Cefditoren Pivoxil

SPECTRACEF® (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 β-lactamase-producing strains), Haemophilus parainfluenzae (including β-lactamase producing strains), Streptococcus pneumoniae (penicillin susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).

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

Pharyngitis/Tonsillitis caused by Streptococcus pyogenes. NOTE: SPECTRACEF® is effective in the eradication of Streptococcus pyogenes from the oropharynx. SPECTRACEF® 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 β-lactamase-producing strains) or Streptococcus pyogenes.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of SPECTRACEF® and other antibacterial drugs, SPECTRACEF® 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.

SPECTRACEF® (cefditoren pivoxil) tablets containing cefditoren pivoxil equivalent to 200 mg or 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” or “CBP 400” in blue. These tablets are available in a multi-dose tamper-evident container, or as the 1-count blister package (Physician Sample), as follows:

NDC 10122-802-60: 400 mg 60 count bottles. SPECTRACEF tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.

NDC 10122-802-20: 400 mg 20 count bottles. SPECTRACEF tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.

NDC 10122-802-02: 400 mg 1 count blister. SPECTRACEF tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.

NDC 10122-801-60: 200 mg 60 count bottles. SPECTRACEF tablets containing cefditoren pivoxil equivalent to 200 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” in blue.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container. Healthcare professionals can telephone Aristos Pharmaceuticals Information Line (1-866-280-5755) for information on this product.

REFERENCES

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100-S22, 2012.

Manufactured by: Tedec-Meiji Farma, S.A Madrid, Spain. Distributed by: Cornerstone Therapeutics Inc. Cary, NC 27518

Pharmacokinetics

Oral Bioavailability

Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) of cefditoren under fasting conditions average 1.8 ± 0.6 μg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing.

Less than dose-proportional increases in Cmax and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%. The absolute bioavailability of cefditoren pivoxil administered with a low fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein) is 16.1 ± 3.0%.

Administration of cefditoren pivoxil following a high fat meal (858 cal, 64 g fat, 43 g carb, 31 g protein) resulted in a 70% increase in mean AUC and a 50% increase in mean Cmax compared to administration of cefditoren pivoxil in the fasted state. After a high fat meal, the Cmax averaged 3.1 ± 1.0 μg/mL following a single 200 mg dose of cefditoren pivoxil and 4.4 ± 0.9 μg/mL following a 400 mg dose. Cefditoren AUC and Cmax values from studies conducted with a moderate fat meal (648 cal, 27 g fat, 73 g carb, 29 g protein) are similar to those obtained following a high fat meal.

The mean volume of distribution at steady state (Vss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to10 μg/mL. Cefditoren is primarily bound to human serum albumin and its binding is decreased when serum albumin concentrations are reduced. Binding to α-1acid glycoprotein ranges from 3.3 to 8.1%. Penetration into red blood cells is negligible.

Maximal concentrations of cefditoren in suction-induced blister fluid were observed 4 to 6 hours following administration of a 400 mg dose of cefditoren pivoxil with a mean of 1.1 ± 0.42 μg/mL. Mean blister fluid AUC values were 56 ± 15% of corresponding plasma concentrations.

In fasted patients undergoing elective tonsillectomy, the mean concentration of cefditoren in tonsil tissue 2 to 4 hours following administration of a 200 mg dose of cefditoren pivoxil was 0.18 ± 0.07 μg/g. Mean tonsil tissue concentrations of cefditoren were 12 ± 3% of the corresponding serum concentrations.

Data on the penetration of cefditoren into human cerebrospinal fluid are not available.

Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Studies with the renal tubular transport blocking agent probenecid indicate that tubular secretion, along with glomerular filtration is involved in the renal elimination of cefditoren. Cefditoren renal clearance is reduced in patients with renal insufficiency. (See Special Populations, Renal Insufficiency and Hemodialysis.) Hydrolysis of cefditoren pivoxil to its active component, cefditoren, results in the formation of pivalate. Following multiple doses of cefditoren pivoxil, greater than 70% of the pivalate is absorbed. Pivalate is mainly eliminated (>99%) through renal excretion, nearly exclusively as pivaloylcarnitine. Following a 200 mg BID regimen for 10 days, the mean decrease in plasma concentrations of total carnitine was 18.1 ± 7.2 nmole/mL, representing a 39% decrease in plasma carnitine concentrations. Following a 400 mg BID regimen for 14 days, the mean decrease in plasma concentrations of carnitine was 33.3 ± 9.7 nmole/mL, representing a 63% decrease in plasma carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 to 10 days after discontinuation of cefditoren pivoxil. (See PRECAUTIONS, General and CONTRAINDICATIONS.)

Special Populations

The effect of age on the pharmacokinetics of cefditoren was evaluated in 48 male and female subjects aged 25 to 75 years given 400 mg cefditoren pivoxil BID for 7 days. Physiological changes related to increasing age increased the extent of cefditoren exposure in plasma, as evidenced by a 26% higher Cmax and a 33% higher AUC for subjects aged ≥ 65 years compared with younger subjects. The rate of elimination of cefditoren from plasma was lower in subjects aged ≥ 65 years, with t1/2 values 16-26% longer than for younger subjects. Renal clearance of cefditoren in subjects aged ≥ 65 years was 20-24% lower than in younger subjects. These changes could be attributed to age-related changes in creatinine clearance. No dose adjustments are necessary for elderly patients with normal (for their age) renal function.

The effect of gender on the pharmacokinetics of cefditoren was evaluated in 24 male and 24 female subjects given 400 mg cefditoren pivoxil BID for 7 days. The extent of exposure in plasma was greater in females than in males, as evidenced by a 14% higher Cmax and a 16% higher AUC for females compared to males. Renal clearance of cefditoren in females was 13% lower than in males. These differences could be attributed to gender-related differences in lean body mass. No dose adjustments are necessary for gender.

Cefditoren pharmacokinetics were investigated in 24 adult subjects with varying degrees of renal function following administration of cefditoren pivoxil 400 mg BID for 7 days. Decreased creatinine clearance (CLcr) was associated with an increase in the fraction of unbound cefditoren in plasma and a decrease in the cefditoren elimination rate, resulting in greater systemic exposure in subjects with renal impairment. The unbound Cmax and AUC were similar in subjects with mild renal impairment (CLcr: 50-80 mL/min/1.73 m²) compared to subjects with normal renal function (CLcr: >80 mL/min/1.73 m²). Moderate (CLcr: 30-49 mL/min/1.73 m²) or severe (CLcr: < 30 mL/min/1.73 m²) renal impairment increased the extent of exposure in plasma, as evidenced by mean unbound Cmax values 90% and 114% higher and AUC values 232% and 324% higher than that for subjects with normal renal function. The rate of elimination from plasma was lower in subjects with moderate or severe renal impairment, with respective mean t1/2 values of 2.7 and 4.7 hours. 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). (See DOSAGE AND ADMINISTRATION.)

Cefditoren pharmacokinetics investigated in six adult subjects with end-stage renal disease (ESRD) undergoing hemodialysis given a single 400 mg dose of cefditoren pivoxil were highly variable. The mean t1/2 was 4.7 hours and ranged from 1.5 to 15 hours. Hemodialysis (4 hours duration) removed approximately 30% of cefditoren from systemic circulation but did not change the apparent terminal elimination half-life. The appropriate dose for ESRD patients has not been determined. (See DOSAGE AND ADMINISTRATION.)

Cefditoren pharmacokinetics were evaluated in six adult subjects with mild hepatic impairment (Child-Pugh Class A) and six with moderate hepatic impairment (Child-Pugh Class B). Following administration of cefditoren pivoxil 400 mg BID for 7 days in these subjects, mean Cmax and AUC values were slightly ( < 15%) greater than those observed in normal subjects. No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of cefditoren in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.

Microbiology

Cefditoren is a cephalosporin with antibacterial activity against gram-positive and gram-negative pathogens. The bactericidal activity of cefditoren results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs).

Cefditoren is stable in the presence of a variety of β-lactamases, including penicillinases and some cephalosporinases. Cefditoren has been shown to be active against most strains of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Staphylococcus aureus (methicillin-susceptible strains, including β-lactamase-producing strains)

Note: Cefditoren is inactive against methicillin-resistant Staphylococcus aureus

Streptococcus pneumoniae (penicillin-susceptible strains only) Streptococcus pyogenes

Haemophilus influenzae (including β-lactamase-producing strains)
Haemophilus parainfluenzae (including β-lactamase-producing strains)
Moraxella catarrhalis (including β-lactamase-producing strains)

The following in vitro data are available, but their clinical significance is unknown . Cefditoren exhibits in vitro minimum inhibitory concentrations (MICs) of ≤ 0.125 μg/mL against most ( ≥ 90%) strains of the following bacteria; however, the safety and effectiveness of cefditoren in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Streptococcus agalactiae
Streptococcus Groups C and G
Streptococcus, viridans group (penicillin-susceptible and -intermediate strains)

Susceptibility Tests

Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth) or equivalent with standardized inoculum concentrations and standardized concentrations of cefditoren powder. The MIC values obtained should be interpreted according to the following criteria:

For testing Haemophilus spp.a and Streptococcus spp. including S. pneumoniaeb:

Susceptibility test criteria cannot be established for S. aureus.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable and that other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control bacterial strains to control the technical aspects of the laboratory procedures. Standard cefditoren powder should provide the following MICs with these quality control strains:

REFERENCES

1. Clinical and Laboratory Standards (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 9th ed. CLSI document M07-A9. CLSI 950 West Valley Road., Suite 2500, Wayne, PA 19087, 2012.

Do not take cefditoren if you are allergic to milk protein (not lactose intolerance), or if you have a carnitine deficiency (a lack of a certain chemical in the body). Talk with your doctor if you are unsure.

You should not take cefditoren if you have ever had an allergic reaction to a penicillin or cephalosporin antibiotic (such as Ceftin, Cefzil, Keflex, Omnicef, and others).

Before taking this medication, tell your doctor if you are allergic to any drugs (especially penicillin). Also tell your doctor if you have kidney disease, liver disease, or if you are malnourished.

Take this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cefditoren will not treat a viral infection such as the common cold or flu.

This medication can cause you to have false results with certain medical tests, including urine glucose (sugar) tests. Tell any doctor who treats you that you are using cefditoren.

Your body will best absorb cefditoren if you take it with food.

Avoid taking cefditoren at the same time that you take any type of antacid or stomach acid reducer.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use any medicine to stop the diarrhea unless your doctor has told you to.

• Impetigo

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

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

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

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

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

Adults

200 mg twice daily for 10 days.1

400 mg twice daily for 10 days.1

400 mg twice daily for 14 days.1

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.)

To help clear up your infection completely, keep taking cefditoren pivoxil for the full time of treatment, even if you begin to feel better after a few days. Also, if you stop taking cefditoren pivoxil too soon, your symptoms may return.

cefditoren pivoxil works best when there is a constant amount in the blood or urine. To help keep the amount constant, do not miss any doses. Also, it is best to take the doses at evenly spaced times, day and night. For example, if you are to take four doses a day, the doses should be spaced about 6 hours apart. If this interferes with your sleep or other daily activities, or if you need help in planning the best times to take your medicine, check with your health care professional.

Dosing

The dose of cefditoren pivoxil will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of cefditoren pivoxil. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Cefditoren should be taken with food to increase absorption of the medicine.

• For oral dosage form (tablets):
  • For acute bacterial bronchitis:
    • Adults and children 12 years of age and older—400 milligrams (mg) twice a day for ten days.
    • Children under 12 years of age—Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
  • For bacterial throat infections or tonsillitis:
    • Adults and children 12 years of age and older—200 mg twice a day for ten days.
    • Children under 12 years of age—Dose must be determined by your doctor.

Missed Dose

If you miss a dose of cefditoren pivoxil, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Allergic reaction, such as, itching, pain, redness, or swelling of eye or eyelid, watering of eyes, troubled breathing or wheezing, severe skin rash or hives, flushing, headache, fever, chills, runny nose, increased sensitivity to sunlight, joint pain, swollen glands
• leukopenia, such as, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, unusual bleeding or bruising, unusual tiredness, or weakness
• pseudomembranous colitis, such as, abdominal or stomach cramps, pain, bloating, abdominal tenderness, diarrhea, watery and severe, which may also be bloody, fever, increased thirst, nausea or vomiting, unusual tiredness or weakness, or unusual weight loss
• or thrombocythemia, such as, pain, warmth or burning in fingers, toes, and legs, dizziness, problems with vision or hearing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• nausea
• or vaginal moniliasis, such as, thick whitish discharge from the vagina or cervical canal

• Abdominal pain
• Dyspepsia, such as, acid or sour stomach, belching, heartburn, indigestion, or stomach discomfort, upset or pain
• or headache

• Abnormal dreams
• anorexia, such as, loss of appetite
• asthenia, such as, lack or loss of strength
• constipation
• dizziness
• dry mouth
• dysgeusia, such as, taste perversion
• eructation, such as, belching, bloated full feeling, excess air or gas in stomach
• fever
• flatulence, such as, passing of gas
• fungal infection
• gastritis, such as, burning feeling in chest or stomach, tenderness in stomach area, stomach upset, or indigestion
• headache
• hyperglycemia, such as, blurred vision, dry mouth, fatigue, flushed, dry skin, fruit-like breath odor, increased hunger, increased thirst, increased urination, loss of consciousness, nausea, stomachache, sweating, troubled breathing, unexplained weight loss, vomiting
• increased appetite
• insomnia, such as, sleeplessness
• leukorrhea, such as, increase in amount of clear vaginal discharge, white vaginal discharge
• mouth ulceration
• myalgia, such as, muscle pain
• nervousness
• oral moniliasis, such as, sore mouth or tongue, white patches in mouth, tongue, or throat
• pain
• peripheral edema, such as, bloating or swelling of face, arms, hands, lower legs, or feet, rapid weight gain, tingling of hands or feet, unusual weight gain or loss
• pharyngitis, such as, body aches or pain, congestion, cough, dryness or soreness of throat, fever, hoarseness, runny nose, tender, swollen glands in neck, trouble in swallowing, or voice changes
• pruritus, such as, itching skin
• rash
• rhinitis, such as, stuffy nose, runny nose, or sneezing
• sinusitis, such as, pain or tenderness around eyes and cheekbones, fever, stuffy or runny nose, headache, cough, shortness of breath or troubled breathing, tightness of chest or wheezing
• somnolence, such as, sleepiness or unusual drowsiness
• stomatitis, such as, swelling or inflammation of the mouth
• sweating
• urinary frequency
• urticaria, such as, hives or welts, itching, redness of skin, or rash
• vaginitis
• vomiting
• or weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Pharmacokinetics

Oral Bioavailability

Following oral administration, Cefditoren Pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing.

Less than dose-proportional increases in Cmax and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of Cefditoren Pivoxil is approximately 14%. The absolute bioavailability of Cefditoren Pivoxil administered with a low fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein) is 16.1 ± 3.0%.

Food Effect

Administration of Cefditoren Pivoxil following a high fat meal (858 cal, 64 g fat, 43 g carb, 31 g protein) resulted in a 70% increase in mean AUC and a 50% increase in mean Cmax compared to administration of Cefditoren Pivoxil in the fasted state. After a high fat meal, the Cmax averaged 3.1 ± 1.0 µg/mL following a single 200 mg dose of Cefditoren Pivoxil and 4.4 ± 0.9 µg/mL following a 400 mg dose. Cefditoren AUC and Cmax values from studies conducted with a moderate fat meal (648 cal, 27 g fat, 73 g carb, 29 g protein) are similar to those obtained following a high fat meal.

The mean volume of distribution at steady state (Vss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to10 µg/mL. Cefditoren is primarily bound to human serum albumin and its binding is decreased when serum albumin concentrations are reduced. Binding to α-1-acid glycoprotein ranges from 3.3 to 8.1%. Penetration into red blood cells is negligible.

Skin blister fluid

Maximal concentrations of cefditoren in suction-induced blister fluid were observed 4 to 6 hours following administration of a 400 mg dose of Cefditoren Pivoxil with a mean of 1.1 ± 0.42 µg/mL. Mean blister fluid AUC values were 56 ± 15% of corresponding plasma concentrations.

Tonsil tissue

In fasted patients undergoing elective tonsillectomy, the mean concentration of cefditoren in tonsil tissue 2 to 4 hours following administration of a 200 mg dose of Cefditoren Pivoxil was 0.18 ± 0.07 µg/g. Mean tonsil tissue concentrations of cefditoren were 12 ± 3% of the corresponding serum concentrations.

Cerebrospinal Fluid (CSF)

Data on the penetration of cefditoren into human cerebrospinal fluid are not available.

Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Studies with the renal tubular transport blocking agent probenecid indicate that tubular secretion, along with glomerular filtration is involved in the renal elimination of cefditoren. Cefditoren renal clearance is reduced in patients with renal insufficiency. (See Special Populations, Renal Insufficiency and Hemodialysis.)

Hydrolysis of Cefditoren Pivoxil to its active component, cefditoren, results in the formation of pivalate. Following multiple doses of Cefditoren Pivoxil, greater than 70% of the pivalate is absorbed. Pivalate is mainly eliminated (>99%) through renal excretion, nearly exclusively as pivaloylcarnitine. Following a 200 mg BID regimen for 10 days, the mean decrease in plasma concentrations of total carnitine was 18.1 ± 7.2 nmole/mL, representing a 39% decrease in plasma carnitine concentrations. Following a 400 mg BID regimen for 14 days, the mean decrease in plasma concentrations of carnitine was 33.3 ± 9.7 nmole/mL, representing a 63% decrease in plasma carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 to 10 days after discontinuation of Cefditoren Pivoxil. (See PRECAUTIONS, General and CONTRAINDICATIONS.)

Geriatric

The effect of age on the pharmacokinetics of cefditoren was evaluated in 48 male and female subjects aged 25 to 75 years given 400 mg Cefditoren Pivoxil BID for 7 days. Physiological changes related to increasing age increased the extent of cefditoren exposure in plasma, as evidenced by a 26% higher Cmax and a 33% higher AUC for subjects aged ≥ 65 years compared with younger subjects. The rate of elimination of cefditoren from plasma was lower in subjects aged ≥ 65 years, with t1/2 values 16-26% longer than for younger subjects. Renal clearance of cefditoren in subjects aged ≥ 65 years was 20-24% lower than in younger subjects. These changes could be attributed to age-related changes in creatinine clearance. No dose adjustments are necessary for elderly patients with normal (for their age) renal function.

Gender

The effect of gender on the pharmacokinetics of cefditoren was evaluated in 24 male and 24 female subjects given 400 mg Cefditoren Pivoxil BID for 7 days. The extent of exposure in plasma was greater in females than in males, as evidenced by a 14% higher Cmax and a 16% higher AUC for females compared to males. Renal clearance of cefditoren in females was 13% lower than in males. These differences could be attributed to gender-related differences in lean body mass. No dose adjustments are necessary for gender.

Renal Insufficiency

Cefditoren pharmacokinetics were investigated in 24 adult subjects with varying degrees of renal function following administration of Cefditoren Pivoxil 400 mg BID for 7 days. Decreased creatinine clearance (CLcr) was associated with an increase in the fraction of unbound cefditoren in plasma and a decrease in the cefditoren elimination rate, resulting in greater systemic exposure in subjects with renal impairment. The unbound Cmax and AUC were similar in subjects with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2) compared to subjects with normal renal function (CLcr: >80 mL/min/1.73 m2). Moderate (CLcr: 30-49 mL/min/1.73 m2) or severe (CLcr: <30 mL/min/1.73 m2) renal impairment increased the extent of exposure in plasma, as evidenced by mean unbound Cmax values 90% and 114% higher and AUC values 232% and 324% higher than that for subjects with normal renal function. The rate of elimination from plasma was lower in subjects with moderate or severe renal impairment, with respective mean t1/2 values of 2.7 and 4.7 hours. 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). (See DOSAGE AND ADMINISTRATION.)

Hemodialysis

Cefditoren pharmacokinetics investigated in six adult subjects with end-stage renal disease (ESRD) undergoing hemodialysis given a single 400 mg dose of Cefditoren Pivoxil were highly variable. The mean t1/2 was 4.7 hours and ranged from 1.5 to 15 hours. Hemodialysis (4 hours duration) removed approximately 30% of cefditoren from systemic circulation but did not change the apparent terminal elimination half-life. The appropriate dose for ESRD patients has not been determined. (See DOSAGE AND ADMINISTRATION.)

Hepatic Disease

Cefditoren pharmacokinetics were evaluated in six adult subjects with mild hepatic impairment (Child-Pugh Class A) and six with moderate hepatic impairment (Child-Pugh Class B). Following administration of Cefditoren Pivoxil 400 mg BID for 7 days in these subjects, mean Cmax and AUC values were slightly (<15%) greater than those observed in normal subjects. No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of cefditoren in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.

Microbiology

Cefditoren is a cephalosporin with antibacterial activity against gram-positive and gram-negative pathogens. The bactericidal activity of cefditoren results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs).

Cefditoren is stable in the presence of a variety of ß-lactamases, including penicillinases and some cephalosporinases. Cefditoren has been shown to be active against most strains of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus (methicillin-susceptible strains, including ß-lactamase-producing strains)

Note: Cefditoren is inactive against methicillin-resistant Staphylococcus aureus

Streptococcus pneumoniae (penicillin-susceptible strains only)

Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae (including ß-lactamase-producing strains)

Haemophilus parainfluenzae (including ß-lactamase-producing strains)

Moraxella catarrhalis (including ß-lactamase-producing strains)

The following in vitro data are available, but their clinical significance is unknown. Cefditoren exhibits in vitro minimum inhibitory concentrations (MICs) of ≤0.125 µg/mL against most (≥90%) strains of the following bacteria; however, the safety and effectiveness of cefditoren in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-Positive Microorganisms

Streptococcus agalactiae

Streptococcus Groups C and G

Streptococcus, viridans group (penicillin-susceptible and -intermediate strains)

Susceptibility Tests

Dilution Techniques

Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth) or equivalent with standardized inoculum concentrations and standardized concentrations of cefditoren powder. The MIC values obtained should be interpreted according to the following criteria:

For testing Haemophilus spp.a and Streptococcus spp. including S. pneumoniaeb:

aThis interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM).1

bThese interpretive standards are applicable only to broth microdilution susceptibility tests with Streptococcus spp. using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.1

Susceptibility test criteria cannot be established for S. aureus

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control bacterial strains to control the technical aspects of the laboratory procedures. Standard cefditoren powder should provide the following MICs with these quality control strains:

aThis quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.1

bThis quality control range is applicable to only H. influenzae ATCC 49247 and ATCC 49766 tested by a microdilution procedure using HTM.1

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

Multiple doses of Cefditoren Pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.

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.

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.

As with other ß-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

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.)