Leaflet KYGEVVI 2g / 2g powder for oral solution

Product code:: W72211001
Quantity:: 30
Indicated for:: genetically confirmed thymidine kinase 2 (TK2) deficiency with symptom onset at or before 12 years of age, in children a
Route of administration:: oral
Substance:: doxecitine + doxribtimine (pyrimidine nucleoside substrate replacement therapy)
ATC: A16AX29 — Alimentary tract and metabolism | Other alimentary tract and metabolism products | Other alimentary tract and metabolism products | Various alimentary tract and metabolism products

Doxecitine + doxribtimine treats children and adults with genetically confirmed thymidine kinase 2 deficiency whose symptoms began at or before 12 years of age. The disease impairs energy production in muscles. These medicines provide mitochondrial DNA precursors and may improve motor function, although their mechanism in humans is not fully confirmed.

Dissolve the powder in water and take it orally in three equal daily doses with food. A specialist calculates the dose by body weight and increases it gradually according to tolerability. Use the recommended measuring devices, not household spoons. Administration through a feeding tube requires specific instructions.

Important side effects are diarrhoea, vomiting, abdominal pain and increased liver enzymes. Digestive fluid losses can cause dehydration and electrolyte imbalance, especially in children. Liver tests are needed before treatment and during follow-up; the doctor may reduce the dose or temporarily interrupt treatment.

Contact the doctor urgently for severe diarrhoea, repeated vomiting, reduced urination, unusual sleepiness, jaundice or dark urine. Report pregnancy, breastfeeding and kidney disease. Treatment does not cure the genetic defect or replace breathing support, nutritional care and rehabilitation. Benefit is assessed through changes in strength and movement.

General data about KYGEVVI 2g / 2g

Substance:: doxecitine + doxribtimine
Date of latest medicines list:: 01-10-2026
Product code:: W72211001
Strength:: 2g / 2g
Pharmaceutical form:: powder for oral solution
Quantity:: 30
Product type:: Original
Prescription status:: P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.

Marketing authorisation

Manufacturer:: CATALENT GERMANY SCHORNDORF GMBH - GERMANIA
Holder:: UCB PHARMA S.A. - BELGIA
Number:: 2013/2026/01
Shelf life:: 30 months

Official documents

EMA product information (SmPC and leaflet)

Added to database:: 15/04/2026

Warnings:

Take with food

Take this medicine with food.

General warning

Read the package leaflet before use.

Colitis / severe diarrhea

Seek medical advice if severe or persistent diarrhea occurs.

Hepatotoxicity

This medicine may affect the liver.

Additional monitoring

This medicine is subject to additional monitoring.

Requires periodic laboratory tests

Periodic laboratory tests may be required during treatment.

Breastfeeding warning

Use during breastfeeding only on medical advice.

Pregnancy warning

Use during pregnancy only on medical advice.

Pediatric warning

Use in children only as recommended in the leaflet or by a doctor.

Electrolyte disturbances

This medicine may change blood electrolyte levels.

Summary of product characteristics for KYGEVVI 2g / 2g powder for oral solution

Summary of product characteristics for KYGEVVI 2g/2g

1. NAME OF THE MEDICINAL PRODUCT

KYGEVVI 2 g/2 g powder for oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet contains 2 g of doxecitine and 2 g of doxribtimine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for oral solution.

White to off-white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

KYGEVVI is intended for use with the instructions and supervision of specialist healthcareprofessionals 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 performedby the prescribing physician.

KYGEVVI is titrated and dosed based on individual patient tolerability, up to a maximumrecommended 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 doxribtimine1For patients with moderate or severe renal impairment a slower titration (at least 4 weeks betweeneach dose increase) should be used.

Tables 2, 3, 4 and 5 show the appropriate number of KYGEVVI powder sachets and required dilutionvolume by body weight for the recommended dosage levels.

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 thenext dose, the dose should not be taken. The patient should take the next dose at the usual time. Adouble 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 betaken. Wait until the next scheduled dose.

Special populations
Elderly

Specific pharmacokinetic evaluations in the elderly have not been performed. No dosage adjustment isrecommended 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 renalimpairment. No dosage adjustment is recommended in patients with mild (estimated glomerularfiltration rate [eGFR] ≥60 and ≤90 ml/min/1.73 m2) renal impairment. Specific dosagerecommendations cannot be made in patients with moderate (eGFR ≥30 and ≤59 ml/min/1.73 m2) orsevere (eGFR ≥15 and ≤29 ml/min/1.73 m2) renal impairment (see section 5.2).

Due to the potential for high exposure in patients with moderate or severe renal impairment (seesection 5.2) a slower titration (at least 4 weeks between each dose increase) should be used to allowfor an assessment of the dose tolerability and to mitigate potential safety consequences of this highexposure to KYGEVVI.

Hepatic impairment

There is limited experience with the use of doxecitine and doxribtimine in patients with hepaticimpairment. No dosage adjustment is required in patients with mild hepatic impairment (National

Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG) criteria) (see section 4.4).

Insufficient data are available to provide a dose adjustment recommendation in patients with moderateor severe hepatic impairment.

Method of administration

KYGEVVI is for oral use.

The reconstituted oral solution should be taken with food 3 times a day in equally divided doses,approximately 6 hours ± 2 hours apart.

Table 2: Recommended initial dosage 130 mg/kg/day of doxecitine and 130 mg/kg/day ofdoxribtimine oral solution preparation and dosing based on body weight

Daily oral solution Individual dose volume (ml)preparation (administered 3 times per day)

Body weight (kg) Number of Watersachet(s) for volumereconstitutionb (ml)a3.0 - 3.4 1 40 2.53.5 - 3.9 34.0 - 4.4 3.54.5 - 4.9 45.0 - 5.9 4.56.0 - 6.9 5.57.0 - 7.9 68.0 - 8.9 79.0 - 10.4 810.5 - 11.9 1012.0 - 13.9 1114.0 - 15.9 1316.0 - 17.4 2 80 1417.5 - 18.9 1619.0 - 20.9 1721.0 - 24.9 2025.0 - 27.9 2228.0 - 31.9 2532.0 - 34.9 3 120 2835.0 - 37.9 3038.0 - 41.9 3542.0 - 47.9 4048.0 - 54.9 4 160 4555.0 - 61.9 5062.0 - 72.9 55c73.0 - 84.9 5 200 6585.0 - 92.9 6 240 7593.0 - 109.9 7 280 85110.0 - 120.0 8 320 100aVolume of water to reconstitute the powder for the preparation of one day's supply of reconstituted oralsolution.bThe number indicates the number of sachets needed for one day supply preparation of reconstituted oralsolution.cThe volume of each individual dose, when multiplied by three, may not match the indicated total daily watervolume, this is not an error. Final volume of the reconstituted oral solution will increase after the powder ofthe prescribed number of sachets is added to the water volume.

Table 3: Recommended day 14 intermediate dosage 260 mg/kg/day of doxecitine and260 mg/kg/day of doxribtimine oral solution preparation and dosing based on body weight

Daily oral solution Individual dose volume (ml)preparation (administered 3 times per day)

Body weight (kg) Number of Watersachet(s) for volumereconstitutionb (ml)a3.0 - 3.4 1 40 5.53.5 - 3.9 6.54.0 - 4.4 7.54.5 - 4.9 85.0 - 5.9 9.56.0 - 6.9 117.0 - 7.9 138.0 - 8.9 2 80 149.0 - 10.4 1710.5 - 11.9 1912.0 - 13.9 2214.0 - 15.9 2616.0 - 17.4 3 120 2917.5 - 18.9 3019.0 - 20.9 3521.0 - 24.9 4025.0 - 27.9 4 160 4528.0 - 31.9 5032.0 - 34.9 55c35.0 - 37.9 5 200 6538.0 - 41.9 70c42.0 - 47.9 6 240 7548.0 - 54.9 7 280 9055.0 - 61.9 8 320 10062.0 - 72.9 9 360 11573.0 - 84.9 10 400 135c85.0 - 92.9 11 440 155c93.0 - 109.9 13 520 175c110.0 - 120.0 15 600 200aVolume of water to reconstitute the powder for the preparation of one day's supply of reconstituted oralsolution.bThe number indicates the number of sachets needed for one day supply preparation of reconstituted oralsolution.cThe volume of each individual dose, when multiplied by three, may not match the indicated total daily watervolume, this is not an error. Final volume of the reconstituted oral solution will increase after the powder ofthe prescribed number of sachets is added to the water volume.

Table 4: Recommended day 28 maintenance dosage 400 mg/kg/day of doxecitine and400 mg/kg/day of doxribtimine oral solution preparation and dosing based on body weight

Daily oral solution preparation Individual dosea

Body weight (kg) Number of sachet(s) Water volume (ml) volume (ml)for reconstitutionb (administered 3 timesper day)3.0 - 3.4 1 40 93.5 - 3.9 104.0 - 4.9 125.0 - 5.9 2 80 156.0 - 6.9 177.0 - 7.9 208.0 - 8.9 229.0 - 10.4 2610.5 - 11.9 3 120 3012.0 - 13.9 3514.0 - 15.9 4016.0 - 17.4 4 160 4517.5 - 18.9 5019.0 - 20.9 55c21.0 - 24.9 5 200 6025.0 - 27.9 70c28.0 - 31.9 6 240 8032.0 - 34.9 7 280 9035.0 - 37.9 8 320 10038.0 - 41.9 110c42.0 - 47.9 9 360 12048.0 - 54.9 10 400 140c55.0 - 61.9 12 480 16062.0 - 72.9 13 520 180c73.0 - 85.0 15 600 210caVolume of water to reconstitute the powder for the preparation of one day's supply of reconstituted oralsolution.bThe number indicates the number of sachets needed for one day supply preparation of reconstituted oralsolution.cThe volume of each individual dose, when multiplied by three, may not match the indicated total daily watervolume, this is not an error. Final volume of the reconstituted oral solution will increase after the powder ofthe prescribed number of sachets is added to the water volume.

NOTE: There is very limited experience with patients weighing >85 kg. In case of a patient weighing>85.0 kg the total daily volume will exceed 640 ml and the individual dose of oral solution should beprepared three times per day instead of preparing the solution once per day.

When the individual dose volume exceeds 225 ml, it should be divided into two separate portionstaken immediately one after the other. The Administration device kit dosing cup must be used toaccurately measure and administer each portion.

Table 5: Recommended day 28 maintenance dosage of KYGEVVI oral solution preparationand dosing for patients weighing >85.0 kg

Number of sachet(s) Water volume (ml)a Individual dosefor reconstitutionb volume (ml)(administered 3 times

Body weight (kg) per day)85.1 - 92.9 6 240 23093.0 - 99.9 250c100.0 - 109.9 7 280 270110.0 - 120.0 8 320 300aVolume of water to reconstitute the powder for the preparation of reconstituted oral solution.bThe number indicates the number of sachets needed for preparation of reconstituted oral solution.cThe volume of each individual dose may not match the indicated total water volume, this is not an error.

Final volume of the reconstituted oral solution will increase after the powder of the prescribed number ofsachets is added to the water volume.

If the patient is unable to swallow, the prescribed dose of KYGEVVI can be administered via afeeding tube. Follow the instructions of the feeding tube to administer the medicine.

* Prepare the oral solution using the recommended Administration device kit.

* Dissolve the prescribed number of powder sachets with room temperature water.

 Use 40 ml of water per sachet. Do not mix with any other medicinal products, liquids, powders or foods.

* Make a one-day supply of oral solution each morning or for a total daily volume exceeding640 ml for patients weighing >85.0 kg, the solution should be prepared for each individual doseseparately. Pour the prescribed amount of water into the mixing bottle first. Then add the powderfrom the sachets. Close the mixing bottle with the dosing cup, and turn it upside down and back at least20 times to mix. After administration, store the mixing bottle at room temperature or in the refrigerator.

* Before each administration, turn the mixing bottle slowly upside down and back at least 3 times.

Any remainder after the third dose of the day is taken should be discarded.

For detailed instructions on reconstitution and administration of the medicinal product, see section 6.6.

4.3 Contraindications

Hypersensitivity to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 aspartateaminotransferase [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 functionmonitored periodically during treatment with KYGEVVI and according to routine patientmanagement.

Diarrhoea is a TK2d-related symptom as well as a known undesirable effect of KYGEVVI (seesection 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, ortemporarily withheld until diarrhoea improves or returns to baseline, and then resumed gradually (seesection 4.2) to a tolerable dose level.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data on the use of doxecitine and doxribtimine in pregnant women. Endogenouspyrimidine nucleosides are transported across the placenta by placental nucleoside transporters to helpmeet 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 clinicalbenefit outweighs the risk.

Breast-feeding

It is unknown whether doxecitine and doxribtimine is excreted in human milk, but endogenouspyrimidine 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 duringbreast-feeding.

Fertility

The effect of doxecitine and doxribtimine on human fertility has not been evaluated. Animal studiesdo not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Doxecitine and doxribtimine have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

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, max157), with a median maintenance dose of 387.2 mg/kg/day of doxecitine and 387.2 mg/kg/day ofdoxribtimine (min 170; max 400).

The most commonly reported adverse reactions were diarrhoea (86%), vomiting (28%), abdominalpain (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(<1/10 000). The low prevalence of TK2d and the small size of the medicinal product safety databasedo 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 abdominalpain 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 aftertreatment initiation (<3 months). The majority of events of diarrhoea were mild to moderate inseverity, and were generally self-limiting or improved with temporary dose reduction. Of 133 eventsof 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, includingdiarrhoea.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

There are no data on symptoms associated with an overdose.

Doses of 130 mg/kg/day of doxecitine and 130 mg/kg/day of doxribtimine titrated up to a maintenancedose of 400 mg/kg/day of doxecitine and 400 mg/kg/day of doxribtimine with an intermediate dose of260 mg/kg/day of doxecitine and 260 mg/kg/day of doxribtimine have been administered in 3 equaldaily doses in clinical studies without dose limiting toxicity.

In the event of overdose, it is recommended that the patients are monitored closely for any signs andsymptoms of adverse reactions and appropriate symptomatic treatment should be institutedimmediately.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX29

Mechanism of action

The primary mechanism of action of doxecitine and doxribtimine is the incorporation of nucleosidesdeoxycytidine (dC) and deoxythymidine (dT) into skeletal muscle mitochondrial deoxyribonucleicacid (DNA) to restore mitochondrial DNA copy number and improve skeletal muscle function inpatients with TK2d. Doxecitine and doxribtimine likely utilize residual TK2 activity as well ascytosolic phosphorylation pathways such as thymidine kinase 1 and deoxycytidine kinase to increasemitochondrial DNA precursors deoxycytidine triphosphate and deoxythymidine triphosphate in themitochondria.

Pharmacodynamic effects

No formal pharmacodynamic studies have been conducted with doxecitine and doxribtimine. Effectsof doxecitine and doxribtimine on cardiac electrophysiology have not been determined in a formalclinical trial because doxecitine and doxribtimine are chemically identical to ubiquitous endogenousnucleosides.

Clinical efficacy

Data from two clinical studies (MT-1621-101 and TK0102) were pooled to study the efficacy andsafety of doxecitine and doxribtimine in patients with genetically confirmed TK2d.

MT-1621-101, a retrospective chart review study, collected data on 38 treated paediatric and adultstudy participants with TK2d who were treated with pyrimidine nucleos(t)ides. TK0102 is an open-label, single arm clinical study in participants with TK2d previously treated with pyrimidinenucleos(t)ides. A total of 47 study participants enrolled in TK0102; 35 originated from MT-1621-101.

After enrolment in Study TK0102, study participants started treatment with (or switched to) doxecitineand doxribtimine.

Together, MT-1621-101 and TK0102 comprise 39 participants with an age of TK2d symptom onset≤12 years. A total of 26 patients (67%) were male; median age of TK2d symptom onset was1.89 years (Q1,Q3 = 1.2, 2.7) and the median duration of treatment was 91.4 months (Q1, Q3=80.2,117.8; all treated >5 years).

Developmental motor milestones, ventilatory support, and feeding support were compared pre- andpost-treatment.

Motor milestones

Pre- and posttreatment developmental motor milestone loss and regain for the MT-1621-101 +

TK0102 treated population subgroup with an age of TK2d symptom onset ≤12 years is summarized in

Table 7.

Table 7: Developmental motor milestones lost and regained, age of TK2d symptom onset≤12 years, MT-1621-101 + TK0102 evaluable population

LOST REGAINED

Before After treatment Before After treatmenttreatment start start (b) treatment start(c) start(d)(a)≥1 milestone abilities 32/39 (82.1%) 10/38 (26.3%) 1/32 (3.1%) 26/31 (83.9%)

Developmental motor milestone ability

Hold head upright, 16/39 (41.0%) 1/38 (2.6%) 0/16 15/17 (88.2%)unassisted

Sit upright, unassisted 13/38 (34.2%) 1/36 (2.8%) 0/13 10/14 (71.4%)

Stand, assisted 13/36 (36.1%) 3/31 (9.7%) 0/13 8/15 (53.3%)unassisted 14/34 (41.2%) 4/29 (13.8%) 0/14 7/15 (46.7%)

Walk, assisted 15/36 (41.7%) 3/30 (10.0%) 0/15 9/16 (56.3%)unassisted 15/34 (44.1%) 1/27 (3.7%) 0/15 6/16 (37.5%)

Climb stairs, assisted 18/31 (58.1%) 2/26 (7.7%) 0/18 9/19 (47.4%)unassisted 16/19 (84.2%) 0/20 0/16 6/16 (37.5%)

Run 17/21 (81.0%) 2/20 (10.0%) 1/17 (5.9%) 7/17 (41.2%)(a)For the pre-treatment summary, the denominator represents the number of participants that initiallyacquired a developmental motor milestone in the pre-treatment period.(b)For the post-treatment summary, the denominator represents the number of participants that initiallyacquired a developmental motor milestone pre-treatment and did not lose it pre-treatment or acquired adevelopmental motor milestone post-treatment.(c)The denominator represents the number of participants that initially acquired a developmental motormilestone and lost that milestone in the pre-treatment period.(d)The denominator represents the number of participants that lost a developmental motor milestone pre-treatment and did not regain it pre-treatment or lost a developmental milestone post-treatment.

Ventilatory and feeding support

In the MT-1621-101 + TK0102 treated population with an age of TK2d symptom onset ≤12 years,prior to treatment start, 18/39 (46%) participants initiated ventilatory support and no participantsdiscontinued ventilatory support. After initiation of treatment, 5/21 (24%) participants startedventilatory support while 5/23 (22%) discontinued ventilatory support.

With regard to feeding support, prior to treatment start, 12/39 (31%) participants had a feeding tube.

After initiation of treatment, 4/28 (14%) participants started feeding support, with 2 of theseparticipants subsequently discontinuing feeding support after initiation of treatment.

Exceptional circumstances

This medicinal product has been authorised under ‘exceptional circumstances’.

This means that due to the rarity of the disease it has not been possible to obtain complete informationon this medicinal product.

The European Medicines Agency will review any new information which may become available everyyear and the SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of doxecitine and doxribtimine have been studied in healthyvolunteers, in participants with moderate and severe renal impairment, and in paediatric and adultparticipants with TK2d.The pharmacokinetics of doxecitine and doxribtimine were characterized bymoderate to high intra- and inter-subject variability.

Absorption

The absolute oral bioavailability of doxecitine and doxribtimine in humans is not known, but isanticipated to be low (< 10%). After oral administration of doxecitine and doxribtimine, mean peakconcentrations (Cmax) of dC and dT are achieved within approximately 1.5 hours (Tmax) in the fastedstate. Systemic exposures (baseline-adjusted Cmax and AUC0-t) following increasing single oral dosesof doxecitine and doxribtimine (86.6 mg/kg, 173.4 mg/kg, and 266.6 mg/kg) in healthy volunteersincrease in a less than dose proportional manner for dC (geometric mean [%geoCV] AUC0-t values of13.49 [94.1], 23.23 [66.7], and 30.79 [76.5] ng*hr/ml, respectively) and in a more than doseproportional manner for dT (geometric mean [%geoCV] AUC0-t values of 12.56 [124.9], 31.71[126.6], and 91.15 [94.1] ng*hr/ml, respectively).

Administration of 266.6 mg/kg doxecitine and doxribtimine with a high-fat, high-calorie mealincreased baseline-adjusted Cmax and AUC0-t by 79% and 137%, respectively, for plasma dC, and by27% and 74%, respectively, for plasma dT compared with the fasted state, confirming a significantfood effect. The high fat and high-calorie meal tended to prolong the Tmax of dC and dT to medianvalues of 2.02 h for dC and 4.00 h for dT, respectively.

KYGEVVI should be taken with food to ensure higher bioavailability of doxecitine and doxribtimine,and to minimize PK variability due to inconsistent dosing in fed and fasted states.

Distribution

Plasma protein binding of doxecitine and doxribtimine is relatively weak (less than 10% bound).

Biotransformation

Deoxycytidine and dT are primarily degraded (catabolized) by cytidine deaminase and thymidinephosphorylase, respectively, to the nucleobases and the 2-deoxy-α-D-ribose 1-phosphate moiety.

Intermediate products of deoxycytidine catabolism are deoxyuridine, uracil and dihydrouracil with theend products β-alanine, ammonia, and CO2. Thymine, the pyrimidine nucleobase of deoxythymidine,is subsequently catabolized to dihydrothymine and ultimately to γ-amino-isobutyric acid and CO2.

Doxecitine and doxribtimine are not substrates of known CYP enzymes.

Elimination

Mass balance of dC and dT following oral administration of doxecitine and doxribtimine has not beendetermined. Hepatic and extrahepatic metabolism is considered to be the main pathway for clearanceof dC and dT at plasma concentrations relevant to the proposed dose range of doxecitine anddoxribtimine.

Urinary excretion of intact dC and dT is exceedingly low (<1% of dose) in healthy volunteersfollowing single oral administration of doxecitine and doxribtimine. However, taking into account theanticipated low oral bioavailability, renal elimination could be more pronounced. Renal elimination ofunchanged dC and dT is likely a minor pathway in the proposed dose range.

Special populations

Based on population pharmacokinetic analysis, age (range: 0.8 to 81 years), sex, and race were notsignificant covariates of variability in the pharmacokinetics of doxecitine and doxribtimine; age was asignificant covariate of the estimated baseline plasma concentrations of dT. No dose adjustments forage, sex or race are recommended.

Renal impairment

In a dedicated clinical study, renal impairment was associated with a substantial increase in systemicexposures (Cmax, AUC0-t) of dC and dT following a single oral administration of 266.6 mg/kgdoxecitine and doxribtimine (133.3 mg/kg doxecitine and 133.3 mg/kg doxribtimine) in adult non-

TK2d volunteers with moderate (eGFR between ≥30 and ≤59 ml/min/1.73 m2) or severe (eGFR ≥15and ≤29 ml/min/1.73 m2) renal impairment when compared with matched healthy volunteers withnormal renal function. Systemic exposures to dC and dT were characterized by high inter-subjectvariability. Baseline-adjusted plasma dC AUC0-t (geometric mean) was 122% (56.4 vs. 25.4 ng*hr/ml)and 66% (52.8 vs. 31.8 ng*hr/ml) higher in participants with moderate and severe renal impairment,respectively, compared with matched healthy study participant control groups. Baseline-adjustedplasma dT AUC0-t (geometric mean) was 447% (23.7 vs. 4.34 ng*hr/ml) and 148% (31.5 vs.12.7 ng*hr/ml) higher in participants with moderate and severe renal impairment, respectively,compared with healthy matched participants. Urinary excretion of intact dC and dT was low (<1% ofdose) in all groups. However, the absolute oral bioavailability is anticipated to be low and thereforethe influence of kidney function may be underestimated based on urinary excretion data alone.

Hepatic impairment

No specific study has been conducted to evaluate the pharmacokinetics of doxecitine and doxribtiminein hepatic impairment.

Paediatric population

Paediatric participants with TK2d in the clinical program were administered doxecitine anddoxribtimine with the same dosing regimen (based on body weight) as in adults. Systematicdifferences in exposures to dC and dT were not apparent between paediatric and adult participantswhen considering interindividual variability and limited number of participants. An impact ofmaturation processes in the metabolic pathways cannot be excluded.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction anddevelopment, and juvenile toxicity.

Increased incidence of distended aorta, narrow pulmonary trunk, misshapen sternebrae, incompletelyossified sternebrae, and incompletely ossified cervical centra were observed in the offspring of rabbits.

However, these malformations and skeletal variations were observed at exposures much in excess ofthe maximum human exposure and occurred only in foetuses born from dams with maternal toxicity.

Furthermore, no embryofoetal toxicity was found in rats. Therefore, these effects are considered oflittle relevance to clinical use.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Silica colloidal anhydrous (E551)

Magnesium stearate (E470b)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts, liquids, powders, or foods.

6.3 Shelf life

30 months.

After reconstitution

Do not store above 25°C. Can be stored in a refrigerator (2°C - 8°C). Do not freeze.

If not used within 16 hours, the oral solution should be discarded.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Laminated foil sachet made of PET/Alu/low density polyethylene.

Pack size of 30 sachets.

6.6 Special precautions for disposal and other handling

Preparation

* Prepare doxecitine and doxribtimine oral solution at room temperature.

* Use the mixing bottle and cup (the “dosing system”) provided in the Administration device kit.

* Dissolve the prescribed number of powder sachets with room temperature water.

 Each sachet contains 2 g of doxecitine and 2 g of doxribtimine. Use 40 ml of water per sachet.

* Once prepared, the oral solution should be ingested within 16 hours.

* Before each administration, turn the mixing bottle slowly upside down and back at least 3 times.

* Discard any remainder after the third dose of the day is taken.

Feeding tubes

KYGEVVI reconstituted oral solution is compatible with the most commonly available feeding tubes(polyurethane, polyvinyl chloride, silicone) from size 4 French and up, with a maximum length of125 cm. To flush the tube, a single flushing step with a volume of water equivalent to the tube’spriming volume is sufficient. Follow the instructions of the feeding tube to administer the medicine.

The reconstituted solution is opalescent and colourless and can have some powder residue at thebottom or top.

See Instructions for Use provided at the end of the Package Leaflet.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

7. MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/25/2013/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

10. DATE OF REVISION OF THE TEXT

DD/MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.

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