Date of approval.
Date of revision.
Compound Sulfamethoxazole Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Compound Sulfamethoxazole Tablets
English name: Compound Sulfamethoxazole Tablets
Hanyu Pinyin: Fufang Huang′ anJia′ ezuo Pian
Ingredients
This product is a compound preparation, the components of which are 0.4g of sulfamethoxazole and 80mg of meperidine per tablet.
Chemical name: Sulfamethoxazole: N-(5-methyl-3-isoxazolyl)-4-aminobenzenesulfonamide
Methicillin: 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine
Chemical structure formula: sulfamethoxazole.
Methoxazole.
Molecular formula: sulfamethoxazole: C10H11N3O3S; methicillin: C14H18N4O3
Molecular weight: Sulfamethoxazole: 253.28; Methicillin: 290.32
Properties
This product is a white tablet.
Indications
In order to reduce the production of drug-resistant bacteria and to maintain the effectiveness of this product and other antibacterial drugs, it is recommended that this product be used only for the prevention or treatment of infections caused by sensitive strains of bacteria. Antibiotic treatment should refer to the results of bacterial culture and drug sensitivity tests. In the absence of such results, empirical treatment may be combined with local epidemiology and bacterial resistance profiles.
1. urinary tract infections due to sensitive strains of Escherichia coli, Klebsiella spp, Enterobacter spp, Aspergillus chimaera, Proteus mirabilis and Morganella spp.
2. Acute otitis media in pediatric patients over 2 years of age due to Streptococcus pneumoniae or Haemophilus influenzae. Prophylaxis or prolonged treatment is not recommended in patients with otitis media of any age.
3. Intestinal infections, Shigella infections caused by sensitive strains of Shigella fowleri or Shigella sonnei.
4. Acute episodes of chronic bronchitis in adults due to Streptococcus pneumoniae or Haemophilus influenzae.
5. Pneumocystis jiroveci pneumonia: Can be used for the treatment of Pneumocystis jiroveci pneumonia and for prophylaxis in immunocompromised and high-risk patients with Pneumocystis jiroveci pneumonia.
6. Diarrhea in adult travelers: Treatment of diarrhea due to sensitive strains of enterotoxigenic Escherichia coli.
【Specifications】.
Sulfamethoxazole 0.4g, Methotrexate 80mg
Dosage】
Urinary tract infections and shigellosis in adult and pediatric patients, acute otitis media in children.
Adults: The usual dose for the treatment of urinary tract infection is 2 tablets once every 12 hours for 10-14 days. For the treatment of shigellosis, the dose is the same as before for 5 days.
Children: Contraindicated in infants under 2 months of age.
The dose for pediatric patients weighing ≥ 40 kg is 40 mg/kg sulfamethoxazole and 8 mg/kg methotrexate every 24 hours divided into doses every 12 hours for 10 days. The daily dose for the treatment of shigellosis is the same as before for 5 days.
Recommended dose for children aged 2 months and above
Body weight (kg) Dose per 12 hours (tablets) 10 -20 130 1½40 2 Patients with impaired renal function In case of impaired renal function, the following table should be used:
Creatinine clearance (mL/min) Recommended dose over 30 usual standard regimen 15-30 ½ usual regimen less than 15 not recommended for adults with acute exacerbation of chronic bronchitis:
The recommended adult dose is two cotrimoxazole tablets at 12-hour intervals for 14 days.
Yersinia pestis pneumonia.
Treatment of adults and children.
For the treatment of Yersinia pneumonia a single dose of methotrexate 3.75-5 mg/kg and sulfamethoxazole 18.75-25 mg/kg every 6 hours for 14-21 days.
The following table shows the maximum single dose reference::
Body weight (kg) Dose per six hours (tablets) 8 -16 124 1½32 2 40 2½48 3 64 4 80 5 The lowest dose (75 mg/kg sulfamethoxazole and 15 mg/kg meperidine given every 24 hours) is 75% of the dose in the table above.
Prophylaxis The recommended dose for prophylaxis in adults is two tablets of compounded sulfamethoxazole daily.
Adult traveler’s diarrhea
The usual adult dosage is two cotrimoxazole tablets every 12 hours for 5 days.
[Adverse Reactions].
The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, anorexia) and skin allergic reactions (e.g., rash and hives). Serious adverse reactions to this product are rare, but there have been cases of serious adverse reactions resulting in death, including Stevens-Johnson syndrome, toxic epidermolysis bullosa, fulminant hepatic failure, granulocyte deficiency, aplastic anemia, and other blood disorders. (See [Caution]).
Hematologic: Granulocyte deficiency, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.
Allergic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis relaxation, anaphylaxis, anaphylactic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, anaphylactic purpura, serum sickness-like syndrome, systemic allergic reactions, systemic rash, photosensitivity, conjunctival and scleral congestion, pruritus, urticaria, rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.
Gastrointestinal: hepatitis (including cholestatic jaundice and hepatic necrosis), elevated serum transaminases and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, tongue inflammation, nausea, vomiting, abdominal pain, diarrhea, and anorexia.
Genitourinary: renal failure, interstitial nephritis, elevated blood urea nitrogen and serum creatinine, toxic nephropathy with oliguria and anuria, crystalluria and nephrotoxicity associated with cyclosporine.
Metabolic and nutritional: hyperkalemia, hyponatremia (see [Precautions] Electrolyte Abnormalities).
Neurologic: aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.
Psychiatric system: hallucinations, depression, apathy, nervousness.
Endocrine: sulfonamides have some chemical similarity to certain thyroid hormones, diuretics (acetazolamide and thiazides), and oral hypoglycemic agents. There may be cross-sensitivity to these drugs. Polyuria and hypoglycemia rarely occur in patients taking sulfonamides.
Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported in association with the administration of cotrimoxazole sulfamethoxazole, primarily in patients with AIDS.
Respiratory: cough, shortness of breath, and pulmonary infiltrates (see [Precautions]).
Other: weakness, fatigue, insomnia.
Post-marketing status
The following adverse reactions were identified during the approval of methotrexate-sulfamethoxazole. Because the number of people reporting these adverse reactions is unclear, it is not possible to calculate their incidence and whether they are drug-related.
Thrombotic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura
QT prolongation leading to ventricular tachycardia and tip-twisting ventricular tachycardia
Contraindicated]
Contraindicated in patients with hypersensitivity to methotrexate or sulfonamides
Contraindicated in patients with previous thrombocytopenia caused by methotrexate and/or sulfonamides
Contraindicated in patients with megaloblastic anemia due to folic acid deficiency.
Contraindicated in infants under 2 months of age.
Contraindicated in patients with severe hepatic injury.
Contraindicated in patients with severe renal insufficiency when changes in renal function cannot be monitored.
Precautions]
Drug-resistant bacteria production
It is unlikely to be beneficial and increases the risk of bacterial resistance in patients without a definite diagnosis, no suspected infection with a sensitive strain, and no indication for prophylactic dosing.
Folic acid deficiency
In patients with impaired renal or hepatic function, patients with possible folate deficiency (e.g., elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, patients with malnutrition), and patients with severe allergies or bronchial asthma.
Hematologic changes in folic acid deficiency may occur in elderly patients or in patients with pre-existing folic acid deficiency or renal failure. With folic acid treatment, these effects are reversible.
Hemolysis
Hemolysis may occur in individuals with glucose-6-phosphate dehydrogenase deficiency. This reaction is often dose dependent (see [DOSAGE]).
Hypoglycemia
Hypoglycemia in non-diabetic patients taking this product is rare and usually occurs after a few days of treatment. It is particularly common in patients with renal dysfunction, hepatic disease, malnutrition, or those receiving high doses of compounded sulfamethoxazole.
Phenylalanine metabolism
Methotrexate can affect phenylalanine metabolism, but has no effect on patients with phenylketonuria who are on a reasonably restricted diet.
Porphyria and hypothyroidism
As with other sulfonamides, caution is required for use in patients with porphyria or thyroid dysfunction.
Prevention and treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome (AIDS)
Patients with AIDS do not tolerate and respond to cotrimoxazole to the same extent as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia, and elevated transaminases, was significantly higher in AIDS patients being treated with cotrimoxazole for Pneumocystis carinii pneumonia compared to non-AIDS patients. Side effects are usually less severe in patients who have compounded sulfamethoxazole for prophylaxis. However, if a patient develops a rash or any signs of an adverse reaction, cotrimoxazole treatment should be re-evaluated. Coadministration of formyl tetrahydrofolate should be avoided in the treatment of Pneumocystis jiroveci pneumonia.
Electrolyte abnormalities
High doses of methotrexate, as used in patients with Pneumocystis jiroveci pneumonia, result in gradual but reversible increases in blood potassium concentrations in a large number of patients. When meperidine is used for disorders of potassium metabolism, renal insufficiency, or in combination with drugs that can trigger hyperkalemia, even the recommended doses may cause hyperkalemia. Close monitoring of blood potassium is required in these patients.
Patients treated with compounded sulfamethoxazole may develop severe symptomatic hyponatremia, particularly for the treatment of Yersinia pneumonia. Evaluation and correction of hyponatremia in symptomatic patients is necessary to prevent the development of life-threatening complications.
During treatment, adequate fluid intake and urine output should be ensured to prevent crystalluria.” Patients with “slow acetylation” may be more likely to have an idiosyncratic response to sulfonamides.
Embryotoxicity
Several epidemiologic studies suggest that exposure to sulfamethoxazole/methoprene during pregnancy may increase the risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and deformed feet. If sulfamethoxazole/methoprene is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazards to the fetus.
Allergic and other fatal reactions
Deaths associated with the use of sulfonamides are rare due to severe reactions, including Stevens-Johnson syndrome, toxic epidermolysis bullosa, fulminant hepatic failure, granulocyte deficiency, aplastic anemia, and other blood abnormalities.
Sulfonamides, including sulfonamide products such as sulfamethoxazole/methoxazole, should be discontinued at the first sign of rash or any adverse reaction. In rare cases, a rash may be followed by more severe reactions such as Stevens-Johnson syndrome, toxic epidermolysis bullosa, hepatic necrosis, and severe blood disorders. Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice, may be early signs of a serious reaction.
Cough, shortness of breath and pulmonary infiltrates are respiratory allergic reactions associated with sulfonamide therapy.
Thrombocytopenia
Sulfamethoxazole/methotrexate induced thrombocytopenia may be an immune-mediated disorder. Life-threatening severe thrombocytopenia has been reported. Thrombocytopenia usually resolves within one week after discontinuation of sulfamethoxazole/methoxazole.
Streptococcal infections and rheumatic fever
This product should not be used for the treatment of group A beta-hemolytic streptococcal infections. It does not prevent sequelae such as rheumatic fever because streptococci are not easily cleared.
Clostridium perfringens-associated diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported in association with the use of almost all antimicrobial drugs, including cotrimoxazole, and ranges in severity from mild diarrhea to fatal colitis. Antimicrobial drug therapy alters the normal colonic flora, leading to Clostridium difficile overgrowth.
Toxins A and B produced by Clostridium contribute to the development of CDAD. Highly virulent strains produced by Clostridium can lead to increased morbidity and mortality because these infections may be difficult to treat antimicrobially and may require colectomy. CDAD must be considered in all patients who develop diarrhea after antibiotic administration. a detailed history is mandatory, as CDAD has been reported to occur more than two months after drug administration.
If CDAD is suspected or confirmed, ongoing antibiotic use against non-Clostridium perfringens may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, Clostridium difficile antibiotic therapy, and surgical evaluation should be performed as clinically indicated.
Adjunctive treatment of Yersinia pneumonia with formyl tetrahydrofolate
Treatment failure and excess mortality were observed in a randomized placebo-controlled trial of methotrexate-sulfamethoxazole combined with tetrahydrofolic acid in HIV-positive patients with Pneumocystis carinii pneumonia. Concomitant administration of meperidine-sulfamethoxazole and tetrahydrofolate should be avoided in the treatment of Pneumocystis jirovecii pneumonia.
[For pregnant and lactating women].
Pregnancy.
Although there are no large controlled studies of sulfamethoxazole and methicillin in the pregnant women population, Brumfitt and Pursell reported the results of 186 pregnancies in a retrospective study in which mothers received either placebo or sulfamethoxazole and methicillin. The incidence of congenital malformations was 4.5% (3 of 66 cases) in the group receiving placebo and 3.3% (4 of 120 cases) in the group receiving sulfamethoxazole and methotrexate. None of the 10 infants of mothers who took the drug in early pregnancy had adverse effects. In another investigation, Brumfitt and Pursell also found no congenital anomalies in 35 children whose mothers were treated with oral sulfamethoxazole and methotrexate at the time of pregnancy or shortly thereafter.
Because sulfamethoxazole and meperidine may interfere with folic acid metabolism, compounded sulfamethoxazole should be used during pregnancy only if the potential benefit is compatible with the potential risk to the fetus.
Human data.
Although there are no large prospective, controlled studies in pregnant women and their infants, several retrospective epidemiologic studies suggest that early gestational exposure to sulfamethoxazole/methoxazole is associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular anomalies, urinary tract defects, oral clefts, and foot malformations. However, the significance of these studies is limited by the small number of cases and the lack of statistical comparisons with the limitation of confounding factors. And they are further limited by recall, selection and information bias, and the shortcomings of the generalizability of the study results. Finally, different outcome measures in different studies limit cross-sectional study comparisons. In addition, other epidemiological studies have not found a statistically significant correlation between sulfamethoxazole/methoprene exposure and specific malformations.
Nursing Mothers: The level of methomyl/sulfamethoxazole in breast milk is approximately 2 – 5% of the recommended daily dose for infants over two months of age. Caution should be exercised when administering cotrimoxazole to nursing women, especially when breastfeeding, jaundice, illness, stress, or preterm infants (because of the possible risk of jaundice and kernicterus).
[For Children].
This product may cause an increased risk of nuclear jaundice and is therefore contraindicated in infants under 2 months of age.
Geriatric use]
Clinical studies of cotrimoxazole sulfamethoxazole did not include a sufficient number of subjects aged 65 years and older to determine whether their reactions differed from those of younger subjects.
Elderly patients may be at increased risk for serious adverse reactions, especially when there are complications such as impaired renal and/or hepatic function, possible folate deficiency, or concomitant use of other medications. Severe skin reactions, extensive myelosuppression (see [Precautions] and [Adverse Reactions] sections), platelet-specific decreases (with or without purpura), and hyperkalemia are the most common serious adverse reactions in elderly patients. The incidence of thrombocytopenia combined with purpura is increased in patients receiving certain concomitant diuretics, primarily thiazides. Elevated digoxin blood levels can occur with compounded sulfamethoxazole therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematologic changes suggestive of folic acid deficiency may occur in older patients. These are reversible by treatment with folic acid. The dose should be adjusted appropriately in patients with impaired renal function and should be used for as short a time as possible to minimize the risk of adverse reactions (see [DOSAGE AND ADMINISTRATION] section). The methotrexate component of compound sulfamethoxazole may cause hyperkalemia when used in conjunction with disorders of potassium metabolism, renal insufficiency, or with drugs known to induce hyperkalemia (e.g., angiotensin-converting enzyme inhibitors). Close monitoring of blood potassium is required in these patients. Discontinuation of cotrimoxazole therapy is recommended to help reduce serum potassium levels. Compound sulfamethoxazole tablets contain 1.08 mg (0.05 mEq) of sodium per tablet.
The pharmacokinetic parameters of sulfamethoxazole were similar to those of elderly subjects and young subjects. The mean maximum concentration of methomyl in serum was higher and the mean clearance of methomyl in the kidney was lower in elderly patients compared to younger patients.
[Drug Interactions].
1. Meperidine is a CYP2C8 inhibitor as well as an OCT2 transport carrier. Sulfamethoxazole is a CYP2C9 inhibitor. Sulfamethoxazole should be used with caution in combination with drugs whose substrates are CYP2C8, CYP2C9 and OCT2.
When the following drugs are used together with this product, this product may replace the protein binding sites of these drugs or inhibit their metabolism, resulting in a prolonged duration of action or toxic reactions, therefore, when these drugs are used together with or after this product, their doses should be adjusted. Such drugs include oral anticoagulants, oral hypoglycemic agents, methotrexate, phenytoin sodium, and thiopental sodium.
In patients receiving anticoagulant warfarin (CYP2C9 substrate), this product may prolong prothrombin time and clotting time should be reassessed.
Compound sulfamethoxazole may inhibit the hepatic metabolism of phenytoin (CYP2C9 substrate). Its administration at ordinary clinical doses increased phenytoin half-life by 39% and decreased phenytoin metabolic clearance by 27%, and the effects of possible increased exposure to polyphenytoin should be noted when administered concomitantly.
Competes with methotrexate for plasma protein binding sites for renal transport, thereby increasing the concentration of free methotrexate.
3. Significant but reversible nephrotoxicity has been reported with the coadministration of cotrimoxazole and cyclosporine in renal transplant recipients.
4. Compound sulfamethoxazole therapy may increase digoxin blood levels, especially in elderly patients. Serum digoxin levels should be monitored.
5. Elevated blood levels of sulfamethoxazole may occur in patients receiving indomethacin.
6. There have been reports of megaloblastic anemia that may occur in patients receiving etanercept as a malaria prophylaxis at doses greater than 25 mg per week in combination with cotrimoxazole sulfamethoxazole.
7. Compound sulfamethoxazole may enhance CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glibenclamide) metabolism and enhance oral hypoglycemic effects via OCT2 (e.g., metformin) adrenaline metabolism, requiring additional monitoring of blood glucose.
8. In the literature, single cases of delirium following concomitant administration of sulfamethoxazole/methoprene and amantadine (OCT2 substrate) have been reported. Cases of interaction with other OCT2 substrates, meperidine and metformin have also been reported.
9. In the literature, hyperkalemia has been reported in three elderly patients after concomitant ingestion of sulfamethoxazole/meperidine and angiotensin-converting enzyme inhibitors.
10. Combined use of urinary alkalinizing agents may increase the solubility of this product in alkaline urine, resulting in increased excretion.
11. It should not be combined with para-aminobenzoic acid, which can be taken up by bacteria instead of this product, and the two antagonize each other.
12. Combined with myelosuppressive drugs may enhance the adverse effects of these drugs on the hematopoietic system. If there are indications for the use of the two drugs together, the possible toxic reactions should be closely observed.
13. Prolonged combination with contraceptives (estrogens) may lead to a decrease in the reliability of contraception and increase the chance of extra-menstrual bleeding.
14. Combination with thrombolytic drugs may increase their potential toxic effects.
15. Combination with hepatotoxic drugs may cause an increased incidence of hepatotoxicity. Liver function should be monitored in such patients, especially if they have been on the drug for a long time and have a previous history of liver disease.
16. When combined with photosensitizing drugs, the addition of photosensitizing effects may occur.
17. The need for vitamin K is increased in patients treated with this product.
18. Should not be combined with urotropine because urotropine can be decomposed in acidic urine to produce formaldehyde, which can form insoluble precipitates with this product. It increases the risk of crystalluria.
19. This product can replace the plasma protein binding site of Pertussisone, and the effect of Pertussisone can be enhanced when the two are used together.
20. The combination of sulfopiridone and this product may reduce the secretion of the latter from the renal tubules, and the blood concentration of the latter may be increased for a long time, which may cause toxic reactions. When the course of sulfinpyrazone is long, it is advisable to monitor the blood concentration of this product to help adjust the dose and ensure the safe use of the drug.
Rifampicin, when combined with this product, can significantly increase the clearance of TMP and shorten the serum half-life of this product.
22. It should not be used in combination with antineoplastic drugs, 2,4-diaminopyrimidines, or between courses of treatment with other folic acid antagonists because of the possibility of bone marrow regeneration or megaloblastic anemia.
23. Do not combine with aminophenyl sulfone because the blood concentration of both aminophenyl sulfone and TMP in this product can be increased, and the increase of aminophenyl sulfone concentration increases and aggravates the adverse effects, especially the occurrence of methemoglobinemia.
24. Avoid combining with penicillins, as this product may interfere with the bactericidal effect of these drugs.
Drug/Laboratory Interactions: When bacterial dihydrofolate reductase is used as the binding protein, cis-sulfamethoxazole, especially the methotrexate component, may interfere with serum methotrexate assays as determined by competitive binding protein assay (CBPA). However, if methotrexate is measured by radioimmunoassay (RIA), no interference occurs. The presence of sulfamethoxazole and methotrexate may also interfere with alkaline picric acid ester reaction measurements of creatinine, resulting in exceeding the normal range of values by approximately 10%.
[Drug overdose].
Acute: No overdose symptoms or life-threatening tendencies have been reported with a single dose of this product. Signs and symptoms of sulfonamide overdose include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness, and coma. Fever, hematuria, and crystalluria should be noted. Hematoma and jaundice are late manifestations of potential overdose. Acute symptoms of overdose with methotrexate include nausea, vomiting, dizziness, headache, depression, confusion, and bone marrow depression.
General principles of treatment include gastric lavage, emetic or copious fluid intake after discontinuation of the drug; intravenous fluids may be given if urine output is low and renal function is normal. Patients should be monitored for biochemical parameters such as blood and electrolytes. If significant hematologic adverse effects or jaundice occur, dialysis should be administered to address these complications. Peritoneal dialysis is not effective, and hemodialysis is generally effective in eliminating sulfamethoxazole and methotrexate.
Chronic: High-dose and/or prolonged use of sulfamethoxazole may result in myelosuppression as evidenced by thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of myelosuppression develop, patients should be given formyl tetrahydrofolate 5 – 15 mg daily until hematopoietic function returns to normal.
Pharmacology and Toxicology
Pharmacological effects
It is a compound preparation of sulfamethoxazole (SMZ ) and methicillin (TMP ), which has good antibacterial effect on non-enzymatic Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella spp, Salmonella spp, Proteus spp, Morganella spp, Shigella spp and other Enterobacteriaceae, gonococcus, Neisseria meningitidis and Haemophilus influenzae. In particular, the antibacterial effect on Escherichia coli, Haemophilus influenzae and Staphylococcus aureus is significantly enhanced compared with that of SMZ alone. In addition, it has good anti-microbial activity in vitro against Chlamydia trachomatis, Nocardia astrophila, Protozoa and Toxoplasma gondii.
The mechanism of action of SMZ is: SMZ acts on dihydrofolate synthase to interfere with the first step of folic acid synthesis, and TMP acts on the second step of folic acid synthesis and selectively inhibits the action of dihydrofolate reductase, which can cause a double blockage of bacterial folic acid metabolism. The synergistic antibacterial effect of this product is enhanced compared with that of single drug, and the strains presenting resistance to it are reduced. However, the resistance of bacteria to this product has been increasing in recent years.
Toxicological studies
Reproductive toxicity.
In rats, oral administration of 533 mg/kg sulfamethoxazole or 200 mg/kg meperidine was found to be teratogenic, mainly in the form of cleft palate. These doses are approximately 5 and 6 times the total recommended daily human dose in terms of body surface area. In two rat studies, no teratogenic effects were seen with 512 mg/kg of sulfamethoxazole in combination with 128 mg/kg of meperidine. In some rabbit studies, an increase in fetal litter loss (stillbirth and resorption) was dose-related to methotrexate, which was 6 times the human therapeutic dose in terms of body surface area.
【Pharmacokinetics】.
This product is rapidly absorbed after oral administration. Both sulfamethoxazole and meperidine are present in the blood in unconjugated, protein-bound and metabolized forms; sulfamethoxazole is also present in conjugated form. Sulfamethoxazole is metabolized in humans to at least five metabolites: N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and N-glucuronide conjugates. formation of the N4-hydroxy metabolite is mediated via CYP2C9.
Sulfamethoxazole is metabolized in vitro to 11 different metabolites, five of which are glutathione adducts and six are oxidative metabolites, including the major metabolites 1- and 3-oxides and 3- and 4-hydroxy derivatives.
The free forms of sulfamethoxazole and methotrexate are considered to be the therapeutically active forms.
In vitro studies have shown that meperidine is a substrate for P-glycoprotein, OCT1 and OCT2, while sulfamethoxazole is not a substrate for P-glycoprotein.
Approximately 70% of sulfamethoxazole and 44% of methicillin are bound to plasma proteins. The presence of 10% sulfamethoxazole in plasma reduced the protein binding of meperidine insignificantly; meperidine did not affect the protein binding of sulfamethoxazole.
Peak blood concentrations of individual components occur 1 to 4 hours after oral administration. The mean half-lives of sulfamethoxazole and meperidine were 10 hours and 8 to 10 hours, respectively. However, the half-lives of both components were increased in patients with severely impaired renal function, requiring adjustment of the dosing regimen. Significant amounts of sulfamethoxazole and meperidine were detectable in the blood 24 hours after administration. Sulfamethoxazole 800 mg and meperidine 160 mg were administered twice daily. The mean steady-state plasma concentration of meperidine was 1.72 µg /ml. Steady-state mean plasma levels of free and total sulfamethoxazole were 57.4µg /ml and 68.0µg /ml, respectively. These reached steady-state levels after 3 days of dosing. The excretion of sulfamethoxazole and meperidine was mainly by the kidneys through glomerular filtration and renal tubular secretion. Urinary concentrations of both sulfamethoxazole and meperidine were significantly higher than those in the blood. The mean percentage of dose recovered in urine from 0 to 72 hours after a single oral dose of sulfonamide sulfonamide and meperidine was 84.5% and free meperidine was 66.8%. Thirty percent of the total sulfonamide was excreted as free sulfamethoxazole, with the remainder as N4-acetylated metabolites. When sulfamethoxazole and meperidine were administered concomitantly, neither sulfamethoxazole nor meperidine affected the other urinary excretion patterns.
Both sulfamethoxazole and meperidine are distributed in saliva, vaginal fluid, and middle ear fluid; meperidine is also distributed in bronchial secretions, and both cross the placental barrier and are excreted in human milk.
Geriatric pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and meperidine 160 mg in 6 elderly subjects (mean age 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) were studied. The pharmacokinetic values of sulfamethoxazole in elderly subjects were similar to those in young subjects. Mean renal clearance was significantly lower in elderly subjects compared to younger subjects (19 ml/h/kg vs. 55 ml/h/kg). However, after normalization of body weight, the apparent total clearance of methotrexate was on average 19% lower in elderly subjects than in young subjects.
Storage】Store under light and seal.
Package】 High-density polyethylene bottle for oral solid medicine, 100 tablets/bottle.
Expiration date】 15 months
Execution Standard
Approval number】 State Drug Administration H33020657
[Drug marketing license holder
Name: Zhejiang Jinhua Kang’enbei Biopharmaceutical Co.
Registered Address: No. 288 Jinqu Road, Jinhua, Zhejiang, China
Postal Code: 321016
Telephone number: 0579-82273929
Fax number: 0579-82273137
Production enterprise
Company name: Zhejiang Jinhua Kang’enbei Biopharmaceutical Co.
Production Address: No. 288 Jinqu Road, Jinhua, Zhejiang Province
Postal Code: 321016
Telephone number: 0579-82273929, 8008579006
Fax number: 0579-82273137
Web address: www.jhconba.com