Drug Interactions between Augmentin and thioguanine

MONITOR: The concomitant or sequential use of other agents known to induce hepatotoxicity may potentiate the risk of liver injury associated with thioguanine. A high risk of liver toxicity characterized by vascular endothelial damage has been reported with long-term continuous use of thioguanine, particularly in children receiving the drug as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Histopathological features include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.

MANAGEMENT: The risk of hepatic injury should be considered when thioguanine is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Baseline and regular monitoring of hepatic function is recommended. Thioguanine therapy should be discontinued if there is evidence of toxic hepatitis or biliary stasis, as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal. Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported, but do not always occur.

The most consistent, dose-related toxicity of thioguanine is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. However, any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood. Therapy with thioguanine should be administered cautiously in patients with myelosuppression. It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy.

The most consistent, dose-related toxicity of thioguanine is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. However, any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood. Therapy with thioguanine should be administered cautiously in patients with myelosuppression. It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy.

Clostridioides difficile-associated diarrhea (CDAD), formerly pseudomembranous colitis, has been reported with almost all antibacterial drugs and may range from mild diarrhea to fatal colitis. The most common culprits include clindamycin and lincomycin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C difficile, whose toxins A and B contribute to CDAD development. Morbidity and mortality are increased with hypertoxin-producing strains of C difficile; these infections can be resistant to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea after antibacterial use. Since CDAD has been reported to occur more than 2 months after antibacterial use, careful medical history is necessary. Therapy with broad-spectrum antibacterials and other agents with significant antibacterial activity should be administered cautiously in patients with history of gastrointestinal disease, particularly colitis; pseudomembranous colitis (generally characterized by severe, persistent diarrhea and severe abdominal cramps, and sometimes associated with the passage of blood and mucus), if it occurs, may be more severe in these patients and may be associated with flares in underlying disease activity. Antibacterial drugs not directed against C difficile may need to be stopped if CDAD is suspected or confirmed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C difficile, and surgical evaluation should be started as clinically indicated.

Thioguanine is closely related structurally and functionally to mercaptopurine. A rare deficiency in the enzyme thiopurine methyltransferase (TMPT) results in an increased sensitivity to the myelosuppressive effects of both drugs causing rapid bone marrow suppression following initial mercaptopurine or thioguanine administration. Therapy with thioguanine or mercaptopurine should be administered cautiously and at a reduced dose in patients with TMPT deficiency.

The most consistent, dose-related toxicity of thioguanine is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. However, any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood. Therapy with thioguanine should be administered cautiously in patients with myelosuppression. It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy.

Because of their cytotoxic effects on rapidly proliferating tissues, antineoplastic agents frequently can, to varying extent, induce myelosuppression. The use of these drugs may be contraindicated in patients with known infectious diseases. All patients should be instructed to immediately report any signs or symptoms suggesting infection such as fever, sore throat, or local infection during antineoplastic therapy. Close clinical monitoring of hematopoietic function is recommended.

Hepatotoxicity usually presented as hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices), has been reported during therapy with thioguanine. Therapy with thioguanine should be administered cautiously in patients with liver disease or predisposed to it. Patients should be instructed to immediately report any signs of hepatotoxicity such as jaundice, dark urine, upper right quadrant pain, or anorexia. Clinical monitoring of hepatic function and determination of the etiology of hepatic dysfunction is recommended.

The administration of amoxicillin-clavulanate has infrequently been associated with hepatotoxicity such as elevations in serum transaminases, bilirubin, and/or alkaline phosphatase. The histologic findings on liver biopsy have consisted of predominantly cholestatic and/or hepatocellular changes. Symptoms may occur during or several weeks after therapy. The hepatotoxicity is generally reversible, although deaths have been reported on rare occasions, mostly in patients with serious underlying diseases or concomitant use of other medications. Liver enzyme abnormalities have also been observed with the use of amoxicillin or ampicillin alone. According to the manufacturer, therapy with amoxicillin-clavulanate should be administered cautiously in patients with evidence of hepatic dysfunction. Periodic monitoring of liver function is recommended during prolonged therapy. The use of amoxicillin-clavulanate is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with the drug.

High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest®, Benedict's Solution or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®) be used.

Penicillin antibiotics (except for agents in the penicillinase-resistant class) are removed by hemodialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis.

Patients with mononucleosis treated with an aminopenicillin antibiotic, may develop a pruritic erythematous maculopapular skin rash. The rash is usually self-limiting and resolves within days of discontinuing the offending agent. An altered drug metabolism or an immune-mediated process unrelated to drug hypersensitivity has been proposed as the underlying mechanism. Therapy with aminopenicillin antibiotics should not be administered in patients with mononucleosis.

Some amoxicillin chewable tablets and suspensions products contain phenylalanine. The phenylalanine content should be considered when these products are used in patients who must restrict their intake of phenylalanine (i.e. phenylketonurics).

Most beta-lactam antibiotics are eliminated by the kidney as unchanged drug and, in some cases, also as metabolites. The serum concentrations of beta-lactam antibiotics and their metabolites may be increased and the half-lives prolonged in patients with impaired renal function. Dosage adjustments may be necessary and modifications should be based on the degree of renal impairment as well as severity of infection in accordance with the individual product package labeling. Renal function tests should be performed periodically during prolonged and/or high-dose therapy, since nephrotoxicity and alterations in renal function have occasionally been associated with the use of these drugs.