Irinotecan Pliva-Lahema - instructions for use, dose, side effects, contraindications

Irinotecan, a semisynthetic derivative of camptothecin, is a specific inhibitor of the cellular enzyme topoisomerase I. In tissues, the drug is metabolized to form an active metabolite SN-38, which excels in its activity irinotecan. Irynotekan and metabolite SN-38 stabilize the topoisomerase I complex with DNA, which prevents its replication.

Pharmacokinetics:

The pharmacokinetic profile of irinotecan is dose independent. The distribution of the drug in the plasma is two- or three-phase. The volume of distribution is 157 l / m². The maximum plasma concentration (C_mOh) of irinotecan and SN-38 is reached by the end of intravenous infusion at the recommended dose of 350 mg / m² and is 7.7 μg / ml and 56 ng / ml, respectively, and the area under the concentration-time curve (AUC) - 34 μg^.h / ml and 451 ng^.h / ml. Metabolized mainly in the liver under the action of the enzyme carboxyesterase to the active metabolite SN-38. The association with blood plasma proteins for irinotecan is approximately 65%, for its active metabolite SN-38 - 95%. Mean half-life of the drug (T_1/2) in the first phase is 12 minutes, in the second phase - 2.5 hours and in the last phase - 14.2 hours. The average value of the plasma clearance is 15 l / h / m². With urine within 24 hours, an average of 20% of unchanged drug and 0.25% in the form of a metabolite SN-38. About 30% of the drug is excreted in bile, both in unchanged form and in the form of a metabolite SN-38 glucuronide. Fluorouracil and calcium folinate do not affect the pharmacokinetics of irinotecan.

Indications:

Locally or metastatic cancer of the colon and rectum:

- in combination with fluorouracil and calcium folinate in patients who have not previously received chemotherapy;

- in monotherapy in patients with disease progression after standard antitumor therapy.

Contraindications:

- Hypersensitivity to irinotecan or other components of the drug;

- chronic inflammatory bowel disease and / or intestinal obstruction;

- severe oppression of bone marrow hematopoiesis;

- the level of bilirubin in the serum, exceeding the upper limit of the norm (VGN) by more than 1.5 times;

- general condition of patients, assessed by WHO scale> 2;

- pregnancy and the period of breastfeeding;

- children's age (data on safety and effectiveness in children are absent).

Carefully:Radiation therapy (in the anamnesis) on the abdominal or pelvic area, leukocytosis, female patients (increased risk of diarrhea), renal failure (safety data not available).

Dosing and Administration:

The drug is intended only for adults.

Irinotecan is administered as an intravenous infusion lasting at least 30 minutes and not more than 90 minutes.

When choosing a dose and mode of administration in each individual case, you should refer to the special literature.

In the monotherapy mode: Irynotekan Pliva-Lachema is used in a dose of 350 mg / m²every 3 weeks.

As part of combined chemotherapy The dose of Irinotecan Pliva-Lachem is:

- with fluorouracil and calcium folinate with weekly administration of 80 mg / m²,

- when administered by continuous infusion once every 2 weeks - 180 mg / m²;

- in combination with jet infusion of fluorouracil and calcium folinate - 125 mg / m²weekly.

Doses and administration of fluorouracil and calcium folinate are described in detail in the literature.

The introduction of Irinotecan Pliva-Lachem should not be carried out until,until the number of neutrophils in the peripheral blood exceeds 1500 cells / μl, and until such complications as nausea, vomiting and especially diarrhea are completely eliminated. The administration of the drug before the resolution of all side effects can be postponed for 1-2 weeks.

When the development of treatment with expressed inhibition of bone marrow hematopoiesis (the number of neutrophils is less than 500 / μL, and / or the number of leukocytes is less than 1000 / μL, and / or the number of platelets is less than 100,000 / μl), febrile neutropenia (neutrophil count 1000 / μL of blood and less in combined with an increase in body temperature of more than 38 ° C), infectious complications, severe diarrhea, or other non-hematological toxicity of 3-4 degrees, subsequent doses of Irinotecan Pliva-Lachem and, if necessary, fluorouracil should be reduced by 15-20%.

Patients with impaired hepatic function. At a level of bilirubin in the blood serum exceeding the upper limit of the norm no more than 1.5 times, in connection with an increased risk of development of severe neutropenia, blood parameters in the patient should be closely monitored. With an increase in the level of bilirubin more than 1.5 times - treatment Irynotekan Pliva-Lahema should be discontinued.

Patients with impaired renal function. Treatment with Irinotecan Pliva-Lachema is not recommended. Data on the use of irinotecan in this category of patients are absent.

Elderly patients. There are no specific instructions for the use of irinotecan in the elderly. The dose of the drug in each case should be selected with caution.

Instructions for preparing a solution for infusions

The necessary amount of the preparation should be diluted in 250 ml of a 0.5% solution of dextrose or 0.9% sodium chloride solution and the resulting solution is mixed by rotating the vial. Before administration, the solution should be visually inspected for clarity. In case of Sludge Detection, the drug must be destroyed.

The solution should be used immediately after dilution.

If dilution is carried out in accordance with aseptic rules (for example, laminar air flow), the Irinotecan Pliva-Lachem solution may be used, if stored at room temperature, for 12 hours (including infusion time) and, if stored at 2 -8 ° С, within 24 hours after opening the vial with concentrate.

Side effects:

On the part of the organs of hematopoiesis: neutropenia is observed on average in 80% of patients, including half of them with a decrease in neutrophils of less than 1000 cells per 1 μl. Restoration of the number of neutrophils is usually observed in 7-20 days from the beginning of treatment.

Anemia of varying severity occurs on average in 60% of patients, thrombocytopenia - in 7% of patients. One case of thrombocytopenia with the formation of antiplatelet antibodies is described.

From the side of the digestive system: late diarrhea that occurs more than 24 hours (on average 5 days) after drug administration is a dose-limiting toxic manifestation and is observed in approximately 87% of patients, with a severe degree in 38%. Nausea and vomiting occurs usually on the first day of administration or after 24 hours in 85% of patients. Dehydration was reported on the background of vomiting and diarrhea, very rarely with the development of renal failure, hypotension and heart failure. Possible abdominal pain, anorexia, mucositis, constipation.

Acute cholinergic syndrome: is observed in 9% of patients during the first 24 hours after the administration of the drug and is manifested by diarrhea, abdominal pains, increased sweating,miosis, vision disorder, lacrimation, drooling, lowering of blood pressure, dizziness, chills and general malaise.

From the central nervous system: involuntary muscle twitching or cramps, paresthesia, asthenia.

Allergic reactions: rarely - a skin rash and very rarely - the development of anaphylactic shock.

Other: shortness of breath, fever, local reactions.

Overdose:

The main expected manifestations of an overdose are neutropenia and diarrhea.

The specific antidote to irinotecan is unknown. Treatment is symptomatic. In case of an overdose, the patient should be hospitalized and closely monitor the function of vital organs.

Interaction:

As irinotecan has anticholinesterase activity, it is possible to increase the duration of neuromuscular blockade when combined with suxamethonium salts and antagonistic interaction with neuromuscular blockade when combined with nondepolarizing muscle relaxants.

With the combined use of irinotecan with myelosuppressive drugs and radiation therapy, the toxic effect on the bone marrow (leukopenia, thrombocytopenia) is aggravated.

In a joint application with irinotecan glucocorticosteroids (eg, dexamethasone) increases the risk of hyperglycemia (particularly in patients with diabetes mellitus or glucose intolerance) and lymphocytopenia.

With the combined use of irinotecan with diuretics, dehydration, resulting from diarrhea and vomiting, can be aggravated.

Joint intake of irinotecan and prochlorperazine increases the likelihood of manifestation of signs of akathisia.

In the joint application of irinotecan with herbal preparations based on St. John's wort (Hypericum perforatum), as well as with antiepileptic drugs inductors CYP3A (carbamazepine, phenobarbital and phenytoin) concentration in plasma of active metabolite SN-38 decreases.

Joint reception of irinotecan with atazanavir, enzyme inhibitor CYP3A4 and UGT1A1, as well as with ketoconazole may cause an increase in the concentration in the blood plasma of the active metabolite SN-38.

Irinotecan should not be mixed with other drugs in one bottle.

Special instructions:

Irinotecan Pliva-Lachema should be carried out in specialized chemotherapy wards under the supervision of a physician who has experience with anticancer drugs.

In patients receiving Irynotekan Pliva-Lachema, it is necessary to do a detailed clinical analysis of blood weekly and monitor liver function.

Diarrhea that occurs as a consequence of the cytotoxic effect of the drug is usually noted no earlier than 24 hours after the administration of Irinotecan Pliva-Lachem (in most patients, an average of 5 days). When the first episode of loose stools necessary appointment plentiful drink containing electrolytes and immediate holding antidiarrheal therapy including reception of Loperamide at high doses (4 mg in the first intake and then 2 mg every 2 hours). This therapy is continued for at least 12 hours after the last episode of a loose stool, but no more than 48 hours because of the possibility of developing a small intestine paresis. If it regarded as severe diarrhea (more than 6 episodes of watery stools during days or expressed tenesmus), and if accompanied by fever or vomiting, the patient must be urgently admitted to the ICU for the comprehensive treatment comprising administering to broad spectrum antibiotics. With moderate or mild diarrhea (less than 6 episodes of loose stool during the day and moderate tenesmus),which does not stop within the first 48 hours, it is necessary to start taking broad-spectrum antibiotics inside. With the simultaneous occurrence of diarrhea and severe neutropenia (the number of white blood cells is less than 500 / mm3), in addition to antidiarrheal therapy, antibiotics of a wide spectrum of action are prescribed internally for prophylactic purposes.

During the treatment of Irinotecan Pliva-Lachem should not take drugs based on St. John's Wort (Hypericum perforatum), antiepileptic drugs (carbamazepine, phenobarbital and phenytoin), atazanavir and ketoconazole, which alter the clearance of irinotecan.

Loperamide should not be administered prophylactically, including to patients who have had diarrhea during previous irinotecan injections.

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

If the treatment of diarrhea is inadequate, a condition threatening the patient's life may develop, especially if diarrhea develops against a background of neutropenia.

Patients with febrile neutropenia (body temperature ≥ 38 ° C and neutrophil count ≤ 1000 / μL) should immediately begin the introduction of broad-spectrum antibiotics in hospital settings.

Acute cholinergic syndrome, usually occurring during the administration of the drug or in the first 24 hours after administration, is quickly and effectively suppressed by subcutaneous administration of 0.25 mg of atropine (caution in patients with bronchial asthma).

The dosage form of the drug as an auxiliary substance contains sorbitol, in connection with which Irynotekan Pliva-Lachema can not be used in patients with hereditary intolerance to fructose.

During the treatment of Irinotecan Pliva-Lahem and for at least three months after cessation of therapy, reliable contraceptive measures should be applied.

If Irinotecan Pliva-Lachema gets on the skin or mucous membranes, the skin should be washed immediately with soap and water, mucous membranes simply with water.

Effect on the ability to drive transp. cf. and fur:Patients should be warned about the possible appearance during the treatment of Irinotecan Pliva-Lahhema dizziness and visual disorders, which develop within 24 hours after the administration of the drug.If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:Concentrate for the preparation of a solution for infusions, 20 mg / ml.

Packaging:

On 40 mg / 2 ml, 100 mg / 5 ml in a bottle of dark glass with a rubber stopper and an aluminum cap of type "flip-off'With a polypropylene lid of yellow color (for 2 ml) or red color (for 5 ml).

1 bottle with instructions for use in a cardboard pack.

Storage conditions:

Concentrate - at a temperature of no higher than 25 ° C, in a place protected from light.

Diluted solution - 48 hours at a temperature of no higher than 25 ° C, in a dark place or 24 hours in the absence of protection from light.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005731/09

Date of registration:15.07.2009

Expiration Date:Unlimited

The owner of the registration certificate:Pliva of Hrvatska dooPliva of Hrvatska doo Croatia

Manufacturer: & nbsp

PLIVA-LACHEMA, a.s. Czech Republic

Representation: & nbspPliva of Hvartska dooPliva of Hvartska doo

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Irinotecan Pliva-Lahema (Irinotecan Pliva-Lachema)