Kygevvi · 4.3 Contraindications · 1

HOS-287789 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The frequencies of adverse reactions are based on pooled data from clinical studies (MT-1621-101 and TK0102) in 50 patients, who were exposed to KYGEVVI during a median of 78.2 months (min 4, max 157), with a median maintenance dose of 387.2 mg/kg/day of doxecitine and 387.2 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 7 (<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. Of 133 events of diarrhoea, 12% (16/133) required dose reduction with a median duration of 80 days (Q1, Q3=33.0, 201.5). 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.

HOS-287785 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to any of the excipients listed in section 6.1.

HOS-287784 · has-indication-information · PDF-Seite 2

KYGEVVI is indicated for the treatment of paediatric and adult patients with genetically confirmed thymidine kinase 2 deficiency (TK2d) with an age of symptom onset on or before 12 years.

HOS-287787 · has-interaction-information · PDF-Seite 7

No in vivo interaction studies have been performed in adult or paediatric patients. Certain cytotoxic and antiviral medicines (eg, cedazuridine, cisplatin, tipiracil, brivudine, stavudine, ribavarin, fludarabine) may interact with doxecitine and doxribtimine by affecting enzymes that metabolize doxecitine or doxribtimine, or nucleoside transporters. These interactions have not been observed in patients with TK2d treated with doxecitine and doxribtimine; their clinical significance is unknown.

HOS-287788 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are limited data on the use of doxecitine and doxribtimine in pregnant women. Endogenous pyrimidine nucleosides are transported across the placenta by placental nucleoside transporters to help meet the foetal requirements for nucleosides. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The use of KYGEVVI when planning for and during pregnancy may be considered if the clinical benefit outweighs the risk. Breast-feeding It is unknown whether doxecitine and doxribtimine is excreted in human milk, but endogenous pyrimidine nucleosides and nucleotides are present naturally in human milk. At therapeutic doses of KYGEVVI no effects on the breastfed newborns are anticipated. KYGEVVI can be used during breast-feeding. Fertility The effect of doxecitine and doxribtimine on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-287786 · has-warning-information · PDF-Seite 6

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. Diarrhoea is a TK2d-related symptom as well as a known undesirable effect of KYGEVVI (see section 4.8). Diarrhoea may be managed according to routine patient management, including anti- diarrhoeals. Based on the severity of the diarrhoea, the dose of KYGEVVI should either be reduced, or 6 temporarily withheld until diarrhoea improves or returns to baseline, and then resumed gradually (see section 4.2) to a tolerable dose level.