Drug Interactions between Augmentin and brentuximab

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.

Serious infections and opportunistic infections (e.g., pneumonia, bacteremia, sepsis/septic shock [including fatalities]) have been reported in patients treated with brentuximab vedotin. Patients should be monitored closely for the emergence of any infection during treatment with this agent. John Cunningham virus (JC virus) infection resulting in progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with this agent. A diagnosis of PML should be considered in any patient presenting with new-onset signs/symptoms of CNS abnormalities. Therapy should be held for any suspected case of PML and discontinued if a diagnosis of PML is confirmed.

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.

Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has occurred in patients receiving certain monoclonal antibodies. Patients with high tumor burden and/or high circulating lymphocyte counts (greater than 25 x 10[9]/L) are at greater risk for developing TLS. Tumor lysis prophylaxis with anti-hyperuricemics and hydration prior to infusion may be recommended or should be considered. Electrolyte abnormalities should be corrected, and renal function and fluid balance should be monitored in patients who develop TLS. It is recommended to monitor for signs/symptoms of TLS, and temporary interruption or discontinuation of therapy might be required.

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.

Serious events of hyperglycemia (e.g., new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, ketoacidosis [including fatalities]) have been reported in brentuximab vedotin-treated patients. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Serum glucose should be monitored and if hyperglycemia develops, antihyperglycemic agents should be administered as clinically indicated.

Fatal and serious events of acute pancreatitis have been reported with brentuximab vedotin. Other fatal and serious gastrointestinal (GI) complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. If new or worsening GI symptoms (including severe abdominal pain) develop, it is recommended to perform a prompt diagnostic evaluation and treat appropriately.

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.

The use of brentuximab vedotin should be avoided in patients with moderate or severe liver dysfunction (Child-Pugh B or C). The frequency of grade 3 or higher adverse reactions and deaths was greater in patients with moderate and severe liver dysfunction compared to those with normal liver function. Fatal and serious cases of hepatotoxicity have occurred in patients receiving this agent. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Liver enzymes and bilirubin should be monitored. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of brentuximab vedotin.

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.

Serious events of hyperglycemia (e.g., new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, ketoacidosis [including fatalities]) have been reported in brentuximab vedotin-treated patients. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Serum glucose should be monitored and if hyperglycemia develops, antihyperglycemic agents should be administered as clinically indicated.

Peripheral neuropathy, predominantly sensory neuropathy, has occurred in patients treated with brentuximab vedotin. Patients should be monitored for symptoms of neuropathy, and those experiencing new or worsening peripheral neuropathy may require a delay, change in dosage, or discontinuation of brentuximab vedotin.

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).

Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported with the use of brentuximab vedotin. Care should be taken when using this agent in patients at risk of pulmonary events. Patients should be monitored for signs/symptoms of pulmonary toxicity (including cough and dyspnea). If new or worsening pulmonary symptoms develop, brentuximab vedotin dosing should be held during evaluation and until symptomatic improvement.

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.

The use of brentuximab vedotin should be avoided in patients with severe renal dysfunction (CrCl less than 30 mL/min). The frequency of grade 3 or higher adverse reactions and deaths was greater in patients with severe renal dysfunction compared to those with normal renal function.