DOJOLVI Oral liquid Ref.[10250] Active ingredients:

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.

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; NCT01886378) followed by an open-label extension study (Study 2; NCT02214160). Twenty-four patients from Study 1 continued into Study 2. Patients ranged from 4 months to 63 years of age and the population was 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 pain, abdominal distension, 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 (NCT01379625), a 4-month double-blind randomized controlled study, commonly reported adverse reactions with triheptanoin were similar to those reported in Study 1 and Study 2.

7.1 Pancreatic Lipase Inhibitors

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

Risk Summary

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

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

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

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

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.

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

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