WARCLOX Capsules. (Amoxicillin/Cloxacillin) DESCRIPTION

Transcription

1 * WARCLOX Capsules (Amoxicillin/Cloxacillin) DESCRIPTION Warclox is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase resistant penicillin - cloxacillin. Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C H N S.3H O and the molecular weight is Cloxacillin is a semisynthetic, penicillinase-resistant penicillin of the isoxazolyl penicillin group. Cloxacillin is chemically the monohydrate of sodium 6-[ 3-( 2- chlorophenyl)- 5- methylisoxazole- 4- carboxamido] penicillanate. Inactive Ingredients: Talc IP, Magnesium stearate IP, Hard gelatin capsules IP. CLINICAL PHARMACOLOGY Amoxicillin and Cloxacillin in Warclox are both bactericidal drugs that act by inhibiting bacterial cell wall synthesis. Amoxicillin is active against non-beta lactam producing gram-positive and gram-negative organisms. It is destroyed by beta-lactamase (also known as penicillinase) enzyme produced by few bacterial organisms e.g. Staphylococcus aureus, few strains of E. coli & H. influenzae. Cloxacillin, a beta-lactamase resistant antibiotic, is stable against beta-lactamase enzymes and hence is active against gram-positive organisms including beta-lactamase producing strains of staphylococcus. Cloxacillin is rapidly bactericidal to all gram-positive organisms except Strep. faecalis but is primarily of interest for its activity against staphylococci and in particular against the high proportion of staphylococci that are resistant to penicillin G. This makes it ideal for the treatment of mixed gram-positive infections e.g. infected burns where the presence of a penicillinase-producing staphylococci may inactivate other penicillins, when given alone before they can exert any effect on the otherwise sensitive organisms. The combination of Cloxacillin and amoxicillin in Warclox, thus widens the antibacterial spectrum of either drug given alone. The pharmacokinetics of Warclox (amoxicillin-cloxacillin combination) has not been studied. Amoxicillin is well absorbed from the gastrointestinal tract after oral administration and is stable in the presence of gastric acid and hence may be given with food. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is approximately 1 hour and protein binding of amoxicillin is roughly 20%. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours; its excretion can be delayed by concurrent administration of probenecid. Cloxacillin is relatively stable to gastric acid and rapidly and adequately absorbed after oral administration. However, absorption is incomplete and about 30-80% of the drug is absorbed from the gastrointestinal tract. Cloxacillin should be taken about one hour before meals or two hours after meals for optimum absorption as food delays absorption. Protein binding of cloxacillin is 94% to 95%; volume of distribution is 6.6 to 10.8 L and elimination half- l i f e is 0.7 to 3 h. Effective blood, tissue and urine levels are readily achieved but normal doses provide insignificant concentrations in cerebrospinal fluid. Cloxacillin enters synovial fluid and peak synovial fluid levels represent 21% to 22% of the peak serum level, although synovial fluid levels peak slightly behind the serum peak level. It was also noted that after 2 hours synovial fluid levels exceeded serum levels.. Peak serum concentrations occur within 1 to 2 h after an oral dose.. With the 500 mg dose, peak blood concentrations range from 7.5 to 15 mcg/ml % of a Cloxacillin dose is metabolized in the liver and the metabolite has been isolated and found to have antibacterial activity very similar to that of the parent compound. * RegisteredTrademark. Registered Office: Thane-Belapur Road, KU Bazar Post, Turbhe, Navi Mumbai

2 Cloxacillin is predominantly excreted by glomerular filtration and renal tubular secretion in a similar manner to the other penicillins. Microbiology: The extended antibacterial spectrum of Warclox includes the following: Gram-positive organisms: Staphylococcus aureus, pencillinase producing Streptococcus pneumoniae, Streptococcus viridans, Streptococcus faecalis, Streptococcus pyogenes, Listeria monocytogenes, Corynebacterium diptheriae, Bacillus anthracis & Clostridium species etc. Gram-negative organisms: E. Coli, Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, B. pertussis, Proteus mirabilis, Shigella sp., Salmonella typhi and Salmonella paratyphi, other Salmonella species and Brucella species etc. (For detailed information on the MICs of these organism and susceptibility testing, refer to the prescribing information on AMOXICILLIN and CLOXACILLIN) INDICATIONS AND USAGE Warclox (amoxicillin-cloxacillin) is indicated in the treatment of infections due to susceptible strains of the designated microorganisms in the conditions listed below: Infections of the ear, nose, and throat due to Streptococcus spp. ((alpha)- and (beta)-hemolytic strains only), Streptococcus pneumoniae, Staphylococcus spp., or H. influenzae Infections of the genitourinary tract due to E. coli, P. mirabilis, or E. faecalis Infections of the skin and skin structure due to Streptococcus spp. ((alpha)- and (beta)-hemolytic strains only), Staphylococcus spp., or E. coli Infections of the lower respiratory tract due to Streptococcus spp. ((alpha)- and (beta)-hemolytic strains only), Streptococcus pneumoniae, Staphylococcus spp., or H. influenzae Lower Respiratory Tract Infections - caused by -lactamase producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Otitis Media - caused by -lactamase producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarhalis. Sinusitis - caused by -lactamase producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Skin and Skin Structure Infections - caused by -lactamase-producing strains of S. aureus, Escherichia coli and Klebsiella spp. Urinary Tract Infections - caused by -lactamase-producing strains of Escherichia coli and Klebsiella spp and Enterobacter spp. The presence of cloxacillin in Warclox widens the spectrum to include infections caused by beta lactamase producing strains of these organisms. Additionally, cloxacillin being a penicillinase-resistant penicillin is the drug of choice for penicillinase-producing staphylococcus aureus or staphylococcus epidermidis infections including those involving the skin, soft tissues, respiratory tract, ear, nose and throat, genitourinary tract, bone (acute and chronic osteomyelitis), intestine, surgical site and infective endocarditis. Bacteriological studies to determine the causative organisms and their susceptibility to Warclox (amoxicillincloxacillin) should be performed together with any indicated surgical procedures. Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies to determine the causative organisms and their susceptibility to Warclox when there is reason to believe the infection may involve any of the -lactamase-producing organisms listed above. Once the results are known, therapy should be adjusted, if appropriate.

3 CONTRAINDICATIONS Warclox is contraindicated in patients with a history of allergic reactions to any penicillin. Attention should be paid to possible cross-sensitivity with other beta lactam antibiotics, e.g. cephalosporins. WARNINGS SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIAING THERAPY WITH WARCLOX, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENCILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, WARCLOX SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINSTERED AS INDICATED. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxicillin and cloxacillin, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic associated colitis." After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. PRECAUTIONS General: While Warclox possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic and hematopoietic function, is advisable during prolonged therapy. A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash.thus, ampicillin class antibiotics (amoxicillin, cloxacillin etc.,) should not be administered to patients with mononucleosis. The possibility of super-infections with mycotic or bacterial pathogens should be kept in mind during therapy. If super-infections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted. Drug Interactions: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Warclox may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended. In common with other broad-spectrum antibiotics, Warclox may reduce the efficacy of oral contraceptives. Drug/Laboratory Test Interactions: Oral administration of Warclox will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Benedict's

4 Solution or Fehling's Solution. Since this effect may also occur with amoxicillin and therefore Warclox, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of ampicillin to pregnant women a transient decrease in plasma concentration of total conjugated estriol, estrol-glucuronide, conjugated estrone and estradiol has been noted. This effect may also occur with amoxicillin and therefore Warclox. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals with both amoxicillin and cloxacillin have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin-clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin-clavulanate was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin-clavulanate was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse 2 reproductive effects were seen at doses up to 500 mg/kg (approximately 3 times the human dose in mg/m ). Teratogenic effects: Both amoxicillin and cloxacillin belong to Pregnancy (Category B). There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Warclox should be used during pregnancy only if clearly needed. Labor and Delivery: Oral ampicillin class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions and duration of contractions. However, it is not known whether the use of amoxicillin or Cloxacillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. Nursing Mothers: Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when Warclox is administered to a nursing woman. Pediatric Use: Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of Warclox should be modified accordingly in pediatric patients 12 weeks or younger (</=3 months). ADVERSE REACTIONS As with other penicillins, it may be expected that untoward reactions will be essentially limited to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria. The following adverse reactions have been reported as associated with the use of penicillins: Gastrointestinal: Nausea, vomiting, diarrhea, and hemorrhagic/pseudomembranous colitis.

5 Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS). Hypersensitivity Reactions: Serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported. NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, Warclox should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to Warclox therapy. Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have also been reported. Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, 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. Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely. Miscellaneous: Superficial tooth discoloration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discoloration as it can usually be removed by brushing. OVERDOSAGE Data on the effects of overdose with Warclox is not available. However, with amoxicillin alone, most patients have been asymptomatic following overdosage or have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdose with amoxicillin. Renal impairment appears to be reversible with cessation of drug administration. DOSAGE AND ADMINISTRATION Dosage Warclox 250 mg

6 Adults : 2-4 capsules three times a day Children 2-12 years : 1-2 capsules three times a day Warclox 500 mg Adults Children 2-12 years : 1-2 capsules three times a day : 1 capsules three times a day Warclox 1 g Adults : 1 capsule three times a day Care must be exercised with the use of Warclox in renal impairment because of its amoxicillin content. High blood levels of amoxicillin may occur more readily in patients with impaired renal function because of decreased renal clearance. Amoxicillin may be removed from circulation by hemodialysis. (See DOSAGE AND ADMINISTRATION in the prescribing information for AMOXICILLIN). However, cloxacillin dosage need not be adjusted in renal failure and the drug is not removed by hemodialysis. Administration: Warclox is preferably taken 1 hour before meals as food delays the absorption of cloxacillin. HOW SUPPLIED Each Warclox 250 mg capsule contains: Amoxicillin Trihydrate I.P. equivalent to amoxicillin Cloxacillin Sodium I.P. Each Warclox 500 mg capsule contains: Amoxicillin Trihydrate I.P. equivalent to amoxicillin Cloxacillin Sodium I.P. Each Warclox 1 g capsule contains Amoxicillin Trihydrate I.P. equivalent to amoxicillin Cloxacillin Sodium I.P. 125 mg 125 mg 250 mg 250 mg 500 mg 500 mg