C Tax-O XL 200

Cefixime, Cloxacillin & Lactic Acid Bacillus Tablets

Each film coated tablet contains:

Cefixime IP (as Trihydrate)

equivalent to Anhydrous Cefixime…………... 200 mg

Cloxacillin Sodium IP equivalent to Cloxacillin……………………...500 mg

(In Prolonged-release form)

Lactic Acid Bacillus …………………………90 million spores

Excipients q.s.

Colour: Titanium Dioxide IP

Appropriate overages of Lactic Acid Bacillus spores added.

Film coated tablet

Cefixime (200mg) Cloxacillin (500mg) & Lactic Acid Bacillus (90 million spores)

4.1 Therapeutic Indication

For the treatment of adult patients with upper & lower respiratory tract infections, skin and soft tissue infections.

4.2 Posology and Method of Administration

Adults: the recommended dosage is 1 tablet twice daily. The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

4.3 Contraindications

Hypersensitivity to the penicillin, or to cephalosporin antibiotics or to any of the components listed in the formulation.

4.4 Special warnings and precautions for use

Cefixime

Encephalopathy: Beta-lactams, including cefixime, predispose the patient to encephalopathy risk (which may include convulsions, confusion, impairment of consciousness, movement disorders), particularly in case of overdose or renal impairment. Severe cutaneous adverse reactions: Severe cutaneous adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in some patients on cefixime. When severe cutaneous adverse reactions occur, cefixime should be discontinued and appropriate therapy and/or measures should be taken. Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs.

Hypersensitivity to penicillins: As with other cephalosporins, cefixime should be given with caution to patients with a history of hypersensitivity to penicillin, as there is some evidence of partial cross- sensitization between the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both classes of drugs. If an allergic effect occurs with cefixime, the drug should be discontinued and the patient treated with appropriate agents if necessary.

Haemolytic anaemia: Drug-induced haemolytic anaemia, including severe cases with a fatal outcome, has been described for cephalosporins (as a class). The recurrence of haemolytic anaemia after re-administration of cephalosporins in a patient with a history of cephalosporin (including cefixime) –associated haemolytic anaemia has also been reported.

Acute renal failure: As with other cephalosporins, cefixime may cause acute renal failure including tubulointerstitial nephritis as an underlying pathological condition. When acute renal failure occurs, cefixime should be discontinued and appropriate therapy and/or measures should be taken.

Renal impairment: Cefixime should be administered with caution in patients with markedly impaired renal function.

Paediatric use: Safety of cefixime in premature or new-born infant has not been established.

Cloxacillin

Hematologic: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

Hepatic: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

Immune: Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients receiving penicillin or cephalosporin

therapy. These reactions are more apt to occur in individuals with a history or sensitivity to multiple allergens. Careful inquiry should be made concerning previous hypersensitivity to reactions to penicillins, cephalosporins or other allergens. If allergic or anaphylactic reactions occurs, discontinue treatment and administer the usual agents, e.g. antihistamines, pressor amines, corticosteroids.

Neurologic: The passage of any penicillin from blood into brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of such factors, particularly in renal failure when high serum concentration can be attained, CNS adverse effects including myoclonia, convulsive seizures and depressed consciousness can be expected. Although this complication has not been reported with cloxacillin, it should be anticipated.

Renal: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

4.5 Drugs interactions

Cefixime

Anticoagulants: In common with other cephalosporins, increases in prothrombin times have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy. Cefixime should be administered with caution to patients receiving coumarin-type anticoagulants, e.g. warfarin potassium. Since cefixime may enhance effects of the anticoagulants, prolonged prothrombin time with or without bleeding may occur.

Other forms of interaction: A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions. A false positive direct Coombs test has been reported during treatment with cephalosporin antibiotics, therefore it should be recognised that a positive Coombs test may be due to the drug.

Cloxacillin

Probenecid: As with other penicillins, concurrent administration of probenecid enhances the serum concentration of cloxacillin.

4.6 Use in special populations

Pregnancy

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.

Lactation:

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

4.7 Effects on ability to drive and use machines

In the case of side effects such as encephalopathy (which may include convulsion, confusion, impairment of consciousness, movement disorders), the patient should not operate machines or drive a vehicle.

4.8 Undesirable effects

Cefixime

Acute generalized exanthematous pustulosis and Mouth ulceration has been reported with Cefixime use.

Blood and lymphatic system disorders: eosinophilia, hypereosinophilia, agranulocytosis, leucopenia, neutropenia, granulocytopenia, haemolytic anaemia, thrombocytopenia, thrombocytosis.

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

Hepatobiliary disorders: jaundice

Infections and infestations: pseudomembranous colitis

Investigations: aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased

Nervous system disorders: dizziness, headache, cases of convulsions have been reported with cephalosporins including cefixime, Beta-lactams, including cefixime, predispose the patient to encephalopathy risk (which may include convulsions, confusion, impairment of consciousness, movement disorders), particularly in case of overdose or renal impairment.

Respiratory, thoracic and mediastinal disorders: dyspnoea

Renal and urinary disorders: Renal failure acute including tubulointerstitial nephritis as an underlying pathological condition

Immune system disorders, administrative site conditions, skin and subcutaneous tissue disorders: anaphylactic reaction, serum sickness-like reaction, drug rash with eaosinophilia and systemic symptoms, pruritus, rash, drug fever, arthralgia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angio-oedema, urticaria, pyrexia, face oedema, genital pruritus, vaginitis.

Cloxacillin

It may be expected the most common untoward reactions will be related to sensitivity. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and cephalosporins and in those with a history of allergy, asthma, hay fever or urticaria. All degrees of hypersensitivity, including fatal anaphylaxis, have been reported with penicillin.

Gastrointestinal: Nausea, vomiting, epigastric discomfort, flatulence and loose stools have been noted in some patients.

Hematologic: Eosinophilia, leucopenia, anemia, thrombocytopenia, thrombocytopenic, purpura, neutropenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Immune: Allergic reactions (rash, urticaria) including wheezing and sneezing have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

4.9 Overdose

There is a risk of encephalopathy in cases of administration of beta-lactam antibiotics, including cefixime, particularly in case of overdose or renal impairment. 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 (Gastric lavage) measures are recommended.

5.1 Mechanism of Action

Mechanism of action

Cefixime is a 3rd generation oral cephalosporin that has excellent activity against variety of Gram -ve organisms and a few Gram +ve organisms like streptococci spp. but, no activity against staphylococci. Cloxacillin is an acid resistant, β-lactamase resistant isoxazolyl penicillin with a spectrum of activity particularly against staphylococci and streptococci. Cloxacillin is resistant to degradation by penicillinase, thus useful against penicillinase-producing staphylococci.

In order to enhance the antibacterial coverage of cefixime against Gram +ve organisms, the addition of cloxacillin helps in Gram +ve coverage. Thus providing broader spectrum of antibiotic coverage.

Clinical evidence demonstrated the synergistic effect of cloxacillin and cefixime used in combination against S. pneumoniae and H. influenzae, the commonest causes of community-acquired pneumonia. Due to this synergistic activity dosage can be given in reduced frequency, thus increasing patient compliance. The usual dosage for this combination is 200 mg cefixime along with 500 mg cloxacillin to be given twice a day.

Lactobacillus preparations have been shown to offset the detrimental effects on the microflora produced with antibiotic administration. The normal bacterial flora of gut that is disturbed by the antibiotic is replenished by the addition of lactobacillus. Lactobacillus spores maintain or restore gut micro-ecology during or after antibiotic treatment. There is an increasing evidence for the effectiveness of probiotics with antimicrobial therapy in preventing or treating antibiotic associated diarrhea.

Pharmacodynamic properties

Cefixime: Cefixime has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms. As with other cephalosporins, bactericidal action of cefixime results from inhibition of cell-wall synthesis. Clinical efficacy has been demonstrated in infections caused by commonly occurring pathogens including Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (beta-lactamase positive and negative), Branhamella catarrhalis (beta-lactamase positive and negative) and Enterobacter species. It is highly stable in the presence of beta-lactamase enzymes. Most strains of enterococci (Streptococcus faecalis, group D Streptococci) and Staphylococci (including coagulase positive and negative strains and meticillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes and Clostridia are resistant to cefixime. Cloxacillin: Cloxacillin exerts a bactericidal action against susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptides. Cloxacillin displays less intrinsic antibacterial activity and a narrower spectrum than penicillin G.

Lactobacillus: Lactobacillus is an aerobic gram-positive, ubiquitous inhabitant of the human oral cavity, vagina and gastrointestinal tract. It inhibits the colonization of pathogenic bacteria upon the intestinal epithelium. The inhibitory process known as 'competitive exclusion' can be expanded by the competition for the adherence sites of the intestinal mucosa between pathogens and lactobacilli and by the inhibitory substance.

5.2 Pharmacokinetic properties

Cefixime: The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. From in vitro studies, serum or urine concentrations of 1 mcg/mL or greater were considered to be adequate for most common pathogens against which cefixime is active. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mcg/mL. Little or no accumulation of cefixime occurs following multiple dosing. The pharmacokinetics of cefixime in healthy elderly (age > 64 years) and young volunteers (11-35) compared the administration of 400 mg doses once daily for 5 days. Mean C and AUC values were slightly greater in the elderly. Elderly patients may be given the same max dose as the general population.

Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.

Serum protein binding is well characterised for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations which are not seen 14 following clinical dosing. Transfer of C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in pregnant rats dosed with labelled cefixime.

Cloxacillin: Cloxacillin is stable in an acid medium and is approximately 50% absorbed orally. After an oral dose of 500mg cloxacillin, a peak serum level of about 8 micrograms/mL is reached in about 1 hour. The serum level after i.m. cloxacillin is approximately twice that obtained when the same dose is given orally to fasting adults. Food in the stomach or small intestine reduces absorption and peak serum levels are approximately 50% those obtained after fasting. As with other penicillins, concurrent administration of probenecid enhances the serum concentration. Once absorbed, approximately 94% are bound to plasma proteins. After oral administration, roughly 20% of the dose is excreted in the urine, together with one or more active metabolites as yet unidentified. The half-life of elimination is about 30 minutes.

Lactobacillus: No pharmacokinetic data is available.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections.

6.1 Animal Toxicology or Pharmacology

C Tax-O XL 200 is a combination of three medicines: Cefixime, Cloxacillin, and Lactobacillus.

Cefixime is a semisynthetic, cephalosporin antibacterial 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, 7 2-( Z)-[ O-(carboxy methyl) oxime] trihydrate.

Molecular weight: 507.50 as the trihydrate.

Chemical Formula: C₁₆H₁₅N₅O₇S₂.3H₂O The structural formula for cefixime is:

Cloxacillin is a semisynthetic penicillin antibiotic carrying a 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido group at position 6. It is a semi-synthetic penicillin antibiotic which is a chlorinated derivative of [oxacillin].

Molecular Weight: 435.9 g/mol

Molecular Formula:C₁₉H₁₈ClN₃O₅S

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

A strip of 10 tablets

8.4 Storage and handing instructions

Store in a cool & dry place. Protect from light.

Keep out of reach of children.

• Counsel patients that antibacterial drugs, including cefixime, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefixime 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 cefixime for oral suspension or cefixime chewable tablets or other antibacterial drugs in the future.
• Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.