Hemin

FDA Drug Information • Also known as: Panhematin

Brand Names: Panhematin
Route: INTRAVENOUS
Dosage Form: POWDER, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION PANHEMATIN (hemin for injection) is an enzyme inhibitor derived from processed red blood cells. Hemin for injection was known previously as hematin. The term hematin has been used to describe the chemical reaction product of hemin and sodium carbonate solution. Hemin and hematin are iron containing metalloporphyrin complexes with either bound chloride or hydroxide ions, respectively. Chemically hemin is represented as chloro [7,12-diethenyl-3,8,13,17-tetramethyl- 21H,23H-porphine-2,18-dipropanoato(2-)-N 21 ,N 22 ,N 23 ,N 24 ] iron. The structural formula for hemin is: PANHEMATIN is formatted as a sterile, lyophilized powder for intravenous administration after reconstitution. Each dispensing vial of PANHEMATIN contains the equivalent of 350 mg hemin, 240 mg sodium carbonate and 335 mg of sorbitol. The pH may have been adjusted with hydrochloric acid. When mixed as directed with Sterile Water for Injection, USP, each 48 mL provides the equivalent of approximately 336 mg hematin (7 mg/ mL). The product contains no preservatives. Structural Formula of Hemin

What Is Hemin Used For?

1 INDICATIONS AND USAGE PANHEMATIN is a hemin for injection indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate. Limitations of Use

Before administering PANHEMATIN, consider an appropriate period of carbohydrate loading (i.e., 400 g glucose/day for 1 to 2 days) [ See Dosage and Administration ( 2.1 ) ].

Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. PANHEMATIN therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. PANHEMATIN is not effective in repairing neuronal damage. PANHEMATIN is a hemin for injection indicated for amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate. ( 1 ) Limitations of Use

Before administering PANHEMATIN, consider an appropriate period of carbohydrate loading (i.e., 400 g glucose/day for 1 to 2 days). ( 1 )

PANHEMATIN is not effective in repairing neuronal damage due to progression of porphyria attacks. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For intravenous infusion only. For intravenous infusion only. Dose ( 2.1 ) 1 to 4 mg/kg/day for 3 to 14 days based on the clinical signs. The standard dose in clinical practice is 3 to 4 mg/kg/day. Repeat dose in more severe cases no earlier than every 12 hours. Do not exceed 6 mg/kg in any 24 hour period. Administration ( 2.2 ) Use sterile 0.45 micron or smaller filter to remove any undissolved particulate matter. The dose may be administered directly from the vial over a period of at least 30 minutes. After the infusion, flush the vein with 100 mL of 0.9% NaCl. 2.1 Dosing

PANHEMATIN should only be used by or in consultation with physicians experienced in the management of porphyrias.

Before PANHEMATIN therapy is begun, the presence of acute porphyria must be diagnosed using the following criteria: 1. Presence of clinical symptoms suggestive of acute porphyric attack. 2. Quantitative measurement of porphobilinogen (PBG) in urine. The single-void urine sample should be refrigerated or frozen without additives and shielded from light for subsequent quantitative δ-aminolevulinic acid (ALA), PBG, and total porphyrin determinations. (Note: the classical Watson-Schwartz or Hoesch tests are considered to be less reliable).

Clinical benefit from PANHEMATIN depends on prompt administration. For mild porphyric attacks (mild pain, no vomiting, no paralysis, no hyponatremia, no seizures), a trial of glucose therapy is recommended while awaiting hemin treatment or if hemin is unavailable. For moderate to severe attacks, immediate hemin treatment is recommended. Symptoms of severe attacks are severe or prolonged pain, persistent vomiting, hyponatremia, convulsion, psychosis, and neuropathy. In addition to treatment with PANHEMATIN, consider other necessary measures such as the elimination of triggering factors.

The dose of PANHEMATIN is 1 to 4 mg/kg/day of hematin for 3 to 14 days based on the clinical signs. The standard dose in clinical practice is 3 to 4 mg/kg/day. In more severe cases this dose may be repeated no earlier than every 12 hours. Do not exceed 6 mg/kg of hematin in any 24 hour period. After reconstitution each mL of PANHEMATIN contains the equivalent of approximately 7 mg of hematin (see dosage calculation table below). Dosage Calculation Table 1 mg hematin equivalent = 0.14 mL PANHEMATIN 2 mg hematin equivalent = 0.28 mL PANHEMATIN 3 mg hematin equivalent = 0.42 mL PANHEMATIN 4 mg hematin equivalent = 0.56 mL PANHEMATIN

Monitor urinary concentrations of the following compounds during PANHEMATIN therapy. Effectiveness is demonstrated by a decrease in one or more of the following compounds. ALA - δ-aminolevulinic acid PBG - porphobilinogen Uroporphyrin Coproporphyrin 2.2 Preparation and Administration

Because PANHEMATIN contains no preservative and undergoes rapid chemical decomposition in solution, it must be reconstituted immediately before use.

Reconstitute PANHEMATIN by aseptically adding 48 mL of...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most common adverse reactions (occurring in >1% of patients) are: headache, pyrexia, infusion site reactions, and phlebitis. Most common adverse reactions in >1% of patients are headache, pyrexia, infusion site reactions, and phlebitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PANHEMATIN use was evaluated in a compassionate use study. A total of 130 patients were treated with hemin for acute attacks, prophylaxis or both. Of those, 111 patients were administered hemin for treatment of 305 acute porphyria attacks and to 40 patients for prophylaxis. The majority (92%) of patients were Caucasian. Most (72%) were female; all adult patients had a mean age ± SD of 40.3 ± 12.3 years. Proportionally more females (15 out of 19) received prophylaxis or a combination of acute treatment and prophylaxis (19 out of 21). For the treatment of acute attacks, patients received 2 to 4 mg/kg/day PANHEMATIN intravenously for 1 to 9 doses. For prophylaxis patients, the most common doses were weekly or biweekly infusions. Table 1 summarizes adverse reactions occurring in >1% of patients treated with PANHEMATIN, categorized by body system and order of decreasing frequency. Table 1: Adverse Reactions in >1% of Patients Treated with PANHEMATIN System Organ Class Preferred Term Adverse Events N (% of Total Adverse Events) Description Total Possibly or Probably Related to Treatment Infections and infestations Cellulitis 3 (1.5%) 2 (1.0%) Nervous System Disorders Headache 18 (9.2%) 5 (2.6%) Vascular Disorders Phlebitis / Injection site phlebitis 7 (3.6%) 6 (3.1%) Skin and subcutaneous tissue disorders Rash 3 (1.5%) 3 (1.5%) General Disorders and Administration Site Conditions Pyrexia 9 (4.6%) 6 (3.1%) Catheter-related Complication 7 (3.6%) 3 (1.5%) 6.2 Postmarketing Experience The following adverse reactions associated with the use of PANHEMATIN were identified in open-label clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombocytopenia, coagulopathy (including prolonged prothrombin time and prolonged partial thromboplastin time), and hemolysis Immune System Disorders: hypersensitivity reactions including a report of infusion-related anaphylactoid reaction presenting as circulatory collapse Vascular Disorders: injection site venous thrombosis including some that occurred in large veins such as venae cavae General Disorders and Administration Site Conditions: infusion site reactions (such as erythema, pain, bleeding and extravasation) Metabolism and Nutrition Disorders: iron overload and serum ferritin increased [See Warnings and Precautions ( 5.2 )]

Drug Interactions

7 DRUG INTERACTIONS PANHEMATIN therapy is intended to limit the rate of porphyria/heme biosynthesis possibly by inhibiting the enzyme δ-aminolevulinic acid synthetase 1 (ALAS1) [See Clinical Pharmacology ( 12.1 )] . Most of the heme synthesized in liver is used for the production of cytochrome P450 (CYP) enzymes. Therefore, avoid CYP inducing drugs (such as estrogens, barbituric acid derivatives and steroid metabolites) while on PANHEMATIN therapy, because these drugs increase the activity of ALAS leading to induction of ALAS1 through a feedback mechanism. Avoid CYP inducing drugs such as estrogens, barbituric acid derivatives and steroid metabolites which induce δ-aminolevulinic acid synthetase 1 (ALAS1) through a feedback mechanism. ( 7 )

Contraindications

4 CONTRAINDICATIONS PANHEMATIN is contraindicated in patients with known hypersensitivity to this drug. Do not use in patients with known hypersensitivity to PANHEMATIN. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary About 50% of the women with acute intermittent porphyria experience an acute attack of porphyria in pregnancy and/or the puerperium. It is most severe in early pregnancy and the puerperium, and can result in fatal outcome. Although anecdotal evidence suggests safe use of hematin during pregnancy, the available human data is not sufficient to establish the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with hematin. It is also not known whether hematin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PANHEMATIN should be given to a pregnant woman only if clearly needed. Avoid administering hematin in severe pre-eclampsia because of a theoretical risk of potentiation of the coagulation disorder [see Warnings and Precautions ( 5.3 )] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Overdosage

10 OVERDOSAGE Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion [see Warnings and Precautions ( 5.4 )] . Treatment of this case consisted of ethacrynic acid and mannitol.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING PANHEMATIN is supplied as a sterile, lyophilized black powder in single dose dispensing vials (NDC 55292-702-54) in a carton (NDC 55292-702-55). The vial stopper contains natural rubber latex. Store lyophilized powder at 20-25°C (68-77°F).

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.