Hafixim 200

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INFORMATION FOR MEDICAL STAFF

COMPOSITION:

Cefixime (as cefixime trihydrate) ............ 200 mg

Excipients q.s ........................................ 1 tablet

(Pregelatinized starch (National 78-1551), microcrystalline cellulose M112, calcium hydrogen phosphate dihydrate, magnesium stearate, hypromellose 2910 (6cp), hypromellose 2910 (15cp), PEG 6000, talc, titanium dioxide, yellow ferric oxide)

PHARMACEUTICAL FORM: Film coated tablet.

PHARMACODYNAMIC PROPERTIES:

ATC code: J01DD08

The active ingredient of Hafixim 200 Tabs is cefixime which is an oral third-generation cephalosporin antibiotic and has marked bactericidal activity. Bactericidal mechanism of cefixime is similar to that of other cephalosporins: Cefixime binds to target proteins (penicillin-binding proteins), resulting in inhibition of mucopeptide synthesis of the bacterial cell wall. Mechanism of bacterial resistance to cefixime is due to reduced affinity of penicillin-binding proteins or outer membrane impermeability.

Cefixime is stable against hydrolysis by many plasmid- and chromosomally medicated beta-lactamases. The drug generally is more stable than are cefaclor, cefoxitin, cefuroxime, cephalexin, and cephradin.

Spectrum:

Gram-positive aerobic bacteria:

Gram-positive aerobic cocci: Streptococcus pyogenes (group A beta-hemolytic streptococci), S. agalactiae (group B streptococci), and groups C, F, and G streptococci. Cefixime is active against some strains of S. pneumoniae; however, the drug generally is less active against this organism than some other oral cephalosporins (e.g., cefdinir, cefpodoxime, cefprozil, cefuroxime). Strains of penicillin-resistant S. pneumoniae are considered resistant to cefixime. Group D streptococci and S. viridans streptococci are considered resistant to the drug. Cefixime is inactive in vitro against penicillinase-producing and nonpenicillinase-producing staphylococci including methicillin-resistant Staphylococcus aureus, S.epidermidis and S. saprophyticus, Staphylococcus.

Gram-positive aerobic bacilli: Corynebacterium, Listeria monocytogenes generally are resistant to cefixime.

Gram-negative aerobic bacteria:

Cefixime is active against Neisseria meningitidis, penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae. The drug also is active in vitro against N. gonorrhoeae with chromosomally medicated resistance to penicillin or plasmid-medicated tetracycline resistance.

Cefixime is active in vitro against most beta-lactamase-producing and non-beta-lactamase-producing strains of             H. influenzae and H. parainfluenzae. Cefixime is more active against beta-lactamase-producing H. influenzae than is cefaclor, cephalexin, cefuroxime, or amoxicillin and clavulanate potassium, but may be equally or slightly less active than is ciprofloxacin, ceftriaxone, or co-trimoxazole against these organisms. Cefixime is active in vitro against multiple-drug resistant strains of H. influenzae that are resistant strains of H. influenzae that are resistant to ampicillin, chloramphenicol, tetracycline, co-trimoxazole, cefaclor and/or erythromycin. However, some strains of non-beta-lactamase-producing        H. influenzae that are resistant to amplicillin and second generation cephalosporins also may have reduced susceptibility to cefixime.

Cefixime is active in vitro against strains of Moraxella catarrhalis resistant to ampicillin, cefaclor, and cephalexin.

Cefixime is active in vitro against most clinically important Enterobacteriaceae. Cefixime is active in vitro against many strains of E. coli, Citrobacter freundii, K. pneumoniae and P. mirabilis resistant to other anti-infectives (e.g., aminoglycosides, tetracycline, ampicillin, amoxicillin, cefaclor, and cephalexin). Cefixime is active in vitro against strains of Salmonella typhi resistant to ampicillin, chloramphenicol and/or co-trimoxazole.

Strains of Pseudomonas are resistant to cefixime.

Anaerobic bacteria: Most strains of Bacteroides fragilis and other Bacteroides spp., most strains of Clostridium (including C. difficile) are considered resistant to cefixime.

Chlamydia and Mycoplasma: Cefixime is inactive against Chlamydia trachomatis and Ureaplasma urealyticum.

Spirochetes: Cefixime has some activity against Borrelia burgdorferi, the causative organism of Lyme disease (concentrations of 0.8 mcg/ml).

Resistance

Cefixime has a high degree of stability and is stable against hydrolysis by many plasmid- and chromosomally medicated beta-lactamases. The drug is hydrolyzed by some beta-lactamases produced by Enterobacter, Klebsiella oxytoca, Proteus vulgaris, Pseudomonas cepacia, Citrobacter freundii, Enterobacter cloacae, Flavobacterium and Bacteroides fragilis.

Resistance to cefixime in staphylococci appears to be related to the drug's poor affinity for PBPs (penicillin-binding proteins) of these organisms. Resistance in enterococci and Listeria monocytogenes may also be related to poor binding of cefixime to the PBPs of these organisms. Resistance to cefixime in Citrobacter freundii and Enterobacter apparently is related to factors that affect permeability to these organisms to the drug and also is related to the production of beta-lactamases. Resistance to cefixime in Pseudomonas and Acinetobacter is related to permeability factors.

Cefixime does induce beta-lactamase production in some strains of Morganella morganii, but the drug remains active in vitro against these M. morganii strains following derepression of inducible beta-lactamases.

Some third generation cephalosporins are active against staphylococci; cefixime usually is inactive against these organisms. Cefixime is inactive in vitro against penicillinase-producing and nonpenicillinase-producing staphylococci, including Staphylococcus aureus, S. epidermidis, and S. saprophyticus. Like other cephalosporins, cefixime is inactive against oxacillin-resistant (methicillin-resistant) staphylococci. Most strains of Staphylococci, Enterococci and Listeria spp. are not susceptible to cefixime. Enterobacter spp., Pseudomonas aeruginosa and Bacteroides spp. are resistant to cefixime. Cefixime has limited in vitro activity against anaerobic bacteria; most strains of Clostridia (including C. difficile) are considered resistant to the drug.

Gram-negative aerobic bacteria including Achromobacter xylosoxidans and Flavobacterium meningosepticum are resistant to cefixime.

Cefixime is inactive against Chlamydia trachomatis and Ureaplasma urealyticum.

PHARMACOKINETIC PROPERTIES:

Approximately 30% - 50% of a single dose of cefixime is absorbed following oral administration, whether taken before or after meals; however, absorption rate is decreased when administered with food. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Cefixime absorption is relatively slow. Following oral administration of a single of 200- and 400-mg dose of cefixime, peak serum concentrations average 2-3 mcg/ml or 3.7-4.6 mcg/ml, respectively, 2-6 hours after the dose. There is no evidence that cefixime accumulates in serum and urine of patients with normal renal function following multiple doses of the drug given once or twice daily. The half-life of cefixime is usually about 3 to 4 hours and may be prolonged when there is renal impairment. About 65% of cefixime in blood is bound to plasma proteins. Serum half-life of cefixime is independent of dosage form and is not dose-dependent.

Information on distribution of cefixime is limited. Following oral administration, cefixime is distributed into bile, sputum, tonsils, maxillary sinus mucosa, middle ear discharge, blister fluid, and prostatic fluid. It is not known whether cefixime is distributed into CFS following oral administration. It crosses the placenta. Relatively high concentrations may be achieved in bile and urine. Approximately 20% of an oral dose (or 50% of an absorbed dose) is excreted unchanged in urine within 24 hours. Up to 60% may be eliminated by nonrenal mechanisms. There is no evidence that cefixime is metabolized, but a part of the drug is excreted from bile to feces. The drug is not removed by hemodialysis.

PRESENTATIONS: Box of 3 blisters x 10 tablets.   Box of 6 blisters x 10 tablets.

THERAPEUTIC INDICATIONS: For the treatment of infections caused by cefixime susceptible bacteria, including:

Uncomplicated urinary tract infections caused by E. coli or Proteus mirabilis.

Otitis media caused by Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes.

Pharyngitis and tonsillitis caused by Streptococcus pyogenes.

Acute and chronic bronchitis caused by Streptococcus pneumonia or Haemophilus influenzae or Moraxella catarrhalis.

Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.

DOSAGE & ADMINISTRATION: The drug may be administered without regard to food.

The tablet(s) should be taken whole or broken in half and are recommended not to chew, crush, or dissolve in water.

The usual duration of cefixime therapy is 7 days, up to 14 days if needed. For the treatment of otitis media caused by Streptococcus pyogenes, the usual duration of therapy is 10 days.

Adults and children older than 12 years or weighing more than 45 kg: The recommended dosage is 400 mg daily given either as a single dose or in two divided doses every 12 hours.

The safety and efficacy of cefixime has not been established in children less than 6 months.

For the treatment of uncomplicated gonococcal infections caused by Neisseria gonorrhoeae, a single oral dose 400 mg is recommended.

Dosage in renal impairment: Normal dose and schedule may be employed in patients with creatinine clearances of           60 ml/min or greater. Adults with creatinine clearances of 21 - 60 ml/min should receive 300 mg of cefixime daily, and adults with creatinine clearances less than 20 ml/min should receive 200 mg of cefixime daily.

Or as directed by the physician.

CONTRAINDICATIONS:

Hypersensitivity to any of the ingredients of the drug.

Patients with known hypersensitivity to cephalosporins.

PRECAUTIONS: Cutaneous adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, including anaphylaxis have been reported in some patients on cefixime. When cutaneous adverse reactions occur, cefixime should be discontinued and appropriate therapy should be taken.

Cefixime should be given with caution to patients with a history of hypersensitivity to penicillin and cephalosporins.

Haemolytic anaemia has been described for cefixime.

Because serum concentrations of cefixime are higher and more prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of the drug should be decreased in patients with impaired renal function, including those undergoing continuous ambulatory peritoneal dialysis.

Safety and efficacy of cefixime in children younger than 6 months of age have not been established.

Cefixime should be used with caution in patients with a history of GI disorders and colitis. Prolonged use of cefixime may result in overgrowth of drug-resistant bacteria, particularly Clostridium difficile which is a primary cause of severe diarrhoea. The cefixime therapy should be discontinued and other antibiotics (metronidazole, vancomycin, etc.) should be substituted. In addition, diarrhea generally appear during the first or second day of cefixime therapy. If the diarrhea state is mild, the cefixime therapy does not require to discontinue. Cefixime also alter intestinal bacteria flora. Modification of the usual dosage of cefixime generally is not necessary in geriatric adults, unless renal function is substantially impaired (creatinine clearance < 60 ml/ min).

Pregnancy and lactation: No evidence of harm to the foetus due to cefixime have revealed. This drug should be used during pregnancy only if clearly needed.

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

Effects on works: Since headache, dizziness may be reported during treatment with cefixime, cautions should be exercised in drivers, machine users, workers at height, and other cases.

INTERACTIONS: Concomitant administration of probenecid reportedly increases peak serum concentration and the AUC of cefixime and decreases renal clearance and volume distribution of the drug.

Cefixime enhances the effect of an anticoagulant (e.g., warfarin). Concomitant administration of cefixime and carbamazepine has resulted in increased plasma carbamazepine concentrations.

The administration of cefixime may be result in a false-positive reaction for glucose in the urine using Clinitest, Benedict's solution, or Fehling's solution.

A false-positive direct Coomb's test has been reported during treatment with cefixime.

Concomitant administration of cefixime and nifedipine increases bioavailability of cefixime as a result of higher peak plasma concentrations and AUC.

UNDESIRABLE EFFECTS:

Blood disorders: eosinophilia, agranulocytosis, leucopenia, neutropenia, haemolytic anaemia, thrombocytopenia, thrombocytosis.

Gastrointestinal disorders: diarrhea, abdominal pain, nausea, vomiting, flatulence, indigestion.

Hepatobiliary effects: jaundice.

Infections: pseudomembranous colitis.

Investigations: increases in AST, ALT, bilirubin, blood urea, blood creatinine.

Nervous system disorders: headache, dizziness.

Respiratory disorders: dyspnea.

Renal and urinary disorders: acute renal failure.

Systemic disorders and administrative site conditions: Anaphylactic reaction, serum sickness-like reaction, drug rash with eosinophilia and systemic symptoms (DRESS), pruritus, rash, drug fever, arthralgia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angio-oedema, urticaria, pyrexia, face oedema, genital pruritus, vaginitis.

Treatment of ADRs:

If hypersensitivity occurs, the therapy should be discontinued; if it is severe, appropriate supportive measures (including epinephrine, oxygen, histamine, corticosteroids) should be instituted.

If diarrhea associated with C. difficile and pseudomembranous colitis occur, in mild cases discontinuation of the drug should be given. In moderate and severe cases, transfusion of fluids and electrolyte, protein supplementation and treatment with metronidazole are needed.

OVERDOSE: There is no experience with overdoses with cefixime.

Adverse reactions seen at dose levels up to 2 g cefixime in normal subjects did not differ from the profile seen in patients treated at the recommended doses. Cefixime is not removed from the circulation in significant quantities by dialysis.

No specific antidote exists. General supportive measures are recommended.

Read the directions carefully before use.

For more information, please consult a physician.

This drug is for prescription only.

STORAGE CONDITIONS: Store in dry places, not exceeding 300C, protect from light.

SHELF-LIFE: 24 months from the manufacturing date.

DATE OF REVISION OF THE TEXT: June 20, 2019.   

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