Panhematin; hematin; chloro[7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipro-panoato-(2--)-N21,N22,N23,N24] iron., reaction product with calcium carbonate
Status: marketed in the U.S.
Organizations involved:
Ovation Pharmaceuticals, Inc. – USA mark.
Cardinal Health – Manuf.
Abbott Labs., Inc. – Manuf.; R&D; Tech.; Former
Cross ref.: See also Red Blood Cells (#806).
Description: Panhematin is a lyophilized (freeze-dried) formulation of alkaline hemin, a derivative of an iron-containing metalloporphyrin derived from hemoglobin of human Red Blood Cells (RBCs; eryth-rocytes). Hemin for injection, formerly known as hematin, is the reaction product of hemin and sodium carbonate solution. Hemin or chloro [7,12-diethenyl-3,8,13,17-tetra-methyl-21H,23H-porphine-2,18-dipropanoato(2-)-N21,N22,N23,N24] iron is an iron-containing metalloporphyrin pigment very similar to the hemotoporphyrin that gives hemoglobin and red blood cells their characteristic color. Hemin is manufactured by reacting RBCs/hemoglobin with acids and bases.
Panhematin is packaged in single-dose vials as a black powder for intravenous administration after reconstitution. Each dispensing vial contains the equivalent of 313 mg hemin, 215 mg sodium carbonate, and 300 mg of sorbitol. The pH may be adjusted with hydrochloric acid. Each 0.14 mL of Panhematin contain 1 mg hematin equivalent. The product contains no antimicrobial preservatives. When reconstituted with 43 mL Sterile Water for Injection, USP, each 43 mL dose provides the equivalent of ~301 mg hemin. Because Panhematin undergoes rapid chemical decomposition in aqueous solution, it should not be reconstituted until immediately before use. Since reconstituted Panhematin is not transparent, any undissolved particulate matter is difficult to see when inspected visually. Therefore, terminal filtration through a sterile 0.45 micron or smaller filter is recommended.
Note, with its defined chemical structure, no involvement of proteins or other biological polymers or molecules, and its final manufacture by chemical reaction, in many respects, hemin is more of a drug and chemical substance than a biopharmaceutical and biological molecule.
Nomenclature: Hemin [FDA BIO CAS]; Panhematin [TR]; ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-N21,N22,N23,N24)-, dihydrogen [CAS]; ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-por-phine-2,18-dipropanoato(4-)-N21,N22,N23,N24), di-hydrogen, (SP-5-13)- [CAS]; ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-kappaN21,kappaN22,kappaN23,kappaN24)-, dihydrogen, (SP-5-13)- [CAS]; haemin [SY]; chloroprotoporphyrin [SY]; chlorohemin [SY]; hematin chloride [SY]; 16009-13-5 [CAS RN]; chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-N(21),N(22),N(23),N(24)) ferrate(2-) dihydrogen [SY]; NDC 67386-701-54 [NDC]
Biological.: Hemin (formerly hematin) is an enzyme inhibitor that acts to limit the hepatic and/or marrow synthesis of porphyrin. This action is likely due to the inhibition of d-aminolevulinic acid synthetase, the enzyme which limits the rate of the porphyrin/heme biosynthetic pathway. The exact mechanism by which hematin produces symptomatic improvement in patients with acute episodes of the hepatic porphyrias has not been elucidated.
In 1930, 1930 Hans Fischer (Germany) was awarded the Nobel Prize for Chemistry for research into the constitution of hemin, chlorophyll and other porphyrins.
Companies.: Panhematin is marketed in the U.S. by Ovation Pharmaceuticals, Inc. Panhematin is manufactured by Cardinal Health (Raleigh, NC). Panhematin was originally developed, manufactured and marketed in the U.S. by Abbott Labs. Abbott continued to manufacture and supply Panhematin to Ovation, until Ovation arranged its own manufacturing. Cardinal Health assumed (was approved for) manufacture of Panhematin in Sept. 2006. Panhematin is the first product to be manufactured at Cardinal’s new Raleigh facilities.
Ovation acquired Panhematin from Abbott in Jan. 2003. It was a small, non-strategic asset in Abbott’s portfolio, and had not been actively promoted by the company since the product was approved in 1983.
FDA class: Biologic BLA
Approvals: Date = 19830720; PLA/ELA (101246/0; now a BLA) granted to Abbott Labs.
Date = 20060909; BLA supplement; Indication = approval of manufacture by Cardinal Health
Indications: [full text of the "INDICATIONS AND USAGE” section of the product insert/labeling]:
Panhematin (hemin for injection) is indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women. Manifestations such as pain, hypertension, tachycardia, abnormal mental status and mild to progressive neurologic signs may be controlled in selected patients with this disorder.
Similar findings have been reported in other patients with acute intermittent porphyria, porphyria variegata and hereditary coproporphyria. Panhematin is not indicated in porphyria. cutanea tarda.
Status: Abbott Labs. received approval for Panhematin on July 20, 1983. Panhematin was one of the the first two products granted orphan designation under the 1983 Orphan Drugs Act. The date of transfer to Ovation Pharmaceuticals (associated FDA supplemental approval) is unknown.
Medical: Clinical benefit from Panhematin depends on prompt administration. Panhematin therapy is intended to prevent an attack of acute porphyria from reaching the critical stage of neuronal degeneration. Attacks of porphyria may progress to a point where Panhematin therapy is not curative. After discontinuation of treatment, symptoms generally return, although in some cases remission is prolonged. Some neurological symptoms have improved weeks to months after therapy, but irreversible neuronal damage has occurred in some cases.
The product insert includes a black box warning that Panhematin “should only be used by physicians experienced in the management of porphyrias in hospitals where the recommended clinical and laboratory diagnostic and monitoring techniques are available. Before administering Panhematin, an appropriate period of alternate therapy (i.e., 400 g glucose/day for 1 to 2 days) must be considered. If improvement is unsatisfactory for the treatment of acute attacks of porphyria, an intravenous infusion of Panhematin containing a dose of 1 to 4 mg/kg/day of hematin should be given over a period of 10-15 minutes for 3-14 days based on the clinical signs. In more severe cases this dose may be repeated no earlier than every 12 hours. No more than 6 mg/kg of hematin should be given in any 24 hour period.”
Disease: Acute intermittent porphyria (AIP) is a rare hereditary (genetic) disorder. AIP is an autosomal dominant disorder caused by a defect in porphobilinogen deaminase activity. Manifestations include pain, hypertension, tachycardia, abnormal mental status, and mild-to-severe neurologic signs. The estimated prevalence of the disorder is 5-10 cases per 100,000 people. About 5,000 people in the U.S. have the genetic predisposition for acute porphyria, but only 20% of this population actually develops symptoms. Before Panhematin’s’ approval, there was no product indicated to treat AIP in the U.S.
Also, In the U.S., approximately 100,000 patients develop bleeding episodes each year due to a fibrinogen deficiency. Current standard of care for patients in the U.S. is the use of impure human blood products such as cryoprecipitate, which is composed mainly of fibrinogen. In select countries in Europe, plasma-derived fibrinogen is used to treat such bleeding. The existing market size for fibrinogen deficiencies is estimated to be over $500 million in the developed world.
Market: Ovation has an assistance plan for people who need Panhematin and are having difficulty securing it or experiencing insurance issues.
The 2007 Average Wholesale Price (AWP) is $2582.93/vial (Red Book, 2007).
Before Ovation acquired the product in 2003, Abbott charged $230.00/vial. After acquisition by Ovation, the company raised the price to $1900.00/vial. Ovation cited the cost of product acquisition, investment in manufacturing facilities, and the need to relaunch and proactively market Panhematin as among the reasons for the price increase.
Competition: A similar product, Normosang (heme arginate) from Orphan Europe (Paris, France) is available in Europe.
R&D: Pharming Group N.V. is developing recombinant human fibrinogen (rhFIB).
Companies involvement:
Full monograph
740 Hemin
Nomenclature:
Hemin [FDA BIO CAS]
Panhematin [TR]
ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-kappaN21,kappaN22,kappaN23,kappaN24)-, dihydrogen, (SP-5-13)- [CAS]
ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-N21,N22,N23,N24)-, dihydrogen [CAS]
ferrate(2-), chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-N21,N22,N23,N24)-, dihydrogen, (SP-5-13)- [CAS]
16009-13-5 [CAS RN]
chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(4-)-N(21),N(22),N(23),N(24)) ferrate(2-) dihydrogen [SY]
chlorohemin [SY]
chloroprotoporphyrin [SY]
haemin [SY]
hematin chloride [SY]
NDC 67386-701-54 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 1983
Date of 1st FDA approval = 19830720
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
biopharmaceutical products
blood products
human materials used<!-- humansource -->
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
SM001 Commerical Marketed Product
US200 Currently Approved in US
EM001 Marketed Product in EU
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