Gemita lyophilizate 1400 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. It is metabolized in cells under the action of 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 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.

The 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

Locally advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin and as monotherapy in elderly patients with an ECOG-WHO performance status of 2;
inoperable, locally recurrent or metastatic breast cancer after neoadjuvant and/or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their use as part of combination therapy with paclitaxel;
locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra);
locally advanced or metastatic ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after first-line therapy based on platinum-containing drugs;
locally advanced or metastatic pancreatic cancer;
locally advanced or metastatic cervical cancer.

Pharmacological effect

Pharmacodynamics

An antitumor drug, an antimetabolite of the group of pyrimidine analogues, inhibits DNA synthesis. It exhibits cycle specificity, acting on cells in the S phase and at the boundary of the G1 and S phases. Metabolized in the cell under the action of 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 cessation of further DNA synthesis and programmed cell lysis (apoptosis).

Gemcitabine is also a strong radiosensitizer, even at concentrations lower than cytotoxic.

Pharmacokinetics

Cmax of gemcitabine (from 3.2 µg/ml to 45.5 µg/ml) is achieved 5 minutes after the end of the infusion. Pharmacokinetic analysis of single and repeated dose studies shows that Vd is significantly dependent on gender. The binding of gemcitabine to plasma proteins is negligible.

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, of which gemcitabine di- and triphosphates are considered active.

Gemcitabine is rapidly excreted from the body by the kidneys, mainly as the inactive metabolite 2′-deoxy-2′, 2′-difluorouridine. Less than 10% of the administered IV dose is found in the urine as unchanged gemcitabine. Systemic clearance, which ranges from approximately 30 l/h/m2 to 90 l/h/m2, depends on age and gender.

T1/2 ranges from 42 minutes to 94 minutes. If the recommended dosage regimen is followed, complete elimination 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 gemcitabine and paclitaxel are coadministered, the pharmacokinetics of the drugs do not change.

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

Renal dysfunction. Mild to moderate renal failure (creatinine clearance 30-80 ml/min) does not have a significant effect on the pharmacokinetics of gemcitabine.

Special instructions

Treatment with Gemita can only be carried out under the supervision of a physician experienced in antitumor chemotherapy.

Before each administration of the drug Gemita, it is necessary to determine the leukocyte formula and the number of platelets 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.

It is necessary to regularly examine the patient and assess kidney and liver function.

Administration of the drug Gemita for liver metastases, a history of hepatitis and alcoholism, as well as cirrhosis of the liver increases the risk of developing liver failure.

If signs of adverse events from the respiratory system (for example, pulmonary edema, interstitial pneumonitis or respiratory distress syndrome in adults) appear during treatment with Gemita, treatment 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 concentrations of bilirubin, creatinine, nitrogen, urea, or an increase in LDH activity, the drug should be discontinued. Increasing the duration of infusion and frequency of administration leads to increased toxicity.

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

During treatment and for 6 months after the end of therapy with Gemita, reliable methods of contraception should be used. Men receiving Gemita are advised to resort to sperm cryopreservation before starting treatment due to the risk of infertility associated with the use of this drug.

Gemcitabine can be administered after resolution of acute radiation reactions or no earlier than 7 days after the end of radiation therapy.

Gemcitabine, alone or in combination with other antineoplastic agents, 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 that require increased concentration

There are no data on the effect of Gemita therapy on the ability to drive a vehicle and operate machinery; however, some side effects of the drug, such as increased drowsiness, may negatively affect the ability to drive a car and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions, which requires caution.

Active ingredient

Gemcitabine

Composition

1 bottle contains:

Active ingredients:

gemcitabine hydrochloride 1594.04 mg, which corresponds to the content of gemcitabine 1400 mg.

Excipients:

mannitol – 1400 mg,

sodium acetate trihydrate – 87.5 mg,

hydrochloric acid – q.s. for pH adjustment,

sodium hydroxide – q.s. to adjust pH.

1400 mg per bottle.

There is 1 bottle in a cardboard package.

Pregnancy

The use of the drug during pregnancy and lactation (breastfeeding) is contraindicated.

Contraindications

Pregnancy;
breastfeeding period;
children under 18 years of age (lack of sufficient data on effectiveness and safety);
hypersensitivity to the active substance or to any of the excipients.

With caution: the drug should be prescribed in case of impaired liver and/or kidney function, suppression of bone marrow hematopoiesis (including against the background of concomitant radiation or chemotherapy), cardiovascular diseases, metastatic liver damage, hepatitis, alcoholism, during simultaneous radiation therapy, acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles lichen).

Side Effects

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

very often (> 10%);
often (> 1% to < 10%); uncommon (>0.1% to <1%); rare (>0.01% to <0.1%); very rare (<0.01%).

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

From the digestive system: very often – nausea, vomiting, increased activity of liver transaminases (AST, ALT), alkaline phosphatase; often – anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely – increased GGT activity.

From the urinary system: very often – mild hematuria and proteinuria; rarely – renal failure, clinical signs and symptoms similar to hemolytic-uremic syndrome (decreased hemoglobin, thrombocytopenia, increased concentrations of bilirubin, creatinine, urea and/or LDH activity in the blood serum).

From the skin and subcutaneous tissues: very often – skin rashes accompanied by itching, alopecia; often – itchy skin, increased sweating; rarely – skin ulceration, blistering; very rarely – severe skin reactions, including desquamation and bullous rashes.

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

From the cardiovascular system: rarely – decreased blood pressure, myocardial infarction, heart failure, arrhythmia.

From the nervous system: often – headache, increased drowsiness, insomnia.

Other: very often – flu-like syndrome, peripheral edema; often – increased body temperature, chills, asthenia, back pain, myalgia; infrequently – swelling of the face; very rarely – anaphylactic reactions.

Interaction

Radiation therapy

Concomitant radiation therapy (concurrent with Gemita or <7 days apart before treatment): In this setting, treatment toxicity depends on many factors, including the dose of gemcitabine and frequency of administration, radiation dose, method of radiation therapy, nature of the tissue treated and volume of tissue treated. Gemcitabine has been shown to have radiosensitizing activity. In one study where patients with non-small cell lung cancer received gemcitabine 1000 mg/m2 for 6 consecutive weeks in combination with therapeutic radiation to the chest, significant toxicity was observed in the form of severe and potentially life-threatening mucosal inflammation, mainly esophagitis and pneumonitis, especially in patients with large tissue volumes irradiated (median volume of tissue irradiated 4795 cm3). Subsequent studies have shown that the combination of lower doses of gemcitabine and radiation therapy is better tolerated by patients and has a predictable toxicity profile. Thus, in one of the phase II studies, patients with non-small cell lung cancer received radiation therapy at a dose of 60 Gy together with the administration of gemcitabine (600 mg/m2 4 times) and cisplatin (80 mg/m2 2 times) for 6 weeks.

Sequential therapy (> 7 days off): Based on existing data, gemcitabine administered more than 7 days before or more than 7 days after radiation therapy is not associated with increased toxicity, with the exception of skin lesions associated with chemotherapy after radiation. Treatment with gemcitabine can be started 7 days after radiation or after all acute radiation reactions have resolved.

With both concomitant and sequential use of gemcitabine and radiation therapy, radiation damage to the irradiated tissues (for example, esophagitis, colitis and pneumonitis) is possible.

Other types of interaction

When used simultaneously with live attenuated vaccines, it is possible to intensify the replication process 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 vaccine.

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

Compatibility studies of the drug Gemita have not been conducted. It is not recommended to mix Gemita with other medications.

Overdose

There is no known antidote for gemcitabine.

When Gemita was administered in doses up to 5700 mg/m2 intravenously over 30 minutes every 2 weeks, the level of treatment toxicity remained acceptable.

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

Storage conditions

At a temperature not exceeding 25 °C (do not freeze)

Shelf life

2 years

Manufacturer

Fresenius Kabi Deutschland GmbH, Germany