Gemcitabin Pliva (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pliva, s.r.o. (Czech Republic)

Manufactured By

Pliva-Lachema, a.s. (Czech Republic)

ATC Code

L01BC05 (Gemcitabine)

Active Substance

Gemcitabine (Rec.INN registered by WHO)

Dosage Forms

	Gemcitabine Pliva	Lyophilisate for preparation of solution for infusion 1 g: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 200 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion white in color.

Excipients: mannitol, sodium acetate trihydrate, hydrochloric acid and/or sodium hydroxide (to maintain pH level).

Colorless glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion white in color.

Excipients: mannitol, sodium acetate trihydrate, hydrochloric acid and/or sodium hydroxide (to maintain pH level).

Colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor drug. Gemcitabine is an antimetabolite from the pyrimidine analog group. The drug suppresses DNA synthesis. It exhibits cycle specificity, acting on cells in the S and G1/S phases. It is metabolized in the cell under the action of nucleoside kinases to form active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which is the only enzyme that catalyzes the formation of deoxynucleoside triphosphates necessary for DNA synthesis. Triphosphate nucleosides can be incorporated 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 potent radiosensitizing agent even at concentrations lower than cytotoxic ones.

Pharmacokinetics

Distribution

V_d depends significantly on the duration of infusions and gender. Plasma protein binding is low – less than 10%.

Metabolism

It is metabolized in the cells of the liver, kidneys, and blood under the action of the enzyme cytidine deaminase stepwise, to form the inactive metabolite 2′-deoxy-2′,2′-difluorouridine.

Elimination

Systemic clearance, which ranges from approximately 30 L/h/m² to 90 L/h/m², depends on age and gender (clearance in women is 25% lower than in men; gemcitabine clearance decreases with age). T_1/2 is 42-94 min. It is excreted mainly by the kidneys as the inactive metabolite 2′-deoxy-2′,2′-difluorouridine (89%), and also unchanged (less than 10%); less than 1% is excreted in feces.

Pharmacokinetics in special clinical cases

In case of reduced renal function, the inactive metabolite may accumulate in the body.

Indications

• Non-small cell lung cancer;
• Pancreatic cancer;
• Bladder cancer;
• Breast cancer;
• Locally advanced or metastatic cervical cancer.

Gemcitabine in monotherapy or in combination with other antitumor agents also shows activity in ovarian cancer, locally advanced small cell lung cancer, and locally advanced refractory testicular cancer.

ICD codes

Dosage Regimen

The drug is administered intravenously by drip (over 30 min).

Gemcitabine is part of many chemotherapeutic regimens, therefore, when selecting doses and administration regimen in each individual case, one should refer to specialized literature.

Non-small cell lung cancer

As monotherapy, the recommended dose is 1000 mg/m² once a week for 3 weeks followed by a one-week break, every 28 days. In combination with cisplatin, Gemcitabine is administered at a dose of 1250 mg/m² on days 1 and 8 of each 21-day cycle or at a dose of 1000 mg/m² on days 1, 8, and 15 of each 28-day cycle.

Pancreatic cancer

The recommended dose is 1000 mg/m² once a week for 7 weeks followed by a one-week break. Subsequent cycles should consist of infusions administered once a week for 3 weeks, followed by a one-week break.

Breast cancer

In case of disease progression after first-line therapy, including anthracyclines or without them (if anthracyclines are contraindicated), Gemcitabine is used as monotherapy at a dose of 1000-1200 mg/m² on days 1, 8, and 15 every 28 days. In combination with paclitaxel, the drug is used at a dose of 1250 mg/m² on days 1 and 8 of each 21-day cycle.

Bladder cancer

The recommended dose is 1250 mg/m² on days 1, 8, and 15 every 28 days for monotherapy or 1000 mg/m² on days 1, 8, and 15 in combination with cisplatin, which is administered immediately after gemcitabine administration at a dose of 70 mg/m² on day 1 or day 2 of each 28-day cycle.

Locally advanced or metastatic cervical cancer

Combination therapy is used for this disease. In sequential chemoradiotherapy (neoadjuvantly), Gemcitabine is administered at a dose of 1250 mg/m² on days 1 and 8 of each 21-day cycle. Cisplatin is administered after gemcitabine administration at a dose of 70 mg/m² on day 1 of the cycle against the background of hyperhydration.

In locally advanced cancer with concurrent chemoradiotherapy, Gemcitabine is administered once a week 1-2 hours before the start of radiation therapy at a dose of 125 mg/m² in combination with cisplatin at a dose of 40 mg/m², which is administered immediately after gemcitabine administration.

In case of development of hematological toxicity, the dose of Gemcitabine Pliva may be reduced, or its administration postponed in accordance with the following recommendations: with an absolute neutrophil count (ANC) greater than 1000/µL and platelets greater than 100,000/µL, the full recommended dose is used; with ANC 500-1000/µL or platelets 50,000-100,000/µL, the dose is reduced to 75% of the recommended dose; if ANC is less than 500/µL or platelets are less than 50,000/µL, administration is postponed. To detect non-hematological toxicity, regular examination of the patient and monitoring of liver and kidney function should be carried out. Depending on the degree of toxicity, the dose can be reduced during each cycle or at the start of a new cycle stepwise. The decision to postpone the next administration of the drug should be based on the physician’s clinical assessment of the toxicity dynamics.

Gemcitabine should be used with caution in patients with hepatic insufficiency or impaired renal function. Studies in patients with severe hepatic and renal impairment have not been conducted.

In mild to moderate renal failure (CrCl from 30 ml/min to 80 ml/min), no significant effect on the pharmacokinetics of gemcitabine was noted.

No dosage regimen adjustment is required for patients over 65 years of age.

The use of gemcitabine in children has not been studied.

Rules for preparation of infusion solution

To prepare the solution of Gemcitabine Pliva, only 0.9% sodium chloride solution without preservatives should be used.

To dissolve Gemcitabine Pliva, add at least 5 ml of solvent to the 200 mg vial, and 25 ml of solvent to the 1 g vial, after which the vial is shaken until the lyophilisate is completely dissolved. The maximum concentration of gemcitabine should not exceed 40 mg/ml. In solutions with a gemcitabine concentration above 40 mg/ml, incomplete dissolution is possible.

The prepared solution containing the required dose of the drug is diluted before administration with a sufficient amount of 0.9% sodium chloride solution for intravenous infusion over 30 min. Before administration, it should be ensured that the solution is free of suspended particles.

The prepared solution can be stored at room temperature (from 15°C (59°F) to 30°C (86°F)) for 24 hours; the solution should not be stored in the refrigerator, as crystallization may occur.

Adverse Reactions

Adverse reactions that occurred more frequently than in isolated cases are listed according to the following gradation: very common (>10%), common (>1%,<10%), uncommon (>0.1%, <1%), rare (>0.01%, <0.1%), very rare (<0.01%).

From the hematopoietic system common – leukopenia, neutropenia, thrombocytopenia, anemia; very rare – thrombocytosis.

From the digestive system very common – nausea, vomiting, increased levels of hepatic transaminases, ALP; common – anorexia, diarrhea, constipation, stomatitis, increased bilirubin levels.

From the urinary system very common – proteinuria and hematuria; rare – hemolytic-uremic syndrome and/or renal failure.

Dermatological reactions common – skin rash, skin itching, alopecia.

From the respiratory system very common – dyspnea; common – cough, rhinitis; uncommon – bronchospasm, interstitial pneumonia, pulmonary edema; rare – acute respiratory distress syndrome (if these symptoms occur, treatment should be discontinued).

From the cardiovascular system rare – decreased BP, myocardial infarction, heart failure, arrhythmia.

From the nervous system common – headache, drowsiness, insomnia, paresthesia.

Allergic reactions very rare – anaphylactic reactions.

Other: very common – flu-like syndrome, peripheral edema; common – increased body temperature, chills, asthenia, back pain, myalgia; uncommon – facial swelling.

Contraindications

• Pregnancy;
• Lactation period;
• Hypersensitivity to gemcitabine or other components of the drug.

With caution the drug should be prescribed for impaired liver and/or kidney function, bone marrow suppression (including against the background of concomitant radiation or chemotherapy), with simultaneously conducted radiation therapy, acute infectious diseases of viral, fungal or bacterial nature (including chickenpox, herpes zoster).

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation.

Women and men during treatment with Gemcitabine Pliva and for at least 6 months after the end of treatment should use reliable methods of contraception.

Use in Hepatic Impairment

Gemcitabine should be used with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Gemcitabine should be used with caution in patients with impaired renal function.

Pediatric Use

The use of gemcitabine in children has not been studied.

Geriatric Use

No dosage regimen adjustment is required for patients over 65 years of age.

Special Precautions

Treatment with Gemcitabine Pliva should be carried out only under the supervision of a physician experienced in anticancer chemotherapy.

Before each administration of the drug, it is necessary to monitor the number of platelets, leukocytes and neutrophils in the blood. If there are signs of bone marrow function suppression, treatment should be suspended or the dose adjusted.

Periodic assessment of kidney and liver function should be performed.

Increasing the duration of infusion and frequency of infusions leads to increased toxicity.

Administration of Gemcitabine Pliva in the presence of liver metastases, history of hepatitis and alcoholism, as well as liver cirrhosis increases the risk of developing hepatic insufficiency.

At the first signs of hemolytic-uremic syndrome, treatment with Gemcitabine Pliva should be discontinued.

In patients with lung cancer or lung metastases, the risk of adverse effects from the respiratory system is increased. At the first signs of pneumonitis or the appearance of infiltrates in the lungs, treatment with Gemcitabine Pliva should be discontinued.

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

Effect on ability to drive vehicles and operate machinery

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms myelosuppression, paresthesia, severe skin rash.

Treatment there is no specific antidote. If an overdose is suspected, the patient should be under constant medical supervision, including blood count monitoring; if necessary, symptomatic treatment is carried out.

Drug Interactions

Gemcitabine Pliva has a radiosensitizing effect, therefore, when using the drug against the background of radiation therapy, an increase in radiation reactions can be expected.

It reduces antibody production and enhances side effects when used concomitantly with inactivated or live viral vaccines (the interval between the use of medicinal products should be from 3 to 12 months).

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

The prepared solution should be stored at a temperature not exceeding 25°C (77°F) for 6 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.