Normosang (Concentrate) Instructions for Use

Marketing Authorization Holder

Recordati Rare Diseases (France)

Manufactured By

Ever Pharma Jena, GmbH (Germany)

Packaging and Quality Control Release

RECORDATI RARE DISEASES (France)

ATC Code

B06AB (Other blood preparations)

Dosage Form

Normosang

Concentrate for solution for infusion 25 mg/1 ml: amp. 10 ml 4 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion dark brown in color.

Excipients: arginine – 26.7 mg, ethanol 96% – 100 mg, propylene glycol – 400 mg, water for injections – up to 1 ml.

10 ml – ampoules of colorless glass (4) – polystyrene foam packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Drug for the treatment of hepatic porphyria

Pharmacotherapeutic Group

Other hematological agents; heme derivatives

Pharmacological Action

Heme arginate is indicated for hepatic porphyria (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria). These diseases are characterized by the existence of an enzymatic block in heme synthesis, which leads to

• A deficiency of heme necessary for the synthesis of various hemoproteins;
• Accumulation of metabolic precursors of heme that have a direct or indirect toxic effect on the body.

When hemin is administered, eliminating the heme deficiency via a negative feedback mechanism, the activity of delta-aminolevulinic acid synthase, a key enzyme in porphyrin synthesis, is suppressed, leading to a decrease in the synthesis of porphyrins and toxic metabolic precursors of heme.

Thus, by promoting the normalization of hemoprotein and respiratory pigment levels, heme corrects the pathophysiological disorders observed in porphyria. Since the bioavailability of heme arginate and methemalbumin (the physiological transport form of heme) are comparable, the administration of the drug is effective both during remission and during an acute attack of porphyria.

In both cases, and especially during an acute attack, hemin infusions are highly likely to normalize the urinary excretion of delta-aminolevulinic acid and porphobilinogen – two substances whose accumulation underlies the pathogenesis of the disease. This is true for both acute intermittent porphyria and variegate porphyria.

Unlike previously produced galenic preparations, heme arginate infusions do not cause significant changes in blood coagulation and fibrinolysis parameters in healthy volunteers. It has been shown that all these parameters remain unchanged except for the concentrations of factors X and XI, which reversibly decrease by 10-15% from baseline values.

Pharmacokinetics

After IV infusion of hemin (3 mg/kg) in healthy volunteers and patients with porphyria, the following pharmacokinetic parameters were determined: C(0) – 60.0 ± 17 µg/ml, T_1/2 – 10.8 ± 1.6 h, Total plasma clearance – 3.7 ± 1.2 ml/min, V_d – 3.4 ± 0.9 L, after the 4th infusion the T_1/2 of heme increases to 18.1 h.

Indications

• Acute attacks of hepatic porphyria (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria).

ICD codes

Dosage Regimen

Concentrate for the preparation of a solution for intravenous infusion. The recommended daily dose is determined at the rate of 3 mg/kg once daily for 4 days. The concentrate is dissolved in 100 ml of 0.9% sodium chloride solution in a glass vial and administered by infusion over at least 30 minutes into a subcutaneous vein of the forearm or a central vein. The maximum daily dose is 250 mg (1 ampoule). In exceptional cases, the course may be repeated if the response to the first course of therapy is insufficient, with strict control of biochemical parameters.

Use in the elderly

Dosage adjustment in elderly patients is not required.

Use in children

Acute attacks of porphyria in children are rare, but limited experience with the drug in tyrosinemia suggests the safety of a dose range not exceeding daily doses, calculated at 3 mg/kg for 4 days, with the same precautions as in adult patients.

The concentrate, diluted in 100 ml of 0.9% sodium chloride solution, is administered into one of the subcutaneous veins of the forearm or into a central vein. Since the infusion solution is hypertonic, it must be administered very slowly. To prevent vein irritation, the infusion duration should be at least 30 minutes.

After the infusion is completed, 100 ml of 0.9% sodium chloride solution should be administered intravenously to flush the vein: first, administer 3-4 bolus injections of 10 ml each, and then the remaining volume over 10-15 minutes by infusion.

Preparation of the infusion solution

Normosang is diluted immediately before administration in 100 ml of 0.9% sodium chloride solution in a glass vial. For this, the amount of drug calculated relative to the patient’s body weight is transferred from the ampoule to the vial. Dissolution should occur in a glass vial because Hemin decomposes faster in polyvinyl chloride containers.

An infusion solution should not be prepared from more than 1 ampoule per patient per day.

The prepared solution must be used within 1 hour after dilution.

Since Normosang has a dark color, it is visually difficult to assess the presence of foreign particles in the resulting suspension after dilution. For this reason, it is recommended to use an infusion set with a filter.

The unused portion of the drug, regardless of its quantity, as well as the consumables used during the infusion, must be disposed of in accordance with current sanitary and hygienic standards.

Adverse Reactions

Among the adverse reactions, reactions at the injection site were most frequently noted, especially in cases where the vein used for the infusion had an insufficient diameter.

Frequency of adverse effects: very common (>10%); common (1-10%); uncommon (0.1-1%) and rare (0.01-0.1%).

Immune system disorders: rare – anaphylactoid reactions, allergic reactions (such as drug dermatitis, tongue edema).

General disorders and administration site conditions: common – infusion site phlebitis, infusion site pain, infusion site swelling; rare – fever.

Laboratory parameters: uncommon – increased plasma ferritin concentration.

Local reactions very common – poor venous access.

An increase in plasma ferritin concentration was noted in patients after several years of therapy with multiple infusions, which may indicate excessive iron intake.

Contraindications

• Hypersensitivity to the active substance or any other component of the drug.

Use in Pregnancy and Lactation

There are no experimental or clinical data on the use of Normosang during pregnancy, the risk of using the drug during pregnancy is unknown. However, to date, no adverse consequences have been reported in children whose mothers received Normosang during pregnancy.

The use of Normosang during lactation has not been studied. Normosang should be prescribed with caution during breastfeeding, as a large number of drugs are excreted in breast milk.

Due to insufficient data on the use of Normosang during pregnancy and breastfeeding, its use is not recommended except in cases of acute necessity.

Use in Hepatic Impairment

With caution.

Pediatric Use

Acute attacks of porphyria in children are rare, but limited experience with the drug in tyrosinemia suggests the safety of a dose range not exceeding daily doses, calculated at 3 mg/kg for 4 days, with the same precautions as in adult patients.

The concentrate, diluted in 100 ml of 0.9% sodium chloride solution, is administered into one of the subcutaneous veins of the forearm or into a central vein. Since the infusion solution is hypertonic, it must be administered very slowly. To prevent vein irritation, the infusion duration should be at least 30 minutes.

After the infusion is completed, 100 ml of 0.9% sodium chloride solution should be administered intravenously to flush the vein: first, administer 3-4 bolus injections of 10 ml each, and then the remaining volume over 10-15 minutes by infusion.

Geriatric Use

Dosage adjustment in elderly patients is not required.

Special Precautions

Before starting therapy, the diagnosis of an acute attack of hepatic porphyria should be confirmed according to the following criteria

• Positive or suspected family or individual history;
• Characteristic clinical picture;
• Quantitative determination of delta-aminolevulinic acid and porphobilinogen in urine (preferable to the less reliable Hoesch and Watson-Schwartz tests).

The earlier treatment with Normosang is started from the onset of the attack, the higher its effectiveness.

As a result of Normosang infusion, abdominal pain and other gastrointestinal symptoms usually disappear within 2-4 days. Neurological complications (paralysis, psychological disorders) are less amenable to treatment. Since porphyria attacks are often associated with various cardiovascular and neurological manifestations, appropriate patient monitoring should be ensured.

Patients must be informed that fasting or taking certain medications (in particular, barbiturates, estrogens, and other steroid hormones) increases the risk of attacks up to their provocation. The aforementioned factors increase the liver’s demand for heme, which directly or indirectly induces the activity of delta-aminolevulinic acid synthase.

To prevent vein irritation, the drug should preferably be administered into a large forearm vein or a central vein, and the infusion duration should be at least 30 minutes. With repeated infusions, changes in peripheral veins are observed, which complicates subsequent access to the same veins and justifies the use of the central venous route. Therefore, after infusion of the drug, it is recommended to flush the vein with 100 ml of 0.9% sodium chloride solution. An increase in plasma ferritin concentration was noted after multiple infusions. It is recommended to regularly measure plasma ferritin concentration to assess iron stores in the body.

The dark color of the Normosang solution may give the blood plasma an unusual hue.

The measures taken during the production of Normosang to prevent infections developing from the use of medical products made from human blood or plasma are recognized as effective against enveloped viruses such as HIV, hepatitis B and C viruses. They include donor selection, screening of individual blood samples for specific infection markers, and the use of virus inactivation or removal steps in the manufacturing process. Despite these measures, when prescribing drugs made from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to unknown and emerging viruses and other pathogens.

With each administration of Normosang, the patient’s name and the drug batch number should be recorded in order to maintain a link between the patient and a specific batch of Normosang.

One ampoule (10 ml) of Normosang contains 1 g of 96% ethanol. This amount may be harmful to patients with liver disease, alcoholism, epilepsy, brain injuries or diseases, as well as pregnant women and children. The presence of ethanol in Normosang may alter or enhance the effect of other drugs.

Normosang should not be used as a means of prophylactic therapy, as the available data are very limited, and a long-term course of regular infusions carries the risk of iron overload in the body.

In addition to therapy with Normosang, other measures are necessary, such as eliminating triggering factors and ensuring sufficient carbohydrates in the diet.

Overdose

Symptoms: 3 cases of Normosang overdose have been recorded. In two of them – due to misinterpretation of the dosage – patients received doses an order of magnitude higher than recommended. The patient’s recovery in one of these cases was uncomplicated: mild vomiting, pain and tenderness in the forearm (at the infusion site) were observed. Another patient, who received 2500 mg of Normosang in a single infusion, experienced acute liver failure. A third patient, who received 6 ampoules (3000 mg) of Normosang over 2 days, experienced hyperbilirubinemia, anemia, and generalized hemorrhagic diathesis. These phenomena persisted for several days from the time of administration, but recovery occurred without residual effects.

There is a report that hematin (another form of heme) in high doses caused transient renal failure in a patient.

Normosang contains 4000 mg/10 ml of propylene glycol in 1 ampoule. Propylene glycol in high doses can cause disorders of the central nervous system, lactic acidosis, increased plasma osmolality, hemolytic reactions, and also have a toxic effect on the kidneys and liver.

Treatment

• Infusion of albumin should be prescribed to bind freely circulating and potentially reactive hemin.
• Administration of activated charcoal will interrupt the enterohepatic recirculation of heme.
• Hemodialysis is necessary to remove propylene glycol from the body.

Coagulation parameters, liver, kidney, and pancreatic function should be continuously monitored until they normalize. The cardiovascular system should also be monitored due to the likelihood of cardiac arrhythmias.

Drug Interactions

This drug should not be mixed with any other agents except 0.9% sodium chloride solution for dilution.

During treatment with Normosang, the activity of cytochrome P450 isoenzymes increases. The metabolism of drugs used concomitantly with Normosang, mediated by the cytochrome P450 system (e.g., estrogens, barbiturates, and steroid hormones), is accelerated, leading to a decrease in their systemic exposure.

Storage Conditions

Store the drug in a place protected from light at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Do not use the drug after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.