Gemcitabine medac lyophilisate for cooki. r-ra for infusion of 1000 mg 1 pc.

The antitumor agent, an antimetabolite group pyrimidine analogs, inhibits DNA synthesis. Exhibits tsiklospetsifichnost, acting on cells in S and Gl / S phases. It is metabolized in the cell by the action of nucleoside kinases to active diphosphate and triphosphate nucleosides.

Diphosphate nucleosides inhibit the action of ribonucleotide reductase (unique enzyme kataliziriruyuschego formation deoxynucleoside triphosphates required to synthesize DNA). Triphosphate nucleosides can be incorporated into the DNA chain of (less RNA) that leads to the cessation of further DNA synthesis and programmed cell death (apoptosis).

Gemcitabine is also strong radiosensitizing agent, even in concentrations lower than cytotoxic.

pharmacokinetics

Cmax gemcitabine (from 3.2 ug / ml to 45.5 ug / ml) was achieved in 5 minutes after the infusion. Pharmacokinetic analysis studies with single and repeated dosing shows that Vd depends largely on the floor. Gemcitabine plasma protein binding is negligible.

In gemcitabine body is rapidly metabolized by the action of cytidine deaminase in the liver, kidneys, blood, and other tissues, resulting in the formation gemcitabine mono-, di-, and triphosphates (dFdCMP, dFdCDPi dFdCTP), from which active considered dFdCDPi dFdCTP.

Gemcitabine is rapidly excreted in the urine mainly as an inactive metabolite 2′-deoxy-2 ‘, 2’-diftoruridina. Less than 10% of the entered I / dose found in the urine in an unmodified form gemcitabine. Systemic clearance, which ranges from about 30 l / hr / m2 to 90 l / hr / m2, depending on the age and sex: elimination rate in women approximately 25% lower than in men; both men and women excretion rate decreases with age.

T1 / 2 ranges from 42 minutes to 94 minutes. In compliance with the recommended dosing regimen of gemcitabine complete elimination occurs within 5-11 hours after the onset nnfuzii. When administered once weekly Gemcitabine does not accumulate in the body.

Combination therapy with gemcitabine and paclitaxel. When co-administration of gemcitabine and paclitaxel pharmacokinetics is not changed.

Combination therapy with gemcitabine and carboplatin. When co-administration of gemcitabine and carboplatin pharmacokinetics of gemcitabine does not change.

Impaired renal function. Renal failure mild or moderate (creatinine clearance of 30-80 ml / min) had no significant effect on the pharmacokinetics of Gemcitabine.

Active substance:
Gemcitabine

Manufacturer

Onkotek Production Pharma GmbH, Germany

Composition

1 vial:

gemcitabine hydrochloride 1138.5 mg, which corresponds to the content of gemcitabine 1000 mg

Excipients:

mannitol,

sodium acetate trihydrate,

sodium hydroxide,

hydrochloric acid.

Indications

– locally advanced or metastatic non-small cell lung cancer, as first line therapy in combination with cisplatin and in monotherapy in elderly patients with performance status of 2;

– unresectable, mestnoretsidiviruyuschy or metastatic breast cancer in a combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy with anthracyclines in the absence of contraindications for their intended purpose;

– locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureter, urethra);

– locally advanced or metastatic epithelial ovarian cancer as a monotherapy or in combination with carboplatin in patients with progressive disease after first-line therapy based platinosoderzhashih preparations;

– locally advanced or metastatic pancreatic cancer;

– locally advanced or metastatic cancer of the cervix.

Contraindications

– increased sensitivity to the active agent or any of the excipients;

– Pregnancy and lactation;

– Children under 18 years of age (lack of sufficient efficacy and safety data).

Caution: in violation of the liver and / or kidney disease, inhibition of bone marrow hematopoiesis (including with concurrent radiotherapy or chemotherapy), cardiovascular diseases, a history of metastatic liver disease, hepatitis, alcoholism, at the same time carried out radiotherapy, acute infectious diseases, viral, fungal or bacterial origin (including chickenpox, shingles).

Side effects

Adverse reactions occur more frequently than in rare cases are listed according to the following gradation: very often (> 10%); often (> 1% to < 10%); infrequently (> 0.1% to < 1%); rarely (> 0.01% to < 0.1%); very rare (< 0.01%).

From the side of hematopoiesis: often – leukopenia, neutropenia, thrombocytopenia, and anemia; often – febrile neutropenia; very rarely – thrombocytosis.

On the part of the digestive system: very often – nausea, vomiting, increased activity of “liver” transaminases (AST, ALT), alkaline phosphatase; often – anorexia, diarrhea, constipation, stomatitis, increased bilirubin; rarely – increased activity of gamma-glutamyl transferase; frequency can not be estimated based on available data, – ischemic colitis, toxic liver damage, including liver failure fatal.

From the urinary system: very often – hematuria and proteinuria is mild; frequency can not be estimated on the basis of existing suburban – acute renal failure, and clinical signs and symptoms similar with hemolytic-uremic syndrome (reduced hemoglobin, thrombocytopenia, increased bilirubin, creatinine, urea and / or serum lactate dehydrogenase).

Skin and skin appendages: very often – skin rash, accompanied by itching, alopecia; often – itching, excessive sweating; rarely – ulceration, blistering, very rarely – expressed skin reactions, including desquamation and bullous rashes; frequency can not be estimated – Lyell’s syndrome, Stevens-Johnson syndrome.

The respiratory system: very often – shortness of breath; often – cough, rhinitis, rarely -bronhospazm, interetitsialnaya pneumonia; frequency can not be estimated – pulmonary edema, acute respiratory distress syndrome.

Since the cardiovascular system: rarely – lowering blood pressure, myocardial infarction, the frequency can not be evaluated – arrhythmia (mainly supraventricular), heart failure, clinical signs of peripheral vasculitis and gangrene.

From the nervous system: often – headache, drowsiness, insomnia; frequency can not be estimated – stroke.

Other: very often – malaise, flu-like symptoms, peripheral edema; often – fever, chills, asthenia, back pain, myalgia; rare – swelling of the face, the reactions at the injection site; very rarely – anaphylactic reactions.

How to accept, acceptance rate and dosage

Gemcitabine is administered in / in infusion for 30 minutes.

Non-small cell lung cancer

Monotherapy: The recommended dose – 1000 mg / m2 at 1, 8 and 15 days of each 28-day cycle.

Combination therapy with cisplatin: The recommended dose – 1250 mg / m2 day 1 and 8 of each 21-day cycle, or 1000 mg / m2 of 1, 8 and 15 days of each 28-day cycle Cisplatin is administered in a dose of 70-100 mg / m2 in the 1st day of the cycle on the background of water load after the infusion of gemcitabine.

Combination therapy with carboplatin: Recommended dose – 1000 mg / m2 or 1200 mg / m2v 1 and day 8 of each 21-day cycle. Carboplatin is administered at a dose AUC 5.0 mg / ml * min in the 1st day of the cycle after the infusion of gemcitabine.

Mammary cancer

Combination Therapy: as therapy 1st line in the progression of disease post neoadjuvant therapy consisting of anthracyclines; recommended dose – 1250 mg / m2 in the 1st and 8th days in combination with paclitaxel 175 mg / m2, which is introduced into the 1st day of each 21-day cycle / drip for approximately 3 hours, before the administration of gemcitabine.

Urotelialny cancer

Monotherapy: The recommended dose – 1250 mg / m2 of 1, 8 and 15 days of each 28-day cycle.

Combination therapy: The recommended dose – 1000 mg / m2 in the 1st, 8th and 15th days, in combination with cisplatin, which is administered in a dose of 70 mg / m2 immediately after the infusion of Gemcitabine in 1st or the 2nd day of each 28-day cycle.

Epithelial ovarian cancer

Monotherapy: The recommended dose – 800-1250 mg / m2 in the 1st, 8th and 15th days of each 28-day cycle.

Combination therapy: The recommended dose – 1000 mg / m2 in the 1st and 8th days in combination with carboplatin at a dose AUC4.0 mg / ml * min, which is input immediately after the infusion of Gemcitabine in 1st day of each 21-day cycle.

Pancreas cancer

Monotherapy: The recommended dose – 1000 mg / m2 1 time per week for 7 weeks, followed by one week apart. Then the drug is administered in the 1st, 8th and 15th days of each 28-day cycle.

Cervical cancer (locally advanced or metastatic)

Combination Therapy: By locally advanced (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m2 in the 1st and 8th days of each 21-day cycle. Cisplatin was administered at a dose of 70 mg / m2 of gemcitabine post administration in the 1st day of the cycle on the background overhydration.

Corrector dose in connection with the phenomena of hematological toxicity

Start the treatment cycle

Regardless of the testimony, before each drug administration must be assessed purely platelets and granulocytes.

The condition for initiation of treatment absolute neutrophil count is at least 1500 / ml and the platelet count of at least 100,000 / L.

Correction of the dose due to the phenomena of hematological toxicity

To identify hematological toxicity should be carried out periodic physical examination and monitoring of liver and kidneys. The dose of drug may be reduced in each subsequent cycle or within a cycle has begun, depending on the degree of drug toxicity, designated patient. In case of severe (Grade 3 or 4) nonhematologic toxicity except nausea / vomiting cases gemcitabine therapy should be stopped or reduced dosage value depending on the decision of the treating physician. The decision to resume the treatment takes a doctor.

Route of administration

Infusion gemcitabine is usually well tolerated by patients and can be conducted in an outpatient setting. If extravasation infusion was stopped and restarted administering the drug in a different vein. After the introduction of gemcitabine patient should be observed for some time.

Active substance

Gemcitabine

Interaction

Specific interaction studies of gemcitabine have been conducted.

Radiation therapy

Concomitant radiation therapy (simultaneously with administration of gemcitabine or interval < 7 days before the treatment): in this situation treatment toxicity depends on many factors including the dose of gemcitabine and its frequency of administration, the dose of radiation, a method of radiation therapy, the nature of the irradiated tissue and its volume. It was shown that gemcitabine has radiosensibilziruyuschey activity.

In one study where patients with NSCLC was prepared gemcitabine 1000 mg / m 2 for 6 consecutive weeks in combination with therapeutic radiation to the chest area was marked significant toxicity in the form of heavy and potentially life-threatening mucositis, especially manner esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median irradiated tissue volume 4795 cm3).

Subsequent studies have shown that the combination of lower doses of gemcitabine and radiation therapy is better tolerated by patients and is characterized by predictable toxicity profile. Thus, in one of phase II studies in patients with non-small cell lung cancer radiation therapy at a dose of 60 Gy in conjunction with administering gemcitabine (600 mg / m2 4 times) and cisplatin (80 mg / m2 2-fold) over 6 weeks.

Sequential therapy (break > 7 days): from existing data, gemcitabine more than 7 days prior to the radiotherapy, or more than 7 days after se completion is not accompanied by an increase in toxicity, with the exception of skin lesions associated with the administration of chemotherapy after irradiation . gemcitabine treatment can be initiated 7 days after exposure or after resolution of acute radiation reactions.

As with concomitant or sequential use of gemcitabine and radiation therapy may radiation injury irradiated tissue (eg., Esophagitis, colitis and pneumonia).

Immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infections.

Other interactions

While the use of live virus vaccines is possible intensification of the process of replication of vaccine virus amplification its side / adverse effects and / or reduce the production of antibodies in the patient’s body in response to the vaccine. Therefore, due to the risk of systemic, possibly fatal complications, particularly in patients with decreased immune status, the interval between the application of such vaccines and gemcitabine should be at least 3 months or more (up to 12 months), depending on the immune status of the patient.

Gemcitabine compatibility studies have not been conducted. Gemcitabine can not mix with other drugs.

Special conditions

Gemcitabine treatment can be carried out only under the supervision of a physician who is experienced in the use of anticancer chemotherapy.

Before each administration of gemcitabine is necessary to control the number of platelets, leukocytes and granulocytes in the blood. When signs of bone marrow function oppression caused by the drug, it is necessary to suspend the treatment or adjust the dose.

Typically, myelosuppression is short-term, it does not require a dose reduction and rarely leads to the necessity of treatment interruption. Peripheral blood may continue to deteriorate after gemcitabine therapy interruption.

In the application of gemcitabine in combination with other antitumor chemotherapy is necessary to consider the risk of cumulative suppression of bone marrow function.

It is necessary to carry out regular inspection of the patient and evaluate renal and hepatic function.

Gemcitabine with metastases in the liver, hepatitis and alcoholism in history, as well as in liver cirrhosis increases the risk of liver failure. When signs of adverse events of the respiratory system (e.g., pulmonary edema, pneumonitis or interstitial respiratory distress syndrome in adults) patients discontinue gemcitabine treatment and prescribe appropriate therapy.

At the first signs of microangiopathic hemolytic anemia, such as the rapid decrease in hemoglobin with accompanying thrombocytopenia, increased serum bilirubin, creatinine, urea nitrogen, or increasing lactate dehydrogenase activity, gemcitabine should be canceled.

Increasing the duration and frequency of administrations infusion leads to an increase in toxicity.

The risk of skin reactions is increased in the presence of radiation therapy history.

Depending on the degree of toxicity the dose may be reduced during each cycle or to start a new cycle steps.

During treatment and for 6 months after therapy with gemcitabine should use reliable methods of contraception. Men receiving gemcitabine recommended resort to semen cryopreservation prior to treatment because of the risk of sterility caused by the use of the drug

When treating patients on a controlled sodium diet should take into account the content of sodium in the formulation in the following amounts:

Gemcitabine 200 mg vial contains Medac 3.5 mg (< 1 mmol) sodium

Gemcitabine 1000 mg vial contains 17.5 mg Medac (< 1 mmol) sodium

Gemcitabine 1500 mg vial contains 26.3 mg Medac (< 1 mmol) sodium.

Effects on ability to drive and use machines. data on the effect of therapy with gemcitabine on ability to drive and work with the absence of a mechanism, however, some side effects of the drug such as hypersomnia, may adversely affect the ability of take such actions. During treatment with gemcitabine should be careful when driving and other lesson potentially dangerous activities which require high concentration and psychomotor speed reactions.

Overdose

Symptoms: mielodeprescia, paresthesia, severe skin rash. When gemcitabine administered at doses up to 5700 mg / m2 / drip for 30 minutes every 2 weeks for signs of overdose was not observed. The antidote to gemcitabine is unknown.

In case of suspected overdose gemcitabine should be monitored and set the degree of cytopenia symptomatic therapy if necessary.