BACKGROUND: The purpose of the US Food and Drug Administration's Marketed Unapproved Drugs Initiative is to decrease marketing of older unapproved medications. The administration has recently extended its rulings by including sterile injectable drugs administered in the inpatient environment. The impact of this initiative on the inpatient environment has been minimally studied. METHODS: Consecutive retrospective purchase data of vasopressin for injection (vasopressin) and neostigmine methylsulfate for injection (neostigmine) from 720 hospitals and 746 hospitals, respectively, were included. Purchases occurred from January 1, 2010 to December 31, 2016. The average noncontract drug price was calculated and compared to the purchase data during the impact of the initiative. Comparison was made of hospital purchases made before and after the initiative. The year 2014 was considered a washout transition year due to the large amounts of discontinued unapproved formulations that were still available and purchased by hospitals. The analysis was completed using a matched paired t test. RESULTS: The noncontract price for vasopressin increased from $12.83 per vial to $158.83 per vial (1138% increase) and for neostigmine from $27.74 per vial to $175.14 per vial (531% increase) across the pre- and postinitiative intervals; however, purchase volumes after the price increases were not found to have a statistically significant difference compared to purchases before the price increases (P = .98 and P = .4, respectively). CONCLUSIONS: Health systems have experienced a significant cost increase of vasopressin and neostigmine and are absorbing price increases for these older, generic sterile injectable drugs.