Spectracef (Tablets) Instructions for Use

Marketing Authorization Holder

Meiji Seika Pharma, Co. Ltd. (Japan)

Manufactured By

Meiji Pharma Spain, S.A. (Spain)

Packaging and Quality Control Release

ORTAT, JSC (Russia)

Contact Information

R-PHARM JSC (Russia)

ATC Code

J01DD16 (Cefditoren)

Active Substance

Cefditoren (Rec.INN registered by WHO)

Dosage Forms

	Spectracef	Film-coated tablets, 200 mg: 14 or 20 pcs.
		Film-coated tablets, 400 mg: 10 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, elliptical, with a blue marking “TMF” on one side; the core is light yellow on the cross-section.

Excipients: mannitol – as needed (approximately 35 mg), sodium caseinate – 100 mg, croscarmellose sodium – 150 mg, sodium tripolyphosphate – 4 mg, magnesium stearate – 5 mg, tablet film coating: Opadry white – 35 mg (hypromellose – 21.9 mg, titanium dioxide – 10.9 mg, macrogol-400 – 2.2 mg, carnauba wax – 0.06 mg), Opacode blue ink – as needed (shellac IN IMS 74 OP – 50.41%, N-butanol – 24.35%, aluminum lake based on brilliant blue FCF dye – 11.25%, titanium dioxide – 4.49%, propylene glycol – 2.91%, isopropanol – 4.65%, concentrated ammonia solution – 1.94%).

7 pcs. – Al/Al blisters (2) – cardboard packs.
10 pcs. – Al/Al blisters (2) – cardboard packs.

Film-coated tablets white, elliptical, with a blue marking “TMF” on one side; the core is light yellow on the cross-section.

Excipients: mannitol – as needed (approximately 70 mg), sodium caseinate – 200 mg, croscarmellose sodium – 300 mg, sodium tripolyphosphate – 8 mg, magnesium stearate – 10 mg, tablet film coating: Opadry white – 55 mg (hypromellose – 34.4 mg, titanium dioxide – 17.2 mg, macrogol-400 – 3.4 mg, carnauba wax – 0.01 mg), Opacode blue ink – as needed (shellac IN IMS 74 OP – 50.41%, N-butanol – 24.35%, aluminum lake based on brilliant blue FCF dye – 11.25%, titanium dioxide – 4.49%, propylene glycol – 2.91%, isopropanol – 4.65%, concentrated ammonia solution – 1.94%).

5 pcs. – Al/Al blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin

Pharmacotherapeutic Group

Antibiotic-cephalosporin

Pharmacological Action

Mechanism of action

Cefditoren pivoxil is a semisynthetic beta-lactam antibiotic, a prodrug of cefditoren (a third-generation cephalosporin). The mechanism of action of the drug is associated with inhibition of bacterial wall synthesis due to its affinity for penicillin-binding proteins.

Pharmacokinetic/pharmacodynamic features

When the drug is prescribed at a dose of 200 mg twice a day, the plasma concentration of cefditoren pivoxil exceeds the minimum inhibitory concentration for 90% of microorganisms (MIC₉₀) for Moraxella catarrhalis, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pyogenes and penicillin-susceptible strains of Streptococcus pneumoniae for at least 50% of the dosing interval. Prescribing cefditoren at a dose of 400 mg twice a day maintains its concentration above the MIC for 51% of the dosing interval, which exceeds the MIC for 50% of microorganisms (MIC₅₀) for penicillin-resistant Streptococcus pneumoniae.

Mechanisms of resistance

Cefditoren, as a third-generation cephalosporin, shares common resistance mechanisms for this group of antibiotics. Resistance of gram-positive microorganisms may be associated with altered penicillin-binding protein in Streptococcus pneumoniae and Streptococcus viridans, or the appearance of an additional penicillin-binding protein (PBP2a) in Staphylococcus spp. Cefditoren is resistant to most common chromosomal and plasmid beta-lactamases of gram-negative bacteria. However, like other cephalosporins, Cefditoren is hydrolyzed by plasmid-mediated broad-spectrum beta-lactamases. Furthermore, resistance can be caused by the production of chromosomal beta-lactamase in mutant strains of Enterobacter spp., Citrobacter spp., Morganella spp. and Serratia spp.

The mechanism of action of cefditoren is similar to other cephalosporin antibiotics and differs from the mechanism of action of other groups of antibiotics. In general, cross-resistance between cefditoren and other groups of antibiotics has not been noted. However, in rare cases, some mechanisms of action (e.g., related to inner membrane impermeability or the presence of an active antibiotic efflux mechanism from the cell) may be similar for all groups of antibiotics. This determines a certain level of resistance to all antibiotics.

Minimum Inhibitory Concentration (MIC)

Recommended MIC values for cefditoren, allowing classification of microorganisms as susceptible, intermediate, and resistant: susceptible – ≤0.5 µg/ml, intermediate – >0.5 µg/ml and <2 µg/ml, resistant - ≥2 µg/ml.

Susceptibility

Information on the susceptibility spectrum of the majority of microorganisms for approved indications is presented below.

The prevalence of acquired resistance may vary by geographic region and for individual pathogens. For this reason, it is desirable to obtain information on the susceptibility of microorganisms in a particular region, especially when treating severe infections. In cases where the resistance of pathogens is in doubt, a specialist should be consulted to assess the advisability of prescribing cefditoren in a specific clinical case.

Usually susceptible species (resistance less than 10%, European data)

Aerobic gram-positive microorganisms: Streptococcaceae groups C and G; methicillin-susceptible strains of Staphylococcus aureus¹, Streptococcus agalactiae, Streptococcus pneumoniae^1,2, Streptococcus pyogenes¹.

Aerobic gram-negative microorganisms: Haemophilus influenzae¹, Moraxella catarrhalis¹.

Anaerobic microorganisms: Clostridium perfringes, Peptostreptococcus spp.

Microorganisms with intrinsic resistance to cefditoren

Aerobic gram-positive microorganisms: Enterococcus spp.; methicillin-resistant strains of Staphylococcus aureus.

Aerobic gram-negative microorganisms: Acinetobacter baumannii, Pseudomonas aeruginosa.

Anaerobic microorganisms: Bacteroides fragilis group, Clostridium difficile.

Other: Chlamydia spp., Mycoplasma spp., Legionella spp.

¹ Clinical efficacy has been demonstrated for susceptible pathogens for approved indications.

² Some strains with high resistance to penicillin may have reduced susceptibility to cefditoren. Strains resistant to cefotaxime and ceftriaxone should not be considered susceptible to cefditoren.

Gram-negative microorganisms that contain chromosomal beta-lactamases, such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Serratia marcescens, must be considered resistant to cefditoren, despite their apparent in vitro susceptibility.

Pharmacokinetics

Absorption

After oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed by esterases to cefditoren. Oral administration of the drug at a dose of 200 mg after meals is accompanied by reaching a C_max of 2.6 µg/ml after approximately 2.5 hours, while administration of the drug at a dose of 400 mg leads to a C_max of 4.1 µg/ml after the same period of time. The absolute bioavailability of cefditoren after oral administration compared to intravenous administration is about 15-20%.

The presence of food in the gastrointestinal tract accelerates the absorption of cefditoren pivoxil, leading to an increase in C_max and AUC by 50% and 70%, respectively, compared to fasting values.

Distribution

The binding of cefditoren to plasma proteins is 88%. After multiple and single doses of the drug, the pharmacokinetic parameters did not differ; this indicates no accumulation.

The V_d of cefditoren at steady-state concentration does not differ significantly from this indicator calculated after a single administration, is practically independent of the administered dose, and always remains within 40-65 L.

After a single administration of the drug at a dose of 400 mg, penetration into the bronchial mucosa and secretion was 60% and 20%, respectively, of the plasma concentration. Results of administering a similar dose to healthy volunteers and subsequent assessment of antibiotic penetration into the interstitial fluid showed that after 8 and 12 hours, the concentration of cefditoren in the interstitial fluid reaches 40% and 56%, respectively, of the plasma AUC.

Metabolism and excretion

Regardless of the dose and duration of treatment, up to 18% of the administered dose of cefditoren is excreted unchanged by the kidneys.

The T_1/2 of the drug from plasma is about 1.0-1.5 hours. The total clearance corrected for bioavailability is about 25-30 L/h, renal clearance is about 80-90 ml/min. Studies of labeled cefditoren in healthy volunteers showed that the unabsorbed part of the drug is excreted through the intestine, and a large proportion of cefditoren is converted into inactive metabolites – P7 and M-OH. During the hydrolysis of cefditoren pivoxil, pivalate is formed, which is excreted by the kidneys as a conjugate of pivaloylcarnitine.

Pharmacokinetics in special patient groups

Gender. The pharmacokinetics of cefditoren pivoxil does not have significant differences in humans depending on gender.

Elderly patients. When the drug is prescribed in the same doses, the concentration of cefditoren in elderly patients (over 65 years of age) is somewhat higher compared to the adult middle-aged population; the C_max and AUC in such patients are approximately 26% and 33% higher, respectively. Except in cases of severe renal and/or hepatic impairment, no dose adjustment is required for elderly patients.

Renal impairment

After multiple administration of cefditoren pivoxil at a dose of 400 mg, the AUC values in healthy volunteers and patients with varying degrees of renal impairment are as follows:

¹ SD – standard deviation.

The noted changes in the pharmacokinetic parameters of cefditoren in patients with mild renal impairment are not considered clinically significant. In patients with moderate and severe renal failure, the AUC is approximately 3 times higher compared to healthy volunteers. Data currently available do not allow recommending any doses of the drug for patients on hemodialysis.

Hepatic impairment

The effect of mild and moderate hepatic impairment on the pharmacokinetics of cefditoren pivoxil after its administration at a dose of 400 mg includes a slight increase in the main pharmacokinetic parameters without statistically significant differences. Furthermore, a slight increase in the amount of the drug excreted by the kidneys was noted compared to healthy volunteers. Similar data in patients with severe hepatic insufficiency have not been obtained to date.

Indications

Treatment of infections caused by microorganisms susceptible to cefditoren

• Upper respiratory tract infections (acute tonsillopharyngitis, acute sinusitis);
• Lower respiratory tract infections (exacerbation of chronic bronchitis, community-acquired pneumonia);
• Uncomplicated skin and subcutaneous tissue infections (cellulitis, infected skin wounds, abscess, folliculitis, impetigo, and furunculosis).

ICD codes

Dosage Regimen

The drug is taken orally, preferably after meals. Tablets should be swallowed whole with plenty of water.

The recommended dose depends on the severity of the infection, the patient’s initial condition, and potential pathogens.

Adults and children over 12 years

Acute pharyngotonsillitis, acute sinusitis and uncomplicated skin and subcutaneous tissue infections: 200 mg every 12 hours for 10 days.

Exacerbation of chronic bronchitis: 200 mg every 12 hours for 5 days.

Community-acquired pneumonia: 200 mg every 12 hours for 14 days. In severe cases, the recommended dose is 400 mg every 12 hours for 14 days.

In elderly patients, except in cases of severe hepatic and/or renal impairment, no dose adjustment is required.

In patients with mild renal impairment, no dose adjustment is required. In patients with moderate renal failure (CrCl 30-50 ml/min) the dose should not exceed 200 mg twice a day. In patients with severe renal failure (CrCl less than 30 ml/min) the maximum daily dose should not exceed 200 mg. In patients on hemodialysis, the recommended dose has not been established.

In patients with mild or moderate hepatic impairment (Child-Pugh classes A or B) no dose adjustment is required. In severe hepatic insufficiency (Child-Pugh class C) data to prescribe a recommended dose have not been obtained.

Adverse Reactions

The adverse events presented below are listed according to the anatomical-physiological classification and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000, including isolated cases).

Blood and lymphatic system disorders uncommon – eosinophilia; rare – granulocytopenia, hemolytic anemia, agranulocytosis, hypoprothrombinemia, bleeding tendency, lymph node enlargement.

Vascular disorders: rare – shock.

Gastrointestinal disorders common – diarrhea; uncommon – soft stools, dyspepsia, abdominal discomfort, abdominal pain; rare – pseudomembranous colitis, feeling of abdominal distension, nausea, vomiting, stomatitis, glossitis.

Hepatobiliary disorders rare – jaundice, impaired liver function.

Immune system disorders rare – anaphylaxis.

Infections and infestations rare – candidiasis.

Metabolism and nutrition disorders rare – anorexia, symptoms due to vitamin K deficiency, symptoms due to vitamin B group deficiency.

Musculoskeletal and connective tissue disorders rare – arthralgia.

Nervous system disorders rare – headache, neuritis, dizziness, numbness; frequency unknown – convulsions.

Renal and urinary disorders rare – acute renal failure, proteinuria.

Respiratory, thoracic and mediastinal disorders: rare – interstitial pneumonia, pulmonary eosinophilic infiltrate.

Skin and subcutaneous tissue disorders uncommon – rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), urticaria, erythema, pruritus.

Investigations uncommon – increased ALT, AST; rare – thrombocytopenia, increased serum creatinine, increased blood urea nitrogen, increased ALP; frequency unknown – decreased serum carnitine concentration.

General disorders and administration site conditions rare – edema, fever.

Contraindications

• Hypersensitivity to cefditoren, other cephalosporins or any other component of the drug;
• Severe allergic reactions to penicillins and other beta-lactam antibacterial drugs;
• Hepatic insufficiency class C according to Child-Pugh;
• Patients on hemodialysis;
• History of hypersensitivity reactions to the protein casein;
• Primary carnitine deficiency;
• Children under 12 years of age;
• Concomitant use of cefditoren pivoxil and histamine H₂-receptor blockers.

With caution

Patients with hypersensitivity to other beta-lactam antibiotics due to the possibility of cross-allergic reactions.

Patients with an individual or family/hereditary predisposition to the development of allergic reactions, such as bronchial asthma, rash, or urticaria.

Patients with severe renal impairment.

Elderly patients.

Concomitant use with aminoglycosides and diuretics (furosemide).

Patients with gastrointestinal pathology (including a history of colitis).

Patients with difficulty eating (with swallowing disorders) or those receiving parenteral nutrition, as well as patients in poor general health (such patients should be closely monitored due to the risk of potassium deficiency).

Use in Pregnancy and Lactation

Pregnancy

Clinical data on the use of cefditoren pivoxil in pregnant women are not available. Although animal studies have not shown embryotoxic or teratogenic effects of the drug, Spectracef should not be used during pregnancy except in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Cases of hypocarnitinemia have also been reported in both women receiving antimicrobial drugs containing pivoxil and in their newborn children.

Breastfeeding period

Data on the penetration of cefditoren into breast milk are insufficient. Therefore, breastfeeding should be discontinued while using Spectracef.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure of class C according to the Child-Pugh scale.

Use in Renal Impairment

The use of the drug is contraindicated in patients on hemodialysis.

The drug should be prescribed with caution to patients with severe renal impairment.

Pediatric Use

Contraindicated in children under 12 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Before prescribing Spectracef, the patient’s history of allergic reactions should be carefully ascertained.

If a hypersensitivity reaction develops, treatment should be discontinued and the patient should be given the necessary treatment.

Elderly patients. The incidence of adverse reactions in elderly patients does not differ from that in the general population. Nevertheless, caution should be exercised when prescribing Spectracef due to reduced physiological functions in the elderly; it is recommended to adjust doses and intervals between them according to the current condition of the patients. For example, delayed excretion of the drug was observed in patients with impaired renal function, and the blood concentration of the drug was increased. A tendency to bleeding in elderly patients due to vitamin K deficiency after the use of cephalosporin group drugs has also been reported.

As with the use of other broad-spectrum antibiotics, treatment with cefditoren may lead to the overgrowth of resistant microflora. For this reason, it is recommended to monitor patients receiving this drug, especially in the case of long-term treatment.

In patients with severe renal failure, periodic monitoring of renal function is recommended.

During a course of treatment with cephalosporins, a decrease in prothrombin activity is possible. For this reason, in patients at risk (with renal or hepatic insufficiency or in case of prior prescription of anticoagulants), monitoring of prothrombin time is necessary.

The development of diarrhea during or after treatment, especially if it is severe, persistent, and contains blood, may indicate pseudomembranous colitis. In mild cases of diarrhea, discontinuation of the drug is sufficient; in more severe cases, therapy with antibiotics to which Clostridium difficile is sensitive and the appointment of infusion therapy are indicated.

Like other cephalosporins, Cefditoren may lead to a false-positive result of the direct Coombs test, detection of glucose in urine using the copper reduction test, but not when using the enzymatic test.

Due to the high risk of a false-negative result of the ferricyanide test for determining plasma glucose, it is recommended that the glucose oxidase or glucose hexokinase methods be used to determine plasma glucose concentration in patients receiving cefditoren treatment.

When combining cephalosporins with aminoglycosides and/or loop diuretics, especially in patients with impaired renal function, the risk of nephrotoxicity may increase.

Neurotoxicity. Cases of neurotoxicity associated with cephalosporin treatment have been reported. Symptoms include encephalopathy, seizures, and/or myoclonus. Risk factors include old age, renal failure, central nervous system diseases, and intravenous administration. If symptoms of neurotoxicity appear, discontinuation of the drug should be considered.

Spectracef contains approximately 13.1 mg (for 200 mg tablets) and 26.2 mg (for 400 mg tablets) of sodium in each dose, which must be taken into account when prescribing the drug to patients on a low-sodium diet.

A decrease in serum carnitine has been reported as a consequence of the metabolism of pivalic acid (a metabolite of pivoxil group drugs) during the administration of drugs containing pivoxil.

Effect on the ability to drive vehicles and mechanisms

No effect of cefditoren pivoxil on the ability to drive a car and/or other mechanisms has been reported. At the same time, it should be taken into account that taking Spectracef may be accompanied by such adverse events as vomiting and headache.

Overdose

Symptoms may include nausea, vomiting, diarrhea.

Treatment in case of clinical manifestations of drug overdose, symptomatic therapy is indicated.

Drug Interactions

Antacids

Concomitant administration after meals of cefditoren pivoxil and antacids containing magnesium or aluminum hydroxide reduces the C_max and AUC of cefditoren by 14% and 11%, respectively. Although the clinical significance of this fact is unknown, it is recommended that the interval between taking antacids and cefditoren pivoxil be 2 hours.

Probenecid

Concomitant use of probenecid and cefditoren pivoxil reduces the renal excretion of the antibiotic, increasing the C_max by 49%, AUC by 122%, and increasing the T_1/2 of cefditoren by 53%.

Histamine H₂-receptor blockers

Simultaneous intravenous administration of famotidine and oral cefditoren pivoxil leads to a decrease in C_max and AUC by 27% and 22%, respectively. Thus, concomitant use of cefditoren pivoxil and histamine H₂-receptor blockers is not recommended.

Oral contraceptives

Concomitant use of cefditoren pivoxil and the oral contraceptive ethinylestradiol does not lead to changes in the pharmacokinetic properties of this contraceptive.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.