Inotrix 40 Mg/2 Ml/100 Mg/5 Ml/300 Mg/15 Ml Solution

INOTRIX is indicated for the treatment of patients with advanced colorectal cancer with a WHO performance status of 2 or lower:

• In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,
• As a single medicine in patients who have failed an established 5-fluorouracil containing treatment regimen.

Posology

Recommended Dosage:

In monotherapy (for previously treated patient): The recommended dosage of INOTRIX is 350 mg/mu00b2 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 INOTRIX in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with either of the following schedules:

1. INOTRIX plus 5FU/FA in weekly schedule:

   The recommended dose of INOTRIX is 80 mg/mu00b2 administered as a weekly intravenous infusion over a 30 - to 90 - minute period, followed by infusion with folinic acid and then by 5-fluorouracil over 6 weeks. This treatment is followed by one week rest. The full dosage regimen is as follows:

   INOTRIX 80 mg/mu00b2 as a 30-to-90-minute infusion on Day 1 and then weekly for 6 weeks. Folinic acid 500 mg/mu00b2 intravenous infusion as a 2-hour infusion, followed by 5-fluorouracil 2 000 mg/mu00b2 intravenous infusion as a 24-hour infusion, on Day 1 and then weekly for 6 weeks. The treatment is to be repeated every 7 weeks.

2. INOTRIX plus 5FU/FA in every 2 weeks schedule:

   The recommended dose of INOTRIX is 180 mg/mu00b2 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. The full dosage regimen is as follows:

   INOTRIX 180 mg/mu00b2 intravenous infusion as a 30 - to 90 - minute infusion on Day 1 only. Folinic acid 200 mg/mu00b2 intravenous infusion as a 2-hour infusion, followed by 5-fluorouracil 400 mg/mu00b2 intravenous infusion bolus, followed by 5-fluorouracil 600 mg/mu00b2 intravenous infusion as a 22-hour infusion. The folinic acid and 5-fluorouracil are repeated for two consecutive days. Repeat the cycle every two weeks.

Dosage Adjustments:

Delayed Dosing: INOTRIX should not be administered until the neutrophil count remains above 1 500 cells/mmu00b3. In patients who experienced severe neutropenia or severe gastrointestinal adverse events such as diarrhoea, nausea and vomiting, dosing of INOTRIX should be delayed until there has been a full recovery of these effects, especially diarrhoea. INOTRIX 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. This must be strictly adhered to. At the start of a subsequent infusion of therapy, the dose of INOTRIX, 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 INOTRIX 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).

Treatment Duration:

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

Method of administration:

INOTRIX infusion solution should be infused into a peripheral or central vein. INOTRIX should not be delivered as an intravenous bolus or an intravenous infusion shorter than 30 minutes or longer than 90 minutes. For instruction on the preparation of INOTRIX see section 6.6.

Contraindications of INOTRIX:

• History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to one of the excipients of INOTRIX (see section 6.1).
• Chronic inflammatory bowel disease, and/or bowel obstruction or ileus. Patients should not be treated with INOTRIX until resolution of the ileus.
• Pregnancy and lactation. Women of childbearing age receiving INOTRIX should be advised to avoid becoming pregnant and to inform the treating medical practitioner immediately should this occur (see section 4.6).
• Bilirubin > 1,5 times the upper limit of the normal range.
• The safety and efficacy of INOTRIX in children have not been established.
• Severe bone marrow failure.
• WHO performance status > 2.
• Concomitant administration of azole antifungals, St. Johnu2019s Wort (see section 4.5).
• Live attenuated vaccines (see section 4.5).

INOTRIX should be used in patients with a WHO good performance status of less than 2.

The use of INOTRIX should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a qualified medical practitioner. It is strongly recommended that INOTRIX be administered only in healthcare institutions with adequately equipped facilities, including an intensive care unit. In all instances where the use of INOTRIX is considered for chemotherapy, it is especially important to ensure that the patient understands the need for sufficiently prolonged antidiarrhoeal treatment and abundant fluid intake. In rare cases where it is predictable that the patient would comply poorly with the guidance for the management of side effects, a strict follow-up of the patient by the treating medical practitioner or hospitalisation is recommended.

Given the nature and frequency of adverse events, the expected benefit must be balanced in case of risk factors, especially WHO Performance status u2265 2 (or Karnofsky Index < 50).

Delayed diarrhoea: Apart from the diarrhoea shortly after the infusion of INOTRIX, patients should be aware of the high risk of delayed diarrhoea occurring more than 24 hours after the administration of INOTRIX 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 INOTRIX. Patients should quickly inform their medical practitioner 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 leukocytosis and those with performance status u2265 2. 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 INOTRIX has been administered. After discharge from the hospital, the patients should obtain the prescribed medicines so that they can treat the diarrhoea as soon as it occurs. The currently recommended antidiarrhoeal treatment is 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 case 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/mmu00b3).

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: Weekly monitoring of complete blood cell counts should be performed during INOTRIX treatment. Patients should be aware of the risk of infection and the significance of a fever. Febrile neutropenia (temperature u2265 38 u00baC and neutrophil count u2264 1 000 cells/mmu00b3) should be urgently treated in the hospital with broad spectrum intravenous antibiotics. INOTRIX administration should be delayed until the neutrophil count is u2265 1 500 cells/mmu00b3. In patients who experienced severe asymptomatic neutropenia (< 500 cells/mmu00b3), fever or infections associated with neutropenia, the dose of INOTRIX should be reduced.

In patients who experienced severe haematologic events, a dose reduction is recommended for subsequent administration. There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea.

Patients with hepatic function impairment: Liver function tests should be performed at baseline and before each cycle. Patients with impaired liver function (bilirubin > 1,0 and u2264 1,5 times the upper limit of the normal range [ULN] and transaminases 5 times ULN) are at greater risk of developing severe neutropenia or febrile neutropenia and should be closely monitored, including complete blood counts. INOTRIX should not be used in patients with a bilirubin > 1,5 times the ULN and the patients with bilirubin > ULN should be followed with caution. In patients with a bilirubin of < 1,5 times ULN a dose of 350 mg/mu00b2 is recommended once every 3 weeks (see section 4.2).

Nausea and vomiting: Prophylactic treatment with an anti-emetic is recommended before each treatment with INOTRIX. 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 an acute cholinergic syndrome appears (defined as early diarrhoea and a group of symptoms such as sweating, abdominal cramping, lacrimation, myosis and salivation), atropine sulphate (0,25 mg subcutaneously) should be administered unless clinically contraindicated. These symptoms may disappear after atropine administration. Caution should be exercised in patients with asthma. In patients who experienced an acute cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of INOTRIX.

Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by INOTRIX, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving INOTRIX. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Elderly: Due to the greater frequency of decreased hepatic, renal or cardiac function in an elderly patient, dose selection with INOTRIX should be cautious in this population.

Respiratory disorders: Interstitial lung disease presenting as lung infiltration is uncommon during INOTRIX 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 INOTRIX 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.

Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with INOTRIX until resolution of the bowel obstruction (see section 4.3).

Renal function: Increases in serum creatinine or blood urea 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. Instances of renal dysfunction due to tumour lysis syndrome have also been reported. No specific pharmacokinetic studies have been performed in patients with renal impairment.

Irradiation therapy: Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of INOTRIX. Medical practitioners 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 as in INOTRIX). Dosing adjustment may apply to this population.

Cardiac disorders: Myocardial ischaemic events have been observed following INOTRIX therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy (see section 4.8). Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Vascular disorders: INOTRIX has been 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: 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.

Pharmacokinetic parameters of INOTRIX combined with 5-fluorouracil-folinic acid are comparable to those observed in monotherapy.

Neuromuscular blocking medicines: Interaction between INOTRIX and neuromuscular blocking medicines cannot be ruled out. Medicines with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising medicines may be antagonised. Excess acetylcholine may impair the muscle relaxant action of the non-depolarising medicines and may impair the return of normal muscle tone at the end of anaesthesia.

Antineoplastic medicines: The adverse effects of INOTRIX, such as myelosuppression and diarrhoea, is expected to be exacerbated by other antineoplastic medicines having a similar adverse-effect profile.

Dexamethasone: Lymphocytopenia has been reported in patients receiving INOTRIX, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. Hyperglycaemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of INOTRIX. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycaemia in some patients.

Laxatives: Laxative use during therapy with INOTRIX is expected to worsen the incidence or severity of diarrhoea.

Diuretics: Dehydration secondary to vomiting and/or diarrhoea may be induced by INOTRIX. The medical practitioner may wish to withhold diuretics during dosing with INOTRIX and during periods of active vomiting or diarrhoea.

Anticonvulsants: Concomitant administration of CYP3A enzyme-inducing anticonvulsant medicines (e.g. carbamazepine, phenobarbitone or phenytoin) leads to reduced exposure to the active metabolite SN-38. Consideration should be given to starting or substituting non-enzyme inducing anticonvulsants at least one week prior to initiation of INOTRIX therapy in patients requiring anticonvulsant treatment.

Azole antifungals: INOTRIX clearance is greatly reduced in patients receiving concomitant azole antifungals, leading to increased exposure to the active metabolite, SN-38. Azole antifungals should be discontinued at least 1 week prior to starting INOTRIX therapy and should not be administered during INOTRIX therapy (see section 4.3).

St. Johnu2019s Wort (Hypericum perforatum): Exposure to the active metabolite of INOTRIX is reduced in patients taking concomitant St. Johnu2019s Wort. St. Johnu2019s Wort should be discontinued at least 1 week prior to the first cycle of INOTRIX and should not be administered during INOTRIX therapy (see Section 4.3).

Atazanavir sulphate: Co-administration of atazanavir sulphate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of INOTRIX. Atazanavir should not be used with INOTRIX.

Bevacizumab: In one study, INOTRIX plasma concentrations were similar in patients receiving INOTRIX/5-FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of INOTRIX, were analysed in a subset of patients. Concentrations of SN-38 were on average 33 % higher in patients receiving INOTRIX/5-FU/FA in combination with bevacizumab compared with INOTRIX/5-FU/FA alone. Due to high inter-patient variability and limited sampling, it is uncertain if the increase in SN-38 levels observed was due to bevacizumab. There was a small increase in diarrhoea and leukopenia adverse events. More dose reductions of INOTRIX were reported for patients receiving INOTRIX/5-FU/FA in combination with bevacizumab.

Vaccines: Yellow fever vaccine: Risk of fatal generalised reaction to vaccine. Live attenuated vaccines: Risk of generalised reaction to vaccines, possibly fatal. Concomitant use is contraindicated during treatment with INOTRIX and for 6 months following discontinuation of chemotherapy. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoral diseases. If vitamin K antagonists are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required.

Immunodepressant medicines: Immunodepressant medicines (e.g. ciclosporin, tacrolimus) may result in excessive immunosuppression with risk of lymphoproliferation.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with INOTRIX. Women of childbearing potential and men have to use effective contraception during and up to 3 months after treatment.

Pregnancy: INOTRIX is contraindicated during pregnancy as it may cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of INOTRIX in pregnant women. If INOTRIX is used during pregnancy, or if the patient becomes pregnant, while receiving INOTRIX, the patient should be apprised of the potential hazard to the foetus (see section 4.3).

Breastfeeding: In lactating rats, 14C-irinotecan was detected in milk. It is unknown whether INOTRIX is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breastfeeding should be discontinued for the duration of INOTRIX therapy (see section 4.3).

Fertility: There is no human data on the effect of INOTRIX on fertility. In animals, adverse effects of INOTRIX on the fertility of offspring has been documented.

INOTRIX has moderate influence on the ability to drive and use machines. Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of INOTRIX and advised not to drive or operate machinery if these symptoms occur.

a. Summary of the safety profile

The most frequent, dose-limiting adverse reactions of INOTRIX are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.

b. Tabulated list of adverse reactions

Frequencies are defined as: Frequent (more frequent, very common, common), Less frequent (single report, isolated report, uncommon, rare, very rare)

The following adverse reactions considered to be possibly or probably related to the administration of INOTRIX have been reported from patients at the recommended dose of 350 mg/mu00b2 in monotherapy. Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).

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 diarrhoea.

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