Cetomedica

Cetomedica is indicated for the treatment of patients with advanced colorectal cancer:

- in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,

- as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Cetomedica in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing RAS wild-type metastatic colorectal cancer, who had not received prior treatment for metastatic disease or after failure of irinotecan-including cytotoxic therapy.

Cetomedica in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

Cetomedica in combination with capecitabine with or without bevacizumab is indicated for first-line treatment of patients with metastatic colorectal carcinoma.

Cetomedica™ is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: Cetomedica is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

Posology

For adults only. Cetomedica solution for infusion should be infused into a peripheral or central vein.

Recommended dosage:

In monotherapy (for previously treated patient)

The recommended dosage of Cetomedica is 350 mg/m² administered as an intravenous infusion over a 30- to 90- minute period every three weeks.

In combination therapy (for previously untreated patient)

Safety and efficacy of Cetomedica in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following schedule.

- Cetomedica plus 5FU/FA in every 2 weeks schedule

The recommended dose of Cetomedica is 180 mg/m² administered once every 2 weeks as an intravenous infusion over a 30- to 90-minute period, followed by infusion with folinic acid and 5 fluorouracil.

For the posology and method of administration of concomitant cetuximab, refer to the product information for this medicinal product.

Normally, the same dose of irinotecan is used as administered in the last cycles of the prior irinotecan-containing regimen. Irinotecan must not be administered earlier than 1 hour after the end of the cetuximab infusion.

For the posology and method of administration of bevacizumab, refer to the bevacizumab summary of product characteristics.

Dosage adjustments:

Cetomedica should be administered after appropriate recovery of all adverse events to Grade 0 or 1 NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved.

At the start of a subsequent infusion of therapy, the dose of Cetomedica, and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.

With the following adverse events a dose reduction of 15 to 20% should be applied for Cetomedica and/or 5FU when applicable:

- haematological toxicity [neutropenia Grade 4, febrile neutropenia (neutropenia Grade 3-4 and fever Grade 2-4), thrombocytopenia and leukopenia (Grade 4)].

- non-haematological toxicity (Grade 3-4).

Recommendations for dose modifications of cetuximab when administered in combination with irinotecan must be followed according to the product information for this medicinal product.

In combination with capecitabine for patients 65 years of age or more, a reduction of the starting dose of capecitabine to 800 mg/m² twice daily is recommended according to the summary of product characteristics for capecitabine. Refer also to the recommendations for dose modifications in combination regimen given in the summary of product characteristics for capecitabine.

Treatment duration:

Treatment with Cetomedica should be continued until there is an objective progression of the disease or an unacceptable toxicity.

Special populations:

Patients with impaired hepatic function

In monotherapy: Blood bilirubin levels [up to 3 times the upper limit of the normal range (ULN)] in patients with performance status ≤ 2, should determine the starting dose of Cetomedica. In these patients with hyperbilirubinemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased and therefore the risk of hepatotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in this patient population.

- In patients with bilirubin up to 1.5 times the ULN, the recommended dosage of Cetomedica is 350 mg/m².

- In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of Cetomedica is 200 mg/m².

- Patients with bilirubin beyond to 3 times the ULN should not be treated with Cetomedica.

No data are available in patients with hepatic impairment treated by Cetomedica in combination.

Patients with impaired renal function

Cetomedica is not recommended for use in patients with impaired renal function, as studies in this population have not been conducted.

Elderly

No specific pharmacokinetic studies have been performed in elderly. However, the dose should be chosen carefully in this population due to their greater frequency of decreased biological functions. This population should require more intense surveillance.

Paediatric population

The safety and efficacy of Cetomedica in children have not yet been established. No data are available.

Method of administration

Precautions to be taken before handling or administering the medicinal product.

Important Use Information

DO NOT SUBSTITUTE Cetomedica for other drugs containing irinotecan HCl.

Recommended Dose

Administer Cetomedica prior to leucovorin and fluorouracil.

• The recommended dose of Cetomedica is 70 mg/m² administered by intravenous infusion over 90 minutes every 2 weeks.
• The recommended starting dose of Cetomedica in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m² administered by intravenous infusion over 90 minutes. Increase the dose of Cetomedica to 70 mg/m² as tolerated in subsequent cycles.

There is no recommended dose of Cetomedica for patients with serum bilirubin above the upper limit of normal.

Premedication

Administer a corticosteroid and an anti-emetic 30 minutes prior to Cetomedica infusion.

Dose Modifications For Adverse Reactions

Table 1: Recommended Dose Modifications for Cetomedica

For recommended dose modifications of fluorouracil (5-FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies (14).

Preparation And Administration

Cetomedica is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Preparation

• Withdraw the calculated volume of Cetomedica from the vial. Dilute Cetomedica in 500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion.
• Protect diluted solution from light.
• Administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2°C to 8°C (36°F to 46°F)]. Allow diluted solution to come to room temperature prior to administration.
• Do NOT freeze.

Administration

Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.

- Chronic inflammatory bowel disease and/or bowel obstruction.

-

- Lactation.

- Bilirubin > 3 times the upper limit of the normal range.

- Severe bone marrow failure.

- WHO performance status > 2.

- Concomitant use with St John's Wort.

- Live attenuated vaccines.

For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.

Cetomedica is contraindicated in patients who have experienced a severe hypersensitivity reaction to Cetomedica or irinotecan HCl.

Given the nature and incidence of adverse events, Cetomedica will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks:

- in patients presenting a risk factor, particularly those with a WHO performance status = 2.

- in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is recommended for such patients.

When Cetomedica is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule (see section 5) may be considered in patients who may need a closer follow-up or who are at particular risk of severe neutropenia.

Delayed diarrhoea

Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of Cetomedica and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day 5 after the infusion of Cetomedica. Patients should quickly inform their physician of its occurrence and start appropriate therapy immediately.

Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic radiotherapy, those with baseline hyperleucocytosis, those with performance status > 2 and women. If not properly treated, diarrhoea can be life-threatening, especially if the patient is concomitantly neutropenic.

As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where Cetomedica has been administered. After discharge from the hospital, the patients should obtain the prescribed medicinal products so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering Cetomedica when/if diarrhoea is occurring.

The currently recommended antidiarrhoeal treatment consists of high doses of loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.

In addition to the antidiarrhoeal treatment, a prophylactic broad-spectrum antibiotic should be given, when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm³).

In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases:

- Diarrhoea associated with fever,

- Severe diarrhoea (requiring intravenous hydration),

- Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles.

In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles.

Haematology

In clinical studies, the frequency of NCI CTC Grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more have also had a significantly greater likelihood of experiencing first-cycle Grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL.

Weekly monitoring of complete blood cell counts is recommended during Cetomedica treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38 °C and neutrophil count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics.

In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration.

There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.

Liver impairment

Liver function tests should be performed at baseline and before each cycle.

Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times the ULN, due to decrease of the clearance of irinotecan and thus increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times the ULN.

Nausea and vomiting

A prophylactic treatment with antiemetics is recommended before each treatment with Cetomedica. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible for treatment.

Acute cholinergic syndrome

If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulfate (0.25 mg subcutaneously) should be administered unless clinically contraindicated.

These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher irinotecan doses.

Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulfate is recommended with subsequent doses of Cetomedica.

Respiratory disorders

Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy. Interstitial lung disease can be fatal. Risk factors possibly associated with the development of interstitial lung disease include the use of pneumotoxic medicinal products, radiation therapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.

Extravasation

While irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.

Elderly

Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Cetomedica should be cautious in this population.

Chronic inflammatory bowel disease and/or bowel obstruction

Patients must not be treated with Cetomedica until resolution of the bowel obstruction.

Renal function

Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhoea. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.

Irradiation therapy

Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation (e.g. > 25% of bone marrow irradiated and within 6 weeks prior to start of treatment with irinotecan). Dosing adjustment may apply to this population.

Cardiac disorders

Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy.

Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Vascular disorders

Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial thromboembolism) in patients presenting with multiple risk factors in addition to the underlying neoplasm.

Others

Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.

Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.

Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) of CYP3A4 may alter the metabolism of irinotecan and should be avoided.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Neutropenia

Cetomedica can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving Cetomedica, occurring in one of 117 patients in the Cetomedica plus fluorouracil/leucovorin (Cetomedica/5-FU/LV) arm and one of 147 patients receiving Cetomedica as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving Cetomedica/5-FU/LV compared to 2% of patients receiving fluorouracil/leucovorin alone (5-FU/LV). Grade 3 or 4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving Cetomedica/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving Cetomedica/5-FU/LV, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold Cetomedica if the absolute neutrophil count (ANC) is below 1500/mm³ or if neutropenic fever occurs. Resume Cetomedica when the ANC is 1500/mm³ or above. Reduce Cetomedica dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.

Severe Diarrhea

Cetomedica can cause severe and life-threatening diarrhea. Do not administer Cetomedica to patients with bowel obstruction.

Severe or life-threatening diarrhea followed one of two patterns: late onset diarrhea (onset more than 24 hours following chemotherapy) and early onset diarrhea (onset within 24 hours of chemotherapy, sometimes occurring with other symptoms of cholinergic reaction). An individual patient may experience both early and late-onset diarrhea.

In Study 1, Grade 3 or 4 diarrhea occurred in 13% receiving Cetomedica/5-FU/LV compared to 4% receiving 5-FU/LV. The incidence of Grade 3 or 4 late onset diarrhea was 9% in patients receiving Cetomedica/5-FU/LV, compared to 4% in patients receiving 5-FU/LV. The incidence of Grade 3 or 4 early onset diarrhea was 3% in patients receiving Cetomedica/5-FU/LV, compared to no Grade 3 or 4 early onset diarrhea in patients receiving 5-FU/LV. Of patients receiving Cetomedica/5-FU/LV in Study 1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold Cetomedica for Grade 2-4 diarrhea. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity. Following recovery to Grade 1 diarrhea, resume Cetomedica at a reduced dose.

Interstitial Lung Disease

Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). Withhold Cetomedica in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue Cetomedica in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reaction

Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue Cetomedica in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity

Based on animal data with irinotecan HCl and the mechanism of action of Cetomedica, Cetomedica can cause fetal harm when administered to a pregnant woman. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with Cetomedica 70 mg/m² in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cetomedica and for one month following the final dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been performed to assess the potential of irinotecan liposome for carcinogenicity, genotoxicity or impairment of fertility. Intravenous administration of irinotecan hydrochloride to rats once weekly for 13 weeks followed by a 91-week recovery period resulted in a significant linear trend between irinotecan HCl dosage and the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan HCl was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite, SN-38, was mutagenic in the in vitro Ames assay.

Dedicated fertility studies have not been performed with irinotecan liposome injection. Atrophy of male and female reproductive organs was observed in dogs receiving irinotecan liposome injection every 3 weeks at doses equal to or greater than 15 mg/kg, (approximately 3 times the clinical exposure of irinotecan following administration to Cetomedica dosed at 70 mg/m² ) for a total of 6 doses. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl in doses of up to 6 mg/kg/day to rats; however, atrophy of male reproductive organs was observed after multiple daily irinotecan HCl doses both in rodents at 20 mg/kg (approximately 0.007 times the clinical irinotecan exposure following Cetomedica administration at 70 mg/m²) and in dogs at 0.4 mg/kg (0.0007 times the clinical exposure to irinotecan following administration of Cetomedica).

Use In Specific Populations

Pregnancy

Risk Summary

Based on animal data with irinotecan HCl and the mechanism of action of Cetomedica, Cetomedica can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with Cetomedica 70 mg/m² in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

No animal studies have been conducted to evaluate the effect of irinotecan liposome on reproduction and fetal development; however, studies have been conducted with irinotecan HCl. Irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan at a dose of 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose resulted in an irinotecan exposure of approximately 0.002 times the exposure of irinotecan based on area under the curve (AUC) in patients administered Cetomedica at the 70 mg/m² dose. Administration of irinotecan HCl resulted in structural abnormalities and growth delays in rats at doses greater than 1.2 mg/kg/day (approximately 0.0002 times the clinical exposure to irinotecan in Cetomedica based on AUC). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

Lactation

Risk Summary

There is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk production. Irinotecan is present in rat milk.

Because of the potential for serious adverse reactions in breastfed infants from Cetomedica, advise a nursing woman not to breastfeed during treatment with Cetomedica and for one month after the final dose.

Data

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan HCl and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations.

Females And Males Of Reproductive Potential

Contraception

Females

Cetomedica can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Cetomedica and for one month after the final dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with Cetomedica and for four months after the final dose.

Pediatric Use

Safety and effectiveness of Cetomedica have not been established in pediatric patients.

Geriatric Use

Of the 264 patients who received Cetomedica as a single agent or in combination with 5-FU and leucovorin in Study 1, 49% were ≥ 65 years old and 13% were ≥ 75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

CLINICAL STUDIES

Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are presented below. The adverse reactions for other indications are expected to be similar to those for colorectal cancer.

The most common (>1/10), dose-limiting adverse reactions of irinotecan are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.

Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.

Very commonly severe transient acute cholinergic syndrome was observed.

The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the infusion of Cetomedica. These symptoms disappear after atropine administration.

MONOTHERAPY

The following adverse reactions considered to be possibly or probably related to the administration of Cetomedica have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), and very rare (< 1/10,000).

Description of selected adverse reactions (monotherapy)

Severe diarrhoea was observed in 20% of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of Cetomedica.

Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.

Constipation has been observed in less than 10% of patients.

Neutropenia was observed in 78.7% of patients and was severe (neutrophil count < 500 cells/mm3) in 22.6% of patients. Of the evaluable cycles, 18 % had a neutrophil count below 1,000 cells/mm³ including 7.6% with a neutrophil count < 500 cells/mm³.

Total recovery was usually reached by day 22.

Febrile neutropenia was reported in 6.2% of patients and in 1.7% of cycles.

Infections occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.

Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9% with haemoglobin < 6.5 g/dl).

Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4 % of patients and 1.8% of cycles with 0.9% with platelets count ≤ 50,000 cells/mm3 and 0.2% of cycles.

Nearly all the patients showed a recovery by day 22.

Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy.

Asthenia was severe in less than 10 % of patients treated in monotherapy. The causal relationship to Cetomedica has not been clearly established.

Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of patients treated in monotherapy.

Laboratory tests Transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in 9.2 %, 8.1 % and 1.8 % of the patients, respectively, in the absence of progressive liver metastasis.

Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3 % of the patients.

COMBINATION THERAPY

Adverse reactions detailed in this section refer to irinotecan.

There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported adverse reactions were those expected with cetuximab (such as dermatitis acneiform 88%). For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summary of product characteristics.

Adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Very common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity, myocardial ischaemia/infarction; Common, Grade 3 and Grade 4 adverse drug reactions: febrile neutropenia. For complete information on adverse reactions of capecitabine, refer to the capecitabine summary product of characteristics.

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan and bevacizumab in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Common, Grade 3 and Grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and myocardial ischaemia/infarction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.

Grade 3 hypertension was the principal significant risk involved with the addition of bevacizumab to bolus Cetomedica/5-FU/FA. In addition, there was a small increase in the Grade 3/4 chemotherapy adverse events of diarrhoea and leukopenia with this regimen compared to patients receiving bolus Cetomedica/5-FU/FA alone. For other information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.

Cetomedica has been studied in combination with 5-FU and FA for metastatic colorectal cancer.

Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or probably-related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System Organ Classes.

The following adverse reactions considered to be possibly or probably related to the administration of Cetomedica have been reported from 145 patients treated by Cetomedica in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m².

Description of selected adverse reactions (combination therapy)

Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % have a severe diarrhoea.

A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively).

Constipation relative to Cetomedica and/or loperamide has been observed in 3.4 % of patients.

Neutropenia was observed in 82.5% of patients and was severe (neutrophil count < 500 cells/mm3) in 9.8% of patients. Of the evaluable cycles, 67.3% had a neutrophil count below 1,000 cells/mm³ including 2.7% with a neutrophil count < 500 cells/mm³. Total recovery was usually reached within 7-8 days.

Febrile neutropenia was reported in 3.4% of patients and in 0.9% of cycles.

Infections occurred in about 2% of patients (0.5% of cycles) and were associated with severe neutropenia in about 2.1% of patients (0.5% of cycles), and resulted in death in 1 case.

Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).

Thrombocytopenia (< 100,000 cells/mm³) was observed in 32.6% of patients and 21.8% of cycles. No severe thrombocytopenia (< 50,000 cells/mm³) has been observed.

Acute cholinergic syndrome severe transient acute cholinergic syndrome was observed in 1.4 % of patients treated in combination therapy.

Asthenia was severe in 6.2 % of patients treated in combination therapy. The causal relationship to Cetomedica has not been clearly established.

Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 6.2 % of patients treated in combination therapy.

Laboratory tests Transient serum levels (Grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15%, 11%, 11% and 10% of the patients, respectively, in the absence of progressive liver metastasis. Transient Grade 3 were observed in 0%, 0%, 0% and 1% of the patients, respectively. No Grade 4 was observed.

Increases of amylase and/or lipase have been very rarely reported.

Rare cases of hypokalaemia and hyponatraemia mostly related with diarrhoea and vomiting have been reported.

OTHER ADVERSE EVENTS REPORTED IN CLINICAL STUDIES WITH THE WEEKLY REGIMEN FOR Cetomedica

The following additional drug-related events have been reported in clinical studies with irinotecan: pain, sepsis, anorectal disorder, GI candida infection, hypomagnesaemia, rash, skin signs, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain, gamma-glutamyltransferase increased, extravasation, and tumour lysis syndrome, cardiovascular disorders (angina pectoris, cardiac arrest, myocardial infarction, myocardial ischaemia, peripheral vascular disorder, vascular disorder), and thromboembolic events (arterial thrombosis, cerebral infarction, cerebrovascular accident, deep vein thrombosis, peripheral embolism , pulmonary embolism, thrombophlebitis, thrombosis, and sudden death).

POST-MARKETING SURVEILLANCE

Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

The following adverse drug reactions are discussed in greater detail in other sections of the label:

• Severe Neutropenia
• Severe Diarrhea
• Interstitial Lung Disease
• Severe Hypersensitivity Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Cetomedica cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

The safety data described below are derived from patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of Cetomedica 70 mg/m² with leucovorin 400 mg/m² and fluorouracil 2400 mg/m² over 46 hours every 2 weeks (Cetomedica/5-FU/LV; N=117), Cetomedica 100 mg/m² every 3 weeks (N=147), or leucovorin 200 mg/m² and fluorouracil 2000 mg/m² over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; N=134). Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the Cetomedica/5-FU/LV arm, 9 weeks in the Cetomedica monotherapy arm, and 6 weeks in the 5-FU/LV arm.

The most common adverse reactions ( ≥ 20%) of Cetomedica were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities ( ≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions ( ≥ 2%) of Cetomedica were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

Adverse reactions led to permanent discontinuation of Cetomedica in 11% of patients receiving Cetomedica/5-FU/LV; the most frequent adverse reactions resulting in discontinuation of Cetomedica were diarrhea, vomiting, and sepsis. Dose reductions of Cetomedica for adverse reactions occurred in 33% of patients receiving Cetomedica/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. Cetomedica was withheld or delayed for adverse reactions in 62% of patients receiving Cetomedica/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.

Table 2 provides the frequency and severity of adverse reactions in Study 1 that occurred with higher incidence ( ≥ 5% difference for Grades 1-4 or ≥ 2% difference for Grades 3-4) in patients who received Cetomedica/5-FU/LV compared to patients who received 5-FU/LV.7

Table 2: Adverse Reactions with Higher Incidence ( ≥ 5% Difference for Grades 1-4* or ≥ 2% Difference for Grades 3 and 4) in the Cetomedica/5-FU/LV Arm

Cholinergic Reactions

Cetomedica can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhea. In Study 1, Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) Cetomedica-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea.

Infusion Reactions

Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of Cetomedica administration were reported in 3% of patients receiving Cetomedica or Cetomedica/5-FU/LV.

Laboratory abnormalities that occurred with higher incidence in the Cetomedica/5-FU/LV arm compared to the 5-FU/LV arm ( ≥ 5% difference) are summarized in the following table.

Table 3: Laboratory Abnormalities with Higher Incidence ( ≥ 5% Difference) in the Cetomedica/5-FU/LV Arm*#

Symptoms

There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea.

Management

There is no known antidote for Cetomedica. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

There are no treatment interventions known to be effective for management of overdosage of Cetomedica.

Absorption

At the end of the infusion, at the recommended dose of 350 mg/m², the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 µg/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 µg.h/ml and 451 ng.h/ml, respectively. A large interindividual variability in pharmacokinetic parameters is generally observed for SN-38.

Distribution

The phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m² every three weeks, the volume of distribution at steady state (Vss): 157 L/m².

In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65% and 95%, respectively.

Biotransformation

Mass balance and metabolism studies with 14C-labelled drug have shown that more than 50% of an intravenously administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.

Two metabolic pathways account each for at least 12% of the dose:

- Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by glucuronidation, and further by biliary and renal excretion (less than 0.5% of the irinotecan dose) The SN-38 glucuronite is subsequently probably hydrolysed in the intestine.

- Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate).

Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38. Only SN-38 has significant cytotoxic activity.

Elimination

In a phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m² every three weeks, irinotecan showed a biphasic or triphasic elimination profile. The mean plasma clearance was 15 L/h/m². The mean plasma half-life of the first phase of the triphasic model was 12 minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal elimination half-life of 13.8 hours.

Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the upper normal limit. In these patients a 200 mg/m² irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters.

Linearity/non-linearity

A population pharmacokinetic analysis of irinotecan has been performed in 148 patients with metastatic colorectal cancer, treated with various schedules and at different doses in phase II trials. Pharmacokinetic parameters estimated with a three compartment model were similar to those observed in phase I studies. All studies have shown that irinotecan (CPT-11) and SN-38 exposure increase proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.

Pharmacokinetic/Pharmacodynamic relationship(s)

The intensity of the major toxicities encountered with Cetomedica (e.g. leukoneutropenia and diarrhoea) are related to the exposure (AUC) to parent drug and metabolite SN-38. Significant correlations were observed between haematological toxicity (decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC values in monotherapy.

The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received Cetomedica, as a single agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m² and 353 patients with cancer using population pharmacokinetic analysis.

The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of Cetomedica 70 mg/m² as a single agent or part of combination chemotherapy are presented in Table 4.

Table 4: Summary of Mean (±Standard Deviation) Total Irinotecan and Total SN-38

Distribution

Direct measurement of irinotecan liposome showed that 95% of irinotecan remains liposome-encapsulated, and the ratios between total and encapsulated forms did not change with time from 0 to 169.5 hours post-dose. The mean volume of distribution is summarized in Table 4.

Plasma protein binding is < 0.44% of the total irinotecan in Cetomedica.

Elimination

Metabolism

The metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In the population pharmacokinetic analysis using the results of a subset with UGT1A1*28 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A1*28 allele, patients homozygous (N=14) and non-homozygous (N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/mL, respectively.

Excretion

The disposition of Cetomedica has not been elucidated in humans. Following administration of irinotecan HCl , the urinary excretion of irinotecan is 11 to 20%; SN-38, < 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide), over a period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).