Other hematological agents

Hemin

Normosang 25 mg/ml, concentrate for solution for infusion

Concentrate for solution for infusion. Normosang is a dark coloured concentrate for solution for infusion.

Treatment of acute attacks of hepatic porphyria (acute intermittent porphyria, porphyria variegata, hereditary coproporphyria).

Posology

The recommended daily dose is 3 mg/kg once daily for four days, diluted in 100 ml of 0.9% sodium chloride in a glass bottle and infused intravenously over at least 30 minutes into a large antebrachial or central vein using an inline filter.

The dose should not exceed 250 mg (1 ampoule) per day.

Exceptionally, the course of the treatment may be repeated under strict biochemical surveillance if there is inadequate response after the first course of treatment.

Elderly patients

No dose adjustment is required.

Children and adolescents

Attacks of porphyria are rare in children but limited experience in tyrosinaemia suggests that it is safe to use a dose of not more than 3 mg/kg daily for 4 days, administered with the same precautions as for adults.

Method of administration

The infusions should be administered in a large antebrachial or central vein over a period of at least 30 minutes. After the infusion, the vein should be rinsed with 100 ml of 0.9 % NaCl. It is recommended to flush the vein initially with 3 to 4 bolus injections of 10 ml 0.9 % NaCl after which the remaining volume of saline can be infused for 10 - 15 minutes.

Children and adolescents - Attacks of porphyria are rare in children but limited experience in tyrosinaemia suggests that it is safe to use a dose of not more than 3 mg/kg daily for 4 days, administered with the same precautions as for adults.

No dose adjustment is required.

Hypersensitivity to the active substance or to any of the excipients.

• Before treatment is started, it is necessary to confirm an attack of hepatic porphyria by series of clinical and biological criteria :

− suggestive family or personal history,

− suggestive clinical signs,

− quantitative determination of urinary delta-amino-laevulinic acid and porphobilinogen (in preference to the classical WATSON-SCHWARZ or HOESCH tests, which are considered to be less reliable).

• The sooner Normosang treatment is started after the onset of an attack, the greater its efficacy.

• As a result of Normosang infusions, abdominal pain and other gastro-intestinal symptoms generally disappear within 2 - 4 days. Neurological complications (paralysis and psychological disorders) are less affected by the treatment.

• As porphyric attacks are often associated with various cardiovascular and neurological manifestations, appropriate monitoring should be ensured.

• It is also important to warn patients of the risk of attacks being worsened or triggered by fasting or taking certain medicinal products (particularly oestrogens, barbiturates and steroids), because by increasing the haem demand of the liver they are capable of indirectly inducing the delta-aminolaevulinic acid synthase activity.

• As the diluted solution is hypertonic, it should be administered by very slow intravenous infusion only. To prevent vein irritation, the infusion should be administered in at least 30 minutes in a large vein of the forearm or in a central vein.

• Peripheral venous alterations have been reported after repeated infusions and can prevent the use of the affected veins for further infusions, necessitating the use of a central venous line. It is therefore recommended to rinse the vein with 100 ml of 0.9 % NaCl after the infusion.

• Increased serum ferritin concentrations have been reported after repeated infusions. It is therefore recommended that serum ferritin be measured at regular intervals to monitor body iron stores. If necessary other investigation methods and therapeutic measures should be undertaken.

• The dark NORMOSANG colour may give the plasma an unusual colouring.

• Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations for specific markers of infections and the inclusion of effective manufacturing steps for the inactivation/ removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

• The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV.

• It is strongly recommended that every time that Normosang is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

• Normosang contains 1 g of ethanol (96 %) per ampoule of 10 ml. This may be harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant woman and children. The ethanol content of Normosang may modify or increase the effect of other medicines.

• Normosang should not be used as a preventive treatment since available data is too limited and long term administration of regular infusions carries the risk of iron overload (see section 4.8. Undesirable effects).

• In addition to treatment with Normosang and other necessary measures such as the elimination of triggering factors, ensuring a sufficient supply of carbohydrates is recommended.

During treatment with Normosang the enzyme activity of the P450 enzymes increases. The metabolism of concomitantly administered drugs that are metabolised by cytochrome P450 enzymes (such as oestrogens, barbiturates and steroids) may increase during administration of Normosang, leading to lower systemic exposure.

The most commonly reported ADRs are infusion site reactions especially occurring if infusion takes place into veins which are too small.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (>10%), common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%).

Immune system disorders

Rare: anaphylactoid reaction, hypersensitivity (such as dermatitis medicamentosa and tongue oedema).

Vascular disorders

Very common: Poor venous access.

General disorders and administration site conditions

Common: infusion site phlebitis, Infusion site pain, infusion site swelling,

Rare: Pyrexia.

Investigations

Uncommon: Serum ferritin increased.

Increased serum ferritin concentrations have been reported after several years of treatment with repeated infusions, which may indicate an iron overload.

Post-marketing experience:

Nervous system disorders:

Frequency unknown: headache.

Orphan Europe (UK) Limited

(POM)