Campto CS, 20 mg/ml concentrate 5 ml

Pharmacodynamics

The antitumor drug of plant origin. Irinotecan is a semi-synthetic derivative of camptothecin and is a specific inhibitor of the cellular enzyme topoisomerase I. The drug is metabolized in tissues with the formation of active metabolite SN-38, which is superior in its activity to irinotecan. Irinotecan and metabolite SN-38 stabilize the complex of topoisomerase I with DNA, which prevents its replication. In in vivo experiments it was shown that irinotecan is also active against tumors expressing P-glycoprotein of multiple drug resistance (vincristine- and doxorubicin-resistant P388 leukemias).

Pharmacokinetics

The pharmacokinetics of irinotecan and the metabolite SN-38 have been studied with a 30-minute IV infusion of the drug at doses of 100-750 mg/m2. The pharmacokinetic profile of irinotecan was not dose-dependent.

Metabolism and distribution

Irinotecan is metabolized in the liver by the enzyme carboxyesterase to form the active metabolite SN-38.

The distribution in plasma is biphasic or triphasic. Average T1/2 in the first phase of the three-phase model is 12 min, in the second phase – 2.5 h, in the third phase – 14.2 h. Cmax of irinotecan and SN-38 was reached by the end of the IV infusion at the recommended monotherapy dose of 350 mg/m2 body surface area.

The plasma protein binding is approximately 65% for irinotecan and 95% for the metabolite SN-38.

Elimation

In the urine within 24 hours, 19.9% is excreted as unchanged irinotecan and 0.25% as metabolite SN-38.

Pharmacokinetics in Special Clinical Cases

Pharmacokinetic studies have confirmed no effect of 5-fluorouracil and calcium folinate on the pharmacokinetics of irinotecan.

Indications

Treatment of locally advanced or metastatic colorectal cancer:

Active ingredient

Composition

1 ml (1 vial) contains:

Active ingredients:

Irinotecan hydrochloride trihydrate 20 mg (100 mg), corresponding to an irinotecan content of 17.33 mg (86.65 mg).

Auxiliary substances:

sorbitol,

lactic acid,

sodium hydroxide and hydrochloric acid (to pH 3.5),

water d/i.

How to take, the dosage

The drug is administered in adults only.

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

In the treatment of colorectal cancer Campto is used both as monotherapy and in combination with 5-fluorouracil and calcium folinate. Reference should be made to specific literature when choosing the dose and regimen of administration.

In monotherapy, Campto is used at a dose of 350 mg/m2 body surface every 3 weeks.

In combination therapy with prolonged infusion of 5-fluorouracil and calcium folinate, Campto is given weekly at a dose of 80 mg/m2; once every 2 weeks, 180 mg/m2; when given in combination with a bolus of 5-fluorouracil and calcium folinate, 125 mg/m2 weekly.

The administration of Campto should not be given until peripheral blood neutrophil counts exceed 1500/μL and until therapy complications such as nausea, vomiting, and diarrhea have completely resolved. Administration of the drug can be postponed for 1-2 weeks until all side effects are resolved.

. If against the background of treatment pronounced inhibition of bone-marrow hematopoiesis develops (neutrophil count is less than 500/μL, and/or leukocyte count is less than 1000/μL, and/or platelet count is less than 100,000/μL), or febrile neutropenia (neutrophil count of 1,000/µL or less combined with fever greater than 38°C), or infectious complications, or severe diarrhea, or other non-hematologic toxicity of grade 3-4, subsequent doses of Campto or 5-fluorouracil are reduced by 15-20% if necessary.

Campto treatment can be continued until objective signs of tumor disease progression or development of unacceptable toxicities appear.

In patients with liver dysfunction with serum bilirubin levels no more than 1.5 times the upper limit of normal, due to the increased risk of pronounced neutropenia, the patient’s blood values should be carefully monitored. In case of bilirubin level increase more than 3 times – treatment with Campto should be stopped.

In patients with impaired renal function, treatment with Campto is not recommended because the use in this category of patients has not been studied.

There are no specific instructions for the use of Campto in elderly patients. The dose should be adjusted with caution in each individual case.

The safety and effectiveness of Campto in children has not been adequately studied.

Interaction

Because Campto has anticholinesterase activity, there may be an increase in the duration of neuromuscular blockade when combined with suxamethonium and an antagonistic interaction regarding neuromuscular blockade when combined with nondepolarizing myorelaxants.

Pharmaceutical Interactions

Campto should not be mixed with other drugs in the same bottle.

Special Instructions

The drug should be treated in specialized chemotherapy departments and only under the supervision of a physician experienced in the use of antitumor drugs.

The drug should be used with caution in patients who have previously received radiation therapy for the abdomen or pelvis, in patients who have previously had hyperleukocytosis, as well as in patients with a general WHO ≥2 condition and in female patients; all these cases have an increased risk of diarrhea.

Diarrhea resulting from the cytostatic effects of the drug (delayed diarrhea) does not usually occur until 24 h after administration of Campto (on average, 5 days in most patients).

When the first episode of liquid stool occurs, administration of copious drinking containing electrolytes and immediate anti-diarrheal therapy including loperamide in high doses (4 mg for the first administration, then 2 mg every 2 hours) are necessary. This therapy is continued for 12 hours after the last episode of liquid stools (but no more than 48 hours because of the risk of bowel paralysis).

If diarrhea is considered severe (more than 6 episodes of liquid stools during 24 hours or severe tenesmus) and if accompanied by vomiting or fever, the patient should be admitted urgently for complex treatment including broad spectrum antibiotics. At moderate or mild diarrhea (less than 6 episodes of liquid stools during 24 hours and moderate tenesmus), which does not relieve during the first 48 hours, oral antibiotics of broad spectrum are started, and the patient should be hospitalized. If diarrhea and severe neutropenia (leukocyte count less than 500/μL) occur simultaneously, broad-spectrum antibiotics are administered orally in addition to antidiarrheal therapy for prophylactic purposes.

Loperamide should not be administered prophylactically, including in patients who have had diarrhea during previous administration of Campto.

The patient should be informed about the possibility of diarrhea. Patients should inform their physician immediately if diarrhea occurs (so that anti-diarrheal therapy can be started immediately).

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

Patients with febrile neutropenia (body temperature ≥38° and neutrophil count ≤1000/μL) should start antibiotic therapy immediately in a hospital setting.

In case of acute cholinergic syndrome, if there are no contraindications, atropine injection by injection with a dose of 0.25 mg is indicated. Caution should be exercised when using the drug in patients with bronchial asthma. In patients with a history of acute cholinergic syndrome (including a severe form) prophylactic administration of atropine sulfate is recommended before prescribing Campto.

With regard to the fact that Campto contains sorbitol, the drug is not prescribed in patients with hereditary fructose intolerance.

In patients receiving Campto, a weekly gross clinical blood count should be performed and liver function should be monitored.

The effect on the ability to drive vehicles and other mechanisms requiring increased concentration

Patients should be warned about the possibility of dizziness and visual disturbances during treatment with Campto, which develop within 24 hours after administration of Campto. If these symptoms occur, patients are advised to refrain from driving or operating machinery.

Contraindications

Side effects

Blood system: neutropenia – in 78.7% of patients in monotherapy (in 82.5% – in combined therapy), including 22.6% of patients with severe neutropenia (neutrophil count less than 500/μl). Neutropenia is reversible and is not cumulative.

The complete recovery of neutrophil counts usually occurs on day 22 when Campto is used as monotherapy and on day 7-8 when Campto is used as part of combination therapy. Fever combined with severe neutropenia was noted in 6.2% and 3.4% of patients, respectively. Infectious complications during monotherapy occurred in 10.3% of patients and in 5.3% of patients in combination with severe neutropenia. Infectious complications with combination therapy occurred in approximately 2% of patients (0.5% of cycles), in approximately 2.1% of patients, and in 0.5% of cycles they were combined with severe neutropenia.

Anemia with monotherapy occurred in 58.7% of patients; with combination chemotherapy, it occurred in 97.2%.

Trombocytopenia (platelet count less than 100,000/μL) is observed in 7.4% of patients with monotherapy, with combined therapy – in 32.6% of patients. No pronounced thrombocytopenia was observed when Campto was used as part of combined chemotherapy. Platelet counts recovered by 22 days.

There was 1 case of thrombocytopenia combined with formation of antiplatelet antibodies.

Digestive system disorders: nausea, vomiting, diarrhea, abdominal pain, anorexia, mucositis, constipation. Rare cases of pseudomembranous colitis, intestinal obstruction, GI bleeding, intestinal perforation, increased amylase or lipase levels have been reported.

When using the drug as monotherapy severe diarrhea was observed in 20% of patients (in combination therapy – in 13.1%) who followed the recommendations for treatment of diarrhea. The average time to the appearance of the first liquid stool after Kampto administration was 5 days.

When Campto was used in monotherapy, significant nausea and vomiting were reported in approximately 10% of patients who used antiemetics. When Campto was used as part of combination therapy, severe nausea and vomiting were observed less frequently, in 2.1% and 2.8%, respectively.

Acute cholinergic syndrome: early diarrhea, abdominal pain, increased sweating, conjunctivitis, rhinitis, decreased BP, vasodilation, lacrimation, salivation, chills, malaise, dizziness, visual disturbance, miosis, was observed in 9% of patients receiving Campto as monotherapy (in 1.4% as part of combination therapy). All symptoms resolved after administration of atropine.

CNS and peripheral nervous system disorders: involuntary muscle twitching or convulsions, paresthesias, asthenia.

Allergic reactions: rare – skin rash, very rare – anaphylactic shock.

Others: alopecia, fever, local reactions, transient increase in serum levels of transaminases, alkaline phosphate, bilirubin and creatinine. In rare cases development of renal failure, arterial hypotension, circulatory failure has been observed in patients who had episodes of dehydration associated with diarrhea and/or vomiting, or in patients with sepsis.

Overdose

The main expected symptoms of overdose are neutropenia and diarrhea.

If necessary, symptomatic therapy is carried out. There is no specific antidote.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breastfeeding).

Patients of reproductive age should avoid conception while using the drug and for at least 3 months after its withdrawal.