Gemzar, lyophilizate 1 g

Pharmacodynamics

Antitumor drug, antimetabolite of pyrimidine analogues group. The drug is cyclo-specific, acting on cells in S phase (replication phase) and G₁/S phase (interval between initial growth phase and replication phase).

Hemcitabine is metabolized within the cell by nucleosidkinases to form active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which acts as the sole catalyst for reactions leading to the formation of deoxynucleoside triphosphates required for DNA synthesis. Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into DNA and RNA molecules. Once the intracellular metabolites of gemcitabine are incorporated into the DNA strand, one additional nucleotide is added to its growing strands, resulting in complete inhibition of further DNA synthesis and programmed cell death, known as apoptosis.

Pharmacokinetics

Distribution

The binding to plasma proteins is negligible.

Elevation

T_1/2 ranges from 32 to 94 minutes. Gemcitabine is rapidly excreted by the kidneys mainly as the inactive metabolite 2′-deoxy-2′,2′-difluoruridine. Less than 10% of the dose administered intravenously is found unchanged in the urine.

The systemic clearance ranges from 30 to 90 L/h/m².

Pharmacokinetics in Special Clinical Cases

The analysis of pharmacokinetic studies with single and multiple administration of the drug shows that V_d is significantly gender dependent.

The systemic clearance, which ranges from approximately 30 L/h/m2 to 90 L/h/m2², depends on sex and age.

Indications

Active ingredient

Composition

1 vial contains:

Active ingredients:

gemcitabine hydrochloride 1.14 g, corresponding to the content of gemcitabine 1 g.

Excipients:

Mannitol – 1000 mg,

Sodium acetate – 62.5 mg.

In a vial of 1 g of lyophilizate.

There is 1 vial in the carton pack.

How to take, the dosage

Gemzar® is given by IV drip for 30 minutes.

Before each administration of gemcitabine, the platelet, leukocyte and granulocyte counts in the blood should be monitored. If there are signs of depression of bone marrow function caused by the drug, treatment should be stopped or the dose adjusted.

Non-small cell lung cancer (locally advanced or metastatic), first-line therapy

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

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/m2 on day 1 of the cycle after gemcitabine infusion against a background of hyperhydration.

Combination therapy with carboplatin: The recommended dose of 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 on day 1 of the cycle after gemcitabine infusion.

Breast cancer (unresectable, locally recurrent or metastatic)

Combination therapy with paclitaxel: as first-line therapy for disease progression after neoadjuvant and/or adjuvant therapy including anthracyclines in the absence of contraindications. Paclitaxel is administered at a dose of 175 mg/m2 by IV drip for 3 h on day 1 of a 21-day cycle, followed by gemcitabine. The recommended dose of drug is 1250 mg/m2 on days 1 and 8 of each 21-day cycle.

Before starting combination therapy (gemcitabine+paclitaxel), the absolute count of granulocytes in the blood must be at least 1500/μL.

Urothelial cancer (bladder cancer (locally advanced, metastatic and superficial), renal pelvis, ureter, and urethra)

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

Combination therapy with cisplatin: 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 gemcitabine infusion on day 1 or day 2 of each 28-day cycle. Clinical studies have shown that more severe myelosuppression is seen at the 100 mg/m2 dose of cisplatin.

Epithelial ovarian cancer (locally advanced or metastatic, resistant to platinum derivatives)

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

Combination therapy with carboplatin: the recommended dose of drug is 1000 mg/m2 on days 1 and 8 combined with carboplatin at an AUC of 4 mg/mL/min, which is administered immediately after the gemcitabine infusion on day 1 of each 21-day cycle.

Pancreatic cancer (locally advanced or metastatic, including those resistant to 5-fluorouracil therapy)

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

Cervical cancer (locally advanced or metastatic)

Combination therapy with cisplatin: In locally advanced cancer on sequential chemoradiotherapy (neoadjuvant) and in metastatic cancer, cisplatin is given at a dose of 70 mg/m2 on day 1 of the cycle against a background of hyperhydration, followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg/m2 on days 1 and 8 of each 21-day cycle.

In locally advanced cancer with concomitant chemoradiotherapy, cisplatin is given at a dose of 40 mg/m2 followed (immediately after cisplatin administration) by gemcitabine. Gemcitabine is administered once a week 1-2 hours before the start of radiation therapy at a dose of 125 mg/m2.

Biliary tract cancer

Combination therapy with cisplatin: cisplatin is administered at a dose of 70 mg/m2 on day 1 of the cycle on hyperhydration followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg/m2 on days 1 and 8 of each 21-day cycle.

Dose adjustment

If hematologic toxicity develops, the dose of gemcitabine may be reduced or its administration delayed according to the following regimens:

A. Dose adjustment of gemcitabine within the cycle in urothelial cancer, non-small cell lung cancer, and pancreatic cancer as monotherapy or in combination with cisplatin.

Absolute number of granulocytes (in 1 µl)

Number of platelets (in 1 µl)

/td>

% of the previous dose

> 1000

and

> 100,000

100

500-1000

or

50,000-100,000

75

< 500

or

< 50,000

Postpone administration

B. Cycle gemcitabine dose adjustment for breast cancer in combination with paclitaxel.

Absolute number of granulocytes (in 1 µl)

Number of platelets (in 1 µl)

/p>

% of the previous dose

≥1200

and

>75,000

100

1000 -<1200

or

50,000-75,000

75

700-

and

≥50,000

50

B. Cycle dose adjustment of gemcitabine in ovarian cancer in combination with carboplatin.

Absolute granulocyte count (in 1 µl)

Platelet count (in 1 µl)

% of previous dose

>1500

and

≥100,000

100

1000-1500

or

75,000 -100,000

or

Postpone administration

In order to detect non-hematologic toxicity, the patient should be evaluated regularly and liver and renal function monitored. Depending on the degree of toxicity, the dose may be reduced during each cycle or in steps with the start of a new cycle.

The administration of the drug should be delayed until, in the opinion of the physician, the toxicity has resolved.

Particular patient groups

There are no data to suggest that dose adjustments are needed in elderly patients.

Patients with hepatic impairment or impaired renal function should use gemcitabine with caution because there are insufficient data on the use of the drug in this category of patients. Renal insufficiency of mild to moderate degree of severity (GFR from 30 ml/min to 80 ml/min) has no appreciable effect on gemcitabine pharmacokinetics.

Gemcitabine has been studied in limited phase 1 and 2 studies in children with different types of neoplasms. Data from these studies are insufficient to prove the efficacy and safety of gemcitabine in children.

The rules for preparation of the solution for infusion

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 shall be dissolved in not less than 5 ml, and 1 g in not less than 25 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. In solutions prepared with a concentration greater than 40 mg/ml, incomplete dissolution is possible.

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

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

Interaction

Radiation therapy

Concomitant use (concurrent or less than 7 days apart): the toxicity associated with this multimodality treatment depends on many different factors: gemcitabine dose, frequency of gemcitabine administration, radiation therapy dose, radiation therapy planning technique, type and volume of tissue irradiated.

Preclinical and clinical studies have shown that gemcitabine has a radiosensitizing effect. In the only study in which gemcitabine was administered at a dose of 1,000 mg/m2 for 6 weeks concurrently with therapeutic chest irradiation in patients with non-small-cell lung cancer, significant toxicity in the form of severe and potentially life-threatening mucosal inflammation, mainly esophagitis, and pneumonitis was reported, especially in patients with high tissue volume irradiation (median volume irradiation 4795 cm3).

Later studies (phase II studies in non-small-cell lung cancer) suggest that gemcitabine administration at lower doses with concomitant radiation therapy with predicted toxicity is appropriate. Radiation therapy to the thoracic area (SOD 66 Gy) was performed concomitantly with chemotherapy with gemcitabine at a dose of 600 mg/m2 (4 injections) and cisplatin at a dose of 80 mg/m2 (2 injections) for 6 weeks.

Few phase I and II studies have shown that gemcitabine monotherapy (at doses up to 300 mg/m2/week) in non-small-cell lung cancer and pancreatic cancer is more appropriate concurrently with radiotherapy. The optimal regimen for the safe administration of gemcitabine with therapeutic doses of radiation therapy has not yet been established for all types of neoplasms.

Several use (interval more than 7 days): Except for a radiation reaction when gemcitabine is administered more than 7 days before or after radiation therapy, no increase in toxicity has been reported. These data suggest that gemcitabine can be administered one week after radiation therapy or after the acute effects of radiation therapy have been eliminated. Both concomitant and sequential use of gemcitabine with radiation therapy have reported radiation damage to irradiated tissues (e.g., esophagitis, colitis and pneumonitis).

Others

The co-administration with live yellow fever vaccines and other live vaccines is not recommended because of the risk of systemic disease with possible lethal outcome, especially in immunosuppressed patients.

Special Instructions

Treatment with gemcitabine should only be done under the supervision of a physician experienced in the use of antitumor chemotherapy.

Before each administration of gemcitabine, the number of platelets, leukocytes and granulocytes in the blood should be monitored. 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 examined regularly and renal and hepatic function should be evaluated. Administration of gemcitabine for liver metastases, a history of hepatitis and alcoholism, and cirrhosis increases the risk of liver failure.

Lengthening the duration of infusion and frequency of administration leads to increased toxicity.

Gemcitabine may suppress bone marrow activity, which is manifested by leukopenia, thrombocytopenia or anemia.

The syndrome of increased capillary permeability with potentially serious consequences has been observed in patients receiving gemcitabine as monotherapy or in combination with other chemotherapy drugs. If capillary permeability syndrome develops during therapy, gemcitabine treatment should be discontinued and appropriate measures taken. According to some literature data, capillary hyperpermeability syndrome has been associated with adult respiratory distress syndrome.

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

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

There have been no studies of the effect of gemcitabine on the ability to drive vehicles and other mechanisms. However, it is known that gemcitabine may cause mild to moderate somnolence, especially in combination with alcohol consumption.

Patients should be cautioned against operating machinery when they feel drowsy.

Contraindications

With caution: the drug is used in patients with liver and/or kidney dysfunction, suppression of medullar hemopoiesis (including in concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature.

Side effects

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

Blood system: very common – anemia, leukopenia, thrombocytopenia; frequent – febrile neutropenia; very rare – thrombocytosis.

Metabolism: often – anorexia.

Nervous system disorders: often – headache, sleep disturbance, somnolence.

Cardiovascular system: very common – edema, peripheral edema; infrequent – heart failure, arrhythmia, predominantly supraventricular; rare – myocardial infarction, decreased blood pressure.

Respiratory system: very common – shortness of breath; common – cough, rhinitis; infrequent – bronchospasm.

The digestive system: very common – impairment of liver function (usually mild, rarely requiring discontinuation of treatment), nausea, vomiting; common – diarrhea, stomatitis, constipation.

Skin and subcutaneous tissues: very common – mild skin rash accompanied by itching, alopecia (usually minimal hair loss); common – itching, sweating; rarely – ulcers, vesicles formation.

Urinary system disorders: very common – mild proteinuria and hematuria.

Muscular system: often – back pain, myalgia.

Allergic reactions: very rare – anaphylactoid reactions, anaphylactic reaction.

Others: very often – flu-like syndrome (increased body temperature, headache, chills, asthenia, malaise); rarely – reactions at the injection site. Body temperature increase and asthenia are often registered as separate symptoms. Radiation toxicity has rarely been reported.

Postmarketing data

Cardiovascular system: infrequent – heart failure, arrhythmia, predominantly supraventricular; rare – gangrene and peripheral vasculitis; very rare – syndrome of increased capillary permeability.

Respiratory system: infrequent – interstitial pneumonitis; rarely – respiratory distress syndrome in adults, pulmonary edema. In case of development of such effects it is necessary to consider discontinuation of gemcitabine therapy. Early supportive therapy may improve the situation.

Digestive system disorders: very rare – ischemic colitis.

Skin and subcutaneous tissue disorders: rare – severe skin reactions, including skin desquamation and bullous lesions.

Urinary system disorders: infrequent – hemolytic-uremic syndrome. At the first sign of any manifestation of microangiopathic hemolytic anemia (e.g., sharp decrease of hemoglobin with accompanying thrombocytopenia, increased bilirubin, serum creatinine, urea or LDH) gemcitabine therapy should be stopped immediately. Renal failure may be irreversible even after discontinuation of therapy and dialysis may be required.

Hepatic and biliary tract disorders: very common – increased liver enzyme activity: ACT, ALT, ALP; often – increase of bilirubin concentration; infrequent – severe hepatotoxicity, including liver failure; rare – increase of GGT activity.

Others: very rare – Lyell syndrome, Stevens-Johnson syndrome; radiation reactions have been reported.

Overdose

Treatment: No known antidote. Clinically tolerated toxicity has been observed with single doses up to 5.7 g/m2 w/v for 30 min every 2 weeks.

In case of suspected overdose the patient should be under constant medical supervision, including blood counts. If necessary symptomatic treatment is administered.

Pregnancy use

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

Similarities