Kygevvi

KYGEVVI is intended for use with the instructions and supervision of specialist healthcare professionals experienced in the management of patients with mitochondrial disorders. Posology Dosing for KYGEVVI is based on weight of the patient; reassessment of weight should be performed by the prescribing physician.

KYGEVVI is titrated and dosed based on individual patient tolerability, up to a maximum recommended maintenance dose of 400 mg/kg/day of doxecitine and 400 mg/kg/day of doxribtimine. KYGEVVI should be administered every day in 3 equal doses with food.

Table 1:

KYGEVVI recommended dosing schedule1: Initial dosage 130 mg/kg/day of doxecitine and 130 mg/kg/day of doxribtimine Day 14 Intermediate Dosage 260 mg/kg/day of doxecitine and 260 mg/kg/day of doxribtimine Day 28 Maintenance Dosage 400 mg/kg/day of doxecitine and 400 mg/kg/day of doxribtimine 1For patients with moderate or severe renal impairment a slower titration (at least 4 weeks between each dose increase) should be used.

Tables 2, 3, 4 and 5 show the appropriate number of KYGEVVI powder sachets and required dilution volume by body weight for the recommended dosage levels. 3 Delayed or missed dose If a dose is missed, the dose should be taken as soon as possible.

However, if it is within 2 hours to the next dose, the dose should not be taken. The patient should take the next dose at the usual time. A double or extra dose should not be taken to make up for the missed dose. If a dose is spit out or if it is uncertain that all of the medicine was taken, another dose should not be taken.

Wait until the next scheduled dose. Special populations Elderly Specific pharmacokinetic evaluations in the elderly have not been performed. No dosage adjustment is recommended in elderly patients based on limited data in patients aged 65 years and older.

Renal impairment There is no experience with the use of doxecitine and doxribtimine in patients with TK2d with renal impairment. 73 m2) renal impairment. 2). 2) a slower titration (at least 4 weeks between each dose increase) should be used to allow for an assessment of the dose tolerability and to mitigate potential safety consequences of this high exposure to KYGEVVI.

Hepatic impairment There is limited experience with the use of doxecitine and doxribtimine in patients with hepatic impairment. 4). Insufficient data are available to provide a dose adjustment recommendation in patients with moderate or severe hepatic impairment.

2 mg/kg/day of doxribtimine (min 170; max 400). The most commonly reported adverse reactions were diarrhoea (86%), vomiting (28%), abdominal pain (including abdominal pain upper) (26%). Tabulated list of adverse reactions Adverse reactions (ADRs) from clinical studies are classified by MedDRA System Organ Class and Preferred Term and frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare 8 (<1/10 000).

The low prevalence of TK2d and the small size of the medicinal product safety database do not allow for detecting adverse reactions that are classified as rare or very rare.

Table 6:

Tabulated list of adverse reactions System organ class Frequency Adverse reaction Gastrointestinal disorders Very common Diarrhoea, Vomiting, Abdominal pain (including abdominal pain upper) Description of selected adverse reactions Gastrointestinal disturbances Gastrointestinal disturbances such as diarrhoea, vomiting, and abdominal pain (including abdominal pain upper) are very commonly reported adverse reactions with doxecitine and doxribtimine treatment.

In the pooled safety population 37 out of 50 participants (74%) experienced diarrhoea early after treatment initiation (<3 months). The majority of events of diarrhoea were mild to moderate in severity, and were generally self-limiting or improved with temporary dose reduction.

5). None of the 50 participants discontinued due to gastrointestinal disturbances, including diarrhoea. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Elevated liver enzymes and liver dysfunction/failure have been observed as a clinical manifestation of TK2d. In clinical studies elevations in alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] have occurred in patients with TK2d following treatment with KYGEVVI.

Transaminase levels should be checked prior to initiation of treatment, and changes in liver function monitored periodically during treatment with KYGEVVI and according to routine patient management. 8). Diarrhoea may be managed according to routine patient management, including anti- diarrhoeals.

2) to a tolerable dose level.

1.