Normosang

Normosang (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. Normosang is not indicated in porphyria cutanea tarda.

Before administering Normosang, 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 Normosang containing a dose of 1 to 4 mg/kg/day of hematin should be given over a period of 10 to 15 minutes for 3 to 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.

After reconstitution each mL of Normosang contains the equivalent of approximately 7 mg of hematin. The drug may be administered directly from the vial.

Dosage Calculation Table

1 mg hematin equivalent = 0.14 mL Normosang
2 mg hematin equivalent = 0.28 mL Normosang
3 mg hematin equivalent = 0.42 mL Normosang
4 mg hematin equivalent = 0.56 mL Normosang

Since reconstituted Normosang 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.

Preparation of Solution

Reconstitute Normosang by aseptically adding 43 mL of Sterile Water for Injection, USP, to the dispensing vial. Immediately after adding diluent, the product should be shaken well for a period of 2 to 3 minutes to aid dissolution. NOTE: Because Normosang contains no preservative and because Normosang undergoes rapid chemical decomposition in solution, it should not be reconstituted until immediately before use. After the first withdrawal from the vial, any solution remaining must be discarded.

No drug or chemical agent should be added to a Normosang fluid admixture unless its effect on the chemical and physical stability has first been determined.

Normosang is contraindicated in patients with known hypersensitivity to this drug.

REFERENCES

7. Dhar, G. J., et al., Transitory Renal Failure Following Rapid Administration of a Relatively Large Amount of Hematin in a Patient with Acute Intermittent Porphyria in Clinical Remission, Acta Med Scand 203:437-443, 1978.

WARNINGS

Normosang is made from human blood. Products made from human blood may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening blood donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Lundbeck, (1-800-455-1141). The physician should discuss the risks and benefits of this product with the patient.

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Normosang therapy is intended to limit the rate of porphyria/heme biosynthesis possibly by inhibiting the enzyme δ-aminolevulinic acid synthetase. For this reason, drugs such as estrogens, barbituric acid derivatives and steroid metabolites which increase the activity of δ-aminolevulinic acid synthetase should be avoided.

Also, because hemin for injection has exhibited transient, mild anticoagulant effects during clinical studies, concurrent anticoagulant therapy should be avoided.⁹ The extent and duration of the hypocoagulable state induced by Normosang has not been established.

PRECAUTIONS

General

Clinical benefit from Normosang depends on prompt administration. Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. Normosang therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. Normosang is not effective in repairing neuronal damage.⁹

Recommended dosage guidelines should be strictly followed. Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Oliguria and increased nitrogen retention occurred although the patient remained asymptomatic.⁴ No worsening of renal function has been seen with administration of recommended dosages of hematin.⁹

A large arm vein or a central venous catheter should be utilized for the administration of Normosang to avoid the possibility of phlebitis.

Since reconstituted Normosang 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.

Because increased levels of iron and serum ferritin have been reported in postmarketing experience, physicians should monitor iron and serum ferritin in patients receiving multiple administrations of Normosang (See “ADVERSE REACTIONS” section).

Tests for Diagnosis and Monitoring of Therapy

Before Normosang therapy is begun, the presence of acute porphyria must be diagnosed using the following criteria:⁹

1. Presence of clinical symptoms.
2. Positive Watson-Schwartz or Hoesch test. (A negative Watson-Schwartz or Hoesch test indicates a porphyric attack is highly unlikely. When in doubt quantitative measures of δ-aminolevulinic acid and porphobilinogen in serum or urine may aid in diagnosis.)

Urinary concentrations of the following compounds may be monitored during Normosang therapy. Drug effect will be demonstrated by a decrease in one or more of the following compounds.^3-6

ALA – δ-aminolevulinic acid
UPG – uroporphyrinogen
PBG – porphobilinogen coproporphyrin

Carcinogenesis, Mutagenesis, Impairment of Fertility

Normosang was not mutagenic in bacteria systems in vitro and was not clastogenic in mammalian systems in vitro and in vivo. No data are available on potential for carcinogenicity or impairment of fertility in animals or humans.

Pregnancy

Teratogenic effects - Pregnancy Category C

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. For this reason Normosang should not be given to a pregnant woman unless the expected benefits are sufficiently important to the health and welfare of the patient to outweigh the unknown hazard to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Normosang is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients under 16 years of age have not been established.

Geriatric Use

Clinical studies in Normosang did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

REFERENCES

3. Lamon, J. M., Hematin Therapy for Acute Porphyria, Medicine 58(3):252-269, 1979.

4. Dhar, G J., et al., Effects of Hematin in Hepatic Porphyria, Ann Intern Med 83:20-30, 1975.

5. Watson, C. J., et al., Use of Hematin in the Acute Attack of the “Inducible” Hepatic Porphyrias, Adv Intern Med 23:265-286, 1978.

6. McColl, K. E., et al., Treatment with Haematin in Acute Hepatic Porphyria, Q J Med, New Series L (198):161-174, Spring, 1981.

9. Pierach, C. A., Hematin Therapy for the Porphyric Attack, Semin Liver Dis 2(2):125-131, May, 1982.

Clinical Trials Experience

Phlebitis with or without leucocytosis and with or without mild pyrexia has occurred after administration of hematin through small arm veins.

Post-marketing Experience

Reversible renal shutdown has occurred with administration of excessive doses (See “PRECAUTIONS” section).

There have been post-marketing literature reports of thrombocytopenia and coagulopathy (including prolonged prothrombin time and prolonged partial thromboplastin time) in patients receiving Normosang.⁸ Iron overload and serum ferritin increased have also been reported (See “PRECAUTIONS” section).

To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Treatment of this case consisted of ethacrynic acid and mannitol.⁷

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain