Meicelin

Cefminox Sodium, MRAPJ occurs as a white to pale yellowish white crystalline powder. It is odorless or has a faint characteristic odor. It is freely soluble in water, sparingly soluble in methanol and practically insoluble in ethanol and ether.
One vial of MEICELIN For Injection contains 1 g (potency) of cefminox sodium as the active ingredient.
When this product is dissolved in Water For Injection, JP, pH and OPR are as follows: See Table 1.

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Chemical name: Sodium (6R,7S)-7-[(S)-2-(2-amino-2-carboxyethylthio)acetamido]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate heptahydrate.
Molecular formula: C₁₆H₂₀N₇NaO₇S₃·7H₂O.
Molecular weight: 667.66.
Potency: The potency is expressed as the weight of cefminox (C₁₆H₂₁N₇O₇S₃) 1.285 mg of standard cefminox (C₁₆H₂₀N₇NaO₇S₃·7H₂O) corresponds to 1 mg (potency) of cefminox.

Pharmacology: In vitro Antibacterial Activity: MEICELIN has a broad antibacterial spectrum against gram-positive and gram-negative bacteria, especially Escherichia coli, Klebsiella sp., Haemophilus influenzae, Proteus sp. and Bacteroides fragilis.
This substance shows an antibacterial activity not only in logarithmic phase but also in early stationary phase of bacterial growth. Even in sub-MIC (minimum inhibitory concentration), it shows quick bactericidal and bacteriolytic action. In vivo antibacterial activity of the substance is stronger than that expected from MIC.
This substance is stable to beta-lactamases produced by various bacteria such as Escherichia coli, Proteus sp. and Bacteroides fragilis.
Mechanism of Action: MEICELIN inhibits the bacterial cell wall synthesis because of its high affinity for penicillin-binding protein, a usual action site of beta-lactams. It also combines with peptidoglycan, i.e., it inhibits bacterial peptidoglycan-lipoprotein binding. Therefore, it promotes bacteriolysis and shows a strong bactericidal activity in a short time.
Clinical Studies: The results of open clinical and comparative trials (respiratory and urinary tract infections) are summarized as follows: In a total of 1,776 patients for clinical efficacy evaluation, the efficacy rate was 73.3% (1,302/1,776). The efficacy rates against main diseases were as follows: See Table 2.

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Pharmacokinetics: Serum concentration: Healthy adults: The serum concentration of the product after intravenous injection (iv) or intravenous drip infusion (div) to adult males with normal renal function was dose-dependent. (See Figure 1 and Table 3.)

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Children: Intravenous injection: The serum concentration of the product after intravenous injection to children (n=9) was dose-dependent. (See Figure 2 and Table 4.)

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Intravenous drip infusion: The serum concentration of the product after 1-hour intravenous drip infusion at a dose of 40 mg/kg or 20 mg/kg was also dose-dependent. (See Figure 3 and Table 5.)

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Patients with renal impairment: The serum concentration of the product after intravenous injection of 0.5 or 1 g to patients with impaired renal function showed a tendency toward continuously high values and prolonged serum half-life depending on the degree of their impairment. (See Figure 4 and Table 6.)

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Distribution: Body fluids and tissue concentrations: When 1 g was administered by intravenous drip infusion to patients suffering from chronic bronchitis, the sputum concentration was 0.38 to 0.48 μg/ml.
When 1 g was administered by intravenous injection to patients suffering from peritonitis, the ascites concentration was 13.4 to 139.5 μg/ml. When 20 mg/kg was administered by intravenous injection to child patients suffering from peritonitis, it was 17.9 to 63.2 μg/ml.
When 1 g was administered by intravenous injection to patients who received panhysterectomy, the concentration in endometrium, ovary and salpinx were 33.7 to 45.8 μg/ml.
When 1 g was administered by intravenous injection to patients with biliary tract diseases, the biliary concentration was 4.6 to 36.0 μg/ml.
Protein binding: The binding rate to human plasma protein as determined by ultrafiltration method was constant within the concentration range of 5 to 100 μg/ml, being about 61% (in vitro).
Metabolism: No metabolites having antibacterial activity have been found in man.
Excretion: Healthy adults: This substance is excreted mainly from the kidney. In adults with normal renal function, the urinary excretion rates are about 80% within 6 hours and about 90% within 12 hours after intravenous injection (n=3) or intravenous drip infusion (n=3) of a single dose of 1 g.
Patients with renal impairment: In patients with severely impaired renal function (Ccr <10), the urinary excretion rate is about 10% within 24 hours after intravenous administration and in case of patients with moderately impaired renal function (Ccr=48), it is about 50% within 6 hours and about 63% within 12 hours.

The following infections caused by cefminox-susceptible strains of Streptococcus sp. (excluding enterococci), Escherichia coli, Klebsiella pneumoniae, Proteus sp, Haemophilus influenzae and Bacteroides sp: Septicemia, tonsillitis, peritonsillar abscess, bronchitis, bronchiolitis, bronchiectasis with infection, secondary infection in chronic respiratory diseases, pneumonia, pulmonary suppuration, pyelonephritis, cystitis, cholecystitis, cholangitis, peritonitis, pelvic peritonitis, uterine adnexitis, intrauterine infections, inflammation of pelvic dead space, parametritis.

Usually for adults, a daily dosage of 2 g (potency) is administered by intravenous injection or intravenous drip infusion in 2 divided doses. For children, a dose of 20 mg (potency)/kg is administered by intravenous injection or intravenous drip infusion 3-4 times a day.
The dose may be adjusted according to the age of patients and severity of symptoms. In septicemia, refractory or severe infections, the daily dosage can be increased up to 6 g (potency) for adults in 3-4 divided doses.
To administer by intravenous injection, 1 g (potency) of this product is dissolved in 20 ml of water for injection, glucose solution or electrolyte solution and injected slowly.
To administer by intravenous drip infusion, 1 g (potency) of this product is dissolved in 100-500 ml of glucose solution or electrolyte solution and infused over a period of 1 to 2 hours.

MEICELIN For Injection is contraindicated in the following patients: Patients with a history of hypersensitivity due to any of the ingredients of this product.
Relative Contraindications: (As a general rule, MEICELIN For Injection is contraindicated in the following patients. If the use of MEICELIN For Injection is considered essential, it should be administered with care.) Patients with a history of hypersensitivity to any of the ingredients of other cephem antibiotics.

Contraindicated in patients hypersensitive to this drug.
Using this drug in penicillin-allergic patients may cause a severe allergic reaction possibly leading to death.
If any of the following symptoms occurs after using this drug, e.g. fever, rashes, blisters, skin peeling, stomatitis, pharyngitis, rhinitis, conjunctivitis, genital inflammation, stop using and consult the physician or pharmacist.

For treatment of tonsillitis (including peritonsillar abscess) and acute bronchitis, Manual of Antimicrobial Stewardship (The Government of Japan, Ministry of Health, Labour and Welfare) should be consulted to decide whether administration of antimicrobials is necessary, and then this drug should be administered in cases where treatment with this drug is determined to be appropriate.
Careful Administration (MEICELIN For Injection should be administered with care in the following patients): Patients with a history of hypersensitivity to penicillins.
Patients with a personal or familial predisposition to allergic symptoms such as bronchial asthma, exanthema or urticaria.
Patients with severely impaired renal function [High drug blood level is maintained (See Pharmacology: Pharmacokinetics under Actions)].
Elderly patients. [See Use in the Elderly as follows.]
Patients who are poorly-nourished, parenterally nourished or in poor general condition. (Sufficient observation should be performed because vitamin K deficiency symptoms may develop.)
Important Precautions: Since no methods are available to reliably predict the potential occurrence of shock or anaphylactic reaction due to this product, the following measures should be taken: Patients should be carefully interviewed in advance to obtain any past history of such reactions to drugs. Any history of allergy to antibiotics or other agents must be ascertained.
Emergency measures must be available readily for the treatment of shock etc., when this product is used.
Patients should be resting and kept under careful observation from the beginning until after the end of administration of this product. Patients should be observed especially carefully immediately after the beginning of administration.
Alcohol intake may cause lushed face, palpitation, dizziness, headache, nausea, etc. Therefore, alcohol intake should be avoided during treatment and at least one week after completion of treatment.
Effects on Laboratory Tests: In the creatinine test using Yaffe's reaction, this product may give a false, high creatinine value.
This product may cause a positive response in the direct Coombs' reaction.
Other Precautions: It has been reported that when this product was administered subcutaneously to juvenile rats, testicular atrophy and spermatogenic suppression occurred.
It has been reported that there is a possibility of development of Clostridium difficile and Klebsiella oxytoca due to administration of the product.
Use in Children: The safety of this product in newborns and premature infants has not been established (few clinical experiences).
Use in the Elderly: The product should be administered carefully to elderly patients, paying attention to the following two points, and dose and dose intervals should be adjusted to meet the patients condition.
Adverse reactions are likely to occur in elderly patients since their physiological function is generally reduced.
A bleeding tendency due to vitamin K deficiency may occur in elderly patients.

This product should be administered to pregnant patients or women suspected of being pregnant, only if the expected therapeutic benefits are evaluated to outweigh the possible risk of treatment. [Safety of use of this product during pregnancy has not been established (few clinical experiences).]

Results of the postmarketing surveillance up to the completion of reexamination are as follows: In a total of 13,431 patients, adverse reactions were found in 237 patients (1.76%). Principal adverse reactions were hepatic/bile duct disorders (hepatic dysfunction, increased GOT and GPT, etc) in 117 patients (0.87%); leucocyte/reticuloendothelial system disorders (eosinophilia, granulocytopenia, etc.) in 32 (0.24%); skin/skin appendage disorders (exanthema, etc.) in 32 (0.24%); gastrointestinal disorders (diarrhea, nausea, etc.) in 22 (0.16%) and others (fever in 7 (0.05%), increased BUN in 4 (0.03%), etc.).
Clinically significant adverse reactions: Shock (<0.1%) may occur. Patients should be carefully monitored and if any symptoms such as feeling unwell, oral cavity discomfort, stridor, vertigo, defecation desire, tinnitus or diaphoresis occur, administration should be discontinued and appropriate measures should be taken.
Pancytopenia (<0.1%) may occur. Patients should be carefully monitored, and periodic laboratory tests should be performed. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken.
Serious colitis with bloody stool such as pseudomembranous colitis (<0.1%) may occur. Patients should be carefully monitored and if abdominal pain or frequent diarrhea occurs, administration should be discontinued immediately and appropriate measures should be taken.
Clinically significant adverse reactions (analogous drugs): It has been reported with other cephems that toxic epidermal necrolysis (TEN) or muco-cutaneo-ocular syndrome (Stevens-Johnson syndrome) (<0.1%) occurs. Patients should be carefully monitored and if any abnormality is observed, administration should be discontinued and appropriate measures should be taken.
It has been reported with other cephems that serious renal disorder such as acute renal failure (<0.1%) occurs. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken.
It has been reported with other cephems that hemolytic anemia (<0.1%) occurs. Patients should be carefully monitored and periodic laboratory tests should be performed. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken.
It has been reported with other cephems that interstitial pneumonia, PIE syndrome (<0.1%), etc., with fever, cough, dyspnea, abnormal chest x-ray, eosinophilia, etc., occur. Patients should be carefully monitored and if these symptoms occur, administration should be discontinued and appropriate measures such as administration of adrenocortical hormones should be taken.
Other adverse reactions: Hypersensitivity: Eruption may infrequently occur. Redness, itchiness, fever, etc., may rarely occur. If such symptoms develop, administration should be discontinued and suitable measures should be taken.
Renal: Rarely, findings indicative of renal disorders such as elevation of BUN and serum creatinine, oliguria and albuminuria may occur. Therefore, periodical clinical tests should be carried out to thoroughly monitor patients. If laboratory test findings such as oliguria, hematuria, urinary protein, and elevations of BUN and serum creatinine occur, suitable measures such as discontinuation of the product should be taken.
Hemolytic anemia: Granulocytopenia and eosinophilia may infrequently occur. Decreases in the erythrocyte count, hematocrit and hemoglobin level, thrombocytopenia, prolongation of the prothrombin time, etc., may rarely occur. Therefore, periodical clinical tests should be carried out to thoroughly monitor patients and when any abnormality appears, suitable measures including discontinuation of administration should be taken.
Hepatic: Elevations of GOT, GPT and AI-P may infrequently occur. γ-GTP, LAP, LDH, bilirubin, etc., may rarely elevate. Rarely, jaundice may develop. Therefore, close observation should be made and if any abnormality appears, suitable measures including discontinuation of administration should be taken.
Gastrointestinal: Diarrhea may infrequently occur. Nausea, vomiting, anorexia, etc., may rarely occur. Therefore, close observation should be made and if any abnormality appears, suitable measures including discontinuation of administration should be taken.
Microbial substitution: Rarely, stomatitis and candidiasis may occur.
Avitaminosis: Rarely, vitamin K deficiency symptoms (hypoprothrombinemia, bleeding tendency, etc.,) and vitamin B group deficiency symptoms (glossitis, stomatitis, anorexia, neuritis, etc.) may occur.
Others: Rarely, systemic malaise may occur.

Careful co-administration: Diuretics such as furosemide [Renal toxicity may be intensified].
Alcohol [In animal experiments using rats, it has been reported that this product influences alcohol metabolism and causes elevation of the acetaldehyde concentration in the blood, showing disulfiram-like action].

Precautions concerning use: Administration route: This product should be used only by intravenous injection or intravenous drip infusion.
Preparation: 1) In the case of intravenous drip infusion, this product should not be dissolved in distilled water for injection alone (The solution is not isotonic). It should be dissolved in glucose or electrolyte solution.
2) Mixing with aminophylline or pyridoxal phosphate reduces the potency of this product and causes coloration. Therefore, injection by mixing with these drugs should be avoided. Mixing with fursultiamine, thioctic acid, hydrocortisone sodium succinate or cobamamide causes coloration with time. Therefore, after mixing, the mixture should be used immediately.
After dissolution: After reconstitution, the product should be used immediately. Even if the solution has to be stored at room temperature or in a refrigerator, use it within 12 hours or 24 hours, respectively.
At the time of administration: Intravenous administration of this product in a large dose may cause vascular pain and phlebitis. To prevent such reactions, due caution should be exercised in reconstituting the product and also regarding the injection site and injection method, and the injection rate should be as slow as possible.

Store below 30°C.

Cephalosporins

J01DC12 - cefminox ; Belongs to the class of second-generation cephalosporins. Used in the systemic treatment of infections.

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