Triheptanoin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Triheptanoin is a source of heptanoate fatty acids that is FDA approved for the treatment of of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).. Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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).
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triheptanoin in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triheptanoin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Triheptanoin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triheptanoin in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triheptanoin in pediatric patients.
Contraindications
None
Warnings
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). Regularly monitor the feeding tube to ensure proper functioning and integrity.
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.
Adverse Reactions
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 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.
Postmarketing Experience
There is limited information regarding Triheptanoin Postmarketing Experience in the drug label.
Drug Interactions
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. Avoid co-administration of DOJOLVI with pancreatic lipase inhibitors.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Triheptanoin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triheptanoin in women who are pregnant.
Labor and Delivery
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.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of DOJOLVI have been established in pediatric patients
Geriatic 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.
Gender
There is no FDA guidance on the use of Triheptanoin with respect to specific gender populations.
Race
There is no FDA guidance on the use of Triheptanoin with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Triheptanoin in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Triheptanoin in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triheptanoin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Triheptanoin in patients who are immunocompromised.
Administration and Monitoring
Administration
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.
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 the 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.
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.
Monitoring
- 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.
- Regularly monitor the containers, dosing components, or utensils that are in contact with DOJOLVI to ensure proper functioning and integrity.
IV Compatibility
There is limited information regarding the compatibility of Triheptanoin and IV administrations.
Overdosage
There is limited information regarding Triheptanoin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Triheptanoin Pharmacology in the drug label.
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.
Structure
There is limited information regarding Triheptanoin Structure in the drug label.
Pharmacodynamics
No formal pharmacodynamic studies have been conducted with DOJOLVI.
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.
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.
Nonclinical Toxicology
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.
Clinical Studies
The efficacy of triheptanoin as a source of calories and fatty acids was evaluated in Study 3 (NCT01379625), a 4-month double-blind randomized controlled study comparing triheptanoin (7-carbon chain fatty acid) with trioctanoin (8-carbon chain fatty acid). The study enrolled 32 adult and pediatric patients with a confirmed diagnosis of LC-FAOD and evidence of at least one significant episode of rhabdomyolysis and at least two of the following diagnostic criteria: disease specific elevation of acylcarnitines on a newborn blood spot or in plasma, low enzyme activity in cultured fibroblasts, or one or more known pathogenic mutations in CPT2, ACADVL, HADHA, or HADHB.
The dosage of study drug was titrated to a protocol-specified target of 20% DCI (actual mean daily dose achieved was 16% for triheptanoin and 14% for trioctanoin). The recommended target dosage of DOJOLVI is up to 35% of DCI. Patients ranged in age from 7 years to 64 years (median 24 years) and 12 were male. Of the 32 patients, 100% were White and 3% were Hispanic.
Baseline cardiovascular function in both groups was normal and within test/retest variability normally observed in repeated echocardiograms. After 4 months, patients in both groups had similar mean changes from baseline in left ventricular ejection fraction and wall mass on resting echocardiogram and similar maximal heart rates on treadmill ergometry.
Five patients experienced 7 events of rhabdomyolysis in the triheptanoin group and 4 patients experienced 7 events of rhabdomyolysis in the trioctanoin group.
No differences were observed between triheptanoin and trioctanoin groups in blood markers of metabolism including glucose, insulin, lactate, total serum, ketones, acylcarnitines, and serum-free fatty acid concentrations.
How Supplied
500 mL bottle
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
Images
Drug Images
{{#ask: Page Name::Triheptanoin |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
{{#ask: Label Page::Triheptanoin |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Advise the patient and/or caregiver to read the FDA-approved patient labeling.
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. Storage
Instruct the patient or caregiver to store DOJOLVI at room temperature in the bottle in which it was dispensed.
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.
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
Precautions with Alcohol
Alcohol-Triheptanoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Dojolvi
Look-Alike Drug Names
There is limited information regarding Triheptanoin Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.