Approval date: November 22, 2010
Revision date: July 12, 2011
November 17, 2015
December 09, 2015
xxxx xx xx
Instructions for Metronidazole Tablets
Please read the instructions carefully and use under the guidance of a physician.
Use in food and feed processing is strictly prohibited
Warning.
Metronidazole has been shown to be carcinogenic in mice and rats (see Pharmacology and Toxicology). Unnecessary administration of this product should be avoided. This product should be used only for the treatment of approved indications.
Drug Name]
Generic name: Metronidazole Tablets
English name: Metronidazole Tablets
Hanyu Pinyin：Jiaxiaozuo Pian
Ingredients
The main ingredient of this product is metronidazole, whose chemical name is 2-methyl-5-nitroimidazole-1-ethanol.
Chemical structure formula.
Molecular formula: C6H9N3O3
Molecular weight: 171.16
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is used for the treatment and prevention of infections identified or suspected to be caused by anaerobic bacteria.
It has inhibitory activity against a variety of pathogenic microorganisms, especially Bacillus spp, Clostridium spp, Clostridium spp, fungal bacteria, Streptococcus spp, Streptococcus spp, anaerobic cocci and Gardnerella vaginalis.
It also has therapeutic effects against Trichomonas, ameba lysis, Giardia, colonic pouch ciliates, and guinea worm.
The indications for this product in adults and children are as follows.
1. Anaerobic bacterial infections
(1) To prevent postoperative anaerobic infections, especially those caused by Bacillus mimicus and Streptococcus anaerobicus.
(2) For the treatment of skin and soft tissue infections, bone and joint infections (as adjuvant therapy), endocarditis, sepsis, bacteremia, peritonitis, abdominal abscess, liver abscess, meningitis, brain abscess, necrotizing pneumonia, abscess chest, lung abscess, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, endometritis, myometritis, tubo-ovarian abscess, postoperative vaginal vault infections and postoperative wound infections where pathogenic anaerobic bacteria have been isolated or where combined anaerobic bacterial infections are highly suspected.
(3) Leg ulcers and pressure sores caused by anaerobic bacterial infections.
2. Trichomoniasis
(1) Trichomoniasis in women (trichomoniasis, urinary tract trichomoniasis, etc.) and genitourinary trichomoniasis in men .
(2) Treatment of asymptomatic sexual partners.
3. bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginitis or Gardnerella vaginitis)
4. Amebiasis
Treatment of all forms of amebiasis, including intestinal and parenteral amebiasis (e.g., amebic liver abscess, pleural amebiasis, etc.), as well as asymptomatic amebiasis.
5. Oral infections
(1) Ulcerative gingivitis.
(2) Odontogenic infections (e.g., acute pericoronitis and acute periapical inflammation).
6. Giardiasis, microcysticercosis, cutaneous leishmaniasis, and guinea worm infections.
To reduce the formation of resistant bacteria and to ensure the effectiveness of metronidazole tablets and other antibacterial drugs, metronidazole tablets should be used only for the treatment or prevention of infections that have been proven or strongly suspected to be caused by bacteria. Official guidelines should also be consulted for the appropriate use of antibacterial drugs.
Specification
0.2g
Dosage]
1. Anaerobic bacterial infections
(1) Prevention of postoperative anaerobic bacterial infections: mainly used in abdominal surgery and obstetrics and gynecology.
Adults: 400mg every 8 hours for 24 hours before surgery, followed by intravenous or rectal administration after surgery until the patient is able to take the tablets.
Children: children less than 12 years of age: single dose of 20-30 mg/kg 1-2 hours preoperatively.
Neonates of gestational age <40 weeks: preoperative single dose at 10 mg/kg.
(2) Treatment of anaerobic bacterial infections
The treatment course is approximately 7 days, but it also depends on the severity of the patient’s condition according to clinical and bacteriological assessment.
Adults: Starting dose of 800 mg, followed by 400 mg every 8 hours.
Children: Children 8 weeks to 12 years of age: The usual daily dose is 20-30 mg/kg given as a single dose or divided into 7.5 mg/kg every 8 hours. the daily dose may be increased to 40 mg/kg depending on the severity of the infection. the duration of treatment is usually 7 days.
Children younger than 8 weeks: daily dose of 15 mg/kg given as a single dose or divided into 7.5 mg/kg every 12 hours. in neonates of gestational age <40 weeks, metronidazole may accumulate during the first week of life, so it is best to monitor serum metronidazole concentrations after a few days of treatment.
(3) Leg ulcers and pressure sores
Adults or children older than 10 years: 400 mg 3 times daily for 7 days.
2. Trichomoniasis
Dosage by metronidazole or metronidazole equivalent: Duration of administration (days) Adults or children >10 years of age Urogenital trichomoniasis in children 1-10 years of age
The likelihood of reinfection is high, and in adults, the spouse should receive similar treatment at the same time.7
or
5-72000 mg single oral dose or 200 mg 3 times daily
or
400mg twice daily 40mg/kg single oral dose or 15-30mg/kg/day in 2-3 doses, each dose should not exceed 2000mg3. Bacterial vaginosis
Duration of administration (days) Bacterial vaginosis in adults or children >10 years of age 5-7 or 400mg twice daily 12,000mg single oral dose 4. Amoebiasis
Dosing by metronidazole or metronidazole equivalents: Duration of administration (days) Adults or children >10 years Children 7-10 years 3-7 years 1-3 years (a) Invasive intestinal disease in susceptible population 5800mg 3 times daily 400mg 3 times daily 200mg 4 times daily 200mg 3 times daily (b) Intestinal disease and chronic amebic hepatitis in non-susceptible population 5- 10400mg daily 3 times 200mg daily 3 times 100mg daily 4 times 100mg daily 3 times (c) amebic liver abscess and other forms of extraintestinal amebiasis 5400mg daily 3 times 200mg daily 3 times 100mg daily 4 times 100mg daily 3 times (d) asymptomatic amebiasis 5-10400-800mg daily 3 times 200- 400mg 3 times a day 100-200mg 4 times a day 100-200mg 3 times a day or, dose according to body weight
35-50mg/kg/day in 3 doses for 5-10 days, daily dose should not exceed 2400mg 5. Oral Infections
Dose according to metronidazole or metronidazole equivalent: Duration of administration (days) Adults or children >10 years Children 7-10 years 3-7 years 1-3 years Ulcerative gingivitis 3200mg 3 times daily 100mg 3 times daily 100mg 2 times daily 50mg 3 times daily Odontogenic infections 3-7200mg 3 times daily 6. Giardiasis, microcysticercosis, cutaneous leishmaniasis and dracunculiasis nematode infections, etc.
Dosage by metronidazole or metronidazole equivalent: Duration of administration (days) Adults or children >10 years Children 7-10 years 3-7 years 1-3 years Giardiasis 32,000mg once daily or 1,000mg once daily 600-800mg once daily 500mg once daily 5,400mg 3 times daily or 7-10,500mg twice daily Or, by body weight Calculate the dose of medication (mg/kg).
15-40mg/kg/day in 2-3 doses according to metronidazole or metronidazole equivalent: Adult children with microcysticercosis 200mg twice daily for a course of 5 days 15-25mg/kg by body weight daily in 3 doses for 10 days. Dracunculiasis 200mg 3 times daily for 7 days Skin leishmaniasis 200mg 4 times daily for 10 days. Repeat a course of treatment after 10 days interval. For protozoa and other infections.
Infants and children weighing less than 10 kg should be given a proportionally lower dose.
Geriatric patients: Metronidazole is well tolerated in the elderly, but a pharmacokinetic study suggests that high doses should be used with caution in elderly patients.
Eradication of H. pylori in pediatric patients.
As part of combination therapy, 20 mg/kg/day, not to exceed 500 mg/twice daily for 7-14 days. Official guidelines should be consulted before starting treatment.
[Adverse reactions].
The following definitions were used for the frequency of the following adverse events.
Very common (≥1/10); Common (≥1/100~<1/10); Uncommon (≥1/1000~<1/100); Rare (≥1/10,000~<1/1000); Very rare (<1/10,000), Unknown (cannot be estimated from available data).
Serious adverse reactions are rare under the recommended standard regimen. Clinicians considering ongoing treatment for remission of chronic disease and treatment duration beyond the recommended duration are advised to consider the benefit of treatment and the risk of peripheral neuropathy.
Hematologic and lymphatic disorders.
Very rare: Granulocytopenia, thrombocytopenia, neutropenia, and allohemocytopenia.
Unknown: leukopenia.
Immune system disorders.
Rare: allergic reactions.
Unknown: angioedema, urticaria, fever.
Metabolic and nutritional disorders.
Unknown: anorexia nervosa.
Psychiatric disorders.
Very rare: Psychiatric disorders, including confusion and hallucinations.
Unknown: Depressed mood.
Neurological disorders.
Very rare.
-Encephalopathy (e.g., confusion, fever, headache, hallucinations, paresis, photosensitivity, visual and motor disturbances, neck stiffness) and subacute cerebellar syndromes (e.g., ataxia, dysarthria, gait disturbances, nystagmus, and tremor) may subside after discontinuation of medication.
-Drowsiness, dizziness, twitching, headache.
Unknowns.
-Peripheral sensory neuropathy or transient epileptiform seizures have been reported during intensive or extended metronidazole therapy. In most cases, neuropathy disappears after discontinuation of treatment or dose reduction.
-Aseptic meningitis
Eye disorders.
Very rare: Visual disturbances, such as diplopia and myopia, are transient in most cases.
Unknown: optic neuropathy/neuritis.
Ear and vagal disorders.
Unknown: Hearing impairment/hearing loss (including sensory nerves), tinnitus.
Gastrointestinal disorders.
Unknown: taste disturbances, oral mucositis, tongue changes, nausea, vomiting, gastrointestinal disturbances (e.g., epigastric pain and diarrhea).
Hepatobiliary disorders.
Very rare.
-increased liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis, reversible after discontinuation of the drug.
-Patients treated with metronidazole in combination with other antibiotics have reported cases of liver failure requiring liver transplantation.
Skin and subcutaneous tissue disorders.
Very rare: rash, impetigo, acute generalized eruptive pustulosis, pruritus, flushing.
Unknown: erythema multiforme, Stevens-Johnson syndrome or toxic epidermolysis bullosa, fixed drug rash
Musculoskeletal, connective tissue and skeletal disorders.
Very rare: myalgia, arthralgia.
Renal and urinary disorders.
Very rare: darkening of the urine (due to metronidazole metabolites)
[Contraindications
1.Allergic reactions
Patients with known hypersensitivity to nitroimidazole, metronidazole or any of the excipient components are prohibited.
2.Early pregnancy
In patients with trichomoniasis, this product is prohibited in the first trimester of pregnancy.
3.Psychotic reactions with disulfiram
Psychotic reactions in alcoholic patients have been associated with concomitant use of disulfiram with oral metronidazole.
Do not use metronidazole in patients who have taken disulfiram within the last two weeks.
4. Interaction with alcohol
Disulfiram-like reactions to alcohol associated with oral metronidazole include abdominal cramps, nausea, vomiting, headache, and flushing. Do not drink alcohol or products containing propylene glycol within three days of discontinuing metronidazole.
[Caution].
Warning.
1. Effects on the central and peripheral nervous system
Encephalopathy and peripheral neuropathy: Cases of metronidazole causing encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported.
Encephalopathy has been reported to be associated with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are usually reversible within a few days to a few weeks after discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.
Peripheral neuropathy, primarily of the sensory type, has been reported and is characterized by numbness or abnormal sensation in the limbs.
Convulsive seizures have been reported in patients treated with metronidazole.
Aseptic meningitis: Cases of aseptic meningitis associated with metronidazole have been reported. Symptoms occur within hours of administration and usually subside after discontinuation of metronidazole therapy.
The presence of abnormal neurologic signs and symptoms requires prompt evaluation of the benefit to risk ratio of continued therapy.
Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of deterioration in neurologic function.
2. Risk of hepatotoxicity and death in patients with Cockayne’s syndrome
Cases of severe hepatotoxicity/acute liver failure have been reported with systemic use of products containing metronidazole, including cases with rapid onset of fatal outcome after initiation of treatment in patients with Cockayne’s syndrome.
Cases of hepatotoxicity and risk of death in patients with Cockayne’s syndrome with severe hepatotoxicity/acute liver failure, including cases with systemic treatment with metronidazole-containing products with rapid onset and fatal outcome after initiation of treatment in patients with Cockayne’s syndrome. In this population, metronidazole should be used after a careful benefit-risk assessment and only in the absence of alternative therapies. Perform liver function tests before or within the first 2-3 days after the start of therapy or frequently during and after the end of therapy. If abnormal liver function tests occur, discontinue metronidazole and monitor liver function until it returns to baseline values.
Advise patients with Cockayne’s syndrome to discontinue metronidazole immediately and contact medical personnel if they develop any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color, or jaundice.
General Precautions.
1. Metronidazole has been reported to cause severe herpetic skin reactions such as Stevens-Johnson syndrome (SJS), toxic necrolytic epidermolysis bullosa (TEN), or acute generalized eruptive pustulosis (AGEP). If signs or symptoms of SJS, TEN or AGEP develop, treatment with this product must be terminated immediately.
2. Hepatic impairment: Metronidazole is metabolized slowly in patients with hepatic impairment, leading to accumulation of metronidazole in plasma. For patients with severe hepatic insufficiency (Child-Pugh C), dose reduction of this product is recommended. For patients with mild to moderate hepatic impairment, no dose adjustment is required, but these patients should be monitored for adverse events associated with metronidazole.
3. Renal impairment: Patients with end-stage renal disease can slowly excrete metronidazole and metabolites through the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole-related adverse events is recommended.
4, Dichotomous fungal infections: Candidiasis known or previously unrecognized may present more prominent symptoms during treatment with this product and require administration of treatment directed against Candida.
5. For patients with blood disorders: Metronidazole is a nitroimidazole and should be used with caution in patients with a history of adverse blood symptoms or disease. Mild leukopenia has been observed during administration; however, no persistent hematologic abnormalities due to metronidazole have been observed in clinical studies. Observation of leukocyte count and leukocyte sorting count before and after treatment is recommended.
6. Metronidazole and its metabolites can be effectively removed after an 8-hour dialysis procedure in patients receiving hemodialysis. Therefore metronidazole should be reintroduced immediately after hemodialysis.
7. Patients with renal failure receiving intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD) do not need to adjust the regular dose of metronidazole.
8. Routine clinical and laboratory monitoring (especially white blood cell counts) is necessary if the product is used for more than 10 days, and patients should be monitored for adverse effects such as peripheral or central nervous system lesions (e.g., abnormal sensation, ataxia, dizziness, convulsive seizures).
9. This product should be taken after discontinuing alcoholic beverages or products containing propylene glycol for at least three days, otherwise abdominal cramps, nausea, vomiting, headache and facial flushing may occur.
10. Patients should be informed that this product should only be used to treat bacterial and parasitic infections. This product does not treat viral infections (such as the common cold) and has no direct activity against aerobic or parthenogenic anaerobic bacteria. When this product is used to treat bacterial infections, patients should be told that they should take the drug as directed and on time, even though they may feel better early in the course of treatment. Missing a dose or not completing the entire course of treatment may (1) reduce the effectiveness of immediate treatment and (2) increase the likelihood that the bacteria will become resistant and may not be treated with this product in the future.
11. In the case of unproven or strongly suspected bacterial or parasitic infections or prophylactic indications, this product is unlikely to provide benefit to the patient and may increase the risk of development of resistant bacteria and parasites.
12. It is possible that gonococcal infections may persist after Trichomonas vaginalis has been eliminated.
13. Patients need to be warned that metronidazole may darken urine.
14. Effects on the ability to drive and operate machinery: Patients should be warned of the potential effects, including dizziness, drowsiness, hallucinations, convulsions or confusion, transient visual disturbances, and are advised not to drive or operate machinery if these symptoms occur.
[For Pregnant and Lactating Women].
Pregnancy.
There have been no adequate and validated controlled studies of metronidazole in pregnant women. Published data from case-control studies, cohort studies, and 2 Meta-analyses included more than 5,000 pregnant women who used metronidazole during pregnancy. Many of the studies included early pregnancy exposure. One study showed an increased risk of cleft lip with or without cleft palate in infants exposed to metronidazole in utero. However, these findings were not confirmed. In addition, more than 10 randomized, placebo-controlled clinical trials enrolled more than 5,000 pregnant women to evaluate the effect of using antibiotics, including metronidazole, for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk of congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies designed to assess metronidazole exposure during pregnancy did not show an increased risk of cancer in infants; however, the ability of these studies to serve as a signal for detection is limited.
The effects of metronidazole crossing the placental barrier and on human fetal organs are unknown. Regeneration studies have been conducted in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There is no evidence that metronidazole is harmful to the fetus.
Lactating Women
Metronidazole is present in human milk at serum concentrations similar to those of the mother and at levels close to or comparable to infant serum levels for treatment. Because metronidazole may be tumorigenic in mouse and rat studies, the importance of the drug to the mother should be considered in deciding whether to discontinue breastfeeding or discontinue the drug. On the other hand, breastfeeding women may choose to pump human milk and discard it during metronidazole treatment and give the infant stored human milk or formula 24 hours after treatment ends.
[For children].
Children should be used under the supervision of a physician.
[Geriatric use].
In elderly patients, monitoring for metronidazole-related adverse events is recommended. Decreased hepatic function in elderly patients may result in increased metronidazole concentrations and may require adjustment of metronidazole dosage.
Drug Interactions]
1.Tyromycin
Combination with hygromycin may interfere with the effect of metronidazole in removing Trichomonas vaginalis.
2. Disulfiram
Psychiatric symptoms have been reported in alcoholic patients who have taken both metronidazole and disulfiram. Patients who have taken disulfiram within the last two weeks should avoid metronidazole.
3. Alcoholic beverages
Abdominal cramps, nausea, vomiting, headache, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or after discontinuation of metronidazole treatment.
4. Warfarin and other oral anticoagulants
Metronidazole has been reported to enhance the anticoagulant effect of warfarin and other oral coumarin anticoagulants, leading to prolongation of prothrombin time. When this product is used in patients on such anticoagulant therapy, prothrombin time and INR should be closely monitored.
5. Lithium
In patients receiving high doses of lithium therapy, short-term application of metronidazole can cause a rise in serum lithium, with some cases showing signs of lithium toxicity. Serum lithium and serum creatinine levels need to be measured a few days after metronidazole treatment to monitor possible elevated serum lithium concentrations prior to the appearance of clinical signs of lithium toxicity.
6. Bacitracin
Metronidazole has been reported to increase plasma concentrations of leucovorin, leading to an increased risk of severe leucovorin toxicity. Metronidazole should not be administered with leucovorin unless the benefits outweigh the risks. If no therapeutic alternative to metronidazole is available and concomitant administration with leucovorin is medically necessary, close monitoring of leucovorin plasma concentrations should be performed and the leucovorin dose should be adjusted accordingly.
7. 5-Fluorouracil
Metronidazole decreases the clearance of 5-fluorouracil and therefore leads to increased toxicity of 5-fluorouracil.
8.Cyclosporine
Patients are at risk of elevated cyclosporine blood levels when receiving cyclosporine therapy. Close monitoring of serum creatinine and serum cyclosporine is necessary when combined.
9. Drugs that inhibit CYP 450 enzyme
Concomitant application of drugs that reduce hepatic microsomal enzymes, such as cimetidine, may prolong the half-life of metronidazole and reduce plasma clearance.
10.Drugs that induce CYP 450 enzyme
Concomitant application of drugs that induce hepatic microsomal enzymes, such as phenytoin or phenobarbital, may accelerate the clearance of metronidazole, leading to a decrease in its blood concentration. Some reports suggest that metronidazole attenuates the clearance of phenytoin.
11. Drug/laboratory test interactions
Metronidazole can affect the determination of certain blood biochemical values, such as aspartate aminotransferase (AST, SGOT glutamate aminotransferase), alanine aminotransferase (ALT, SGPT glutamate aminotransferase), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose, which can result in a value of 0. All of the affected assays are associated with enzymatic coupling during coenzyme redox (NAD+
⇋ NADH). The influencing factor was due to the similarity of the peak absorption of reduced nicotinamide dinucleotide (340 nm) and metronidazole (322 nm) at pH 7.
[Drug overdose].
Single oral doses of metronidazole up to 15 g have been reported in cases of suicide attempts or accidental overdose. Reported symptoms include nausea, vomiting, ataxia, and mild disorientation. Oral metronidazole has been studied as a sensitizer for radiotherapy treatment of malignancies. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of administration at doses of 6 to 10.4 g every other day.
Management and treatment of drug overdose: There is no specific antidote for metronidazole overdose; therefore, patient management measures should include symptomatic treatment and supportive therapy.
Pharmacology and Toxicology
Pharmacological effects
Mechanism of action
Metronidazole is a nitroimidazole derivative that exerts antibacterial effects against most of the specialized anaerobic bacteria in an anaerobic environment. When metronidazole enters the organism by passive diffusion and is activated in the cytoplasm of sensitive anaerobic bacteria, metronidazole is reduced; this process involves the transfer of electrons from intracellular electron transfer proteins (e.g., iron oxygen reduction proteins) to the nitro group of metronidazole and the formation of transient nitrosyl radicals. As a result of this alteration of the metronidazole molecule, a concentration gradient is generated and maintained, thus promoting the endocytosis of the drug. The reduced form of metronidazole and free radicals can interact with DNA and inhibit DNA synthesis and DNA degradation, leading to bacterial death. The exact mechanism of action of metronidazole is not known.
Drug resistance
There is potential for the development of resistance to metronidazole.
Resistance may be due to multiple mechanisms, including reduced drug uptake, altered reduction efficiency, overexpression of efflux pumps, drug inactivation, and/or enhanced DNA damage repair.
Metronidazole does not have any clinically relevant activity against parthenogenic anaerobes or exclusively aerobic bacteria.
Activity in vitro and in clinical infections
In in vitro tests and in clinical infections as described in [indication], metronidazole showed antibacterial activity against most strains of the following bacteria
Gram-positive anaerobic bacteria
Clostridium spp.
Fungi spp.
Digestive cocci spp.
Streptococcus digestiveis spp.
Gram-negative anaerobic bacteria
Bacteroides fragilis group (Bacteroides fragilis, Bacteroides gigas, Bacteroides ovale, Bacteroides polymorphicus, Bacteroides vulgaris)
Clostridium spp.
Protozoan parasites
Amoebas in lysate tissues
Trichomonas vaginalis
The following in vitro test data have been obtained, but their clinical significance is unknown.
In vitro minimum inhibitory concentrations (MICs) of ≤8 μg/mL have been obtained for metronidazole against most strains (≥90%) of the following bacteria, but the safety and efficacy of metronidazole in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials
Gram-negative anaerobic bacteria
Bacteroides fragilis group (Faecalibacterium, Monomorphobacterium)
Prevotella spp. (Prevotella diropora, Prevotella buccalis, Prevotella desaccharolyticum)
Drug sensitivity testing.
Whenever possible, clinical microbiology laboratories should regularly report and provide physicians with the results of relevant in vitro drug sensitivity tests for antimicrobial drugs used in their hospitals that reflect the drug sensitivity characteristics of hospital- and community-acquired pathogens. These reports may assist physicians in the selection of antimicrobial drugs for treatment.
For anaerobic bacteria.
A quantitative method is used to determine the minimum inhibitory concentration (MIC), and these MIC values can be used to assess the susceptibility of bacteria to antimicrobial drugs. For anaerobic bacteria, the susceptibility of metronidazole can be determined by standard broth and/or agar methods. MIC values should be interpreted according to the criteria provided in the table below.
Criteria for the interpretation of the sensitivity test of metronidazole against anaerobic bacteria*†
MIC (g/mL) determination ≤ 8 Sensitive (S) 16 Intermediary (I) ≥ 32 Resistant (R) * Agar dilution method is applicable to all anaerobic bacteria
†Broth dilution is recommended for the Bacteroides fragilis group only; for this group, MIC values measured by agar and broth dilution are considered equal. A report of “intermediate” (I) indicates that the drug is likely to treat infections caused by isolates appropriately when administered at body sites where the drug is physiologically aggregated or at high doses. A report of “resistant” (R) indicates that the antimicrobial drug is likely to fail to inhibit the growth of the pathogen if it is administered at concentrations normally achievable at the site of infection; other treatment options should be used in this case.
Quality control
Standardized susceptibility testing methods require the use of laboratory controls to monitor and ensure the accuracy and precision of the test specimens and reagents used for the test as well as the skill of the test personnel. Metronidazole standards should provide the range of MIC values indicated in the table below.
Acceptable quality control ranges for inhibition of anaerobic bacteria by metronidazole
Quality Control Strain Minimum Inhibitory Concentration (g/mL) Agar Method Broth Method Bacteroides fragilis ATCC 252850.25-1.00.25-2.0 Bacteroides polymorphicus ATCC 297410.5-2.00.5-4.0 Clostridium difficile ATCC 7000570.125-0.5-late Eggerts ATCC 43055-0.125-0.5 For protozoan parasites.
There are no standardized test methods available for clinical microbiology laboratories.
Toxicological studies
Genotoxicity: Metronidazole has shown mutagenic activity in in vitro test systems, including the Ames test. No potential genetic damage was seen in mammalian in vivo tests.
Reproductive toxicity: At doses up to 400 mg/kg/day (similar to the maximum recommended clinical dose in terms of body surface area) administered for 28 days, no adverse effects on fertility or testicular function were observed in male rats. However, rats administered the same dose for 6 months or longer showed sterility, severe degeneration of the testicular spermatogenic epithelium, and a significant decrease in testicular sperm cell count and epididymal sperm count. Most rats regained fertility after an 8-week recovery period from drug withdrawal.
Results of reproductive toxicity tests in rats, rabbits and mice showed no damage to fetuses from metronidazole at doses similar to the maximum recommended human dose (in terms of body surface area).
Carcinogenicity: Metronidazole was detected in several rat and mouse tests affecting tumors in liver, lung, mammary gland and lymphoid tissue, but not in hamsters.
Pulmonary tumors were observed in all six mouse tests, including an intermittent dosing test with dosing every four weeks. Malignant liver tumors were increased in male mice at a dose of approximately 1500 mg/m2 (similar to the clinically recommended maximum daily dose in terms of body surface area). Malignant lymphomas and lung tumors were also increased in mice given ad libitum throughout their lives. Mammary and hepatic tumors were increased in female rats given metronidazole orally compared to concurrent controls. Both hamster lifetime tumorigenicity tests were negative.
[Pharmacokinetics].
Absorption
The in vivo distribution of metronidazole is similar when administered orally or intravenously. Metronidazole is well absorbed after oral administration, with peak blood concentrations occurring 1 to 2 hours after administration.
The blood concentration of metronidazole was linear with the administered dose. Peak plasma concentrations were 6 μg/ml, 12 μg/ml, and 40 μg/ml after oral administration of 250 mg, 500 mg, and 2000 mg, respectively. studies showed that bioavailability did not differ significantly between males and females; plasma concentration levels were generally lower in males due to differences in body weight.
Distribution
The major component of plasma is metronidazole, with small amounts of metabolites also present. Less than 20% of circulating metronidazole is bound to plasma proteins. Metronidazole is distributed in cerebrospinal fluid, saliva, and breast milk at concentrations similar to those in plasma. Bactericidal concentrations of metronidazole have also been detected in the pus of liver abscesses.
Metabolism/excretion
Metronidazole and its metabolites are eliminated primarily in the urine (60% to 80% of the dose), with excretion in the feces accounting for 6% to 15% of the dose. The metabolites present in urine are mainly oxidized side chains [1-(β-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-acetic acid] and glucuronide conjugates, with metronidazole prototypes accounting for about 20% of the total drug in urine. Both the parent compound and the hydroxyl metabolite had in vitro antibacterial activity.
The renal clearance of metronidazole was approximately 10 ml/min/1.73 m2. the mean elimination half-life of metronidazole in healthy subjects was 8 h.
Renal impairment
Decreased renal function does not alter the pharmacokinetics of a single dose of metronidazole.
Compared to healthy subjects with normal renal function (CLCR = 126 ± 6 ml/min), the pharmacokinetics of metronidazole did not change significantly with a single intravenous dose of metronidazole 500 mg in patients with end-stage renal disease (ESRD; CLCR = 8.1 ± 9.1 ml/min), but the peak concentrations of hydroxymetronidazole and metronidazole acetate were 2-fold and 5-fold higher, respectively. Therefore, considering the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole-related adverse events is recommended.
Effect of dialysis
The clearance of metronidazole in ESRD patients receiving hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) was studied after a single intravenous infusion or oral dose of metronidazole 500 mg. The clearance for hemodialysis lasting 4 to 8 hours was 40% to 65% of the metronidazole dose, depending on the type of dialysis membrane used and the duration of the dialysis procedure. If metronidazole administration cannot be separated from the dialysis process, a supplemental dose of metronidazole should be considered after hemodialysis. The clearance of 7.5 hours of peritoneal dialysis is approximately 10% of the metronidazole dose. Patients with ESRD receiving peritoneal dialysis do not require dose adjustment of metronidazole.
Hepatic impairment
Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 for metronidazole was 114% higher in patients with severe hepatic impairment (Child Pugh C) and 54% and 53% higher in patients with mild hepatic impairment (Child Pugh A) and moderate hepatic impairment (Child Pugh B), respectively, compared to the healthy control subject group. In these patients with hepatic impairment, there was no significant change in AUC24 for hydroxymetronidazole. The recommended dose for patients with severe hepatic impairment (Child Pugh C) is 50% of the normal dose (see Dosage and Administration). No dose adjustment is required in patients with mild to moderate hepatic impairment. Adverse events associated with metronidazole should be monitored in patients with mild to moderate hepatic impairment.
Geriatric Patients
After a single oral or intravenous dose of 500 mg metronidazole, the mean AUC of hydroxymetronidazole (active metabolite) was 40% to 80% higher and the mean AUC of metronidazole (parent compound) was not significantly increased in subjects aged >70 years without significant renal or hepatic abnormalities compared with <40 years in healthy controls. In elderly patients, monitoring for metronidazole-related adverse events is recommended.
Pediatric patients
In one study, neonates exhibited lower elimination capacity. The elimination half-life in the first three days of life was negatively correlated with gestational age. In infants with a gestational age of 28 to 40 weeks, the corresponding elimination half-life was 109 to 22.5 hours.
Storage】Store under shade and seal.
Package】Aluminium-plastic blister package (polyvinyl chloride/polyvinylidene chloride solid pharmaceutical composite rigid tablets and aluminum foil for pharmaceutical packaging); 10 tablets/plate×2 plates/box.
Expiration date】24 months
Execution Standard
Approval number】State Drug Administration H42022087
[Drug Marketing Licensee
Company name: Yichang Renfu Pharmaceutical Co.
Registered address: No. 19 Dalian Road, Yichang Development Zone, Hubei Province
Postal Code: 443005
Manufacturer
Enterprise name: Yichang Renfu Pharmaceutical Co.
Production Address: No. 99, Mingfeng Avenue, Yuanan County, Hubei Province
Postal Code: 444299
Telephone number: 0717-6345005
0717-6345020 (sales)
0717-6343387（Quality)
Fax number: 0717-6345002
Web
Address: http://www.ycrenfu.com.cn
If you have questions, you can contact directly with the drug marketing license holder, the manufacturer.