Gemita - instructions for use, doses, side effects, contraindications

200 mg
Active substance:
Gemcitabine hydrochloride,	227.72 mg
is equivalent to gemcitabine	200 mg
Excipients:
Mannitol	200 mg
Sodium acetate trihydrate	12.5 mg
Hydrochloric acid	q.s. to adjust the pH
Sodium hydroxide	q.s. to adjust the pH
1000 mg
Active substance:
Gemcitabine hydrochloride,	1138.60 mg
is equivalent to gemcitabine	1000 mg
Excipients:
Mannitol	1000 mg
Sodium acetate trihydrate	62.5 mg
Hydrochloric acid	q.s. to adjust the pH
Sodium hydroxide	q.s. to adjust the pH
1400 mg
Active substance:
Gemcitabine hydrochloride,	1594.04 mg
is equivalent to gemcitabine	1400 mg
Excipients:
Mannitol	1400 mg
Sodium acetate trihydrate	87.5 mg
Hydrochloric acid	q.s. to adjust the pH
Sodium hydroxide	q.s. to adjust the pH

Description:

Lyophilized powder or lyophilized mass of white or almost white color.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.B.C.05 Gemcitabine

Pharmacodynamics:

Gemcitabine is an antimetabolite of the group of pyrimidine analogues. The drug exhibits cyclospecificity, acting on cells in phases S (replication phase) and G₁/S (the gap between the initial growth phase and the replication phase).

Gemcitabine is metabolized within the cell by the action of nucleoside kinases with the formation of active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which acts as the only reaction catalyst leading to the formation of deoxynucleoside triphosphates required for the synthesis of deoxyribonucleic acid (DNA). Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into DNA and ribonucleic acid (RNA) molecules. After integrating the intracellular metabolites of gemcitabine into the DNA strand, another additional nucleotide is added to its growing strands, which leads to complete inhibition of further DNA synthesis and programmed cell death, known as apoptosis.

Pharmacokinetics:

Gemcitabine is rapidly excreted from the body by the kidneys mainly as an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. Less than 10% of the intravenous dose is detected in the urine in the form of an unchanged drug. The binding of gemcitabine to plasma proteins is negligible.

Pharmacokinetic analysis of studies with single and multiple doses shows that the volume of distribution is largely dependent on sex. System clearance, which ranges from about 30 l / h / m² up to 90 l / h / m², depends on age and sex. The half-life period ranges from 32 minutes to 94 minutes.

Indications:

- Locally advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin or carboplatin, as well as in monotherapy in elderly patients with a functional status of 2 (on a scale ECABOUTG-BOZ).

- Unresectable, local regenerative or metastatic breast cancer as part of combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy with anthracyclines included in the absence of contraindications to their prescription.

- Locally or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureter, urethra).

- Locally or metastatic epithelial ovarian cancer as monotherapy or in combination with carboplatin in patients with progression of the disease after the first line of therapy based on platinum derivatives.

- Locally or metastatic pancreatic cancer.

- Locally or metastatic cervical cancer.

- Cancer of the biliary tract.

The effectiveness of gemcitabine in advanced small cell lung cancer and refractory testicular cancer spread.

Contraindications:

- Hypersensitivity to gemcitabine or other components of the drug.

- Pregnancy and the period of breastfeeding.

- Age to 18 years.

Carefully:

If abnormal liver function and / or kidney disease, inhibition of bone marrow hematopoiesis (including with concurrent radiotherapy or chemotherapy), acute infectious diseases, viral, fungal or bacterial origin, patients with cardiovascular disease (including history).

Pregnancy and lactation:

Pregnancy and the period of breastfeeding are contraindications.

Dosing and Administration:

Gemcitabine is administered intravenously drip for 30 minutes.

Before each administration of gemcitabine, it is necessary to control the number of platelets, leukocytes and granulocytes in the blood.At signs of oppression of bone marrow function caused by the drug, it is necessary to suspend treatment or adjust the dose.

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

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

Combination therapy with cisplatin: recommended dose of the drug - 1250 mg / m²on the 1 st and 8 th day of each 21-day cycle or 1000 mg / m² in the 1st, 8th and 15th days of each 28-day cycle. Cisplatinum is administered at a dose of 70 mg / m² in the 1st day of the cycle after the infusion of gemcitabine against a background of hyperhydration.

Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg / m² or 1200 mg / m² on the 1 st and 8 th day of each 21-day cycle. Carboplatin is introduced from the calculation AUC (area under the concentration-time curve) 5.0 mg / ml / min on the 1st day of the cycle after the infusion of gemcitabine.

Mammary cancer (unresectable, local-recurring or metastatic)

Combination therapy with paclitaxel: as first-line therapy for the progression of the disease after neoadjuvant and / or adjuvant therapy, including anthracyclines, in the absence of contraindications to them.

Paclitaxel is administered at a dose of 175 mg / m² intravenously drip for 3 hours on day 1 of the 21-day cycle, followed by gemcitabine. The recommended dose of the drug is 1250 mg / m² on the 1 st and 8 th day of each 21-day cycle.

Before the start of combination therapy (gemcitabine + paclitaxel) the absolute number of granulocytes in the blood in patients should be at least 1500 / μL.

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

Monotherapy: recommended dose of the drug - 1250 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

Combination therapy with cisplatin: the recommended dose of the drug is 1000 mg / m in the 1 st, 8 th and 15 th days in combination with cisplatin, which is administered at a dose of 70 mg / m² immediately after the infusion of gemcitabine on the 1st or 2nd day of each 28-day cycle. Clinical studies have shown that with a dose of cisplatin 100 mg / m² more pronounced myelosuppression.

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

Monotherapy: the recommended dose of the drug is 800-1250 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg / m² in the 1st and 8th day in combination with carboplatin at the rate of AUC 4.0 mg / ml / min, which is injected immediately after the infusion of gemcitabine on the 1st day of each 21-day cycle.

Pancreas cancer (locally advanced or metastatic, including resistant to fluorouracil therapy)

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

Cervical cancer (locally advanced or metastatic)

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

With locally advanced cancer with simultaneous chemoradiotherapy cisplatin is administered at a dose of 40 mg / m² with the subsequent (immediately after the introduction of cisplatin) by the administration of gemcitabine. Gemcitabine is administered once a week 1-2 hours before the start of radiotherapy in a dose of 125 mg / m².

Bile duct cancer

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

Correction of dose

In case of development of hematological toxicity The dose of gemcitabine can be reduced, or its administration postponed in accordance with the following schemes:

A. Correction of the dose of gemcitabine within the cycle for urothelial cancer, non-small cell lung cancer, pancreatic cancer as monotherapy or in combination with cisplatin.

Correction of the dose of gemcitabine within the cycle for urothelial cancer, non-small cell lung cancer, pancreatic cancer as monotherapy or in combination with cisplatin
Absolute amount of granulocytes (x 10⁹/ l)		The number of platelets (x 10⁹/ l)	% of previous dose
>1	and	>100	100
0,5-1	or	50-100	75
<0,5	or	<50	Postpone the introduction

B. Correction of the dose of gemcitabine within the cycle for breast cancer in combination with paclitaxel.

Correction of the dose of gemcitabine within the cycle for breast cancer in combination with paclitaxel
Absolute amount of granulocytes (x 10⁹/ l)		The number of platelets (x 10⁹/ l)	% of previous dose
≥1,2	and	>75	100
1-<1,2	or	50-75	75
0,7-<1	and	≥50	50
<0,7	or	<50	Postpone the introduction

B. Correction of the dose of gemcitabine within the cycle for ovarian cancer in combination with carboplatin.

Correction of the dose of gemcitabine within the cycle for ovarian cancer in combination with carboplatin
Absolute amount of granulocytes (x 10⁹/ l)		The number of platelets (x 10⁹/ l)	% from the previous dose
>1,5	and	≥100	100
1-1,5	or	75-100	50
<1	or	<75	Postpone the introduction

To detect nonhematological toxicity, a regular examination of the patient and control of the liver and kidney function should be carried out. Depending on the degree of toxicity, the dose can be reduced during each cycle or with the onset of a new cycle stepwise.

The drug should be delayed until, according to the doctor, toxicity is not resolved.

Special patient groups

Elderly patients:

There is no evidence to suggest that elderly patients need to adjust the dose.

Patients with impaired hepatic and renal function:

use gemcitabine in patients with hepatic insufficiency or with impaired renal function, caution should be exercised, since there is insufficient data on the use of the drug in this category of patients.

Renal failure of mild or moderate severity (glomerular filtration rate from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine.

Children:

gemcitabine was studied in limited studies of I and II phases in children with different types of neoplasms. The data of these studies are not enough to prove the effectiveness and safety of gemcitabine in children.

Recommendations for the preparation of a solution for infusions

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

For the preparation of a solution for infusions, the contents of a 200 mg bottle are dissolved in at least 5 ml and 1000 mg in at least 25 ml and 1400 mg in at least 35 ml of a 0.9% sodium chloride solution for injection . Each vial is gently shaken until the lyophilizate is completely dissolved. 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.

A prepared gemcitabine solution containing the desired dose of the preparation 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, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration.

From the microbiological point of view, the prepared solution should be used immediately. If the product has not been used immediately, the consumer is responsible for observing the terms and conditions of storage after opening before use, the time to use should not exceed 8 hours at a temperature of no higher than 25 ° C when stored in an original vial or syringe under natural light, except for cases when the opening and dilution method excludes the risk of microbiological contamination.

Side effects:

Adverse reactions occurring more often than in single cases are listed according to the following gradation: very often (≥ 10%); often (≥ 1%, <10%); infrequently (≥0.1%, <1%); rarely (≥ 0.01%, <0.1%); very rarely (<0.01%).

Disorders from the blood and lymphatic system: very often - anemia, leukopenia and thrombocytopenia; often - febrile neutropenia; very rarely - thrombocytosis.

Immune system disorders: very rarely an anaphylactic reaction.

Disorders from the metabolism and nutrition: often - anorexia.

Disturbances from the nervous system: often - headache, insomnia, drowsiness; infrequently - impaired cerebral circulation; very rarely - a syndrome of reversible posterior encephalopathy.

Heart Disease: infrequently - heart failure; arrhythmia, predominantly supraventricular; rarely - myocardial infarction.

Vascular disorders: very often - swelling, peripheral edema; rarely - lowering blood pressure, peripheral vasculitis, gangrene; very rarely - the syndrome of increased permeability of capillaries.

Disturbances from the respiratory system: very often - shortness of breath; often - cough, rhinitis; infrequently - bronchospasm, interstitial pneumonitis; rarely - pulmonary edema, adult respiratory distress syndrome.

Disturbances from the gastrointestinal tract system: very often - nausea, vomiting, increased activity of "hepatic" enzymes aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and alkaline phosphatase; often - diarrhea, stomatitis, ulcerative lesions of the oral mucosa, constipation,increased bilirubin concentration; infrequent - severe hepatotoxicity, including hepatic insufficiency, in some cases with a fatal outcome; rarely - increase in the concentration of gamma-glutamyl transferase (GGT); very rarely is ischemic colitis.

Disturbances from the skin and subcutaneous tissues: very often - allergic skin rashes of mild degree, accompanied by itching; alopecia (usually minimal hair loss); often - itching, excessive sweating; rarely - skin ulceration, vesicle formation, peeling, severe skin reactions, including desquamation and bullous skin damage; very rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome.

Disorders from the kidneys and urinary tract: very often - mild proteinuria and hematuria; infrequent - renal insufficiency; rarely - an increase in the concentration of creatinine, urea and lactate dehydrogenase (LDH) in hemolytic-uremic syndrome.

Disturbances from musculoskeletal and connective tissue: often - back pain, myalgia.

Other: aboutChen is often an influenza-like syndrome.

There have also been cases of malaise,sweating; often - fever, asthenia, chills; rarely - reactions at the injection site of a predominantly mild degree.

Hypersensitivity: anaphylactoid reactions were recorded very rarely.

Radiation toxicity was rarely reported (see "Interaction with other types of therapy ").

The use of gemcitabine in combination with paclitaxel in breast cancer

Undesirable phenomena of the third degree of severity

Hematological toxicity: anemia - 5,7%, thrombocytopenia - 5,3%, neutropenia - 31,3%.

Non-hematological toxicity: febrile neutropenia - 4.6%, fatigue - 5.7%, diarrhea - 3.1%, motor neuropathy - 2.3%, sensory neuropathy - 5.3%.

Undesirable phenomena of the IV degree of severity

Hematological toxicity: anemia 1.1%, thrombocytopenia 0.4%, neutropenia 17.2% (grade IV neutropenia lasting more than 7 days was recorded in 12.6% of patients).

Non-hematological toxicity: febrile neutropenia - 0,4%, fatigue - 0,8%, motor neuropathy - 0,4%, sensory neuropathy - 0,4%.

The use of gemcitabine in combination with cisplatin in bladder cancer

Undesirable phenomena of the third degree of severity

Hematological toxicity: Anemia - 24%, thrombocytopenia - 29%.

Non-hematological toxicity: nausea and vomiting - 22%, diarrhea - 3%, infection - 2%, stomatitis - 1%.

Undesirable phenomena of the IV degree of severity

Hematological toxicity: Anemia - 4%, thrombocytopenia - 29%.

Non-hematological toxicity: infection - 1%.

The use of gemcitabine in combination with carboplatin in ovarian cancer

Undesirable phenomena of the third degree of severity

Hematological toxicity: anemia 22.3%, neutropenia 41.7%, thrombocytopenia 30.3%, and leukopenia 48.0%.

Non-hematological toxicity: bleeding - 1.8%, febrile neutropenia - 1.1%.

Undesirable phenomena of the IV degree of severity

Hematological toxicity: anemia - 5,1%, neutropenia - 28,6%, thrombocytopenia - 4,6%, leukopenia - 5,1%.

Non-hematological toxicity: infection without neutropenia - 0,6%.

Overdose:

The antidote for gemcitabine is unknown. Clinically tolerable toxicity was observed when single doses were administered up to 5.7 g / m² intravenously for 30 minutes every two weeks. In case of suspected overdose, the patient should be under constant medical supervision, including counting the blood formula. If necessary, the patient is symptomatically treated.

Interaction:

Radiation therapy

Simultaneous application (joint or with an interval of less than 7 days): the toxicity associated with such multimodal treatment depends on many different factors: doses of gemcitabine, the frequency of administration of gemcitabine, the dose of radiotherapy, techniques for planning radiation therapy, the type and volume of the irradiated tissue.

Pre-clinical and clinical studies have shown that gemcitabine has a radiosensitizing effect. In a single study in which gemcitabine was administered at a dose of 1000 mg / m² for 6 weeks simultaneously with the therapeutic irradiation of the chest in patients with non-small cell lung cancer, significant toxicity was recorded in the form of severe and potentially life-threatening inflammation of the mucous membranes, mainly esophagitis; as well as pneumonitis, especially in patients with a large volume of tissue irradiation (median volume of irradiation of 4795 cm³). Subsequent studies (Phase II studies with non-small cell lung cancer) suggest that gemcitabine should be administered at lower doses with concomitant radiotherapy with predictable toxicity.

Radiation therapy on the chest region (SOD 66 Gy) was carried out simultaneously with chemotherapy gemcitabine at a dose of 600 mg / m² (4 injections) and cisplatin at a dose of 80 mg / m² (2 injections) for 6 weeks. Several studies of phases I and II showed that for non-small cell lung cancer and pancreatic cancer, it is more appropriate to use gemcitabine monotherapy (up to 300 mg / m3²/ week) in parallel 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.

Sequential application (interval more than 7 days): in addition to radiation reaction with gemcitabine administration more than 7 days before or after radiation therapy, no increase in toxicity was recorded. These data suggest that gemcitabine can be administered one week after radiotherapy or after acute consequences of radiation therapy are resolved.

And with simultaneous, and with the consistent use of gemcitabine with radiation therapy, radiation damage to irradiated tissues (eg, esophagitis, colitis and pneumonitis) has been reported.

Other

Joint use with live yellow fever vaccines and other live vaccines is not recommended, due to the risk of a systemic disease with possible fatal outcome, especially in patients with immunosuppression.

It is not recommended to mix the preparation of Gemita with other medications.

Special instructions:

Treatment with gemcitabine can be done only under the supervision of a doctor who has experience in carrying out anti-tumor chemotherapy.

Hematological toxicity

Gemcitabine can suppress bone marrow function, which is manifested by leukopenia, thrombocytopenia or anemia. Before each administration of gemcitabine, it is necessary to control the number of platelets, leukocytes and granulocytes in the blood. At signs of oppression of bone marrow function caused by the drug, it is necessary to suspend treatment or adjust the dose.

Function of kidney and liver

It is necessary to conduct regular examination of the patient and assess the function of the kidneys and liver.

The introduction of gemcitabine in metastases in the liver, with hepatitis and alcoholism in history, as well as with cirrhosis increases the risk of hepatic insufficiency. In patients who received gemcitabine, hemolytic-uremic syndrome was recorded in rare cases.

Gemcitabine therapy should be discontinued with the appearance of the first signs of microangiopathic hemolytic anemia, such as a rapid decrease in hemoglobin, thrombocytopenia, an increase in the serum bilirubin concentration. Renal failure may be irreversible after cessation of therapy with gemcitabine, which may require hemodialysis.

Vascular disorders

The syndrome of increased capillary permeability, adult respiratory distress syndrome, reversible rear encephalopathy syndrome with potentially serious consequences were observed in patients receiving gemcitabine in monotherapy or in combination with other chemotherapeutic drugs. These syndromes can be associated with damage to the vascular endothelium, possibly induced by gemcitabine. In the case of their development during therapy should stop treatment with gemcitabine and take the necessary measures.

Lung Function

In addition to adult respiratory distress syndrome, other lung function disorders, sometimes severe (eg pulmonary edema, interstitial pneumonitis) have been reported in patients,who received gemcitabine in monotherapy or in combination with other cytostatics. The etiology of these disorders is unknown. With the development of such side effects, it is necessary to stop gemcitabine therapy and take the necessary measures. Early use of symptomatic therapy can improve the situation.

Fertility

In fertility studies gemcitabine induced hypospermatogenesis in male mice. Therefore, men receiving gemcitabine therapy are not recommended for paternity during treatment and for 6 months after the end of it. Before starting treatment, you should seek additional advice regarding the cryopreservation of sperm due to possible infertility due to gemcitabine therapy.

Increasing the duration of infusion and the frequency of administration leads to an increase in toxicity.

Depending on the degree of toxicity, the dose can be reduced during each cycle or with the onset of a new cycle stepwise.

Special precautions for the destruction of unused medicinal product

The unused medicinal product remaining after the dilution must be destroyed in accordance with the current requirements for the disposal of medications taken in this hospital.

Effect on the ability to drive transp. cf. and fur:

Studies of the effects of gemcitabine on the ability to drive motor vehicles and other mechanisms have not been conducted. Nevertheless, it is known that gemcitabine may cause drowsiness from mild to moderate severity, especially when taken with alcohol.

Patients should be cautioned against controlling the mechanisms when they feel drowsy.

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions, 200 mg, 1000 mg and 1400 mg.

Packaging:

For 200 mg, 1000 mg and 1400 mg of active substance (gemcitabine) in clear glass bottles, type I (US Pharm.). The vials are sealed with a rubber stopper with aluminum rolling and a safety cap (flip-off) of plastic.

Each vial is enclosed in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000054

Date of registration:25.11.2010 / 01.03.2016

Expiration Date:Unlimited

The owner of the registration certificate:Fresenius Kabi Deutschland GmbHFresenius Kabi Deutschland GmbH Germany

Manufacturer: & nbsp

FRESENIUS KABI ONCOLOGY, Limited India

Representation: & nbspFresenius Kabi, OOOFresenius Kabi, OOORussia

Information update date: & nbsp21.03.2017

Illustrated instructions

Instructions

Hemita (Gemita)