What s s up with Omegaven????? Kathleen Gura PharmD Children s s Hospital Boston
Disclosures Funding : March of Dimes FDA Orphan Drug Grants Program NIH Children s s Hospital Surgical Foundation Patent application by Children s Hospital Boston
PN liver Injury Histology Fatty deposits Ballooning of hepatocytes Inflammation Bile duct proliferation Laboratory Elevations of serum liver enzymes (LFTs( LFTs) Cholestasis:: Direct bilirubin >2.0 mg/dl
Omegaven Typically used in combination with Intralipid Max labeled dose 0.2g/kg/day Not indicated for use in children Not intended to be used as monotherapy Not FDA approved
OIL Intralipid Soybean 10 5 Safflower 5 Liposyn II Fish 10 % FATS Comparison of Parenteral Fat Emulsions (10 grams fat/100 ml) Omegaven Linoleic 50 65 0.1-0.7 0.7 α-linolenic 9 4 <0.2 E.P.A. 1.3-2.8 D.H.A. 1.4-3.1 Glycerol 2.3 2.5 2.5 Egg Phospholipid 1.2 1.2 1.2
Biosynthesis of Fatty Acids Δ 6 desaturase elongase n-3 α-linolenic acid (18:3) octadecatetraenoic acid (18:4) eicosatetraenoic acid (20:4) Δ 5 desaturase n-6 linoleic acid (18:2) γ-linolenic acid (18:3) dihomo-γ-linolenic acid (20:3) n-9 oleic acid (18:1) octadecadienoic acid (18:2) eicosadienoic acid (20:2) elongase eicosapentaenoic acid (20:5) arachidonic acid (20:4) eicosatrienoic acid (20:3) elongase docosapentaenoic acid (22:5) Δ 6 desaturase retroconvertase docosahexaenoic acid (22:6) Gura PSAP 5 th Edition
Potential Benefits of Omega-3 3 Fatty Acids Anti-inflammatory inflammatory properties - decreased production of proinflammatory cytokines Clearance Omega-3 3 Fatty acids diminish de novo lipogenesis
Liver Histology H&E 400x Normal chow PN alone Omegaven oral
Liver Histology H&E 400x Normal chow PN alone Omegaven IV
Normal Liver PAS
PN Alone PAS
PN + IV Intralipid PAS
PN + IV Omegaven PAS
H&E CHOW PN + IL PN + SMOF PN + OM
CHB Omegaven Protocol
Protocol Details Patients must have pre-existing existing PNALD Direct bili > 2 mg/dl or histological evidence of cholestasis Patient must be expected to be on PN/IFE at least 30 additional days Neither patient nor their insurer can be charged without FDA approval
Dosing/Administration Conventional fat emulsions are discontinued Dosing: Omegaven 1 g/kg/day infused over 12 hours Additional NPC given as carbohydrates May co-administer into PN line (no TNA) May be filtered through 1.2 micron filter Do not mix with other drugs
Exclusion Criteria Other causes of chronic liver disease - hepatitis C - cystic fibrosis - biliary atresia Allergy to eggs or fish Involvement in any other clinical trial unless approved by other investigators
Clinical Experience Recent Findings.
Accepted Annals of Surgery Direct Bilirubin (n=51) Direct Bilirubin (mg/dl) 0 10 20 30-8 -4 0 4 8 12 16 20 24 28 32 (29) (44) (47) (82) (55) (34) (23) (14) (11) (6) (3) Weeks from Enrollment (Omegaven Started)
Triene/Tetraene Ratio (n=51) Triene/tetraene ratio 0.0 0.05 0.10 0.15 0.20 0.25 0.30-8 -4 0 4 8 12 16 20 24 28 32 (2) (44) (81) (53) (35) (23) (14) (12) (7) (5) (NA) Weeks from Enrollment (Omegaven Started) Accepted Annals of Surgery
Triglycerides Triglycerides (mg/dl) 0 100 200 300 400 500-8 -4 0 4 8 12 16 20 24 28 32 (22) (35) (43) (77) (50) (35) (23) (15) (12) (8) (5) Weeks from Enrollment (Omegaven Started)
Platelets Platelets 0 200 400 600 800-8 -4 0 4 8 12 16 20 24 28 32 (23) (40) (45) (83) (55) (36) (23) (15) (12) (8) (5) Weeks from Enrollment (Omegaven Started) Accepted Annals of Surgery
Coagulation (INR) INR 1.0 1.5 2.0 2.5 3.0-8 -4 0 4 8 12 16 20 24 28 32 (6) (11) (43) (80) (52) (33) (24) (15) (12) (8) (5) Weeks from Enrollment (Omegaven Started) Accepted Annals of Surgery
Efficacy of Omegaven in Comparison to Soybean Controls in Children with PNALD Patients < 2 years of age All had PNALD (dbili( > 2mg/dL) Omegaven cohort n=57 -treated from Sept 2004 Dec 2008 Soybean control n=49 -treated from Feb 2000 Dec 2007
Highlights Mean time from baseline to reversal of cholestasis while on PN among survivors who did not undergo liver transplantation while on PN in the Omegaven cohort was 78 days vs. 200 days in the Soybean control cohort (P =0.0005) For patients still on PN 40/52 Omegaven patients exhibited reversal of cholestasis, only 2/26 Soybean control patients exhibited reversal of cholestasis while on PN.
Other published evidence..
Results 12 patients with PNALD treated (Canada) EFA profiles not routinely followed Complete resolution of PNALD occurred in 9 patients In 8 cases, hepatic function while on the blended regimen continue to worsen until Intralipid stopped and Omegaven was given alone Concluded that Omegaven has the ability to restore liver function without complications or mortality
Comments Case series describing 4 preterm infants (China) Intralipid stopped and patients switched to Omegaven Three of the four infants had complete resolution of their cholestasis while on Omegaven Two eventually weaned off PN; discharged home on full EN One infant did not improve had multiple bouts of sepsis and ongoing intra-abdominal abdominal inflammation and later expired Suggests some patients with ongoing complex multi-organ disease may be beyond the point of rescue
Comments Case report (Italy) Infant with PNALD treated with Omegaven Goal dose 1.5g/kg/day Cholestasis resolved after 8 months of treatment with Omegaven monotherapy despite being on 50% EN and 50% PN No clinical signs of fatty acid deficiency or evidence of bleeding
Comments case report (Kentucky) infant who suffered from midgut volvulus by 5 months of age, this patient developed severe PNALD listed for transplant Within two months, his serum bilirubin began to decrease, and returned to normal by 7 months. At the same time, the patient reached his enteral nutrition goal, and was weaned from PN
122 patients and growing.
If you can t t get Omegaven Avoid overfeeding Limit lipid dose Consider enteral fish oil Prevent infection (? Ethanol lock) Early, aggressive and appropriate treatment of CVC infections
The Center for Advanced Intestinal Rehabilitation (CAIR)
Questions? Kathleen.Gura@childrens.harvard.edu