Dojolvi (Triheptanoin): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE DOJOLVI is indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). DOJOLVI is a medium-chain triglyceride indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).

Dosage and administration

Assess metabolic requirements by determining daily caloric intake (DCI) prior to calculating the dose of DOJOLVI. ( 2.1 ) For patients receiving another medium-chain triglyceride product, discontinue prior to the first dose of DOJOLVI. ( 2.3 ) 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 food/liquid or medical food/formula at mealtimes or with snacks. ( 2.2 ) See the full prescribing information for instructions on how to calculate the volume per dose; initiate and titrate the dosage to achieve the target; and prepare and administer DOJOLVI. ( 2.2 , 2.3 , 2.4 ) 2.1 Important Recommendations Prior to DOJOLVI Treatment 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. 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. 2.2 Recommended Dosage 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 administered by mixing thoroughly into semi-solid food/liquid or medical food/formula at mealtimes or with snacks. In order to reach a target daily dosage, patients may require an increase in their total fat intake. The neonatal population may require higher fat intake and therefore an increased amount of DOJOLVI. Consider current nutritional recommendations when dosing the neonatal population. 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. Image 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. 2.3 Dosage Initiation and Titration 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. 2.4 Preparation and Administration Instructions Administer DOJOLVI by mixing thoroughly with semi-solid food/liquid (oral administration) or medical food/formula (feeding tube administration). Do not administer DOJOLVI alone to avoid gastrointestinal upset and feeding tube degradation [see Adverse Reactions (6.1) ] . Prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of compatible materials such as stainless steel, glass, high density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane, and silicone. Do not prepare or administer DOJOLVI using containers, oral 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 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).

Dosage forms and strengths

Oral liquid: clear, colorless to light yellow liquid supplied in a 500 mL bottle containing 100% w/w of triheptanoin. Oral Liquid, 100% w/w of triheptanoin. ( 3 )

Contraindications

None. None.

Warnings and precautions

Feeding Tube Dysfunction : Regularly monitor the feeding tube to ensure proper functioning and integrity. ( 5.1 ) Intestinal Malabsorption in Patients with Pancreatic Insufficiency : Low or absent pancreatic enzymes may reduce absorption of DOJOLVI. Avoid administration of DOJOLVI in patients with pancreatic insufficiency. ( 5.2 ) 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 (2.4 ] . 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.

Side effects

Most common adverse reactions are (≥10%): abdominal pain, diarrhea, vomiting, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ultragenyx Pharmaceutical Inc. at 1-888-756-8657 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 79 patients with LC-FAOD exposed to DOJOLVI in two studies: one open-label 78-week study of DOJOLVI in 29 patients (Study 1) followed by an open-label extension study (Study 2). Twenty-four patients from Study 1 continued into Study 2. Patients ranged from 4 months to 63 years of age and the population was 52% male. Of the 79 patients, 87% were White, 5% were Black or African-American, 4% were Asian, and 4% other. The daily dosage of DOJOLVI ranged between 12% and 41% 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 1.3 g/kg/day for adult patients) for a mean duration of 23 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) [60%], diarrhea [44%], vomiting [44%], and nausea [14%]. 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.

Drug interactions

Pancreatic Lipase Inhibitors : Avoid co-administration due to potential for reduced clinical effect of DOJOLVI. ( 7.1 ) 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.

Use in specific populations

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. 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 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 maternal condition. 8.4 Pediatric Use The safety and effectiveness of DOJOLVI have been established in pediatric patients [see Adverse Reactions (6.1) , Clinical Studies (14) ]. 8.5 Geriatric Use Clinical studies of DOJOLVI did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

Pregnancy

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. 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 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.

Pediatric use

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

Geriatric use

8.5 Geriatric Use Clinical studies of DOJOLVI did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

Description

(triheptanoin) is a synthetic medium odd-chain (C7) triglyceride supplied as a colorless to light yellow clear oral liquid. The chemical name of triheptanoin is heptanoic acid, 1,1',1''-(1,2,3-propanetriyl) ester. The empirical formula is C 24 H 44 O 6 and its molecular weight is 428.6 g/mol. The chemical structure is: The caloric value of triheptanoin is 8.3 kcal/mL. The fat content is 0.96 g/mL. Chemical Structure

Mechanism of action

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.

How supplied

(triheptanoin) oral liquid is supplied in a glass bottle as follows: 500 mL bottle NDC 69794-050-50 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Do not freeze. DOJOLVI can be used for up to 9 months after opening but not beyond the expiration date on the bottle. Do not dose or store using materials made of polystyrene or polyvinyl chloride (PVC) containers [see Dosage and Administration (2.4) ] . Pharmacist : Dispense only in glass or HDPE bottles.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Do not freeze. DOJOLVI can be used for up to 9 months after opening but not beyond the expiration date on the bottle. Do not dose or store using materials made of polystyrene or polyvinyl chloride (PVC) containers [see Dosage and Administration (2.4) ] . Pharmacist : Dispense only in glass or HDPE bottles.

Patient information

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Preparation and Administration Instruct the patient or caregiver: To read the Instructions for Use for appropriate preparation and administration instructions on oral versus feeding tube administration. Before administration, to mix DOJOLVI thoroughly into semi-solid food/liquid (oral) or medical food/formula (feeding tube) at mealtimes or with snacks. To not prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of polystyrene or polyvinyl chloride (PVC) plastics. That if a dose is missed, to 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 [see Dosage and Administration (2.2) ] . Storage Instruct the patient or caregiver to store DOJOLVI at room temperature in the bottle in which it was dispensed [see How Supplied/Storage and Handling (16) ] . Feeding Tube Dysfunction Advise the patient or caregiver to regularly monitor the feeding tube for proper functioning and integrity and report to the healthcare provider if any issues are identified [see Warnings and Precautions (5.1) ]. Intestinal Malabsorption in Patients with Pancreatic Insufficiency Inform the patient or caregiver that pancreatic insufficiency may reduce the clinical effect of DOJOLVI. Any known pancreatic insufficiency should be reported to the healthcare provider [see Warnings and Precautions (5.2) ]. Pregnancy Advise a patient who is exposed to DOJOLVI during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage the patient to report the pregnancy to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657 [see Use in Specific Populations (8.1) ] .

Active ingredients

Triheptanoin in 1 product

Dojolvi NDC products (1)

NDC	Strength & form	Labeler	Type
69794-050	Triheptanoin .96 g/mL Liquid	Ultragenyx Pharmaceutical Inc.	NDA

Frequently asked questions

What is Dojolvi used for?

1 INDICATIONS AND USAGE DOJOLVI is indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). DOJOLVI is a medium-chain triglyceride indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty…

What are the side effects of Dojolvi?

Most common adverse reactions are (≥10%): abdominal pain, diarrhea, vomiting, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ultragenyx Pharmaceutical Inc. at 1-888-756-8657 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials… See the full label for the complete list.

Who makes Dojolvi?

Dojolvi is listed by 1 labeler in the FDA NDC directory, including Ultragenyx Pharmaceutical Inc..