Active substanceGeminGemin Similar drugsTo uncover Normosang concentrate d / infusion Orphan Europe France Dosage form: & nbspconcentrate for solution for infusion Composition:In 1 ml of concentrate contains Active substance: hemin - 25.0 mg.Excipients: arginine 26.7 mg, ethanol 96% 100.0 mg, propylene glycol 400.0 mg, water for injection up to 1 ml. Description:dark brown solution Pharmacotherapeutic group:porphyria acute remedy ATX: & nbspB.06.A.B Other hematological preparations Pharmacodynamics:Heme arginatum is indicated in hepatic porphyria (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria). These diseases are characterized by the existence of an enzymatic blockade of heme synthesis, which leads to: - deficiency of heme necessary for the synthesis of various hemoproteins- cumulation of metabolic precursors of heme, which have a direct or indirect toxic effect on the body. In the appointment of hemin, which eliminates heme deficiency, the activity of the synthase of delta-aminolevulinic acid, a key enzyme in the synthesis of porphyrins, is suppressed by the negative feedback mechanism, which leads to a decrease in the synthesis of porphyrins and toxic metabolic heme precursors.Thus, by promoting the normalization of the level of hemoproteins and respiratory pigments, gem corrects the pathophysiological disturbances observed in porphyria. Since the bioavailability of heme and methemalbumin arginate (physiological form of heme transfer) is comparable, the administration of the drug is effective both in remission and in acute porphyria.In both cases, and especially in an acute attack, hemin infusions are highly likely to normalize urinary excretion of delta-aminolevulinic acid and porphobilinogen-twosubstances, whose cumulation is the basis of the pathogenesis of the disease. This is true for acute intermittent, and for varigata porphyria.Unlike previously produced galenic preparations, infusions of heme arginat do not cause significant changes in the coagulation and fibrinolysis in healthy volunteers. It is shown that all these indices remain unchanged except for concentrations of factors X and XI, reversibly decreasing by 10-15% of the initial values. Pharmacokinetics:After intravenous 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, T1 / 2 -10.8 ± 1.6 h, Total plasma clearance - 3.7 ± 1.2 ml / min, Volume of distribution - 3 , 4 ± 0.9 L; after the 4th infusion of T1 / 2, the heme increases to 18.1 h. Indications:Acute attacks of hepatic porphyria (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria). Contraindications:Hypersensitivity to the active substance or any other component of the drug. Carefully:Pregnancy and the period of breastfeeding. Pregnancy and lactation:Experimental and clinical data on the use of Normosang during pregnancy are absent, the risk of using the drug during pregnancy is unknown. However, until now no adverse effects have been reported in children whose mothers received Normosang during pregnancy. The use of Normosang during breastfeeding has not been studied. The appointment of Normosang during breastfeeding should be carried out with caution, since a large number of drugs are excreted in breast milk.Due to the lack of data on the use of Normosang during pregnancy and breastfeeding, its appointment is not recommended except in cases of acute necessity. Dosing and Administration:Concentrate for the preparation of a solution for intravenous infusion.The recommended daily dose is determined from the calculation of 3 mg / kg once a day for 4 days.The concentrate is dissolved in 100 ml of a 0.9% sodium chloride solution in a glass vial and injected for at least 30 minutes into the subcutaneous vein of the forearm or central vein. The maximum daily dose is 250 mg (1 ampoule). In exceptional cases, the course can be repeated if there is insufficient response to the first course of therapy, with strict control of biochemical parameters. . Application in the elderly Dose adjustments in elderly patients are not required.Use in childrenAcute porphyria attacks in children are rare, but limited experience with tyrosinemia presupposes the safety of a range of doses not exceeding daily doses at a dose of 3 mg / kg for 4 days, with the same precautions as in adult patients.Mode of applicationConcentrate, diluted in 100 ml of 0.9% sodium chloride solution, is injected into one of the subcutaneous veins of the forearm or into the central vein. Since the infusion solution is hypertonic, it must be administered very slowly. To prevent irritation of the vein, the duration of the infusion should be at least 30 minutes.At the end of the infusion, 100 ml of 0.9% sodium chloride solution should be injected intravenously to wash the vein: first, insert 3-4 bolus injections of 10 ml each, and then the remaining volume for 10-15 minutes infusion.Preparation of solution for infusionNormosang is diluted immediately before administration to 100 ml of 0.9% sodium chloride solution in a glass vial. For this purpose, the amount of preparation calculated from the patient's body weight is transferred from the ampoule to the vial. Dissolution should occur in a vial of glass, because hemin faster decomposes in containers made of polyvinyl chloride.Do not prepare a solution for infusion of more than 1 ampoule per patient per day.The prepared solution should be used within 1 hour after dilution.Since Normomang has a dark color, it is visually difficult to assess the presence of foreign particles in the resulting suspension after dilution. For these reasons, it is recommended to use an infusion set with a filter.Unused portion of the drug, regardless of its quantity, as well as consumables used during infusion, must be disposed of in accordance with the current sanitary and hygienic standards. Side effects:Of the adverse reactions, the most frequent reactions were intravenous injection, especially in those cases where the vein through which the infusion was performed had an insufficient diameter (see section "Special instructions").Frequency of occurrence of side effects: "very often" (≥10%); "often" (1-10%); "infrequently" (0.1-1%) and "rarely" (0.01-0.1%).Immune system disordersRarely: anaphylactoid reactions, allergic reactions (such as drug dermatitis, edema of the tongue).General disorders and disorders at the site of administrationOften: phlebitis in the field of infusion, pain in the field of infusion, edema in the field of infusion; Rarely: fever.Laboratory and instrumental dataInfrequent: an increase in the concentration of ferritin in the blood plasma Trauma, intoxication and complications of manipulationVery often: insufficient venous access. An increase in ferritin concentration in plasma was noted in patients after several years of therapy with multiple infusions, which may indicate excess iron intake (see section "Special instructions"). Overdose:SymptomsThree cases of an overdose of Normosang were recorded. In two of them - due to misinterpretation of the dosage, patients received doses in excess of the recommended ones.Recovering the patient in one of these cases passed without complications: vomiting of low intensity, pain and soreness in the forearm area (at the site of infusion) were observed. In another patient who received 2500 mg of Normosanga with a single infusion, acute hepatic insufficiency was observed. In the third patient who received 6 ampoules (3000 mg) of Normosanga for 2 days, hyperbilirubinemia, anemia and generalized hemorrhagic diathesis were observed. These phenomena persisted for several days from the time of administration, but recovery was achieved without residual effects.There is a report that hematin (another form of heme) in high doses caused transient renal failure in the patient.Normosang contains 4000 mg / 10 ml of propylene glycol in 1 ampoule. Propylene glycol in high doses can cause damage from the central nervous system, lactic acidosis, increased osmolality of the plasma, hemolytic reactions, and also have toxic effects on the kidneys and liver.TreatmentIt is necessary to prescribe an albumin infusion to bind a freely circulating and potentially reactive hemin. -The designation of activated carbon will interrupt the enterohepatic recirculation of the gem.- We need hemodialysis to remove propylene glycol from the body. Continuously monitor the indicators of coagulability, liver, kidney and pancreas function before their normalization. Also, the condition of the cardiovascular system should be monitored because of the likelihood of developing cardiac arrhythmias. Interaction:Pharmaceutical This drug should not be mixed with any other means except for 0.9% sodium chloride solution when diluted (see section "Method of administration and dose").PharmacokineticDuring the treatment with Normosang, the activity of cytochrome P-450 isoenzymes increases.Metabolism of medications used together with Normosang mediated by cytochrome P-450 (for example, estrogens, barbiturates and steroid hormones) is accelerated, which leads to a decrease in their systemic exposure. Special instructions:Before the beginning of therapy it is necessary to confirm the diagnosis of an acute attack of hepatic porphyria according to the following criteria:-Positive or suspected family or individual history-Characteristic clinical picture-The quantification of delta-aminolevulinic acid and porphobilinogen in the urine (preferably, the less reliable Hosh and Watson-Schwartz tests)The earlier treatment started with Normosang from the moment of the onset of an attack, the higher its effectiveness.As a result of the infusion of Normosang, abdominal pain and other symptoms from the gastrointestinal tract, as a rule, disappear within 2-4 days. Neurological complications (paralysis, psychological disorders) are less likely to be treated.Since porphyria attacks are often associated with various cardiovascular and neurological manifestations, it is necessary to ensure appropriate monitoring of the condition of patients.Patients should be informed of the fact that fasting or taking certain medications (in particular barbiturates, estrogens and other steroid hormones) increases the risk of attacks until they are provoked.The above factors increase the need for the liver in gemma, which directly or indirectly induces the activity of delta-aminolevulinic acid synthase.To prevent irritation of the vein, the drug should preferably be injected into the large vein of the forearm or central vein, and the duration of the infusion should be at least 30 minutes (see section "Method of administration and dose"). 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 bed; Therefore, after the infusion of the drug is recommended to wash the vein> 100 ml of 0.9% solution of sodium chloride (see section "Method of administration and dose").An increase in ferritin concentration in the plasma was noted after multiple infusions. It is recommended to regularly measure the concentration of ferritin in the plasma to assess the iron deposited in the body. The dark color of the Normosang solution can give an unusual shade to the blood plasma.The measures taken to prevent infections developing with the use of medical products made from human blood or plasma are recognized as effective in the production process of the Normosang preparation against envelope viruses such as HIV, hepatitis B and C viruses.They include the selection of donors, screening of individual blood samples for specific markers of infections, and the use of inactivation or removal of viruses in the manufacturing process.Despite these measures, when prescribing drugs prepared from human blood or plasma, the possibility of transmitting infectious agents can not be completely ruled out. This also applies to unknown and emerging viruses and other pathogens.With each introduction of Normosang, the patient's name and the serial number of the drug should be recorded in order to maintain communication between the patient and a certain series of Normosang.In 1 ampoule (10 ml) of Normosanga contains 1 g of 96% ethanol. This amount can harm patients with liver disease, alcoholism, epilepsy, with injuries or brain diseases, as well as pregnant women and children. The presence of ethanol in Normosang can alter or enhance the effect of other drugs.Normosang should not be used as a preventative therapy, because the available data are very limited, and the long-term course of regular infusions carries the risk of glut of the body (see.section "Side effect").In addition to the Normosang therapy, other measures are needed, such as eliminating triggering factors and having enough carbohydrates in food. Form release / dosage:Concentrate for the preparation of a solution for infusions of 25 mg / ml. Packaging:By, 10 ml concentrate into ampoules g of colorless glass (type I) with a capacity of 10 ml with a white ring of a break. 4 ampoules per package of expanded polystyrene.One package of expanded polystyrene with instructions for use in a pack of cardboard. Storage conditions:Store in a dark place at a temperature of 2 to 8 ° C. Keep out of the reach of children! Shelf life:2 years.Do not use the product after the expiry date printed on the package. Terms of leave from pharmacies:On prescription Registration number:P N002375 Date of registration:05.09.2011 The owner of the registration certificate:Orphan EuropeOrphan Europe France Manufacturer: & nbspORPHAN EUROPE France Representation: & nbspRAYFARM, LLCRAYFARM, LLC Information update date: & nbsp2015-12-10 Illustrated instructions × Illustrated instructions Instructions