Total Daily Dosage Calculation

The target daily dosage from DOJOLVI (%) is converted to a volume of DOJOLVI (mL) to be administered using the following calculation:

• Caloric value of DOJOLVI = 8.3 kcal/mL
• Round the total daily dosage to the nearest whole milliliter.
• Divide the total daily dosage into at least four approximately equal individual doses.

Missed Doses

If a dose is missed, take the next dose as soon as possible with subsequent doses taken at 3 to 4-hour intervals. Skip the missed dose if it will not be possible to take all doses in a day.

For patients not currently taking an MCT product

Initiate DOJOLVI at a total daily dosage of approximately 10% DCI divided into at least four times per day. Increase to the recommended total daily dosage by approximately 5% DCI every 2 to 3 days until the target dosage of up to 35% DCI is achieved.

For patients switching from another MCT product

Discontinue use of MCT products before starting DOJOLVI.

Initiate DOJOLVI at the last tolerated daily dosage (mL) of MCT divided into at least four times per day. Increase the total daily dosage by approximately 5% DCI every 2 to 3 days until the target dosage of up to 35% DCI is achieved.

Tolerability

• Consider more frequent smaller doses if a patient has difficulty tolerating 1/4 of the total daily dosage at one time based on gastrointestinal adverse reactions [see Adverse Reactions (6.1)].
• Monitor the patient's total caloric intake during dosage titration, especially in a patient with gastrointestinal adverse reactions, and adjust all components of the diet as needed.
• If a patient experiences gastrointestinal adverse reaction(s), consider dosage reduction until the gastrointestinal symptoms resolve [see Adverse Reactions (6.1)].
• If a patient is unable to achieve the target daily dosage of up to 35% DCI during dosage titration, maintain the patient at the maximum tolerated dosage.

Oral Preparation and Administration

• Use an oral syringe or measuring cup made of compatible materials as listed above to withdraw the prescribed volume of DOJOLVI from the bottle.
• DOJOLVI can be mixed with soft food or liquid such as:
  • plain or artificially sweetened fat free yogurt
  • fat free milk, formula, or cottage cheese
  • whole grain hot cereal
  • fat free low carbohydrate pudding, smoothies, applesauce, or baby food
• Add the prescribed amount of DOJOLVI to a clean bowl, cup, or container, made of the compatible materials as listed above, which contains an appropriate amount of semi-solid food or liquid that takes into consideration the age, size, and fluid needs of the patient to ensure administration of the full dose.
• Mix DOJOLVI thoroughly into the food or liquid.
• Any unused mixture may be stored for up to 24 hours in refrigerated conditions.
• If not used within 24 hours, discard DOJOLVI mixture in the trash. Do not pour down the sink. Do not save for later.

Feeding Tube Preparation and Administration

DOJOLVI is administered as an oral or enteral bolus medication. Do not add DOJOLVI to the feeding bag, as the feeding equipment may degrade over time.

DOJOLVI can be administered via oral or enteral feeding tubes manufactured of silicone or polyurethane. Do not use feeding tubes manufactured of polyvinyl chloride (PVC). Feeding device performance and functionality can degrade over time depending on usage and environmental conditions. Regularly monitor the feeding tube to ensure proper functioning and integrity [see Warnings and Precautions (5.1)].

• Use an oral syringe or measuring cup made of compatible materials as listed above to withdraw the prescribed volume of DOJOLVI from the bottle.
• Add the prescribed amount of DOJOLVI to a clean bowl, cup, or container, made of compatible materials as listed above, which contains an amount of medical food or formula that takes into consideration the age, size, and fluid needs of the patient in order to ensure administration of the full dose.
• Mix DOJOLVI thoroughly into the medical food or formula prior to administering via feeding tube, y-connector, or feeding tube extension set made of silicone or polyurethane.
• Draw up the entire amount of the DOJOLVI mixture into a slip tip syringe.
• Remove the residual air from the syringe and connect the syringe directly into the feeding tube port.
• Push the syringe contents into the feeding tube port using steady pressure until empty.
• Flush the feeding tubes with between 5 mL to 30 mL of water. Flush volume should be modified based on specific patient needs and in cases of fluid restriction.
• Discard any unused DOJOLVI mixture in the trash. Do not pour down the sink. Do not save for later use.

Gastrointestinal (GI) Adverse Reactions

In Study 1 and Study 2, median time to onset of a first occurrence of a GI adverse reaction was 7.3 weeks. GI adverse reactions led to dose reductions in 35% and 12% of patients in Study 1 and Study 2, respectively.

In Study 3, a 4-month double-blind randomized controlled study, commonly reported adverse reactions with triheptanoin were similar to those reported in Study 1 and Study 2.

Risk Summary

There are no available data on triheptanoin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits administered triheptanoin during the period of organogenesis, the primary toxicological effect (reduced body weight gain) was considered to be specific to decreased food consumption related to taste aversion in animals, and therefore is not relevant to clinical use in the intended populations.

There is a pregnancy safety study for DOJOLVI. If a patient becomes pregnant while receiving DOJOLVI, healthcare providers should report DOJOLVI exposure by calling Ultragenyx Pharmaceutical Inc. at 1-888-756-8657.

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 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There are no data on the presence of triheptanoin or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Medium-chain triglycerides and other fatty acids are normal components of breastmilk and the composition of breastmilk varies within feedings, over stages of lactation, and between mothers and populations due to maternal factors including genetics, environment, and diet. The developmental and health benefits of breastfeeding should be considered along with the clinical need for DOJOLVI and any potential adverse effect on the breastfed infant from DOJOLVI or from the underlying maternal condition.

Absorption

The pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized in Table 1.

Distribution

The plasma protein binding of heptanoate is approximately 80% and is independent of total concentration.

Elimination

After a single dose of either 0.3 g/kg or 0.4 g/kg triheptanoin to healthy subjects, the mean apparent clearance (CL/F) of heptanoate was 6.05 and 4.31 L/hr/kg, respectively. Half-life (t1/2) of heptanoate could not be determined due to multiple peak concentrations of heptanoate observed.

Drug Interaction Studies

Carcinogenesis

Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug. In a published chronic 9-month dietary study conducted in rats, daily administration of triheptanoin at dose levels up to 1.14 g/kg was associated with atrophy or hyperplasia of the intestinal villa. In a chronic 9-month dietary study conducted in juvenile minipigs, treatment with triheptanoin at dose levels up to 10 g/kg was well tolerated with no changes in histopathology suggestive of any carcinogenic potential.

Published studies with structurally similar triglycerides (i.e., MCTs) were also evaluated. In a 2-year dietary study of rats fed tricaprylin (C8 MCT) at dose levels up to 9.5 g/kg (approximately 1.2 times the anticipated maximum clinical dose), there were increased incidences of pancreatic and forestomach hyperplasia and adenomas but not carcinomas. Chronic administration of a diet containing approximately 17% MCT was not shown to promote effects on colon tumor incidence in an azomethane-induced colon tumorigenicity rat model.

Mutagenesis

Triheptanoin was not genotoxic in a battery of genotoxicity tests including the in vitro bacterial reverse mutation in S. typhimurium and E. coli, in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes and the in vivo mammalian erythrocyte micronucleus test in rat bone marrow.

Impairment of Fertility

Triheptanoin had no effect on fertility or any other parameters of mating performance in rats exposed to repeat dietary administration at dose levels equivalent to up to 50% daily caloric intake (16 g/kg) that resulted in systemic drug exposure (AUC) of heptanoate approximately equal to the maximum recommended human dose.