ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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 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; NCT01886378) followed by an open-label extension study (Study 2; NCT02214160). Twenty-four patients from Study continued into Study 2. Patients ranged from 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 mean duration of 23 months. The most common adverse reactions to DOJOLVI reported in the pooled safety population of Study and Study were gastrointestinal (GI)-related, and included abdominal pain (abdominal discomfort, abdominal pain, abdominal distension, abdominal pain upper, GI pain) [60%], diarrhea [44%], vomiting [44%], and nausea [14%]. Gastrointestinal (GI) Adverse ReactionsIn Study and Study 2, median time to onset of first occurrence of GI adverse reaction was 7.3 weeks. GI adverse reactions led to dose reductions in 35% and 12% of patients in Study and Study 2, respectively.In Study (NCT01379625), 4-month double-blind randomized controlled study, commonly reported adverse reactions with triheptanoin were similar to those reported in Study and Study 2.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Triheptanoin is medium-chain triglyceride consisting of three odd-chain 7-carbon length fatty acids (heptanoate) that provide 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.AbsorptionThe pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized in Table 1.Table 1: Summary of Pharmacokinetic Parameters of Heptanoate after Single and Multiple Oral Administration of DOJOLVI to Healthy Adults (N=13)DOJOLVI DoseMean (SD) Cmax (umol/L) Mean (SD) AUC0-8h (umolhr/L) Time to First Peak Concentration Median (range)(hours)Single 0.3 g/kg178.9 (145)336.5 (223)0.5 (0.4 to 1.0)Dose0.4 g/kg259.1 (134)569.1 (189)0.8 (0.4 to 6.4)Multiple Doses0.3 g/kg administered times day for days(total daily dosage of 1.3 g/kg/day) 319.9 (164)789.8 (346)1.2 (0.0 to 2.4) After oral administration of DOJOLVI, more than one peak concentration of heptanoate is observed.DistributionThe plasma protein binding of heptanoate is approximately 80% and is independent of total concentration.EliminationAfter 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.MetabolismHeptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver. ExcretionAfter single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine. Drug Interaction StudiesIn Vitro StudiesHeptanoate 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of triheptanoin as source of calories and fatty acids was evaluated in Study 3, 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 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 new born 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 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 [see Dosage and Administration 2.1 )]. Patients ranged in age from years to 64 years (median 24 years) and 12 were male.Baseline cardiovascular function in both groups was normal and within test/retest variability normally observed in repeated echocardiograms. After 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 events of rhabdomyolysis in the triheptanoin group and patients experienced 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION DOJOLVI (triheptanoin) is synthetic medium odd-chain (C7) triglyceride supplied as 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 C24H44O6 and its molecular weight is 428.6 g/mol. The chemical structure is: The caloric value of triheptanoin is 8.3 kcal/mL.. The chemical structure of triheptanoin.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Assess metabolic requirements by determining daily caloric intake (DCI) prior to calculating the dosage of DOJOLVI. (2.1) For patients receiving another medium-chain triglyceride product, discontinue prior to the first dose of DOJOLVI. (2.1) The recommended target daily dosage of DOJOLVI is up to 35% of the patients total prescribed DCI divided into at least four doses and administered orally diluted with foods, liquids, or formula via silicone or polyurethane feeding tube. (2.1, 2.3) 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. (2.1, 2.2, 2.3). Assess metabolic requirements by determining daily caloric intake (DCI) prior to calculating the dosage of DOJOLVI. (2.1) For patients receiving another medium-chain triglyceride product, discontinue prior to the first dose of DOJOLVI. (2.1) The recommended target daily dosage of DOJOLVI is up to 35% of the patients total prescribed DCI divided into at least four doses and administered orally diluted with foods, liquids, or formula via silicone or polyurethane feeding tube. (2.1, 2.3) 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. (2.1, 2.2, 2.3). Daily dose calculation.. 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 patients total prescribed DCI divided into at least four doses and administered at mealtimes or with snacks. In order to reach target daily dosage, patients may require an increase in their total fat intake. All patients treated with DOJOLVI should be under the care of 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 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.. 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 MCT productInitiate DOJOLVI at total daily dosage of approximately 10% DCI divided into at least four times per day and increase to the recommended total daily dosage of up to 35% DCI over period of to weeks. For patients switching from another MCT productDiscontinue 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 to days until the target dosage of up to 35% DCI is achieved. TolerabilityIf 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 patient experiences gastrointestinal adverse reaction(s), consider dosage reduction until the gastrointestinal symptoms resolve [see Adverse Reactions 6.1 )]. If 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 with semi-solid food or liquids orally or enterally via silicone or polyurethane feeding tube. Do not administer DOJOLVI alone to avoid gastrointestinal upset. 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 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 average consumption of the patient in order to ensure administration of the full dose. Mix DOJOLVI thoroughly into the food or liquid. The mixture may be stored for up to 24 hours in refrigerated conditions. Feeding Tube Preparation and Administration 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 )].Preparation and Administration InstructionsUse 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 clean bowl, cup or container, made of compatible materials as listed above, which contains an amount of formula that takes into consideration the age, size and average consumption of the patient in order to ensure administration of the full dose. Mix DOJOLVI thoroughly into the formula. Draw up the entire amount of the DOJOLVI-formula mixture into 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 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-formula mixture. Do not save for later use. Administer DOJOLVI over 15 to 20 minutes for patients receiving bolus delivery of enteral feeds. For patients receiving continuous feeds, administer DOJOLVI over 30 to 60 minutes alternating with formula alone.Missed DosesIf dose is missed, take the next dose as soon as possible with subsequent doses taken at to 4-hour intervals. Skip the missed dose if it will not be possible to take all four doses in day. 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 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 average consumption of the patient in order to ensure administration of the full dose. Mix DOJOLVI thoroughly into the food or liquid. The mixture may be stored for up to 24 hours in refrigerated conditions. 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 clean bowl, cup or container, made of compatible materials as listed above, which contains an amount of formula that takes into consideration the age, size and average consumption of the patient in order to ensure administration of the full dose. Mix DOJOLVI thoroughly into the formula. Draw up the entire amount of the DOJOLVI-formula mixture into 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 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-formula mixture. Do not save for later use. Administer DOJOLVI over 15 to 20 minutes for patients receiving bolus delivery of enteral feeds. For patients receiving continuous feeds, administer DOJOLVI over 30 to 60 minutes alternating with formula alone.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Oral liquid: clear, colorless to light yellow liquid supplied in 500 mL bottles containing 100% w/w of triheptanoin.. Oral Liquid, 100% w/w of triheptanoin. (3).

DRUG INTERACTIONS SECTION.

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

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. DOJOLVI (triheptanoin) oral liquid is supplied in glass bottles as follows:500 mL bottleNDC 69794-050-50Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) (see USP Controlled Room Temperature). Do not freeze. Opened bottles of DOJOLVI can be used for up to 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 2.3 )]. Pharmacist: Dispense only in Glass or HDPE bottles.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).Preparation and AdministrationInstruct the patient or caregiver:To read the instructions in the Patient Package Insert on appropriate preparation and administration techniques for oral administration or via feeding tube. To mix DOJOLVI thoroughly into semi-solid foods, liquids, or formula. That DOJOLVI is not compatible with certain plastics. Do not prepare or administer DOJOLVI using containers or utensils made of polystyrene or polyvinyl chloride (PVC) plastics. That if dose is missed, to take the next dose as soon as possible with subsequent doses taken at to 4-hour intervals. Skip the missed dose if it will not be possible to take all four doses in day [see Dosage and Administration 2.3 )]. StorageInstruct 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 DysfunctionAdvise the patient or caregiver to regularly inspect 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 InsufficiencyInform 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 )] PregnancyAdvise patients that there is pregnancy safety study that collects pregnancy outcome data in women taking DOJOLVI during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657. Manufactured for: Ultragenyx Pharmaceutical Inc. 60 Leveroni CourtNovato, CA 94949. To read the instructions in the Patient Package Insert on appropriate preparation and administration techniques for oral administration or via feeding tube. To mix DOJOLVI thoroughly into semi-solid foods, liquids, or formula. That DOJOLVI is not compatible with certain plastics. Do not prepare or administer DOJOLVI using containers or utensils made of polystyrene or polyvinyl chloride (PVC) plastics. That if dose is missed, to take the next dose as soon as possible with subsequent doses taken at to 4-hour intervals. Skip the missed dose if it will not be possible to take all four doses in day [see Dosage and Administration 2.3 )].

INSTRUCTIONS FOR USE SECTION.

Instructions for UseDOJOLVI (doh-johl-vee)(triheptanoin)Oral LiquidRead this Instructions for Use before you start taking DOJOLVI and each time you get refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.Important information about DOJOLVI:Use an oral syringe or measuring cup to measure your prescribed dose. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose. Mix or give DOJOLVI using containers, dosing syringes or measuring cups made of materials such as stainless steel, glass, or high-density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane and silicone (types of plastic materials). Do not mix or give DOJOLVI using containers, dosing syringes or measuring cups of polystyrene (a type of plastic that can be solid or foam) or polyvinyl chloride (PVC), solid plastic material. DOJOLVI should be taken at least times day with meals or snacks, and always mixed well with soft food or drink. DOJOLVI can be mixed with the following soft food or drink: 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 The mixture may be stored for up to 24 hours in the refrigerator. Your healthcare provider may advise you on maintaining proper diet when taking DOJOLVI. If you miss dose, take the next dose as soon as possible. Take the following doses to hours apart. If it is not possible to take all the doses for the day, skip the missed dose.Taking DOJOLVI liquid by mouth:Use an oral syringe or measuring cup made of the materials listed above to measure the prescribed amount of DOJOLVI from the bottle. Add the prescribed amount of DOJOLVI to clean bowl, cup, or container, made of the materials listed above, containing the appropriate amount of soft food or drink as instructed by your healthcare provider. Mix DOJOLVI well into the soft food or liquid and swallow the DOJOLVI mixture. The DOJOLVI mixture may be stored for up to 24 hours in the refrigerator.Giving DOJOLVI liquid by feeding tube:Do not give DOJOLVI in feeding tubes made of polyvinyl chloride (PVC), type of plastic. DOJOLVI can be given in feeding tubes made of silicone or polyurethane. Use an oral syringe or measuring cup made of the materials listed above to measure the correct dose of DOJOLVI from the bottle and mix with formula. Draw up the entire amount of the DOJOLVI-formula mixture into slip tip syringe. Remove the air from the syringe and connect the syringe directly into the feeding tube port. Push the contents of the syringe (DOJOLVI-formula mixture) into the feeding tube port using steady pressure until empty. Draw up about mL to 30 mL of water with the slip tip syringe and flush the feeding tube feeding port with the water. Throw away any unused DOJOLVI-formula mixture. Do not save for later use. Check the feeding tube often to make sure it is working properly.How should store DOJOLVIStore DOJOLVI at room temperature between 68F to 77F (20C to 25C). Do not freeze DOJOLVI.When the bottle of DOJOLVI has been opened, use within months or by the expiration date on the bottle, whichever comes first. Do not store DOJOLVI in containers made of polystyrene or polyvinyl chloride (PVC).Keep DOJOLVI and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Approved: 06/2020. Use an oral syringe or measuring cup to measure your prescribed dose. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose. Mix or give DOJOLVI using containers, dosing syringes or measuring cups made of materials such as stainless steel, glass, or high-density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane and silicone (types of plastic materials). Do not mix or give DOJOLVI using containers, dosing syringes or measuring cups of polystyrene (a type of plastic that can be solid or foam) or polyvinyl chloride (PVC), solid plastic material. DOJOLVI should be taken at least times day with meals or snacks, and always mixed well with soft food or drink. DOJOLVI can be mixed with the following soft food or drink: 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 The mixture may be stored for up to 24 hours in the refrigerator. Your healthcare provider may advise you on maintaining proper diet when taking DOJOLVI. If you miss dose, take the next dose as soon as possible. Take the following doses to hours apart. If it is not possible to take all the doses for the day, skip the missed dose.. Use an oral syringe or measuring cup made of the materials listed above to measure the prescribed amount of DOJOLVI from the bottle. Add the prescribed amount of DOJOLVI to clean bowl, cup, or container, made of the materials listed above, containing the appropriate amount of soft food or drink as instructed by your healthcare provider. Mix DOJOLVI well into the soft food or liquid and swallow the DOJOLVI mixture. The DOJOLVI mixture may be stored for up to 24 hours in the refrigerator.. Do not give DOJOLVI in feeding tubes made of polyvinyl chloride (PVC), type of plastic. DOJOLVI can be given in feeding tubes made of silicone or polyurethane. Use an oral syringe or measuring cup made of the materials listed above to measure the correct dose of DOJOLVI from the bottle and mix with formula. Draw up the entire amount of the DOJOLVI-formula mixture into slip tip syringe. Remove the air from the syringe and connect the syringe directly into the feeding tube port. Push the contents of the syringe (DOJOLVI-formula mixture) into the feeding tube port using steady pressure until empty. Draw up about mL to 30 mL of water with the slip tip syringe and flush the feeding tube feeding port with the water. Throw away any unused DOJOLVI-formula mixture. Do not save for later use. Check the feeding tube often to make sure it is working properly.. Store DOJOLVI at room temperature between 68F to 77F (20C to 25C). Do not freeze DOJOLVI.. When the bottle of DOJOLVI has been opened, use within months or by the expiration date on the bottle, whichever comes first. Do not store DOJOLVI in containers made of polystyrene or polyvinyl chloride (PVC).

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug. In 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 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 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 diet containing approximately 17% MCT was not shown to promote effects on colon tumor incidence in an azomethane-induced colon tumorigenicity rat model.MutagenesisTriheptanoin was not genotoxic in 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 FertilityTriheptanoin 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 69794-050-50DOJOLVITRIHEPTANOINOral liquid, 100% w/wRx only500 mL1 bottle. PRINCIPAL DISPLAY PANELNDC 69794-050-50DOJOLVITRIHEPTANOINOral liquid, 100% w/wRx only500 mL1 bottle. PRINCIPAL DISPLAY PANELNDC 69794-050-50DOJOLVITRIHEPTANOINOral liquid, 100% w/wRx only500 mL1 bottle.

PEDIATRIC USE SECTION.

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 )].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. No formal pharmacodynamic studies have been conducted with DOJOLVI.

PHARMACOKINETICS SECTION.

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.AbsorptionThe pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized in Table 1.Table 1: Summary of Pharmacokinetic Parameters of Heptanoate after Single and Multiple Oral Administration of DOJOLVI to Healthy Adults (N=13)DOJOLVI DoseMean (SD) Cmax (umol/L) Mean (SD) AUC0-8h (umolhr/L) Time to First Peak Concentration Median (range)(hours)Single 0.3 g/kg178.9 (145)336.5 (223)0.5 (0.4 to 1.0)Dose0.4 g/kg259.1 (134)569.1 (189)0.8 (0.4 to 6.4)Multiple Doses0.3 g/kg administered times day for days(total daily dosage of 1.3 g/kg/day) 319.9 (164)789.8 (346)1.2 (0.0 to 2.4) After oral administration of DOJOLVI, more than one peak concentration of heptanoate is observed.DistributionThe plasma protein binding of heptanoate is approximately 80% and is independent of total concentration.EliminationAfter 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.MetabolismHeptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver. ExcretionAfter single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine. Drug Interaction StudiesIn Vitro StudiesHeptanoate 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no available data on triheptanoin use in pregnant women to evaluate for 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 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 to 4% and 15 to 20%, respectively.Data Animal DataEmbryofetal 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 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationDOJOLVI (doh-johl-vee)(triheptanoin) Oral LiquidWhat is DOJOLVIDOJOLVI is prescription medicine used to treat long-chain fatty acid oxidation disorders (LC-FAOD) in children and adults.Before taking DOJOLVI, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if DOJOLVI will harm your unborn baby. Pregnancy Safety Study. There is pregnancy safety study for women who take DOJOLVI during pregnancy. The purpose of this study is to collect information about your health and your babys health. You can talk to your healthcare provider or contact 1-888-756-8657 to enroll in this study or get more information. are breastfeeding or plan to breastfeed. It is not known if DOJOLVI passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take DOJOLVI. are taking pancreatic lipase inhibitor, such as orlistat, as it may affect how well DOJOLVI works.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take DOJOLVISee the detailed Instructions for Use at the end of this Patient Information Leaflet for instructions about how to mix and take DOJOLVI by mouth in soft foods or drinks or how to mix and give DOJOLVI through feeding tubes. Take DOJOLVI exactly as your healthcare provider tells you. Your healthcare provider may start you on low dose of DOJOLVI and slowly increase your dose to help avoid side effects. If you are taking another medium chain triglyceride (MCT) product, stop taking the MCT before starting DOJOLVI. Do not mix or give DOJOLVI using containers, dosing syringes or measuring cups made of polystyrene (a type of plastic that can be solid or foam) or polyvinyl chloride (PVC), solid plastic material. DOJOLVI should be taken at least times day with meals or snacks, and always mixed well with soft food or drink. What are the possible side effects of DOJOLVIFeeding tube problems. Feeding tubes may not work as well or stop working over time when taking DOJOLVI. Do not use DO JO LVI in feeding tubes made of polyvinyl chloride (PVC). Monitor the feeding tube to make sure it is working properly. Intestinal absorption problems in patients with pancreatic insufficiency. If you have pancreatic insufficiency, consult with your healthcare provider as it may affect how well DOJOLVI works.The most common side effects of DOJOLVI include:stomach (abdominal) pain diarrhea vomiting nausea These are not all the possible side effects of DOJOLVI. Call your healthcare provider for medical advice about side effects. You may report side effects to Ultragenyx at 1-888-756-8657 or FDA at 1-800-FDA-1088. How should store DOJOLVIStore DOJOLVI at room temperature between 68F to 77F (20C 25C). Do not freeze DOJOLVI. When the bottle of DOJOLVI has been opened, use within months or by the expiration date on the bottle, whichever comes first. Do not store DOJOLVI in containers made of polystyrene or polyvinyl chloride (PVC).General information about the safe and effective use of DOJOLVI.Medicines are sometimes prescribed for purposes other than those listed in Patient Information Leaflet. Do not use DOJOLVI for condition for which it was not prescribed. Do not give DOJOLVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DOJOLVI that is written for health professionals.What are the ingredients in DOJOLVIDOJOLVI is made of 100% triheptanoin and contains no other ingredients.Manufactured for: Ultragenyx Pharmaceutical Inc. 60 Leveroni CourtNovato, CA 94949For more information, go to www.dojolvi.com or call 1-888-756-8657.This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 06/2020. are pregnant or plan to become pregnant. It is not known if DOJOLVI will harm your unborn baby. Pregnancy Safety Study. There is pregnancy safety study for women who take DOJOLVI during pregnancy. The purpose of this study is to collect information about your health and your babys health. You can talk to your healthcare provider or contact 1-888-756-8657 to enroll in this study or get more information. are breastfeeding or plan to breastfeed. It is not known if DOJOLVI passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take DOJOLVI. are taking pancreatic lipase inhibitor, such as orlistat, as it may affect how well DOJOLVI works.. See the detailed Instructions for Use at the end of this Patient Information Leaflet for instructions about how to mix and take DOJOLVI by mouth in soft foods or drinks or how to mix and give DOJOLVI through feeding tubes. Take DOJOLVI exactly as your healthcare provider tells you. Your healthcare provider may start you on low dose of DOJOLVI and slowly increase your dose to help avoid side effects. If you are taking another medium chain triglyceride (MCT) product, stop taking the MCT before starting DOJOLVI. Do not mix or give DOJOLVI using containers, dosing syringes or measuring cups made of polystyrene (a type of plastic that can be solid or foam) or polyvinyl chloride (PVC), solid plastic material. DOJOLVI should be taken at least times day with meals or snacks, and always mixed well with soft food or drink. Feeding tube problems. Feeding tubes may not work as well or stop working over time when taking DOJOLVI. Do not use DO JO LVI in feeding tubes made of polyvinyl chloride (PVC). Monitor the feeding tube to make sure it is working properly. Intestinal absorption problems in patients with pancreatic insufficiency. If you have pancreatic insufficiency, consult with your healthcare provider as it may affect how well DOJOLVI works.. The most common side effects of DOJOLVI include:stomach (abdominal) pain diarrhea vomiting nausea stomach (abdominal) pain diarrhea vomiting nausea. Store DOJOLVI at room temperature between 68F to 77F (20C 25C). Do not freeze DOJOLVI. When the bottle of DOJOLVI has been opened, use within months or by the expiration date on the bottle, whichever comes first. Do not store DOJOLVI in containers made of polystyrene or polyvinyl chloride (PVC).

SPL UNCLASSIFIED SECTION.

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 patients total prescribed DCI divided into at least four doses and administered at mealtimes or with snacks. In order to reach target daily dosage, patients may require an increase in their total fat intake. All patients treated with DOJOLVI should be under the care of 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 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.. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no available data on triheptanoin use in pregnant women to evaluate for 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 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 to 4% and 15 to 20%, respectively.Data Animal DataEmbryofetal 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 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Feeding Tube Dysfunction: Regularly monitor the 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). Feeding Tube Dysfunction: Regularly monitor the 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 2.3 )]. 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.