Kuvans - instructions for use, doses, side effects, contraindications

Active substanceSaprotherinSaprotherin

Similar drugsTo uncover

Couvan®

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EFKURIA®

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Genfa Medica S.A. Switzerland

Dosage form: & nbsptablets, dispersible

Composition:

1 tablet contains:

Active substance: sapropeterin dihydrochloride - 100 mg (equivalent to 76.80 mg sapropterin).

Excipients: ascorbic acid 5.00 mg, crospovidone 13,50 mg, calcium hydrophosphate 6.54 mg, mannitol 171.18 mg, riboflavin 0.03 mg, sodium stearyl fumarate 3.75 mg.

Description:Round tablets from almost white to light yellow with a marble surface and embossed "177" on one side.

Pharmacotherapeutic group:Fermentopathy is an hereditary remedy

ATX: & nbsp

A.16.A.X Other drugs for the treatment of digestive and metabolic diseases

A.16.A.X.07 Saprotherin

Pharmacodynamics:

Mechanism of action

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 fennlalanine hydroxylase, and in the case of tetrahydrobiopterin (BH4) metabolism disorders, 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 deletions in genes encoding any of the five enzymes responsible for the biosynthesis or recycling of BH4.As in this, and in the other case, the process is broken phenylalanine conversion to amino acid tyrosine, which leads to an increase in blood concentration of phenylalanine. Moreover, in patients with impaired BH4 exchange in addition to disruption of phenylalanine hydroxylase activity of tryptophan hydroxylase function is disrupted and tyrosine hydroxylase and nitric oxide synthase.

Sapropterin - it artificially synthesized equivalent natural 6R-BH4, which is a co-factor hydroxylases for phenylalanine, tyrosine and tryptophan. Rationale KUVAN® drug application in patients with PKU sensitive to tetrahydrobiopterin therapy lies in restoring the activity of phenylalanine hydroxylase damaged and consequently in strengthening or restoring oxidative metabolism of phenylalanine to a level sufficient to reduce or retention in the blood concentration in the prevention or amelioration of further accumulation of phenylalanine, as well as in increasing tolerance to phenylalanine, supplied with food. Justification of the application of the Couvan® preparation in patients with diseases of tetrahydrobiopterin metabolism is the replacement of the deficiency of BH4 and,thereby restoring the activity of phenylalanine hydroxylase, tryptophan hydroxylase, tyrosine hydroxylase and nitric oxide synthase.

Clinical Trials Data

The Phase III clinical phase of the KUVAN® preparation included 2 randomized, placebo-controlled trials in patients with PKU. In these studies, the effectiveness of the drug KUVAN® in reducing the concentration of phenylalanine in the blood and increasing tolerance to phenylalanine, ingested with food was shown.

Pharmacokinetics:

Suction

After ingestion of the dissolved in water tablets KUVAN®, the active component of the preparation - sapropterine is absorbed in the gastrointestinal tract, while the maximum concentration in blood plasma (Сmах) on an empty stomach 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 absorption of sapropeterin, compared with the administration of the drug on an empty stomach, which after 4 to 5 hours leads to an increase in its Cmax, on average, by 40-85%.

Distribution

Sapropterin was mainly distributed in the kidneys, adrenals and liver. In rats after intravenous administration of radioactively labeled sapropeter, the radioactive label was determined in the fetal tissues. When 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.

Metabolism

Sapropeterin 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.

Excretion

After 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:

Pregnancy

There are no confirmed data on clinical studies of the use of the drug KUVAN® in pregnancy. 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. It is necessary to strictly control the concentration of phenylalanine in the blood of women suffering from this disease and planning pregnancy, both before and during pregnancy.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 the appointment of the drug KUVAN® to a pregnant woman should be considered only if strict adherence to the diet does not ensure an adequate decrease in the concentration of phenylalanine in the blood. The drug should be given to pregnant women with caution.

Breast-feeding

Confirmed data from clinical studies on the admission of sapropterin or its metabolites into breast milk of women are absent. Therefore, the drug KUVAN® is not recommended for use during breastfeeding.

Dosing and Administration:

Treatment with KUVAN® is prescribed and controlled by a physician with experience in the treatment of PKU and tetrahydrobiopterin metabolism disorders.

The drug KUVAN® should be taken daily during meals once a day, at the same time, preferably in the morning.

Strict regulation of the intake of phenylalanine and the total protein with food on the background of taking the drug KUVAN® is necessary to ensure adequate control of the level of phenylalanine in the blood and food balance.

Since hyperphenylalaninemia is a chronic condition both in PKU and in violation of tetrahydrobiopterin metabolism, with a positive response to treatment, KUVAN® is prescribed for long-term use. However, the experience of long-term use of the drug is limited.

Doses

One tablet of the drug KUVAN® 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.

PKK

The initial dose of the drug KUVAN® 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 metabolism

The initial dose of the drug KUVAN® in adults and children with BH4 deficiency is 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 treatment

Treatment with KUVAN® should be started as early as possible to prevent the development of irreversible neurological disorders in children, and in adults - cognitive deficits and mental disorders due to a prolonged increase in the concentration of phenylalanine in the blood.

Response to treatment with KUVAN® is evaluated by the degree of decrease in the concentration of phenylalanine in the patient's blood. The concentration of phenylalanine should be determined before starting the administration of the drug KUVAN® at the recommended starting dose and after 1 week of treatment. If the decrease in phenylalanine concentration is not enough, the dose of KUVAN® 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 this 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.

With a positive response to treatment with KUVAN®, the dose of the drug, depending on the severity of the response to treatment, can be increased from 5 to 20 mg / kg of body weight per day.

After 1-2 weeks after each dose increase, it is recommended to determine the concentration of phenylalanine and tyrosine in the blood. Patients receiving the drug KUVAN® should follow a diet with a restriction of phenylalanine, as well as regularly undergo clinical and laboratory tests (including control of phenylalanine and tyrosine in the blood, assessment of nutrient intake and psychomotor development).

Mode of application

Tablets 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 adults

The number of tablets prescribed by the doctor is dissolved in 120-240 ml of water and stirred until complete dissolution.

Use in children

The number of tablets prescribed by the doctor is dissolved in not more than 120 ml of water and stirred until complete dissolution.

Correction of dose

When taking KUVAN®, the concentration of phenylalanine in the blood can 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.

After 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 also to monitor these parameters on a regular basis 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 treatment with KUVAN®, it is necessary to check the accuracy of the patient's compliance with the therapeutic regimen and diet before making a decision to correct the dose of the drug. Stop taking the drug KUVAN® only under the supervision of the attending physician. Since the concentration of phenylalanine in the blood after the discontinuation of the drug KUVAN® may increase, more frequent monitoring is required during the period of the change in the treatment regimen, as well as the correction of dietary recommendations.

Side effects:

In clinical studies, about 35% of the 579 patients who received the drug KUVAN® (in doses of 5-20 mg / kg body weight per day), there were adverse reactions. The most common headache and rhinorrhea were observed.

To denote the frequency of adverse events when taking KUVAN®, the following classification is used:

Very often (≥1 / 10 cases)

Often (≥1 / 100, <1/10)

Infrequently (≥1 / 1,000, <1/100)

Rarely (≥ 1 / 10,000, <1 / 1,000)

Very rarely (<1 / 10,000)

Impaired nervous system: Very often - a headache.

Disturbances from the respiratory system, chest and mediastinal organs: Very often - rhinorrhea. Often - pharyngolaryngeal pain, nasal congestion, cough.

Disorders from the gastrointestinal tract: Often - diarrhea, vomiting, pain in the abdomen.

Disorders from the metabolism and nutrition: Often - hypophenylalanineemia.

After discontinuation of the drug KUVAN®, 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

Headache and dizziness were noted after taking saprotherin in doses exceeding the recommended maximum dose (20 mg / kg body weight per day).

Treatment

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. Caution should be used to prescribe these medications while using KUVAN®.

BH4 is a cofactor of nitric oxide synthase (NO). The drug KUVAN® should be used with caution with drugs that have a vasodilating effect, including agents for topical application, 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. The drug KUVAN® should be carefully administered to patients receiving levodopa,since 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, a correction of the dose of levodopa may be required.

Interaction with food products

Absorption 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, the KUVAN® preparation should be taken with food once a day at the same time, preferably in the morning.

Special instructions:

Treatment with the drug KUVAN® should be carried out by specialists who are well informed in the field of treatment of PKU and metabolic disorders of tetrahydrobiopterin. Patients receiving the KUVAN® preparation 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, nutritional 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.

Before the appointment of the drug KUVAN® patients with concomitant diseases require a doctor's consultation, as in some diseases the concentration of phenylalanine in the blood can increase.

Data on long-term use of the drug KUVAN® are limited.

In patients who are predisposed to convulsions, the drug KUVAN® should be administered with caution. Such patients may experience the appearance or aggravation of seizure activity, especially at the beginning of therapy.

Patients should be warned that in each vial of tablets a moisture absorbing capsule is inserted, which can not be ingested!

Application in elderly patients

The safety and effectiveness of the drug KUVAN® in patients older than 65 years is not established.

Application in renal and hepatic insufficiency

The safety and efficacy of the KUVAN® preparation in patients with renal or hepatic insufficiency was not assessed.

Use in children

Clinical studies on the use of the drug KUVAN® were performed in children with hyperphenylalanemia caused by phenylketonuria and a violation of tetrahydrobiopterin exchange, aged 4 years and older. However, published data show that more than 2,700 children with PKU aged 0-4 years received treatment with tetrahydrobiopterin and at least 43 of them received therapy for 2 or more months. The maximum daily dose was 20 mg / kg body weight. Despite the fact that metabolic disorders of tetrahydrobiopterin are extremely rare, the published data indicate that at least 120 patients were treated at the age of 4 years, which allowed the pathogenetic treatment to avoid serious neurological abnormalities associated with deficiency of neurotransmitters.Prescribing the drug to children, especially infants, care should be taken, since the degree of absorption in this population may be higher. It is recommended to carry out frequent blood monitoring to maintain the recommended level of phenylalanine in the blood.

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. Nevertheless, in connection with 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 or 120 tablets of the drug in bottles of high-density polyethylene with a capacity of 40 ml and 100 ml respectively, sealed with a lid of polypropylene, equipped with a device to protect children from opening the bottle, and sealed with an internal membrane of laminated aluminum foil. Fibers are also placed in polyester fibers and a container of high-density polypropylene with silica gel.The bottle with 30 tablets is equipped with a two-layer label.

For 1 bottle together with instructions for use in a pack of cardboard with the control of the first autopsy.

Storage conditions:Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002533

Date of registration:15.07.2014 / 31.08.2017

Expiration Date:15.07.2019

Manufacturer: & nbsp

EXCELLA, GmbH Germany

Information update date: & nbsp06.02.2018

Illustrated instructions

Instructions

Couvan® (Kuvan® )