What Is Liposomal Irinotecan (Onivyde)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes
• Initial Approval Date: October 22, 2015
• Brand Name: Onivyde
• Active Ingredient: Liposomal irinotecan (PEP02 / MM-398)
• Route of Administration: Intravenous infusion
• Class: Chemotherapy agent, topoisomerase I inhibitor
• Category: Cytotoxic antineoplastic drug
• Manufacturer: Ipsen Bioscience (original developer: Merrimack Pharmaceuticals)
• Distribution in Turkey: Limited access in Turkey; may be obtained through special import procedures
• Cancers for Which It Is Approved: Metastatic pancreatic cancer after a gemcitabine-containing regimen, combined with 5-FU and leucovorin

What Is Onivyde? How Does It Work?

Onivyde is a liposomal formulation of the chemotherapy drug irinotecan. Used particularly in metastatic pancreatic cancer, it has a different pharmacokinetic profile from conventional irinotecan. Its liposomal carrier allows irinotecan to remain in tumor tissue longer and reach its target more effectively.

How Does It Work?

• Onivyde's therapeutic effect is mediated by SN-38, irinotecan's active metabolite. SN-38 inhibits topoisomerase I, the enzyme responsible for relaxing DNA during cell division. Inhibiting it prevents proper DNA strand rejoining and causes double-strand breaks. This DNA damage arrests the cell cycle and initiates apoptosis, or programmed cell death.
• The liposomal formulation prolongs irinotecan circulation and increases accumulation in tumor cells. This improves effectiveness and may limit damage to healthy tissues. It provides more balanced distribution and a longer half-life than conventional irinotecan.
• This mechanism is particularly effective in rapidly dividing tumor cells, triggering cell death in the G2/M phase, when DNA replication is critical. Onivyde is therefore considered an effective option for rapidly proliferating pancreatic adenocarcinoma cells.

FDA (US Food and Drug Administration) Approval History

• April 27, 2015: Merrimack Pharmaceuticals and Baxter BioScience announced completion of the New Drug Application process for MM-398 for metastatic pancreatic cancer after gemcitabine.
• June 25, 2015: The US Food and Drug Administration (FDA) granted Priority Review to the MM-398 New Drug Application.
• October 22, 2015: The FDA approved Onivyde (irinotecan liposome injection) for advanced pancreatic cancer.
• February 13, 2024: The FDA approved Ipsen's Onivyde regimen as a potential new first-line standard for metastatic pancreatic adenocarcinoma.

Authorization and Reimbursement in Turkey

Onivyde (liposomal irinotecan injection) is not yet authorized by Turkey's Ministry of Health. It is therefore not officially marketed in Turkey or covered by the Social Security Institution (SGK). However, it is included on the Turkish Pharmacists' Association (TEB) Active Overseas Medicine List, which covers drugs not authorized in Turkey but obtainable abroad. Onivyde may be supplied through special imports and patient-specific applications.

Resistance Mechanisms

• Efflux Pump Activation (ABC Transporters): Tumor cells may overproduce ATP-dependent transporters such as P-gp (P-glycoprotein; ABCB1), BCRP (ABCG2) and MRP (ABCC). This increases SN-38 efflux and reduces effectiveness.
• Topoisomerase I Mutations or Reduced Expression: Reduced expression or structural mutations in topoisomerase I, the target bound by SN-38, prevent the drug from effectively stabilizing DNA.
• Increased DNA Repair: Increased activity of pathways such as homologous recombination (HR), nonhomologous end joining (NHEJ) and base excision repair (BER) may repair SN-38-induced DNA damage and reduce cytotoxicity.
• Disrupted Apoptotic Pathways: p53 mutations or increased anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, may prevent cell death despite drug-induced DNA damage.
• Microenvironmental Factors: Hypoxia, low pH and cytokine release in the tumor microenvironment may limit drug uptake and activity.
• Liposomal Breakdown or Irregular Release: Disrupted tumor targeting by the liposomal structure or uncontrolled SN-38 release may prevent adequate tissue concentrations.

Absorption

Onivyde is given by intravenous infusion, so there is no conventional gastrointestinal absorption. It enters the systemic circulation directly. The liposomal structure prolongs irinotecan circulation in plasma.

Distribution

• Liposomal irinotecan distributes more slowly and remains in circulation longer than conventional irinotecan.
• Volume of distribution (Vd): approximately 3.5 L/m².
• The liposomal form accumulates particularly in tumors through passive targeting, known as the enhanced permeability and retention (EPR) effect.
• Blood-brain barrier penetration is limited.

Metabolism

• Irinotecan, Onivyde's active ingredient, is converted in the liver by carboxylesterases to the active metabolite SN-38.
• SN-38 is the main compound responsible for cytotoxicity.
• SN-38 is then glucuronidated by UGT1A1 to the inactive form SN-38G.
• UGT1A1 polymorphisms, such as UGT1A1 *28/*28, may increase SN-38 levels and toxicity risk.

Elimination

• Most irinotecan and its metabolites are eliminated through the hepatobiliary route, entering the gastrointestinal tract through bile.
• Urinary elimination is lower (<20%).
• Elimination half-life (t1/2): approximately 6–22 hours,
• SN-38: approximately 20 hours
• Elimination may change in hepatic impairment, requiring dose adjustment.

Dose Range

• Standard Dose: 70 mg/m² irinotecan liposome (Onivyde)
• Administration: Intravenous infusion over approximately 90 minutes.
• Frequency: Every two weeks (every 14 days)
• Combination: Onivyde is given with 5-fluorouracil (5-FU) and leucovorin; 5-FU: 2400 mg/m² (continuous infusion over 46 hours); leucovorin: 400 mg/m² (IV bolus or infusion)
• In UGT1A1*28 homozygotes: The starting dose is generally reduced to 50 mg/m².
• Liver dysfunction: Caution is required with bilirubin >1.5 x ULN; reduce the dose if necessary.

Drug Interactions

Interactions With Enzyme Inhibitors (Increased SN-38 Levels): These drugs may inhibit enzymes involved in irinotecan metabolism, such as carboxylesterase or UGT1A1, causing SN-38 accumulation.

• Ketoconazole, itraconazole, voriconazole (CYP3A4 inhibitors)
• Atazanavir, ritonavir (antiviral protease inhibitors – UGT1A1 inhibitor)
• Gemfibrozil (CYP2C8 and UGT inhibitor)
• Fluconazole
• Cimetidine

Result: increased SN-38 levels causing severe diarrhea, neutropenia and mucositis!

Interactions With Enzyme Inducers (Decreased SN-38 Levels): These agents accelerate irinotecan metabolism and lower SN-38 levels, potentially reducing effectiveness. Examples include phenytoin, phenobarbital and carbamazepine, rifampicin and rifabutin, St. John's wort. Reduced effectiveness and treatment response

Interactions With Other Chemotherapy Drugs: Careful monitoring is needed with fluorouracil (5-FU) and leucovorin because gastrointestinal toxicity and myelosuppression increase. Combinations with anti-VEGF agents such as bevacizumab may increase intestinal perforation and bleeding risks.

Anticoagulants: Warfarin or other oral anticoagulants may increase bleeding risk when used concomitantly. INR monitoring is important.

Anticholinergics and Antidiarrheals: Irinotecan may cause early-onset cholinergic syndrome. Pretreatment with anticholinergics such as atropine may be used. Loperamide is commonly used for delayed diarrhea, but excessive use increases toxicity risk.

Situations Requiring Attention

• UGT1A1 Polymorphism: UGT1A1*28 homozygotes have slower SN-38 metabolism and increased toxicity risk, particularly severe neutropenia and diarrhea. A 25-30% reduction in starting dose is recommended. Pretreatment genetic testing is clinically valuable.
• Risk of Severe Diarrhea: Delayed diarrhea beginning ≥24 hours after Onivyde is common and may be serious. Atropine prophylaxis may be needed for early cholinergic diarrhea. Delayed diarrhea requires prompt high-dose loperamide and fluid/electrolyte replacement. Prolonged or severe diarrhea may require hospitalization and dose reduction.
• Hematological Toxicity: Neutropenia, leukopenia and thrombocytopenia may develop, particularly severely in patients with reduced marrow reserve from previous chemotherapy. Complete blood counts are required before each cycle. Febrile neutropenia requires treatment interruption and dose adjustment.
• Hepatic Impairment: Onivyde is eliminated through the liver. Caution is required with total bilirubin >1.5 x ULN; reduce the dose if needed. Liver metastases may increase drug accumulation and toxicity.
• Risk of Gastrointestinal Perforation: Previous abdominal radiotherapy, tumor invasion or concomitant anti-VEGF therapy, such as bevacizumab, increases GI perforation risk. Severe abdominal pain requires urgent assessment.
• Older Patients: Hematological and gastrointestinal toxicities are more frequent in patients older than 65. Close monitoring and dose adjustment when needed are required.
• Pregnancy and Breastfeeding: Pregnancy category D. Teratogenic and embryotoxic effects have been demonstrated in animals. Do not use during pregnancy; effective contraception is recommended for women of reproductive potential. Contraindicated during breastfeeding.
• Drug Interactions: Use with CYP3A4 and UGT1A1 inhibitors/inducers requires careful monitoring.
• Before Treatment: Complete blood count, liver function tests and UGT1A1 testing if available
• During Treatment: Hydration to address dehydration and diarrhea risk. Regular hematological monitoring. Follow the dose-modification protocol according to toxicity.

Side Effects

• Diarrhea 44–50%
• Fatigue / Asthenia 40%
• Nausea 30–40%
• Vomiting 25–35%
• Anemia 30–35%
• Neutropenia 30–40%
• Loss of Appetite (Anorexia) 30%
• Leukopenia 15–25%
• Abdominal Pain 15–20%
• Mucositis / Mouth Sores 10–20%
• Thrombocytopenia 10–15%
• Dehydration 15%
• Hypokalemia 10–15%
• Fever 10–15%
• Febrile Neutropenia: 3–5%
• Cholinergic Syndrome (Early Diarrhea, Sweating, Abdominal Cramps) 1–3%
• Hepatotoxicity (Elevated ALT/AST) 5–10%
• Dry Mouth 5%
• Infections 5–10%