Onivyde^® pegylated liposomal (Concentrate) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Ipsen Pharma Biotech (France)

Labeled By

IPSEN PHARMA BIOTECH (France)

Or

DERET LOGISTIQUE (France)

Packaging and Quality Control Release

Les Laboratoires Servier Industrie (France)

ATC Code

L01CE02 (Irinotecan)

Active Substance

Irinotecan (Rec.INN registered by WHO)

Dosage Form

Onivyde® pegylated liposomal

Concentrate for dispersion for infusion 4.3 mg/1 ml: vial 10 ml

Dosage Form, Packaging, and Composition

Concentrate for dispersion for infusion is an opalescent liquid ranging from white to light yellow in color.

Excipients: liposomal lipids: DSPC, cholesterol, MPEG-2000-DSPE; other excipients: sucrose octasulfate, HEPES, sodium chloride, water for injections.

The pH of the concentrate is 7.2, osmolality is 295 mOsm/kg.

10 ml – glass vials (1) – cardboard packs.

Additionally, a first-opening control feature may be applied.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Plant alkaloids and other natural substances. Topoisomerase 1 (TOP1) inhibitors. Irinotecan

Pharmacological Action

Antineoplastic agent. The mechanism of action is associated with inhibition of the cellular enzyme topoisomerase I, which is involved in DNA synthesis. It has immunosuppressive activity.

Inhibits acetylcholinesterase.

Pharmacokinetics

Following intravenous infusion, Irinotecan is metabolized in the liver by the enzyme carboxylesterase to the active metabolite SN-38.

Plasma distribution is bi- or triphasic. The mean T_1/2 in the initial phase is 12 min, in the second phase – 2.5 h, and in the final phase – 14.2 h. C_max of irinotecan and SN-38 was reached by the end of the intravenous infusion at the recommended dose of 350 mg/m². On average, 20% of unchanged irinotecan and 0.25% as the metabolite SN-38 are excreted by the kidneys within 24 hours. Approximately 30% of irinotecan is excreted in the bile – both unchanged and as the metabolite SN-38 glucuronide.

Plasma protein binding for irinotecan is approximately 65%, and for its active metabolite SN-38 – 95%.

Indications

Locally advanced or metastatic colorectal cancer (as part of mono- or combination therapy).

ICD codes

Dosage Regimen

Determine the dose based on body surface area (BSA) calculated using the patient’s actual height and weight.

Administer as an intravenous infusion over 90 minutes.

For monotherapy, the recommended dosage is 70 mg/m² administered every 3 weeks.

For combination therapy with fluorouracil and leucovorin, the recommended dosage is 50 mg/m² administered every 2 weeks.

Premedicate with a corticosteroid and an antihistamine 30 to 60 minutes prior to infusion to minimize the risk of infusion reactions.

Premedicate with atropine (unless contraindicated) for patients experiencing cholinergic syndrome.

Adjust dosage based on tolerability and hematologic parameters from prior cycles.

Withhold treatment for absolute neutrophil count (ANC) below 1500/µL or platelet count below 100,000/µL.

Reduce the dose for severe neutropenia, febrile neutropenia, thrombocytopenia, or severe non-hematologic adverse reactions.

Permanently discontinue for severe and persistent neutropenia, severe hypersensitivity reactions, or severe cutaneous reactions.

Do not substitute Onivyde for other irinotecan-containing products due to differences in dosage and administration.

Adverse Reactions

From the hematopoietic system very common – neutropenia, febrile neutropenia, leukopenia, anemia, thrombocytopenia.

From the digestive system nausea, vomiting, diarrhea, abdominal pain, anorexia, mucositis, constipation, gastrointestinal candidiasis, hiccups, decreased appetite; rarely – pseudomembranous colitis, intestinal obstruction, gastrointestinal bleeding, intestinal perforation, increased activity of amylase or lipase. Diarrhea occurring later than 24 hours after irinotecan administration (delayed diarrhea) is its dose-limiting toxic effect.

Acute cholinergic syndrome early diarrhea (within 8 hours after irinotecan administration), abdominal pain, conjunctivitis, rhinitis, decreased blood pressure, bradycardia, vasodilation, increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lacrimation, salivation.

From the nervous system involuntary muscle contractions or cramps, paresthesia, asthenia; very rarely – transient speech disorders.

From the cardiovascular system sometimes – decreased blood pressure, hypovolemic shock due to dehydration; rarely – increased blood pressure during or after infusion.

From the respiratory system sometimes – dyspnea, fever, pulmonary infiltrates.

From the skin and subcutaneous tissues: very common – reversible alopecia; sometimes – skin reactions.

From laboratory parameters very common – transient increase in serum transaminase activity, alkaline phosphatase or bilirubin concentration (combination therapy); common – transient increase in serum transaminase activity, alkaline phosphatase or bilirubin concentration (monotherapy), increased serum creatinine concentration; rarely – hypokalemia and hyponatremia; very rarely – increased serum amylase and/or lipase activity.

Allergic reactions rarely – skin rash; very rarely – development of anaphylactic shock.

Other: increased fatigue, secondary infections, increased body temperature, local reactions.

Contraindications

Hypersensitivity to irinotecan; chronic inflammatory bowel diseases and/or intestinal obstruction; severe bone marrow suppression; serum bilirubin concentration more than 3 times the upper limit of normal (ULN); general patient condition assessed by the ECOG (Eastern Cooperative Oncology Group) scale >2; pregnancy, breastfeeding period; childhood (no safety and efficacy data in children), renal failure (no safety data).

With caution history of radiation therapy to the abdominal or pelvic area (high risk of myelosuppression), leukocytosis, female patients (increased risk of diarrhea), hypovolemia, increased risk of venous thromboembolic complications, elderly age.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Patients of childbearing potential should use reliable methods of contraception during treatment and for 3 months after its completion.

Use in Hepatic Impairment

If serum bilirubin concentration exceeds the ULN by no more than 1.5 times, blood counts should be carefully monitored due to the increased risk of severe neutropenia. If the bilirubin concentration increases more than 3 times, irinotecan therapy should be discontinued.

Use in Renal Impairment

Use is contraindicated in patients with renal failure. The use of Irinotecan is not recommended in patients with impaired renal function.

Pediatric Use

The use of irinotecan in children is contraindicated.

Geriatric Use

Should be prescribed with caution to patients over 65 years of age due to the increased risk of early diarrhea in this category of patients.

Special Precautions

Treatment with irinotecan should be carried out in specialized chemotherapy departments under the supervision of a physician experienced in working with anticancer drugs.

In patients receiving Irinotecan, a complete blood count should be performed weekly and liver function should be monitored.

The patient should be warned in advance about the possibility of developing delayed diarrhea. Patients should immediately inform their doctor about the onset of diarrhea and immediately begin appropriate treatment.

When the first episode of diarrhea develops, measures must be taken immediately to correct it. The duration of neutropenia is most often 8 days, with complete recovery of neutrophils observed by day 22. Acute cholinergic syndrome is observed in approximately 83% of patients, occurring during administration or within 24 hours after administration.

Inadequate treatment of diarrhea can lead to a life-threatening condition, especially if diarrhea develops against the background of neutropenia.

If neutropenia, nausea, vomiting, or diarrhea develop during treatment, dose adjustment is required. Do not use until the neutrophil count in the peripheral blood has recovered (>1500/µl).

Patients of childbearing potential should use reliable methods of contraception during treatment and for 3 months after its completion.

Effect on ability to drive vehicles and operate machinery

During treatment with irinotecan, especially within 24 hours after its administration, it is not recommended to engage in potentially hazardous activities that require concentration and high speed of psychomotor reactions.

Drug Interactions

Due to the anticholinesterase activity of irinotecan, it is possible to prolong the duration of neuromuscular blockade caused by suxamethonium chloride; antagonistic interaction regarding neuromuscular blockade caused by non-depolarizing muscle relaxants.

When irinotecan is used concomitantly with myelosuppressive drugs and radiation therapy, the toxic effect on the bone marrow (leukopenia, thrombocytopenia) is enhanced.

When irinotecan is used concomitantly with corticosteroids (e.g., dexamethasone), the risk of hyperglycemia (especially in patients with diabetes or reduced glucose tolerance) and lymphocytopenia increases.

Concomitant use of irinotecan with diuretics may worsen dehydration resulting from diarrhea and vomiting. Concomitant use of laxatives during irinotecan therapy may worsen the frequency or severity of diarrhea.

Concomitant administration of irinotecan and prochlorperazine increases the likelihood of signs of akathisia.

When irinotecan is used concomitantly with herbal preparations based on St. John’s wort, as well as with anticonvulsant drugs – inducers of the CYP3A isoenzyme (carbamazepine, phenobarbital and phenytoin), the plasma concentration of the active metabolite SN-38 decreases. The possibility of taking anticonvulsant drugs that do not induce isoenzymes, or switching to them, should be assessed at least 1 week before starting irinotecan therapy in patients requiring treatment with anticonvulsant drugs. St. John’s wort should not be taken concomitantly with irinotecan; it must be discontinued at least 1 week before starting irinotecan therapy.

Irinotecan and the active metabolite SN-38 are metabolized via the CYP3A4 isoenzyme and UGT1A1. Concomitant use of irinotecan and inhibitors of the CYP3A4 isoenzyme and/or UGT1A1 may lead to an increase in the systemic exposure of irinotecan and the active metabolite SN-38.

Concomitant administration of irinotecan with atazanavir, an inhibitor of CYP3A4 and UGT1A1 isoenzymes, as well as with ketoconazole, may cause an increase in the plasma concentration of the active metabolite SN-38. Ketoconazole should be discontinued at least 1 week before starting therapy and should not be taken during irinotecan therapy.

Irinotecan should not be mixed with other drugs in the same vial.

Administration of a live or attenuated vaccine to patients undergoing a course of treatment with anticancer agents, including Irinotecan, may lead to serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Irinotecan. A killed or inactivated vaccine may be administered, but the response to such a vaccine may be weakened.

When irinotecan is used concomitantly with phenytoin, there is a risk of exacerbation of seizures due to decreased absorption of phenytoin in the gastrointestinal tract when used concomitantly with anticancer drugs or an increased risk of increased toxicity due to more active metabolism in the liver induced by phenytoin.

When irinotecan is used concomitantly with cyclosporine, tacrolimus, significant immunosuppression with a risk of lymphoproliferation is possible.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.