PONDOCILLIN®
Leo
Pivampicillin
Antibiotic
Action And Clinical Pharmacology: Pivampicillin is the pivaloyloxymethyl ester of (the semi-synthetic penicillin) ampicillin. It is an inactive pro-drug, which is converted during its absorption from the gastrointestinal tract to the microbiologically active ampicillin, together with formaldehyde and pivalic acid, by non-specific esterases present in most body tissues. Amounts in excess of 99% of the pivampicillin absorbed are converted to ampicillin within 15 minutes of absorption. Ampicillin has a bactericidal action resulting from inhibition of cell wall mucopeptide biosynthesis.
The absorption of pivampicillin was virtually unaffected by taking the dose with food. Although the peak serum level may be reduced and delayed when compared to doses given in the fasting state, the total bioavailability was not affected.
Oral administration of 500 mg produced a mean peak serum level of 13 g/mL ampicillin within 1 hour.
In healthy volunteers the plasma half-life of ampicillin is approximately one hour and there is no significant accumulation on repeated dosing.
The urinary excretion of ampicillin in healthy volunteers in the first 6 hours, expressed as a percentage of the dose administered, was around 70% for pivampicillin and 25 to 30% for ampicillin. Similar results have been obtained in patients.
The pivalic acid, released during the conversion of pivampicillin to ampicillin is excreted mainly in the urine in the form of labile conjugates with glycine.
Indications And Clinical Uses: For the treatment of respiratory tract infections (including acute bronchitis, acute exacerbations of chronic bronchitis and pneumonia); ear, nose and throat infections; gynecological infections; urinary tract infections (including acute uncomplicated gonococcal urethritis) when caused by non penicillinase-producing susceptible strains of the following organisms: gram-positive organisms, e.g., streptococci, pneumococci and staphylococci; gram-negative organisms, e.g., H. influenzae, N. gonorrhoeae, E. coli, P. mirabilis.
Contra-Indications: In patients with a history of hypersensitivity to any of the penicillins or cephalosporins; in secondary infections associated with infectious mononucleosis or lymphatic leukemia, because of the high frequency or exanthemata associated with ampicillin therapy in these conditions; in infections caused by b-lactamase (penicillinase)-producing bacteria.
Manufacturers’ Warnings In Clinical States: Pivampicillin suspension is not recommended for the treatment of severe infections in children.
Precautions: Before therapy, inquiry as to past penicillin, cephalosporin or other allergies is essential as reactions occur more frequently in hypersensitive persons. If allergic or anaphylactic reactions occur during therapy, discontinue treatment and initiate usual measures, i.e., antihistamines, pressor amines or corticosteroids.
During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically. Candidiasis and other super-infections may occur especially in debilitated and malnourished patients or in those with low resistance to infection due to corticosteroids, immunosuppressors or irradiation.
Long-term treatment or frequently repeated treatment courses should be used with caution as pivampicillin has been associated with an increased excretion of carnitine in urine and a reduction of serum carnitine. During absorption pivampicillin is hydrolyzed to pivalic acid and ampicillin. Pivalic acid is excreted partly as a conjugate with carnitine. Treatment with pivalic acid liberating antibiotics for a duration of 22 and 30 months in children resulted in total muscle carnitine depletion to 10% of reference values, however, no adverse clinical effects were reported which could be associated with primary or secondary carnitine deficiency. Following 7 to 10 days treatment at the highest recommended doses of pivampicillin there was a significant reduction in serum carnitine which returned to the normal range within 2 weeks of stopping therapy. Despite these reductions in serum carnitine, total body stores of carnitine were reduced by approximately 10%. The increased excretion of carnitine associated with the use of pivampicillin is considered to be without clinical significance in short-term treatment. Adverse effects which could be related to carnitine deficiency occur with similar frequency as with other antibiotics not liberating pivalic acid. Carnitine is synthesized in the liver and kidney of man. Carnitine is also available from the diet in meat and dairy products; however, endogenous biosynthesis can meet normal metabolic needs in vegetarians. Carnitine functions in the transport of fatty acids across the mitochondrial membrane as an essential cofactor in fatty acid oxidation. Almost all the body stores of carnitine (100 to 200 mmol, 16 to 32 g) are found in muscle (98%), liver and kidney (1.6%) and serum (0.4%). In patients with the extremely rare condition of carnitine deficiency, treatment with pivampicillin should be avoided. Concurrent treatment with valproic acid or other medications liberating pivalic acid should be avoided.
Neither measurement of serum carnitine nor concomitant administration of prophylactic doses of carnitine is recommended as a general measure for patients receiving pivalic acid liberating antibiotics.
Children: Endogenous carnitine production begins at birth and in normal children is fully developed during the first months of life. Although no adverse events which can be explained by a pivalic acid induced reduction in carnitine have been documented, use of pivampicillin in children less than 3 months of age should be avoided.
Pregnancy and Lactation: Safety for use during pregnancy has not been established. Ampicillin crosses the placenta and small amounts have been detected in breast milk. It is not known whether the pivalic acid component of pivampicillin is excreted in human milk. The administration of pivampicillin to a mother who is breast-feeding a child less than 3 months of age should take into account the importance of the drug to the mother and the possible risk to the infant (see precaution on carnitine above).
The passage of any penicillin from blood into brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of such factors and particularly in the presence of renal failure when high serum concentrations can be attained, CNS adverse effects including myoclonia, convulsive seizures and depressed consciousness can be expected. Although this complication has not been reported with pivampicillin it should be anticipated.
Cases of gonorrhea with a suspected primary lesion of syphilis should have dark field examination before receiving treatment. In all other cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of 4 months.
Adverse Reactions: Hypersensitivity: Like ampicillin, erythematous maculopapular rashes have been reported fairly frequently. Urticarial reactions have also been reported. Anaphylactic reactions have occurred as with other penicillins. Rare cases of erythema multiforme and exfoliative dermatitis, though not observed with pivampicillin have been reported with ampicillin and, therefore, may be anticipated.
Note: Urticaria, other skin rashes and serum sickness-like reactions may be controlled with antihistamines and if necessary, systemic corticosteroids. Serious anaphylactic reactions require the immediate use of epinephrine, oxygen and i.v. corticosteroids. In some cases of infectious mononucleosis, where ampicillin has been administered, an extremely high incidence of generalized rash has been reported.
Gastrointestinal: nausea, vomiting, retrosternal pain and flatulence. Diarrhea has been reported but less frequently than with ampicillin. The incidence of these effects can be reduced by taking the medication with food. Glossitis, stomatitis, black ‘hairy’ tongue and enterocolitis have been associated with ampicillin therapy and therefore, may be anticipated with pivampicillin.
Hematologic: Eosinophilia, anemia, thrombocytopenia, thrombocytopenic purpura, leukopenia and agranulocytosis have been reported with ampicillin and, therefore, may be anticipated with pivampicillin.
Others: dizziness and pruritus. Transient changes in AST.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience of overdosage with pivampicillin. However, excessive doses are likely to induce nausea, vomiting and gastritis.
Treatment should be restricted to symptomatic and supportive measures.
Dosage And Administration: Suspension: Adults and children over 10 years: 15 mL (525 mg) twice daily; double in severe infections.
Children 7 to 10 years: 10 mL (350 mg) twice daily; 4 to 6 years: 7.5 mL (262.5 mg) twice daily; 1 to 3 years: 5 mL (175 mg) twice daily. In children 10 years of age or less the dosage range is 25 to 35 mg/kg/day and should not exceed the recommended adult dose of 500 mg twice daily.
Infants 3 to 12 months: 40 to 60 mg/kg body weight daily divided into 2 equal doses.
In short-term therapy (treatment less than 14 days), continue treatment for 72 hours beyond the time that evidence of bacterial eradication has been obtained (patient is asymptomatic). In group A beta hemolytic streptococci, continuation of therapy for at least 10 days is recommended.
In the treatment of urinary tract infection, frequent bacteriological and clinical appraisal is necessary. Smaller doses than those recommended should not be used.
In the management of acute exacerbations of chronic bronchitis 10 to 14 days of pivampicillin is usually recommended.
Tablets: Adults and children over 10 years: 500 mg twice daily; double in severe infections.
Gonococcal Urethritis: 1.5 g as a single dose with 1 g probenecid concurrently.
Availability And Storage: Suspension: Each mL of reconstituted suspension contains: pivampicillin 35 mg. Nonmedicinal ingredients: aspartame, banana dry flavor, magnesium stearate, polyvidone, propylparahydroxybenzoate, sodium carraghenate, sodium chloride, sodium citrate, sorbitol and vanilla dry flavor. Bottles containing powder for suspension to prepare 100, 150 and 200 mL of reconstituted solution. Store powder for suspension below 25°C. The reconstituted suspension may be stored for 7 days at room temperature and 14 days under refrigeration.
Tablets: Each white film-coated, ovoid tablet, embossed with 128 on one side and an Assyrian Lion on the other, contains: pivampicillin 500 mg (equivalent to 377 mg ampicillin). Nonmedicinal ingredients: starch carboxy-methylsodium glycolate, magnesium stearate, methylcellulose (methocel A15), STA-RX 1500 and hydroxypropylmethylcellulose. Bottles of 100 and 500.
PONDOCILLIN® Leo Pivampicillin Antibiotic
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