Active substanceSaprotherinSaprotherin Similar drugsTo uncover Couvan® pills inwards EFKURIA® pills inwards Genfa Medica S.A. Switzerland Dosage form: & nbspTablets are dispersible. Composition:One tablet contains:active substance: sapropeterin dihydrochloride - 100 mg.Excipients: ascorbic acid 2.30 mg, sodium stearyl fumarate 9.00 mg, copovidone 30.00 mg, mannitol 119.65 mg, crospovidone 36.00 mg, riboflavin 0.05 mg, silicon dioxide colloid 3.00 mg . Description:Round flat tablets from white to almost white, with an embossed "11" on one side and a risk on the other. Pharmacotherapeutic group:Fermentopathy is an hereditary remedy. ATX: & nbspA.16.A.X Other drugs for the treatment of digestive and metabolic diseasesA.16.A.X.07 Saprotherin Pharmacodynamics:Hyperphenylalanineemia (HFA) is defined as a pathological increase in the concentration of phenylalanine in the blood. This condition is usually caused by autosomal recessive mutations of genes encoding, in the case of phenylketonuria (PKU), the enzyme phenylalanine hydroxylase, and in cases of metabolic disorder tetrahydrobiopterin (BH4), enzymes involved in the biosynthesis or regeneration of 6R-tetrahydrobiopterin (6R-BH4). BH4 deficiency is determined by a number of disorders resulting from mutations or fissions in genes encoding any of the five enzymes responsible for the biosynthesis or recycling of BH4.In addition, in patients with impaired metabolism of BH4, in addition to impairing the function of phenylalanine hydroxylase, the activity of tryptophan hydroxylase and tyrosine hydroxylase, as well as nitric oxide synthase, is disrupted.Sapropterin is an artificially synthesized equivalent of natural 6R-BH4, which is a cofactor of hydroxylases for phenylalanine, tyrosine and tryptophan. The rationale for the use of Efkuria® in patients with PKU sensitive to tetrahydrobiopterin therapy is to restore the activity of the damaged phenylalanine hydroxylase and, consequently, to enhance or restore the oxidative metabolism of phenylalanine to a level sufficient to reduce or retain its concentration in the blood, to prevent or reduce further accumulation of phenylalanine, as well as an increase in tolerance to phenylalanine, which comes with food. The rationale for prescribing Efkuria® in patients with disorders of tetrahydrobiopterin metabolism is the replacement of BH4 deficiency and, thus, the restoration of the activity of phenylalanine hydroxylase, tryptophan hydroxylase, tyrosine hydroxylase and nitric oxide synthase. Pharmacokinetics:AbsorptionAfter ingestion of a dissolved in water tablet Efkuria® active component of the drug - sapropterine absorbed in the gastrointestinal tract, while the maximum concentration in the blood plasma (Cmax) is reached in 3-4 hours from the moment of taking the drug. The speed and extent of absorption of sapropeterin depends on the type of food taken with it. High-calorie food with a high fat content increases the absorption of sapropeterin, compared with the administration of the drug on an empty stomach, which, after 4-5 hours after ingestion, increases its Cmax, on average, by 40-85%. DistributionSapropterin is mainly distributed in the kidneys, adrenals and liver. MetabolismSapropeterin dihydrochloride is metabolized, mainly in the liver, to dihydrobiopterin and biopterin. Since sapropeterin dihydrochloride is an artificially synthesized analogue of 6R-BH4, it can reasonably be expected that it is metabolized in the same way as natural 6R-BH4. Folic acid and vitamin B12 can increase the level of BH4.ExcretionAfter oral administration, most of the drug is excreted through the intestine, and only a small part of it is caused by the kidneys. Indications:Hyperphenylalaninemia in adults and children with phenylketonuria or a violation of tetrahydrobiopterin metabolism (in combination with diet). Contraindications:- Hypersensitivity to sapropterin or any other component of the drug;- The period of breastfeeding. Carefully:Predisposition to convulsions.Elderly (over 65 years of age).Renal or hepatic insufficiency.Pregnancy and children's age up to 4 years.Simultaneous administration with levodopa, inhibitors of dihydrofolate reductase (incl. methotrexate, trimethoprim), vasodilators, incl. with topical application (nitroglycerine, isosorbide dinitrate, sodium nitroprusside, molsidomine, type 5 phosphodiesterase inhibitors, minoxidil). Pregnancy and lactation:PregnancyConfirmed data from clinical studies of the use of Efkuria® in pregnancy is not available. In experimental studies on animals, direct or mediated adverse effects on the development of the embryo and fetus, as well as on the genus and postnatal development, were not found. In rats after intravenous administration of radioactively labeled sapropterin, the radioactive label is determined in the fetal tissues.It is necessary to strictly control the concentration of phenylalanine in the blood of women suffering from this disease and planning a pregnancy, both before the onset of pregnancy, and throughout. Otherwise, an inadequate control of the concentration of phenylalanine can lead to dangerous consequences for both the mother and the fetus. The controlled by the doctor restriction of the intake of phenylalanine with food before and during pregnancy is the first choice in the treatment of these patients.The question of prescribing Efkuria® to a pregnant woman should be considered only if strict adherence to the diet does not provide an adequate reduction in the concentration of phenylalanine in the blood. The drug should be given to pregnant women with caution.Breast-feedingWhen administered intravenously in rats, it was found that the biopterin (one of the products of sapropeterin metabolism) is excreted with milk. However, with oral administration of sapropterin dihydrochloride to rats at a dose of 10 mg / kg, no increase in the total bioptin concentration in both the fetal tissues and in the female milk was noted.Confirmed data from clinical studies on the admission of sapropterin or its metabolites into breast milk of women are absent. Therefore, Efkuria® is not recommended for breastfeeding. Dosing and Administration:Inside, taken daily during meals once a day, at the same time, preferably in the morning.Treatment with Efkuria® is prescribed and controlled by a physician with experience in the treatment of PKU and tetrahydrobiopterin metabolism disorders.Strict regulation of the intake of phenylalanine and total protein with food against the background of Efkuria® is necessary to ensure adequate control of phenylalanine levels in the blood and food balance.Since hyperphenylalaninemia is a chronic condition both in PKU and in violation of tegrahydrobiopterin metabolism, with a positive response to treatment, Efkuria® is prescribed for long-term use. However, the experience of prolonged use of the drug is limited.DosesOne tablet of Efkuria® contains 100 mg of sapropterin. The daily dose, calculated on the basis of the patient's body weight, should be rounded to the nearest multiple of 100.For example, doses of 401 to 450 mg should be rounded to 400 mg, which corresponds to 4 tablets, and doses from 451 to 499 mg should be rounded to 500 mg, i.e. up to 5 tablets.PKKThe initial dose of Efkuria® in adults and children suffering from PKU is 10 mg / kg body weight. The dose can be changed by the attending physician in the range of 5-20 mg / kg of body weight per day to achieve and maintain the recommended concentration of phenylalanine in the blood.Disorders of tetrahydrobiopterin metabolismThe initial dose of Efkuria® in adults and children with BH4 deficiency ranges from 2 to 5 mg / kg of body weight when taken once a day. The dose may be increased to 20 mg / kg of body weight per day. To achieve the optimal therapeutic effect, the total daily dose of the drug can be divided into 2 or 3 doses during the day to achieve the optimal therapeutic effect.Determining the response to treatmentTreatment with Efkuria® should be started as early as possible to prevent the development of irreversible neurological disorders in children, and in adults - cognitive insufficiency and mental disorders due to a prolonged increase in the concentration of phenylalanine in the blood.Response to Efkuria® treatment is assessed by the degree of decrease in phenylalanine concentration in the patient's blood. The concentration of phenylalanine should be determined before starting Efkuria® at the recommended starting dose and after 1 week of treatment. If the decrease in phenylalanine concentration is not enough, the dose of Efkuria® should be increased once a week to a maximum of 20 mg / kg of body weight per day with weekly monitoring of phenylalanine concentration in the blood for 1 month. The intake of phenylalanine with food should be maintained at a constant level throughout the period.The therapeutic response is characterized by a decrease in the concentration of phenylalanine in the blood by at least 30% or by reaching its target value, which is determined by the attending physician individually for each patient.Patients who did not achieve this therapeutic response within 1 month should be regarded as not responding to treatment. Such patients should not use the drug in the future.After 1-2 weeks after each dose increase, it is recommended to determine the concentration of phenylalanine and tyrosine in the blood.Patients receiving Efkuria® should follow a diet with a restriction of phenylalanine, and regularly undergo clinical and laboratory tests (including control of phenylalanine and tyrosine in the blood, nutritional intake and psychomotor development).Mode of applicationTablets should be taken once at the same time, preferably in the morning, during meals to increase absorption.The recommended amount of tablets is dissolved in water, stirring the solution. The dissolution time can be several minutes. To accelerate the dissolution, the tablets can be ground. In the resulting solution, small particles can be seen, their presence does not affect the effectiveness of the preparation. After preparation, the solution should be drunk within 15-20 minutes.For doses less than 100 mg, one tablet is dissolved in 100 ml of water. Accordingly, 1 ml of the solution will contain 1 mg of sapropterin. To take the recommended dose (in mg), you need to take the appropriate amount of ml of the solution obtained.To prepare the solution exactly in accordance with the required volume, a suitable container with a graduated in ml should be used.Preparation of the drug solution for individual patient groups Application in adultsThe number of tablets prescribed by the doctor is dissolved in 120-240 ml of water and stirred until completely dissolved Use in childrenThe number of tablets prescribed by the doctor is dissolved in not more than 120 ml of water and stirred until complete dissolution.Correction of doseWhen taking Efkuria®, the concentration of phenylalanine in the blood may decrease below the target therapeutic level. To maintain the concentration of phenylalanine in the blood within the recommended therapeutic range, you may need to adjust the dose of sapropeterin or change the intake of phenylalanine with food.1-2 weeks after each dose adjustment, especially in children, it is recommended to determine the concentration of phenylalanine and tyrosine in the blood, and regularly monitor these indicators in the future under the supervision of the attending physician.If it is not possible to achieve the target concentration of phenylalanine in the blood on the background of Efkuria® treatment, the accuracy of the patient's compliance with the therapeutic regimen and diet should be checked before deciding whether to correct the dose of the drug.You can stop taking Efkuria® only under the supervision of your doctor. Since the concentration of phenylalanine in the blood after the discontinuation of Efkuria® can increase, more frequent monitoring during the period of the change in the treatment regimen is necessary, as well as the correction of dietary recommendations. Side effects:Frequency of side effects: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000 ), very rarely (<1/10000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).In clinical trials, approximately 35% of the 579 patients who received the drug Saprotherin (in doses of 5-20 mg / kg of body weight per day), adverse reactions were noted. The most common headache and rhinorrhea were observed.From the nervous system: very often - a headache.From the respiratory system, chest and mediastinum: very often-gynorrhea, often - pharyngolaryngeal pain, nasal congestion, cough.From the gastrointestinal tract: often - diarrhea, vomiting, abdominal pain.From the side of metabolism and nutrition: often - hypophenylalanineemia.After discontinuation of Efkuria®, there may be a "cancellation" syndrome, which is manifested by an increase in the concentration of phenylalanine in the blood above the initial values.There were several cases of hypersensitivity reactions (including severe allergic reactions) and rash when the drug was used. Overdose:Symptoms of drug overdose:Headache and dizziness were noted after taking sapropterin in doses exceeding the recommended maximum dose (20 mg / kg body weight per day). Treatment and care:When these symptoms are detected, symptomatic therapy is performed. Interaction:Despite the fact that the concomitant use of drugs from the group of dihydrofolate reductase inhibitors (eg, methotrexate, trimethoprim) has not been studied, such drugs can affect the metabolism of BH4. It should be cautious to prescribe these medications while using Efkuria®.BH4 is a cofactor of nitric oxide synthase (NO). Efkuria® should be used with caution with vasodilating drugs, including topical agents, due to its effect on the metabolism or mechanism of action of NO.These include classic NO donators (for example, nitroglycerine, isosorbide dinitrate, sodium nitroprusside, molsidomine), phosphodiesterase type 5 inhibitors (such as sildenafil, vardenafil, tadalafil) and minoxidil. Efkuria® should be given with caution to patients receiving levodopa, as combination therapy with levodopa and sapropterin in patients with BH4 deficiency can increase excitability and irritability, as well as cause the appearance and frequency of seizures, especially at the beginning of therapy. In this case, correction of the dose of levodopa may be required.Interaction with food productsAbsorption of sapropterin is higher when consuming high-calorie food with a high fat content in comparison with taking on an empty stomach. On the average in 40-85% of cases, the maximum concentration in the blood is reached after 4-5 hours after administration.To prevent possible fluctuations in bioavailability, Efkuria® is recommended to be taken with food once a day at the same time, preferably in the morning. Special instructions:Treatment with Efkuria® should be carried out by specialists who are well informed in the field of treatment of PKU and tetrahydrobiopterin metabolism disorders.Patients receiving Efkuria® should follow a diet with a limited content of phenylalanine, and regularly undergo clinical and laboratory tests, including control of phenylalanine and tyrosine levels in the blood, assessment of nutrient intake and psychomotor development.Continuous or recurring metabolic disorder phenylalanine - tyrosine-dihydroxy-L-phenylalanine (DOPA) may be expressed in insufficient production of the protein and neurotransmitters by the body.Long-term decrease in the concentration of phenylalanine and tyrosine in early childhood can lead to disorders of the development of the nervous system.Strict regulation of the intake of phenylalanine and total protein with food against the background of Efkuria® is necessary to ensure adequate control of phenylalanine levels in the blood and food balance.Before prescribing Efkuria®, patients with concomitant diseases require a doctor's consultation, as in some diseases, phenylalanine in the blood can increase.Data on the long-term use of Efkuria® are limited.In patients who are predisposed to convulsions, Efkuria® should be administered with caution. Such patients may experience the appearance or aggravation of seizure activity, especially at the beginning of therapy.Patients need to be warned that in each vial of tablets a moisture absorbing capsule is inserted that can not be swallowed!Application in elderly patientsThe safety and efficacy of Efkuria® in patients older than 65 years is not established.Application in renal and hepatic insufficiencyThe safety and efficacy of Efkuria® in patients with renal and hepatic insufficiency was not assessed.Use in childrenThe safety and efficacy of Efkuria® in children under 4 years of age have not been evaluated. Effect on the ability to drive transp. cf. and fur:Studies of the effects of the drug on the ability to drive vehicles and other mechanisms have not been carried out. However, due to the possible development of unwanted reactions from the central nervous system (headache), care should be taken when managing transport and performing other activities,requiring increased attention and speed of psychomotor reactions. Form release / dosage:Tablets are dispersible, 100 mg. Packaging:For 30, 60 or 120 tablets in bottles of high-density polyethylene, sealed with a screw cap made of polypropylene, equipped with a device to protect children from opening the bottle. A container of polypropylene with silica gel and a polyester spiral are placed in the vials.On 1 bottle together with the instruction on application place in a pack a cardboard. Storage conditions:At a temperature of no higher than 25 ° C.Keep out of the reach of children. Shelf life:Do not use after the expiry date printed on the package.2 years. Terms of leave from pharmacies:On prescription Registration number:LP-003907 Date of registration:17.10.2016 Expiration Date:17.10.2021 The owner of the registration certificate: Genfa Medica S.A. Genfa Medica S.A. Switzerland Manufacturer: & nbspRubicon Research Private Limited India Representation: & nbspHEAD OF MEDICA SAHEAD OF MEDICA SASwitzerland Information update date: & nbsp2016-11-10 Illustrated instructions × Illustrated instructions Instructions