Эксондис 51 инструкция по применению

Generic name: eteplirsen 50mg in 1mL
Dosage form: injection
Drug class: Miscellaneous uncategorized agents

Medically reviewed by Drugs.com. Last updated on Mar 14, 2022.

Frequently asked questions

• Is Exondys 51 a type of gene therapy?
• Is there a specific age range for which Exondys 51 will work?
• What types of DMD can Exondys 51 be used for?
• How is Exondys 51 administered?
• What are the new drugs for Duchenne muscular dystrophy?

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Exondys 51 — первое одобренное лечение, направленное на основополагающую причину Мышечной дистрофии Дюшенна, утверждено FDA 19 сентября 16 года.

Exondys 51, препарат пропуска экзонов, который получил от ФДА сертификацию быстрого отслеживания, приоритетное рассмотрение, а также сертификацию в качестве препарата для орфанных (редких) заболеваний и был также одобрен к использованию. Он оказывает лечебное воздействие на пациентов с МДД и подтвержденной мутацией в гене дистрофина, поддающейся лечению путем пропуска экзона 51, что составляет примерно 13 процентов популяции пациентов с МДД.

Первопричиной МДД является ошибка в гене дистрофина, важнейшего белка, вовлеченного в мышечную функцию.

Exondys 51 потенциально может уменьшить серьезную мышечную слабость и атрофию, вызванную этой мутацией.

Как работает Exondys 51?

Пропуск экзонов это подход в лечении специфических генных мутаций, который может восполнить дефицит белка дистрофина. Синтез дистрофина включает транскрипцию ДНК в РНК, и трансляцию РНК в дистрофин путем клеточного механизма. РНК состоит из экзонов и каждый экзон кодирует набор аминокислот. Аминокислоты являются строительными блоками (кирпичиками) протеинов. Некоторые генетические мутации при МДД включают и делецию экзонов. В некоторых из этих случаев, остающииеся экзоны оказываются вне рамок, прерывая правильный перевод/трансляцию  генетического кода в белок.

Люди с такими мутациями, как правило производят мало дистрофина или дистрофин, который не функционален.

Пропуск экзонов подразумевает пропуск через один экзон в РНК чтобы перестроить оставшиеся экзоны, помещая или возвращая их в «рамку». Путем восстановления рамок считывания, клеточный механизм будет способен транслировать РНК в функциональную, но укороченную форму дистрофина.

Этот терапевтический подход предназначен для решения основной причины МДД, путем содействия синтезу укороченного или усеченного белка дистрофина, и может стабилизировать или замедлить прогрессию заболевания.

Клинические испытания Exondys 51

Данные клинических испытаний этеплирсена на небольшом количестве людей с МДД показали соответствующую безопасность и переносимость. Базовые исследования не были рассчитаны на оценку долгосрочной безопасности, а клинический эффект не был установлен.

Экзондис 51 оценивался тремя клиническими исследованиями с участием людей у которых имеются подтвержденные мутации в гене DMD (Дистрофин), поддающиеся пропуску 51 экзона.

В первом исследовании, 12 юношей-участников еженедельно, случайным образом получали инъекции Экзондиза 51 или плацебо общей сложностью в течение 24 недель. Основною целью (конечной точкой) были выработка дистрофина, а величина клинического результата (6 минутный тест ходьбы) также подлежала оценке. Какой-либо значительной разницы в изменениях результатов прогулочного (пешего) теста между группой получающей лечение Экзондисом 51 и плацебо выявлено не было.

Все участники первого испытания продолжили свое участие в открытом исследовании с еженедельным приемом Exondys 51 более 4 х лет по сравнению с контрольной группой. Исследование не смогло представить доказательство клинического эффекта Exondys 51 по сравнению с внешней контрольной группой. Ввиду недостатка информации по уровням дистрофина до начала первого исследования было невозможно оценить выработку дистрофина в ответ на Exondys 51 в первом исследовании.

В третьем открытом исследовании 13 участников получали лечение в течении 48 недель. В отношении участников была проведена мышечная биопсия, как до, так и после лечения. Средний рост (мышечный) составлял 0,1 процента по истечению 48 недель.

Самыми основными побочными реакциями были нарушение равновесия и тошнота.

Имели место также и сообщения об эритеме (сильное покраснение кожи), гиперимии кожи лица и повышении температуры в дни приема препарата.

Чтобы узнать больше о прошедших и текущих исследованиях, смотрите про Exondys 51 на сайте clinical trials.

Дальнейшие шаги по Exondys 51

Exondys 51 был одобрен ФДА по пути ускоренного утверждения, который позволяет экспериментальным методам лечения получить одобрение FDA, если таковые показывают перспективу значимого преимущества перед существующими видами лечения. В случае с Экзондисом от Сарепты, поскольку не было никаких предварительных утвержденных терапий для МДД, предварительные результаты по эффективности препарата в испытаниях, хоть и будучи незначительными, предлагают улучшенные в сравнении с обычными, возможности поддержания состояния здоровья при МДД.

Тем не менее каких-либо ясных клинически положительных эффектов по Exondys 51 установлено не было, так как продолжающееся ФДА утверждение для его сертификации (одобрения) может  зависеть от проверки клинических эффектов в подтверждающих рандомизированных исследованиях, которые продлятся еще в течении следующих двух лет.

Требуемое исследование предназначено для оценки улучшения двигательной функции у людей с МДД с подтвержденной мутацией в гене дистрофина, подходящей для лечения пропуском экзона 51. Если по результатам испытания не удасться установить клинический эффект, ФДА может инициировать процедуру отклонения одобрения препарата.

EXONDYS 51- eteplirsen injection
Sarepta Therapeutics, Inc.

1 INDICATIONS AND USAGE

EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51 [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended dose of EXONDYS 51 is 30 milligrams per kilogram administered once weekly as a 35 to 60 minute intravenous infusion via an in-line 0.2 micron filter.

If a dose of EXONDYS 51 is missed, it may be administered as soon as possible after the scheduled time.

2.2 Preparation Instructions

EXONDYS 51 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique.

1. Calculate the total dose of EXONDYS 51 to be administered based on the patient’s weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of EXONDYS 51 needed and the correct number of vials to supply the full calculated dose.
2. Allow vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake.
3. Visually inspect each vial of EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence, and may contain trace amounts of small, white to off-white amorphous particles. Do not use if the solution in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
4. With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the calculated volume of EXONDYS 51 from the appropriate number of vials.
5. Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
6. Administer the diluted solution via an in-line 0.2 micron filter.
7. EXONDYS 51 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted EXONDYS 51 solution within 4 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51.

2.3 Administration Instructions

Application of a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered.

EXONDYS 51 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion.

Infuse the diluted EXONDYS 51 solution over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line.

If a hypersensitivity reaction occurs, consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

3 DOSAGE FORMS AND STRENGTHS

EXONDYS 51 is a clear and colorless solution that may have some opalescence, and may contain trace amounts of small, white to off-white amorphous particles, and is available as follows:

• Injection: 100 mg/2 mL (50 mg/mL) solution in a single-dose vial
• Injection: 500 mg/10 mL (50 mg/mL) solution in a single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including bronchospasm, chest pain, cough, tachycardia, and urticaria, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Dosage and Administration (2.3)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

EXONDYS 51 was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1), followed by an open label extension (Study 2). In Study 1, 12 patients were randomized to receive weekly intravenous infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks. All 12 patients continued in Study 2 and received open-label EXONDYS 51 weekly for up to 208 weeks

In Study 1, 4 patients received placebo, 4 patients received EXONDYS 51 30 mg/kg, and 4 patients received EXONDYS 51 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6 patients received EXONDYS 51 30 mg/kg/week and 6 patients received EXONDYS 51 50 mg/kg/week [see Clinical Studies (14)].

Adverse reactions that occurred in 2 or more patients who received EXONDYS 51 and were more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50 mg/kg groups are pooled). Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended [see Dosage and Administration (2.1)].

The most common adverse reactions were balance disorder and vomiting.

Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week¹ EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1)

1 50 mg/kg/week = 1.7 times the recommended dosage
Adverse Reactions	EXONDYS 51 (N=8)	Placebo (N=4)
	%	%
Balance disorder	38	0
Vomiting	38	0
Contact dermatitis	25	0

Adverse Reactions from Observational Clinical Studies

The following adverse reactions have been identified during observational studies that were conducted as part of the clinical development program and continued postapproval.

In open-label observational studies, 163 patients received at least one intravenous dose of EXONDYS 51, with doses ranging between 0.5 mg/kg (0.017 times the recommended dosage) and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 months to 19 years. Most (85%) patients were Caucasian.

The most common adverse reactions seen in greater than 10% of the study population were headache, cough, rash, and vomiting.

Hypersensitivity reactions have occurred in patients treated with EXONDYS 51 [see Warnings and Precautions (5.1)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of EXONDYS 51. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing adverse reactions that occurred during infusion include bronchospasm, cyanosis of the lips, and malaise. The following adverse reactions have also been reported in patients receiving EXONDYS 51: pyrexia, flushing, protein urine present, and dehydration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no human or animal data available to assess the use of EXONDYS 51 during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4% and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

There are no human or animal data to assess the effect of EXONDYS 51 on milk production, the presence of eteplirsen in milk, or the effects of EXONDYS 51 on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXONDYS 51 and any potential adverse effects on the breastfed infant from EXONDYS 51 or from the underlying maternal condition.

8.4 Pediatric Use

EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping, including pediatric patients [see Clinical Studies (14)].

Intravenous administration of eteplirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once weekly for 10 weeks beginning on postnatal day 14 resulted in renal tubular necrosis at the highest dose tested and decreased bone densitometry parameters (mineral density, mineral content, area) at all doses. The kidney findings were associated with clinical pathology changes (increased serum urea nitrogen and creatinine, decreased urine creatinine clearance). No effects were observed on the male reproductive system, neurobehavioral development, or immune function. An overall no-effect dose was not identified. Plasma eteplirsen exposure (AUC) at the lowest dose tested (100 mg/kg) was similar to that in humans at the recommended human dose (30 mg/kg).

8.5 Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with EXONDYS 51.

8.6 Patients with Renal Impairment

Renal clearance of eteplirsen is reduced in non-DMD adults with renal impairment based on estimated creatinine clearance [see Clinical Pharmacology (12.3)]. However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment.

10 OVERDOSAGE

There is no experience with overdose of EXONDYS 51.

11 DESCRIPTION

EXONDYS 51 (eteplirsen) injection is a sterile, aqueous, preservative-free, concentrated solution for dilution prior to intravenous administration. EXONDYS 51 is clear and colorless, and may have some opalescence, and may contain trace amounts of small, white to off-white amorphous particles. EXONDYS 51 is supplied in single dose vials containing 100 mg or 500 mg eteplirsen (50 mg/mL). EXONDYS 51 is formulated as an isotonic, phosphate buffered saline solution with an osmolality of 260 to 320 mOsm and a pH of 7.5. Each milliliter of EXONDYS 51 contains 50 mg eteplirsen; 0.2 mg potassium chloride, 0.2 mg potassium phosphate monobasic, 8 mg sodium chloride, and 1.14 mg sodium phosphate dibasic, anhydrous, in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust pH.

Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Eteplirsen contains 30 linked subunits. The molecular formula of eteplirsen is C₃₆₄ H₅₆₉ N₁₇₇ O₁₂₂ P₃₀ and the molecular weight is 10305.7 daltons.

The structure and base sequence of eteplirsen are:

2.1 Dosing Information

The recommended dose of EXONDYS 51 is 30 milligrams per kilogram administered once weekly as a 35 to 60 minute intravenous infusion via an in-line 0.2 micron filter.

If a dose of EXONDYS 51 is missed, it may be administered as soon as possible after the scheduled time.

2.2 Preparation Instructions

EXONDYS 51 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique.

• Calculate the total dose of EXONDYS 51 to be administered based on the patient’s weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of EXONDYS 51 needed and the correct number of vials to supply the full calculated dose.
• Allow vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake.
• Visually inspect each vial of EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence, and may contain trace amounts of small, white to off-white amorphous particles. Do not use if the solution in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
• With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the calculated volume of EXONDYS 51 from the appropriate number of vials.
• Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
• Administer the diluted solution via an in-line 0.2 micron filter.
• EXONDYS 51 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted EXONDYS 51 solution within 4 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51.

2.3 Administration Instructions

Application of a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered.

EXONDYS 51 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion.

Infuse the diluted EXONDYS 51 solution over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line.

If a hypersensitivity reaction occurs, consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].