Tegopen (Cloxacillin Sodium)

TEGOPEN® Bristol Cloxacillin Sodium Antibiotic

Action and Clinical

Cloxacillin is a penicillinase-resistant, acid resistant, semi-synthetic penicillin. 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 is readily absorbed following i.m. administration and rapidly reaches therapeutically effective blood levels. Serum levels are approximately proportional to dosage. Peak plasma concentrations of 15 g/mL have been observed 30 minutes after an i.m. injection of cloxacillin 500 mg; plasma concentrations may be doubled by administration of a doubled dose.

At the end of a 3-hour i.v. infusion of cloxacillin 250 mg given to normal subjects, plasma concentrations of the drug were 15 g/mL. After 2 hours, plasma concentrations were 0.6 g/mL.

Approximately 94% of cloxacillin binds to circulating plasma proteins, mainly albumin. It is distributed in therapeutic concentrations into the pleural, synovial, bile and amniotic fluids and attains insignificant concentrations in cerebrospinal and ascitic fluids.

The plasma half-life of cloxacillin is between 0.5 and 1.5 hours. Cloxacillin is partially metabolized to microbiologically active and inactive metabolites. Cloxacillin and its metabolites are rapidly excreted in the urine by glomerular filtration and active tubular secretion. The urinary clearance rate was 162.2 mL/minute and a total of 62% of the dose was excreted in the urine in a study of normal subjects receiving an i.v. infusion of 250 mg of cloxacillin. The drug is also partly eliminated in the feces via biliary excretion.

Reduced plasma concentrations of cloxacillin seen in patients with cystic fibrosis have been attributed to enhanced nonrenal clearance of the drug.

Cloxacillin demonstrates activity against strains of beta-hemolytic streptococci, pneumococci, penicillin G sensitive staphylococci and, due to its resistance to penicillinase, penicillin G resistant (penicillinase producing) staphylococci, cloxacillin displays less intrinsic antibacterial activity and a narrower spectrum than penicillin G.

Indications And Clinical Uses :

In the treatment of beta-hemolytic streptococcal and pneumococcal infections as well as staphylococcal infections (including those caused by penicillinase producing organisms). It is not effective against the so-called methicillin-resistant strains of staphylococcus. In severe staphylococcal infections (septicemia, osteomyelitis, endocarditis, pneumonia) or when staphylococci are suspected and treatment is required before sensitivity results are available, parenteral cloxacillin should be administered at once, followed by cloxacillin orally, when indicated. If the results of identification and susceptibility testing indicate that the infection is due to an organism other than a penicillinase producing staphylococcus susceptible to cloxacillin sodium, treatment should be discontinued and therapy with an alternative agent instituted.

Contra-Indications:

Persons who have shown hypersensitivity to any of the penicillins or any component of the formulation.

Warnings in Clinical States:

Serious and occasionally fatal anaphylactic reactions have been reported in patients receiving penicillin or cephalosporin therapy. These reactions are more apt to occur in individuals with a history of sensitivity to multiple allergens. Careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, i.v. fluids and steroids, oxygen and airway management, including intubation, as indicated.

Precautions:

Before therapy with a penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. There is clinical and laboratory evidence of cross-allergenicity among the penicillins and partial cross-allergenicity among bicyclic b-lactam antibiotics including penicillins, cephalosporins, cepharmycins, 1-oxa-b-lactams, and carbapenems. If an allergic reaction occurs, the drug should be discontinued and appropriate measures taken.:

Candidiasis and other superinfections may occur, especially in debilitated and malnourished patients, or those with low resistance to infection due to corticosteroids, immunosuppressors or irradiation. If superinfection occurs, institute appropriate measures.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antimicrobial agents. After the diagnosis of colitis has been established, therapeutic measures should be initiated.

Bacteriologic studies to determine the causative organisms and their susceptibility to the penicillinase-resistant penicillins should be performed. In the treatment of suspected staphylococcal infections, therapy should be changed to another active agent if culture tests fail to demonstrate the presence of staphylococci.

Periodic assessment of organ system function including renal, hepatic and hematopoietic should be made during prolonged therapy with the penicillinase-resistant penicillins.

White blood cell counts and differential cell counts should be obtained prior to initiation of therapy and at least weekly during therapy with penicillinase-resistant penicillins.

Periodic urinalysis should be performed, and blood urea nitrogen, creatinine, AST and ALT concentrations should be determined during therapy with the penicillinase-resistant penicillins. Dosage alterations should be considered if these values become elevated.

Drug Interactions :

Probenecid administered concomitantly with penicillins increases and prolongs serum penicillin levels. Probenecid slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillins.

Aminoglycosides and penicillins are physically and/or chemically incompatible and can mutually inactivate each other in vitro. In vitro mixing of penicillinase-resistant penicillins and aminoglycosides should be avoided during concomitant therapy, and the drugs should be administered separately. Penicillins can also inactivate aminoglycosides in vitro in serum samples from patients receiving both drugs, which could produce falsely decreased results in serum aminoglycoside assays of the serum samples.

Pregnancy : Safety in pregnancy has not been established. Cloxacillin passes through the placenta into the fetal circulation. This drug should be used in pregnancy only if clearly needed.

Lactation: Cloxacillin is distributed into human milk. Therefore, caution should be exercised when cloxacillin is administered to a nursing woman.

Children: Because of incompletely developed renal function in newborns, penicillinase-resistant penicillins (especially methicillin) may not be completely excreted, resulting in abnormally high blood levels. Frequent blood levels determinations and dosage adjustments when necessary are advisable in these patients. All newborns treated with penicillins should be monitored closely for clinical and laboratory evidence of toxic or adverse effects.

Adverse Reactions:

Hypersensitivity: Two types of allergic reactions to penicillins are noted clinically, immediate and delayed.

Immediate reactions usually occur within 20 minutes of administration and range in severity from urticaria and pruritus to angioedema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death. Such events are very rare. They usually occur after parenteral therapy but have occurred in patients receiving oral therapy. Another type of immediate reaction, an accelerated reaction, may occur 20 minutes to 48 hours after administration and include urticaria, pruritus, wheezing, sneezing and fever. Although laryngeal edema, laryngospasm and hypotension occasionally occur, fatality is uncommon.

Delayed allergic reactions to penicillin therapy usually occur after 48 hours and sometimes as late as 2 to 4 weeks after initiation of therapy. Manifestations of this type of reaction include serum sickness-like symptoms (i.e., fever, malaise, urticaria, myalgia, arthralgia, abdominal pain) and various skin rashes.

Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation may occur. Antibiotic-associated pseudomembranous colitis has been reported rarely with penicillinase-resistant penicillins.

Neurologic: Neurotoxicity similar to that observed with penicillin G (e.g., lethargy, confusion, twitching, multifocal myoclonus, localized or generalized epileptiform seizures) may occur with large i.v. doses of the penicillinase-resistant penicillins especially in patients with renal insufficiency.

Renal: Renal tubular damage and interstitial nephritis have been associated with the administration of methicillin sodium and infrequently with the administration of nafcillin and oxacillin and cloxacillin. Manifestations of this may include rash, fever, eosinophilia, hematuria, proteinuria, and renal insufficiency. Nephropathy does not appear to be dose-related and is generally reversible upon prompt discontinuation of therapy.

Hematologic: Eosinophilia, hemolytic anemia, agranulocytosis, neutropenia, leukopenia, granulocytopenia, thrombocytopenia, and bone marrow depression have been associated with the use of penicillinase-resistant penicillins.

Hepatic: Hepatotoxicity, characterized by fever, nausea, and vomiting associated with abnormal liver function tests, mainly elevated AST levels, has been associated with the use of penicillinase-resistant penicillins. Asymptomatic, transient increases in serum concentrations of alkaline phosphatase, AST, and ALT have been reported.

Symptoms And Treatment Of Overdose :

OverdoseTreatment is likely needed only in patients with severely impaired renal function, since patients with normal kidneys excrete penicillins at a fast rate. No specific treatment can be recommended.:

In patients with severe allergic reactions, general supportive measures (if the patient is in shock) or symptomatic therapy similar to that applied in all cases of hypersensitivity are recommended.

Cloxacillin is only minimally removed by hemodialysis and peritoneal dialysis up to 5%.

Dosage And Administration:

Bacteriologic studies to determine the causative organisms and their susceptibility to the penicillinase-resistant penicillins should be performed. Duration of therapy varies with the type and severity of infection as well as the overall condition of the patient. Therefore, it should be determined by the clinical and bacteriological response of the patient. Therapy should be continued for at least 48 to 72 hours after the patient has become afebrile, asymptomatic, and cultures are negative. In severe staphylococcal infections, therapy with penicillinase-resistant penicillins should be continued for at least 14 days. The treatment of endocarditis and osteomyelitis requires a longer term of therapy.

Adults and Children weighing >20 kg: 250 to 500 mg every 6 hours, depending on severity of infection. Children <20 kg: 25 to 50 mg/kg/day in 4 equal doses administered every 6 hours. For severe infections, the dosage may be increased. Maximum dosage for adults is 6 g/day.

Renal Impairment: Adjustment of dosage is generally unnecessary in patients with renal impairment.

Preparation of Solution: Prepare solution for parenteral use with Sterile Water for Injection. The reconstituted solution is stable for 24 hours at room temperature (25°C) and for 96 hours under refrigeration (2 to 10°C).

When i.v. therapy is required, cloxacillin should be given by slow injection (3 to 4 minutes) or infusion (30 to 40 minutes). The equivalent of 500 mg in 10 mL of water for injection may be given by slow i.v. injection over 3 to 4 minutes every 4 to 6 hours or by i.v. infusion.

Caution: More rapid administration may result in convulsive seizures.

Administration by I.V. Drip: The 2 000 mg vial should be reconstituted by adding 20 mL of Sterile Water for Injection.

Stability studies at concentrations of 1 and 2 mg/mL in the following various i.v. solutions indicate that the drug will lose less than 10% activity at 25°C during 8 hours: Normal Saline Solution; 5% Dextrose in Water w/v; 10% D-Fructose in Water w/v; 10% D-Fructose in Normal Saline w/v; M/6 Sodium-Lactate Solution; Lactate Ringer Injection; 10% Invert Sugar in Water w/v; 10% Invert Sugar in Normal Saline w/v.

Cloxacillin should not be mixed with an aminoglycoside in the syringe, i.v. fluid or administration set because mutual inactivation and loss of antibacterial activity can occur (see Precautions, Drug Interactions). In general, it is advisable to administer these antibiotics separately.

Availability And Storage:

500 mg: Each dry filled vial contains: cloxacillin (as the sodium salt) 500 mg. Nonmedicinal ingredients: none. Sodium: <1.1 mmol (25 mg)/500 mg.

2 000 mg: Each dry filled vial contains: cloxacillin (as the sodium salt) 2 000 mg. Nonmedicinal ingredients: none. Sodium: <4.3 mmol (100 mg)/2 000 mg.

Store at controlled room temperature not exceeding 25°C.

TEGOPEN® Bristol Cloxacillin Sodium Antibiotic

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