Open-Label Study of Hemin for Acute Porphyria: Clinical Practice Implications

The American Journal of Medicine (2006) 119, 801.e19-801.e24 CLINICAL RESEARCH STUDY AJM Theme Issue: GI and Nutrition Open-Label Study of Hemin for Acute Porphyria: Clinical Practice Implications Karl E. Anderson, MD, a,b Stephen Collins, MD, PhD c a Department of Preventive Medicine and Community Health, and b Department of Internal Medicine, University of Texas Medical Branch, Galveston; c Ovation Pharmaceuticals, Deerfield, Ill. ABSTRACT BACKGROUND: The acute porphyrias are rare inherited diseases characterized by acute episodes of life-threatening symptoms. Hemin was approved for treating these disorders in 1983. This open-label study of hemin therapy, conducted to demonstrate the safety of hemin manufactured in a new facility, is the largest to date and provides an overview of the use of hemin in clinical practice in the United States. METHODS: During 8 months when hemin was available only through study participation, 130 patients with a clinical diagnosis of acute porphyria received hemin as regularly prescribed by their doctor. Laboratory information and data on use of hemin for acute and prophylactic treatment were analyzed from case report forms. RESULTS: Hemin was administered to 111 patients for treatment of 305 acute attacks and to 40 patients for prophylaxis (usually by weekly or biweekly infusions). Diagnostic laboratory findings reported for 69 patients were confirmatory in only 26. Hemin was regarded as effective for all attacks in 73% of patients. Doses for acute attacks were less than the recommended 3-4 mg/kg/day in 20% of patients. Among 31 patients who received hemin prophylaxis for 1 month, 68% did not require subsequent hemin treatment for acute attacks. Most adverse events were attributed to porphyria and not treatment, and were more common in patients treated for acute attacks rather than prophylaxis. CONCLUSIONS: Safety and perceived efficacy of hemin were consistent with previous studies. Physician education is needed regarding use of diagnostic tests and recommended dosing. Preventive regimens are common and deserve further study. 2006 Elsevier Inc. All rights reserved. KEYWORDS: Acute porphyria; Hemin treatment; Adverse events; Hemin prophylaxis The acute porphyrias are 4 metabolic diseases with lifethreatening neurovisceral and neuropsychiatric manifestations. Each disease (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and ALA-dehydratase porphyria) is caused by an inherited deficiency of an enzyme involved in heme biosynthesis acting in concert Dr. Anderson has served as a consultant for and has received an institutional grant from Ovation Pharmaceuticals, manufacturers of hemin for injection (Panhematin ). Dr. Collins is the Chief Scientific Officer of Ovation Pharmaceuticals. Requests for reprints should be addressed to Karl E. Anderson, MD, Department of Preventive Medicine and Community Health, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1109. E-mail address: kanderso@utmb.edu with known and unknown endogenous and exogenous precipitating factors. The resultant imbalance in hepatic heme biosynthesis leads to overproduction of porphyrin precursors, which can give rise to acute and sometimes chronic neuropathic manifestations. 1,2 In addition to treatment of symptoms and electrolyte imbalances, intravenous hemin should be given as soon as possible after onset of symptoms. 2-6 Hemin and intravenous glucose act by repressing -aminolevulinic acid synthase, the initial and rate-limiting enzyme for heme synthesis in the liver. However, hemin leads to more rapid resolution of symptoms and, to a greater extent than glucose, suppresses the overproduction of porphyrin precursors. 7-10 Hemin is available in the United States as lyophilized hematin (Panhematin, Ovation Pharmaceuticals, Deerfield, Ill). The 0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.05.026

801.e20 The American Journal of Medicine, Vol 119, No 9, September 2006 and product labeling mostly describe use of hemin for acute treatment rather than prevention. However, weekly or biweekly hemin infusions have been recommended for prevention of frequent attacks that recur despite removal of all known precipitating factors, based on limited data. 1,3,5,6,17-19 Most of the published literature on treatment of these rare diseases consists of case studies and case series. Hemin was approved under the Orphan Drug Act of 1983 based on 5 open-label studies 8-10,14,20,21 involving over 100 patients, case reports on an additional 15 patients, and an FDA/ NIH workshop. Later studies using heme arginate (the approved form of hemin in Europe and South Africa) provided further evidence for efficacy and safety of hemin. 4,13,22,23 In 2000, the Food and Drug product insert recommends a daily infusion of 1-4 mg/kg for 3-14 days, with doses to be repeated no more often than every 12 hours and not to exceed 6 mg/kg in 24 hours. Most experts and reviews recommend a more specific regimen: 3-4 mg/kg once daily for 4 days with more extended treatment for severe cases. 2-5,11 Published case series, treatment recommendations, 3-5,8,9,12-16 CLINICAL SIGNIFICANCE Administration (FDA) required Abbott Laboratories, the former manufacturers of hemin, to withdraw hemin from the market and conduct an open-label study to confirm the safety of hemin manufactured at a new facility. During this period, hemin was available only through study participation. Continued access to hemin throughout the study period was considered essential, both for existing patients and for those newly diagnosed with this life-threatening condition. Thus, for this compassionate-use study, patients were not assigned to specific treatment regimens, nor was biochemical confirmation of diagnosis required. In addition to adverse event data, patient demographics, episode characterization, dose regimen, and impressions of treatment efficacy were recorded. On the basis of data collected during this study, the FDA judged hemin manufactured at the new facility to be safe and allowed it to be re-introduced commercially in May 2001. When Ovation Pharmaceuticals acquired hemin from Abbott Laboratories in January of 2003, the company also acquired the data from this study. Because this is the largest trial or case series to date of hemin therapy, Ovation sponsored a further analysis. Because of the limitations of the study design, this analysis was focused on obtaining real Laboratory documentation of acute porphyria is often inadequate, and hemin dose is often above or below the recommended dose. Prophylactic use of hemin for patients with frequently recurring acute attacks is common (31% of patients) and is perceived as effective in up to 68% of patients. The variable regimens used for prophylaxis in some patients may reflect the lack of published guidelines for prophylactic use of hemin. There is a need for better physician education regarding the recommended dose of hemin and the use and interpretation of laboratory tests to confirm an acute porphyria. world information about how the acute porphyrias are diagnosed, how hemin is used for treatment and prophylaxis, and how physicians perceive its efficacy. MATERIALS AND METHODS Any patient diagnosed with acute porphyria by the treating physician could enroll in the study and receive hemin (Panhematin, Abbott Laboratories, Abbott Park Ill, now manufactured by Ovation Pharmaceuticals). The study was not designed to measure efficacy of treatment. There were no specific outcome measures, exclusion criteria, or follow-up requirements. Patients received hemin as normally prescribed by their physicians. All patients gave their written informed consent using a form approved by the Institutional Review Board (IRB) at each site. Hemin was provided free, and certain study-related costs were reimbursed to study sites. Physicians were required to fill out a Patient Information Record (PIR) each time hemin was administered; although for prolonged prophylaxis, separate PIRs were not required for each administration. Information from selected PIR data fields was entered into a Data Management System compatible with the Code of Federal Regulations (CFR, 21 CFR Part 11) by ACCESS Medical Group, Ltd (Chicago, Ill). Recorded patient information included date of birth, body weight, precipitating factors and start of presenting signs and symptoms (recorded on a brief checklist), nature of the decision to treat, purpose of treatment (for acute symptoms or for prophylaxis), start and end of treatment, clinical response, resolution or clinically acceptable response, remission, discharge, nature and start and end of adverse event(s), start and end of other medications and supplements for treatment of adverse events, death, and autopsy. If the reason for treatment was not specified on the PIR, repeated daily infusions were considered to be for acute treatment, and less frequent infusions (more than 1 day apart) over an extended period (at least 1 week) were considered prophylaxis. Laboratory characterization was recorded as rapid urinary tests (Watson-Schwartz or Hoesch tests or other) for qualitative detection of increased porphobilinogen and confirmatory urine/serum tests (porphobilinogen, [ -]aminolevulinic acid or other). Dates (during or before the study) and conditions of testing (before or after beginning hemin treatment) were not recorded. Adequacy

Anderson and Collins Hemin for Acute Porphyria 801.e21 Table 1 Sex and Average Ages of 130 Patients Treated with Hemin for Acute Attacks, Prophylaxis or Both Total Number (% of total) Age (years) Type of Treatment n (% Males or Females) Acute attack Prophylaxis Both acute attack and prophylaxis Male 37 (28%) 45.4 14* 31 (84%) 4 (11%) 2 (5.4%) Female 93 (72%) 36.9 11.2 59 (63%) 15 (16%) 19 (20%) Total 130 (100%) 40.3 12.3 90 (69%) 19 (15%) 21 (16%) *Mean SD. of laboratory substantiation of the diagnosis was determined retrospectively by author review. A urinary porphobilinogen (PBG) level over 20 or a urinary -aminolevulinic acid (ALA) level over 15 mg/day or mg/l was considered quantitative confirmation of an acute porphyria. The physician was determined to have perceived the treatment as effective if the PIR noted that admitting symptoms were resolved, there was a clinically acceptable response, or the patient went into remission. Space was provided for recording dose (mg or mg/kg), dose frequency ( BID or other [specify] ), details and narrative description of medical history, adverse events, and other information. RESULTS Study Population Between August 2000 and June 2001, 108 investigators treated 130 patients with a diagnosis of acute porphyria for acute attacks, prophylaxis, or both (Table 1). The majority (92%) of patients were Caucasian. Most (72%) were female; on average, males were 7 years older than females, and proportionally more females received prophylaxis or a combination of acute treatment and prophylaxis (Table 1). Precipitating factors were recorded for only 40 of the 130 patients; the most common overall were drugs (22%, prescription or over the counter, but not otherwise identified) and in women, hormonal factors (24%). Diagnosis Treating physicians reported availability of laboratory tests to confirm the diagnosis of acute porphyria in 71 patients; test results were provided for 69 patients. Quantitative methods confirmed the diagnosis in 16 of these patients (23%); a qualitative test for PBG was positive in an additional 10 (15%). Reported abnormalities did not support the diagnosis in 20 patients (29%), ALA or PBG was reported as normal in 18 (26%), and the recorded results in 7 patients could not be interpreted. Acute Treatment Overall, 305 courses of therapy were administered for what was presumed to be an acute attack of porphyria. Signs and symptoms (eg, abdominal pain in 87%, constipation in 24%, altered mental status in 30%, and seizures in 11%) were typical of acute porphyria and were not significantly different among the 26 patients with laboratory substantiation of acute porphyria. Most patients (68, 61.3%) received 1 course of acute therapy during the study, 20 (18%) received 2 courses, 16 (14%) between 3 and 9 courses, and 7 (6.3%) received 10 or more courses. Among the 234 courses of therapy with sufficient date information, treatment was begun immediately in 33%, within 1 day of symptom onset in 50%, and within 3 days in 75%. Six patients received doses exceeding 6 mg/kg/day for 1 or more treatment courses, 22 received less than 200 mg or 3 mg/kg/day, and 3 received less than 2 mg/kg/day. Although most courses consisted of multiple days of treatment, 21 of the 111 patients were treated on at least 1 occasion for only 1 day. Treatment was judged by the treating physicians to be successful for all acute attacks in 81 (73%) of the treated patients; 94 patients (85%) had at least 1 treatment success, and 17 (15%, including 2 patients with biochemical confirmation of acute porphyria) had no successes. Of the 305 treatment courses for an acute attack, 266 (87%) were perceived as successful. Perceived efficacy was somewhat higher in those with convincing biochemical confirmation of the diagnosis or confirmation by qualitative testing (always successful in 86% of 14 patients and 90% of 10 patients, respectively). Prophylactic Treatment Among the 40 patients who received prophylaxis, the most common regimen was an infusion once a week (16 patients). Other regimens included an infusion thrice weekly (1 patient), twice weekly (4 patients), every 2 weeks (4 patients), every month (4 patients), daily infusions over 3 days every 6 weeks (1 patient), twice-daily infusions every 1-2 weeks (1 patient), and 2 or 4 consecutive daily infusions given only once (1 patient). The dose of hemin for each infusion ranged from 82 to 313 mg (dose per kg was not always provided) and remained constant for most patients. The regimen varied greatly in some patients over the course of the study, for reasons not recorded. For example, dosing frequency for 1 patient was approximately weekly for 63 weeks (12 of 19 infusions 7 days apart), increased to every 1-4 days for 2 weeks (8 infusions), returned to approximately weekly for an extended period, and then intervals lengthened to 14-177 days.

801.e22 The American Journal of Medicine, Vol 119, No 9, September 2006 Table 2 Number of Patients with Adverse and Serious Adverse Events among Those Treated with Hemin Only for Prophylaxis and Those Treated Only for Acute Attacks Type of Treatment Number of patients (%) Prophylaxis only (n 19) Acute treatment only (n 90) Adverse events 3 (16%) 40 (44%) Serious adverse events 1 (5.3%) 18 (20%) Of the 31 patients who received prophylaxis for at least 1 month, 15 (48%) received hemin only for prophylaxis and thus presumably had no acute attacks during the study. An additional 6 patients had up to 3 treatments for acute attacks, then began receiving prophylaxis and had no subsequent hemin treatments for acute attacks. Thus, prophylaxis may have successfully prevented attacks in 21 of 31 patients (68%). Two additional patients who received regular prophylaxis for the entire 8 months of the study were treated for only 1 acute attack during the study. The 3 patients with biochemical confirmation of acute porphyria who received prophylaxis for at least 1 month had no treatments for an attack during 5 weeks, 5 months, or 9 months of prophylaxis. Adverse Events Adverse and serious adverse events were recorded without respect to causality in 57 (44%) and 26 (20%), respectively, of the 130 patients enrolled and were much more frequent in patients treated only for acute attacks than in those only for prophylaxis (Table 2). The nature of many of the most commonly reported adverse events are also signs and symptoms of acute porphyric attacks, and 75% of occurrences were considered not related to hemin (Table 3). Four serious adverse events were noted as probably or possibly related to treatment: adverse drug reaction (moderate, probably related), injection site reaction (severe, probably related), phlebitis (severe, probably related), and pyrexia, bacteremia (moderate, possibly related). None of the 3 deaths was thought to be related to hemin. These patients died when acutely ill and after lengthy hospitalizations. Review of their records revealed convincing evidence of porphyria in 1 patient whose death was attributed to the disease, but in the other 2 the clinical findings were atypical for porphyria, laboratory documentation was not convincing, and there was evidence of another underlying illness. DISCUSSION Clinical studies and expert opinion strongly support the importance of initial and early treatment of acute porphyrias with hemin. 2-5,11,12 However, there is little information on how hemin is actually used in clinical practice. This study, which was intended to support FDA approval of the introduction of hemin manufactured at a new facility, made hemin available on a compassionate basis to all patients judged by their physicians to need it. Therefore, it provides a unique snapshot of how physicians use hemin in the United States. The reanalysis of the study data, despite substantial limitations imposed by the study design, provided information on laboratory diagnosis, how often hemin is used for acute treatment and prophylaxis, and how physicians perceive its efficacy. The recorded demographic and clinical data were comparable to other large case series, but unfortunately, this information is not definitive because the study did not require documentation of the diagnosis. Diagnostic laboratory values were reported for only 53% of patients and appear to confirm impressions that choosing and interpreting the most pertinent diagnostic tests is often problematic in the US, and that hemin may be prescribed for some patients who do not have porphyria. Among the 69 patients with recorded test results, the results in 33 were either normal or not sufficiently abnormal to support the diagnosis. Furthermore, among the 26 with confirmatory data, 10 patients had qualitative testing no longer considered optimal rather than substantial increases in PBG or ALA determined by a quantitative or semi-quantitative method. 2,24 The manner of treating acute attacks corresponded quite closely to that recommended in the literature and the product insert, and treatment for acute attacks was started promptly in the majority of cases. However, a significant number of treatment courses were shorter and used doses Table 3 Adverse Events Including Symptoms of Porphyria and Those Possibly Related to Treatment Adverse Events n (% of Total Adverse Events) Description* Total Possibly or probably related to treatment Headache 18 (9.2%) 5 (2.6%) Nausea 15 (7.7%) 8 (4.1%) Pyrexia 9 (4.6%) 6 (3.1%) Phlebitis/injection 7 (3.6%) 6 (3.1%) site phlebitis Vomiting 7 (3.6%) 4 (2.1%) Catheter-related 7 (3.6%) 3 (1.5%) Complication Pain 4 (2.1%) 3 (1.5%) Convulsion 4 (2.1%) 0 (0.0%) Rash 3 (1.5%) 3 (1.5%) Pharyngitis 3 (1.5%) 0 (0.0%) Diarrhea 3 (1.5%) 3 (1.5%) Adverse drug reaction 3 (1.5%) 3 (1.5%) Cellulitis 3 (1.5%) 2 (1.0%) Dizziness 3 (1.5%) 1 (0.5%) All others 106 (54%) 24 (12%) Total 195 (100%) 48 (25%) *Listed in order of total occurrence. Also can be a manifestation of an acute porphyric attack. Number of occurrences 3.

Anderson and Collins Hemin for Acute Porphyria 801.e23 that may have been less effective than the standard dose of 3-4 mg/kg/day for 4 days. Some patients received amounts of drug that exceeded what is recommended in the product insert. Because there are no known benefits to giving less than 3 mg/kg/day or more than 4 mg/kg/day, practicing physicians may need guidance about the recommended dose levels for this drug. The 73% to 84% perceived success rate is somewhat lower than in some other studies, 4,9,14,20-22 perhaps due to inclusion of some patients who did not have acute porphyria, to some short treatment courses, to some doses less than 3-4 mg/kg/day, or to delays in starting treatment. Surprisingly, hemin prophylaxis was used in almost one third of patients, despite very limited published data on its effectiveness. This indicates that attacks of porphyria do recur frequently in some patients, despite efforts to avoid precipitating factors. The absence of recorded exacerbating factors in many patients in this study suggests that known precipitants were already being avoided. The variable regimens used for prophylaxis in some patients may further reflect the lack of published guidelines for prophylactic use of hemin. Observations in this study do suggest that prophylaxis is often beneficial, but this conclusion must be tempered because diagnostic criteria were not established (biochemical confirmation of acute porphyria was recorded in only 10% of patients who received prophylaxis), clinical indications for acute versus prophylactic treatment were not specified, and information about duration of prophylactic treatment and the frequency of attacks before and during treatment was not recorded. However, given that prophylactic use is common in this population, further clinical studies are needed to explore efficacy and optimal dosage regimens. The finding that hemin manufactured at a new facility was safe warranted FDA approval for re-introducing the drug commercially. Although 44% of patients experienced adverse events, most could be attributed to porphyria, and none of the 3 deaths were attributed to hemin. Phlebitis at the injection site due to the rapid formation of degradation products is a common concern with hemin. 25-27 Information about how hemin was administered was not collected, and the low incidence of phlebitis (7 occurrences in 933 treatment and prophylactic cycles of hemin therapy) may reflect wide usage of central venous catheters or reconstitution with albumin. 28,29 In summary, the study results suggest several needs, including physician education regarding laboratory diagnosis and hemin dosage and treatment guidelines. Study of preventive regimens for prevention of recurrent attacks of porphyria in a substantial proportion of patients after known exacerbating influences are eliminated is clearly needed. Measures to address these needs can be implemented in the near term, and their effectiveness demonstrated by a future study designed more specifically to assess how acute porphyrias are managed in clinical practice in this and other countries. ACKNOWLEDGMENTS The authors thank Ewa Greenier, Amanda Stronczek, and Brett Campbell from ACCESS Medical Group, Ltd for data compilation and analysis and Lisa Underhill for writing and editing assistance. References 1. Anderson K, Sassa S, Bishop D, Desnick R. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver C, Beaudet A, Sly W, et al., eds. Metabolic and Molecular Bases of Inherited Disease, 8 th edition. New York, NY: McGraw Hill; 2001:2991-3062. 2. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439-450. 3. Elder GH, Hift RJ, Meissner PN. The acute porphyrias. Lancet. 1997; 349:1613-1617. 4. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Intern Med. 1993;153:2004-2008. 5. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ. 2000;320:1647-1651. 6. Anderson KE. Approaches to treatment and prevention of human porphyrias. In: Kadish K, Smith K, Guilard R, eds. The Porphyrin Handbook, Part II, Vol. 14, Medical Aspects of Porphyrins. Amsterdam, Elsevier Science; 2003:247-283. 7. Bonkowsky HL, Tschudy DP, Collins A, et al. Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc Natl Acad Sci U S A. 1971;68:2725-2729. 8. Watson CJ, Pierach CA, Bossenmaier I, Cardinal R. Use of hematin in the acute attack of the inducible hepatic prophyrias. Adv Intern Med. 1978;23:265-286. 9. Lamon JM, Frykholm BC, Hess RA, Tschudy DP. Hematin therapy for acute porphyria. Medicine (Baltimore). 1979;58:252-269. 10. Dhar GJ, Bossenmaier I, Petryka ZJ, Cardinal R, Watson CJ. Effects of hematin in hepatic porphyria. Further studies. Ann Intern Med. 1975;83:20-30. 11. European Porphyria Initiative Steering Committee (Badminton M, Deybach J-C, Elder G, et al.). Information for physicians: The porphyrics. Available as www.porphyria-europe.com. Accessed July 19, 2006. 12. Anderson KE. The porphyrias. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, Vol. 2. Philadelphia, PA: W. B. Saunders Co.; 2004:1292-1300. 13. Herrick AL, McColl KE, Moore MR, Cook A, Goldberg A. Controlled trial of haem arginate in acute hepatic porphyria. Lancet. 1989;1:1295-1297. 14. McColl KE, Moore MR, Thompson GG, Goldberg A. Treatment with haematin in acute hepatic porphyria. Q J Med. 1981;50:161-174. 15. Mustajoki P, Tenhunen R, Tokola O, Gothoni G. Haem arginate in the treatment of acute hepatic porphyrias. Br Med J (Clin Res Ed). 1986; 293:538-539. 16. Wilson J, de Rooij F. Management and treatment of the porphyrias. In: Kadish KM, Smith KM, Guilard R, eds. The Porphyrin Handbook, Part II. Vol. 14, Medical Aspects of Porphyrins. Amsterdam, Elsevier Science. 17. Lamon JM, Frykholm BC, Bennett M, Tschudy DP. Prevention of acute porphyric attacks by intravenous haematin. Lancet. 1978;2:492-494. 18. Gross U, Puy H, Meissauer U, et al. A molecular, enzymatic and clinical study in a family with hereditary coproporphyria. J Inherit Metab Dis. 2002;25:279-286. 19. Doss MO, Stauch T, Gross U, et al. The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. J Inherit Metab Dis. 2004;27:529-536. 20. Pierach CA. Hematin therapy for the porphyric attack. Semin Liver Dis. 1982;2:125-131.

801.e24 The American Journal of Medicine, Vol 119, No 9, September 2006 21. Pierach CA, Bossenmaier I, Cardinal R, Weimer M, Watson CJ. Hematin therapy in porphyric attacks. Klin Wochenschr. 1980;58:829-832. 22. Kostrzewska E, Gregor A, Tarczynska-Nosal S. Heme arginate (Normosang) in the treatment of attacks of acute hepatic porphyrias. Mater Med Pol. 1991;23:259-262. 23. Elder GH, Hift RJ. Treatment of acute porphyria. Hosp Med. 2001; 62:422-425. 24. Deacon AC, Peters TJ. Identification of acute porphyria: evaluation of a commercial screening test for urinary porphobilinogen. Ann Clin Biochem. 1998;35(Pt 6):726-732. 25. Green D, Reynolds N, Klein J, Kohl H, Ts ao CH. The inactivation of hemostatic factors by hematin. J Lab Clin Med. 1983;102:361-369. 26. Green D, Furby FH, Berndt MC. The interaction of the factor VIII/von Willebrand factor complex with hematin. Thromb Haemost. 1986;56: 277-282. 27. Goetsch CA, Bissell DM. Instability of hematin used in the treatment of acute hepatic porphyria. N Engl J Med. 1986;315:235-238. 28. Bonkovsky HL, Healey JF, Lourie AN, Gerron GG. Intravenous hemealbumin in acute intermittent porphyria: evidence for repletion of hepatic hemoproteins and regulatory heme pools. Am J Gastroenterol. 1991;86:1050-1056. 29. Anderson KE, Bonkovsky HL, Bloomer JR, Shedlofsky SI. Reconstitution of hematin for intravenous infusion. Ann Intern Med. 2006;144: 537-538.