Meiact/Meiact MS Fine Granules 10%

Meiact/Meiact MS Fine Granules 10%

cefditoren

Manufacturer:

Meiji
Full Prescribing Info
Contents
Cefditoren pivoxil.
Description
Meiact: Cefditoren pivoxil is (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. It has the molecular formula C25H28N6O7S3 and a molecular weight of 620.73.
Cefditoren pivoxil occurs as a light yellowish white to light yellow crystalline powder. It is freely soluble in diluted hydrochloric acid, sparingly soluble in methanol, slightly soluble in acetonitrile and ethanol, very slightly soluble in ether and practically insoluble in water. Its melting point is 196-201°C (decomposition). The partition coefficient, log101-octanol layer/water layer, 25±2°C, is 0.92 at pH 2 and >3 at pH 4-6.
1.225 mg of cefditoren pivoxil contains 1 mg (potency) of cefditoren. Potency is indicated as the weight (potency) of cefditoren (C19H18O5S3).
Meiact MS Fine Granules 10%: Each sachet contains 100 mg of Cefditoren pivoxil in 1 g granule (10%). (See Table 1.)


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Action
Pharmacology: Mechanism of action: Cefditoren inhibits the synthesis of bacterial cell walls. It has high affinity to penicillin binding proteins (PBPs) in various bacteria, showing a bactericidal effect.
Meiact MS Fine Granules 10%: Antibacterial activity: Cefditoren pivoxil is metabolized into cefditoren on absorption in the intestinal wall and shows its antibacterial activity.
Cefditoren exerts broad spectrum antibacterial activity in vitro against gram-positive and gram-negative bacteria. Especially it showed strong antibacterial activity against gram¬≠ positive bacteria such as Staphylococcus sp., Streptococcus sp., and Streptococcus pneumoniae, and gram-negative bacteria such as Escherichia coli, Moraxella (Branhamella) catarrhalis, Klebsiella sp., Proteus sp. and Haemophilus lnfluenzae, and against anaerobic bacteria such as Peptostreptococcus sp., Propionibacterium acnes, Bacteroides sp. and Prevotella sp. Cefditoren also showed antibacterial activity against β-lactamase nonproducing ampicillin resistant Haemophilus influenzae (BLNAR).
In vitro, cefditoren was stable against β-lactamases produced by various bacteria, and showed strong antibacterial activity against β-lactamase-producing strains.
Therapeutic effect on experimental infection: Cefditoren pivoxil demonstrated excellent therapeutic effects on experimental infections in mice caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumonia and Proteus sp. Its therapeutic effect on infections caused by β-lactamase-producing strains was equivalent or superior to similar drugs.
Meiact: Microbiology: Cefditoren pivoxil is metabolized into cefditoren upon absorption from the intestinal wall and shows its antibacterial activity.
Cefditoren exerts antibacterial activity in vitro against a wide-spectrum of gram-positive and gram-negative bacteria. Its activity against gram-positive bacteria including Staphylococcus sp and Streptococcus sp eg, Streptococcus pneumoniae as well as against gram-negative bacteria including E. coli, B. catarrhalis, Klebsiella sp, Proteus sp and H. influenzae and anaerobic bacteria including Peptostreptococcus sp, P. acnes and Bacteroides sp, is particularly noteworthy.
In vitro, cefditoren demonstrated stability against β-lactamase produced by various bacteria. It also shows strong antibacterial activity against strains that produce β-lactamase.
Susceptibility Testing: Cefditoren pivoxil demonstrated excellent therapeutic efficacy on experimental infections by Staphylococcus aureus, S. pneumoniae, E. coli, Klebsiella pneumoniae and Proteus sp in mice. Its therapeutic efficacy on the infections by β-lactamase-producing strains was equivalent or superior to similar drugs.
Pharmacokinetics: Meiact: Absorption and Distribution: Blood Concentration: The serum concentrations and pharmacokinetics (Table 2) of cefditoren after oral administration of 100 or 200 mg to healthy adults after meals demonstrated dose dependency. Absorption was better when administered after meals than when given at fasting. See Table 2.


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Body Fluid and Tissue Concentrations: The drug transferred to the sputum, tonsillar tissue, mucous membrane of maxillary sinus, skin tissue, mammary gland tissue, gallbladder tissue, vagina, uterine neck, tarsal gland tissue and wound after tooth extraction. No transfer to the milk was noted.
Protein-Binding: In vitro binding rate to human serum protein determined by ultrafiltration method was 91.5% at a concentration of 25 mcg/mL.
Metabolism and Excretion: Cefditoren pivoxil is metabolized upon absorption and becomes cefditoren, which has antibacterial activity, and pivalic acid. The latter is conjugated with carnitine and excreted into urine as pivaloil carnitine. Cefditoren is hardly metabolized and is excreted mainly into urine and bile. The urinary excretion rate (0-24 hrs) of cefditoren upon oral administration after meals at doses of 100 and 200 mg to healthy adults was about 20%.
No accumulation of the drug was observed after continuous administration (200 mg 3 times/day for 8 days).
Serum Concentration and Urinary Excretion in Patients With Renal Function Disorder: The serum concentrations and pharmacokinetic parameters (Table 3) of cefditoren are as follows. Oral administration of 200 mg to adult patients with renal function disorder or to those receiving artificial dialysis after meals demonstrated higher levels in all the cases, showing delay in t½ in parallel with degree of renal function disorder. (See Table 3.)


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Meiact MS Fine Granules 10%: This product has been verified to be bioequivalent to Meiact MS Fine Granules 10% which has been verified to be bioequivalent to M Granules.
Data for M Granules at the time of approval: Absorption and distribution: Blood concentration: Figure 1 and Table 4 show serum concentrations and pharmacokinetic parameters, respectively, of cefditoren obtained after single oral administration of 3 mg/kg or 6 mg/kg to pediatric patients with normal renal function after meals. Dose dependency was observed. (See Figure 1 and Table 4.)


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Body fluid and tissue concentrations (in the case of patients given MEIACT Tablets 100): Transfer to sputum, tonsillar tissue, mucous membrane of maxillary sinus, cutaneous tissue, wound after tooth extraction, etc. was observed.
Protein binding: Binding rate to human serum protein determined by the ultrafiltration method was 91.5% at a concentration of 25 μg/mL (in vitro).
Metabolism and Excretion: Cefditoren pivoxil is metabolized on absorption and becomes cefditoren which has antibacterial activity, and pivalic acid. Pivalic acid forms a conjugate with carnitine and is excreted, into urine as pivaloyl carnitine. Cefditoren is hardly metabolized and is excreted mainly into urine and bile. The urinary excretion rate (0-8 hours) of cefditoren on oral administration after meals at doses of 3 and 6 mg/kg to pediatric patients with normal renal function was about 20% and 17%, respectively.
Serum concentration and urinary excretion (in the case of patients with renal function disorder given MEIACT Tablets 100): The serum concentrations (Figure 2) and pharmacokinetic parameters (Table 5) of cefditoren are as follows. Oral administration of 200 mg to adult patients with renal function disorder or to those receiving artificial dialysis after meals demonstrated higher levels in all cases, showing a delay in T1/2 in parallel with the degree of renal function disorder. (See Figure 2 and Table 5.)


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Urinary excretion rate lowered in parallel with the degree of renal function disorder, showing a delay in excretion.
Meiact: Toxicology: Clinical Studies: Clinical trials were conducted on 2642 patients (1971 in open clinical trials and 491 in comparative clinical trials) in medical institutions nationwide to investigate the efficacy of Meiact. The results are summarized as follows: Superficial Suppurative Diseases: The efficacy rate of Meiact in patients with folliculitis, furuncle, furunculosis, carbuncle, impetigo contagiosa, erysipelas, phlegmon, lymphangitis (lymphadenitis), suppurative perionychia (paronychia), felon, SC abscess, hidradenitis, infectious atheroma and chronic pyoderma was 87.8% (288/328). The usefulness of Meiact in the treatment of patients with superficial suppurative diseases was also confirmed in double blind clinical trials.
Infections in Surgical Field: The efficacy rate of Meiact in patients with mastitis, perianal abscess and superficial secondary infections in trauma and surgical wound was 78.9% (105/133).
Respiratory Tract Infection: The efficacy rate of Meiact in patients with pharyngolaryngitis (throat abscess), acute bronchitis, tonsillitis (peritonsillitis, peritonsillar abscess), chronic bronchitis, bronchiectasis with infection, secondary infections in chronic respiratory disease, pneumonia and pulmonary suppuration was 84.9% (666/784). The usefulness of Meiact in the treatment of patients with bacterial pneumonia and chronic respiratory tract infection was confirmed in double blind comparative trials.
Urinary Tract Infections: The efficacy of Meiact in patients with pyelonephritis and cystitis was 77.7% (453/583). The usefulness of Meiact in the treatment of patients with complicated urinary tract infections was also confirmed in double blind comparative trials.
Biliary Tract Infections: The efficacy rate of Meiact in patients with cholecystitis and cholangitis was 85.7% (30/35).
Gynecological Infections: The efficacy rate of Meiact in patients with uterine adnexitis, intrauterine infections and bartholinitis was 92.9% (143/154).
Otorhinologic Infections: The efficacy rate of Meiact in patients with otitis media and sinusitis was 72.3% (141/195).
Ophthalmological Infections: The efficacy rate of Meiact in patients with blepharitis, hordeolum, eyelid abscess, dacryocystitis and tarsadenitis was 90.3% (84/93).
Infections in the Field of Dentistry and Oral Surgery: The efficacy rate of the drug in patients with periodontal tissue inflammation, pericoronitis and gnathitis was 85.4% (134/157).
Indications/Uses
Meiact: Treatment of the following infections which are caused by susceptible strains: Community-acquired pneumonia (CAP), acute exacerbation of chronic bronchitis (AECB), pharyngotonsillitis, acute sinusitis, uncomplicated skin and soft structure infections.
Meiact MS Fine Granules 10%: Tonsilitis and Acute otitis media.
Indicated bacteria: Cefditoren - susceptible strains of Staphylococcus sp., Streptococcus sp., Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, Escherichia coli, Citrobacter sp., Klebsiella sp., Enterobacter sp., Serratia sp., Proteus sp., Morganella morganii, Providencia sp., Haemophilus influenzae, Bordetella pertussis, Peptostreptococcus sp., Bacteroides sp., Prevotella sp., and Propionibacterium acnes.
Dosage/Direction for Use
Meiact: Community-Acquired Pneumonia: 400 mg twice daily for 14 days.
Acute Exacerbation of Chronic Bronchitis: 400 mg twice daily for 10 days.
Pharyngotonsillitis and Acute Sinusitis: 200 mg twice daily for 10 days.
Uncomplicated Skin and Soft Structure Infections: 200 mg twice daily for 10 days.
Meiact should be taken after meals.
Meiact MS Fine Granules 10%: In case of Acute otitis media: For children, cefditoren pivoxil is usually administered in a single oral dose of 6 mg (potency)/kg 3 times a day, after meals. (The dosage may be decreased according to the patient's age and symptoms. Meanwhile, be sure not to exceed 600 mg a day (potency)).
In case of tonsilitis: For children, cefditoren pivoxil is usually administered in a single oral dose of 3 mg (potency)/kg 2 times a day, after meals. (The dosage may be increased according to the patient's age and symptoms as needed. However, be sure not to exceed 600 mg a day (potency)).
Precautions: As a general rule, the duration of administration of this drug should be limited to the minimum period required for the treatment of the patient's condition, after susceptibility of the microorganism to the drug has been confirmed, in order to prevent the emergence of drug-resistant microorganisms.
In patients with severe renal renal disorder, the dosing interval should be prolonged.
Overdosage
Meiact MS Fine Granules 10%: Information on cefditoren pivoxil overdosage in humans is not available. However, with other ¬≠ β-lactam antibiotics, adverse effects following overdosage have included nausea, vomiting, epigastric distress, diarrhea and convulsions. Hemodialysis may aid in the removal of cefditoren from the body, particularly if renal function is compromised (30% reduction of plasma concentrations following 4 hours of hemodialysis). Treat overdosage symptomatically and institute supportive measures as required.
Contraindications
Meiact: History of anaphylactic shock due to any of the ingredients of Meiact. Cow's milk allergy (Meiact contains sodium caseinate as an inactive ingredient).
Meiact MS Fine Granules 10%: MS FINE GRANULES 10% is contraindicated in patients with a history of shock due to any of the ingredients of the product.
Relative contraindications: As a general rule, MEIACT MS FINE GRANULES 10% is contraindicated in patients with a history of hypersensitivity to any of the ingredients of the product or to other cephem antibiotics. If the use of MEIACT MS FINE GRANULES 10% is considered essential, it should be administered with care.
Special Precautions
Laboratory Tests: False-positive results may occur in urine glucose tests with Benedict's solution, Fehling's solution, and Clinitest, but not with Tes-Tape.
Positive results may occur in the direct Coombs test. Caution is required.
Meiact: As a general rule, the duration of administration of Meiact should be limited to the minimum period required for the treatment of the patient's condition after susceptibility of the microorganism to Meiact has been confirmed, in order to prevent the emergence of drug-resistant microorganisms.
In patients with severely impaired renal function, the administration interval should be prolonged.
As a general rule, Meiact is contraindicated in patients with hypersensitivity to any of its ingredients or other cephem antibiotics. If the use of Meiact is considered essential, it should be administered with care.
Meiact should be administered with care in patients with any of the following: History of hypersensitivity to penicillins; personal or familial predisposition to allergic symptoms eg, bronchial asthma, exanthema or urticaria; severely impaired renal function (serum concentration persists) (see Pharmacokinetics under Actions); elderly; poor oral food intake or receiving parenteral alimentation and in poor general health (should be observed carefully because vitamin K deficiency may develop).
The patients should be carefully interviewed to assess the risk of shock.
It has been reported that Meiact reduces serum carnitine.
Meiact MS Fine Granules 10%: Careful Administration (MEIACT MS FINE GRANULES 10% should be administered with care in the following patients): Patients with a history of hypersensitivity to penicillin antibiotics.
Patients with a personal or familial predisposition to allergic reactions such as bronchial asthma, rash or urticaria.
Patients with severe renal disorder [Serum concentration persists (see Pharmacology: Pharmacokinetics under Actions)].
Patients with poor oral food intake or who are receiving parenteral alimentation and patients in poor general health [Patients should be observed carefully because vitamin K deficiency symptoms may develop].
Important Precautions: Since shock may occur, patients should be carefully interviewed.
It has been reported that administration of antibiotics which have a pivoxil group (including this product, cefcapene pivoxil hydrochloride hydrate, cefteram pivoxil and tebipenem pivoxil) cause serum carnitine decrease resulting from the metabolism/excretion of pivalic acid (a metabolite of antibiotics with a pivoxil group).
Administration of antibiotics with a pivoxil group may cause hypoglycemia accompanying hypocarnitinemia in children (in particular, infants and small children). Therefore when an antibiotic with a pivoxil group is administered, patients should be carefully monitored, paying particular attention to carnitine decrease. Do not administer this product if patients are found to have inborn errors of metabolism which may cause serum carnitine to decrease. (See Adverse Reactions.)
When this product is administered to children younger than 3 years in a single dose of 6 mg (potency)/kg 3 times a day, diarrhea/loose stool may occur with high frequency. If these symptoms are observed, approriate measures such as symptomatic treatment should be taken according to the symptoms. [See Use in Children as follows].
Effects on ability to drive and use machines: Meiact MS Fine Granules 10% has no effects on the ability to drive and use machines.
Use in Pregnancy & Lactation: Meiact should be administered to pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment. The safety and efficacy in this population have not been established.
Use in Children: The safety of Meiact/Meiact MS Fine Granules 10% in low birth weight infants and newborns (Meiact: suckling infants, infants & children) has not been established.
Meiact MS Fine Granules 10%: When this product is administered to children younger than 3 years in a single dose of 6 mg (potency)/kg 3 times a day, diarrhea/loose stool may occur with high frequency. Caution is required. [In a clinical study in which this product was administered to children with Community-acquired pneumoniae, Acute otitis media or Acute sinusitis in a single dose of 6 mg (potency)/kg 3 times a day, the incidence of the adverse reaction of diarrhea/loose stool was 36.2% (17/47) in children younger than 3 years old and 16.2% (11/68) in children 3 years or older. (See Important Precautions previously mentioned.)
Use in Elderly: Meiact: The incidence of adverse reactions in the elderly does not differ from that in nonelderly adult patients. However, since the physiological functions are generally reduced in the elderly, Meiact should be administered carefully, paying attention to the following 2 points: Dose and dose intervals should be adjusted according to the patient's condition.Delay in excretion has been observed in patients with impaired renal function. Therefore, high serum levels of Meiact may persist for a longer period of time in the elderly.As for other analogous drugs, bleeding tendency due to vitamin K deficiency has been reported to occur in the elderly.
Use In Pregnancy & Lactation
Meiact should be administered to pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment. The safety and efficacy in this population have not been established.
Adverse Reactions
Clinically Significant Adverse Reactions: Shock, or anaphylaxis/anaphylactoid symptoms (<0.1%) may occur. Therefore, patients should be monitored thoroughly and if any abnormalities/anaphylactic shock-related signs or symptoms develop such as feeling unwell/discomfort, oral cavity discomfort, stridor, vertigo, defecation desire, tinnitus and diaphoresis/sweating, administration should be discontinued and suitable measures should be taken.
Serious colitis with bloody stool such as pseudomembranous colitis (<0.1%) may occur. Therefore, patients should be carefully monitored and if abdominal pain or frequent diarrhea occurs, administration should be discontinued immediately and suitable/appropriate measures should be taken.
Mucocutaneo-ocular syndrome (Stevens-Johnson syndrome) or Toxic Epidermal Necrolysis (TEN or Lyell's syndrome) (<0.1%) may occur. Therefore, patients should be thoroughly monitored and if any abnormality occurs, administration should be discontinued and suitable measures should be taken.
Interstitial pneumonia, PIE syndrome (<0.1%) accompanied by fever, coughing, dyspnea, abnormal chest x-ray images, eosinophilia, etc., may occur. Therefore, patients should be monitored thoroughly and if these symptoms occur, administration should be discontinued and suitable measures such as administration of corticosteroid should be taken.
Hepatic function disorders (<0.1%) associated with jaundice and markedly increased AST (GOT), ALT (GPT) and AL-P may occur. Therefore, periodic clinical examinations should be carried out to thoroughly monitor patients and if any abnormality occurs, administration should be discontinued and suitable measures should be taken.
Serious renal dysfunction (<0.1%) such as acute renal failure may occur. Therefore, periodic clinical examinations should be carried out to thoroughly monitor patients and if any abnormality occurs, administration should be discontinued and suitable measures should be taken.
Agranulocytosis (<0.1%) and/or hemolytic anemia (<0.1%) may occur. Therefore, periodic clinical examinations should be carried out to thoroughly monitor patients and if any abnormality occurs, administration should be discontinued and suitable measures should be taken.
Meiact: Adverse reactions occurred in 127 (4.37%) of the 2909 patients evaluated for the safety of Meiact. Digestive symptoms including diarrhea, loose stools, nausea and stomach discomfort accounted for 121 patients (4.16%), followed by 16 (0.55%) patients with allergic symptoms eg, exanthema. Changes in laboratory test values were observed in 8.17% (187/2289). These included abnormal hepatic function eg, increased AST (GOT) in 3.37% (73/2167) and increased ALT (GPT) in 4.21% (91/2164); and abnormal hematology eg, eosinophilia in 2.63% (47/1790) (at the time of approval).
Others: See Table 6.


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Meiact MS Fine Granules 10%: This product has been verified to be bioequivalent to Meiact MS Fine Granules 10% which has been verified to be bioequivalent to M Granules.
Data for Meiact Granules at the time of approval: Incidences of adverse reactions by Meiact Granules were as follows.
Adverse reactions occurred in 19 (4.17%) of 456 patients evaluated for the safety. Principal symptoms observed were diarrhea in 17 (3.73%) patients and allergic symptoms in 2 (0.44%) patients (1 patient each with rash and redness). Changes in laboratory test value were observed in 3.60% (10/278). They included abnormal hepatic function such as AST (GOT) in creased in 0.45% (1/222) and ALT (GPT) increased in 0.90% (2/222), and abnormal hematology such as eosinophilia in 1.97% (5/254).
Data at the end of re-examination of Meiact MS Fine Granules 10% and Meiact Granules: In post-marketing drug-use results surveys for Meiact MS Fine Granules 10% and Meiact Granules, a total of 5,821 clinical cases was reported from 875 medical institutions nationwide. Adverse reactions occurred in 136 (2.34%) patients with 146 episodes. The main adverse reactions were gastrointestinal system disorders (diarrhea, loose stool, etc.) in 121 (2.08%) patients and skin and appendages disorders (rash, urticaria) in 10 (0.17%) patients.
Data for this product at the time of approval for a partial change in dosage and administration: As a result of a clinical study in which this product was administered to pediatric patients with pneumonia, otitis media or sinusitis in a single dose of 6 mg (potency)/kg 3 times a day, adverse reactions occured in 36 (31.3%) of 115 patients evaluated for safety. The main adverse reaction was diarrhea/loose stool in 28 (24.3%) patients. Abnormal changes in laboratory test values were observed in 7 (6.2%) of 113 patients who had a laboratory test and evaluated for safety. They included increased platelet count.
Administration of an antibiotic which has a pivoxil group may cause hypoglycemia accompanying hypocarnitinemia (incidence unknown) in children (in particular, infants and small children). When symptoms of hypoglycemia such as convulsions or consciousness disorder are observed, administration should be discontinued and appropriate measures should be taken. (See Important Precautions under Precautions.)
Other adverse reactions1: See Table 7.


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Drug Interactions
Meiact MS Fine Granules 10%: The use of Cefditoren pivoxil (CDTR-PI) with antacids or histamine H2 antagonists receptor will decrease the bioavailability of CDTR-PI. Besides the use together with probenecid will reduce the renal excretion of CDTR-PI.
Caution For Usage
Meiact: In the case of press-through packages, the patient should be instructed to remove Meiact from the package prior to use. (If the PTP sheet is swallowed, its sharp corners may penetrate the esophageal mucosa, leading to severe complications eg, mediastinitis.)
Meiact MS Fine Granules 10%: Precautions for handling: Sachets should be protected from light and moisture.
Furthermore, instructions should be given to keep divided preparations (prepackaged) dry and to only open them immediately before use.
Incompatibilities: Not applicable.
Storage
Meiact: Store below 25°C. Protect from moisture and direct light.
Meiact MS Fine Granules 10%: Store below 30°C and protect from light.
Shelf life: 3 years.
MIMS Class
ATC Classification
J01DD16 - cefditoren ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.
Presentation/Packing
Meiact: Tab (white, film-coated) 200 mg x 2 x 10's.
Meiact MS Fine Granules 10%: Granules for oral soln (sachet) 30 mg x 0.3 g x 15's. 50 mg x 0.5 g x 15's, 60's.
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