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Executive Summary

METOCLOPRAMIDE IN A READY-TO-INFUSE CONTAINER IMPLIES FIXED DOSING and, therefore, is not a suitable product for approval via the ANDA process, FDA Office of Drug Standards Director Peter Rheinstein told International Medication Systems in a Feb. 8 letter. Responding to the firm's request to submit an ANDA for metoclopramide HCl 1 mg/ml in 50 ml, 75 ml and 100 ml ready-to-infuse containers, Rheinstein explained that "such packaging would promote the use of doses that were not properly adjusted for a specific patient and thus would raise . . . safety and efficacy questions regarding a fixed does of drug products in cases where dosage adjustments must be made based on the patient's weight or body surface area." International Medication Systems had previously requested the agency to allow ANDAs for the same drug products and was told that clinical trials would be necessary because of the agency's concern over fixed dosing. The firm resubmitted its request in March 1987. IMS is arguing that individual doses can still be given from a ready-to-infuse container and that labeling could address dosage adjustments. The innovator product, Robin's Reglan, is supplied in 5 mg/ml strengths in 2 ml, 10 ml and 30 ml vials. FDA, Rheinstein responded, "is not persuaded by your new argument that 'having the solution in an already diluted form suitable for direct infusion does not make the unit a fixed dose any more than having a 5 mg/ml 30 ml single dose container constitutes a fixed dose.'" With the innovator product, Rheinstein explained, a specific dose, "calculated on an individual patient's weight, must be consciously withdrawn and further diluted in an appropriate vehicle prior to infusion. In contrast, the product that you propose is a prediluted product . . . [in a container] for direct infusion. Such containers are routinely viewed as containing a single 'ready-to-hang' dose of drug product (i.e., a fixed dose)." Even with proposed labeling discussing dosage adjustment, Rheinstein continued, "the agency is not convinced . . . that such a packaging configuration would be recognized as other than a standard fixed dose." Rheinstein also noted that the proposed product "would supply a significant additional fluid load than the listed drug product." For example, he said, "if a dose of 120 mg of the proposed product is ordered, the total volume administered over the usual six doses is 720 ml by the IMS system and only 300 ml by the listed drug product." FDA has received a number of ANDA suitability petitions for changes in dosage form or strength that have been either denied by the agency or voluntarily withdrawn by the requesting companies. Abbott, for example, requested permission to submit ANDAs for metoclopramide 10 mg/ml and 20 mg/ml injections and was originally told that the products would be suitable for ANDAs. The agency then withdrew its approval letter citing concerns about appropriate dosing for individual patients. Purdue Frederick has submitted a number of petitions for oral formulations of metoclopramide and then withdrawn the petitions. ANDA suitability petitions are often withdrawn by firms if FDA notifies the companies by telephone that the petitions are unlikely to receive approval. FDA has, however, approved petitions for metoclopramide in pharmacy bulk packages.

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