Gemcitabine-Actavis (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

Actavis Italy, S.p.A. (Italy)

ATC Code

L01BC05 (Gemcitabine)

Active Substance

Gemcitabine (Rec.INN registered by WHO)

Dosage Forms

	Gemcitabine-Actavis	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 as a porous mass from white to almost white.

Excipients: mannitol – 1 g, sodium acetate trihydrate – 103.7 mg (corresponding to anhydrous sodium acetate – 62.5 mg), sodium hydroxide (1M solution) – to pH 3.0 (2.8-3.2).

Colorless glass vials with a capacity of 50 ml (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a porous mass from white to almost white.

Excipients: mannitol – 200 mg, sodium acetate trihydrate – 20.74 mg (corresponding to anhydrous sodium acetate – 12.5 mg), sodium hydroxide (1M solution) – to pH 3.0 (2.8-3.2).

Colorless glass vials with a capacity of 10 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor agent, an antimetabolite of the pyrimidine analog group, 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 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 incorporate 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

Pharmacokinetic data were evaluated in patients receiving infusions over 0.4-1.2 h at doses from 500 to 2592 mg/m².

C_max in blood plasma (measured within 5 min after the end of infusion) ranges from 3.2 to 45.5 µg/ml. After a single 30-minute infusion at a dose of 1 g/m², the plasma concentration of the parent substance is above 5 µg/ml for about 30 minutes after the end of infusion and above 0.4 µg/ml for another hour after that.

Binding to plasma proteins is low (less than 10%).

V_d in the central compartment for women is 12.4 L/m² and 17.5 L/m² for men (with interindividual variability of 91.9%). V_d in the peripheral compartment is 47.4 L/m². The volume of the peripheral compartment does not depend on gender.

It is metabolized in the cells of the liver, kidneys, blood and other tissues by the enzyme cytidine deaminase. Intracellular metabolism of gemcitabine produces mono-, di-, and triphosphates, the latter two being active metabolites. These intracellular metabolites are not detected in plasma and urine. The primary metabolite 2′-deoxy-2′,2′-difluorouridine is not active and is detected in plasma and urine. One week after administration, 92-98% of gemcitabine is metabolized.

T_1/2 depends on gender and age and is 42-94 min. When gemcitabine is administered at recommended doses, the drug is eliminated 5-11 hours after the start of infusion.

Systemic clearance ranges from 29.2 L/h/m² to 92.2 L/h/m² and depends on age and gender (with interindividual variability of 52.2%). Clearance in women is somewhat lower than in men (by approximately 25%). With age, clearance values decrease for both men and women. When gemcitabine is administered as a 30-minute infusion at a dose of 1 g/m², no dose reduction is required for either men or women with decreased clearance values.

Renal clearance is 2-7 L/h/m².

It is excreted mainly by the kidneys (99%) and less than 1% through the intestine. Less than 10% of the drug is excreted by the kidneys unchanged.

With a once-weekly administration regimen, Gemcitabine does not accumulate in the body.

Pharmacokinetics in special clinical cases

When used in combination therapy with paclitaxel, the pharmacokinetics of both components are not impaired.

When used in combination therapy with carboplatin, the pharmacokinetics of gemcitabine are not impaired.

Renal impairment

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

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 a functional status of 2;
• Unresectable, locally recurrent or metastatic breast cancer as part of combination therapy with paclitaxel after neoadjuvant and/or adjuvant therapy including anthracyclines, provided there are no contraindications to their use;
• Locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra);
• Locally advanced or metastatic epithelial ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after first-line platinum-based therapy;
• Locally advanced or metastatic pancreatic cancer;
• Locally advanced or metastatic cervical cancer.

ICD codes

Dosage Regimen

Gemcitabine-Actavis is administered by IV drip over 30 minutes.

For non-small cell lung cancer (locally advanced or metastatic) as monotherapy, the recommended dose of the drug is 1000 mg/m² on days 1, 8 and 15 of each 28-day cycle.

When used as part of 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 after gemcitabine infusion against a background of hyperhydration.

When used as part of 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 a dose of AUC 5.0 mg/ml*min on day 1 of the cycle after gemcitabine infusion.

For breast cancer (locally advanced or metastatic) as monotherapy upon disease progression after first-line therapy including anthracyclines, provided there are no contraindications to them, the recommended dose of the drug is 1000-1200 mg/m² on days 1, 8 and 15 of each 28-day cycle.

When used as part of combination therapy as first-line therapy upon disease progression after neoadjuvant and/or adjuvant therapy including anthracyclines, the recommended dose of the drug is 1250 mg/m² on days 1 and 8 in combination with paclitaxel, which is administered after gemcitabine at a dose of 175 mg/m² on day 1 of each 21-day cycle by IV drip over approximately 3 hours.

For urothelial cancer (locally advanced, metastatic and superficial) as monotherapy, the recommended dose of the drug is 1250 mg/m² on days 1, 8 and 15 of each 28-day cycle.

When used as part of 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 day 1 or 2 of each 28-day cycle.

For epithelial ovarian cancer (locally advanced or metastatic) as monotherapy, the recommended dose of the drug is 800-1250 mg/m², on days 1, 8 and 15 of each 28-day cycle.

When used as part of 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 AUC 4.0 mg/ml*min, which is administered immediately after gemcitabine infusion on day 1 of each 21-day cycle.

For pancreatic cancer (locally advanced or metastatic) as 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 days 1, 8 and 15 of each 28-day cycle.

For cervical cancer (locally advanced or metastatic), combination therapy is performed. For locally advanced cancer with sequential chemo- and radiotherapy (neoadjuvantly) and for 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 after gemcitabine at a dose of 70 mg/m² on day 1 of the cycle against a background of hyperhydration.

For locally advanced cancer with concurrent chemo- and radiotherapy, Gemcitabine is administered once a week 1-2 hours before the start of radiotherapy at a dose of 125 mg/m² followed by (immediately after gemcitabine administration) administration of cisplatin at a dose of 40 mg/m².

Dose adjustment of the drug due to hematological toxicity

Start of treatment cycle

Regardless of the indications, before each administration of gemcitabine, it is necessary to monitor the platelet, leukocyte and granulocyte counts in the blood. If there are signs of bone marrow suppression, treatment should be suspended or the dose adjusted.

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.

In case of development of hematological toxicity, the dose of gemcitabine can be reduced, or the administration of the drug should be postponed according to the following scheme.

Dose modification of gemcitabine used in monotherapy or in combination with cisplatin for the treatment of urothelial cancer, non-small cell lung cancer and pancreatic cancer.

^*When the neutrophil count increases to 500/µl and platelets to 50000/µl, gemcitabine administration can be continued within the cycle.

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

^*Treatment within the cycle is not resumed. The next administration of gemcitabine is carried out on day 1 of the next cycle when the neutrophil count recovers to at least 1500/µl and platelets to 100000/µl.

Dose modification of gemcitabine used in combination with carboplatin for the treatment of ovarian cancer.

^*Treatment within the cycle is not resumed. The next administration of gemcitabine is carried out on day 1 of the next cycle when the neutrophil count recovers to at least 1500/µl and platelets to 100000/µl.

The dose of gemcitabine in the next cycle should be reduced by 25% for all indications in cases where the previous cycle showed

• Decrease in absolute neutrophil count <500/µl, lasting more than 5 days,
• Decrease in absolute neutrophil count <100/µl, lasting more than 3 days,
• Febrile neutropenia,
• Decrease in platelet count <25000/µl,
• The cycle was delayed by more than 1 week due to hematological toxicity.

Dose adjustment of the drug due to non-hematological toxicity

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

There is no data proving that dose adjustment is necessary in elderly patients, although gemcitabine clearance and T_1/2 change with age.

Gemcitabine should be used with caution in patients with hepatic insufficiency or renal impairment, as there is insufficient data on the use of the drug in this category of patients.

Mild or moderate renal failure (glomerular filtration rate from 30 ml/min to 80 ml/min) does not have a noticeable effect on the pharmacokinetics of gemcitabine.

The use of gemcitabine in children has not been studied.

Rules for preparation of infusion solution

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

C_max of gemcitabine should not exceed 40 mg/ml. In solutions prepared with a concentration of more than 40 mg/ml, incomplete dissolution of the lyophilisate is possible.

1. For the preparation of the solution, the requirements for the preparation of solutions for IV administration must be followed.

2. To prepare the infusion solution, the contents of a 200 mg vial are dissolved in 5 ml, and 1 g – in 25 ml of 0.9% sodium chloride solution for injection (without preservatives). The total volume after dilution is 5.26 ml (for 200 mg) and 26.3 ml (for 1000 mg) respectively. With this dilution, the concentration of gemcitabine is 38 mg/ml, taking into account the volume of the lyophilisate. Shake the vial until the lyophilisate is completely dissolved. The prepared gemcitabine solution containing the required dose of the drug is diluted before administration with 0.9% sodium chloride solution for injection (without preservatives) in an amount sufficient for a 30-minute IV infusion. The resulting solution should be clear, from colorless to pale yellow.

3. Before parenteral administration, the prepared solution must be visually inspected for mechanical impurities and color change. Do not administer the solution if particles are found in it.

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, thrombocytopenia, anemia; very rare – thrombocytosis.

From the digestive system very common – nausea, vomiting, increased activity of “liver” transaminases, alkaline phosphatase; common – anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rare – increased activity of ALT, AST, gamma-glutamyltransferase, alkaline phosphatase; frequency unknown – ischemic colitis, serious complications due to hepatotoxicity, including fatal liver failure.

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

From the skin and soft tissues very common – skin rash, usually accompanied by itching, alopecia; common – increased sweating, pruritus; rare – ulceration, formation of vesicles and sores on the skin; very rare – severe skin reactions, including epithelial desquamation and bullous rash; frequency unknown – Lyell’s syndrome, Stevens-Johnson syndrome.

From the respiratory system very common – dyspnea; common – cough, rhinitis; uncommon – bronchospasm, interstitial pneumonia; frequency unknown – pulmonary edema, adult respiratory distress syndrome.

From the cardiovascular system rare – decreased blood pressure, myocardial infarction; frequency unknown – stroke, heart failure, arrhythmia (usually supraventricular), clinical signs of peripheral vasculitis and gangrene.

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

Local reactions rare – reactions at the injection site, usually mild.

Other very common – flu-like syndrome (accompanied by the following symptoms: fever, headache, chills, myalgia, asthenia and anorexia, development of cough, rhinitis, malaise, increased sweating and sleep disturbance has also been reported), peripheral edema, including facial edema (edema usually resolves after discontinuation of the drug); common – increased body temperature, chills, asthenia, back pain, myalgia; very rare – anaphylactoid reactions; frequency unknown – radiation toxicity.

Contraindications

• Hypersensitivity;
• Pregnancy, lactation period;
• Children under 18 years of age (efficacy and safety have not been studied).

With caution: hepatic insufficiency, severe renal insufficiency, bone marrow hematopoiesis suppression (including against the background of concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature (including chickenpox, herpes zoster).

Use in Pregnancy and Lactation

There is insufficient data on the use of Gemcitabine-Actavis during pregnancy. The use of the drug during pregnancy is contraindicated. It is not known whether Gemcitabine is excreted in breast milk. If Gemcitabine-Actavis is used, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution: hepatic insufficiency.

Administration of gemcitabine in hepatitis, liver cirrhosis increases the risk of liver failure. Regular monitoring of peripheral blood counts, activity of “liver” transaminases and serum creatinine levels is necessary.

Use in Renal Impairment

With caution severe renal insufficiency.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

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

The drug is well tolerated when administered by infusion and can be administered on an outpatient basis.

If extravasation occurs, the infusion should be stopped and the drug administration should be continued through another vein. The patient’s condition should be carefully monitored after drug administration.

Hematological toxicity

Gemcitabine can suppress bone marrow function, which may manifest as leukopenia, thrombocytopenia and anemia. If bone marrow function is suppressed, treatment should be suspended or the dose adjusted.

Prior treatment with cytostatics increases the frequency and severity of leukopenia and thrombocytopenia (progressive decrease in the number of leukocytes and platelets may be observed after completion of therapy).

The drug should be used with caution in patients with suppressed bone marrow hematopoiesis.

Hepatic insufficiency

Administration of gemcitabine in liver metastases, hepatitis, history of alcoholism and liver cirrhosis increases the risk of liver failure. Regular monitoring of peripheral blood counts, activity of “liver” transaminases and serum creatinine levels is necessary.

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

Other precautions

Women and men of reproductive age should use reliable methods of contraception during treatment with gemcitabine and for at least 6 months after therapy. If pregnancy occurs, the patient should immediately inform the attending physician. Before starting treatment with Gemcitabine-Actavis, men should donate sperm for cryopreservation, as infertility may develop after treatment.

Administration of live vaccines during treatment with gemcitabine is not recommended.

Due to the possible development of side effects from the cardiovascular system during treatment with gemcitabine, caution should be exercised in patients with a history of cardiovascular diseases.

During treatment with gemcitabine, side effects from the respiratory system (pulmonary edema, pneumonitis or adult respiratory distress syndrome) have been reported. The etiology of these phenomena is unknown. At the first signs of pneumonitis or the appearance of infiltrates in the lungs, treatment with gemcitabine should be discontinued.

In rare cases, symptoms of hemolytic-uremic syndrome have been reported during treatment with gemcitabine. At the first signs of microangiopathic hemolytic anemia, such as a sharp decrease in hemoglobin against the background of thrombocytopenia, an increase in bilirubin concentration, serum creatinine, blood urea nitrogen or LDH, gemcitabine administration should be discontinued. Renal function impairment may not resolve upon discontinuation of therapy; in this case, hemodialysis may be required.

The prepared solution should be stored at room temperature not exceeding 25°C (77°F) and used within 24 hours; it should not be cooled or frozen, as this may lead to crystallization.

When preparing the solution, protective measures necessary when working with cytostatic drugs (mask and gloves) should be used. If the drug gets into the eyes during preparation of the solution, it may cause severe irritation. In this case, the eyes should be immediately rinsed with water.

If the irritation does not go away, a doctor should be consulted. If the solution gets on the skin, it should be washed off with water. Prior treatment with cytostatics increases the frequency and severity of leukopenia and thrombocytopenia (progressive decrease in the number of leukocytes and platelets may occur after completion of therapy). Increasing the infusion duration and frequency of administration leads to greater toxicity. The optimal regimen for the safe administration of gemcitabine in combination with therapeutic radiotherapy regimens has not been determined to date.

Effect on driving and operating machinery

During treatment, 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 myelodepression, anemia (excessive fatigue or weakness), leukopenia, neutropenia, manifestation of infection (chills, cough, hoarseness, pain in the side or lower back, painful or difficult urination), thrombocytopenia (bleeding, hemorrhage, black tarry stools, blood in urine and stool, ecchymoses), paresthesia, pronounced skin rash.

Treatment in case of suspected overdose, the patient should be under constant medical supervision, including blood count monitoring, and if necessary, symptomatic treatment. An antidote is unknown.

Drug Interactions

Concomitant radiation therapy causes additive suppression of bone marrow function (when gemcitabine was administered at a dose of 1 g/m² (up to 6 weeks of treatment) against the background of ongoing radiation therapy to the chest area in patients with non-small cell lung cancer, significant toxicity in the form of severe and potentially life-threatening esophagitis and pneumonia was noted).

Immunosuppressants (azathioprine, chlorambucil, glucocorticoid agents, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infections.

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

Storage Conditions

Store the drug out of the reach of children at a temperature not exceeding 25°C (77°F), do not cool or freeze. The prepared solution should be stored at a temperature of about 25°C (77°F) for no more than 24 hours, do not cool or freeze.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

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.