Irinotecan

Irinotecan is a derivative of camptothecin that inhibits the enzyme DNA topoisomerase I. It is a prodrug: carboxylesterase enzymes convert it to the active metabolite SN-38, which is about 1,000 times as potent against topoisomerase I. In the EU the substance is used in two formulations that behave differently in the body and cannot be substituted for one another: conventional irinotecan, a solution of irinotecan hydrochloride (nationally authorised), and pegylated liposomal irinotecan, in which the drug is enclosed in lipid vesicles (Onivyde pegylated liposomal, centrally authorised).

Mechanism of Action

• Topoisomerase I inhibition: topoisomerase I is a nuclear enzyme that relieves torsional strain in DNA during replication and transcription by making reversible single-strand breaks. Irinotecan and SN-38 bind to the enzyme–DNA complex and stop the breaks from being resealed.
• DNA damage and cell death: the stabilised complex blocks the advancing replication fork and turns the single-strand breaks into lethal double-strand breaks. Mammalian cells cannot repair these efficiently, so the cancer cell dies by apoptosis. The effect falls on cells in the S and G2 phases of the cell cycle.
• Activation and inactivation: carboxylesterase in the liver and gastrointestinal tract cleaves irinotecan to SN-38. UGT1A1 then converts SN-38 to its glucuronide (SN-38G), the main route of inactivation. CYP3A4 oxidises irinotecan to further metabolites that are unlikely to contribute to its activity.
• Reduced UGT1A1 activity: in patients with low UGT1A1 activity (for example Gilbert’s syndrome or the UGT1A1*28 variant), SN-38 builds up and the risk of severe neutropenia and diarrhoea rises (see Special Instructions).
• Liposomal formulation: in Onivyde pegylated liposomal the irinotecan is enclosed in a lipid bilayer vesicle. In animal models this extended the time irinotecan stayed in plasma and prolonged exposure to SN-38 at the tumour site.

Pharmacokinetics

• Conventional irinotecan, distribution: after intravenous infusion the AUC of irinotecan increases linearly with dose between 50 and 350 mg/m², whereas the AUC of SN-38 increases less than proportionally. The volume of distribution is large (138 L/m²). Irinotecan is 30 to 68% bound to plasma proteins and SN-38 about 95%, mainly to albumin.
• Conventional irinotecan, metabolism and elimination: SN-38 usually peaks within 1 hour of the end of a 90-minute infusion, at much lower concentrations than irinotecan. The terminal half-life is about 6 to 12 hours for irinotecan and 10 to 20 hours for SN-38. Total clearance is about 13 to 14 L/h/m². Urinary excretion accounts for 11 to 20% of the dose as irinotecan, below 1% as SN-38 and about 3% as SN-38 glucuronide.
• Liposomal irinotecan, distribution: encapsulation prolongs circulation and limits distribution compared with conventional irinotecan. About 95% of the irinotecan stays inside the liposomes while in the circulation. The volume of distribution is about 4 L, so the drug is largely confined to the vascular space, and plasma protein binding is negligible (below 0.44% of total irinotecan).
• Liposomal irinotecan, exposure and elimination: irinotecan released from the liposomes is metabolised in the same way as the conventional drug. The terminal half-life of total irinotecan is about 1.9 days. At 50 mg/m² (oxaliplatin combination) the geometric mean peak concentration was 25.1 µg/mL for total irinotecan and 2.09 ng/mL for total SN-38; at 70 mg/m² (5-FU and leucovorin combination) it was 29.0 µg/mL and 2.50 ng/mL.
• Special populations: in patients with raised bilirubin, total SN-38 concentrations are higher, which increases the risk of neutropenia. In a population analysis of the liposomal form, Asian patients had lower irinotecan and higher SN-38 exposure than white patients. No dedicated hepatic or renal impairment study has been done with the liposomal form.

Pegylated liposomal irinotecan (Onivyde pegylated liposomal), adults:

• First-line pancreatic cancer: in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) for metastatic adenocarcinoma of the pancreas.
• Pancreatic cancer after gemcitabine: in combination with 5-FU and LV for metastatic adenocarcinoma of the pancreas in adults who have progressed following gemcitabine-based therapy.

Conventional irinotecan (nationally authorised; wording of the Spanish SmPC of a 1.5 mg/mL ready-to-use bag), adults with advanced colorectal cancer:

• With 5-FU and folinic acid: in patients who have not received chemotherapy before for advanced disease.
• Monotherapy: in patients in whom an established regimen containing 5-FU has failed.
• With cetuximab: metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) and is RAS wild-type, either without previous treatment for metastatic disease or after failure of cytotoxic therapy that included irinotecan.
• With 5-FU, folinic acid and bevacizumab: first-line treatment of metastatic carcinoma of the colon or rectum.
• With capecitabine, with or without bevacizumab: first-line treatment of metastatic colorectal carcinoma.

The two forms have different indications and must not be substituted for each other. The SmPCs of other nationally authorised conventional irinotecan products may word their indications differently.

Pegylated liposomal irinotecan:

• History of severe hypersensitivity to irinotecan or to any of the excipients.
• Breastfeeding.

Conventional irinotecan:

• Chronic inflammatory bowel disease and/or bowel obstruction.
• Hypersensitivity to irinotecan or to any of the excipients.
• Breastfeeding.
• Bilirubin above 3 times the upper limit of normal.
• Severe bone marrow failure.
• WHO performance status above 2.
• Concomitant use of St John’s wort.
• Live attenuated vaccines.
• The contraindications of cetuximab, bevacizumab or capecitabine also apply when irinotecan is combined with them.

Diarrhoea and neutropenia are the main side effects of both forms. The two forms have separate SmPC tables, so they are given separately here.

Pegylated Liposomal Irinotecan (Onivyde pegylated liposomal)

In 370 patients given it with oxaliplatin, 5-FU and leucovorin (NAPOLI-3), the most common reactions (at least 20%) were diarrhoea, nausea, vomiting, decreased appetite, fatigue, asthenia, neutropenia, decreased neutrophil count and anaemia. In 264 patients given it with 5-FU and leucovorin after gemcitabine, they were diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis and pyrexia. Side effects led to permanent discontinuation in 9.5% of patients (oxaliplatin combination) and 11% (5-FU and leucovorin combination). In the oxaliplatin combination, 52.4% of patients needed a dose reduction. The groups below list the two regimens separately.

Very common (≥1/10):

• With oxaliplatin, 5-FU and leucovorin: anaemia, neutropenia, thrombocytopenia, hypokalaemia, decreased appetite, peripheral neuropathy, dysgeusia, paraesthesia, diarrhoea, nausea, vomiting, abdominal pain or discomfort, stomatitis, alopecia, asthenia, mucosal inflammation, weight decreased.
• With 5-FU and leucovorin: neutropenia, leucopenia, anaemia, thrombocytopenia, hypokalaemia, hypomagnesaemia, dehydration, decreased appetite, dizziness, diarrhoea, vomiting, nausea, abdominal pain, stomatitis, alopecia, pyrexia, peripheral oedema, mucosal inflammation, asthenia, weight decreased.

Common (≥1/100 to <1/10):

• With oxaliplatin, 5-FU and leucovorin: sepsis, urinary tract infection, candida infection, nasopharyngitis, febrile neutropenia, leucopenia, lymphopenia, dehydration, hyponatraemia, hypophosphataemia, hypomagnesaemia, hypoalbuminaemia, hypocalcaemia, tremor, neurotoxicity, dysaesthesia, cholinergic syndrome, headache, dizziness, blurred vision, tachycardia, hypotension, thromboembolic events, pulmonary embolism, hiccups, dyspnoea, epistaxis, colitis, enterocolitis, constipation, dry mouth, flatulence, abdominal distension, dyspepsia, gastro-oesophageal reflux disease, haemorrhoids, dysphagia, hyperbilirubinaemia, dry skin, palmar-plantar erythrodysaesthesia syndrome, rash, skin hyperpigmentation, muscular weakness, myalgia, muscle spasms, acute kidney injury, pyrexia, oedema, chills, infusion-related reaction, raised transaminases, alkaline phosphatase, gamma-glutamyltransferase and blood creatinine.
• With 5-FU and leucovorin: septic shock, sepsis, pneumonia, febrile neutropenia, gastroenteritis, oral candidiasis, lymphopenia, hypoglycaemia, hyponatraemia, hypophosphataemia, insomnia, cholinergic syndrome, dysgeusia, hypotension, pulmonary embolism, thromboembolic events, dyspnoea, dysphonia, colitis, haemorrhoids, pruritus, acute renal failure, infusion-related reaction, oedema, raised bilirubin, transaminases and international normalised ratio.

Uncommon (≥1/1,000 to <1/100):

• With oxaliplatin, 5-FU and leucovorin (selection): diverticulitis, pneumonia, anal abscess, Clostridium difficile infection, herpes simplex, sinusitis, peritumoral oedema, pancytopenia, haemolytic anaemia, hypersensitivity, hypercalcaemia, hyperglycaemia, hyperkalaemia, gout, malnutrition, confusional state, depression, seizure, cerebral haemorrhage, cerebral ischaemia, ischaemic stroke, transient ischaemic attack, syncope, vertigo, angina pectoris, acute myocardial infarction, palpitations, hypertension, pneumonitis, gastrointestinal toxicity, duodenal obstruction, paralytic ileus, rectal haemorrhage, cholangitis, toxic hepatitis, cholestasis, hepatic cytolysis, generalised exfoliative dermatitis, bullous dermatitis, urticaria, renal impairment and renal failure, proteinuria, multi-organ dysfunction syndrome, prolonged QT interval, increased troponin I, and others listed in the SmPC.
• With 5-FU and leucovorin: biliary sepsis, hypersensitivity, hypoxia, interstitial lung disease (including pneumonitis), oesophagitis, proctitis, urticaria, rash, nail discolouration.

Not known: with 5-FU and leucovorin, anaphylactic or anaphylactoid reaction, angioedema and erythema.

Important serious reactions: diarrhoea of any grade occurred in 64.3% of patients on the oxaliplatin combination (grade 3 or 4 in 19.5%), and grade 3 or 4 diarrhoea in 12.8% on the 5-FU and leucovorin combination, in which early diarrhoea (within 24 hours) occurred in 29.9% and cholinergic events in 3.4%. Grade 3 or higher neutropenia occurred in 27.4% on 5-FU and leucovorin (1.5% with 5-FU and leucovorin alone), with the lowest counts a median of 23 days after the first dose; with the oxaliplatin combination grade 3 or 4 neutropenia occurred in 14.1% and febrile neutropenia in 1.9%, and fatal febrile neutropenia or pancytopenia in 0.3% each. Acute renal failure, usually with dehydration from vomiting or diarrhoea, occurred in 5.1% of patients on 5-FU and leucovorin. Infusion-related reactions occurred in 1.4% of patients on the oxaliplatin combination and in 6.8% on the 5-FU and leucovorin combination.

Conventional Irinotecan

The most frequent dose-limiting reactions are delayed diarrhoea (starting more than 24 hours after the infusion) and blood disorders, including neutropenia, anaemia and thrombocytopenia. Neutropenia is the dose-limiting toxicity; it is reversible and not cumulative, with the lowest count a median of 8 days after the dose. An acute cholinergic syndrome is very common. The groups below cover 765 patients given 350 mg/m² every 3 weeks as monotherapy; reactions in other indications are expected to be similar to those in colorectal cancer.

Very common (≥1/10): neutropenia, anaemia, decreased appetite, cholinergic syndrome, diarrhoea, vomiting, nausea, abdominal pain, alopecia (reversible), mucosal inflammation, pyrexia, asthenia.

Common (≥1/100 to <1/10): infection, thrombocytopenia, febrile neutropenia, constipation, increased blood creatinine, increased transaminases (ALT and AST), increased blood bilirubin, increased blood alkaline phosphatase.

The acute cholinergic syndrome consists of early diarrhoea with abdominal pain, sweating, miosis and increased salivation, during the infusion or within 24 hours; it settles after atropine.

The statements on enzyme inducers and inhibitors in the liposomal SmPC come from published data on non-liposomal irinotecan.

• St John’s wort: lowered the plasma level of SN-38 by 42% in a small study of five patients (irinotecan 350 mg/m² with 900 mg St John’s wort). It is contraindicated with conventional irinotecan, and liposomal irinotecan should not be given with it.
• Strong CYP3A4 and/or UGT1A1 inducers (anticonvulsants such as phenytoin, phenobarbital and carbamazepine; rifampicin; rifabutin; apalutamide): with non-liposomal irinotecan, the irinotecan AUC fell by 57 to 79% and the SN-38 AUC by 36 to 92% with the anticonvulsants, reducing the effect. Conventional irinotecan should avoid them. Liposomal irinotecan should not be given with them unless there is no alternative; the right starting dose has not been defined, and a switch to a non-inducing medicine at least 2 weeks before treatment should be considered.
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole, voriconazole, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, nefazodone, grapefruit juice): ketoconazole, an inhibitor of CYP3A4 and UGT1A1, raised the SN-38 exposure of non-liposomal irinotecan by 109%. Conventional irinotecan should avoid them. Liposomal irinotecan should not be given with them; strong CYP3A4 inhibitors should be stopped at least 1 week before it starts.
• UGT1A1 inhibitors (atazanavir, gemfibrozil, indinavir, regorafenib): may raise exposure. Liposomal irinotecan should not be given with strong UGT1A inhibitors unless there is no alternative.
• Other cytotoxic medicines: antineoplastic agents with a similar side-effect profile, including flucytosine (a prodrug of 5-FU), can worsen effects such as myelosuppression.
• Live vaccines: conventional irinotecan is contraindicated with live attenuated vaccines (for example yellow fever vaccine) during treatment and for 6 months after chemotherapy stops. For liposomal irinotecan live vaccines should be avoided because of the risk of serious or fatal infection. Killed or inactivated vaccines may be given, but the response may be reduced.
• 5-FU and leucovorin: given with liposomal irinotecan, they did not change its pharmacokinetics in the population analysis.

Both forms are cytotoxic and are given by intravenous infusion, prescribed and supervised by a physician experienced in anti-cancer chemotherapy. They differ in dose, schedule, concentration and indication, and one must never be used in place of the other. The liposomal doses are expressed as irinotecan free base, whereas the conventional SmPC expresses doses as milligrams of irinotecan hydrochloride trihydrate.

Pegylated Liposomal Irinotecan: Doses

• Not as a single agent: Onivyde pegylated liposomal is always combined, and treatment continues until disease progression or intolerance.
• With oxaliplatin, 5-FU and leucovorin (first line): 50 mg/m² intravenously over 90 minutes, then oxaliplatin 60 mg/m² over 120 minutes, then leucovorin 400 mg/m² over 30 minutes, then 5-FU 2,400 mg/m² over 46 hours, every 2 weeks. Oxaliplatin may be stopped if it is not well tolerated, and the liposomal irinotecan with 5-FU and leucovorin can continue. The starting dose stays at 50 mg/m² in patients known to be homozygous for UGT1A1*28.
• With 5-FU and leucovorin (after gemcitabine): 70 mg/m² intravenously over 90 minutes, then leucovorin 400 mg/m² over 30 minutes, then 5-FU 2,400 mg/m² over 46 hours, every 2 weeks. For patients known to be homozygous for UGT1A1*28, a reduced starting dose of 50 mg/m² should be considered, with an increase to 70 mg/m² if it is tolerated in later cycles.

Pegylated Liposomal Irinotecan: Premedication, Adjustments and Method

• Premedication: standard doses of dexamethasone (or an equivalent corticosteroid) with a 5-HT3 antagonist or other antiemetic, at least 30 minutes before the infusion.
• Dose adjustments: all changes are based on the worst preceding toxicity; the leucovorin dose does not need adjusting. The SmPC tables set the reductions and delays for each toxicity.
• Administration: the concentrate is diluted and given as a single intravenous infusion over 90 minutes. It is cytotoxic: gloves, goggles and protective clothing are recommended, and pregnant staff should not handle it.

Conventional Irinotecan: Doses

• Adults only; use is restricted to units specialised in cytotoxic chemotherapy.
• Monotherapy (previously treated patients): 350 mg/m² as an intravenous infusion over 30 to 90 minutes every 3 weeks. A weekly schedule can be considered for patients who need closer monitoring or are at particular risk of severe neutropenia.
• With 5-FU and folinic acid (previously untreated patients): 180 mg/m² every 2 weeks as an infusion over 30 to 90 minutes, followed by the folinic acid and 5-FU infusions.
• With cetuximab: usually the dose of irinotecan used in the last cycles of the previous irinotecan regimen, given at least 1 hour after the end of the cetuximab infusion. For bevacizumab and capecitabine, see their own SmPCs.
• Dose adjustments: irinotecan is given after all adverse events have recovered to grade 0 or 1 and treatment-related diarrhoea has fully resolved. After severe diarrhoea or severe haematological events the dose is reduced in later cycles; see the SmPC for the detail.
• Bags: the 1.5 mg/mL ready-to-use bags allow 180, 200, 220 or 240 mL (270, 300, 330 or 360 mg) to be given. If the dose cannot be reached with these presentations, an alternative irinotecan product such as a concentrate is used.

Special Populations

• Hepatic impairment: for the liposomal form there is no dedicated study, and it should be avoided if bilirubin is above 2.0 mg/dL, or AST and ALT are above 2.5 times the upper limit of normal (above 5 times with liver metastases). For the conventional form, liver function is checked before treatment and before each cycle; with bilirubin between 1.5 and 3 times the upper limit, blood counts are taken weekly; above 3 times the upper limit, it must not be given.
• Renal impairment: for the liposomal form, no adjustment in mild to moderate impairment; it is not recommended in severe impairment (creatinine clearance below 30 mL/min).
• Elderly: no dose adjustment for the liposomal form (41 to 50% of trial patients were 65 or older). For the conventional form, the dose is chosen with care because liver function is more often reduced.
• Children and adolescents: the conventional form is for adults only; safety and efficacy of the liposomal form at 18 years or younger have not been established.

Liposomal and Conventional Irinotecan Are Not Interchangeable

The liposomal SmPC states that Onivyde pegylated liposomal has different pharmacokinetics from non-liposomal irinotecan, with a different concentration and strength, is not equivalent to it and should not be interchanged. A dose of one form cannot be read across to the other. In the few patients previously exposed to non-liposomal irinotecan, no benefit of the liposomal form was shown.

Diarrhoea

Liposomal irinotecan

• It can cause severe and life-threatening diarrhoea and must not be given to patients with bowel obstruction or chronic inflammatory bowel disease.
• Diarrhoea is early (within 24 hours of starting the infusion) or late (after 24 hours). With early diarrhoea or cholinergic symptoms (runny nose, increased salivation, flushing, sweating, slow heart rate, small pupils, hyperperistalsis), prophylactic or therapeutic atropine should be considered unless contraindicated.
• Late diarrhoea can be debilitating and, rarely, life-threatening, through dehydration, electrolyte imbalance, colitis, gastrointestinal ulceration, infection or sepsis. At the first liquid stool the patient drinks large volumes of electrolyte-containing drinks. Loperamide (or equivalent) is kept ready and started at the first loose stool or when bowel movements become more frequent than normal (maximum 16 mg a day), and continued until the patient has been free of diarrhoea for at least 12 hours. Lactose-containing products are stopped, hydration is maintained and a low-fat diet is advised.
• If diarrhoea continues for more than 24 hours on loperamide, oral antibiotic support (for example a fluoroquinolone for 7 days) should be considered. Loperamide is not used for more than 48 consecutive hours because of the risk of paralytic ileus; if diarrhoea lasts beyond 48 hours, loperamide is stopped, fluids and electrolytes are replaced and antibiotics continue until symptoms resolve.
• A new cycle does not begin until diarrhoea has fallen to grade 1 or lower (2 to 3 stools a day more than before treatment). After grade 3 or 4 diarrhoea the next dose is reduced.

Conventional irinotecan

• Patients are warned of delayed diarrhoea, which can start more than 24 hours after the infusion and at any time before the next cycle; in monotherapy the first liquid stool came a median of 5 days after the infusion. They must report it promptly and start treatment at once.
• The risk is higher after abdominal or pelvic radiotherapy, with a high baseline white cell count, with performance status 2 or worse, and in women. Untreated, diarrhoea can be fatal, particularly with neutropenia.
• At the first liquid stool the patient drinks large volumes of electrolyte-containing drinks and starts antidiarrhoeal treatment, prescribed by the department that gave the cycle. The patient takes the medicine home so that treatment can begin as soon as diarrhoea appears and tells the doctor or hospital.
• The recommended treatment is high-dose loperamide: 4 mg first, then 2 mg every 2 hours, continued for 12 hours after the last liquid stool and not changed. At these doses it must never be given for more than 48 consecutive hours (risk of paralytic ileus) or for less than 12 hours. Loperamide must not be given as prophylaxis, even after delayed diarrhoea in earlier cycles.
• With severe neutropenia (neutrophils below 500/mm³), a broad-spectrum antibiotic is given as prophylaxis alongside the antidiarrhoeal. Hospital treatment, with an antibiotic, is recommended for diarrhoea with fever, severe diarrhoea needing intravenous fluid, or diarrhoea that persists more than 48 hours after starting high-dose loperamide, and for vomiting associated with delayed diarrhoea. After severe diarrhoea the dose is reduced in later cycles.

Acute Cholinergic Syndrome and Hypersensitivity

• Conventional irinotecan: acute cholinergic syndrome (early diarrhoea with sweating, abdominal cramps, miosis and salivation) can occur during or soon after the infusion, is thought to reflect the anticholinesterase activity of irinotecan, and is more frequent at higher doses. Atropine sulfate 0.25 mg subcutaneously is given unless clinically contraindicated; caution in asthma. After a severe episode, atropine is advised as prophylaxis with later doses.
• Liposomal irinotecan: infusion reactions, mainly rash, urticaria, periorbital oedema or pruritus (all grade 1 or 2), occur mostly early in treatment. Hypersensitivity, including anaphylactic or anaphylactoid reactions and angioedema, may occur; treatment is stopped for severe hypersensitivity.

Neutropenia and Infections

• Both forms: blood counts are monitored. Febrile neutropenia (temperature above 38 °C with neutrophils of 1,000 cells/mm³ or fewer) needs urgent hospital treatment with broad-spectrum intravenous antibiotics, and patients should report any fever. Severe haematological events call for a dose reduction in later cycles.
• Liposomal irinotecan: sepsis with neutropenic fever and fatal septic shock have been seen in metastatic pancreatic cancer. Patients with severe bone marrow failure should not be treated. Previous abdominal radiation raises the risk of severe and febrile neutropenia, so blood counts are watched closely and myeloid growth factors considered, with caution if irradiation is given at the same time. After a Whipple procedure the risk of serious infection is higher.
• Conventional irinotecan: weekly full blood counts are advised. Neutropenia is more frequent after abdominal or pelvic irradiation (take particular care after extensive irradiation, for example more than 25% of bone marrow in the previous 6 weeks) and with baseline bilirubin of 1.0 mg/dL or more. Severe diarrhoea increases the risk of infection and haematological toxicity, so a blood count is taken then.

UGT1A1 Activity and Gilbert’s Syndrome

• Liposomal irinotecan: patients with deficient glucuronidation of bilirubin, such as Gilbert’s syndrome, may be at greater risk of myelosuppression. People homozygous for the UGT1A1*28 allele are at higher risk of neutropenia with non-liposomal irinotecan. In NAPOLI-1, grade 3 or higher neutropenia occurred in 2 of 7 such patients (28.6%), similar to the 30 of 110 (27.3%) of non-homozygous patients on 70 mg/m²; this was not assessed in NAPOLI-3. Dosing for these patients is given under Administration and Dosage.
• Conventional irinotecan: poor UGT1A1 metabolisers, such as patients with Gilbert’s syndrome (for example homozygous for the UGT1A1*28 or *6 variants), are at increased risk of severe neutropenia and diarrhoea, and the risk rises with the dose. No exact reduction of the starting dose has been established, but a reduced starting dose should be considered, especially for doses above 180 mg/m² or in frail patients, following applicable clinical guidelines. Later doses may be increased if tolerated. UGT1A1 genotyping can identify patients at higher risk, but its clinical usefulness is uncertain because the polymorphism does not explain all the toxicity.

Liver, Kidney, Lung and Vascular Warnings

• Liver: with the liposomal form, raised bilirubin increases SN-38 levels and the risk of neutropenia; blood counts are checked regularly if total bilirubin is 1.0 to 2.0 mg/dL, and care is needed in hepatic impairment (bilirubin above 2 times the upper limit, transaminases above 5 times) and with other hepatotoxic medicines.
• Kidney: serum creatinine and urea nitrogen rises and acute renal failure have been seen with the conventional form, usually after infection or dehydration from nausea, vomiting or diarrhoea; rare renal dysfunction from tumour lysis syndrome has been reported.
• Lung: interstitial lung disease-like events, some fatal, have occurred with irinotecan (pneumonitis in 0.3% with the liposomal oxaliplatin combination). Risk factors are pre-existing lung disease, pneumotoxic medicines, colony-stimulating factors and previous radiotherapy. New or worsening dyspnoea, cough or fever should prompt interruption pending investigation, and the liposomal form is stopped if interstitial lung disease is confirmed.
• Vascular and heart: thromboembolic events (pulmonary embolism, venous thrombosis, arterial thromboembolism) are associated with the liposomal form and rarely with the conventional form. Myocardial ischaemic events have been seen with the conventional form, mostly in patients with heart disease or other risk factors, who need close monitoring.
• Underweight patients: with the liposomal form, 5 of 8 patients with a body mass index below 18.5 kg/m² had grade 3 or 4 reactions and 7 of 8 needed a dose change; use with caution.
• Other conventional-form precautions: antiemetic prophylaxis before each dose; caution to avoid extravasation (irinotecan is not a vesicant; if it occurs, rinse the area and apply ice); bowel obstruction must be resolved before treatment; prescribing is weighed carefully in patients with performance status 2 or who may not follow the advice for managing adverse events, who need close hospital follow-up.

Pregnancy, Breastfeeding and Fertility

• Contraception: with the liposomal form, women of childbearing potential use effective contraception during treatment and for 7 months afterwards, and men use condoms during treatment and for 4 months afterwards. With the conventional form, women use highly effective contraception during treatment and up to 6 months after the last dose, and men with partners of childbearing potential use effective contraception during treatment and for 3 months afterwards, because of the potential for genotoxicity.
• Pregnancy: irinotecan was embryotoxic and teratogenic in animals. The liposomal form should not be used in pregnancy unless clearly necessary, and any patient who becomes pregnant must be told of the hazard to the foetus.
• Breastfeeding: contraindicated with both forms. After the last dose of the liposomal form, patients should not breastfeed for one month.
• Fertility: with the liposomal form there are no human data; non-liposomal irinotecan caused atrophy of the male and female reproductive organs in animals, and advice on preserving gametes should be considered before treatment.

Sodium, Sorbitol and Glucose

The liposomal vial contains 33.1 mg of sodium (1.65% of the WHO recommended maximum daily intake of 2 g for an adult). The conventional bags contain less than 1 mmol (23 mg) of sodium per dose. They also contain sorbitol, a source of fructose (607.5 mg in the 180 mL bag, up to 810 mg in the 240 mL bag), and patients with hereditary fructose intolerance should not receive them unless strictly necessary. The glucose content (8.325 g in the 180 mL bag, up to 11.100 g in the 240 mL bag) matters for patients with diabetes mellitus.

Effect on Driving

The liposomal form has a moderate influence on the ability to drive and use machines, and patients should take care.

Pegylated liposomal irinotecan (Onivyde pegylated liposomal): store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. It is shipped and held in the cold chain until it is prepared. After dilution the dispersion is stable for up to 6 hours at 15–25 °C or for no more than 24 hours at 2–8 °C. From a microbiological point of view it should be used immediately; otherwise in-use times and conditions are the responsibility of the user.

Conventional irinotecan (1.5 mg/mL ready-to-use bags): store below 25 °C in the original package to protect from light. Once the bag is opened it must be used immediately. Keep out of the sight and reach of children.

• Onivyde pegylated liposomal: 3 years for the unopened vial. After dilution, 6 hours at 15–25 °C or up to 24 hours at 2–8 °C.
• Conventional irinotecan bags: 2 years. Once the bag is opened it must be used immediately.

Prescription only (Rx). Both forms must be prescribed and administered by healthcare professionals experienced in anti-cancer therapy, and the conventional form only in units specialised in cytotoxic chemotherapy. They are intravenous infusions given in hospital or clinic, so they are supplied to the hospital or clinic that administers them. Onivyde pegylated liposomal is delivered refrigerated at 2–8 °C in the cold chain; conventional irinotecan bags are stored below 25 °C. Because the SmPC says the liposomal form must not be interchanged with non-liposomal irinotecan, the product named on the prescription is the one that must be supplied.