DRUG INTERACTIONS-summary

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

 DRUG INTERACTIONS- details

.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 

Avoid co-administration of DOJOLVI with pancreatic lipase inhibitors. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  25

ADVERSE REACTIONS-

Most common adverse reactionsare (=10%): abdominal pain, diarrhea, vomiting, and nausea. 

CONTRAINDICATION-                                                                                                   None. 

WARNINGS AND PRECAUTIONS-

­ • Feeding Tube Dysfunction: Regularly monitor the tube to ensure proper functioning and integrity. 

• 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.

 PATIENT COUNSELING INFORMATION-

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).

Preparation and Administration Instruct the patient or caregiver:

• To read the instructions in the Patient Package Insert on appropriate preparation and administration techniques for oral administration or via a 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 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 four 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 inspect the feeding tube for proper functioning and integrity and report to the healthcare provider if any issues are identified 

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 patients that there is a 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 Court Novato, CA 94949

 CLINICAL PHARMACOLOGY

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.

2. Pharmacodynamics-                                                                                              No formal pharmacodynamic studies have been conducted with DOJOLVI.

3. Pharmacokinetics-                                                                                            Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. The exposure of triheptanoin in the human plasma is minimal.

Pharmacokinetics of heptanoate exhibits high inter-patient variability. Heptanoate exposure increases greater than dose-proportional in the dose range between triheptanoin 0.3 and 0.4 g/kg.

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

Table 1: Summary of Pharmacokinetic Parameters of Heptanoate after Single and Multiple Oral Administration of DOJOLVI to Healthy Adults                               (N=13) DOJOLVI Dose Mean (SD) Cmax (µmol/L) Mean (SD) AUC0-8h (µmol*hr/L)

Time to First Peak Concentration* Median (range) (hours) Single 0.3 g/kg 178.9 (145) 336.5 (223) 0.5 (0.4 to 1.0) Dose 0.4 g/kg 259.1 (134) 569.1 (189) 0.8 (0.4 to 6.4)

Multiple Doses 0.3 g/kg administered 4 times a day for 2 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. 

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.

 USE IN SPECIFIC POPULATIONS-

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.

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. 

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.

3.Pediatric Use-                                                                                                         The safety and effectiveness of DOJOLVI have been established in pediatric patients aged birth and older 

4. 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.