Data from FDA - Curated by EPG Health - Last updated 20 December 2016

Indication(s)

INDICATIONS AND USAGE Cefditoren Pivoxil is indicated for the treatment of mild to moderate infections in adults and adolescents (12 years of age or older) which are caused by susceptible strains of the designated microorganisms in the conditions listed below.

Acute Bacterial Exacerbation of Chronic Bronchitis caused by Haemophilus influenzae (including?-lactamase-producing strains), Haemophilus parainfluenzae (including?-lactamase producing strains), Streptococcus pneumoniae (penicillin susceptible strains only), or Moraxella catarrhalis (including?-lactamase-producing strains).

Community-Acquired Pneumonia caused by Haemophilus influenzae (including?-lactamase-producing strains), Haemophilus parainfluenzae (including?-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including?-lactamase producing strains).

Pharyngitis/Tonsillitis caused by Streptococcus pyogenes.

NOTE:

Cefditoren Pivoxil is effective in the eradication of Streptococcus pyogenes from the oropharynx.

Cefditoren Pivoxil Tablets has not been studied for the prevention of rheumatic fever following Streptococcus pyogenes pharyngitis/tonsillitis.

Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.

Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including?-lactamase-producing strains) or Streptococcus pyogenes.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefditoren Pivoxil and other antibacterial drugs, Cefditoren Pivoxil should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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Advisory information

contraindications

CONTRAINDICATIONS Cefditoren Pivoxil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or any of its components.

Cefditoren Pivoxil is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of Cefditoren Pivoxil causes renal excretion of carnitine.

(See PRECAUTIONS, General.)

Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein.

Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.

Special warnings and precautions

PRECAUTIONS General Prescribing Cefditoren Pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Cefditoren Pivoxil is not recommended when prolonged antibiotic treatment is necessary, since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months.

No clinical effects of carnitine decrease have been associated with short-term treatment.

The effects on carnitine concentrations of repeat short-term courses of Cefditoren Pivoxil are not known.

In community-acquired pneumonia patients (N= 192, mean age 50.3 ± 17.2 years) given a 200 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 13.8 ± 10.8 nmole/mL, representing a 30 % decrease in serum carnitine concentrations.

In community-acquired pneumonia patients (N= 192, mean age 51.3 ± 17.8 years) given a 400 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 21.5 ± 13.1 mole/mL, representing a 46 % decrease in serum carnitine concentrations.

Plasma concentrations of carnitine returned to the normal control range within 7 days after discontinuation of cefditoren pivoxil.

Comparable decreases in carnitine were observed in healthy volunteers (mean age 33.6 ± 7.4 years) following a 200 mg or 400 mg BID regimen.

(See CLINICAL PHARMACOLOGY.)

Community-acquired pneumonia clinical trials demonstrated no adverse events attributable to decreases in serum carnitine concentrations.

However, some sub-populations (e.g., patients with renal impairment, patients with decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren pivoxil therapy.

Furthermore, the appropriate dose in patients with end-stage renal disease has not been determined.

(See DOSAGE AND ADMINISTRATION, Patients with Renal Insufficiency).

As with other antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms.

Careful observation of the patient is essential.

If superinfection occurs during therapy, appropriate alternative therapy should be administered.

Cephalosporins may be associated with a fall in prothrombin activity.

Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy.

Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.

In clinical trials, there was no difference between cefditoren and comparator cephalosporins in the incidence of increased prothrombin time.

Information for Patients Patients should be counseled that antibacterial drugs including

Cefditoren Pivoxil should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When Cefditoren Pivoxil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefditoren Pivoxil or other antibacterial drugs in the future.

Cefditoren Pivoxil should be taken with meals to enhance absorption.

Cefditoren Pivoxil may be taken concomitantly with oral contraceptives.

It is not recommended that Cefditoren Pivoxil be taken concomitantly with antacids or other drugs taken to reduce stomach acids.

(See PRECAUTIONS, Drug Interactions.)

Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein.

Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.

Drug Interactions Oral Contraceptives Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.

Antacids Co-administration of a single dose of an antacid which contained both magnesium (800 mg) and aluminum (900 mg) hydroxides reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 14 % decrease in mean Cmax and an 11 % decrease in mean AUC.

Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with antacids.

H2-Receptor Antagonists Co-administration of a single dose of intravenously administered famotidine (20 mg) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 27 % decrease in mean Cmax and a 22 % decrease in mean AUC.

Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists.

Probenecid As with other?-lactam antibiotics, co-administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren, with a 49 % increase in mean Cmax, a 122 % increase in mean AUC, and a 53 % increase in t1/2.

Drug/Laboratory Test Interactions Cephalosporins are known to occasionally induce a positive direct Coombs ' test.

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict 's or Fehling 's solution or with CLINITEST® tablets), but not with enzyme-based tests for glycosuria (e.g., CLINISTIX®, TES-TAPE®).

As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood/plasma glucose levels in patients receiving cefditoren pivoxil.

Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal carcinogenicity studies have been conducted with cefditoren pivoxil.

Cefditoren pivoxil was not mutagenic in the Ames bacterial reverse mutation assay, or in the mouse lymphoma mutation assay at the hypoxanthineguanine phosphoribosyltransferase locus.

In Chinese hamster lung cells, chromosomal aberrations were produced by cefditoren pivoxil, but not by cefditoren.

Subsequent studies showed that the chromosome aberrations were due to the release of formaldehyde from the pivoxil ester moiety in the in_vitro assay system.

Neither cefditoren nor cefditoren pivoxil produced chromosomal aberrations when tested in an in_vitro human peripheral blood lymphocyte assay, or in the in_vivo mouse micronucleus assay.

Cefditoren pivoxil did not induce unscheduled DNA syntheses when tested.

In rats, fertility and reproduction were not affected by cefditoren pivoxil at oral doses up to 1000 mg/ kg/day, approximately 24 times a human dose of 200 mg BID based on mg/ m2/day.

Pregnancy-Teratogenic Effects Pregnancy Category B Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits.

In rats, this dose was 1000 mg/kg/day, which is approximately 24 times a human dose of 200 mg BID based on mg/ m2/day.

In rabbits, the highest dose tested was 90 mg/kg/day, which is approximately four times a human dose of 200 mg BID based on mg/ m2/day.

This dose produced severe maternal toxicity and resulted in fetal toxicity and abortions.

In a postnatal development study in rats, cefditoren pivoxil produced no adverse effects on postnatal survival, physical and behavioral development, learning abilities, and reproductive capability at sexual maturity when tested at doses of up to 750 mg/kg/day, the highest dose tested.

This is approximately 18 times a human dose of 200 mg BID based on mg/ m2/day.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery Cefditoren pivoxil has not been studied for use during labor and delivery.

Nursing Mothers Cefditoren was detected in the breast milk of lactating rats.

Because many drugs are excreted in human breast milk, caution should be exercised when cefditoren pivoxil is administered to nursing women.

Pediatric Use Use of cefditoren pivoxil is not recommended for pediatric patients less than 12 years of age.

The safety and efficacy of cefditoren pivoxil tablets in this population, including any effects of altered carnitine concentration, have not been established.

(See PRECAUTIONS, General.)

Geriatric Use Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg BID, 308 (12 %) were >65 years of age.

Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg BID, 307 (14 %) were >65 years of age.

No clinically significant differences in effectiveness or safety were observed between older and younger patients.

No dose adjustments are necessary in geriatric patients with normal (for their age) renal function.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

(See DOSAGE AND ADMINISTRATION.

)

Adverse reactions

ADVERSE EVENTS Clinical Trials - Cefditoren Pivoxil Tablets (Adults and Adolescent Patients?12 Years of Age) In clinical trials, 4834 adult and adolescent patients have been treated with the recommended doses of cefditoren pivoxil tablets (200 mg or 400 mg BID).

Most adverse events were mild and self-limiting.

No deaths or permanent disabilities have been attributed to cefditoren.

The following adverse events were thought by the investigators to be possibly, probably, or definitely related to cefditoren tablets in multiple-dose clinical trials: Treatment-Related Adverse Events in Trials in Adults and Adolescent Patients?

12 Years of age) Cefditoren Pivoxil Comparatorsa 200 mg BID 400 mg BID N=2675 N=2159 N=2648 Incidence?

Diarhea 11 % 15 % 8 % 1 % Nausea 4 % 6 % 5 % Headache 3 % 2 % 2 % Abdominal Pain 2 % 2 % 1 % Vaginal Moniliasis 3 % b 6 % c 6 % d Dyspepsia 1 % 2 % 2 % Vomiting 1 % 1 % 2 % aincludes amoxicillin/clavulanate, cefadroxil monohydrate, cefuroxime axetil, cefpodoxime proxetil, clarithromycin, and penicillin b1428 females c1135 females d1461 females The overall incidence of adverse events, and in particular diarrhea, increased with the higher recommended dose of Cefditoren Pivoxil.

Treatment related adverse events experienced by <1 % but >0.1 % of patients who received 200 mg or 400 mg BID of cefditoren pivoxil were abnormal dreams, allergic reaction, anorexia, asthenia, asthma, coagulation time increased, constipation, dizziness, dry mouth, eructation, face edema, fever, flatulence, fungal infection, gastrointestinal disorder, hyperglycemia, increased appetite, insomnia, leukopenia, leukorrhea, liver function test abnormal, myalgia, nervousness, oral moniliasis, pain, peripheral edema, pharyngitis, pseudomembranous colitis, pruritus, rash, rhinitis, sinusitis, somnolence, stomatitis, sweating, taste perversion, thirst, thrombocythemia, urticaria, and vaginitis.

Pseudomembranous colitis symptoms may begin during or after antibiotic treatment.

(See WARNINGS.)

Sixty-one of 2675 (2 %) patients who received 200 mg BID and 69 of 2159 (3 %) patients who received 400 mg BID of cefditoren pivoxil discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefditoren therapy.

The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea.

Diarrhea was the reason for discontinuation in 19 of 2675 (0.7 %) patients who received 200 mg BID and in 31 of 2159 (1.4 %) patients who received 400 mg BID of cefditoren pivoxil.

Changes in laboratory parameters of possible clinical significance, without regard to drug relationship and which occurred in?1 % of patients who received cefditoren pivoxil 200 mg or 400 mg BID, were hematuria (3.0 % and 3.1 %), increased urine white blood cells (2.3 % and 2.3 %), decreased hematocrit (2.1 % and 2.2 %), and increased glucose (1.8 % and 1.1 %).

Those events which occurred in <1 % but >0.1 % of patients included the following: increased/decreased white blood cells, increased eosinophils, decreased neutrophils, increased lymphocytes, increased platelet count, decreased hemoglobin, decreased sodium, increased potassium, decreased chloride, decreased inorganic phosphorus, decreased calcium, increased SGPT/ALT, increased SGOT/AST, increased cholesterol, decreased albumin, proteinuria, and increased BUN.

It is not known if these abnormalities were caused by the drug or the underlying condition being treated.

Cephalosporin Class Adverse Reactions In addition to the adverse reactions listed above which have been observed in patients treated with cefditoren pivoxil, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: Adverse Reactions: Allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection.

Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coombs ' test, false-positive test for urinary glucose, elevated alkaline phosphatase, elevated bilirubin, levated LDH, increased creatinine, pancytopenia, neutropenia, and agranulocytosis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced.

(See DOSAGE AND ADMINISTRATION.)

If seizures associated with drug therapy occur, the drug should be discontinued.

Anticonvulsant therapy can be given if clinically indicated.

Postmarketing Experience The following adverse experiences, regardless of their relationship to cefditoren pivoxil, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1994: pneumonia interstitial, eosinophilic pneumonia acute , acute renal failure, arthralgia, thrombocytopenia, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis and anaphylactoid reactions which may be accompanied by hypotension.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION (See INDICATIONS AND USAGE for Indicated Pathogens.)

Cefditoren Pivoxil Dosage and Administration * Adults and Adolescents (?

12 Years) Type of Infection Dosage Duration (Days) Community-Acquired Pneumonia 400 mg BID 14 Acute Bacterial Exacerbation of Chronic Bronchitis 400 mg BID 10 Pharyngitis/Tonsillitis 200 mg BID Uncomplicated Skin and Skin Structure Infections * Should be taken with meals Patients with Renal Insufficiency No dose adjustment is necessary for patients with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2).

It is recommended that not more than 200 mg BID be administered to patients with moderate renal impairment (CLcr: 30-49 mL/min/1.73 m2) and 200 mg QD be administered to patients with severe renal impairment (CLcr: <30 mL/min/1.73 m2).

The appropriate dose in patients with end-stage renal disease has not been determined.

Patients with Hepatic Disease No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).

The pharmacokinetics of cefditoren have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Pregnancy and lactation
Nursing Mothers Cefditoren was detected in the breast milk of lactating rats. Because many drugs are excreted in human breast milk, caution should be exercised when cefditoren pivoxil is administered to nursing women.

Interactions

Drug Interactions Oral Contraceptives Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.

Antacids Co-administration of a single dose of an antacid which contained both magnesium (800 mg) and aluminum (900 mg) hydroxides reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 14 % decrease in mean Cmax and an 11 % decrease in mean AUC.

Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with antacids.

H2-Receptor Antagonists Co-administration of a single dose of intravenously administered famotidine (20 mg) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 27 % decrease in mean Cmax and a 22 % decrease in mean AUC.

Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists.

Probenecid As with other?-lactam antibiotics, co-administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren, with a 49 % increase in mean Cmax, a 122 % increase in mean AUC, and a 53 % increase in t1/2.

More information

Category Value
Authorisation number NDA021222
Orphan designation No
Product NDC 44009-802,44009-801
Date Last Revised 04-06-2013
Type HUMAN PRESCRIPTION DRUG
RXCUI 351127
Marketing authorisation holder Pharma RomLev Inc.