Kygevvi Drug Information

KYGEVVI is indicated for the treatment of thymidine kinase 2 deficiency (TK2d) in adults and pediatric patients with an age of symptom onset on or before 12 years.

Important Recommendation Prior to KYGEVVI Treatment Initiation Obtain baseline liver transaminase (alanine aminotransferase and aspartate aminotransferase ) and total bilirubin levels in patients prior to treatment initiation with KYGEVVI.

Recommended Dosage

The recommended dosage of KYGEVVI is based on the patient's weight (Table 1). Titrate to the next dosage level based on tolerability after a minimum of 2 weeks at the current dosage level. After calculating the daily dose, use Table 2 to determine the required number of KYGEVVI packets, volume of water needed to reconstitute the powder from the packet(s), and individual volume that is administered 3 times a day.

Dosage and Administration Modifications and Monitoring Liver Test Abnormalities If signs or symptoms consistent with liver injury are observed, interrupt treatment with KYGEVVI until liver transaminase (ALT, AST) and total bilirubin levels have either returned to baseline or stabilized at a new baseline value. Consider re-starting KYGEVVI at the last tolerated dose and increase the dose based on tolerability. Consider permanently discontinuing KYGEVVI if signs or symptoms consistent with liver injury persist or worsen.

Monitor liver transaminases and total bilirubin levels yearly and as clinically indicated. Gastrointestinal Based on the severity of the diarrhea and/or vomiting, reduce the dose of KYGEVVI or interrupt treatment until diarrhea and/or vomiting improves or returns to baseline. For persistent or recurring diarrhea and/or vomiting, consider discontinuing KYGEVVI permanently.

Monitor for dehydration and treat promptly with electrolyte replacement.

Preparation and Administration Instructions Use Table 2 for preparation and administration information. Table 2: Recommended Dosage - Preparation and Dosing by Daily-Dose Range 0 administration kit provided separately to prepare and administer the prescribed dose. Refer to the Instructions for Use for full preparation and administration information on use of KYGEVVI with the ZX2000 administration kit.

Household devices such as measuring cups or spoons are not adequate measuring devices. KYGEVVI should be prepared and administered by adults only. Preparation Instructions Preparation of KYGEVVI with a liquid other than water has not been studied clinically and is not recommended.

Obtain the required number of KYGEVVI packets to prepare a one-day supply of solution each morning. Use 40 mL of water per packet. Pour the prescribed volume of room temperature water (between 20°C - 25°C or 68°F - 77°F) into the mixing bottle.

Add the powder from the required number of KYGEVVI packets into the mixing bottle. Screw the dosing cup tightly onto the mixing bottle and gently invert the mixing bottle back and forth at least 20 times. If powder remains, repeat until the powder dissolves.

The mixed solution may appear cloudy and have some residual powder (inactive ingredients) remaining at the bottom or top. Administration Instructions Oral Administration Before each administration, gently invert the tightly closed mixing bottle slowly back and forth at least 3 times. Use 1 of 2 methods (dosing cup or oral syringe) to administer KYGEVVI solution.

Choose the method based on the volume of solution to be administered per dose. Take KYGEVVI solution in 3 equally divided doses approximately 6 hours apart (plus or minus 2 hours) with food. Do not administer another dose if the dose is spit out or if a complete dose is not taken.

Take the next dose at the next scheduled time. Discard any remaining KYGEVVI solution 16 hours after reconstitution or after taking or giving the 3 doses, whichever comes first. Feeding Tube Administration KYGEVVI is compatible with most commonly available feeding tubes.

KYGEVVI is compatible with feeding tubes made with polyvinylchloride (PVC) free from DEHP (Phthalates), polyurethane (PUR), and silicone (SIL) material. Follow the instructions of the feeding tube manufacturer to administer KYGEVVI. Draw up the KYGEVVI solution using a syringe compatible with the feeding tube.

Administer the solution immediately through the feeding tube. Flush any residual solution in the syringe or feeding tube until no solution is left. To flush the tube, a single flushing step with a volume of water equivalent to the tube's priming volume is sufficient.

Storage Instructions for Prepared KYGEVVI Solution

Store reconstituted KYGEVVI solution at controlled room temperature between 20°C to 25°C (68°F to 77°F) or in the refrigerator between 2°C to 8°C (36°F to 46°F).

Missed Dose If a dose is missed, take the missed dose as soon as possible but do not take within 2 hours of the next scheduled dose. In that case, skip the missed dose and resume the regular schedule. A double dose should not be taken to make up for the missed dose.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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. The safety of KYGEVVI was evaluated in a prospective, open-label, single-arm study in pediatric and adult patients with genetically confirmed TK2d previously treated with pyrimidine nucleosides (Trial 1). Additional safety information was derived from retrospective chart review studies (Study 1, Study 2) and from an expanded access program.

The adverse reactions which resulted in permanent discontinuation of KYGEVVI in >2% of patients were diarrhea (3%) and elevated liver enzymes (3%). In the expanded access program, diarrhea resulted in permanent discontinuation in 2 patients. Adverse reactions which required dose reduction in >2% of patients included diarrhea (21%) and abdominal pain (3%).

Diarrhea resulted in hospitalization in 2 pediatric patients (Study 1 and expanded access program). KYGEVVI is not approved for use in patients with an age of TK2d symptom onset > 12 years. The mean (SD) KYGEVVI or pyrimidine nucleosides exposure during Trial 1 was 6.6 years.

Table 3 summarizes the adverse reactions reported in ≥ 5% patients treated with KYGEVVI or pyrimidine nucleosides. Table 3: Adverse Reactions That Occurred in ≥5% Adult and Pediatric Patients with TK2d Treated with KYGEVVI or Pyrimidine Nucleosides (Trial 1), vomiting and elevated liver transaminases, were observed in a higher percentage of pediatric patients than in adult patients. Laboratory Adverse Reaction Elevated liver enzymes have been observed as a clinical manifestation of TK2d.

In Trial 1 and Study 1, elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) occurred in of patients respectively. In Trial 1, of all the patients who started treatment with elevated AST/ALT at baseline, 5% had last post-baseline ALT values that were higher severity than the baseline severity while continuing treatment.

Pregnancy Risk Summary There are no available data on KYGEVVI use during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Endogenous pyrimidine nucleosides are transported across the placenta. There are risks for adverse maternal and fetal outcomes during pregnancy with mitochondrial myopathies, including TK2 deficiency ( see Clinical Considerations ).

In animal reproduction studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal and fetal toxicities in the rabbit at dose exposures 1233 and 811 times the maximum recommended human dose (MRHD) of 400 mg/kg/day doxecitine and 400 mg/kg/day doxribtimine, respectively, based on plasma exposure, but were not observed in the rat ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Mitochondrial myopathies are associated with increased adverse perinatal outcomes, including preterm birth, pre-eclampsia and gestational diabetes. No maternal or embryofetal toxicity was observed up to 2000 mg/kg/day (1223 times and 425 times the MRHD of doxecitine and doxribtimine, respectively, based on plasma exposure).

Marked maternal toxicity and fetal malformations (dilated aorta with an associated narrow pulmonary trunk) were observed at the highest dose (1233 times and 811 times the MRHD of doxecitine and doxribtimine, respectively, based on plasma exposure).

Pediatric Use The safety and effectiveness of KYGEVVI for the treatment of thymidine kinase 2 deficiency (TK2d) have been established in pediatric patients with an age of symptom onset on or before 12 years. Use of KYGEVVI for this indication in this population is supported by evidence from two retrospective studies (Study 1, Study 2), one open-label study (Trial 1), and an expanded access program in which a total of 68 patients 0.7 years of age to less than 17 years of age were treated. In Trial 1, compared to adults, a higher percentage of pediatric patients experienced adverse reactions of vomiting and elevated liver transaminases.

Serious adverse reactions in the pediatric population included hospitalization due to diarrhea in two patients.