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  • Name: Ethambutol Hydrochloride, Pyrazinamide, Rifampicin and Isoniazid Tablets (Ⅱ)
  • Add time: 2015-05-14
  • Views : 98

[Drug Name]
Generic Name:乙胺吡嗪利福异烟片(Ⅱ)
English name:Ethambutol Hydrochloride, Pyrazinamide, Rifampicin and Isoniazid Tablets (Ⅱ)
Pinyin:Yi’an Biqin Lifu Yiyan Pian (Ⅱ)
Ingredient
This product is compound, the group were as follows: Each tablet contains rifampicin (C43H58N4O12) 0.15g, isoniazid (C6H7N3O) 0.075g, pyrazinamide (C5H5N3O) 0.4g, ethambutol hydrochloride (C10H24N2O2 • 2HCl ) 0.275g.
[Character]
This product is film-coated tablets, were removed after coating red.
Indications
Suitable for short-term therapy of tuberculosis first two months of intensive treatment, at this stage must be taken daily.
[Specification]
Each tablet contains 75mg rifampicin 150mg and isoniazid and pyrazinamide and ethambutol hydrochloride 275mg 400mg
【Dosage】
Oral. 30 ~ 37kg of body weight per day two patients weighing 38 ~ 54kg patient three daily, in patients weighing 55 ~ 70kg four a day, weight 71kg more than five patients per day, one hour before meals Dayton clothing. This product is not available for patients weighing 30kg or less.
This product is used to strengthen the anti-TB treatment phase of short-term therapy that initially two-month course. According to WHO recommendations, after which the stage with rifampicin and isoniazid continue therapy for at least four months.
If you make the initial FDA intensive treatment is interrupted for reasons including medication or appear contraindicated in patients unwilling to continue treatment, rifampin, isoniazid, pyrazinamide, ethambutol hydrochloride must be administered alone, because rifampicin needs to be again taking lower doses.
Or compliance.
【Adverse reactions】
According to the literature as follows:
Frequency of occurrence:
Common adverse reactions:> 1/100
Not common adverse reactions: ≥1 / 1,000 and ≤1 / 100
Rare adverse reactions: ≥1 / 10,000 and ≤1 / 1,000
Adverse reactions very rare: <1 / 10,000
Rifampicin continuous and intermittent treatment during the following adverse reactions
Blood and lymphatic system disorders Rare: transient leukopenia, increased eosinophils. In a few cases, intermittent therapy than continuous treatment is more prone to thrombocytopenia, thrombocytopenic purpura symptoms. It has been reported that, if it continues in the event of purpura after taking rifampicin, will appear and the occurrence of cerebral hemorrhage to death. Hemolysis and hemolytic anemia.
Endocrine disorders rare: menstrual disorders (amenorrhea rare cases); caused Addison's disease patients crisis.
Insane insanity.
Nervous system disorders common: fatigue, drowsiness, headache, mild headache, dizziness. Rare: ataxia, muscle weakness.
Eye abnormalities common: jealous, and may cause permanent discoloration of contact lenses. Rare: visual disturbances. Severe symptoms, e.g., exudative conjunctivitis.
Gastrointestinal abnormalities Common: anorexia, nausea, abdominal pain and bloating. Rare: vomiting, diarrhea, erosive gastritis and pseudomembranous colitis.
Skin and subcutaneous tissue abnormalities common: flushing, itching, rash, urticaria. Rare: severe systemic allergic reactions, such as: exfoliative dermatitis, Lyell's syndrome, pemphigoid.
Hepatobiliary abnormalities Common: asymptomatic elevated liver drug metabolizing enzyme. Rare: hepatitis, jaundice, induction of porphyria.
Kidney and urinary system abnormalities rare: blood urea nitrogen, uric acid levels increased, acute renal failure caused hemoglobinuria, hematuria and chronic interstitial nephritis, glomerulonephritis, tubular necrosis.
Generally poor condition common: body fluids and secretions such as urine, saliva, tears, feces, sputum and sweat may be in orange. Rare: collapse, shock, edema.
Recovery of adverse reactions after treatment intermittent therapy or withdrawal of rifampicin
When patients with rifampicin level, not by the daily routine of medication or treatment temporarily interrupted recovery after administration, the common "flu-like syndrome" occurs, probably due to the immune response induced pathology. Fever, tremors, headache, dizziness and muscle pain. Can occur even thrombocytopenia, purpura, dyspnea, asthma, hemolytic anemia, shock and acute renal failure. When rifampicin temporarily discontinued restore one dose (≥25mg / kg) when this serious syndrome may suddenly occur or rifampicin treatment administered weekly, without showing progress of "flu-like syndrome" in ʱ??
Adverse reactions Isoniazid
Blood and lymphatic system abnormalities rare: increased eosinophils, thrombocytopenia, anemia (blood insoluble anemia, iron deficiency anemia). Very rare: agranulocytosis.
Endocrine abnormalities rare: liver metabolism hormones interfere with the individual, leading to menstrual disorders, gynecomastia, Cushing's syndrome, uncontrolled diabetes, hyperglycemia, metabolic acidosis.
Mental disorders Rare: insane, over-excitement, euphoria, insomnia.
Nervous system abnormalities common: peripheral neuropathy (common in large doses, malnutrition, alcoholism, slow acetylation and diabetes) showed numbness, tingling. Rare: optic nerve damage, convulsions, dizziness, headache, viral encephalitis, large doses can increase the frequency of epileptic seizures.
Gastrointestinal abnormalities common: nausea, vomiting, abdominal pain.
Hepatobiliary abnormal common: liver dysfunction (serum transaminase levels usually mild or a transient increase), common prodromal symptoms are poor appetite, nausea, vomiting, fatigue, depression and weakness. Rare: hepatitis, severe hepatitis.
Generally poor condition common: allergy, rash and fever. Rare: allergy, dry mouth, heartburn, frequent urination, rheumatism, systemic lupus erythematosus disease, pellagra, vasculitis, lymphadenopathy, acne.
Adverse reactions pyrazinamide
Blood and lymphatic system abnormalities rare: thrombocytopenia, iron deficiency anemia, blood clotting disorders, splenomegaly.
Gastrointestinal abnormalities common: nausea, vomiting, anorexia, abdominal pain.
Hepatobiliary abnormal common: Early treatment of moderate or a serum transaminases transient increase, porphyria. Rare: severe dose-related hepatotoxicity, hepatomegaly, jaundice.
Kidney and urinary system abnormalities common: hyperuricemia (usually asymptomatic), gout. Rare: chronic interstitial nephritis, urinary retention.
Generally poor condition common: allergies, mild joint pain, muscle pain. Rare: allergy, rash, photosensitivity, urticaria, pruritus, fever, acne.
Adverse reactions ethambutol
Blood and lymphatic system abnormalities rare: thrombocytopenia, leukopenia.
Mental disorders Uncommon: hallucinations.
Nervous system abnormalities Uncommon: dizziness, disorientation, confusion, headache, malaise. Rare: peripheral neuropathy (numbness, tingling, burning, weakness).
Rare eye abnormalities: Dose-dependent retrobulbar optic neuritis (blurred vision, eye pain, color blindness, blindness).
Gastrointestinal abnormalities Uncommon: abdominal pain, loss of appetite, nausea, vomiting, anorexia.
Skin and subcutaneous tissue abnormalities uncommon: pruritus, urticaria, rash.
Kidney and urinary system abnormalities Uncommon: increased blood uric acid, causing gout (chills, joint pain, swelling, especially the thumb, ankle and knee).
Generally poor condition rare: hypersensitivity reactions (rash, fever, joint pain), allergic reactions.
Taboo
1. Rifampin, pyrazinamide, isoniazid, ethambutol hydrochloride or any of the excipients allergies were banned;
2. Normal liver function, biliary obstruction, within 3 months pregnant, gout, mental illness, epilepsy, diabetes retinopathy who porphyria disabled.
3. Patients with severe renal insufficiency (creatinine clearance <30ml / min) Disable
4. Taboo and voriconazole and protease inhibitors used in combination (see drug interactions).
【Precautions】
caveat

Because of acetylation subtypes in the crowd, so the patient has the ability to fast or slow acetylation should take four drugs were so easy to adjust the dose of isoniazid.
If the FDA severe acute allergic reaction should immediately stop, such as: thrombocytopenia, purpura, hemolytic anemia, dyspnea, and asthma-like symptoms, shock or renal failure, in rare use of rifampicin treatment of cases these adverse reactions may also occur when patients these adverse reactions should not be re-taking rifampin.
In any other allergy symptoms should also be disabled, such as: fever or skin reactions. For security reasons, we should continue to use or restore use of rifampicin during treatment.
In patients using this treatment for vision defects, should pay more attention. Is recommended at the beginning and during use (especially when using higher doses) should have regular eye examination, including resolution, color discrimination and visual field examination. It should be recorded for each patient during treatment made by visual inspection, if there during the clinical treatment of vision disorders Patients should be advised to discontinue use.
Precautions
This product medication precautions and rifampin, isoniazid, ethambutol and pyrazinamide various drugs use the same precautions.
We recommend that patients should be continuous treatment.
Damage to liver function, malnutrition, alcoholism
Rifampin, isoniazid, ethambutol, pyrazinamide, mainly in the liver metabolism, it is in the process of taking usually occurs transaminase elevation, above the upper limit of the normal range (ULN). In just a few weeks before the start of treatment of liver dysfunction may occur, but there is no interruption of treatment, in the first three months of treatment will naturally return to the normal range.
Lifestyle usually use, although often mild transaminase elevation, but extremely rare jaundice or hepatitis. While taking isoniazid and rifampicin patients, elevated alkaline phosphatase is mainly caused by rifampicin, but it may be caused by elevated transaminase isoniazid, rifampicin, pyrazinamide were caused, or It is caused by the combined effects of the three.
Patients with impaired liver function during therapy should be used with caution, and strict drug monitoring. In these patients, liver function should be carefully monitored, especially the emergence of serum glutamic pyruvic transaminase (SGPT / ALAT) and serum aspartate transaminase (SGOT / ASAT) when, before treatment and every week or every two weeks to monitor liver function ʱ?? If symptoms of liver damage should be immediately discontinued.
Bilirubin and / or moderately elevated transaminases without stopping the treatment; however, after repeated tests of liver function, should bilirubin and / or transaminase trends and linked to the physical condition of the patient's clinical judgment.
When patients with jaundice or transaminases exceeding the upper limit of its normal range (ULN) three times, it is recommended to stop using isoniazid. In order to facilitate the treatment of this clinical situation, you should replace the present complex drug products, and the use of rifampin, isoniazid, pyrazinamide, ethambutol, or a single component.
If hepatic function fails to return to normal or transaminases exceed 5 times the upper limit of the normal range, it should be deactivated rifampicin, pyrazinamide and ethambutol. In order to facilitate treatment, should FDCs replacement of the product as a single ingredient of pharmaceutical preparations.
When using isoniazid, chronic liver disease patients should be closely monitored. Isoniazid can cause serious, even fatal hepatitis, this situation may occur in use within a few months after their treatment. Although the use of isoniazid hepatotoxicity caused by reactions in patients around 20 years of age is rare, but its frequency of occurrence increases with age, occurred in 50 patients over the age of 3% chance. It will closely monitor liver function of liver cells reduced the incidence of toxicity. Patients should be monitored and precursory symptoms associated with hepatitis, such as: fatigue, weakness, malaise, anorexia, nausea, vomiting. Once these symptoms appear, or find liver damage, drug treatment should be stopped immediately. If the FDA should continue treatment might increase the degree of liver damage.
Patients with chronic liver disease in patients with chronic alcoholism and malnutrition as the FDA in the treatment of tuberculosis should minimize the damage to the liver this product. If TB treatment is required, then rifampin, isoniazid, pyrazinamide, ethambutol dose should be adjusted, but the product is not available for such patients.
Due to high doses of isoniazid make malnutrition or elderly patients generate insufficient vitamin B6, vitamin B6 and therefore may be necessary.
Renal damage
Patients with severe renal insufficiency, isoniazid, pyrazinamide, ethambutol eliminated slowly, so that the body of drug concentration, increased adverse reactions in patients with moderate renal impairment (creatinine clearance 30 ~ 60ml / min ) should be careful.
Gout
Used with caution in patients with a history of gout application pyrazinamide, ethambutol should be in. During the taking regularly check blood uric acid. When patients with gouty arthritis should be discontinued.
Blood disease
When prolonged treatment process, as well as the treatment of patients with liver dysfunction, should be done to check blood cells. Once purpura or thrombocytopenia should appear immediately disable rifampicin. Pyrazinamide may affect clotting time or vascular integrity should be advised of the symptoms of patients with hemoptysis.
Diabetes
It has been reported that diabetic patients taking isoniazid, will increase the difficulty of controlling the disease diabetes.
Epilepsy
Since isoniazid and ethambutol have neurotoxic effects, so in the treatment of patients with a history of seizures should be closely observed.
Neuropathy
Patients with peripheral or optic neuritis should be used with caution. When patients with history of alcohol abuse, you should have regular check nervous system. Vitamin B6 can delay or reduce the patient isoniazid nervous system damage, especially in elderly patients and malnutrition. Vitamin B6 dose should medication under the guidance of a medical practitioner.
Contraception
In the process of applying rifampicin therapy should be used an additional non-hormonal method of contraception.
Alcohol
During the FDA should treatment, patients should stop drinking.
Laboratory examination
Before and during treatment should have regular complete blood count test, liver function tests (SGPT / ALAT, SGOT / ASAT), renal function tests and uric acid monitoring. In the application of ethambutol therapy, it is recommended to do visual inspection.
Combination therapy
Rifampicin is an effective inducer of cytochrome P450 system, can promote the combination therapy drug metabolism, so that the plasma concentration decreased efficacy weakened. If you have the ability to monitor in the liver metabolism of drugs and dose adjustment, the drug can still be used in combination with rifampin.
This product is not suitable for combination with the following drugs: nevirapine, simvastatin, oral contraceptives and ritonavir (when low doses of medication, will be significantly reduced plasma concentration).
This product will slightly affect the medication's ability to drive and use machines capabilities. Ethambutol induced insanity, disorientation, hallucinations, dizziness, discomfort and visual disorders, medication side effects that may affect the ability to drive and use machines.
[Pregnant women and lactating women drug]
Contraindicated in pregnancy before three months pregnant.
If drugs can be beneficial to the patient, the treatment regimen should be considered. Only when the potential benefits to the mother outweigh the potential risk to the fetus, to the FDA.
Rifampicin
Limited clinical data on use during pregnancy published in the show, will not increase the likelihood of fetal teratogenicity. Rifampicin through the placenta. In the last few weeks of pregnancy can lead to the use of rifampicin postpartum maternal and neonatal bleeding. Animal studies have shown that the dose ≥150mg / kg, reproductive toxicity occurs.
Isoniazid
According to the limited data, this product is not expected to appear congenital teratogenicity. Through the placenta, young children produce neurotoxic effects, animal studies show reproductive toxicity.
Pyrazinamide
No reproductive toxicity studies on animals pyrazinamide, pregnant women taking pyrazinamide whether there is damage to the fetus, not yet confirmed.
Ethambutol
Through the placenta and may cause fetal blood concentration of 30% of the parent's. Limited clinical data suggest that the human body does not increase the likelihood of fetal teratogenicity, and animal studies have shown that there is a potential teratogenic risk.
Recommended in the last month of pregnancy, the mother and the newborn after delivery of oral vitamin K, because rifampicin can lead to maternal and neonatal bleeding.
Since isoniazid for young children may have neurotoxic effects, need vitamin supplements during pregnancy B6.
Rifampin, isoniazid, pyrazinamide and ethambutol can enter the milk, but not yet observed adverse reactions in nursing infants. But given isoniazid and ethambutol theoretically have neurotoxic effects in medication during breastfeeding is not recommended.
Pediatric Use
This product is not for children.
[Geriatric medicine]
The elderly often accompanied by physiological renal dysfunction, renal function should therefore adjust the dosage. Or compliance.
Drug interactions
Effect of other drugs on this product

Antacids can reduce rifampin, isoniazid, ethambutol bioavailability. To avoid such situations, the product should be taken at least 1 hour before taking antacids. Corticosteroids can reduce the plasma concentration by promoting the metabolism of isoniazid and / or increased renal clearance.
The impact of the product on other drugs
Rifampicin strong cytochrome P450 system (CYP450) induction of cytochrome P450 system mainly consists of two subfamilies CYP3A and CYP2C, representing the cytochrome P450 isoenzyme system 80%. When combined with medication, can accelerate the metabolism of rifampin combination of drugs, while taking these drugs part or all of the two isoenzymes through metabolism. But also induction of rifampicin uridine-5'-diphosphate - glucuronide transferases (which is another enzyme drug metabolism), which causes the plasma concentration of other drugs at the same time the application of sub-therapeutic dose The plasma concentration, increase or reduce the effect of side effects. Isoniazid can inhibit the metabolism of these drugs lead to its increased blood concentration.
Moreover, rifampicin and isoniazid may affect some drugs antagonism, such as: phenytoin, warfarin and theophylline. The net effect of unpredictable and may change over time.
Mainly metabolized by the liver eliminate drugs, if we can monitor their blood concentration or adverse reactions, and can adjust their dosage, and the product can still be combined. Stop taking this period and in 2 to 3 weeks after treatment should be checked regularly.
Rifampicin role in enzyme induction, within ten days to reach the peak, and gradually reduced to two weeks after withdrawal, the FDA's process if other drug use increased dose, these factors need to be considered disabled.
If you want to consider the compatibility with the goods on the drug concentration is affected, refer to the following:
Interaction rifampicin
The product with the following drugs is strictly prohibited while using: voriconazole and protease inhibitors, but except ritonavir 600mg twice daily dose or adequate dose.
This product should not be used simultaneously with the following drugs: nevirapine, simvastatin, oral contraceptives and ritonavir (when low doses of medication, will be significantly reduced plasma concentration).
When this product with the following medicines at the same time, you need to be monitored for some specific parameters or clinical monitoring, such as: calcium antagonists, Ia antiarrhythmic drugs (quinidine, disopyramide), oral anticoagulants, pyrrole antifungal agents (except voriconazole), buspirone, carvedilol (because of its insufficiency and the low therapeutic window in cardiac symptoms), immunosuppressants (such as cyclosporine, tacrolimus, sirolimus), clozapine, corticosteroids, gestrinone, combined estrogen and progestin hormone replacement therapy, haloperidol, thyroid hormones, methadone, morphine, efavirenz, propafenone, terbinafine Finland, tiagabine, zidovudine, zolpidem, zaleplon, carbamazepine, phenytoin, theophylline, diazepam, digitalis, dapsone, atovaquone, repaglinide and sulfur ureide class of oral diabetes drugs, β receptor antagonists (such as by the hepatic metabolism of metoprolol, propranolol), chloramphenicol, clarithromycin, telithromycin, tricyclic antidepressants, amino water salicylic acid, cimetidine, mexiletine, nevirapine, fluvastatin, rofecoxib, imidapril, Topsy dragon.
Isoniazid Interaction
When this product with the following medicines at the same time, we need to be monitored for some specific parameters or clinical monitoring, such as: anesthetics, corticosteroids, ketoconazole, phenytoin, pyrazinamide, stavudine, carbamazepine, diazepam Pan, ethosuximide, theophylline.
Interaction pyrazinamide
When this product with the following medicines at the same time, we need to be monitored for some specific parameters or clinical monitoring, such as: probenecid, sulfinpyrazone.
Rifampicin can reduce the effects of oral contraceptives, so that patients using this treatment approach should use non-hormonal contraception. At the same time the use of antibiotics may make oral typhoid vaccine inactivation.
Should avoid food rich in tyrosine and histidine food. Isoniazid may inhibit monoamine oxidase and diamine oxidase. Food containing tyrosine (such as cheese, red wine) or containing histidine (such as tuna) food can cause headaches, palpitations, flushing and other symptoms.
Radiological examination in the gallbladder, rifampicin may delay the secretion of bile.
During use of rifampicin, microbiological methods can not be used to determine folate and cyanocobalamin acid (vitamin B12) plasma concentrations, because rifampicin and bilirubin and BSP will compete. To avoid false positive reactions in the morning before taking rifampin BSP test should be carried out.
Overdosage
Rifampicin

Poisoning: Infants (1-4 years) Oral 100mg / kg rifampicin typical skin symptoms appear; adults take 15 g of severe poisoning, take 12g moderate poisoning, take 60g can produce extremely serious poisoning.
Symptoms: gastrointestinal discomfort, vomiting, sweating, difficulty breathing, seizures, kidney failure, liver failure, confusion, generalized itching, skin and urine was orange, facial edema, pulmonary swelling.
Treatment: gastric lavage, given after gastric lavage activated charcoal to absorb the remnants of rifampicin in the gastrointestinal tract; symptomatic treatment; renal failure requiring dialysis.
Isoniazid
Poisoning: Alcohol can induce toxicity. Lethal dose infant is 80 ~ 150mg / kg; 15-year-olds taking 5 g fatal poisoning; 8-year-old children taking 900mg moderate poisoning; 3-year-old children taking 2 ~ 3 g serious poisoning; 15-year-olds taking 3g, adults take 5 ~ 7.5g can produce extremely serious poisoning.
Symptoms: Typical symptoms are seizures and metabolic acidosis, ketone, hyperglycemia; orbital myoclonus, dizziness, tinnitus, tremor, hyperreflexia, confusion, hallucinations; respiratory depression, apnea; tachycardia, arrhythmia, hypertension ; nausea, vomiting, fever, rhabdomyolysis, disseminated intravascular coagulation, hyperglycemia, hyperkalemia, liver damage. Isoniazid doses greater than 10mg / kg may affect the peripheral nervous system, damage to the patient's ability to drive or operate machinery.
Remedy: No history of seizures in patients with gastric lavage, gastric lavage after administration of isoniazid residue activated carbon adsorption. Blood samples were collected from blood gas measurement should be done immediately, ions, blood urea nitrogen, blood sugar levels. Seizures and metabolic acidosis, per gram of isoniazid given vitamin B61 g; seizures and isoniazid dose of uncertainty, with 5 grams of vitamin B6 intravenously; no seizures, prevent giving vitamin B6 2 ~ 3 grams intravenously. To reduce the vascular stimulation, vitamin B6 diluted before use, and the drug using an infusion pump or a syringe pump into the body within 30min, repeated administration of vitamin B6 if necessary. Stability and enhance the role of vitamin B6, use of high doses of diazepam alone treat seizures. Severe cases have respiratory depression, timely rescue; correction of metabolic acidosis and ion imbalance; diuresis, when severe intoxication hemodialysis; symptomatic treatment.
Pyrazinamide
Liver dysfunction, hyperuricemia.
Ethambutol
Loss of appetite, gastrointestinal disorder, fever, headache, dizziness, confusion, hallucinations.
Pharmacology and Toxicology
ACTION:

Rifampicin is a rifamycin class of fungicides; isoniazid, pyrazinamide and ethambutol was antituberculosis fungicides.
Mechanism
Rifampicin: in vivo tests show a significant bactericidal effect of this product against Mycobacterium tuberculosis and other atypical mycobacterium tuberculosis are; inside and outside the cells of microorganisms have a bactericidal effect; the goods sensitive to inhibition of DNA-dependent strain of RNA polymerase, but it does not affect the host cell enzyme system.
Isoniazid: The rapid propagation of Mycobacterium tuberculosis has a strong bactericidal effect, its mechanism may primarily inhibit the synthesis of mycolic acids, mycobacterial mycolic acid is an important component of the cell wall.
Pyrazinamide: The exact mechanism of action is not very clear, in vivo studies have shown that having a bacteriostatic and bactericidal effect pyrazinamide only in the slightly acidic (PH 5.5) conditions.
Ethambutol: mechanism of action has not been fully elucidated, the product can penetrate the synthesis of mycobacteria in vivo RNA interference, thereby inhibiting the proliferation of bacteria, this product only to the growth and reproduction of mycobacteria effective.
Microbial sensitivity
In vitro rifampicin concentration of 0.005 ~ 0.2μg / ml, inhibition of mycobacterial growth; vitro tests showed that the drug can enhance the activity of streptomycin and isoniazid, but had no effect on the activity of ethambutol ʱ??
Isoniazid for "resting" bacterial inhibitory effect, "rapid proliferation of" bacteria sterilization; the lowest concentration of anti-TB was 0.025 ~ 0.05μg / ml.
Pyrazinamide MIC is 12.5 ~ 20μg / ml.
Ethambutol various dosage forms MIC is 0.5 ~ 2μg / ml. Antibacterial ethambutol can be delayed 24 hours, its inhibitory effect may be due to drug exposure intensity time-related, rather than increasing the drug concentration.
Toxicology:
Rifampicin

Taking large doses of female mice (clinical maximum dose of 2 to 10 times) rifampicin year, it can be observed a significant increase in liver cancer, other studies in mice and rats germline found no carcinogenic.
Studies have shown that the product of the bacteria, mice no mutagenicity; FDA blood cell cultures were found chromosome increased; studies have reported, the product of rabbits, mice, rats, guinea pigs, and human lymphocytes in vitro have immunosuppression.
Pregnant rats, mice and rabbits daily doses greater than 150mg / kg, may be non-specific embryonic Taidu; the same dose can be increased in rats and mice, and cleft spine split phenomenon.
Isoniazid
This product has weak genotoxic, mutagenic agents produced before the formation of toxic metabolites during hydralazine and acetylation of hydralazine; no change lymphocytes in patients after taking this chromosome, but in combination therapy , the frequency of chromosomal changes increase occurs. Whether the product can induce animal deformities remains controversial, but studies prove that the product has a role in embryo Taidu, its role has not been reported in the genital area. Statistics show that after a few mice in various ways medication can cause lung cancer, but there is evidence that the human therapeutic dose prophylactic doses of anti-TB and non-carcinogenic.
Pyrazinamide
This pair of rats and male mice no carcinogenic effects in the Ames bacterial test, this product has no mutagenic effects, but can induce chromosome aberrations in human lymphocytes.
Ethambutol
Whether the goods have genotoxic still controversial (human lymphocyte culture test was negative, positive test results in rat nucleus). Mouse while using this service and sodium nitrite, the incidence of lymphoma and lung cancer increased, while the single FDA has no effect on the incidence of cancer.
In reproductive toxicity studies in mice, the animals can occur after taking high doses of this product cleft lip, brain malformations and spinal deformity; rats and rabbits after high doses of this product in their offspring occasionally occur cervical abnormalities, eyed short limb defects, cleft lip and cleft lip phenomenon.
【Pharmacokinetics】
Rifampicin

Fasting rifampicin absorption, medication after eating can reduce the rate and extent of absorption of the drug. 2h plasma concentration peak, is widely distributed in the body after absorption; In addition to meningitis, cerebrospinal fluid drug concentration is low. The apparent volume of distribution of this product is about 55L, protein binding rate of 80%. This product after deacetylation reaction, become active metabolite deacetylation rifampin. This product and its metabolites mainly by biliary excretion, and this product has enterohepatic circulation. Approximately 10% of unchanged drug excreted in the urine.
Plasma elimination half-life of the product is 3 ~ 5h, shortened half-life after multiple dosing, is 2 ~ 3h. Because of its hepatic drug metabolizing enzyme induction, rifampicin dose 6 to 10 days after the elimination of the rate increase. High-dose using, since biliary excretion reaches saturation, excretion may be delayed.
Isoniazid
Oral absorption of fast, using this service after eating rate and extent of absorption are decreased. 1 ~ 2h after the plasma concentration peak. After absorption of isoniazid is widely distributed in body fluids and tissues, the apparent volume of distribution is about 43 L; low protein binding, only 0-10%. This product is by N- acetyltransferase acetylation into acetyl isoniazid, then biotransformation isonicotinic and single acetohydrazide, single acetohydrazide liver toxicity. This product is acetylated speed influenced by genetic factors, often slow acetylation liver N- acetyltransferase enzyme deficiency, about 50 percent of Caucasians and African Indians belong slow metabolizers; the vast majority of Eskimos and Japan, China, Vietnam and other Asian belonging fast metabolizers.
Half-life of this product is usually 1 ~ 4h, but because of the different speeds of acetylation, which range in 0.5 ~ 6h. Nearly 75% to 95% within 24 h of isoniazid excreted by the kidneys, mostly inactive metabolite N- acetyl isoniazid and isonicotinic acid.
Pyrazinamide
After oral administration in the gastrointestinal tract rapidly and completely absorbed, eating no effect on absorption. Adult 1 ~ 2h after the peak plasma concentration, children Tong Dafeng time of 3h. This product is by microsomal deaminase hydrolysis of an active metabolite - pyrazine acid, followed by a xanthine oxidase into 5- hydroxylated pyrazine hydroxy acid. This product is mainly in the form of metabolites excreted by the kidneys, only 3% of the urine is discharged in the form of prototype drug. Plasma half-life is about 10 h.
Ethambutol
Good oral absorption, bioavailability of nearly 80%, eating does not affect its absorption. 2 ~ 4h peak plasma concentration, widely distributed in body tissues and fluids (except for the cerebrospinal fluid), but the drug concentration in the cerebrospinal fluid of patients with tuberculous meningitis in up treatment values. Drug concentration of red blood cells may be a plasma drug concentration of 2 to 3 times, low protein binding, only 20% to 30%, apparent volume of distribution is about 20L. This product is mainly metabolized by the liver, about 15% metabolized to inactive metabolites. Half-life of 3 ~ 4 h, but in patients with renal insufficiency, the half-life of up to 8 h. Approximately 80% within 24 h (at least 50% of the parent drug and nearly 15% inactive metabolites) excreted by the kidneys, excreted in the feces about 20%.
Special Populations
Rifampicin
Patients with renal insufficiency, daily 600mg (10mg / kg) allows the elimination half-life of drugs, resulting in drug accumulation. Rifampicin can not be eliminated by hemodialysis.
In patients with liver dysfunction, plasma drug concentration increased, the elimination half-life.
Isoniazid
Slow acetylation metabolic patients with renal insufficiency, isoniazid drug accumulation may occur. Isoniazid blood concentration should be monitored and, if necessary, reduce the dose. Patients with hepatic dysfunction, the elimination half-life of isoniazid.
Pyrazinamide
Patients with cirrhosis of the product significantly reduced clearance, half-life, pyrazine acid (the main metabolite) of AUC increase threefold. This product is on patients with renal insufficiency has not been reported drug metabolism, clear the goods through the hemodialysis.
Ethambutol
This product in patients with renal insufficiency prolonged elimination half-life in vivo, need to adjust the dose. This product is not cleared by hemodialysis.
[Storage]
Shading, sealed and stored in a dry place.
[Packaging]
(1) Blister Packing, 6 / plate; composite bag, 5 boards / bag; carton packaging, 2 bags / boxes.
(2) blister packaging, 6 / plate; composite bag, 5 boards / bag; carton, 3 bags / boxes.
[Validity]
24 months.
[Executive standard]
"Chinese Pharmacopoeia" 2010 edition Third Supplement
【Approval Number】
Zhunzi H20051903
【manufacturer】
Company Name: Shenyang Hongqi Pharmaceutical Co., Ltd.
Production Address: Shenyang Hunnan new network on the 6th Street Postcode: 110179
Phone Number: (024) 2,378,626,023,786,261
Fax: (024) 23786263

 

The above is for reference
If you have questions can contact the manufacturer