Active ingredients: Irinotecan (Irinotecan hydrochloride trihydrate)
Irinotecan Hospira 20 mg / ml concentrate for solution for infusion
Why is Irinotecan used - Generic Drug? What is it for?
Irinotecan Hospira belongs to a group of medicines called cytostatics (anti-cancer medicines).
Irinotecan Hospira is used for the treatment of advanced metastatic cancer of the colon or rectum in adults and when the disease is at an advanced stage in the intestine, either in combination with other anticancer medicines (combination therapy) or alone (monotherapy). .
Doctors may use a combination of irinotecan with 5-fluorouracil / folinic acid (5-FU / FA) and bevacizumab to treat colon and rectal cancer.
To treat colon and rectal cancer, doctors may use a combination of irinotecan with capecitabine with or without bevacizumab.
To treat colon cancers (KRAS wild-type) expressing the epidermal growth factor receptor (EGFR) that are blocked by monoclonal antibody the doctor may use the combination of irinotecan with cetuximab.
For more information on the disease, ask your doctor.
Contraindications When Irinotecan - Generic Drug should not be used
Do not use Irinotecan Hospira:
- If you are sensitive (allergic) to "Irinotecan hydrochloride or any of the ingredients in this medicine (listed in section 6)
- If you suffer from other intestinal problems or if you have suffered from intestinal obstruction
- If you are breastfeeding
- If you have high levels of bilirubin in your blood (above three times the upper limit of the normal range)
- If you suffer from severe blood cell failure (severe bone marrow failure)
- If your general health is poor (determined according to international standards)
- If you are using the natural remedy St. John's wort (Hypericum perforatum)
For additional contraindications to cetuximab or bevacizumab or capecitabine, which can be used in combination with irinotecan, consult the information on these medicinal products.
Precautions for use What you need to know before taking Irinotecan - Generic Drug
This medicine is intended for use in adults only. Check with your doctor if this medicine has been prescribed for use in a child.
Particular care should also be taken in elderly patients.
As Irinotecan Hospira is an anti-cancer medicine it will be given to you in a special unit and under the supervision of a doctor qualified in the use of anti-cancer medicines. The staff of the unit will explain to you what you need to watch out for during and after treatment. This leaflet can help you remember this.
If you are receiving irinotecan in combination with cetuximab or with bevacizumab or capecitabine, please take care to read the leaflet accompanying the pack of these medicines.
Before using this medicine tell your doctor if any of the following applies to you:
- If you have heart problems.
- If you smoke, you suffer from high blood pressure or high cholesterol, as these factors can increase the risk of heart problems during treatment with this medicine.
- If you have had or need to undergo any vaccinations
Interactions Which drugs or foods can modify the effect of Irinotecan - Generic Drug
Tell your doctor if you are taking or have recently taken any other medicines, including non-prescription medicines, this also applies to herbal medicines.
The following medicines may modify the effects of irinotecan:
- carbamazepine, phenobarbital or phenytoin (drugs used in the management of epilepsy)
- ketoconazole (used to treat fungal infections)
- rifampicin (used in the treatment of tuberculosis)
- St. John's wort (Hypericum perforatum) should not be taken during treatment with irinotecan or between treatment courses as it may reduce the effects of irinotecan.
- Atazanavir (used to treat HIV)
- Anticoagulants (used to thin the blood)
- Vaccines. Tell your doctor if you have had or are due to have any vaccinations
- Ciclosporin or tacromilus (used to depress the immune system)
If you have to have an operation, tell your doctor or anesthetist that you are taking this medicine, as it may change the effect of some medicines used during surgery.
Warnings It is important to know that:
During the administration of irinotecan (30 - 90 minutes) and up to 24 hours after administration you may experience some of the following symptoms:
- Diarrhea
- Sweating
- Abdominal pain
- Excessive tearing
- Visual disturbances
- Excessive salivation
The medical term for these symptoms is "acute cholinergic syndrome" which can be treated (with atropine). If you experience any of these symptoms, immediately inform your doctor who will give you the most suitable treatment.
From the first day after treatment with irinotecan and until the next, you may experience various symptoms, which can be serious and need immediate treatment and careful supervision. These symptoms are:
Diarrhea
If diarrhea starts more than 24 hours after irinotecan treatment ("delayed diarrhea") it can be serious. It often occurs around 5 days after therapy. This diarrhea must be treated immediately and monitored closely. Immediately after the first diarrheal discharge follow the instructions below:
- Take the anti-diarrheal treatment that your doctor has given you, strictly follow the instructions received. Treatment should not be changed without first checking with your doctor. The recommended anti-diarrheal treatment is loperamide (4mg the first time and then 2mg every 2 hours, even at night). This should be continued for at least 12 hours after the last diarrheal discharge. The recommended dosage for loperamide should not be taken for more than 48 hours.
- Immediately drink large amounts of water, moisturizing fluids (eg, water, fizzy drinks, broth or oral moisturizing therapy).
- Immediately inform the doctor who supervises the treatment of diarrhea. If you are unable to reach it, contact the hospital and the operating unit that supervises the treatment with irinotecan. It is very important that they are informed of diarrhea.
For the management of diarrhea, hospitalization is recommended in the following cases:
- You suffer from diarrhea and have a fever (above 38 ° C)
- You have severe diarrhea (and vomiting) with excessive water loss that requires intravenous hydration
- You still suffer from diarrhea 48 hours after starting the anti-diarrheal treatment
Note! Do not follow any other treatments and fluid intake for diarrhea other than those prescribed by your doctor. Follow your doctor's instructions. Even if you have experienced delayed diarrhea in previous cycles, anti-diarrheal treatment should not be used for prevention.
Fever
If your body temperature rises above 38 ° C it can be a sign of infection, particularly if you also have diarrhea. If you have a fever (higher than 38 ° C) contact your doctor or hospital immediately in order to start the necessary treatment.
Nausea (feeling sick) and vomiting
If you suffer from nausea and / or vomiting immediately contact your doctor or hospital.
Neutropenia
Irinotecan can cause a drop in the number of some white blood cells that play an important role in fighting infections. This is known as neutropenia. Neutropenia is often reported following irinotecan treatment and is reversible. Your doctor must perform blood tests regularly in order to monitor these white blood cells. Neutropenia is severe and must be treated promptly and closely monitored.
Difficulty in breathing
If you have difficulty breathing contact your doctor immediately.
Impaired liver function
Before starting treatment with irinotecan and before each course of treatment, your doctor checks your liver function (using blood tests).
Impaired renal function
This medicine has not been tested in patients with kidney problems, if you have kidney problems, please check with your doctor.
After returning home from the hospital, if you get one or more of the above symptoms, you should immediately contact your doctor or the hospital unit supervising your treatment with irinotecan.
Pregnancy and breastfeeding
Do not use Irinotecan Hospira:
- If you are breastfeeding
You must not be treated with irinotecan if you are pregnant unless the clinical condition requires treatment with irinotecan.
If you or your partner are treated with irinotecan you must avoid becoming pregnant during treatment. Women of childbearing potential and men must use adequate contraceptive methods during treatment and for at least:
- In women one month after the end of treatment
or
- In men three months after the end of treatment
Also, should you become pregnant during this period, you should immediately inform your doctor.
Driving and using machines
In some cases Irinotecan Hospira can cause side effects that affect the ability to drive and use machines. If in doubt, contact your doctor or pharmacist.
You may experience dizziness or visual disturbances during the first 24 hours after treatment with Irinotecan Hospira. Should this happen to you, you should neither drive nor use machines.
Irinotecan Hospira contains sorbitol. If you have been told by your doctor that you have an intolerance to some sugars (eg fructose intolerance), contact your doctor before taking this medicinal product. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, ie essentially "sodium-free".
Dosage and method of use How to use Irinotecan - Generic Drug: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
For adults only.
Irinotecan will be given by infusion into a vein over a period of 30-90 minutes.
The dose to be infused depends on your age, height, weight and your state of health. Your doctor will calculate your body surface area in square meters (m2) based on your height and weight. The dosage also depends on any other treatments you may have received for your cancer.
- If you have already been treated with 5-fluorouracil you will normally be treated with irinotecan alone starting with a dose of 350 mg / m2 every three weeks.
- If you have never been treated with chemotherapy you will normally receive 180 mg / m2 of irinotecan every two weeks followed by folinic acid and 5-fluorouracil.
If you are treated with irinotecan in combination with cetuximab, irinotecan cannot be administered for one hour after the end of the cetuximab infusion.
Always follow your doctor's advice regarding ongoing treatment.
These dosages can be adjusted by your doctor according to your condition and any unwanted effects you may experience.
Overdose What to do if you have taken too much Irinotecan - Generic Drug
If you are given a higher dose of irinotecan than required, the side effects may be more serious. You will receive maximum support to prevent dehydration secondary to diarrhea and to treat infectious complications. If you think you have been treated with a higher dose, contact your doctor.
If you have any further questions on the use of this medicine, talk to your doctor or pharmacist or nurse.
Side Effects What are the side effects of Irinotecan - Generic Drug
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Your doctor will inform you of these side effects and will explain the risks and benefits of the treatment.
Some of these side effects need to be treated immediately, these are:
- diarrhea
- a drop in the number of neutrophil granulocytes, a type of white blood cell, which plays an important role in fighting infections
- fever
- nausea and vomit
- difficulty breathing (likely symptom of severe allergic reactions)
Please read the instructions in the "Warnings and Precautions" section carefully and follow them in case you experience any of the effects described above.
Other side effects include:
Very common side effects (in more than 1 in 10 patients)
- blood disorders including an abnormally low number of neutrophil granulocytes, a type of white blood cell (neutropenia) and a drop in the amount of hemoglobin in the blood (anemia)
- in combination therapy, thrombocytopenia (reduction in the number of platelets) with resulting bruising, tendency to bleed and abnormal bleeding
- alone, fever
- in monotherapy, infections
- severe delayed diarrhea
- on its own, severe nausea (feeling sick) and vomiting (feeling sick)
- hair loss (hair grows back after treatment is finished)
- in combination therapy, transient mild to moderate increase in serum levels of certain liver enzymes (SGPT, SGOT, alkaline phosphatase) or bilirubin
Common side effects (in less than 1 in 10 patients but more than 1 in 100)
- severe acute transient cholinergic syndrome: The main symptoms are defined as early diarrhea and several other symptoms such as abdominal pain; red, painful, itchy, or watery eyes (conjunctivitis); runny nose (rhinitis); low blood pressure; flushing secondary to dilation of blood vessels (vasodilation); sweating; chills; a feeling of general malaise and illness; dizziness visual disturbances; contraction of the pupil; tearing and increased salivation occurring during or within the first 24 hours after the infusion of Irintoecan Hospira
- in monotherapy, thrombocytopenia (reduction in the number of blood platelets) which causes bruising, a tendency to bleed and abnormal bleeding
- in combination therapy, fever
- in combination therapy, infections
- infections associated with a severe drop in the number of certain types of white blood cells (neutropenia), which resulted in 3 deaths
- fever associated with a severe drop in the number of some white blood cells (febrile neutropenia)
- in combination therapy, severe nausea (feeling sick) and vomiting (feeling sick)
- water loss (dehydration), commonly associated with diarrhea and / or vomiting
- constipation
- feeling weak (asthenia)
- in monotherapy, transient mild to moderate increase in serum levels of some liver enzymes (transaminase, alkaline phosphatase) or bilirubin
- transient mild to moderate increase in blood creatinine levels
- in combination therapy, transient and marked (grade 3) increase in serum bilirubin levels
Uncommon side effects (in less than 1 in 100 patients but more than 1 in 1,000)
- mild allergic reactions (skin redness including itchy red skin, hives, conjunctivitis, rhinitis)
- mild skin reactions
- at the infusion site, modest reactions
- lung disease manifesting as shortness of breath, dry cough and inspiratory rales (interstitial lung disease); early effects such as difficulty in breathing
- partial or total intestinal obstruction (intestinal obstruction, blockage of the intestine), stomach and bleeding of the intestine
- inflammation of the intestine causing abdominal pain and / or diarrhea (a condition known as pseudo-membranous colitis)
- kidney failure, low blood pressure or cardiac decompensation in patients with previous episodes of dehydration associated with diarrhea and / or vomiting or sepsis
Rare side effects (in less than 1 in 1,000 patients but more than 1 in 10,000)
- severe allergic reactions (anaphylactic / anaphylactoid reaction) which include swelling of the hands, feet, ankles, face, lips, mouth or throat which may cause difficulty in swallowing or extremely difficult breathing
- muscle twitching or cramps or numbness (paraesthesia)
- inflammation of the large intestine with resulting abdominal pain (colitis including typhlitis, ischemic and ulcerative colitis)
- intestinal perforation
- loss of appetite
- abdominal pain
- inflammation of the mucous membranes
- reduced levels of potassium and sodium in the blood, mainly related to diarrhea and vomiting
- symptomatic and asymptomatic inflammation of the pancreas (especially abdominal pain)
- increase in blood pressure during and after treatment
Very rare side effects (in less than 1 in 10,000 patients)
- reversible speech problems
- increased levels of some digestive enzymes that metabolize sugars (amylases) and fats (lipases)
- a case of low blood platelet count secondary to the presence of antibodies against platelets
Side effects with frequency not known:
- rash
- abnormally low white blood cell count (leukopenia).
If you are treated with irinotecan in combination with cetuximab, some of the side effects you may experience may be secondary to this combination. Such side effects may include acne-like redness. Therefore, be sure to also read the package leaflet included with the cetuximab package.
If you are treated with irinotecan in combination with capecitabine, some of the side effects you may experience may be secondary to this combination. These side effects may include: very common blood clots, common allergic reactions, heart attack and fever in patients with low white blood cell counts. Therefore, be sure to also read the package leaflet included with the capecitabine pack.
If you are treated with irinotecan in combination with capecitabine and bevacizumab, some of the side effects you may experience may be secondary to this combination. Such side effects may include: reduced number of white blood cells, blood clots, high blood pressure and heart attacks. Therefore, be sure to also read the capecitabine and bevacizumab package leaflets.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine. .
Expiry and Retention
How to store Irinotecan Hospira
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the outer carton and vial label. The expiry date refers to the last day of the month.
- Concentrate: To protect the medicine from light, keep the vial in the original package. Do not freeze. After first opening, as they do not contain an antimicrobial preservative, the vials should be used immediately.
- Diluted concentrate: For single use only. The residual solution must be discarded.
- After dilution: Chemical and physical in-use stability has been demonstrated in glucose 50 mg / ml (5%) and sodium chloride 9 mg / ml (0.9%) for 72 hours between 2 ° C and 8 ° C. From a microbiological point of view, the medicine should be used immediately. If not used immediately, in-use storage times and conditions prior to use remain the responsibility of the user and would normally not exceed 24 hours at 2 ° C to 8 ° C, unless dilution has taken place. under controlled and validated aseptic conditions.
Do not use this medicine if you notice visible particles in the concentrate or infusion solution.
Do not dispose of any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer usable. These measures help protect the environment.
Deadline "> Other information
What Irinotecan Hospira contains
- The active substance is irinotecan hydrochloride trihydrate. Each milliliter (ml) of solution contains 20 milligrams (mg) of irinotecan hydrochloride trihydrate equivalent to 17.33 mg of irinotecan.
- The other ingredients are sorbitol (E420), lactic acid and water for injections and sodium hydroxide, hydrochloric acid (for pH adjustment).
Appearance of Irinotecan Hydrochloride and contents of the pack
Irinotecan Hospira is in the pharmaceutical form of concentrate for solution for infusion (a concentrated solution that is diluted before being administered by slow intravenous infusion).
This medicine is packaged in glass vials containing 2 ml, 5 ml and 25 ml of irinotecan hydrochloride trihydrate.
The vials are covered with a protective plastic layer which reduces the risk of spillage if the vial breaks - these are known under the term ONCO-TAIN. The vials are available in single packs.
Not all pack sizes may be marketed.
Deadline "> Information for healthcare professionals
The following information is intended for healthcare professionals only
INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL
As with other potentially toxic compounds, caution should be exercised when handling or preparing irinotecan solutions.
Instructions on use / handling
As with other antineoplastic medicinal products, irinotecan must be prepared and handled with care. The use of goggles, mask and gloves is required. Pregnant women should never handle cytotoxics. If the solution of irinotecan concentrate for infusion or the solution prepared for the infusion should come into contact with the skin, wash immediately and abundantly with soap and water. If irinotecan concentrate for infusion or the solution prepared for infusion should come into contact with mucous membranes, wash immediately with water.
Preparation of the intravenous infusion
As with all injectable drugs, the Irinotecan solution must be prepared aseptically.
If any precipitate is observed to form in the vials or solution for infusion, the product should be discarded following standard hospital procedures applicable to cytotoxic drugs.
Under aseptic conditions, withdraw the required amount of the concentrated Irinotecan solution from the vial using a graduated syringe and inject it into a 250 ml infusion bag or bottle containing only sodium chloride 9 mg / ml (0.9% ) or glucose solution 50 mg / ml (5%). The infusion must then be mixed perfectly by manual rotation.
Elimination
All materials used for dilution and administration should be discarded according to standard hospital procedures applicable to cytotoxic medicinal products.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
IRINOTECAN HOSPIRA 20 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One milliliter contains 20 mg of Irinotecan hydrochloride trihydrate, equivalent to 17.33 mg of Irinotecan.
One vial of 2 ml of solution for injection contains 40 mg of Irinotecan hydrochloride trihydrate
One vial of 5 ml of solution for injection contains 100 mg of Irinotecan hydrochloride trihydrate
One vial of 25 ml of solution for injection contains 500 mg of Irinotecan hydrochloride trihydrate
Excipients:
Contains Sorbitol, (E420) 45.0 mg / ml
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM -
Concentrate for solution for infusion.
A clear, colorless to pale yellow solution.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Irinotecan is indicated for the treatment of advanced colorectal cancer.
• In combination with 5-fluorouracil (5-FU) and folinic acid (FA) in patients who have not previously been treated with chemotherapy for advanced disease
• As monotherapy in patients in whom conventional 5-fluorouracil-containing treatment has failed
Irinotecan in combination with Cetuximab is indicated for the treatment of patients with wild-type KRAS-expressing epidermal growth factor (EGFR) receptor-expressing metastatic colorectal cancer, who have not previously been treated for metastatic disease or after failure of cytotoxic therapy containing irinotecan (see section 5.1).
Irinotecan in combination with 5-FU, FA and Bevacizumab is indicated in the first-line therapy of patients with metastatic cancer of the colon or rectum.
04.2 Posology and method of administration -
For use in adult patients only. The diluted Irinotecan solution for infusion should be infused into a central or peripheral vein.
Recommended dosage
The dosages of Irinotecan reported in this Summary of Product Characteristics refer to mg of Irinotecan hydrochloride trihydrate.
As monotherapy (for previously treated patients)
The recommended dosage of Irinotecan is 350 mg / m² administered by intravenous infusion lasting 30 - 90 minutes every 3 weeks (see sections 4.4 and 6.6).
In combination therapy (for previously untreated patients)
The safety and efficacy of Irinotecan in combination with 5-fluorouracil (5FU) and folinic acid (FA) were determined with the following treatment regimen (see section 5.1)
• Irinotecan hydrochloride plus 5-FU / AF every 2 weeks
The recommended dose of Irinotecan is 180 mg / m² administered every 2 weeks as an intravenous infusion lasting 30 - 90 minutes, followed by infusion of FA and 5-FU.
For the posology and method of administration concomitantly with Cetuximab, consult the information for this medicinal product. Normally, the same dose of Irinotecan is used as that given in the last cycle of the previous Irinotecan-containing regimen. Irinotecan should not be administered earlier than one hour after the end of the Cetuximab infusion.
For the dose and method of administration of Bevacizumab, please refer to the respective Summary of Product Characteristics.
Dosage adjustment
Irinotecan should be administered after all NCI-CTC (National Cancer Institute Common Toxicity Criteria) grade 0 or 1 adverse events have subsided and treatment-related diarrhea has completely resolved.
At the start of a subsequent course of infusions, the dose of Irinotecan, and if applicable 5-FU, should be decreased in accordance with the degree of more serious adverse events observed during the previous infusion. Treatment should be delayed for 1-2 weeks until complete recovery from treatment-related adverse events.
With the following adverse events, apply a 15-20% dose reduction of Irinotecan and / or 5-FU as appropriate:
• 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 dosage adjustment of Cetuximab when given in combination with Irinotecan should be followed according to the product information for this specific medicinal product.
For bevacizumab dose adjustment when given in combination with Irinotecan / 5-FU / FA, see the bevacizumab summary of product characteristics.
Duration of treatment
Irinotecan treatment should be continued as long as objective progression of the disease is observed and no symptoms of unacceptable toxicity appear.
Special populations
Patients with impaired liver function:
Monotherapy
Bilirubin values (up to 3 times the upper limit of the normal range), in patients with WHO performance status ≤2, determine the initial dosage of Irinotecan. In these patients with hyperbilirubinemia and a prothrombin time greater than 50%, clearance of Irinotecan is reduced (see section 5.2), therefore there is an increased risk of haematic toxicity. Therefore, weekly complete blood counts should be monitored in this patient population.
• In patients with bilirubin values up to 1.5 times the upper limit of the normal range, the recommended dose of Irinotecan is 350 mg / m².
• In patients with bilirubin values between 1.5 - 3 times the upper limit of the normal range, the recommended dose of Irinotecan is 200 mg / m².
• Patients with bilirubin values greater than 3 times the upper limit of the normal range should not be treated with Irinotecan (see sections 4.3 and 4.4).
No data are available for patients with hepatic impairment treated with irinotecan in combination therapy.
Patients with impaired renal function
As no specific studies have been conducted with this medicinal product in this patient group, the use of Irinotecan in patients with impaired renal function is not recommended (see sections 4.4 and 5.2).
Senior citizens
No specific pharmacokinetic studies have been performed in the elderly. However, due to the increased frequency of decrease in vital functions, the choice of dosage should be made with caution in this population. These patients require more supervision (see section 4.4).
04.3 Contraindications -
Chronic inflammatory bowel disease and / or intestinal obstruction (see section 4.4).
History of severe hypersensitivity reactions to Irinotecan hydrochloride trihydrate or to any of the excipients of Irinotecan.
Lactation (see sections 4.6 and 4.4).
Bilirubin values> 3 times the upper limit of the normal range (see section 4.4).
Severe bone marrow failure.
"WHO performance status"> 2.
Concomitant use of St. John's wort (see section 4.5).
For additional contraindications of Cetuximab or Bevacizumab, consult the product information of these medicines.
04.4 Special warnings and appropriate precautions for use -
The use of Irinotecan should be reserved for units specialized in the administration of cytotoxic therapies under the supervision of a physician qualified in the use of antineoplastic therapies.
Given the nature and incidence of side effects, Irinotecan should be prescribed in the following cases only after evaluation of the expected benefit in relation to any risk factors:
• patients with risk factors, particularly those with a WHO = 2 "Performance Status".
• in those rare cases for which poor adherence of the patient to the instructions for the treatment of adverse events is foreseeable (need for immediate and prolonged antidiarrheal treatment associated with the intake of large quantities of fluids upon the onset of delayed diarrhea). such patients a "careful surveillance in the hospital.
When Irinotecan is used on its own, it is usually given according to the dosing schedule every 3 weeks. However, the weekly schedule (see section 5) may be considered for patients who need more frequent monitoring or who are particularly at risk for severe neutropenia.
Delayed diarrhea
Patients should be aware of the risk of delayed diarrhea which may occur more than 24 hours after administration of Irinotecan and at any time prior to the next cycle. In monotherapy, the mean time to first liquid evacuation was day 5 after the infusion of Irinotecan. Patients should promptly notify their physician if diarrhea develops and initiate appropriate therapy immediately.
Patients at greatest risk of diarrhea are those previously treated with abdominal / pelvic radiotherapy, those with basal hyperleukocytosis and those with "Performance Status"> 2 and women. If not treated properly, diarrhea can threaten survival, especially in cases where the patient is simultaneously neutropenic.
As soon as the first liquid stool appears, the patient should begin drinking large volumes of liquids in the form of electrolyte-containing beverages and appropriate antidiarrheal therapy initiated immediately. Appropriate antidiarrheal treatment will be prescribed by the doctor who administered Irinotecan. After discharge from the hospital, patients should have the prescribed medications available so that they can treat diarrhea as soon as it occurs. They should also inform their doctor or the ward that administered Irinotecan of the onset of diarrhea.
The currently recommended antidiarrheal treatment is high-dose Loperamide (4 mg to begin with, and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be changed. Under no circumstances should Loperamide be administered at these doses for more than 48 hours, due to the risk of paralytic ileus, and treatment should last at least 12 hours.
When diarrhea is associated with severe neutropenia (neutrophil count cells / mm³), broad spectrum antibiotic prophylaxis should be added to the antidiarrheal treatment.
In addition to antibiotic treatment, hospitalization is recommended for the control of diarrhea in the following cases:
§ Diarrhea associated with fever,
§ Severe diarrhea (such as to require intravenous rehydration),
§ Persistent diarrhea 48 hours after the start of high dose Loperamide therapy.
Loperamide should not be given as a prophylaxis, even in patients who have experienced delayed diarrhea in previous courses of treatment with the medicinal product.
Dosage reduction is recommended in patients who have experienced severe diarrhea in subsequent cycles (see 4.2).
Hematology
A complete weekly check of blood counts is recommended during treatment with Irinotecan. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature> 38 ° C and neutrophil count ≤ 1000 cells / mm³ ) needs to be treated urgently in hospital with intravenous broad-spectrum antibiotics.
In patients who have experienced severe haematological events, a dose reduction is recommended for subsequent administrations (see section 4.2).
The risk of infections and haematological toxicity is increased in patients with severe diarrhea. A complete blood count should be checked in these patients.
Patients with reduced activity of uridine diphosphate glucuronosyltransferase (UGT1A1)
SN-38 is detoxified from UGT1A1 into SN-38 glucuronide. Individuals with genetic deficiency of UGT1A1 (Crigler-Najjar syndrome type 1 and type 2 or individuals who are homozygous for the UGT1A1 * 28 allele [Gilbert's syndrome]) have an increased risk of irinotecan toxicity. consider using a reduced starting dose of Irinotecan.
Altered liver function
Liver function tests should be performed under baseline conditions and before each treatment cycle.
Weekly monitoring of complete blood cell counts should be conducted in patients with bilirubin values 1.5 to 3 times the upper limit of the normal range due to decreased clearance of Irinotecan (see section 5.2) and therefore these present a higher risk of haematotoxicity. For patients with bilirubin values> 3 times the upper limit of the normal range see section 4.3.
Nausea and vomit
Prophylactic treatment with an antiemetic is recommended before each treatment with Irinotecan. Nausea and vomiting have often been reported. Patients with vomiting associated with delayed diarrhea should be hospitalized as soon as possible.
Acute cholinergic syndrome
If acute cholinergic syndrome (defined as early diarrhea associated with various other signs and symptoms such as sweating, abdominal cramps, myosis and salivation) occurs, atropine sulfate (0.25 mg subcutaneously) should be given unless present. clinical contraindications (see section 4.8).
Caution should be exercised in patients with asthma. If the patient reports acute and severe cholinergic syndrome, the prophylactic use of atropine sulfate is recommended with subsequent administrations of Irinotecan.
Respiratory diseases
Interstitial lung diseases presenting as pulmonary infiltrates are uncommon during irinotecan therapy. Interstitial lung disease can be fatal. The probable risk factors associated with the development of pulmonary infiltrates are the use of drugs toxic to the lungs, radiation therapy and the use of growth factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during Irinotecan therapy.
Extravasation
Although irinotecan is not blistering, care should be taken to avoid extravasation and the infusion site should be observed for signs of inflammation. In case of extravasation, redness at the injection site, washing of the site is recommended. and the application of ice.
Cardiac pathologies
Myocardial ischemic events have been observed following irinotecan therapy predominantly in patients with pre-existing heart disease, with other known risk factors for heart disease or with a history of cytotoxic chemotherapy (see section 4.8 Undesirable Effects).
It follows that patients with known risk factors must be carefully monitored and appropriate measures taken to minimize variable risk factors (e.g. smoking, hypertension and hyperlipidaemia)
Immunosuppressive Effects / Increased Susceptibility to Infections Administration of live or attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan may cause serious or fatal infections. Vaccination with a live vaccine should be avoided in patients treated with irinotecan. They can be administered. vaccines killed or inactivated; however, the response to such vaccines may be reduced.
Senior citizens
In elderly patients, due to the higher frequency of decreased biological functions, e.g. liver function, dose reduction of Irinotecan in this population requires greater caution (see section 4.2).
Patients with intestinal obstruction
Patients should not be treated with Irinotecan until the bowel obstruction resolves (see section 4.3).
Patients with impaired renal function
No specific studies have been conducted in this population (see sections 4.2 and 5.2).
Others
The medicine is unsuitable for patients with hereditary fructose intolerance, as it contains sorbitol. Rare cases of renal failure, hypotension or circulatory failure have been observed in patients with dehydration associated with diarrhea and / or vomiting, or with sepsis.
The use of a contraceptive method is required during and for at least 3 months after the end of therapy in women of childbearing potential and in men (see section 4.6).
Concomitant treatment of Irinotecan with a strong inhibitor (e.g. Ketoconazole) or inducer (e.g. Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, St. John's Wort) of Cytochrome P4503A4 (CYP3A4) may alter the metabolism of Irinotecan and should be avoided. (see section 4.5).
04.5 Interactions with other medicinal products and other forms of interaction -
Interactions between Irinotecan and neuromuscular blocking drugs cannot be excluded. Since Irinotecan has anticholinesterase activity, drugs with anticholinesterase activity can prolong the neuromuscular blocking effect of suxamethonium and antagonize neuromuscular blockade from non-depolarizing drugs.
Numerous studies have shown that concomitant treatment with cytochrome P450 3A (CYP3A) -inducing anticonvulsants (eg. Carbamazepine, Phenobarbital or Phenytoin) results in reduced exposure to Irinotecan, SN-38 and SN-38 glucuronate and reduced effects pharmacodynamics.
The effects of these anticonvulsant drugs were reflected in a decrease in SN-38 and SN-38G AUC by 50% or more. In addition to induction of P450 3A enzymes, increased glucuronidation and increased biliary excretion may play a role. important in reduced exposure to Irinotecan and its metabolites.
One study found that concomitant treatment with ketoconazole resulted in a decrease in the AUC of its major oxidative metabolite APC by 87% and an increase in the AUC of SN-38 by 109% compared to irinotecan administered alone. Caution should be exercised. to patients on concomitant treatment with drugs known to inhibit (e.g. Ketoconazole) or induce (e.g. Carbamazepine, Phenobarbital, Phenytoin, Rifampicin) drug metabolism via P450 3A4. Concomitant treatment of Irinotecan with an inhibitor / inducer of this route metabolism may alter the metabolism of irinotecan and should be avoided (see section 4.4).
In a small pharmacokinetic study (n = 5), in which Irinotecan 350 mg / m² was administered concomitantly with 900 mg of St. John's wort (Hypericum perforatum), a 42% decrease in plasma concentrations of the active metabolite of Irinotecan, SN-38, was reported.
St. John's wort decreases plasma levels of SN-38, therefore it should not be administered together with Irinotecan (see section 4.3).
Combined treatment of 5-FU / FA does not change the pharmacokinetics of Irinotecan.
There is no evidence that the safety profile of Irinotecan is affected by Cetuximab or vice versa.
In one study, concentrations of Irinotecan were similar in patients treated with Irinotecan / 5-FU / FA alone or in combination with Bevacizumab. Concentrations of SN-38, the active metabolite of Irinotecan, were analyzed in a subset of patients (approximately 30 per treatment arm).
SN-38 concentrations on average were 33% higher in patients receiving Irinotecan / 5-FU / FA in combination with bevacizumab compared to patients receiving Irinotecan / 5-FU / FA alone. Due to the high inter-variability between patients and limited number of samples, it is uncertain whether the observed increases in SN-38 levels were secondary to Bevacizumab. There was a modest increase in the adverse events of diarrhea and leukocytopenia. Greater dose reduction of Irinotecan was reported for patients treated with irinotecan / 5-FU / FA in combination with Bevacizumab.
In patients who develop severe diarrhea, leukocytopenia or neutropenia with Bevacizumab and Irinotecan in combination the dose of Irinotecan should be adjusted as described in section 4.2.
Atazanavir sulfate.
Co-administration of atazanavir sulfate, an inhibitor of CYP3A4 and UGT1A1, has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into account when administering these drugs in combination.
Interactions common to all cytotoxics: The use of anticoagulants is common due to an increased risk of thrombotic events in tumor diseases. If therapy with anticoagulants vitamin K antagonists is deemed appropriate, a greater frequency of monitoring of the INR is necessary. (International Normalized Ratio), due to their narrow therapeutic margin, the high individual variability of blood thrombogenicity and the possibility of interactions between oral anticoagulants and anticancer chemotherapy.
Concomitant use contraindicated
- Yellow fever vaccine: risk of generalized fatal reaction to vaccines
Simultaneous use not recommended
- Live attenuated vaccines (except yellow fever): risk of possible fatal systemic disease (e.g. infections). This risk is greater in patients who are already immunosuppressed due to a pre-existing disease.
Use of an inactivated vaccine where available (poliomyelitis)
- Phenytoin: risk of exacerbation of convulsions resulting from the decrease in intestinal absorption of phenytoin by the cytotoxic drug. Concomitant use to be considered - Ciclosporin, Tacrolimus: excessive immunosuppression with risk of lymphoproliferation
04.6 Pregnancy and breastfeeding -
Pregnancy
There is no information on the use of Irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic in animals (see section 5.3). The results of animal studies and the mechanism of action of Iirinotecan mean that the medicinal product does not it should be used during pregnancy, particularly during the first trimester, unless absolutely necessary. The benefits of treatment must outweigh the possible risks to the fetus in each individual case.
Fertility
Women of childbearing potential and men should use effective contraception during and for at least three months after the end of therapy (see section 4.4).
There are no human data on the effect of irinotecan on fertility. Adverse events of irinotecan on offspring fertility have been recorded in animals (see section 5.3).
Feeding time
It is not known whether Irinotecan is excreted in human milk. 14C-Irinotecan has been found in the milk of lactating rats. Due to potential side effects in the infant, breastfeeding is contraindicated during treatment with Irinotecan (see section 4.3).
04.7 Effects on ability to drive and use machines -
Patients should be advised of the possible occurrence of dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan, and not to drive or operate machinery if these symptoms occur.
04.8 Undesirable effects -
The following adverse reactions are related to the administration of Irinotecan. There is no evidence that the safety profile of Irinotecan is affected by Cetuximab or vice versa. In combination with Cetuximab, the additional side effects reported were those expected for Cetuximab (such as acne-like rash in 88%). Therefore also refer to the information on the medicine Cetuximab.
For information on adverse reactions in combination with Bevacizumab, see the Bevacizumab Summary of Product Characteristics.
The following adverse reactions believed possibly or probably related to the administration of Irinotecan were observed in 765 patients treated with the recommended dose of 350 mg / m² monotherapy and in 145 patients treated with Irinotecan in combination with 5FU / FA for administration every 2 weeks at recommended dose of 180 mg / m².
Side effects are summarized in the table below by MedDRA frequency. Undesirable effects are presented in order of decreasing severity within each frequency subgroup.
Very common:> 1/10
Municipality:> 1/100 a
Uncommon:> 1 / 1,000 y
Rare:> 1 / 10,000 a
Very rare
The most common (> 1/10) dose-limiting adverse reactions of Irinotecan are delayed diarrhea (occurring beyond 24 hours after administration) and blood disorders including neutropenia, anemia and thrombocytopenia.
Severe transient acute cholinergic syndrome has generally been reported. The main symptoms have been described as early diarrhea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilation, sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation and increased salivation, which appeared within the first 24 hours. after the infusion of Irinotecan. These symptoms disappeared after administration of atropine (see section 4.4).
Delayed diarrhea
In monotherapy: Severe diarrhea was reported in 20% of patients who followed recommendations for control of diarrhea. 14% of evaluable cycles reported severe diarrhea. The mean time to onset of the first liquid stool was the 5th day after the infusion of Irinotecan.
In combination therapy: Severe diarrhea was reported in 13.1% of patients who followed recommendations for management of diarrhea. Of the evaluable treatment courses, severe diarrhea was reported in 3.9%.
Blood disorders
Neutropenia
Neutropenia was reversible and non-cumulative; the mean time to nadir was 8 days for both monotherapy and combination therapy use.
Monotherapy: Neutropenia was observed in 78.7% of patients and was severe (neutrophil count
In combination therapy: neutropenia was observed in 82.5% of patients and was severe (neutrophil count
Fever with neutropenia was reported in 3.4% of patients and 0.9% of treatment courses. Infectious episodes occurred in approximately 2% of patients (0.5% of treatment courses) and were associated with severe neutropenia in approximately 2.1% of patients (0.5% of treatment courses), resulting in a fatal outcome. in 1 case.
Anemia
In monotherapy:
Anemia was reported in 58.7% of patients (8% with hemoglobin
In combination therapy:
Anemia was reported in 97.2% of patients (2.1% with hemoglobin
Thrombocytopenia
In monotherapy:
Thrombocytopenia (platelets
In combination therapy:
Thrombocytopenia (
A case of peripheral thrombocytopenia associated with the formation of antiplatelet antibodies has been reported in the post-marketing period of pharmacovigilance.
04.9 Overdose -
Cases of overdose have been reported, at doses up to approximately twice the recommended therapeutic dose, which could be fatal. The main adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for Irinotecan. Supportive care should be started immediately to prevent dehydration secondary to diarrhea and to treat any infectious complications.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: other antineoplastic agents
ATC code: L01XX19
Experimental data
Irinotecan is a semi-synthetic derivative of Camptothecin. It is an antineoplastic agent that acts as a specific inhibitor of DNA topoisomerase type I. It is metabolized by carboxylesterase in most tissues thus producing SN-38, which is more active than Irinotecan on type I topoisomerase. purified and more cytotoxic than irinotecan against various mouse and human tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 induces single strand DNA lesions that block the replication fork of DNA and are responsible for cytotoxicity.This cytotoxic activity has been recognized as time-dependent and specific for the S phase.
In vitro, Irinotecan and SN-38 are not recognized by P-glycoprotein (MDR) and Irinotecan exhibits cytotoxic activity against cell lines resistant to Doxorubicin and Vinblastine.
Furthermore, "Irinotecan has a" broad anticancer activity in vivo against mouse tumor models (pancreatic duct adenocarcinoma P03, breast adenocarcinoma MA16 / C, colon adenocarcinomas C38 and C51) and against human xenografts (colon adenocarcinoma Co-4, breast adenocarcinoma MX-1, gastric adenocarcinoma ST-15 and SC- 16). Irinotecan is also active against tumors expressing P-glycoprotein (MDR) (Doxorubicin and Vincristine resistant P388 leukemias).
Apart from the anticancer activity of Irinotecan, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
Clinical data
As monotherapy for second-line therapy of metastatic colorectal cancer
Phase II / III clinical trials have been performed on more than 980 patients with metastatic colorectal cancer after failure of previous 5-FU treatment, with a dosing schedule every 3 weeks. The efficacy of Irinotecan was evaluated in 765 patients with disease progression during documented 5FU therapy at study entry.
NA: Not applicable
In the Phase II clinical trials, involving 455 patients treated with the dosing schedule every 3 weeks, the progression-free survival rate at 6 months was 30% and the median survival was 9 months. The median time to progression was 18 weeks.
In addition, non-comparative phase II studies were conducted in 304 patients treated according to a weekly schedule, at a dose of 125 mg / m² administered as an intravenous infusion over 90 minutes for 4 consecutive weeks followed by 2 weeks of rest. In these studies, the median time to onset of progression was 17 weeks and the median survival was 10 months. A comparable safety profile was observed in 193 patients treated with the weekly dosing schedule at the starting dose of 125 mg / m² versus the once every 3 week schedule. The mean time to onset of the first liquid evacuation was 11 days.
Combination therapy for first-line treatment of metastatic colorectal cancer
In combination therapy with Folinic Acid and 5-Fluorouracil
A phase III first-line treatment study of 385 patients with metastatic colorectal cancer was conducted with drug dosing every 2 weeks (see section 4.2) or once a week. In treatment with administration every 2 weeks, on day 1 Irinotecan is administered at a dose of 180 mg / m² every 2 weeks followed by infusion of FA (200 mg / m² as a 2-hour intravenous infusion) and 5-FU (400 mg / m² as an intravenous bolus, followed by 600 mg / m² as a 22-hour intravenous infusion). On day 2 AF and 5-FU were administered at the same dosage and with the same schedule. In weekly treatment, the dose of Irinotecan at 80 mg / m² was followed by infusion of FA (500 mg / m² as a 2-hour intravenous infusion) and then 5-FU (2,300 mg / m² as a 24-hour intravenous infusion). for 6 weeks.
In the combination therapy study with the 2 dosing regimens described above, the efficacy of Irinotecan hydrochloride was evaluated in 198 treated patients:
Irin: Irinotecan
5-FU: 5-fluorouracil,
AF: folinic acid
NS: not significant
*: as per protocol population analysis
In the weekly dosing schedule, the "incidence of severe diarrhea was 44.4% in patients treated with Irinotecan in combination with 5-FU / FA and 25.6% in patients treated with 5-FU / FA alone. L" incidence of severe neutropenia (neutrophil count
Furthermore, the mean time to define deterioration in Performance Status was significantly longer in the group treated with Irinotecan in combination with 5-FU / AF compared to the 5-FU / AF group (p = 0.046) alone.
In this phase III study, quality of life was assessed using the EORTC QLQ-C30 questionnaire. The time to onset of definitive deterioration always occurred later in the irinotecan groups. Overall health status / quality of life was slightly better, albeit not significantly, in the group treated with Irinotecan in combination, supporting the fact that the efficacy of Irinotecan in combination can be achieved without compromising the quality of life.
In combination therapy with cetuximab
EMR 62 202-013: This randomized study in patients with previously untreated metastatic colorectal cancer for metastatic disease were compared to the combination of Cetuximab and Irinotecan plus 5-fluorouracil / folinic acid (5-FU / FA) infusion (599 patients) versus the same chemotherapy without Cetuximab (599 patients). The proportion of patients with wild-type KRAS tumors within the patient population evaluable for KRAS status was 64%.
The efficacy data generated in this study are summarized in the table below:
CI = Confidence Interval, FOLFIRI = Irinotecan plus 5-FU / FA infusion, ORR = objective response rate (patients with complete or partial response), PFS = disease-free survival time
In combination with Cetuximab after failure of cytotoxic therapy including Irinotecan
The efficacy of the combination of Cetuximab and Irinotecan was studied in two clinical studies. A total of 356 patients with EFFR-expressing metastatic colorectal cancer in whom recent Irinotecan-including therapy had failed and with Karnofsky performance status of 60% minimum, while the majority of them had a Karnofsky performance status> 80%.
EMR 62 202-007: This randomized study compared the combination of Cetuximab and Irintoecan (218 patients) with Cetuximab alone (111 patients).
IMCL CP02-9923: This open-label single-arm study studied combination therapy in 138 patients.
The efficacy data from these studies are summarized below.
CI = confidence interval; DCR = disease control rate (patients with complete or partial response or stationary disease for at least 6 weeks); ORR = objective response rate (patients with complete or partial response); OS = overall survial time; PFS progression-free survival
In terms of frequency of objective response (ORR), disease control (DCR) and disease-free survival (PFS) the efficacy of the combination of Cetuximab and Irinotecan was higher than that of Cetuximab alone. In the randomized study, they are not effects on overall survival have been demonstrated (hazard ratio 0.91, p = 0.48).
In combination therapy with Bevacizumab
A double-blind, randomized, controlled phase III clinical trial evaluated bevacizumab in combination with Irinotecan / 5-FU / FA as first-line therapy for metastatic colorectal cancer (study AVD2170g). The addition of Bevacizumab to the Irinotecan / 5-FU / FA combination resulted in a statistically significant increase in overall survival. Clinical benefit, as measured by overall survival, was evident in all pre-specified patient subgroups, including those defined by age. , gender, performance status, primary tumor location, number of organs involved and duration of metastatic disease. See also Bevacizumab Summary of Product Characteristics. The table below summarizes the efficacy results from study AVF2107g.
Pharmacokinetic / pharmacodynamic data
The intensity of the main toxic effects seen with irinotecan hydrochloride (eg diarrhea and neutropenia) is related to the exposure (AUC area under the curve) to the parent drug and the metabolite SN-38. A significant correlation was observed between haematological toxicity (decreased leukocytes and neutrophils at nadir) or between intensity of diarrhea and AUC values of both irinotecan and metabolite SN-38 alone.
Patients with reduced UGT1A1 activity: Uridine diphosphate-glucuronosyl 1A1 transferase (UGT1A1) is involved in the metabolic deactivation of SN-38, the active metabolite of irinotecan, to the inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacity between individuals. A specific variant of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1 * 28 variant. This variant and other congenital deficiencies of UGT1A1 expression (such as Crigler-Najjar and Gilbert) are associated with a reduced activity of this enzyme.
Meta-analysis data indicate that individuals with Crigler-Najjar syndrome (types 1 and 2) or homozygous for the UGT1A1 * 28 allele (Gilbert syndrome) are at increased risk of haematological toxicity (grade 3 and 4). following administration of irinotecan at moderate or high doses (> 150 mg / m²). A relationship between the UGT1A1 genotype and the occurrence of irinotecan-induced diarrhea has not been established. Patients known to be homozygous for UGT1A1 * 28 should be treated with the normally indicated starting dose of irinotecan. However, these patients should be monitored for haematological toxicity. A reduced starting dose of irinotecan should be considered for patients who have experienced haematological toxicity with previous treatment. rate of starting dose reduction in this patient population has not been established and any subsequent dose changes should be based on tolerance to patient treatment. (see sections 4.2 and 4.4) There are currently insufficient data to draw conclusions on the clinical utility of UGT1A1 genotyping.
05.2 "Pharmacokinetic properties -
In a phase I study in 60 patients with a 30-minute intravenous infusion dosing regimen of 100 to 750 mg / m² once every three weeks, Irinotecan exhibited a biphasic or triphasic elimination profile.The mean plasma clearance was 15 l / h / m² and the volume of distribution at steday state (Vdss) was 157 l / m². The plasma half-life of the first phase of the triphasic model was 12 minutes, that of the second phase was 2.5 hours and the terminal phase half-life was 14.2 hours. SN-38 exhibited a biphasic elimination profile with a mean elimination half-life in the terminal phase of 13.8 hours. 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 mcg / ml and 56 ng / ml, respectively, with corresponding mean values of the area under the curve (AUC) of 34 mcg.h / ml and 451 ng.h / ml, respectively. A "wide interindividual variability of pharmacokinetic parameters was observed especially for SN-38".
A "pharmacokinetic analysis of irinotecan" was conducted in a population of 148 patients with metastatic colorectal cancer treated with different schedules and at different doses in phase II studies. The pharmacokinetic parameters calculated in the three-compartment model were very similar to those observed in the phase I studies. All studies showed that exposure to Irinotecan (CPT-11) and SN-38 increases proportionally with the administered dose of CPT-11; their pharmacokinetics are independent of the number of previous cycles and of the treatment regimen.
The binding to plasma proteins in vitro, of Irinotecan and SN-38 were approximately 65% and 95%, respectively.
Mass balance and metabolic studies conducted with the 14-C labeled drug have shown that more than 50% of an intravenously administered dose of Irinotecan is excreted unchanged, 33% is excreted in the faeces mainly with bile. and 22% in the urine.
Two metabolic pathways are each responsible for at least 12% of the dose:
• Carboxylesterase-mediated hydrolysis to activate the active metabolite SN-38. SN-38 is eliminated primarily by glucuronidation and is further excreted via the biliary and renal routes (less than 0.5% of the dose of Irinotecan). SN-38-glucuronide is likely to be subsequently hydrolyzed in the intestine.
• Oxidation promoted by the enzyme P450 3A resulting in opening of the piperidine outer ring with formation of the derivative of aminopentanoic acid (PCA) and primary amine derivative (NPC) (see section 4.5).
In plasma the major entity is unchanged Irinotecan, followed by APC, SN-38-glucuronide and SN-38. Only SN-38 has a significant cytotoxic effect.
The clearance of irinotecan is reduced by approximately 40% in patients with bilirubin between 1.5 and 3 times the upper limit of the normal range. In these patients a dose of Irinotecan of 200 mg / m² results in a plasma exposure of the drug comparable to that found for 350 mg / m² in cancer patients with normal liver parameters.
05.3 Preclinical safety data -
Irinotecan and SN-38 have been shown to be mutagenic in vitro in the chromosomal aberration test on CHO cells as well as in vivo in the mouse micronucleus test. However, in the Ames test they proved to be devoid of any mutagenic potential.
In rats treated once weekly for 13 weeks with the maximum dose of 150 mg / m² (which is less than half the recommended human dose), no treatment-related tumors were reported within the 91-week period thereafter. therapy.
Single and repeated dose toxicity studies were conducted in mice, rats and dogs. The main toxic effects were observed in the hematopoietic and lymphatic systems. In dogs, delayed diarrhea associated with focal atrophy and necrosis of the intestinal mucosa has been reported. Alopecia was also observed in dogs. The severity of these effects is dose-related and reversible.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Sorbitol (E420)
Lactic acid (E270)
Sodium hydroxide and / or hydrochloric acid (to adjust the pH)
Water for injections
06.2 Incompatibility "-
This medicinal product must not be mixed with other medical products except those mentioned in section 6.6.
06.3 Period of validity "-
The shelf life of unopened vials is 3 years.
Vials of Irinotecan for infusion should be used immediately once opened, as they do not contain antimicrobial preservatives.
Stability after dilution:
Chemical-physical stability in use has been demonstrated in glucose 50 mg / ml (5%) and in sodium chloride 9 mg / ml (0.9%) for 72 hours between 2 ° C and 8 ° C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not exceed 24 hours at 2 ° C to 8 ° C, unless dilution is done under aseptic conditions. checked and validated.
06.4 Special precautions for storage -
Keep the vial in the original package. Do not freeze.
Vials of Irinotecan hydrochloride concentrate for solution for infusion must be protected from light.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package -
• 40 mg / 2 ml: One 5 ml brown Onco-Tain Type I glass vial with a fluorobutyl rubber closure covered with Teflon on the inside.
• 100 mg / 5 ml: One 5ml brown Onco-tain Type I glass vial, with a fluorobutyl rubber closure covered with Teflon on the inside.
• 500 mg / 25 ml: One Onco-Tain Type I brown 30ml glass vial, with a fluorobutyl rubber closure covered with Teflon on the inside.
Each pack contains one vial. Not all approved and highlighted pack sizes may be marketed.
Onco-Tain is Hospira's proprietary external vial protection system.
06.6 Instructions for use and handling -
The solution must be diluted before use. Single use packs. Any residue remaining in the vial should be discarded.
As with other antineoplastic drugs, Irinotecan infusions should be prepared and handled with care. The use of goggles, mask and gloves is required. Pregnant women should not handle cytotoxics.
If the solution of Irinotecan concentrate for infusion or the solution prepared for infusion should come into contact with the skin, wash immediately with plenty of water and soap. If Irinotecan concentrate for infusion or the solution prepared for infusion should be in contact with mucous membranes, wash immediately with water.
Preparation for administration of the intravenous infusion: Like all injectable drugs, the Irinotecan solution must be prepared aseptically (see section 6.3).
If any precipitate is observed to form in the vials or solution for infusion, the product should be discarded following standard hospital procedures applicable to cytotoxic drugs.
Under aseptic conditions, withdraw the required amount of the concentrated Irinotecan solution from the vial using a graduated syringe and inject it into a 250 ml infusion bag or bottle containing only sodium chloride 9 mg / ml (0.9% ) or glucose solution 50 mg / ml (5%). The infusion must then be mixed perfectly by manual rotation.
Elimination. All materials used for dilution and administration should be discarded according to standard hospital procedures applicable to cytotoxic drugs.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Hospira Italia S.r.l.
Via Orazio, 20/22
80122 Naples
Italy
08.0 MARKETING AUTHORIZATION NUMBER -
Irinotecan Hospira 20mg / ml Concentrate for Solution for Infusion 2ml vial
A.I.C. n. 037037013
Irinotecan Hospira 20mg / ml Concentrate for Solution for Infusion 5ml vial
A.I.C. n. 037037025
Irinotecan Hospira 20mg / ml Concentrate for Solution for Infusion in 25 ml vial
A.I.C. n. 037037037
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Determination no. 258 of 19 July 2006
Official Gazette no. 178 of 02 August 2006
10.0 DATE OF REVISION OF THE TEXT -
02/2014
