2.1 Recommended Dosage

Assess the metabolic requirements of the patient by determining their daily caloric intake (DCI) prior to calculating the dose of DOJOLVI.

For patients receiving another medium-chain triglyceride (MCT) product, discontinue prior to the first dose of DOJOLVI.

The recommended target daily dosage of DOJOLVI is up to 35% of the patient's total prescribed DCI divided into at least four doses and mixed thoroughly into semi-solid foods and liquids at mealtimes or with snacks.

In order to reach a target daily dosage, patients may require an increase in their total fat intake. All patients treated with DOJOLVI should be under the care of a clinical specialist knowledgeable in appropriate disease-related dietary management based upon current nutritional recommendations.

The neonatal population may require higher fat intake and therefore an increased amount of DOJOLVI. Current nutritional recommendations should be considered when dosing the neonatal population.

The total daily dosage is converted to a volume of DOJOLVI to be administered in mL using the following calculation:

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

2.2 Dosage Initiation and Titration

For patients not currently taking a 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 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

If a patient has difficulty tolerating 1/4 of the total daily dosage at one time, more frequent smaller doses may be considered [see Adverse Reactions (6.1)].

Monitor patients' total caloric intake during dosage titration, especially in patients 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.

2.3 Preparation and Administration Instructions

Administer DOJOLVI mixed thoroughly with semi-solid foods or liquids either orally or via a silicone or polyurethane feeding tube. Do not administer DOJOLVI undiluted to avoid gastrointestinal upset and feeding tube degradation.

Prepare or administer DOJOLVI using containers, dosing syringes or measuring cups made of compatible materials such as stainless steel, glass, high density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane and silicone.

DOJOLVI is not compatible with certain plastics. Do not prepare or administer DOJOLVI using containers, dosing syringes or measuring cups made of polystyrene or polyvinyl chloride (PVC) plastics.

Regularly monitor the containers, dosing components or utensils that are in contact with DOJOLVI to ensure proper functioning and integrity.

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 into the following semi-solid foods and liquids:
  ○ 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, baby food, etc.
  
• 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.

Feeding Tube Preparation and Administration

Mix DOJOLVI with medical food or formula prior to administering via feeding tube, y-connector, or feeding tube extension set made of silicone or polyurethane. Do not administer DOJOLVI undiluted to avoid gastrointestinal upset and feeding tube degradation. DOJOLVI is administered as a bolus medication. Do not add DOJOLVI to the feeding bag, as the feeding equipment may degrade over time.

DOJOLVI can be administered via 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)].

Preparation and Administration Instructions

• 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 feeding port.
  
• Push the syringe contents into the feeding tube feeding 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 portion of the DOJOLVI mixture. Do not save for later use.
  

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.

5.1 Feeding Tube Dysfunction

Feeding tube performance and functionality can degrade over time depending on usage and environmental conditions. In clinical trials, feeding tube dysfunction was reported in patients receiving triheptanoin. The contribution of DOJOLVI cannot be ruled out. Do not administer DOJOLVI in feeding tubes manufactured of polyvinyl chloride (PVC) [see Dosage and Administration (2.3)]. Regularly monitor the feeding tube to ensure proper functioning and integrity.

5.2. Intestinal Malabsorption in Patients with Pancreatic Insufficiency

Pancreatic enzymes hydrolyze triheptanoin and release heptanoate as medium-chain fatty acids in the small intestine. Low or absent pancreatic enzymes may result in reduced absorption of heptanoate subsequently leading to insufficient supplementation of medium-chain fatty acids. Avoid administration of DOJOLVI in patients with pancreatic insufficiency.

6.1 Clinical Trial 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 population included 99 patients with LC-FAOD exposed to DOJOLVI in two studies: one open-label 78-week study of DOJOLVI in 29 patients (Study 1; NCT01886378) followed by an open-label extension study (Study 2; NCT02214160). Twenty-four patients from Study 1 continued into Study 2. Patients ranged from 4 months to 63 years of age and the population was 53% male. Of the 99 patients, 87% were white, 4% were black or African-American, 4% were Asian and 5% other. The daily dosage of DOJOLVI ranged between 8% and 49% DCI (which corresponds to 0.7 g/kg/day to 6.0 g/kg/day for pediatric patients and 0.5 g/kg/day to 1.6 g/kg/day for adult patients) for a mean duration of 44 months.

The most common adverse reactions to DOJOLVI reported in the pooled safety population of Study 1 and Study 2 were gastrointestinal (GI)-related, and included abdominal pain (abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper, GI pain) [58%], diarrhea [53%], vomiting [47%], and nausea [20%].

Gastrointestinal (GI) Adverse Reactions

In Study 1 and Study 2, median time to onset of a first occurrence of a GI adverse reaction was 3.1 weeks. GI adverse reactions led to dose reductions in 35% and 17% of patients in Study 1 and Study 2, respectively.

In Study 3 (NCT01379625), 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.

7.1 Pancreatic Lipase Inhibitors

Co-administration of triheptanoin with a pancreatic lipase inhibitor (e.g., orlistat) may reduce exposure to the triheptanoin metabolite, heptanoate, and reduce the clinical effect of triheptanoin [see Clinical Pharmacology (12.3)]. Avoid co-administration of DOJOLVI with pancreatic lipase inhibitors.

8.1 Pregnancy

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.

Advise women to report pregnancies to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657.

The estimated 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

Animal Data

Embryofetal developmental studies have been conducted with triheptanoin in rats and rabbits following oral administration of 10% (3.2 g/kg), 30% (9.7 g/kg) and 50% (16 g/kg) DCI in rats and 10% (1.2 g/kg), 20% (2.3 g/kg) and 30% (3.5 g/kg) DCI in rabbits during the period of organogenesis. Reduced body weight gain, associated with decreased food consumption, was observed in pregnant rats and rabbits following administration of triheptanoin food mixture and was attributed to taste aversion. The NOAEL for this maternal toxicity (lack of body weight gain) was 10% DCI for both rats and rabbits. Administration of dietary triheptanoin to pregnant rats at doses approximately 2 times above, and pregnant rabbits approximately equal to the targeted clinical dose of 35% DCI resulted in increased incidence of skeletal malformations and decreased litter weights in both species and reduced number of viable litters in rabbits. The adverse effects on rat and rabbit embryofetal development were associated with the reduced body weight gain observed in pregnant animals. The NOAEL for embryofetal development toxicity was 30% and 20% DCI for rats and rabbits, respectively. In a pre- and postnatal developmental study in rats, reduced birthweights and delayed sexual maturation in pups were observed at 50% DCI and were considered secondary to the reductions in body weight gain in pregnant rats.

8.2 Lactation

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 condition.

8.4 Pediatric Use

The safety and effectiveness of DOJOLVI have been established in pediatric patients aged birth and older [see Adverse Reactions (6.1), Clinical Studies (14)].

8.5 Geriatric Use

Clinical studies of DOJOLVI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

12.1 Mechanism of Action

Triheptanoin is a medium-chain triglyceride consisting of three odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the long-chain FAOD enzyme deficiencies for energy production and replacement.

12.2 Pharmacodynamics

No formal pharmacodynamic studies have been conducted with DOJOLVI.

12.3 Pharmacokinetics

Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. The exposure of triheptanoin in the human plasma is minimal. Pharmacokinetics of heptanoate exhibits high inter-patient variability. Heptanoate exposure increases greater than dose-proportional in the dose range between triheptanoin 0.3 and 0.4 g/kg.

Absorption

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

* After oral administration of DOJOLVI, more than one peak concentration of heptanoate is observed.

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.

Metabolism

Heptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver.

Excretion

After single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine.

Drug Interaction Studies

In Vitro Studies

Heptanoate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Heptanoate and BHP are not CYP substrates nor UGT substrates. Heptanoate increases the unbound fraction of valproic acid by approximately 2-fold.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.