Physicochemical properties, pharmacokinetics, and pharmacodynamics of intravenous hematin: a literature review.

INTRODUCTION: Intravenous (i.v.) hematin has been used in the treatment of acute intermittent porphyria (AIP) since the early 1970s and commercially available as Panhematin (hemin for injection; Ovation Pharmaceuticals, Inc., USA) since 1983, yet no publication to date has attempted to summarize the known pharmacodynamics and toxicological actions of hematin and the implications on treatment. It is the objective of this literature review to identify, consolidate, and summarize the available scientific literature regarding the physicochemical properties, pharmacokinetics, toxicology, and hemostatic effects of i.v. hematin injections. METHODS: A comprehensive search of the available literature was performed and resulting data were summarized. Furthermore, previously unpublished toxicology data extracted from the original New Drug Application were included. RESULTS: Hematin, reconstituted with sterile water, rapidly degrades and it is hypothesized that the degradation products lead to morbidities such as thrombophlebitis, thrombocytopenia, and transient anticoagulation. Reconstitution with human serum albumin produces a well-tolerated hematin preparation and improves its stability significantly. The clearance of i.v. hematin infusions are shown to fit a two-compartment model consisting of a rapid initial rate followed by a slower and prolonged second phase. This model is supported by the evidence demonstrating that hematin is first bound by hemopexin and, upon saturation, second by albumin. The highest i.v. human hematin dose reported in the literature was 12.2 mg/kg (1000 mg) and resulted in acute gastrointestinal pain, paresthesia, and acute tubercular necrosis. The patient's renal function returned to normal over the following 15 hours. CONCLUSION: Hematin, at doses approved by the US Food and Drug Administration, is generally well tolerated. Reconstitution with albumin produces a significantly more stable preparation than reconstitution with sterile water and may lead to a more tolerable administration with less hemostatic interference. Hematin, once administered, is cleared hepatically and is best represented pharmacokinetically by a two-compartment model comprised of a rapid initial phase followed by a slower second phase.

Physical Compatibility of Ibuprofen Lysine Injection with Selected Drugs During Simulated Y-site Injection.

PURPOSE: To study the physical compatibility of ibuprofen lysine injection (NeoProfen, Ovation Pharmaceuticals Inc., Deerfield, IL) with medications commonly used in the premature neonatal population during simulated Y-site administration. MATERIALS AND METHODS: Commonly used intravenous medications in preterm infants were evaluated for physical compatibility with ibuprofen lysine injection. A 20-mL sample of ibuprofen lysine drug product solution was mixed with a 20-mL sample of each of the 34 medications at concentrations used clinically. The mixtures were stored at room temperature and each sample was evaluated for turbidity and physical appearance at time 0 (immediately after preparation) and at 4 hours after preparation. RESULTS: THE FOLLOWING DRUGS WERE DEEMED COMPATIBLE WITH IBUPROFEN LYSINE: ceftazidime, epinephrine, furosemide, heparin lock flush, diluted insulin, morphine sulfate, phenobarbital, potassium chloride, and sodium bicarbonate. Diluted dopamine was initially compatible at time 0 but showed a small precipitate at the 4-hour time point. CONCLUSION: Of the 37 drug solutions tested, 14 preparations (10 medications; several with more than one diluent) showed physical compatibility with ibuprofen lysine, 1 was compatible at time 0 and incompatible at 4 hours, and 1 could not be evaluated. The remaining preparations were considered to be incompatible.