rsi ad
 
drx ad
 
ad space

Cefixime Capsules, Tablets and Oral Suspension

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MICROBIOLOGY 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

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

1. DESCRIPTION

Cefixime is a semisynthetic, cephalosporin antibiotic for oral administration. Chemically, it is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-[O-(carboxymethyl)oxime]trihydrate.

The structural formula for cefixime is:

Empirical formula: C16H15N5O7S2•3H2O - Molecular weight: 507.50 as the trihydrate

• Inactive ingredients contained in cefixime 400 mg tablets are: dibasic calcium phosphate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, titanium dioxide, and triacetin.

• Inactive ingredients contained in cefixime 400 mg capsules are: colloidal silicon dioxide, crospovidone, low substituted hydroxy propyl cellulose, magnesium stearate, and mannitol. The capsule shell contains the following inactive ingredients: ferric oxide black, ferric oxide red, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate, and titanium dioxide.

• Inactive ingredients contained in cefixime 100 mg or 150 mg or 200 mg chewable tablets are: aspartame, colloidal silicon dioxide, crospovidone, FD&C Red # 40 Aluminium Lake, low substituted hydroxypropyl cellulose, magnesium stearate, mannitol, fantasy flavor permaseal, and tutti frutti flavor.

• Inactive ingredients contained in cefixime powder for oral suspension are: colloidal silicon dioxide, sodium benzoate, strawberry flavor, sucralose (only in 500 mg/5 mL strength), sucrose, and xanthan gum.

2. INDICATIONS AND USAGE

To reduce the development of drug resistant bacteria and maintain the effectiveness of cefixime and other antibacterial drugs, cefixime 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 antimicrobial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Cefixime is a cephalosporin antibacterial indicated in the treatment of adults and pediatric patients six months of age or older with the following infections when caused by susceptible isolates of the designated bacteria:

2.1 Uncomplicated Urinary Tract Infections

Uncomplicated urinary tract infections caused by Escherichia coli and Proteus mirabilis.

2.2 Otitis Media

Otitis media caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes. (Efficacy for Streptococcus pyogenes in this organ system was studied in fewer than 10 infections.)

Note: For patients with otitis media caused by Streptococcus pneumoniae, overall response was approximately 10% lower for cefixime than for the comparator.

2.3 Pharyngitis and Tonsillitis

Pharyngitis and Tonsillitis caused by Streptococcus pyogenes. (Note: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infections. Cefixime is generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, data establishing the efficacy of cefixime in the subsequent prevention of rheumatic fever is not available.)

2.4 Acute Exacerbations of Chronic Bronchitis

Acute Exacerbations of Chronic Bronchitis caused by Streptococcus pneumoniae and Haemophilus influenzae.

2.5 Uncomplicated Gonorrhea (cervical/urethral)

Uncomplicated Gonorrhea (cervical/urethral) caused by Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates).

3. DOSAGE AND ADMINISTRATION

3.1 Adults

The recommended dose of cefixime is 400 mg daily. This may be given as a 400 mg tablet or capsule daily or the 400 mg tablet may be split and given as one half tablet every 12 hours. For the treatment of uncomplicated cervical/urethral gonococcal infections, a single oral dose of 400 mg is recommended. The capsule and tablet may be administered without regard to food.

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days.

3.2 Pediatric Patients (6 months or older)

The recommended dose is 8 mg/kg/day of the suspension. This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.

Table 1. Suggested Doses for Pediatric Patients

* The preferred concentrations of oral suspension to use are 100 mg/5 mL or 200 mg/5 mL for pediatric patients in these weight ranges.

Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose.

Otitis media should be treated with the chewable tablets or suspension. Clinical trials of otitis media were conducted with the chewable tablets or suspension, and the chewable tablets or suspension results in higher peak blood levels than the tablet when administered at the same dose.

Therefore, the tablet or capsule should not be substituted for the chewable tablets or suspension in the treatment of otitis media.

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days.

3.3 Renal Impairment

Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater. Refer to Table 2 for dose adjustments for adults with renal impairment. Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.

Table 2. Doses for Adults with Renal Impairment

* The preferred concentrations of oral suspension to use are 200 mg/5 mL or 500 mg/5 mL for patients with this renal dysfunction

3.4 Reconstitution Directions for Oral Suspension

Bottle size 100 mL (100 mg/5 mL and 200 mg/5 mL): To reconstitute, suspend with 68 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 75 mL (100 mg/5 mL and 200 mg/5 mL): To reconstitute, suspend with 51 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 50 mL (100 mg/5 mL and 200 mg/5 mL): To reconstitute, suspend with 34 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 37.5 mL (200 mg/5 mL): To reconstitute, suspend with 26 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 25 mL (200 mg/5 mL): To reconstitute, suspend with 17 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 20 mL (500 mg/5 mL): To reconstitute, suspend with 14 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

Bottle size 10 mL (500 mg/5 mL): To reconstitute, suspend with 8 mL water. Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well.

After reconstitution the suspension may be kept for 14 days either at room temperature, or under refrigeration, without significant loss of potency. Keep tightly closed. Shake well before using. Discard unused portion after 14 days.

4. CONTRAINDICATIONS

Cefixime is contraindicated in patients with known allergy to cefixime or other cephalosporins.

5. MICROBIOLOGY

As with other cephalosporins, bactericidal action of cefixime results from inhibition of cell-wall synthesis. Cefixime is highly stable in the presence of beta-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins due to the presence of betalactamases, may be susceptible to cefixime. Cefixime has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of harm to the fetus due to cefixime. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

6.2 Labor and Delivery

Cefixime has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.

6.3 Nursing Mothers

It is not known whether cefixime is excreted in human milk. Consideration should be given to discontinuing nursing temporarily during treatment with this drug.

6.4 Pediatric Use

Safety and effectiveness of cefixime in children aged less than six months old have not been established.

The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.

6.5 Geriatric Use

Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. A pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters. These differences were small and do not indicate a need for dosage adjustment of the drug in the elderly.

6.6 Renal Impairment

The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully [See DOSAGE AND ADMINISTRATION].

7. WARNINGS AND PRECAUTIONS

7.1 Hypersensitivity Reactions

Anaphylactic/anaphylactoid reactions (including shock and fatalities) have been reported with the use of cefixime.

Before therapy with cefixime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefixime occurs, discontinue the drug.

7.2 Clostridium difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefixime, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

7.3 Dose Adjustment in Renal Impairment

The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully [See DOSAGE AND ADMINISTRATION].

7.4 Coagulation Effects

Cephalosporins, including cefixime, 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.

7.5 Development of Drug-Resistant Bacteria

Prescribing cefixime in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most commonly seen adverse reactions in U.S. trials of the tablet formulation were gastrointestinal events, which were reported in 30% of adult patients on either the twice daily or the once daily regimen. Five percent (5%) of patients in the U.S. clinical trials discontinued therapy because of drug-related adverse reactions. Individual adverse reactions included diarrhea 16%, loose or frequent stools 6%, abdominal pain 3%, nausea 7%, dyspepsia 3%, and flatulence 4%. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in pediatric patients receiving the suspension was comparable to the incidence seen in adult patients receiving tablets.

8.2 Post-marketing Experience

The following adverse reactions have been reported following the use of cefixime. Incidence rates were less than 1 in 50 (less than 2%).

Gastrointestinal: Several cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy.

Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported.

Hepatic: Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice.

Renal: Transient elevations in BUN or creatinine, acute renal failure.

Central Nervous System: Headaches, dizziness, seizures.

Hemic and Lymphatic System: Transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia.

Abnormal Laboratory Tests: Hyperbilirubinemia.

Other Adverse Reactions: Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis.

Adverse Reactions Reported for Cephalosporin-class Drugs

Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. [See DOSAGE AND ADMINISTRATION and OVERDOSAGE] If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

9. OVERDOSAGE

Gastric lavage may be indicated; otherwise, no specific antidote exists. Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis. Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.

10. DRUG INTERACTIONS

10.1 Carbamazepine

Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly. Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations.

10.2 Warfarin and Anticoagulants

Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly.

10.3 Drug/Laboratory Test Interactions

A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide.

The administration of cefixime may result in a false-positive reaction for glucose in the urine using Clinitest, Benedict’s solution, or Fehling’s solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape) be used. A false-positive direct Coombs test has been reported during treatment with other cephalosporin antibiotics; therefore, it should be recognized that a positive Coombs test may be due to the drug.

11. PHARMACOKINETICS

Cefixime chewable tablets are bioequivalent to oral suspension.

Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range 1 to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension in the treatment of otitis media [See DOSAGE AND ADMINISTRATION]. Cross-over studies of tablet versus suspension have not been performed in children.

The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on Cmax.

Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg capsule.

Distribution

Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.

Metabolism and Excretion

There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.

Special Populations

Geriatrics: Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:

Table 3. Pharmacokinetic Parameters (mean ± SD) for Cefixime in Both Young & Elderly Subjects

* Difference between age groups was significant. (p<0.05)

However, these increases were not clinically significant [See DOSAGE AND ADMINISTRATION].

Renal Impairment: In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: SUPRAX, by Lupin Pharms.

b) Generic drugs: None.

2) How Supplied:

Suprax® is available for oral administration in following dosage forms, strengths and packages listed in the table below:

3) Storage:

Store capsules and tablets at controlled room temperature 20° to 25°C (68° to 77°F).

SUPRAX Powder for Oral Suspension: Prior to reconstitution, store at controlled room temperature 20° to 25°C (68° to 77°F).

After reconstitution store at room temperature or under refrigeration.

Rx only

Rev 02/13