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Spectracef

Generic Name: Cefditoren Pivoxil
Class: Third Generation Cephalosporins
Chemical Name: (+) - (6R,7R) - 7 - [2 - (2 - Amino - 4 - thiazolyl)glyoxylamido - 3 - [(Z) - 2 - (4 - methyl - 5 - thiazolyl)vinyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid
Molecular Formula: C19H18N6O5S3
CAS Number: 104145-95-1

Introduction

Antibacterial; β-lactam antibiotic; aminothiazolyl third generation cephalosporin.2 3

Uses for Spectracef

Pharyngitis and Tonsillitis

Treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes (group A β-hemolytic streptococci).1 3 Generally effective in eradicating S. pyogenes from the nasopharynx; efficacy in prevention of subsequent rheumatic fever not established to date.1

AAP, IDSA, AHA, and others recommend a penicillin regimen (10-day regimen of oral penicillin V or oral amoxicillin or single dose of IM penicillin G benzathine) as treatment of choice for S. pyogenes pharyngitis and tonsillitis;10 11 16 17 other anti-infectives (oral cephalosporins, oral macrolides, oral clindamycin) recommended as alternatives in penicillin-allergic patients.10 16 17

Slideshow: Flashback: FDA Drug Approvals 2013

If an oral cephalosporin used, 10-day regimen of first generation cephalosporin (cefadroxil, cephalexin) preferred instead of other cephalosporins with broader spectrums of activity (e.g., cefaclor, cefdinir, cefixime, cefpodoxime, cefuroxime).10 16 17

Respiratory Tract Infections

Treatment of mild to moderate acute bacterial exacerbations of chronic bronchitis caused by susceptible Haemophilus influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), S. pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).1 3

Treatment of community-acquired pneumonia (CAP) caused by H. influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), S. pneumoniae (penicillin-susceptible strains only), or M. catarrhalis (including β-lactamase-producing strains).1 If an oral cephalosporin used as an alternative to penicillin G or amoxicillin for treatment of CAP caused by penicillin-susceptible S. pneumoniae, ATS and IDSA recommend cefdinir, cefditoren, cefpodoxime, cefprozil, or cefuroxime.9

Skin and Skin Structure Infections

Treatment of uncomplicated skin and skin structure infections caused by susceptible Staphylococcus aureus (including β-lactamase-producing strains) or S. pyogenes.1 3

Spectracef Dosage and Administration

Administration

Oral Administration

Administer orally with meals (to enhance GI absorption).1 3 (See Food under Pharmacokinetics.)

Dosage

Available as cefditoren pivoxil; dosage expressed in terms of cefditoren.1

Pediatric Patients

Pharyngitis and Tonsillitis
Oral

Children ≥12 years of age: 200 mg twice daily for 10 days.1

Respiratory Tract Infections
Acute Bacterial Exacerbations of Chronic Bronchitis
Oral

Children ≥12 years of age: 400 mg twice daily for 10 days.1

Community-acquired Pneumonia
Oral

Children ≥12 years of age: 400 mg twice daily for 14 days.1

Skin and Skin Structure Infections
Oral

Children ≥12 years of age: 200 mg twice daily for 10 days.1

Adults

Pharyngitis and Tonsillitis
Oral

200 mg twice daily for 10 days.1

Respiratory Tract Infections
Acute Bacterial Exacerbations of Chronic Bronchitis
Oral

400 mg twice daily for 10 days.1

Community-acquired Pneumonia
Oral

400 mg twice daily for 14 days.1

Skin and Skin Structure Infections
Oral

200 mg twice daily for 10 days.1

Special Populations

Hepatic Impairment

Dosage adjustments not required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustments not required in patients with mild renal impairment (Clcr 50–80 mL/min per 1.73 m2).1

Maximum dosage of 200 mg twice daily recommended for those with moderate renal impairment (Clcr 30–49 mL/min per 1.73 m2).1

Maximum dosage of 200 mg once daily recommended for those with severe renal impairment (Clcr <30 mL/min per 1.73 m2).1

Appropriate dosage for patients with end-stage renal disease not determined.1

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 3 Cautious dosage selection because of age-related decreases in renal function.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Spectracef

Contraindications

  • Known hypersensitivity to cefditoren, other cephalosporins, or any ingredient in the formulation.1

  • Carnitine deficiency or an inborn error of metabolism that may result in clinically important carnitine deficiency.1

  • Milk protein hypersensitivity (not lactose intolerance).1

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Possible emergence and overgrowth of nonsusceptible organisms with prolonged use.1 Careful observation of the patient is essential.1 Institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 42 C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including cefditoren, and may range in severity from mild diarrhea to fatal colitis.1 42 C. difficile produces toxins A and B which contribute to development of CDAD.42

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 42 Obtain careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.42

If CDAD is suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible.42 Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1 42

Sensitivity Reactions

Hypersensitivity Reactions

Possible hypersensitivity reactions such as urticaria, pruritus, rash (maculopapular, erythematous, morbilliform), fever and chills, eosinophilia, joint pain or inflammation, edema, erythema, genital and anal pruritus, angioedema, shock, hypotension, vasodilatation, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, and anaphylaxis reported with cephalosporins.1

If hypersensitivity reactions occur, discontinue cefditoren and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).1

Cross-hypersensitivity

Partial cross-sensitivity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.1

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.1 Cautious use recommended in patients with a history of hypersensitivity to penicillins:1 avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction 1 and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.a

Hypersensitivity to Milk Protein

Cefditoren tablets contain sodium caseinate, a milk protein, and should not be used in patients with milk protein hypersensitivity (not lactose intolerance).1

General Precautions

Carnitine Deficiency

Cefditoren pivoxil should not be used when prolonged anti-infective therapy is required since use of other pivalate-containing compounds over periods of months have caused clinical manifestations of carnitine deficiency.1

In individuals receiving short-term treatment with cefditoren pivoxil (200 or 400 mg of cefditoren twice daily for 14 days), a 30–63% decrease in serum carnitine concentrations has occurred; no adverse effects attributable to decreased carnitine concentrations were reported and concentrations returned to normal 7–10 days after the drug was discontinued.1

Cefditoren pivoxil causes renal excretion of carnitine,1 and asymptomatic reductions in plasma carnitine concentrations have been reported with short-term (10–14 days) treatment with the drug.1 The possible effects of repeated short-term use on carnitine concentrations are not known.1

Cefditoren should not be used in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically important carnitine deficiency.1 In addition, the fact that some patients (e.g., those with renal impairment or decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren therapy should be considered.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefditoren and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Hematologic Effects

Reduction in prothrombin activity reported rarely with cephalosporins.1 Monitor PT and administer vitamin K as indicated in patients at risk for reduced prothrombin activity (e.g., patients with renal or hepatic impairment or poor nutritional status, patients receiving prolonged antimicrobial therapy or previously stabilized on anticoagulant therapy).1

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; use with caution in nursing women.1

Pediatric Use

Safety and efficacy (including any effect of altered carnitine concentrations) not established in infants and children <12 years of age;1 use in this age group not recommended.1 3

Geriatric Use

Safety and efficacy in those >65 years of age similar to that in younger adults.1

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.1 Select dosage with caution and consider monitoring renal function because of age-related decreases in renal function.1 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

AUC increased slightly in adults with mild or moderate hepatic impairment (Child-Pugh class A or B);1 no dosage adjustments required in these patients.1

Not studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Decreased clearance.1

Reduce dosage in those with Clcr <50 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 3 nausea,1 3 headache,1 3 abdominal pain,1 3 vaginal moniliasis,1 3 dyspepsia,1 vomiting.1 3

Interactions for Spectracef

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antacids (aluminum- or magnesium-containing)

Decreased absorption of cefditoren1

Do not administer antacids containing aluminum or magnesium concomitantly with cefditoren1

Histamine H2-receptor antagonists (famotidine)

Possible decreased absorption of cefditoren.1 3

Do not administer H2-receptor antagonists concomitantly with cefditoren1

Hormonal contraceptives

No effect on the pharmacokinetics of ethinyl estradiol.1 3

May be used concomitantly with oral contraceptives1

Probenecid

Increased cefditoren plasma concentrations and half-life 1

Tests for glucose

Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1

Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)1

Spectracef Pharmacokinetics

Absorption

Bioavailability

Cefditoren pivoxil is a prodrug that is absorbed from the GI tract and hydrolyzed by esterases to the active metabolite, cefditoren.1

Absolute bioavailability only 14% when given without food;1 peak plasma concentrations of cefditoren attained within 1.5–3 hours.1

Food

Administration with a moderate- or high-fat meal increases the rate and extent of absorption.1

Distribution

Extent

Distributed into tonsils and skin blister fluid.1

Distributed into milk in rats.1

Plasma Protein Binding

88%;1 binding is independent of concentration.1

Binds principally to albumin; 3.3–8.1% bound to α-1-acid glycoprotein.1

Elimination

Metabolism

Cefditoren pivoxil is a prodrug and has little, if any, antibacterial activity until hydrolyzed in vivo by esterases to cefditoren.1 Hydrolysis of the drug also results in the formation of pivalate, which is absorbed and excreted as pivaloylcarnitine in urine.1

Cefditoren is not appreciably metabolized.1

Elimination Route

Principally eliminated in urine by renal tubular excretion and glomerular filtration.1

Half-life

Terminal elimination half-life is 1.6 hours in adults with normal renal function.1

Special Populations

AUC only slightly increased in adults with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Pharmacokinetics have not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Clearance of the drug reduced in those with renal impairment.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from light and moisture; dispense in a tight, light-resistant container.1

Actions and Spectrum

  • Third-generation cephalosporin with an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.1 3 4 In addition, the methylthiazolyl group in cefditoren enhances activity against gram-positive bacteria.3

  • Cefditoren pivoxil is a prodrug and has little, if any, antibacterial activity until hydrolyzed in vivo to cefditoren.1 3

  • Usually bactericidal.1

  • Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 a

  • In vitro spectrum of activity includes many gram-positive aerobic bacteria and some gram-negative aerobic bacteria; inactive against fungi and viruses.1 a

  • Gram-positive aerobes: active in vitro and in clinical infections against Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains, including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Streptococcus pyogenes (group A β-hemolytic streptococci).1 Also active in vitro against Streptococcus agalactiae (group B streptococci), groups C and G streptococci, and viridans streptococci (penicillin-susceptible and -intermediate strains).1 Methicillin-resistant (oxacillin-resistant) staphylococci are resistant.1

    Gram-negative aerobes: active in vitro and in clinical infections against Haemophilus influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), and Moraxella catarrhalis (including β-lactamase-producing strains).1

Advice to Patients

  • Advise patients that antibacterials (including cefditoren) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefditoren or other antibacterials in the future.1

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.a Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.a

  • Importance of avoiding use of cefditoren tablets in patients with milk protein hypersensitivity (not lactose intolerance).1 3

  • Importance of taking cefditoren with meals for optimum absorption.1 3

  • Advise patients that cefditoren may be used concomitantly with oral estrogen-progestin contraceptives.1 3

  • Importance of discontinuing cefditoren and informing clinician if an allergic reaction occurs.1 3

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 3

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 3

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Cefditoren Pivoxil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg (of cefditoren)

Spectracef

Vansen

400 mg (of cefditoren)

Spectracef

Vansen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Spectracef 200MG Tablets (CORNERSTONE BIOPHARMA): 20/$299.98 or 40/$575.97

Spectracef 200MG Tablets (CORNERSTONE BIOPHARMA): 60/$342.01 or 180/$992.02

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Vansen Pharma Inc. Spectracef (cefditoren pivoxil) tablets prescribing information. Westmount, QC; 2011.

2. Johnson DM, Biedenbach DJ, Beach ML et al. Antimicrobial activity and in vitro susceptibility test development for cefditoren against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus species. Diagn Microbiol Infect Dis. 2000; 37:99-105. [PubMed 10863104]

3. Kuti JL. Cefditoren pivoxil: a novel broad-spectrum oral cephalosporin. Formulary. 2001; 36:265-75.

4. Yamaguchi K, Domon H, Miyazaki S et al. In vitro and in vivo antibacterial activities of CS-834, a new oral carbapenem. Antimicrob Agents Chemother. 1998; 42:555-63. [IDIS 401366] [PubMed 9517932]

9. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44 Suppl 2:S27-72. [PubMed 17278083]

10. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

11. Anon. Drugs for bacterial infections. Med Lett Treat Guid. 2010; 8:43-52.

16. Shulman ST, Bisno AL, Clegg HW et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012; 55:1279-82. [PubMed 23091044]

17. Gerber MA, Baltimore RS, Eaton CB et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009; 119:1541-51. [PubMed 19246689]

42. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. [PubMed 20307191]

a. AHFS Drug Information 2009. McEvoy GK, ed. Cephalosporins General Statement. American Society of Health-System Pharmacists; 2009.

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