Irinotecan

Brand C.K.Sindan-Pharma

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Available since: 2019-09-19

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Clinical Pharmacology

Irinotecan, a semisynthetic derivative of camptothecin, is a specific inhibitor of the cellular enzyme topoisomerase I. In tissues, the drug is metabolized by the carboxylesterase enzyme to form the active metabolite SN-38, which is superior to irinotecan in its activity. By inhibiting topoisomerase I, irinotecan and its SN-38 metabolite cause linear damage to DNA, which prevents its replication in the S-phase of the cell cycle. In in vivo experiments, it was shown that irinotecan is also active against tumors expressing P-glycoprotein of multidrug resistance (vincristine and doxorubicin-resistant P388 leukemia).

Another pharmacological effect of irinotecan is its ability to inhibit acetylcholinesterase.

Pharmacokinetics

The pharmacokinetic profile of irinotecan is not dose dependent. The distribution of the drug in plasma is two- or three-phase. V_d - 157 l / m². C_max irinotecan and SN-38 is achieved by the end of the intravenous infusion at the recommended dose of 350 mg / m² and is 7.7 mcg / ml and 56 ng / ml, respectively, and the area under the concentration-time curve (AUC) is 34 mcg / h / ml and 451 ng / h / ml. In blood plasma, irinotecan is mostly unchanged. The drug is metabolized in the liver in two ways: under the action of the enzyme carboxylesterase to the active metabolite SN-38, followed by glucuronidation and under the action of the isoenzyme CYP3A4 to form aminopentanoic acid derivatives and amines. Only SN-38 has significant cytotoxic activity. The link with plasma proteins for irinotecan is approximately 65%, for its active metabolite SN-38 - 95%. The average half-life of the drug in the first phase is 12 minutes, in the second phase - 2.5 hours and in the last phase - 14.2 hours. The average plasma clearance is 15 l / h / m². Excreted by the kidneys in unchanged form (on average 19.9%) and in the form of the SN-38 metabolite (0.25%). About 30% of the drug is excreted in the bile, both unchanged and in the form of the metabolite SN-38 glucuronide.

Fluorouracil and calcium folinate do not affect the pharmacokinetics of irinotecan.

Irinotecan elimination is reduced by about 40% in patients with a bilirubin concentration exceeding the upper limit of normal by 1.5–3 times.

Indications

Locally advanced colorectal cancer:

in combination with fluorouracil and calcium folinate in patients who have not previously received chemotherapy;
as monotherapy in patients with disease progression after standard antitumor therapy.

Composition

1 ml of solution contains:

Active substances: Irinotecan hydrochloride trihydrate 20 mg.

Excipients: sorbitol - 45 mg, lactic acid - 0.9 ml, sodium hydroxide 5% - q.s., hydrochloric acid 5% - q.s., water d / and - q.s. up to 1 ml.

Irinotecan is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Irinotecan	C.K.Sindan-Pharma	Romania	solution concentrate
Iriten	Lance farm	Russia	solution concentrate
Campto	Pfizer	USA	solution
Iriten	Lance farm	Russia	bottle

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Dosage and Administration

The drug is intended for adults only.

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

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

In monotherapy mode dose of Irinotecan-Teva is 125 mg / m² body surfaces weekly for 4 weeks as a 90-minute IV infusion with a break of 2 weeks, as well as 350 mg / m² as an hourly w / v infusion every 3 weeks.

As part of combination chemotherapy the dose of the drug Irinotecan-Teva is with fluorouracil and calcium folinate with weekly administration - 125 mg / m², with the introduction by continuous infusion 1 time in 2 weeks - 180 mg / m².

The dose and mode of administration of fluorouracil and calcium folinata are described in detail in the special literature.

Dose Modification Recommendations

In monotherapy mode, reducing the initial dose of the drug Irinotecan-Teva from 125 mg / m² up to 100 mg / m² and from 350 mg / m² up to 300 mg / m²as well as dose reduction from 125 mg / m² up to 100 mg / m² and from 180 mg / m² up to 150 mg / m² in the combination therapy mode can be recommended in patients aged 65 years and older, with previous extensive radiation therapy, with a patient's general condition, assessed on a scale of WHO, equal to 2.

Irinotecan-Teva administration should not be given until the neutrophil count in the peripheral blood exceeds 1500 cells / μl of blood, and until such complications as nausea, vomiting and especially diarrhea are completely stopped.

The introduction of the drug until the resolution of all side effects can be postponed for 1-2 weeks. If during treatment, pronounced inhibition of bone marrow hematopoiesis develops (neutrophil count less than 500 / μl blood and / or leukocytes less than 1000 / μl blood and / or platelet count less than 100000 / μl) or febrile neutropenia (neutrophil count 1000 / μl less in combination with fever more than 38 ° C), or infectious complications, or severe diarrhea, or other non-hematologic toxicity of 3–4 degrees, subsequent doses of Irinotecan-Teva and, if necessary, fluorouracil should be reduced by 15-20%.

If there are objective signs of progression of the tumor disease, or the development of unacceptable toxic manifestations, treatment with Irinotecan-Teva should be stopped.

Patients with impaired liver function

Monotherapy

if the concentration of bilirubin does not exceed 1.5 times VGN, then dose adjustment is not required, the patient’s hematological parameters should be carefully monitored due to an increased risk of developing severe neutropenia;
if the concentration of bilirubin exceeds VGN from 1.5 to 3 times, then the recommended dose of Irinotecan-Teva is 200 mg / m², hematological parameters of the patient should be carefully monitored due to an increased risk of developing severe neutropenia;
if the concentration of bilirubin exceeds VGN more than 3 times, then treatment with irinotecan should not be performed.

Combination therapy

Data on the use of irinotecan in combination therapy for abnormal liver function are not available.

Patients with impaired renal function

Application data not available.

Infusion Solution Preparation Instructions

Irinotecan-Teva solution should be prepared under aseptic conditions.

Dilute the required amount of the drug in 250 ml of 5% dextrose solution or 0.9% sodium chloride solution and mix the resulting solution by rotating the bottle.

Before the introduction of the solution should be visually examined for transparency. If sediment is detected, the preparation should be destroyed.

The solution should be used immediately after dilution.

If the dilution is performed in compliance with aseptic rules (for example, in a laminar air flow unit), the drug solution can be used if stored at room temperature for 12 hours (including infusion time) and if stored at 2-8 ° C for 24 hours after opening the bottle with the concentrate.

Adverse reactions

Side effects are classified according to the following frequency:

very often: ≥10%;
often: ≥1% - <10%;
sometimes: ≥0.1 - <1%;
rarely: ≥0.01 - <0.1;
very rarely: <0.01, including isolated cases.

From the hemopoietic system: very often - neutropenia, leukopenia, anemia; often - febrile neutropenia, thrombocytopenia in the appointment of the drug as part of monotherapy; very rarely - the formation of anti-platelet antibodies.

Neutropenia was observed in 78.7% of patients with monotherapy (with combined chemotherapy in 82.5%), including in 22.6% of patients it was severe (neutrophil count less than 500 cells / mcl). Neutropenia was reversible and not cumulative. The full recovery of neutrophil count usually occurred on the 22nd day after the end of monotherapy and on the 7-8th day after the end of the use of the drug Irinotecan-Teva as part of combination chemotherapy.

Fever in combination with severe neutropenia was observed in 6.2% and 3.4% of patients, respectively. Infectious complications in monotherapy occurred in 10.3% of patients, in 5.3% of patients they were combined with severe neutropenia in monotherapy and in 2% of patients who received Irinotecan-Teva as part of combination therapy.

When using the drug Irinotecan-Teva as part of monotherapy, anemia developed in 58.7% of patients. When using the drug Irinotek-Teva as part of combination chemotherapy, anemia was observed in 97.2%.

When using the drug Irinotecan-Teva as part of monotherapy, thrombocytopenia (

There was one case of thrombocytopenia with the formation of anti-platelet antibodies.

From the gastrointestinal tract:very often late diarrhea; often - nausea, vomiting, constipation; sometimes - pseudomembranous colitis (in one case C.difficile), intestinal obstruction, gastrointestinal bleeding; rarely - colitis, including typhlitis, ischemic and ulcerative colitis, intestinal perforation, anorexia, abdominal pain, inflammation of the mucous membranes, pancreatitis.

When using the drug as a monotherapy, severe diarrhea was observed in 20% of patients (with combination therapy in 13.1%). The average time until the first liquid stool after administration of the drug Irinotecan-Teva was 5 days.

When using the drug as monotherapy in approximately 10% of patients who used antiemetic drugs, there was marked nausea and vomiting. When using the drug Irinotecan-Teva as part of combination chemotherapy, severe nausea and vomiting were observed less frequently: in 2.1% and 2.8%, respectively.

Acute cholinergic syndrome,manifested by symptoms such as early diarrhea, abdominal pain, conjunctivitis, rhinitis, lowering blood pressure, bradycardia, vasodilation, increased intestinal motility, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, tearing, saliva treated in 9% received the drug Irinotecan-Teva as monotherapy and as part of combination chemotherapy in only 1.4% of patients. All these symptoms disappeared after administration of atropine.

The nervous system: rarely - involuntary muscle contractions, convulsions, paresthesias, asthenia; very rarely - transient speech disorders.

Since the cardiovascular system: sometimes - lowering blood pressure, hypovolemic shock due to dehydration; rarely, increased blood pressure during or after infusion.

On the part of the respiratory system: sometimes - shortness of breath, fever, pulmonary infiltrates.

Allergic reactions:sometimes a skin rash; rarely - the development of anaphylactic shock.

From the skin and subcutaneous fat: very often - reversible alopecia; sometimes - light skin reactions.

From the laboratory indicators: very often - a transient increase in the activity of serum transaminases; alkaline phosphatase or bilirubin concentrations (combination therapy); often - a transient increase in the activity of serum transaminases, alkaline phosphatase or bilirubin concentration (monotherapy), an increase in the concentration of serum creatinine; rarely, hypokalemia and hyponatremia; very rarely - increased activity of serum amylase and / or lipase.

Other: very often - an increase in body temperature; often - increased fatigue; rarely, local post-infusion reactions, the addition of secondary infections.

Carefully: the general condition of the patient, as measured by the WHO scale, is 2; leukocytosis; female patients (increased risk of diarrhea); radiation therapy (in history) in the region of the abdominal cavity or pelvis; neutropenia; abnormal liver function; simultaneous use of pneumotoxic drugs; colony stimulating therapy; elderly age; hypovolemia; tendency to thrombosis and thromboembolism.

Drug interactions

Since irinotecan has acetylcholinesterase activity, it is possible to increase the duration of neuromuscular blockade when used in conjunction with the salts of Suxamethonia and antagonistic interaction with non-depolarizing muscle relaxants.

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

The combined use of irinotecan with glucocorticosteroid drugs (for example, dexamethasone) increases the risk of developing hyperglycemia (especially in patients with diabetes mellitus or with reduced glucose tolerance) and lymphocytopenia.

When combined, the use of irinotecan diuretics can be aggravated by the dehydration resulting from diarrhea and vomiting. The combined use of laxatives during irinotecan therapy may increase the frequency or severity of diarrhea.

The combined use of irinotecan and prochlorperazine increases the likelihood of signs of akathisia.

When combined, irinotecan with herbal preparations based on Hypericum perforatum (Hypericum perforatum), as well as with anticonvulsant drugs - inducers of CYP3A isoenzyme (carbamazepine, phenobarbital and phenytoin) - the concentration in the active metabolite of SN-38 in the plasma decreases.

Combined use of irinotecan with atazanavir, an inhibitor of CYP3A and UGT1A1 isoenzymes, as well as ketoconazole may cause an increase in plasma concentration of the active metabolite SN-38.

The introduction of live attenuated vaccines to patients undergoing treatment with anticancer agents, including irinotecan, can lead to serious or fatal infections. Vaccination with live vaccines of patients receiving irinotecan should be avoided. A killed or inactivated vaccine may be administered, however, the immune response to such a vaccine may be weakened.

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

Pregnancy and Lactation

It is contraindicated to use the drug during pregnancy and lactation.

Special instructions

Treatment with Irinotecan-Teva should be carried out in specialized chemotherapeutic units under the supervision of a physician with experience in working with anticancer drugs.

In patients receiving the drug Irinotecan-Teva, it is necessary to do a detailed blood count every week and monitor liver function. Diarrhea, which occurs as a result of the cytotoxic effect of the drug (delayed diarrhea), is usually noted no earlier than 24 hours after administration of Irinotecan-Teva (in most patients, on average, after 5 days). With the appearance of the first episode of liquid stool, it is necessary to prescribe a heavy drink containing electrolytes, and immediate anti-diarrheal therapy, including loperamide in high doses (4 mg for the first dose and then 2 mg every 2 h). This therapy is continued for at least 12 hours after the last episode of loose stool, but not more than 48 hours due to the possibility of paresis of the small intestine. If diarrhea is regarded as severe (more than 6 episodes of liquid stool within 24 hours or marked tenesmus), and also if it is accompanied by vomiting or fever, the patient should be urgently hospitalized for a comprehensive treatment involving the administration of broad-spectrum antibiotics.In case of moderate or mild diarrhea (less than 6 episodes of liquid stool within 24 hours and moderate tenesmus) that does not stop within the first 48 hours, it is necessary to start taking broad-spectrum antibiotics inside, and the patient is recommended to be hospitalized. With the simultaneous occurrence of diarrhea and severe neutropenia (the number of leukocytes is less than 500 cells / μl of blood), in addition to antidiarrheal therapy with prophylactic purpose, broad-spectrum antibiotics are administered orally. Loperamide should not be prescribed prophylactically, including patients who have had diarrhea during previous injections of the drug Irinotecan-Teva.

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

With inadequate treatment of diarrhea, a condition that threatens the patient’s life may develop, especially if diarrhea has developed against the background of neutropenia.

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With the development of acute cholinergic syndrome, signs of which are the appearance of early diarrhea and a combination of symptoms such as sweating, abdominal cramping, tearing, miosis and increased salivation, in the absence of contraindications, administration of 0.25 mg of atropine is shown subcutaneously. Caution must be exercised when using the drug in patients with bronchial asthma. In patients with indications of a history of the development of an acute cholinergic syndrome, including in severe form, prophylactic administration of atropine is recommended before prescribing Irinotecan-Teva.

Before each cycle of therapy with Irinotecan-Teva, prophylactic anti-emetic drugs are recommended.

Since the medicinal form of the drug as an excipient contains sorbitol, Irinotecan-Teva cannot be used in patients with hereditary fructose intolerance.

Simultaneous administration of inhibitors (ketoconazole) or inducers (rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort), the CYP3A4 isoenzyme due to changes in the pharmacokinetics of irinotecan should be avoided.

During treatment with Irinotecan-Teva and for at least 3 months after discontinuation of therapy, reliable methods of contraception should be used.

When preparing a solution of the drug Irinotecan-Teva and handling the drug, as well as when using other antitumor agents, caution should be exercised. You must use gloves, mask and goggles.

If irinotecan solution or infusion solution comes in contact with the skin, immediately wash it with soap and water. If irinotecan or its solution gets on the mucous membranes, immediately rinse them with water.

All materials used for the preparation of the solution and for its introduction should be disposed of in accordance with the standard procedure for the disposal of cytotoxic drugs adopted in this hospital.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Patients should be warned about the possibility of dizziness and visual disorders that develop within 24 hours after administration of irinotecan during the treatment with irinotecan. Irinotecan may trigger seizures. When these symptoms occur, patients are advised to refrain from driving and other mechanisms, and also to be careful when engaging in potentially hazardous activities.

Overdosage

Symptoms: The main expected manifestations of overdose are neutropenia and diarrhea. The specific antidote to irinotecan is unknown. At excess of a therapeutic dose in 2 times the lethal outcome is possible. In case of overdose, the patient should be hospitalized and the function of vital organs should be carefully monitored.

Treatment: symptomatic.