Gemita lyophilizate 200 mg

Pharmacodynamics

Antitumor drug, antimetabolite of pyrimidine analogues group, inhibits DNA synthesis. It is cyclo-specific, acting on cells in S phase and on the border of G1 and S phase. Metabolized in the cell under the action of nucleosidkinases to active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit the action of ribonucleotide reductase (the only enzyme that catalyzes the formation of deoxynucleoside triphosphates required for DNA synthesis). Triphosphate nucleosides are capable of being incorporated into the DNA strand (to a lesser extent RNA), which leads to the cessation of further DNA synthesis and programmed cell lysis (apoptosis).

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

Pharmacokinetics

The C_max of gemcitabine (3.2 µg/mL to 45.5 µg/mL) is reached 5 minutes after completion of infusion. Pharmacokinetic analysis of single- and multiple-dose administration studies shows that V_d is significantly gender dependent. The binding of gemcitabine to plasma proteins is negligible.

In the body, gemcitabine is rapidly metabolized by citidine deaminase in the liver, kidneys, blood and other tissues, producing gemcitabine mono-, di- and triphosphates, of which gemcitabine di- and triphosphates are considered active.

Hemcitabine is rapidly excreted by the kidneys mainly as the inactive metabolite 2′-deoxy-2′, 2′-difluoruridine. Less than 10% of the administered IV 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 sex.

T_1/2 ranges from 42 min to 94 min. If the recommended dosing regimen is followed, complete excretion of gemcitabine occurs within 5-11 hours from the start of the infusion. When administered once a week, gemcitabine does not accumulate in the body.

Combination therapy with gemcitabine and paclitaxel. When co-administering gemcitabine and paclitaxel the pharmacokinetics of the drugs are not altered.

Combination therapy with gemcitabine and carboplatin. The pharmacokinetics of gemcitabine and carboplatin are not altered when gemcitabine and carboplatin are coadministered.

Renal dysfunction. Mild to moderate renal failure (creatinine clearance 30-80 ml/min) has no significant effect on the pharmacokinetics of gemcitabine.

Indications

Active ingredient

Composition

1 vial contains:

Active ingredients:

gemcitabine hydrochloride 227.72 mg, corresponding to gemcitabine 200 mg.

Auxiliary substances:

Mannitol – 200 mg,

Sodium acetate trihydrate – 12.5 mg,

Hydrochloric acid – q.s. for pH correction,

sodium hydroxide – q.s. for pH correction.

In a bottle of 200 mg.

There is 1 vial in the carton pack.

How to take, the dosage

Non-small cell lung cancer

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

In combination therapy with cisplatin, the recommended dose of 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 mg/m22 on day 1 of the cycle against a water load after the Gemita infusion.

In 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 the Gemita infusion.

Breast cancer

In combination therapy as 1st-line therapy for disease progression after neoadjuvant therapy including anthracyclines, the recommended dose of the drug is 1250 mg/msup>2 on days 1 and 8 in combination with paclitaxel, which is administered after administration of Gemita at a dose of 175 mg/m2 on day 1 of each 21-day cycle by IV drip for approximately 3 hours.

Urothelial cancer

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

In combination therapy, the recommended dose of the drug is -1000 mg/m2 on days 1, 8, and 15 combined with cisplatin, which is administered at a dose of 70 mg/m2 immediately after the Gemita infusion on day 1 or day 2 of each 28-day cycle.

Ovarian cancer

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

Pancreatic cancer

In monotherapy, the recommended dose of drug is 1000 mg/m2 once weekly for 7 weeks, followed by a one-week break. Thereafter, the drug is administered on days 1, 8, and 15 of each 28-day cycle.

Cervical cancer (locally advanced or metastatic)

Combination therapy: For locally advanced cancer (neoadjuvant) and for metastatic cancer, gemcitabine is given at a dose of 1,250 mg/m2 on days 1 and 8 of each 21-day cycle. Cisplatin is administered after Gemita at a dose of 70 mg/m2 on day 1 of the cycle against a background of hyperhydration.

In locally advanced cancer with concurrent radiation therapy, Gemita is administered once a week for 6 weeks at a dose of 125 mg/m2 followed immediately by cisplatin at a dose of 40 mg/m2 1-2 hours before the start of radiotherapy. Radiation therapy is given in 28 fractions, at a single focal dose of 1.8 g, 5 days per week up to a total focal dose of 50.4 g.

Changing the dose of the drug due to the phenomenon of hematologic toxicity

The beginning of the treatment cycle

Whatever the indication, platelet and granulocyte counts must be assessed before each administration of the drug. A minimum absolute neutrophil count of 1,500/µL and a platelet count of 100,000/µL are prerequisites for treatment initiation.

If hematologic toxicity develops during a cycle of therapy, the dose of Gemita may be reduced or its administration delayed according to the following guidelines.

The dose modification of Gemite used in monotherapy or in combination with cisplatin in the treatment of bladder cancer, non-small cell lung cancer and pancreatic cancer.

Absolute granulocyte count (in 1 µl)

Platelet count (in 1 µl)

% of the previous dose

> 1000

and

> 100,000

100

500-1000

or

50,000-100,000

75

< 500

or

< 50,000

Postpone administration*

* – When neutrophil counts increase to 500/µl and platelet counts increase to 50,000/µl, administration of Gemita may be continued as part of the cycle.

Dose modification of Gemite used in combination with paclitaxel in the treatment of breast cancer.

Absolute granulocyte count (in 1 µl)

Platelet count (in 1 µl)

% of previous dose

≥1200

and

> 75,000

100

/p>

1000-1200

or

50,000-75,000

75

and

≥ 50,000

50

* – Treatment within a cycle is not renewed. The next injection of Gemita is given on the 1st day of the next cycle when the neutrophil count is at least 1,500/μL and the platelet count is up to 100,000/μL.

The dose modification of Gemita used in combination with carboplatin in the treatment of ovarian cancer.

Absolute granulocyte count (in 1 µl)

Platelet count (in 1 µl)

% of the previous dose

> 1500

and

≥ 100,000

100

1000-< 1500

or

50

< 1000

or

< 75,000

Postpone administration*

* – Treatment within the cycle is not resumed. The next injection of Gemita is given on the 1st day of the next cycle when the neutrophil count is at least 1,500/μL and the platelet count is up to 100,000/μL.

The dose of Gemite on the next cycle should be reduced by 25% for all indications in cases where the previous cycle was observed:

Method of administration

Infusion administration of Gemita is usually well tolerated by patients and can be performed as an outpatient. If extravasation occurs, the infusion is stopped and the drug is restarted in another vein. After administration of Gemita, the patient should be monitored for some time.

Gemita should be used with caution in patients with hepatic impairment or impaired renal function because there are insufficient data on its use in these patients. Moderate to moderate renal insufficiency (glomerular filtration rate from 30 ml/min to 80 ml/min) has no significant effect on gemcitabine pharmacokinetics.

Gemitabine is well tolerated in elderly patients over 65 years of age. There are no specific recommendations to change the dose of the drug for this population.

Gemita is not recommended for use in children less than 18 years of age due to insufficient information on the safety and effectiveness of the drug in this population.

Regulations for preparation of the infusion solution

Only 0.9% sodium chloride solution without preservatives is used as a solvent.

In order to prepare solution for infusion the contents of 200 mg vial is dissolved in at least 5 ml, 1000 mg in at least 25 ml, and 1400 mg in at least 35 ml of 0.9% sodium chloride solution for injection. Each vial is shaken gently until complete dissolution of the lyophilizate. The resulting solution should be clear.

The maximum concentration of gemcitabine should not exceed 40 mg/ml. Solutions prepared with a concentration higher than 40 mg/ml may be accompanied by incomplete dissolution.

The prepared solution of Gemitabine containing the desired dose of the drug is diluted with 0.9% sodium chloride solution for injection in an amount sufficient for 30-minute intravenous infusions before administration.

Before parenteral administration the prepared solution should be visually checked for mechanical impurities and color changes.

The prepared solution of Gemita is physically and chemically stable for 24 h provided it has been stored at controlled room temperature (20°C to 25°C). From the microbiological point of view the prepared solution should be used immediately. If the prepared solution was not used immediately and it was prepared under controlled and validated aseptic conditions, the storage time is usually no more than 24 h at room temperature (20° to 25° C).

Interaction

Radiation therapy

Companion radiation therapy (concomitantly with Gemitabine or at < 7-day intervals prior to treatment): in this situation, the toxicity of treatment depends on many factors, including the gemcitabine dose and frequency of administration, radiation dose, method of radiation therapy, nature of the tissue being irradiated, and 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 irradiation to the chest area, significant toxicity in the form of severe and potentially life-threatening mucosal inflammation, primarily esophagitis and pneumonitis, was noted, particularly in patients with a large volume of tissue irradiated (median volume of tissue irradiated 4795 cm3). In subsequent studies, the combination of lower doses of gemcitabine and radiation therapy has been shown to be better tolerated by patients and to have a predictable toxicity profile. For example, in one phase II study, patients with non-small-cell lung cancer received radiation therapy at a dose of 60 Gy combined with gemcitabine (600 mg/m2 4 times) and cisplatin (80 mg/m2 2 times) for 6 weeks.

Consecutive therapy (break > 7 days): Current evidence suggests that administration of gemcitabine more than 7 days before radiation therapy or more than 7 days after completion of radiation therapy is not associated with increased toxicity, except for skin lesions associated with chemotherapy administration after irradiation. Treatment with gemcitabine may be initiated 7 days after irradiation or after resolution of all acute radiation reactions.

With both concomitant and sequential use of gemcitabine and radiation therapy, radiation damage of irradiated tissues (e.g., esophagitis, colitis and pneumonitis) is possible.

Other interactions

Concomitant use with live attenuated vaccines may intensify the replication of the vaccine virus, increase its adverse/ adverse effects and/or decrease antibody production in the patient in response to vaccine administration.

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

There have been no studies on the compatibility of Gemita. Mixing Gemita with other medicinal products is not recommended.

Special Instructions

The treatment with Gemita should only be carried out under the supervision of a doctor experienced in anticancer chemotherapy.

Pefore each administration of Gemita, the white blood cell count and platelet count in the blood must be determined. If there are signs of inhibition of bone marrow function caused by the drug, treatment should be stopped or the dose adjusted.

The patient should be evaluated regularly and renal and hepatic function should be assessed.

The administration of Gemita for liver metastases, a history of hepatitis and alcoholism, and cirrhosis increases the risk of liver failure.

In case of signs of respiratory adverse events (e.g. pulmonary edema, interstitial pneumonitis or respiratory distress syndrome in adults) during treatment with Gemita, treatment should be stopped and appropriate therapy should be given.

In case of the first signs of microangiopathic hemolytic anemia, such as rapid decrease of hemoglobin with associated thrombocytopenia, increased serum bilirubin, creatinine, nitrogen, urea or increased LDH activity, the drug should be stopped. Increased duration of infusion and frequency of administration leads to increased toxicity.

Depending on the degree of toxicity, the dose may be decreased during each cycle or in steps with the start of a new cycle.

Safe contraception should be used during treatment and for 6 months after therapy with Gemita. Men who receive Gemita are advised to cryopreserve sperm before starting treatment because of the risk of infertility associated with the use of the drug.

Hemcitabine can be started after acute radiation reactions have resolved or no earlier than 7 days after completion of radiation therapy.

Gemcitabine in monotherapy or in combination with other antitumor drugs is active in advanced small cell lung cancer, advanced testicular cancer and bile duct cancer.

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

Impact on the ability to operate vehicles and other mechanisms requiring increased concentration There are no data about the effect of Gemita therapy on the ability to drive vehicles and operate machinery, but some side effects of the drug, such as increased somnolence, may adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and quick psychomotor reactions, which requires caution.

Contraindications

With caution: The drug should be used in patients with impaired hepatic and/or renal function, suppression of medullary hematopoiesis (including against concomitant radiation exposure.

With caution: the preparation should be used in patients with hepatic and/or renal dysfunction, inhibition of bone marrow formation (including in concomitant radiation and chemotherapy), cardiovascular diseases, metastatic liver injury, hepatitis, alcoholism, concurrent radiation therapy, acute infectious diseases of viral, fungal or bacterial nature (including varicella and herpes zoster).

Side effects

Adverse reactions that occurred more frequently than isolated cases are listed according to the following gradation:

Blood organs: very common – leukopenia, neutropenia, thrombocytopenia, anemia; often – febrile neutropenia; very rare – thrombocytosis.

The digestive system: very often – nausea, vomiting, increased liver transaminase activity (AST, ALT), ALP; often – anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely – increased GGT activity.

Urinary system disorders: very common – mild hematuria and proteinuria; rare – renal failure, clinical signs and symptoms similar to hemolytic-uremic syndrome (decrease of hemoglobin, thrombocytopenia, increased concentration of bilirubin, creatinine, urea and/or LDH activity in serum).

Skin and subcutaneous tissue: very common – skin rash accompanied by itching, alopecia; common – skin itching, increased sweating; rare – skin ulceration, blistering; very rare – marked skin reactions, including desquamation and bullous rash.

The respiratory system: very often – shortness of breath; often – cough, rhinitis; infrequently – bronchospasm, interstitial pneumonitis, pulmonary edema; rarely – acute respiratory distress syndrome.

Cardiovascular system: rare – decrease of BP, myocardial infarction, heart failure, arrhythmia.

Nervous system disorders: often – headache, increased somnolence, insomnia.

Others: very often – flu-like syndrome, peripheral edema; often – elevated body temperature, chills, asthenia, back pain, myalgia; infrequently – swollen face; very rarely – anaphylactic reactions.

Overdose

The antidote for gemcitabine is unknown.

When Gemitabine was administered at doses up to 5700 mg/m2 by IV drip for 30 min every 2 weeks, treatment toxicity levels remained acceptable.

If gemcitabine overdose is suspected, the degree of cytopenia should be monitored and maintenance therapy administered if necessary.

Pregnancy use

The drug is contraindicated in pregnancy and lactation (breast-feeding).

Similarities