Irinotecan-Teva, 20 mg/ml 5 ml

Antitumor agent of plant origin, also has immunosuppressive effect.

The specific inhibitor of DNA topoisomerase I, causes single linear DNA lesions, disrupts DNA replication.

The cytotoxic activity is time-dependent and specific for S phase.

Indications

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

Active ingredient

Composition

Concentrate for preparation of solution for infusion

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/i – q.s. up to 1 ml.

How to take, the dosage

The drug is intended for adults only.

The drug is administered as an IV infusion lasting at least 30 minutes and no longer than 90 minutes.

The specific literature should be consulted when choosing the dose and mode of administration for each individual case.

In monotherapy, the dose of Irinotecan-Teva is 125 mg/m2 body surface weekly for 4 weeks as a 90-minute IV infusion with a 2-week break, and 350 mg/m2 as an hourly IV infusion every 3 weeks.

In combination chemotherapy the dose of Irinotecan-Teva with fluorouracil and calcium folinate when administered weekly is 125 mg/m2, when administered by continuous infusion once every 2 weeks – 180 mg/m2.

The doses and regimen of administration of fluorouracil and calcium folinate are described in detail in the special literature.

Recommendations for dose modification

. In monotherapy, a reduction in the initial dose of Irinotecan-Teva from 125 mg/m2 to 100 mg/m2 and from 350 mg/m2 to 300 mg/m2, and a reduction in the dose from 125 mg/m2 to 100 mg/m2 and from 180 mg/m2 to 150 mg/m2 in combination therapy may be recommended in patients aged 65 years or older, with prior extensive radiation therapy, and with a WHO score of 2 for the overall patient status.

The administration of Irinotecan-Teva should not be performed until the neutrophil count in the peripheral blood exceeds 1500 cells/μL of blood and until complications such as nausea, vomiting and especially diarrhea have completely resolved.

Injection of the drug until all side effects have resolved may be delayed for 1-2 weeks. If against the background of treatment marked suppression of medullary hematopoiesis develops (neutrophil count less than 500/μl of blood and/or leukocyte count less than 1000/μl of blood, and/or platelet count less than 100000/μl) or febrile neutropenia (neutrophil count 1000/μl or less in combination with body temperature higher than 38°C) or infectious complications, or severe diarrhea, or other non-hematologic toxicity of grade 3-4, subsequent doses of Irinotecan-Teva and, if necessary, fluorouracil should be reduced by 15-20%.

In the event of objective signs of tumor disease progression, or development of unacceptable toxic manifestations, therapy with Irinotecan-Teva should be discontinued.

Patients with impaired liver function

Monotherapy

Combination therapy

There are no data on the use of irinotecan in combination therapy for hepatic impairment.

Patients with impaired renal function

There are no data on its use.

Infusion solution preparation instructions

The Irinotecan-Teva solution must 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 stir the resulting solution by rotating the bottle.

The solution should be visually inspected for transparency before administration. If a precipitate is found, the drug should be destroyed.

The solution must be used immediately after dilution.

If the dilution is done in an aseptic manner (such as in a laminar flow facility), 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 vial of concentrate.

Interaction

As irinotecan has acetylcholinesterase activity, the duration of neuromuscular blockade in co-administration with suxamethonium salts and antagonistic interaction with nondepolarizing myorelaxants may be increased.

In co-administration of irinotecan with myelosuppressive drugs and radiation therapy the toxic effect on bone marrow is aggravated (leukopenia, thrombocytopenia).

The co-administration of irinotecan with glucocorticosteroid drugs (e.g., dexamethasone) increases the risk of hyperglycemia (especially in patients with diabetes or reduced glucose tolerance) and lymphocytopenia.

When irinotecan is coadministered with diuretics, dehydration due to diarrhea and vomiting may be aggravated. Co-administration of laxatives with irinotecan therapy may increase the frequency or severity of diarrhea.

The co-administration of irinotecan and prochlorperazine increases the likelihood of signs of akathisia.

In co-administration of irinotecan with preparations of herbal origin on the basis of Hypericum perforatum, as well as with anticonvulsants – CYP3A isoenzyme inducers (carbamazepine, phenobarbital and phenytoin) the plasma concentration of the active metabolite SN-38 decreases.

The co-administration of irinotecan with atazanavir, an inhibitor of CYP3A and UGT1A1 isoenzymes, as well as with ketoconazole may increase plasma concentration of the active metabolite SN-38.

The administration of live attenuated vaccines to patients being treated with anticancer drugs, including irinotecan, can lead to serious or fatal infections. Vaccination with live vaccines should be avoided in patients receiving irinotecan. Killed or inactivated vaccine may be administered, but the immune response to such vaccine may be impaired.

The drug Irinotecan-Teva should not be mixed with other drugs in the same vial.

Special Instructions

The treatment with Irinotecan-Teva should be performed in specialized chemotherapy departments under the supervision of a physician experienced in working with antitumor drugs.

In patients receiving Irinotecan-Teva it is necessary to perform weekly detailed clinical blood tests and monitor the liver function. Diarrhea due to cytotoxic action of the drug (delayed diarrhea) usually occurs not earlier than 24 hours after Irinotecan-Teva administration (on average in most patients in 5 days). In case of the first episode of liquid stools it is necessary to administer abundant drinking containing electrolytes and immediate anti-diarrheal therapy including high doses of loperamide (4 mg at first administration and then 2 mg every 2 hours).

This therapy is continued for at least 12 hours after the last episode of liquid stool, but no more than 48 hours because of the possibility of small-bowel paresis. If the diarrhea is considered severe (more than 6 episodes of liquid stool per day, or persistent tenesmus), or if it is accompanied by vomiting or fever, the patient should be transferred to a hospital urgently for treatment, including administration of a broad spectrum of antibiotics. In mild to moderate diarrhea (less than 6 episodes of liquid stools per day, and moderate tenesmus) which does not resolve within the first 48 hours, oral antibiotics should be started, and the patient should be hospitalized.

In case of simultaneous diarrhea and marked neutropenia (leukocyte count less than 500 cells/μL of blood), broad-spectrum antibiotics are prescribed orally in addition to antidiarrheal therapy for prophylactic purposes. Loperamide should not be administered prophylactically, including patients who have had diarrhea during previous administration of Irinotecan-Teva.

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

If diarrhea is not adequately treated, it can lead to a life-threatening condition, particularly if it occurs with a background of neutropenia.

Patients with febrile neutropenia (body temperature > 38°C and neutrophil count < 1000 cells/µl) should start broad spectrum antibiotics promptly in a hospital setting.

In the development of acute cholinergic syndrome, the signs of which are the appearance of early diarrhea and a combination of symptoms such as sweating, spastic abdominal pain, lacrimation, miosis and increased salivation, 0.25 mg of atropine subcutaneously should be administered in the absence of contraindications. Caution should be exercised when using the drug in patients with bronchial asthma. Prophylactic administration of atropine is recommended before administration of Irinotecan-Teva in patients with signs in history of acute cholinergic syndrome, including in severe form.

Preventive administration of antiemetics is recommended before each cycle of therapy with Irinotecan-Teva.

Because the dosage form of the drug contains sorbitol as an excipient, Irinotecan-Teva should not be used in patients with hereditary fructose intolerance.

The concomitant use of CYP3A4 isoenzyme inhibitors (ketoconazole) or inducers (rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort) should be avoided because of changes in the pharmacokinetics of irinotecan.

Secure contraception should be used during treatment with Irinotecan-Teva and for at least 3 months after discontinuation of therapy.

Precautions should be taken when preparing a solution of Irinotecan-Teva and when handling the drug, as well as when using other antitumor agents. Gloves, mask and goggles should be used.

If irinotecan solution or infusion solution comes into contact with the skin, wash immediately with soap and water. If irinotecan or its solution comes into contact with mucous membranes, rinse immediately with water.

All materials used to prepare the solution and to administer it must be disposed of according to the hospital’s standard procedure for disposal of cytotoxic drugs.

Impact on ability to drive vehicles and other mechanisms requiring high concentration

Patients should be cautioned about the possibility of dizziness and visual disturbances during treatment with irinotecan, which develop within 24 hours after irinotecan administration. Irinotecan administration may provoke seizures. In case of the above symptoms, patients are advised to refrain from driving a vehicle and other mechanisms, as well as to exercise caution when engaging in potentially dangerous activities.

Contraindications

– chronic inflammatory bowel disease and/or impaired intestinal patency;

– marked suppression of bone marrow hematopoiesis;

– serum bilirubin level greater than 1.5 times VGN;

– patients’ general condition as assessed by the WHO scale >2;

– pregnancy and breastfeeding period;

– childhood (no data on safety and efficacy in children);

– hypersensitivity to irinotecan or other components of the drug.

With caution: Radiation therapy (history) on the abdominal or pelvic area, leukocytosis, female patients (increased risk of diarrhea).

Side effects

Hematopoietic system disorders:very often – neutropenia, leukopenia, anemia; often – febrile neutropenia, thrombocytopenia when the drug is used in monotherapy; very rarely – formation of antiplatelet antibodies.

Neutropenia was observed in 78.7% of patients on monotherapy (82.5% on combined chemotherapy), including 22.6% of patients with severe neutropenia (neutrophil count less than 500 cells/μL). Neutropenia was reversible and was not cumulative. Complete recovery of neutrophil count usually occurred on day 22 after the end of monotherapy and on day 7-8 after termination of Irinotecan-Teva as part of combined chemotherapy.

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

When Irinotecan-Teva was used as part of monotherapy, anemia developed in 58.7% of patients. When Irinotecan-Teva was used as part of combined chemotherapy anemia was observed in 97.2%.

In Irinotecan-Teva monotherapy thrombocytopenia was observed in one case of thrombocytopenia with formation of antiplatelet antibodies.

Gastrointestinal tract: very frequently – late-onset diarrhea; frequently – 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, mucosal inflammation, pancreatitis.

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

When using the drug as monotherapy, approximately 10% of patients who used anti-emetics experienced significant nausea and vomiting. Severe nausea and vomiting were less frequently observed with Irinotecan-Teva as part of combination chemotherapy: 2.1% and 2.8% of patients, respectively.

Acute cholinergic syndrome, manifested by symptoms such as early diarrhea, abdominal pain, conjunctivitis, rhinitis, decreased BP, bradycardia, vasodilation, increased bowel peristalsis, increased sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation, salivation were observed in 9% of patients treated with Irinotecan-Teva as monotherapy and only 1.4% of patients as part of combination chemotherapy. All these symptoms disappeared after administration of atropine.

Nervous system disorders: rare – involuntary muscle contractions, seizures, paresthesias, asthenia; very rare – transient speech disorders.

Cardiovascular system disorders:sometimes – decrease in BP, hypovolemic shock due to dehydration; rarely – increase in BP during or after infusion.

Respiratory system:sometimes – shortness of breath, fever, pulmonary infiltrates.

Allergic reactions: sometimes – skin rash; rarely – development of anaphylactic shock.

Skin and subcutaneous fatty tissue: very often – reversible alopecia; sometimes – mild skin reactions.

On the side of laboratory parameters: very common – transient increase in serum transaminase activity; alkaline phosphatase or bilirubin concentration (combination therapy); common – transient increase in serum transaminase activity, alkaline phosphatase or bilirubin concentration (monotherapy), increased serum creatinine concentration; rare – hypokalemia and hyponatremia; very rare – increased serum amylase and/or lipase activity.

Others:very often – increase in body temperature; often – increased fatigue; rarely – local postinfusion reactions, accession of secondary infections.

Overdose

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

Treatment:symptomatic.