Drug Interaction Report

GENERALLY AVOID: Concomitant use of pivmecillinam with valproate or other pivalate-generating medications (e.g., cefditoren pivoxil, adefovir dipivoxil) may increase the risk of carnitine depletion. The proposed mechanism is additive reduction of carnitine levels that occur when pivmecillinam is coadministered with other pivalate-generating medications. Pivmecillinam has been reported to reduce serum carnitine concentrations due to the reaction of pivalic acid with carnitine to form pivaloyl carnitine, which is excreted in the urine. Reduced carnitine levels may increase the risk of valproate-induced hyperammonemic encephalopathy. A case report describes hyperammonemic encephalopathy that developed in a 72-year old woman on valproate monotherapy (1500 mg/day) for partial epilepsy who was given pivmecillinam (200 mg three times daily) for a urinary tract infection. Her condition resolved after discontinuation of pivmecillinam and valproate and replacement with IV cefuroxime and gabapentin. Drug interaction studies with other pivalate-generating medications are unavailable. However, carnitine depletion can be expected. Additionally, a similar interaction with pivalate-generating medications may occur following the use of pivampicillin.

MANAGEMENT: The manufacturer of pivmecillinam advises that concomitant use with valproate or other pivalate-generating medications should be avoided. If concomitant use is required, patients should be monitored for signs and symptoms of carnitine depletion (such as muscle aches, fatigue, confusion, and hypoglycemia) and hyperammonemic encephalopathy (such as acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting). Discontinuation of both medicines and initiation of appropriate therapeutic management should be considered if these signs and symptoms develop.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of cefditoren pivoxil. According to the manufacturer, administration of cefditoren pivoxil following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 50% and 70%, respectively, compared to administration in the fasting state. The absolute bioavailability of cefditoren pivoxil is approximately 14% under fasting conditions and 16% when given with a low-fat meal.

MANAGEMENT: To ensure maximal oral absorption, cefditoren pivoxil should be administered with or immediately after a meal.

The recommended maximum number of medicines in the 'beta-lactam antibiotics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'beta-lactam antibiotics' category:

• pivmecillinam
• Spectracef (cefditoren)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.