efficacy of valsartan combined with nifedipine controlled-release tablets in the treatment of essential hypertension is significant, which can be Promote applications. (Electronic Journal of Cardiovascular Diseases of Integrated Traditional Chinese and Western Medicine, 2019,7(06):53-55.)
ADVERSE REACTION
Frequency according to CIOMSIII category (placebo-controlled study: nifedipine N=2661; placebo N=1486; as of February 22, 2006; ACTION study: nifedipine N=3825; placebo N=3840) The adverse drug reactions based on clinical research are as follows:
1. The frequency of common adverse reactions is less than 3%, except for edema (9.9%) and headache (3.9%).
2. Other adverse reactions include:
(1) Abnormal blood and lymphatic system: agranulocytosis, leukopenia.
(2) Immune system disorders: allergies, allergic edema/angioedema (including laryngeal edema 1), itching, urticaria, skin rash, allergic/anaphylactic reactions.
(3) Mental disorders: anxiety, abnormal sleep.
(4) Abnormal metabolism and nutrition: high blood sugar.
(5) Nervous system disorders: headache, dizziness, migraine, dizziness, tremor, (bilateral) dullness, dullness, lethargy.
(6) Eye abnormalities: abnormal vision and eye pain.
(7) Heart abnormalities: tachycardia, palpitations, chest pain (angina).
(8) Vascular abnormalities: edema, vasodilation, hypotension, and fainting.
(9) Abnormal breathing, chest and mediastinum: epistaxis, nasal congestion, and difficulty breathing.
(10) Gastrointestinal symptoms: constipation, gastrointestinal and abdominal pain, nausea, dyspepsia, flatulence, dry mouth, gingival hyperplasia, gastric calculi, dysphagia, intestinal obstruction, intestinal ulcer, vomiting, gastroesophageal sphincter dysfunction .
(11) Hepatobiliary symptoms: transient elevated liver enzymes, jaundice.
(12) Skin and subcutaneous tissue symptoms: erythema, toxic epidermal necrolysis, photosensitivity allergy, palpable purpura.
(13) Musculoskeletal and connective tissue abnormalities: muscle cramps, joint swelling, arthralgia, and myalgia.
(14) Abnormalities of the kidneys and urinary system: polyuria, dysuria.
(15) Reproductive system abnormalities: erectile dysfunction.
(16) Symptoms of general malaise and administration site: feeling unwell, non-specific pain, chills.
(14) Note 1: It may be life-threatening.
3.For dialysis patients with malignant hypertension and hypovolemia, blood pressure may drop significantly due to vasodilation.
CONTRAINDICATIONS
1.This product is forbidden to people who are known to be allergic to nifedipine or any ingredients in this product.
2.It is contraindicated in patients with small KOCK capsules (ileostomy after proctocolectomy).
3.Due to enzyme induction, when combined with rifampicin, nifedipine cannot reach the effective plasma concentration. Therefore, it should not be combined with rifampicin.
4.Nifedipine is contraindicated in women within 20 weeks of pregnancy and breastfeeding women..
Warning
1. For patients with heart failure and severe aortic stenosis, when the blood pressure is very low (severe hypotension with systolic pressure <90mmHg), you should be very cautious when taking this product.
2. This product contains non-deformable substances, so patients with severe gastrointestinal tract stricture should be cautious when using this product, because obstruction symptoms may occur. The occurrence of gastric calculi is very rare, and if it occurs, surgery may be required.
3. There have been case reports that patients without gastrointestinal diseases have symptoms of obstruction.
4. When X-ray barium meal imaging is performed, this product can cause false positive results (it is mistaken for polyps due to filling defects).
5. Patients with mild, moderate or severe liver damage based on the ChildPugh score should be carefully monitored and the dose may need to be reduced. The pharmacokinetics of nifedipine has not been studied in patients with severe liver damage (see [Usage and Dosage] and [Pharmacokinetics]). Therefore, patients with severe liver damage should use nifedipine with caution.
6. Nifedipine is eliminated through the metabolism of the cytochrome P4503A4 system. Therefore, drugs that inhibit or induce the cytochrome P4503A4 system may change the first pass effect or clearance rate of nifedipine (see [Drug Interactions] for details). Therefore, weak to moderate inhibitors of the cytochrome P4503A4 system may increase the plasma concentration of nifedipine, such as:
(1) Macrolide antibiotics (such as erythromycin).
(2) Anti-HIV protease inhibitors (such as ritonavir).
(3) Pyrrole antifungal drugs (such as ketoconazole).
(4) The antidepressants nefazodone and fluoxetine.
(5) Quinupudine/Dafopristin.
(6) Valproic acid.
(7) Cimetidine.
When nifedipine is used in combination with the above drugs, blood pressure should be monitored, and if necessary, the dose of nifedipine should be reduced.
7. Impact on the ability to drive and operate machinery: The response to drugs varies from person to person, so it may affect the ability to drive and operate machinery. This effect is especially obvious in the initial treatment, when changing drugs and drinking alcohol.
8. This product has a non-absorbable shell, so that the medicine can be slowly released into the human body for absorption. When this process is over, a complete empty tablet can be found in the stool.
9. Nifedipine controlled-release tablets contain photosensitive active ingredients, so this product should be stored away from light. The tablets should be protected from moisture and should be taken immediately after being taken out of the aluminum-plastic board
10. Medication for pregnant women and lactating women:
(1) Pregnant women and fertility:
①Pregnant women within 20 weeks of pregnancy are contraindicated. There is not enough research on pregnant women. Animal experiments showed embryo toxicity, fetal toxicity and teratogenicity.
②Although there have been reports of an increase in perinatal asphyxia, caesarean section, premature delivery and intrauterine growth retardation, the existing clinical evidence does not show a special prenatal risk. It is not clear whether these reports are caused by underlying hypertension and its treatment or special drug effects.
③The existing information is not enough to rule out the adverse effects of this product on the fetus and newborn. Therefore, women who are pregnant for more than 20 weeks should carefully weigh the pros and cons when using this product, and consider using this product only when other treatment methods are not applicable or ineffective.
④When pregnant women are given nifedipine and magnesium sulfate intravenously at the same time, blood pressure may be too low and affect the mother and fetus, so blood pressure should be closely monitored.
⑤In some cases of in vitro fertilization, nifedipine calcium ion antagonists are related to the reversible biochemical changes of the sperm head, thereby impairing sperm function. Those men who have repeatedly failed in vitro fertilization should consider nifedipine calcium antagonists as the cause when there is no other reason.
(2) Lactating women: Nifedipine can pass into breast milk. Because there is no report on the possible effects on the baby, when nifedipine must be taken during breastfeeding, the first thing to do is to stop breastfeeding.
11. Children's medication: There is no data on the safety and effectiveness of children's medication.
12. Elderly medication: There is no data on the use of this product in elderly patients.
13. Overdose:
(1) Symptoms:
When severe nifedipine poisoning occurs, the following symptoms can be seen: disturbance of consciousness or even coma, drop in blood pressure, tachycardia/bradycardia arrhythmia, hyperglycemia, metabolic acidosis, hypoxemia, cardiogenic shock with Pulmonary Edema.
(2) Treatment measures after adult overdose:
① In the treatment of nifedipine overdose, the elimination of active ingredients and the restoration of cardiovascular stability should be considered first.
②After gastric lavage, small intestine enema can be given if necessary, especially in the case of poisoning caused by this product and similar products (such as other sustained-release tablets), it should be as comprehensive as possible, including enema, to prevent the absorption of active ingredients.
③ Hemodialysis is of little significance, because dialysis cannot exclude nifedipine, but plasma exchange (high plasma protein binding, relatively low volume of distribution) can be performed.
④ Beta-sympathomimetic drugs can be given for bradycardia arrhythmia, and a temporary pacemaker can be placed for life-threatening bradycardia.
⑤ Low blood pressure caused by cardiogenic shock and arterial dilation can be treated with calcium preparations (slowly push 10% calcium gluconate 10ml-20ml, repeat if necessary). Serum calcium can reach the upper limit of normal or slightly increase. If the blood pressure rise is not obvious after the application of calcium preparations, consider giving sympathomimetic vasoconstrictors, such as dopamine and norepinephrine, and the dosage is determined according to the curative effect.
⑥Because of the risk of heart overload, care should be taken when rehydrating or replenishing blood volume.
DRUG INTERACTION
1. Drugs that affect nifedipine:
Nifedipine is metabolized and eliminated by the cytochrome P4503A4 system located in the intestinal mucosa and liver. Therefore, drugs that inhibit or induce the cytochrome P4503A4 system may change the first pass effect (after oral administration) or clearance rate of nifedipine.
The degree and duration of the interaction should be considered when nifedipine is used in combination with the following drugs:
(1) Rifampin:
① It has a strong effect of inducing the cytochrome P4503A4 system. If used in combination with it, the bioavailability of nifedipine will decrease and affect its efficacy. Therefore, the combination of nifedipine and rifampicin is prohibited.
②When nifedipine is used in combination with the following weak to moderate inhibitors of the cytochrome P4503A4 system, blood pressure should be monitored, and the dose of nifedipine should be reduced if necessary.
(2) Macrolide antibiotics (such as erythromycin):
①The research on the interaction between nifedipine and macrolide antibiotics has not been carried out. It is known that certain macrolide antibiotics can inhibit the metabolism of other drugs mediated by cytochrome P4503A4. Therefore, it cannot be ruled out that the combined use of nifedipine can increase the potential effect of nifedipine blood concentration.
②Although Azithromycin is a macrolide antibiotic in structure, it has no inhibitory effect on the cytochrome P4503A4 system.
(3) Anti-HIV protease inhibitors (such as ritonavir): There is no clinical research on the possible drug interactions between nifedipine and anti-HIV protease inhibitors. Such drugs are known to inhibit the cytochrome P4503A4 system. In addition, these drugs can inhibit the metabolism of nifedipine mediated by cytochrome P4503A4 in vitro. Therefore, it cannot be ruled out that when these drugs are used with nifedipine at the same time, the possibility of increased nifedipine plasma concentration due to the decrease of the first pass effect and the decrease in the amount of elimination can not be ruled out.
(4) Pyrrole antifungal drugs (such as ketoconazole): There is no clinical research on the interaction between nifedipine and azole antifungal drugs. Such drugs are known to inhibit the cytochrome P4503A4 system. Therefore, when taking nifedipine at the same time, the possibility that the bioavailability of nifedipine will increase due to the reduced first-pass effect cannot be ruled out.
(5) Fluoxetine: There is no clinical research on the possible drug interaction between nifedipine and fluoxetine. Fluoxetine can inhibit the metabolism of nifedipine mediated by cytochrome P4503A4 in vitro. Therefore, the possibility that the blood concentration of nifedipine will increase when these two drugs are used at the same time cannot be ruled out.
(6) Nefazodone: There is no clinical research on the possible drug interaction between nifedipine and nefazodone. It is known that nefazodone can inhibit the metabolism of other drugs mediated by cytochrome P4503A4. Therefore, the possibility that the blood concentration of nifedipine will increase when these two drugs are used at the same time cannot be ruled out.
(7) Quinupridine/Dafopristin: The combined use of nifedipine and quinupridine/dalfopristin can increase the plasma concentration of nifedipine.
(8) Valproic acid: There is no research on the potential interaction between nifedipine and valproic acid, but because valproic acid can inhibit enzyme activity, it causes calcium ion channel blockade similar in structure to nifedipine. The plasma concentration of nimodipine increases, so it cannot be ruled out that the combination of the two can increase the plasma concentration of nifedipine, thereby improving the efficacy.
(9) Cimetidine: This drug can inhibit the cytochrome P4503A4 system, so it can increase the plasma concentration of nifedipine and enhance the antihypertensive effect.
(10) Cisapride: Combination of cisapride and nifedipine can increase the plasma concentration of nifedipine.
(11) Anti-epileptic drugs that induce cytochrome P4503A4 system, such as phenytoin, carbamazepine and phenobarbital
① Phenytoin can induce the cytochrome P4503A4 system. When combined with phenytoin, the bioavailability of nifedipine is reduced, which leads to a decrease in efficacy. When the two drugs are used in combination, the clinical efficacy of nifedipine should be monitored, and the dose of nifedipine should be increased if necessary. If the dose of nifedipine has been increased when the two drugs are used in combination, the dose of nifedipine should be reduced after stopping phenytoin.
②At present, there is no research on whether there is a potential interaction between nifedipine and carbamazepine or phenobarbital, but because both carbamazepine and phenobarbital can induce enzyme activity, it leads to a structure similar to nifedipine. The calcium channel blocker nimodipine has a reduced blood concentration, so it cannot be ruled out that the combination of nifedipine and carbamazepine or phenobarbital can reduce the blood concentration of nifedipine, thereby reducing the efficacy.
2. Drugs affected by nifedipine:
(1) Antihypertensive drugs:
① Combination of nifedipine and other antihypertensive drugs will enhance the antihypertensive effect of nifedipine, such as diuretics, β-receptor blockers, ACE inhibitors, angiotensin II receptor antagonists, and other calcium antagonists , Α-adrenergic blockers, PDE5 inhibitors, α-methyldopa.
②When nifedipine and β-blockers are used at the same time, because individual cases are known to have worsening heart failure, the patients must be strictly monitored.
(2) Digoxin:
When used with nifedipine at the same time, it will reduce the clearance rate of digoxin, thereby increasing the blood concentration of digoxin. Therefore, the blood concentration of the drug should be monitored to prevent overdose, and if necessary, the drug dose can be reduced according to the blood concentration of digoxin.
(3) Quinidine:
①When nifedipine and quinidine were taken at the same time, the quinidine concentration decreased, or after stopping nifedipine, the blood concentration of quinidine increased significantly in individual cases. Therefore, when taking quinidine, if you add or stop taking nifedipine, the concentration of quinidine in plasma should be monitored on average, and the dose can be adjusted according to the doctor's advice if necessary. Some authors reported that the plasma concentration of nifedipine increased when nifedipine was combined with quinidine, while other authors reported no changes in the pharmacokinetics of nifedipine.
② Therefore, if a patient who has taken nifedipine is taking quinidine, blood pressure should be closely monitored, and the dose of nifedipine can be reduced if necessary.
(4) Tacrolimus:
Metabolized by the cytochrome P4503A4 system. Published data shows that when combined with nifedipine, the dose of tacrolimus needs to be reduced in individual cases. When the two drugs are used in combination, the blood concentration of tacrolimus should be monitored, and the dose of tacrolimus should be reduced if necessary.
3. Drug-food interaction:
Grapefruit juice:
Can inhibit the cytochrome P4503A4 system. For example, combined use with nifedipine can increase the blood concentration of nifedipine and prolong the action time of nifedipine due to the reduced first-pass effect or reduced clearance rate, thereby enhancing the antihypertensive effect. For those who take grapefruit juice regularly, this effect can last for at least 3 days after the last dose. Therefore, grapefruit/grapefruit juice should be avoided when taking nifedipine.
4. There is no interaction:
(1) Nifedipine and benazepril, doxazosin, orlistat, pantoprazole, ranitidine, talinolol, triamteridine, hydrochlorothiazide and p-nifedipine The generation kinetics has no effect.
(2) Aimalin: The combination of nifedipine and aimalin has no effect on the metabolism of aimalin.
(3) Aspirin: The combination of nifedipine and 100mg aspirin has no effect on the pharmacokinetics of nifedipine. At the same time, the combination of the two does not affect the effect of 100mg aspirin on platelet aggregation and bleeding time.
(4) Isoquinguanidine: The combined use of nifedipine and isoquinguanidine has no effect on the metabolic rate of isoquinguanidine.
(5) Candesartan: The combination of nifedipine and candesartan has no effect on the pharmacokinetics of both.
(6) Irbesartan: The combination of nifedipine and irbesartan has no effect on the pharmacokinetics of irbesartan.
(7) The combination of nifedipine, omeprazole and rosiglitazone has no clinically relevant effects on the pharmacokinetics of nifedipine.
5. Other forms of interaction:
Nifedipine can cause a false increase in the spectrophotometric value of urinary vanillic mandelic acid, but the HPLC measurement is not affected.
PHARMACOLOGIC ACTION
1.Nifedipine is a 1,4-dihydropyridine calcium antagonist. Calcium antagonist can reduce the entry of calcium ions into cells through slow calcium channels; nifedipine specifically acts on cardiomyocytes, coronary arteries and peripheral resistance vessels Smooth muscle cells.
2.Nifedipine can expand coronary arteries, especially large blood vessels, and even healthy blood vessels in incompletely blocked areas. Nifedipine can also reduce the tension of coronary artery smooth muscles and prevent vasospasm. Eventually increase the blood flow of the narrowed blood vessels and increase the oxygen supply. At the same time, nifedipine reduces the oxygen demand due to reduced peripheral resistance (afterload). Long-term use of nifedipine can prevent the occurrence of new coronary atherosclerotic lesions.
3.Nifedipine can reduce the increased peripheral resistance and blood pressure by reducing the tension of arterial smooth muscle. In the early stage of nifedipine treatment, there may be a short-term reflex heart rate increase that may lead to an increase in cardiac output. But this increase is not enough to compensate for the expansion of blood vessels. In addition, short-term or long-term use of nifedipine can increase the excretion of sodium and water. For patients with hypertension, nifedipine's blood pressure lowering effect is particularly significant.
4.The results of a multinational, randomized, double-blind, prospective study of 6321 hypertensive patients with at least one additional risk factor who followed 3-4.8 years showed that Nifedipine Controlled Release Tablets can reduce the heart and brain The occurrence of vascular events is equivalent to that of standard diuretic combinations.
Toxicological effects
Preclinical data based on conventional single-dose and multiple-dose toxicity, genotoxicity, and carcinogenicity show that nifedipine has no special harm to humans.
1. Long-term toxicity: Dogs take orally 100 mg/kg nifedipine once a day by body weight for 1 year, and no symptoms of toxicity are seen. In the rat test, when the drug concentration in the feed exceeds 100ppm (about 5-7mg/kg body weight), the animal has a toxic reaction.
2. Carcinogenicity: Rats have been given nifedipine orally for 2 years and no carcinogenic effects have been seen.
3. Mutagenicity: Ames test, micronucleus and dominant lethality test on mice were carried out. Nifedipine has not been found to be mutagenic.
4. Reproductive toxicity:
(1) Nifedipine can cause teratogenicity in rats, mice and rabbits, including abnormal toes, deformities of limbs, cleft palate, cleft sternum and rib deformities. Toe abnormalities and limb deformities may be the result of damaged uterine bleeding, but after organ formation, toe abnormalities and limb deformities were also observed in animals taking nifedipine.
(2) After administration of nifedipine, there may be some embryo toxicity, placental toxicity and fetal toxicity, including slow fetal growth (rats, mice, rabbits), small placenta and chorionic hypoplasia (monkey), embryos And fetal death (rats, mice, rabbits), prolonged pregnancy and reduced survival rate of newborn pups (rats, other animals have not been evaluated). The doses of all drugs that cause teratogenic effects, embryotoxic effects and fetal toxicity in animals are several times the maximum recommended dose for humans.
Pharmacokinetics
This product releases nifedipine at a nearly constant rate within 24 hours, and the drug is released at a zero-order rate through the principle of a push-pull osmotic pump controlled by a membrane. It is not affected by gastrointestinal motility and pH. After taking the medicine, the inactive ingredients in the tablets pass through the gastrointestinal tract intact, and are excreted with the feces in an insoluble shell.
1. Absorption:
(1) Nifedipine is almost completely absorbed after oral administration. Due to the first pass effect, the bioavailability of immediate-release nifedipine capsules after oral administration is 45-56%. The bioavailability of nifedipine controlled-release tablets at steady state is equivalent to 68-86% of nifedipine capsules. Taking the drug while eating slightly affects the early absorption rate of the drug, but does not affect the range of bioavailability.
(2) Plasma drug concentration increases at a controlled rate after administration of nifedipine controlled-release tablets, and reaches a high stable level 6-12 hours after the first administration. The relatively constant blood drug concentration is maintained after multiple doses, and the peak and valley fluctuations of the blood drug concentration within 24 hours during the administration period are small (0.9-1.2).
2. Distribution: The binding rate of nifedipine and plasma protein (albumin) is about 95%. The distribution half-life of nifedipine after intravenous injection is 5-6 minutes.
3. Biotransformation:
(2) After oral administration, nifedipine is mainly metabolized in the intestinal wall and liver through oxidation. Its metabolites have no drug activity.
(2) Nifedipine is mostly excreted in the kidneys in the form of metabolites, and about 5-15% is excreted in feces via bile. There is only a trace amount of the original drug in the urine (less than 0.1%).
4. Eliminate:
(1) The terminal elimination half-life of the conventional dosage form of nifedipine (nifedipine capsules) is 1.7-3.4 hours. Because the plasma drug concentration during drug release and absorption of controlled-release tablets is plateau-like, the pharmacokinetic parameter of terminal elimination half-life after administration of nifedipine controlled-release tablets has no practical significance. After the last administration of nifedipine controlled-release tablets, the plasma drug concentration gradually decreases, and the elimination half-life is the same as that of conventional dosage forms.
(2) Compared with healthy volunteers, there was no significant change in the elimination of drugs in patients with low renal function after taking the drug.
(3) A study comparing the pharmacokinetics of nifedipine between patients with mild (ChildPughA) or moderate (ChildPughB) liver damage and patients with normal liver function showed that oral clearance of nifedipine decreased by an average of 48% ( ChildPughA) and 72% (ChildPughB). Correspondingly, compared with patients with normal liver function, nifedipine AUC and Cmax increased by an average of 93% and 64% (ChildPughA), 253% and 171% (ChildPughB), respectively. The pharmacokinetics of nifedipine has not been studied in patients with severe liver damage (see [Precautions]).
STORAGE
Hermetically sealed,keep in cool and dry places.
PERIOD OF VALIDITY
24 months.
CERTIFICATE NO
Stage Food and Drug Administration Approval number:J20080025.
Manufactured
BAIER PHARMACEUTICAL HEALTH CO.,LTD
Tips: Please read the directions for use in retail or directed by physician.
Part of the goods frequent replacement of packaging, such as goods and pictures are not exactly the same, please refer to the goods you receive.
General Cautions
Keep away from animals and children.This product has not been evaluated by the FDA. It is not intended to diagnose, treat, cure, or prevent any disease.We highly recommend that you consult with a Traditional Chinese Medical practitioner or physician before taking any products or if you have any questions regarding your health.
