Gemcitabine medac lyophilisate 1000mg vial, 1pc

Composition

of 1 fl:

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

Auxiliary substances:

mannitol,

sodium acetate trihydrate,

sodium hydroxide,

hydrochloric acid.

Pharmacological action

Antitumor agent, an antimetabolite of the pyrimidine analog group, suppresses DNA synthesis. It exhibits cyclospecificity, acting on cells in the S and Gl/S phases. It is metabolized in the cell by nucleoside kinases to active diphosphate and triphosphate nucleosides.

Diphosphate nucleosides inhibit the action of ribonucleotide reductase (the only enzyme that catalyzes the formation of deoxynucleoside triphosphates necessary for DNA synthesis). Triphosphate nucleosides are able to integrate into the DNA chain (to a lesser extent, RNA), which leads to the termination of further DNA synthesis and programmed cell death (apoptosis).

Gemcitabine is also a strong radiosensitizing agent, even at concentrations lower than cytotoxic ones.

The pharmacokinetics

of gemcitabine Cmax (from 3.2 mcg / ml to 45.5 mcg / ml) is reached 5 minutes after the end of infusions. Pharmacokinetic analysis of single-and multiple-dose studies shows that Vd is largely gender-dependent. The binding of gemcitabine to plasma proteins is insignificant.

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

Gemcitabine is rapidly excreted in the urine, mainly as an inactive metabolite of 2’ – deoxy-2′,2’ – difluoruridine. Less than 10% of the administered intravenous dose is detected in the urine in the form of unchanged gemcitabine. Systemic clearance, which ranges from approximately 30 l / h / m2 to 90 l/h/m2, depends on age and gender: the rate of elimination in women is approximately 25% lower than in men; in both men and women, the rate of elimination decreases with age.

T1 / 2 ranges from 42 min to 94 min. If the recommended dosage regimen is followed, complete elimination of gemcitabine occurs within 5-11 hours after the start of the infusion. When administered once a week, gemcitabine does not accumulate in the body.

Combination therapy with gemcitabine and paclitaxel. When gemcitabine and paclitaxel are co-administered, the pharmacokinetics of the drugs do not change.

Combination therapy with gemcitabine and carboplatin. When gemcitabine and carboplatin are co-administered, the pharmacokinetics of gemcitabine do not change.

Impaired renal function. Mild or moderate renal insufficiency (creatinine clearance 30-80 ml / min) does not significantly affect the pharmacokinetics of gemcitabine.

Indications

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

— unresectable, mestorozhdenii or metastatic breast cancer in combination therapy with paclitaxel after neoadjuvant and/or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their destination;

— locally advanced or metastatic urothelial carcinoma (bladder cancer, renal pelvis, ureter, urethra);

— locally advanced or metastatic epithelial ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after the first-line therapy on the basis of Latinoamerica drugs;

— locally advanced or metastatic pancreatic cancer;

— locally advanced or metastatic cervical cancer.

Contraindications

-hypersensitivity to the Active ingredient or to any of the excipients;

– pregnancy and lactation;

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

With caution: in case of violation of the liver and/or kidneys, suppression of bone marrow hematopoiesis (including on the background of concomitant radiotherapy or chemotherapy), cardiovascular disease history, metastatic liver disease, hepatitis, alcoholism, while simultaneously conducted radiation therapy, acute infectious diseases of viral, fungal or bacterial origin (including chickenpox, shingles).

Side effects

Side effects that occurred more frequently than in isolated cases are listed according to the following gradation: very common (> 10%); common (>>1% to >>< 10%); infrequent (> 0.1% to < 10%); infrequent (>< 1%); rare (> 0.01% to < 1%); rare (>< 0.1%); very rare (

From the side of hematopoietic organs:  often-leukopenia, neutropenia, thrombocytopenia, anemia; often-febrile neutropenia; very rarely – thrombocytosis.

From the digestive system:  very often-nausea, vomiting, increased activity of “hepatic” transaminases (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase; often – anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely-increased activity of gamma-glutamyltransferase; frequency cannot be estimated on the basis of available data-ischemic colitis, toxic liver damage, including fatal liver failure.

From the urinary system:  very often – hematuria and mild proteinuria; the frequency cannot be estimated based on the available dacha-acute renal failure, clinical signs and symptoms similar to hemolytic-uremic syndrome (decreased hemoglobin, thrombocytopenia, increased bilirubin, creatinine, urea and/or lactate dehydrogenase in blood serum).

From the side of the skin and skin appendages:  very common-itchy skin rashes, alopecia; often-pruritus, excessive sweating; rarely-ulceration, blistering, very rarely-severe skin reactions, including desquamation and bullous rashes; frequency cannot be estimated-Lyell’s syndrome, Stevens-Johnson syndrome.

Respiratory system disorders:  very often-shortness of breath; often-cough, rhinitis, infrequently-bronchospasm, interetitial pneumonia; frequency cannot be estimated-pulmonary edema, acute respiratory distress syndrome.

From the cardiovascular system:  rarely-low blood pressure, myocardial infarction, frequency can not be estimated-arrhythmia (mainly supraventricular), heart failure, clinical signs of peripheral vasculitis and gangrene.

Nervous system disorders:  often – headache, increased drowsiness, insomnia; frequency can not be estimated-stroke.

Other services:  very often-feeling unwell, flu-like syndrome, peripheral edema; often-fever, chills, asthenia, back pain, myalgia; rarely-swelling of the face, reactions at the injection site; very rarely-anaphylactic reactions.

Interaction

Specific studies of gemcitabine interactions have not been conducted.

Radiation therapy

Concomitant radiation therapy (concomitant with gemcitabine or at intervals of:  in this situation, the toxicity of treatment depends on many factors, including the dose of gemcitabine and the frequency of its use, the radiation dose, the method of radiation therapy, the nature of the irradiated tissue and its volume. Gemcitabine has been shown to have radiosensitizing activity.

In one study where patients with non-small cell lung cancer received gemcitabine at a dose of 1000 mg / m2 for 6 consecutive weeks in combination with therapeutic radiation to the chest area, significant toxicity was noted, in the form of severe and potentially life-threatening mucosal inflammation, mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median volume of irradiated tissue 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 a predictable toxicity profile. So, in one phase II study, patients with non-small cell lung cancer received radiation therapy at a dose of 60 Gy together with gemcitabine (600 mg/m2 4 times) and cisplatin (80 mg/m2 2 times) for 6 weeks.

Sequential therapy (break > 7 days):  according to available data, use of gemcitabine more than 7 days before the start of radiation therapy or more than 7 days after its completion is not accompanied by an increase in toxicity, with the exception of skin damage associated with the use of chemotherapy after radiation. Gemcitabine treatment can be initiated 7 days after radiation exposure or after all acute radiation reactions have resolved.

Both concomitant and sequential use of gemcitabine and radiation therapy may cause radiation damage to the exposed tissues (e. g., esophagitis, colitis, and pneumonitis).

Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infection.

Other types of interaction

When used concomitantly with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side/adverse effects and / or reduce the production of antibodies in the patient’s body in response to the introduction of the vaccine.Therefore, due to the risk of systemic, possibly fatal complications, especially in patients with reduced immune status, the interval between the use of gemcitabine and such vaccines should be at least 3 months or more (up to 12 months), depending on the patient’s immune status.

Gemcitabine compatibility studies have not been conducted. Gemcitabine should not be mixed with other medications.

How to take, course of use and dosage

Gemcitabine is administered intravenously for 30 minutes.

Non-small cell lung cancer

Monotherapy: the recommended dose of the drug is 1000 mg / m2 on days 1,8 and 15 of each 28-day cycle.

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

Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg / m2 or 1200 mg/m2 on days 1 and 8 of each 21-day cycle. Carboplatin is administered at an AUC of 5.0 mg / ml * min on day 1 of the cycle after gemcitabine infusion.

Breast cancer

Combination therapy: as a first-line therapy for disease progression post-neoadjuvant therapy, including anthracyclines; the recommended dose of the drug is 1250 mg / m2 on days 1 and 8 in combination with paclitaxel at a dose of 175 mg/m2, which is administered on the 1st day of each 21-day cycle intravenously for about 3 hours, before gemcitabine use.

Urothelial cancer

Monotherapy: the recommended dose of the drug is 1250 mg / m2 on days 1,8 and 15 of each 28-day cycle.

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

Epithelial ovarian cancer

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

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

Pancreatic cancer

Monotherapy:the recommended dose of the drug is 1000 mg / m2 once a week for 7 weeks, followed by a one-week break. Then the drug is administered on the 1st,8th and 15th days of each 28-day cycle.

Cervical cancer (locally advanced or metastatic)

Combination therapy: In locally advanced cancer (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m2 on days 1 and 8 of each 21-day cycle. Cisplatin is administered at a dose of 70 mg / m2 after gemcitabine use on the 1st day of the cycle against the background of hyperhydration.

Dose corrector of the drug in connection with the phenomena of hematological toxicity

Beginning of the treatment cycle

Regardless of the indications, platelet and granulocyte counts should be evaluated before each drug use.

The condition for starting treatment is an absolute neutrophil count of at least 1500 / µl and a platelet count of at least 100,000/µl.

Dose adjustment of the drug due to non-hematological toxicity

To detect non-hematological toxicity, periodic physical examination and monitoring of liver and kidney functions should be performed. The dose of the drug can be reduced in each subsequent cycle or during the cycle already started, depending on the degree of toxicity of the drugs prescribed to the patient. In cases of severe (grade 3 or 4) non-hematological toxicity, except in cases of nausea/vomiting, gemcitabine therapy should be suspended or the dosage should be reduced depending on the decision of the attending physician. The decision to resume treatment is made by the doctor.

Method of use

Gemcitabine infusion is usually well tolerated by patients and can be performed on an outpatient basis. In case of extravasation, the infusion is stopped and the drug is reintroduced into another vein. After gemcitabine use, the patient should be monitored for some time.

Overdose

Symptoms: myelodepression, paresthesia, severe skin rash. When gemcitabine was administered in doses up to 5700 mg/m2 intravenously for 30 minutes every 2 weeks, no signs of overdose were observed. The antidote for gemcitabine is unknown.

If an overdose of gemcitabine is suspected, the degree of cytopenia should be monitored and, if necessary, symptomatic therapy should be prescribed.

Special instructions

Treatment with gemcitabine should only be carried out under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

Before each use of gemcitabine, it is necessary to monitor the number of platelets, white blood cells and granulocytes in the blood. If there are signs of bone marrow suppression caused by the drug, it is necessary to suspend treatment or adjust the dose.

Usually, suppression of bone marrow function is short-term, does not require dose reduction, and rarely leads to the need to interrupt treatment. Peripheral blood counts may continue to deteriorate after gemcitabine therapy is discontinued.

When gemcitabine is used in combination with other antitumor chemotherapeutic agents, the risk of cumulative suppression of bone marrow function should be considered.

It is necessary to conduct a regular examination of the patient and assess the function of the kidneys and liver.

The use of gemcitabine in patients with liver metastases, hepatitis and alcoholism in the anamnesis, as well as in patients with cirrhosis of the liver increases the risk of developing liver failure. If there are signs of developing adverse events from the respiratory system (for example, pulmonary edema, interstitial pneumonitis or respiratory distress syndrome in adults), treatment with gemcitabine should be discontinued and appropriate therapy should be prescribed.

When the first signs of microangiopathic hemolytic anemia appear, such as a rapid decrease in hemoglobin with concomitant thrombocytopenia, an increase in serum bilirubin, creatinine, urea nitrogen, or an increase in lactate dehydrogenase activity, gemcitabine should be discontinued.

An increase in the duration of the infusion and the frequency of use leads to an increase in toxicity.

The risk of skin reactions increases with a history of radiation therapy.

Depending on the degree of toxicity, the dose can be reduced during each cycle or with the start of a new cycle in stages.

Reliable methods of contraception should be used during treatment and for 6 months after the end of gemcitabine therapy. Men receiving gemcitabine are advised to resort to cryopreservation of sperm prior to treatment due to the risk of infertility due to the use of this drug.

When treating patients on a controlled sodium diet, the sodium content in the preparation should be taken into account in the following amounts::

a 200 mg bottle of Gemcitabine medac contains 3.5 mg (<1 mmol) of sodium,

a 1000 mg bottle of Gemcitabine medac contains 17.5 mg (<1 mmol) of sodium,

a 1500 mg bottle of Gemcitabine medac contains 26.3 mg (

Influence on the ability to drive a vehicle and work with mechanisms. There are no data on the effect of gemcitabine therapy on the ability to drive a vehicle and work with mechanisms, however, some side effects of the drug, such as increased drowsiness, may negatively affect the ability to perform such actions. During treatment with gemcitabine, caution should be exercised when driving vehicles and engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Active ingredient

Gemcitabine

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Breast Cancer, Cancer