Eloxatin - description of the drug, instructions for use, reviews. Special instructions for admission

Catad_pgroup Anticancer

Eloxatin - official instruction by application

Registration number:

LSR-004213/08.

Trade name of the drug:

Eloxatin ® .

International non-proprietary name:

oxaliplatin.

Dosage form:

concentrate for solution for infusion.

Compound

1 ml of concentrate contains: active substance: oxaliplatin 5 mg; excipient: water for injection up to 1.0 ml.

Description

Clear colorless solution.

Pharmacotherapeutic group:

an antitumor agent, an alkylating compound.

ATX code: L01XA03.

Pharmacological properties

Pharmacodynamics

Oxaliplatin is an anticancer drug belonging to a new class of platinum derivatives in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane. Oxaliplatin exhibits wide range cytotoxic action. He is also active in vitro and in vivo in various models of cisplatin-resistant tumors. In combination with fluorouracil, a synergistic cytotoxic effect is observed. .

The study of the mechanism of action of oxaliplatin confirms the hypothesis that biotransformed aqueous oxaliplatin derivatives, interacting with DNA by forming inter- and intra-strand bridges, inhibit DNA synthesis, which leads to cytotoxicity and an antitumor effect.

Metastatic colorectal cancer (combination of oxaliplatin with fluorouracil/calcium folinate and bevacizumab)

The efficacy of oxaliplatin in combination with fluorouracil/calcium folinate (FOLFOX) and bevacizumab in metastatic colorectal cancer was evaluated in two clinical research, as first-line chemotherapy (TREE study) and second-line chemotherapy (ECOG study).

Pharmacokinetics

In vivo, oxaliplatin undergoes active biotransformation and is not detected in blood plasma by the end of its 2-hour administration at a dose of 85 mg / m 2, while 15% of the administered platinum is in the blood, and the remaining 85% is rapidly distributed through the tissues or excreted by the kidneys . Platinum binds to plasma albumin and is excreted by the kidneys within the first 48 hours. By the fifth day, about 54% of the total dose is found in the urine and less than 3% in the feces.

Excretion of oxaliplatin in patients with impaired renal functionvarying degrees of severity

Elimination of oxaliplatin significantly correlates with creatinine clearance (CC). The total plasma clearance of ultrafilterable platinum decreases with CC 50-80 ml / min by 34%, with CC 30-49 ml / min - by 57%, and with CC less than 30 ml / min. by 79% compared with that with CC more than 80 ml / min. With a decrease in kidney function, the renal clearance of ultrafiltrating platinum and the excretion of platinum by the kidneys also decrease.

Indications for use

• Adjuvant Cancer Therapy colon Stage III (Duke grade C) after radical resection of the primary tumor (in combination with fluorouracil/calcium folinate).
• Disseminated colorectal cancer (in combination with fluorouracil/calcium folinate).
• Metastatic colorectal cancer (as first-line therapy in combination with fluorouracil/calcium folinate and bevacizumab).
• Ovarian cancer (as second-line therapy).

Contraindications

• Hypersensitivity to oxaliplatin and other components of the drug, as well as other platinum derivatives.
• Myelosuppression (neutrophil count<2000/мкл и/или тромбоцитов <100000/мкл) до начала первого курса лечения.
• Peripheral sensory neuropathy with functional disorders
• before the start of the first course of treatment.
• Pregnancy.
• breastfeeding period .
• Children's age up to 18 years.

With caution

Severe renal impairment (creatinine clearance<30 мл/мин) (требуется мониторирование функции почек и коррекция режима дозирования, см. разделы «Способ применения и дозы», «Особые указания»).

In patients with a history of QT interval prolongation or in patients with predisposing factors for QT interval prolongation (eg, concomitant use with drugs that prolong the QT interval; electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia) (see sections "Special instructions" and "Interaction with other drugs").

With simultaneous use with drugs that can cause the development of rhabdomyolysis (see sections "Special instructions" and "Interaction with other drugs").

Use during pregnancy and during breastfeeding Pregnancy

Currently, there is no information on the safety of the use of oxaliplatin in pregnant women. Based on the results of preclinical studies, it is expected that Eloxatin ®, when used at therapeutic doses in humans, will lead to fetal death and / or be teratogenic, and therefore the use of Eloxatin ® is contraindicated during pregnancy. Effective contraceptive methods must be used during treatment and continue after treatment for 4 months for women and 6 months for men.

breastfeeding period

The excretion of oxaliplatin into breast milk has not been studied. During treatment with Eloxatin®, breastfeeding should be discontinued.

Dosage and administration

Oxaliplatin is used only in adults.

Dosing regimen

Adjuvant therapy for colon cancer: intravenously at 85 mg/m 2 once every 2 weeks in combination with fluorouracil and calcium folinate for 12 cycles (6 months).

Treatment of disseminated colorectal cancer: intravenously at 85 mg / m 2

1 every 2 weeks in combination with fluorouracil and calcium folinate (until disease progression or development of unacceptable toxicity).

Metastatic colorectal cancer: intravenously at 85 mg / m 2 1 time in 2

weeks in combination with fluorouracil/calcium folinate and bevacizumab (until disease progression or unacceptable toxicity develops).

For dosing regimens of fluorouracil, calcium folinate and bevacizumab when combined with oxaliplatin, see the instructions for use of these drugs.

When using this combination, the infusion of oxaliplatin should always be carried out after the administration of bevacizumab, but precede the administration of fluorouracil.

Treatment for ovarian cancer: intravenously at 85 mg/m 2 once every 2 weeks in monotherapy or in combination with other chemotherapeutic drugs.

For dosing regimens of fluorouracil, calcium folinate when combined with oxaliplatin, see the instructions for use of these drugs.

Mode of application

The infusion of oxaliplatin should always precede the administration of fluorouracil.

Intravenous infusion of the drug is carried out through an infusion system into peripheral veins or through a central venous catheter simultaneously with intravenous infusion of calcium folinate in 5% dextrose solution for 2-6 hours using a Y-shaped system for intravenous administration, connected immediately before the injection site. These two drugs must not be mixed in the same infusion container. Calcium folinate should not contain trometamol as an excipient and should only be diluted with 5% dextrose and should never be diluted alkaline solutions or solutions of sodium chloride and chloride-containing solutions. Oxaliplatin solution should not be mixed in the same infusion container with other drugs.

In the event of extravasation (the infusion solution with the drug enters the tissues surrounding the vein), its administration should be immediately stopped and the usual local symptomatic treatment should be started. When using oxaliplatin, hyperhydration is not required. Repeated injections of oxaliplatin are performed only when the number of neutrophils> 1500/µl and platelets> 75000/µl.

The administered dose should be adjusted according to tolerance. In the case of hematological disorders (the number of neutrophils< 1500/мкл и/или тромбоцитов < 75000/мкл) после цикла химиотерапии или до начала лечения (до первого цикла лечения) следующий цикл или первый цикл откладывают до восстановления количества форменных элементов крови до приемлемых значений (до количества нейтрофилов >1500/µl and/or platelets > 75000/µl). Before starting treatment and before each subsequent cycle, general analysis blood with the determination of the number of leukocytes, leukocyte formula and platelets.

With the development of severe / life-threatening diarrhea, severe neutropenia (the number of neutrophils< 1000/мкл), фебрильной нейтропении (лихорадка неизвестного генеза без клинически или микробиологически подтвержденной инфекции; определяется как сочетание нейтропении [absolute number leukocytes< 1000/мкл] с однократным повышением температуры тела >38.3 ºС or persistent increase in body temperature >38 ºС for more than 1 hour), severe thrombocytopenia (platelet count< 50000/ µl), oxaliplatin administration should be discontinued until improvement or recovery of these indicators and the dose of oxaliplatin on subsequent injections should be reduced by 25% in addition to each dose reduction of fluorouracil required in this case. When neurological symptoms(paresthesia, dysesthesia - manifestations of peripheral sensory neuropathy) the following changes in dosing regimen are recommended, based on their duration and severity:

If neurological symptoms are observed in the patient for more than 7 days, or if paresthesia without functional impairment persists until the next cycle of treatment, the subsequent dose of oxaliplatin should be reduced by 25%;

With paresthesia with functional impairment, which persists until the next cycle, the administration of oxaliplatin should be discontinued;

With a decrease in the severity of neurological symptoms after discontinuation of oxaliplatin, consideration may be given to resuming treatment.

Patients with kidney failure

In patients with normal function kidneys or lungs and medium degree impaired renal function, the recommended dose of the drug is 85 mg / m 2. In patients with severely impaired renal function, a reduction in the initial dose of oxaliplatin to 65 mg / m 2 is required.

Patients with impaired liver function

Dose changes in patients with mild and moderate impairment liver function is not required. There are no data on the use of oxaliplatin in patients with severe hepatic impairment.

Elderly patients

The safety profile of oxaliplatin when combined with fluorouracil in patients over 65 years of age is similar to that observed in patients under 65 years of age. Correction of the dosing regimen in elderly patients is not required.

Instructions for preparing a solution of the drug

When preparing and administering Eloxatin ®, needles and other equipment containing aluminum should not be used. To dilute the drug, use only recommended solvents.

Do not dilute with 0.9% sodium chloride solution and do not mix with other alkaline solutions or sodium chloride solutions and chloride-containing solutions.

To prepare an infusion solution, the Eloxatin ® concentrate is diluted in 250-500 ml of a 5% dextrose solution to obtain a concentration of at least 0.2 mg / ml. Solution for infusion is recommended to enter immediately after preparation. If the solution was not administered immediately after preparation, it can be stored for 24 hours at a temperature of +2 to +8 °C, unless the dilution of the drug was carried out under controlled, validated aseptic conditions (in these cases, store the diluted solution at a temperature from +2 to +8 °С should not exceed 48 hours).

Solution with signs of precipitation must be destroyed.

Only a clear solution can be administered to the patient.

The drug should not be administered undiluted.

Side effect

Development frequency side effects listed below was determined according to the following gradation: very often (≥ 1/10); often (≥ 1/100,< 1/10); нечасто (≥ 1/1000, < 1/100); редко (≥ 1/10000, < 1/1000); очень редко (< 1/10000), включая отдельные сообщения; частота неизвестна (по имеющимся данным определить частоту встречаемости не представляется возможным).

Combination therapy with oxaliplatin and fluorouracil/calcium folinate

Laboratory and instrumental data

Often

• Increased activity of "liver" transaminases, alkaline phosphatase, hyperbilirubinemia, increased activity of lactate dehydrogenase, weight gain. Often
• Hypercreatininemia, weight loss.

Often

Infections.

Often

Upper infections respiratory tract, neutropenic sepsis (including deaths).

Infrequently

Sepsis (including deaths).

Often

Anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia.

The incidence of these side effects is increased when treated with Eloxatin ® (85 mg/m 2 every 2 weeks) in combination with fluorouracil +/- calcium folinate compared with Eloxatin ® monotherapy at a dose of 130 mg/m 2 every 3 weeks, for example, anemia (80% vs 60%), neutropenia (70% vs 15%), thrombocytopenia (80% vs 40%).

Severe anemia (hemoglobin< 8 г/дл) или тяжелая тромбоцитопения (количество тромбоцитов < 50000/мкл) возникали с одинаковой частотой (< 5 % пациентов, когда препарат Элоксатин ® применялся в виде монотерапии или в комбинации с фторурацилом).

Severe neutropenia (neutrophil count<1000/мкл) возникала с большей частотой при применении препарата Элоксатин ® в комбинации с фторурацилом по сравнению с монотерапией препаратом Элоксатин ® (40 % по сравнению с < 3 % пациентов). Often

• Febrile neutropenia (including 3-4 degree). Rarely
• Immuno-allergic hemolytic anemia and thrombocytopenia.
• Disseminated intravascular coagulation, including deaths (see section "Special Instructions").

Digestive system disorders

Often

• Nausea, vomiting, diarrhea, constipation.
• With severe diarrhea and / or vomiting, the development of dehydration, hypokalemia, metabolic acidosis, paralytic ileus, obstruction of the small intestine, impaired renal function may be associated, especially when using a combination of the drug Eloxatin ® and fluorouracil.
• Stomatitis or mucositis (inflammation of the mucous membranes).

Stomach ache.

Often

• Dyspepsia.
• Gastroesophageal reflux disease.
• Gastrointestinal bleeding.
• Bleeding from the rectum.

Rarely

Colitis, including pseudomembranous colitis caused by

Clostridiumdifficile.

Pancreatitis.

Liver and biliary tract disorders

Rarely

Hepatic sinusoidal obstruction syndrome, also known as
called veno-occlusive liver disease or pathological
manifestations associated with this liver disease, including peliosis
hepatitis, nodular regenerative hyperplasia, perisinusoidal
fibrosis, the clinical manifestations of which may be portal
hypertension and / or increased activity of "liver" transaminases in
blood serum.

Often

Acute neurosensory manifestations.

These symptoms usually occur at the end of a 2-hour infusion of Eloxatin® or within a few hours after administration of the drug and decrease on their own over the next few hours or days and often reappear in subsequent cycles. They can occur or worsen when exposed to low temperatures or cold objects. Usually they are expressed in the appearance of transient paresthesia, dysesthesia and hypesthesia.

Acute laryngeal-pharyngeal dysesthesia syndrome occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or dyspnea/suffocation without any objective respiratory distress (no cyanosis or hypoxia), or laryngospasm or bronchospasm (no stridor or wheezing).

Other, sometimes occurring symptoms, in particular, dysfunction of the cranial nerves, both associated with the above adverse events, and occurring in isolation: ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness, sometimes described as paralysis of the vocal cords; impaired language sensitivity or dysarthria, sometimes described as aphasia; trigeminal neuralgia, facial pain, eye pain, decreased visual acuity, narrowing of the visual fields. In addition, the following symptoms were observed: spasm of masticatory muscles, muscle spasms, involuntary muscle contractions, muscle twitches, myoclonus; impaired coordination, gait disturbance, ataxia, balance disorders; tightness/pressure sensation/discomfort/pain in the throat or chest.

Dysesthesia or paresthesia of limbs and peripheral sensory
neuropathy.

The limiting toxicity of Eloxatin ® is neurological toxicity. It manifests as a peripheral sensory neuropathy characterized by peripheral dysesthesia and/or paresthesia with or without the development of convulsive muscle contractions, often provoked by cold (85%-95% of patients).

The duration of these symptoms (the severity of which usually decreases between treatment cycles) increases with the number of treatment cycles. The occurrence of pain or functional disorders, as well as their duration, are indications for adjusting the dosing regimen or even discontinuing treatment (see the section "Method of application and dose, recommendations for adjusting the dosing regimen of oxaliplatin"). These functional impairments, including difficulty in performing precise movements, are consequences of sensory impairments. The risk of functional impairment for a cumulative dose of approximately 800 mg/m 2 (eg 10 cycles) is< 15 %. В большинстве случаев неврологические проявления и симптомы уменьшаются после прекращения лечения.

• Dysgeusia (disturbance of taste sensations).
• Headache.

Often

• Dizziness.
• Meningism.

Rarely

• Dysarthria.
• Loss of deep tendon reflexes.
• Symptom of Lhermitte.
• Posterior reversible leukoencephalopathy syndrome (see section "Special Instructions").

Mental disorders

Often

• Depression.
• Insomnia.

Infrequently

Nervousness.

Often

Back pain.

In the event of such an adverse reaction, the patient should be examined to rule out hemolysis, since there have been rare reports of its development.

Often

• Arthralgia.
• Pain in the bones.

mediastinum

Often

• Dyspnea.
• Cough.

Often

• Hiccup.
• Pulmonary embolism.

Rarely

• Acute interstitial lung disease, sometimes fatal; pulmonary fibrosis (see section "Special Instructions").

Vascular disorders

Often

Nose bleed.

Often

• "Tides".
• Deep vein thrombosis.
• Thromboembolism.
• Increase in blood pressure.

Renal and urinary tract disorders

Often

• Hematuria.
• Dysuria.

Rarely

Acute tubular necrosis, acute interstitial nephritis, acute renal failure.

Skin and subcutaneous tissue disorders

Often

Skin lesion.

Often

• Alopecia (less than 5% of patients with monotherapy).
• Erythematous rash.
• Palmar-plantar erythrodysesthesia.
• Increased sweating.
• Nail changes.

Violations of the organ of vision

Rarely

• Transient decrease in visual acuity; narrowing of visual fields, optic neuritis.
• Transient loss of vision, reversible after discontinuation of treatment.

Hearing and labyrinth disorders

Infrequently

Ototoxicity.

Rarely

Deafness.

Immune System Disorders

Often

Allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis.

Often

Anaphylactic reactions including bronchospasm, angioedema, hypotension, chest pain and anaphylactic shock.

General disorders and disorders at the injection site

Often

• Increased fatigue.
• Fever, chills (trembling) or due to the development of infections (with or without febrile neutropenia), or possibly due to immunological mechanisms.
• Asthenia.
• Reactions at the injection site.

It was reported about the development of reactions at the injection site, including pain, flushing, swelling and thrombosis. Extravasation (infusion of the infusion solution with the drug into the tissues surrounding the vein) can also lead to local pain and inflammation, which can be pronounced and lead to complications, including necrosis, especially when Eloxatin ® is administered through a peripheral vein.

Metabolic and nutritional disorders

Often

Anorexia, hyperglycemia, hypernatremia.

Often

Hypocalcemia.

Post-marketing experience

Frequency unknown

Septic shock (including deaths).

Blood and lymphatic system disorders

Frequency unknown

Hemolytic-uremic syndrome.

Nervous System Disorders

Frequency unknown

Seizures.

Heart disorders

Frequency unknown

Prolongation of the QT interval, which can lead to the development of severe ventricular arrhythmias, including torsades de pointes, is possibly fatal.

Respiratory, thoracic and mediastinum

Frequency unknown

Laryngospasm.

Gastrointestinal disorders

Frequency unknown

Intestinal ischemia (including deaths) (see section "Special Instructions").

Duodenal ulcer and its potential complications, such as ulcer bleeding and ulcer perforation (including deaths) (see section "Special Instructions").

Musculoskeletal and connective tissue disorders

Frequency unknown

Rhabdomyolysis (including deaths) (see section "Special Instructions").

Combination therapy of oxaliplatin with fluorouracil/calcium folinate ( FOLFOX) and bevacizumab

The safety of the combination of oxaliplatin with fluorouracil/calcium folinate (FOLFOX) and bevacizumab as first-line therapy was evaluated in 71 patients with metastatic colorectal cancer (TREE study). In addition to the adverse reactions expected from the FOLFOX regimen, adverse reactions with the combination of FOLFOX with bevacizumab included bleeding, proteinuria, impaired wound healing, gastrointestinal perforations, and hypertension.

For more information regarding the safety of using bevacizumab, see the appropriate prescribing information for this drug.

Overdose

Symptoms

In case of an overdose, more pronounced side effects can be expected.

Treatment

Interaction with other drugs.

A significant change in the binding of oxaliplatin to plasma proteins in vitro with simultaneous use with erythromycin, salicylates, granisetron, paclitaxel and sodium valproate was not observed.

When interacting with aluminum, the formation of a precipitate and a decrease in the activity of oxaliplatin are possible.

Caution is advised when using oxaliplatin in conjunction with other drugs that prolong the QT interval (because of the risk of severe ventricular arrhythmias, including torsades de pointes). In the case of combination with such drugs, it is necessary to carefully monitor the QT interval during the ECG (see section "Special Instructions").

Caution is advised when using oxaliplatin in conjunction with other drugs that can cause the development of rhabdomyolysis (due to an increased risk of rhabdomyolysis, see section "Special Instructions").

Eloxatin ® is pharmaceutically incompatible with 0.9% sodium chloride solution and other saline (alkaline) solutions or solutions containing chlorides. In patients receiving Eloxatin ® at a dose of 85 mg / m 2 immediately before the introduction of fluorouracil, there were no changes in the concentrations of fluorouracil in the blood.

special instructions

Eloxatin ® should only be used in specialized oncology departments and should be administered under the supervision of an oncologist experienced in anticancer drugs.

Constant monitoring of the development of possible toxic effects in the treatment of oxaliplatin is required.

Regularly (once a week), as well as before each administration of Eloxatin ®, it is necessary to monitor the content of formed elements in peripheral blood and indicators of kidney and liver function.

Due to the limited data on the safety of the drug in patients with severe renal impairment, it is recommended to carefully balance the risk and benefit before using the drug. It is necessary to strictly monitor renal function, and the initial dose of oxaliplatin in patients with severely impaired renal function should be 65 mg / m 2.

When using the drug Eloxatin ® allergic reactions may occur during any cycle. In the event of the development of anaphylactic-like reactions to the drug Eloxatin ®, its infusion should be immediately stopped and appropriate symptomatic therapy should be started immediately. In this case, repeated administration of the drug Eloxatin ® is contraindicated.

Before each administration and periodically after the administration of oxaliplatin, a neurological examination should be performed to detect signs of neurotoxicity (peripheral sensory neuropathy), especially if the drug is combined with other drugs that have neurotoxicity.

Recommendations for dose adjustment and regimen of administration of oxaliplatin in case of neurotoxicity, hematological and gastrointestinal manifestations of toxicity are given in the section "Method of administration and doses". Patients should be informed about the possibility of persistent symptoms of peripheral sensory neuropathy after the end of treatment. Local moderate paresthesia with functional impairment can last up to 3 years after the end of treatment according to the adjuvant use of the drug.

In patients who develop acute laryngo-pharyngeal dysesthesia during the infusion or within a few hours after the 2-hour infusion, the next infusion of oxaliplatin should be carried out within 6 hours. To prevent the development of dysesthesia, the patient is advised to avoid hypothermia, as well as taking too cold food and drinks during administration and for several hours after the administration of Eloxatin®.

If unexplained respiratory symptoms (dry cough, shortness of breath, wheezing, or evidence of lung infiltration on x-ray) develop, treatment with oxaliplatin should be withheld until excluded by additional testing for interstitial lung disease.

Gastrointestinal toxicity, which is manifested by nausea and vomiting, can be significantly reduced or eliminated with the use of antiemetics. Severe diarrhea and/or vomiting may be associated with the development of dehydration, hypokalemia, metabolic acidosis, paralytic ileus, small bowel obstruction, and even renal dysfunction, especially when using the combination of Eloxatin® and fluorouracil.

Patients should be informed in detail about the possibility of developing diarrhea / vomiting and neutropenia after the use of oxaliplatin in combination with fluorouracil, with a recommendation, if they occur, immediately contact their doctor for urgent treatment for the development of these symptoms.

When using the drug Eloxatin ®, cases of intestinal ischemia, including deaths, have been reported. In the event of intestinal ischemia, the use of oxaliplatin should be discontinued and appropriate therapeutic measures should be taken.

If oxaliplatin is combined with fluorouracil (with or without calcium folinate), the usual dose adjustment of fluorouracil should be used if fluorouracil-related toxicity develops (see fluorouracil prescribing information).

Signs and symptoms of posterior reversible leukoencephalopathy syndrome may include headache, mental impairment, seizures, visual disturbances (from blurry vision to blindness) with or without an increase in blood pressure (see section " Side effect"). The diagnosis of posterior reversible leukoencephalopathy syndrome is confirmed by magnetic resonance or computed tomography of the brain.

During treatment with Eloxatin ®, side effects such as sepsis, neutropenic sepsis or septic shock (including deaths) have been reported (see section "Side Effects"). The use of the drug should be discontinued in case of development of any of the listed conditions.

When using the drug Eloxatin ®, cases of the development of disseminated intravascular coagulation, including deaths, have been reported. With the development of this condition, the use of oxaliplatin should be discontinued and appropriate therapeutic measures should be taken.

Hemolytic uremic syndrome is a life-threatening side effect. The use of oxaliplatin should be discontinued when the first symptoms of microangiopathic hemolytic anemia appear, such as a rapid decrease in hemoglobin with concomitant thrombocytopenia, an increase in the concentration of bilirubin, creatinine, urea nitrogen, and serum lactate dehydrogenase (LDH) activity. The resulting renal failure may be irreversible upon discontinuation of therapy and may require dialysis. In the event of abnormal laboratory values ​​of liver function or the development of portal hypertension, which are not obviously a consequence of the presence of liver metastases, the patient should be examined for the very rare oxaliplatin-induced hepatic vascular disease.

When using oxaliplatin, QT interval prolongation may develop (see section "Side effects"), which can lead to severe ventricular arrhythmias, including ventricular tachycardia of the "pirouette" type, possibly fatal. In patients with a history of QT interval prolongation or in patients with predisposing factors for QT interval prolongation (eg, concomitant use with drugs that prolong the QT interval; electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia), Eloxatin should be apply with caution. With the development of prolongation of the QT interval, treatment with oxaliplatin should be discontinued. When using the drug Eloxatin ®, the development of rhabdomyolysis, including deaths, was noted. In the event of muscle pain and swelling in combination with weakness, fever or dark urine, treatment with Eloxatin ® should be discontinued. If the diagnosis of rhabdomyolysis is confirmed, then appropriate therapeutic measures should be taken. It is recommended to be careful when prescribing medicinal products that can cause the development of rhabdomyolysis with Eloxatin ® (see sections "Side effect", "Interaction with other drugs").

When using the drug Eloxatin ®, the development of duodenal ulcers and its potential complications, such as ulcerative bleeding and ulcer perforation, which can be fatal, is possible.

In the event of the development of a duodenal ulcer, treatment with Eloxatin ® must be discontinued and appropriate therapeutic measures should be taken.

Eloxatin ® should not be administered intraperitoneally, as bleeding into the abdominal cavity may develop with such administration.

In the event of extravasation, the infusion should be stopped immediately and local symptomatic treatment initiated.

Women and men should use reliable methods of contraception during treatment with oxaliplatin and after the end of treatment for 4 months for women and 6 months for men.

When handling oxaliplatin, all usual recommendations for handling cytotoxic drugs should be followed. If oxaliplatin gets on the skin or mucous membranes, they should be washed immediately and thoroughly with water.

Influence on the ability to drive vehicles and engage in other potentially hazardous activities

Visual disturbances, especially transient loss of vision (reversible after discontinuation of therapy) may pose a risk to patients when driving vehicles and engaging in other potentially hazardous activities. Therefore, patients should be warned about the possible impact of these phenomena on their ability to drive vehicles and engage in other potentially hazardous activities. If the described adverse events occur, you should refrain from performing these activities.

Release form

Concentrate for solution for infusion 5 mg/ml. 10 ml of the drug in a transparent glass vial, sealed with a dark gray rubber stopper with an aluminum rim and a green flip-off® cap.

20 ml of the drug in a transparent glass vial, sealed with a dark gray rubber stopper with an aluminum rim and a blue flip-off® cap.

40 ml of the drug in a transparent glass vial, sealed with a dark gray rubber stopper with an aluminum rim and an orange flip-off® cap.

1 vial in a coated plastic blister pack. 1 blister pack along with instructions for use in a cardboard box.

Storage conditions

Store in a place protected from light at a temperature not exceeding 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life

Do not use the drug after the expiration date indicated on the package.

Holiday conditions

Released by prescription.

Legal entity in whose name the registration certificate is issued

SANOFI-AVENTIS FRANCE, France.

Manufacturer

1. Aventis Pharma (Dagenham), UK. Aventis Pharma (Dagenham), United Kingdom. Rainham Road South, Dagenham, Essex, RM10 7XC, United Kingdom.

2. Sanofi-Aventis Deutschland GmbH, Germany. Sanofi-Aventis Deutschland GmbH, Germany. Bruningstrasse 50, D-65926, Frankfurt (Main), Germany.

Claims of consumers should be sent to the address in Russia:

125009, Moscow, st. Tverskaya, 22.

In the case of packaging of the drug at CJSC Sanofi-Aventis Vostok, Russia, consumer claims should be sent to:

302516, Russia, Orel region, Orlovsky district, s / p

Bolshekulikovskoe, st. Livenskaya, 1.

Oxaliplatin is an anticancer drug belonging to a new class of platinum derivatives in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane (DACH). Oxaliplatin is the only enantiomer, cis-[oxalato(trans-1-1-1,2-DACH)-platinum].

Oxaliplatin exhibits a broad spectrum of both in vitro cytotoxicity and in vivo antitumor activity in various tumor models, including human colorectal cancer. It also exhibits in vitro and in vivo activity in various cisplatin-resistant cell cultures. In combination with 5-fluorouracil, a synergistic cytotoxic effect was observed in vitro and in vivo.

The study of the mechanism of action of oxaliplatin, even if not yet fully understood, supports the hypothesis that biotransformed, hydrated oxaliplatin derivatives interact with DNA through the formation of inter- and intra-strand bridges and inhibit DNA synthesis, which leads to cytotoxicity and an antitumor effect.

Within the three lin Studies have demonstrated the efficacy of oxaliplatin (85 mg/m 2 every 2 weeks) in combination with 5-fluorouracil and folinic acid in patients with metastatic colorectal cancer.

The EFC2962 trial was a Phase III comparative study of first choice therapy in which patients were randomized to two treatment groups - 5-fluorouracil/folinic acid alone (LV5FU2) and 5-fluorouracil/folinic acid/oxaliplatin combination (FOLFOX4).

As part of the EFC4584 study, a comparative study (Phase III) was conducted in patients who had previously received anticancer treatment with a combination of irinotecan (CPT-11) and 5-fluorouracil/folinic acid and were refractory to it, in which they were randomized into three treatment groups: only 5-fluorouracil/folinic acid (LV5FU2),

oxaloplatin alone and 5-fluorouracil/folinic acid/oxaliplatin combination (FOLFOX4)

The EFC2964 study was a non-control (Phase II) study in patients previously treated with 5-fluorouracil/folinic acid alone and refractory to it, in which they were treated with the 5-fluorouracil/folinic acid/oxaliplatin (FOLFOX4) combination. ).

Two randomized trials (EFC2962 - in patients treated with first choice therapy, EFC4584 in patients previously treated with anticancer drugs) showed a significantly higher response rate and a longer progression-free survival (PFS) / time to onset of disease progression (STP) when compared with treatment with 5-fluorouracil/folinic acid alone.

Among patients previously treated with anticancer drugs (EFC4584) who were symptomatic at baseline, a significant improvement in symptoms associated with the underlying disease was seen in more patients in the 5-FU/folinic acid oxaliplatin group than in the 5-FU/folinic acid group. group treated with 5-FU/folinic acid alone (27.7% vs. 14.6% p=0.0033).

In patients not previously treated with anticancer drugs, there was no significant difference between the two treatment groups in terms of quality of life. However

scores on the quality of life rating scale were generally higher in the control group in terms of general health and pain, and lower in the oxaliplatin group in terms of nausea/vomiting.

In the adjuvant drug regimen in the phase III comparative trial MOSAIC (EFC3313), 2246 patients (899 Duke stage II/B2 and 1347 Duke stage III (Duke C)) were randomized after complete resection of the primary colon cancer to receive only 5- FU/ folinic acid (LV5FU2, N=1123; B2/C=448/675) or a combination of oxaliplatin and 5-FU/ folinic acid (FOLFOX4, N=1123; B2/C=451/672).

Overall survival (ITT analysis)

At the time of analysis of 3-year progression-free survival, which was the primary end point in the MOSAIC trial, 85.1% of patients were alive in the FOLFOX4 group, compared with only 83.8% in the LV5FU2 group. Converting these figures into an overall reduction in the risk of mortality, we get 10% in favor of FOLFOX4, which does not reach the threshold of statistical significance (hazard ratio = 0.90). The numbers were 92.2% compared to 92.4% in the subgroup of patients in stage II (Duke B2) (hazard ratio = 1.01) and 80.4% compared to 78.1% in stage III (Duke C). Duke)

(hazard ratio = 0.87) in the FOLFOX4 and LV5FU2 groups, respectively.

Pharmacokinetics

The pharmacokinetic properties of the various active metabolites have not been established. Pharmacokinetics of ultrafiltered platinum, that is, all forms of unconjugated active and inactive platinum in plasma after a 2-hour administration of the drug at a dose of 130 mg / m 2, every three weeks for 1-5 courses, and also at a dose of 85 mg / m 2, every two weeks for 1-3 courses.

At the end of the 2-hour administration, 15% of the injected platinum is in the systemic circulation, and the remaining 85% is rapidly distributed to the tissues or excreted in the urine. Irreversible binding to erythrocytes and plasma leads to half-life in these environments, close to the natural turnover of erythrocytes and serum albumin. There is no significant accumulation of the drug in ultrafiltered plasma, either with the 85 mg / m 2 every two weeks or with the 130 mg / m 2 every three weeks, and the state of equilibrium is reached in it already during the first cycle; inter- and intra-patient differences are generally low.

Biotransformation in vitro is the result of non-enzymatic degradation and no cytochrome P450 mediated metabolism of the diaminocyclohexane (DACH) ring is observed.

In the human body, oxaliplatin undergoes extensive biotransformation and the parent drug is not detected in the plasma ultrafiltrate by the end of the two-hour infusion. Several cytotoxic metabolites, such as monochloro-, dichloro and DACH-platinum dihydrate, have been identified in the systemic circulation, along with a number of inactive conjugates at later times.

Platinum is excreted primarily in the urine, mainly within the first 48 hours after administration.

By the fifth day, about 54% of the total dose is found in the urine and less than 3% in the feces.

A study was made of the effect of renal failure on the systemic exposure of oxaliplatin in patients with varying degrees of impaired renal function. Oxaliplatin was used at a dose of 85 mg/m 2 in the control group with normal renal function (ClCr > 80 ml/min, n = 12) and in patients with mild (ClCr = 50-80 ml/min, n = 13) and moderate ( ClCr = 30 - 49 ml / min, n = 11) insufficiency, as well as at a dose of 65 mg / m 2 in patients with severe renal insufficiency (ClCr< 30 мл/мин, п = 5).

The median exposure of the drug was V, 4, 6 and 3 cycles, respectively, PK data in 1 cycle were obtained in 11, 13, 10 and 4 patients, respectively. In a (small) group of patients with severe renal insufficiency in plasma ultrafiltrate (PFP), an increase in platinum AUC and AUC/dose ratio was observed, as well as a decrease in total and renal clearance and volume of distribution at steady state concentration (Vss) with increasing severity of renal dysfunction: point estimates (90% CI) of estimated mean ratios compared with patients with normal renal function for the AUC/dose ratio were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01), and 4.81 (3.49, 6.64), respectively, for patients with mild, moderate, and severe renal impairment.

Excretion of oxaliplatin significantly correlated with creatinine clearance. The total UFP clearance of platinum was 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29), and Vss was 0.52 (0.41, 0.65), 0.73 (0.59, 0.91), and 0.27 (0.20, 0.36) for patients with mild, moderate, and severe renal impairment, respectively. Total UFP clearance of platinum in easy, moderate and severe renal failure compared with the group with normal renal function was reduced by 26%, 57% and 79%, respectively.

Renal clearance of platinum from UFP in the mild, moderate, and severe renal impairment groups decreased by 30%, 65%, and 84%, respectively, compared to the group with normal renal function. There was an increase in the half-life of platinum from UFP in the beta phase with an increase in the severity of impaired renal function, mainly in the group of severe renal insufficiency. Despite the small number of patients in the group with severe renal impairment, these data are very relevant for patients with severe renal insufficiency and should be taken into account when prescribing oxaliplatin to patients with impaired renal function (see sections Dosage and method of administration, Contraindications and Special warnings and precautions for use).

Preclinical safety data

Target organs identified in species used for preclinical testing ny(mice, rats, dogs and/or monkeys), in single dose and repeat dose experiments, are: Bone marrow, gastrointestinal system, kidneys, testicles, nervous system and heart. Target organ toxicity in animals, with the exception of cardiotoxicity, was similar to that observed with other platinum compounds and other DNA-interacting cytotoxic drugs used to treat human cancer.

Cardiac effects, manifesting as electrophysiological abnormalities with lethal ventricular fibrillation, have only been observed in dogs. Cardiotoxicity is considered species-specific, not only because it has only been reported in dogs, but also because dog-lethal doses (150 mg/m 2 ) are well tolerated in humans. Preclinical studies performed on rat sensory neurons indicate that the acute neurosensory symptoms induced by oxaliplatin may be related to effects on voltage-dependent sodium channels.

It has been shown that oxaliplatin is mutagenic and clastogenic in mammalian test systems and exhibits embryotoxicity in rats. Possibly, oxaliplatin is carcinogenic, however experiments on carcinogenesis were not conducted.

Indications for use

Oxaliplatin, in combination with 5-fluorouracil and folinic acid, is indicated for:

adjuvant treatment of stage III colorectal cancer (Duke C) after complete

resection of the primary tumor

treatment of metastatic colorectal cancer.

Contraindications

Oxaliplatin is contraindicated:

Patients with a known history of allergy to oxaliplatin,

When breastfeeding,

with myelosuppression (the number of neutrophils<2х10 9 /л и/или число тромбоцитов <100х10 9 /л) до начала первого курса лечения,

With peripheral sensory neuropathy with functional impairment before the first course of treatment.

In severe renal insufficiency (creatinine clearance<30 мл/мин).

Pregnancy and lactation

For use in pregnant women, see the Pregnancy and lactation section.

Focus on reproductive function

In preclinical studies, oxaliplatin has been observed to have genotoxic effects. Men receiving treatment with oxaliplatin are not recommended to have children during treatment and for 6 months after its completion. It is also recommended to conserve sperm before starting treatment, since oxaliplatin can lead to irreversible effects on reproductive function.

Women during treatment with oxaliplatin should avoid pregnancy and use effective contraception (see Pregnancy and lactation).

There is currently no information available on the safety of oxaliplatin in pregnant women. Based on preclinical data, oxaliplatin is likely to be lethal and/or teratogenic to the human fetus at the recommended therapeutic dose. Accordingly, oxaliplatin is not recommended for use during pregnancy and in women of childbearing age who are not using contraceptives. The possibility of use can be weighed only after the patient has been specifically informed about the risk to the fetus and with her consent.

During treatment, as well as for the next 4 months for women and 6 months for men, it is necessary to use appropriate contraception.

The penetration of the drug into breast milk has not been studied. Breast-feeding is contraindicated during treatment with oxaliplatin.

Oxaliplatin may have an antifertility effect (see Special Warnings and Precautions for Use).

Dosage and administration

Dosage

ADULTS ONLY

The recommended adjuvant dose of oxaliplatin is 85 mg/m IV repeated every two weeks for 12 cycles (6 months). The recommended dose of oxaliplatin in the treatment of metastatic colorectal cancer is 85 mg/m 2 intravenously repeated every two weeks.

Dosage should be adjusted according to tolerance (see Special Warnings and Precautions for Use).

Oxaliplatin should always be used before fluoropyrimidines.

Oxaliplatin is usually administered as a 2-6 hour intravenous infusion in 250-500 ml of 5% glucose so that the concentration is in the range of 0.2-0.70 mg/ml; 0.70 mg/ml is the maximum concentration in clinical practice for a dose of oxaliplatin 85 mg/m 2 .

Most often, oxaliplatin is used in combination with 5-fluorouracil in continuous infusion. For a biweekly repeat treatment, a dosing regimen consisting of a 5-fluorouracil bolus and continuous infusion was used.

Special groups of patients:

Patients with impaired renal function:

Oxaliplatin should not be used in patients with severe renal insufficiency (see Contraindications and Pharmacokinetics).

In patients with moderate renal impairment, treatment should begin with the recommended dose of oxaliplatin 85 mg/m2 (see Special Warnings and Precautions for Use and Pharmacokinetics). For patients with mild renal impairment, there is no need for dose adjustment.

Patients with impaired liver function:

In a phase I study including patients with severe hepatic impairment, the frequency and severity of biliary hepatic impairment appeared to be associated with disease progression and worsening of baseline liver dysfunction. During clinical development, no dosage changes were made in patients with impaired liver function.

Elderly patients:

There was no increase in the toxicity of oxaliplatin when used alone or in combination with 5-fluorouracil in patients over 65 years of age. Therefore, dosage adjustment in the elderly is not required.

Pediatric patients:

There are no significant indications for the use of oxaliplatin in children. The efficacy of oxaliplatin alone in pediatric patients with solid tumors has not been established (see Pharmacodynamics)

Application method

Oxaliplatin is administered as an intravenous infusion.

The use of oxaliplatin does not require hyperhydration.

Oxaliplatin, diluted with 250-500 ml of 5% glucose solution to obtain a concentration of at least 0.2 mg/ml, should be administered either by a peripheral vein or central venous infusion system over 2-6 hours, and always up to 5-fluorouracil

In case of extravasation, the administration of oxaliplatin should be stopped immediately.

Handling the drug:

Oxaliplatin should be diluted before use. Only a 5% lucose solution should be used to dilute the concentrate (see Method of Use, Handling Instructions).

Side effect

The most common side effects of oxaliplatin when used in combination with 5-fluorouracil/folinic acid were gastrointestinal (diarrhea, nausea, vomiting and mucositis), hematologic (neutropenia, thrombocytopenia) and neurological (acute and cumulative peripheral sensory neuropathy). In general, these side effects were more frequent and more severe with the combination of oxaliplatin with 5-fluorouracil/folinic acid than with 5-fluorouracil/folinic acid alone.

The frequencies shown in the table below are taken from clinical trials in metastatic cancer and adjuvant regimens after resection of the primary tumor (involving 416 and 1108 patients, respectively, in the oxaliplatin plus 5-fluorouracil/folinic acid combination arms), as well as from post-marketing experience.

The frequency of adverse reactions indicated in the table below was determined using the following criteria: very often (> 1/10), often (> 1/100,<1/10), нечасто (>1/1000, <1/100), редко (>1/10000, <1/1000); очень редко (< 1/10000), включая отдельные сообщения.

Very often, allergies/allergic reactions occurred predominantly during the infusion and sometimes were fatal. Common allergic reactions include skin rashes, in particular urticaria, conjunctivitis and rhinitis. Common anaphylactic or anaphylactoid reactions include bronchospasm, angioedema, hypotension, chest pain, and anaphylactic shock.

Very often there is an increase in body temperature, chills (trembling), both of infectious origin (with or without the appearance of febrile neutropenia), and possibly of immunological origin.

There are reports of reactions at the injection site, including pain at the injection site, redness, swelling, and thrombosis. Extravasation can lead to local pain and inflammation, which can be severe and lead to complications, including necrosis, especially when oxaliplatin is infused into a peripheral vein (see Special Warnings and Precautions for Use).

Nervous System Disorders

Dose restrictions are due to the neurological toxicity of oxaliplatin. Neurological disorders are manifested by peripheral sensory neuropathy, characterized by dysesthesia and/or paresthesia of the extremities with or without convulsions, which are often provoked by cold. These symptoms occur in up to 95% of treated patients. The duration of symptoms, which usually regress between courses of treatment, increases with the number of courses.

The appearance of pain or functional impairment requires dose adjustment or even discontinuation of the drug, depending on the duration of the symptoms (see Special Warnings and Precautions for Use).

Functional impairments, which are difficulties in performing precise movements, are possible consequences of sensory damage. The risk of functional impairment for a cumulated dose of about 850 mg/m 2 (10 courses) is about 10%, reaching 20% ​​in the case of a cumulated dose of 1020 mg/m 2 (12 courses).

In most cases, neurological symptoms improve or disappear completely after treatment is stopped. In adjuvant treatment of colon cancer 6 months after the end of treatment, 87% of patients were asymptomatic or mild. According to the results of a 3-year follow-up, approximately 3% of patients had either stable localized paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%).

Acute neurosensory symptoms have been reported during treatment with oxaliplatin (see Preclinical Safety Data). They usually begin within a few hours of drug administration and are often triggered by exposure to cold. Transient paresthesia, dysesthesia, and hypoesthesia are commonly seen. Acute pharyngolaryngeal dysesthesia syndrome occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or dyspnea/suffocation, without objective evidence of respiratory distress (no cyanosis or hypoxia), or laryngospasm or bronchospasm (no stridor or dyspnea). Although antihistamines and bronchodilators were commonly administered in such cases, the symptoms quickly regressed even in the absence of treatment. Jaw spasm, tongue dysesthesia, dysarthria, and chest pressure were also observed. Although antihistamines and bronchodilators have been used in such cases, symptoms are usually rapidly reversible even in the absence of intervention. Lengthening the infusion time in subsequent cycles helps to reduce the incidence of this syndrome (see "Special warnings and precautions for use"). Rarely, other symptoms have been reported including jaw spasm/muscle spasms/involuntary muscle contractions/muscle cramps/myoclonic spasms/coordination/gait disturbance/ataxia/balance/chest and throat tightness/discomfort/pain. In addition, there may be cranial nerve dysfunctions, which may be the result of the above phenomena or develop independently, in particular, eyelid drooping, diplopia, aphonia / dysphonia / hoarseness, sometimes described as paralysis of the vocal cords.

abnormal tongue sensation or dysarthria sometimes described as aphasia, trigeminal neuralgia/facial pain/eye pain, decreased visual acuity, visual field disturbances.

Other neurological symptoms such as dysarthria, loss of deep tendon reflexes, and Lhermitte's symptom have been frequently reported in association with oxaliplatin treatment. Several cases of optic neuritis have been described.

Reactions from post-marketing experience with unknown frequency convulsions

Severe diarrhea and/or vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and impaired renal function, especially when oxaliplatin is combined with 5-FU (see Special Warnings and Precautions for Use).

Liver and biliary tract disorders

very rare (<1/10,000):

Sinusoidal liver occlusive syndrome, also known as veno-occlusive liver disease, or pathological manifestations associated with this liver disease, including peliotic hepatitis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may include portal hypertension and/or elevated transaminase levels.

Renal and urinary tract disorders

very rare (<1/10,000):

Acute tubular necrosis, acute interstitial nephritis, and acute renal failure.

Overdose

There is no known antidote for oxaliplatin. In case of an overdose, an increase in side effects can be expected. Hematological parameters should be monitored and symptomatic treatment should be carried out.

Incompatibilities

This drug should not be mixed with other drugs, except for those indicated in the section "Instructions for handling / use.

DO NOT MIX with alkaline preparations or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient, and other medicinal products containing trometamol salts. Alkaline preparations or solutions adversely affect the stability of oxaliplatin.

DO NOT DILUTE oxaliplatin with saline or other solutions containing chloride ions (including calcium, potassium and sodium chloride).

DO NOT MIX with other drugs in the same vial or infusion system (see instructions for simultaneous use with folinic acid).

DO NOT use IV equipment containing aluminum.

Interaction with other drugs

Patients who received a single dose of 85 mg/m 2 oxaliplatin immediately prior to 5-FU administration showed no change in 5-FU exposure.

There was no significant change in the binding of oxaliplatin to proteins in vitro when used with the following compounds: erythromycin, salicylates, granisetron, paclitaxel, sodium valproate.

Application features

Kidney dysfunction

Patients with mild or moderate renal impairment should be carefully monitored for adverse reactions, and the dose should be adjusted according to the degree of toxicity (see Pharmacokinetics).

Hypersensitivity reactions

Patients with allergic reactions to other PCB compounds other history should be closely monitored for allergic symptoms. In the event of an anaphylactic-like reaction, the infusion should be interrupted immediately and appropriate symptomatic treatment instituted. New attempts to use oxaliplatin in such patients are contraindicated.

In case of extravasation, the infusion should be stopped immediately and the usual local symptomatic treatment should be started.

Neurological symptoms

The neurological toxicity of oxaliplatin should be strictly controlled, especially if the drug is combined with drugs that have neurological toxicity. Neurological examination should be carried out before the start of each injection, and then periodically.

Patients who develop acute laryngealopharyngeal dysesthesia during an infusion or within a few hours after a two-hour infusion (see Adverse Effects), the next infusion of oxaliplatin should be given within six hours.

If symptoms persist for more than seven days and are painful, the subsequent dose of oxaliplatin should be reduced from 85 to 65 mg/m 2 (metastatic regimen) or 75 mg/m 2 (adjuvant regimen).

If paresthesia without functional impairment persists until the next cycle, the subsequent dose of oxaliplatin should be reduced from 85 to 65 mg / m 2 (metastatic regimen) or 75 mg / m (adjuvant regimen).

If paresthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.

If these symptoms improve after discontinuation of oxaliplatin, consideration may be given to resuming treatment.

Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy after the end of treatment. Localized moderate paresthesias, which may interfere with functional activity, may be present up to 3 years after the end of treatment according to the adjuvant drug regimen.

Syndrome of late reversible leukoeniphalopathy (LPOL)

Late reversible leukoencephalopathy syndrome has been reported in patients treated with oxaliplatin in combination with chemotherapy. LPOL is a rare, reversible, rapidly progressive neurological condition that may be accompanied by seizures, hypertension, headache, confusion, blindness, and other visual and neurological disorders (see Adverse Effects). The diagnosis of POL is based on brain imaging, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhoea, dehydration and haematological changes

The toxicity of oxaliplatin, which manifests itself as nausea and vomiting, predetermines the use of antiemetics as a preventive and / or therapeutic measure (see Adverse Effects).

Severe diarrhea and/or vomiting can lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and impaired renal function, especially when oxaliplatin is combined with 5-fluorouracil.

In the case of hematological disorders (the number of neutrophils<1,5х10 9 /л и/или число тромбоцитов <50x10 9 /л) задерживают назначение следующего курса до возвращения гематологических показателей к приемлемым значениям. Анализ крови с дифференциальным определением лейкоцитов должен проводиться до начала лечения и перед каждым следующим курсом.

Patients should be properly informed about the possibility of diarrhea/vomiting, mucositis/stomatitis, and neutropenia following the use of oxaliplatin and 5-fluorouracil, so that they can promptly contact their doctor for the necessary treatment.

If mucositis/stomatitis is observed, with or without neutropenia, then the next course should be delayed until recovery from mucositis/stomatitis to at least grade 1 and/or an increase in the number of neutrophils to values ​​greater than 1.5 x 10 9 /l.

If oxaliplatin is combined with 5-fluorouracil (with or without folinic acid), due to the toxicity of 5-fluorouracil, dose adjustment is usually recommended.

With diarrhea of ​​4 degrees (WHO), neutropenia of 3-4 degrees (neutrophils<1х10 9 /л) или тромбоцитопении 3-4 степени (число тромбоцитов <50x10 9 /л) доза оксалиплатина должна быть снижена с 85 до 65 мг/м 2 (метастатическая схема) или 75 мг/м 2 (схема адъювантного лечения), в дополнение к снижению дозы 5-фторурацила.

Pulmonary disorders

In the event of unexplained respiratory symptoms such as dry cough, dyspnea, wheezing, or pulmonary infiltrate confirmed by radiological diagnostic methods, oxaliplatin should be discontinued until the cause of pulmonary disorders is clarified and the possibility of interstitial lung disease is ruled out (see Adverse Effects).

Hepatic disorders n

In case of abnormal liver function test results ii il and portal hypertension not associated with liver metastases, the possibility of very rare drug-induced vascular disorders of the liver should be considered.

DO NOT use injection materials containing aluminum.

DO NOT USE undiluted.

DO NOT DILUTE with solutions containing chlorides.

DO NOT MIX or USE simultaneously with any other drugs in the same infusion system or in the same infusion line.

DO NOT MIX with alkaline preparations and solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and other preparations with trometamol salts. Alkaline preparations or solutions adversely affect the stability of oxaliplatin. Oxaliplatin can be used simultaneously with folinic acid using a Y-shaped infusion system, with a fork just before the injection site, since the drugs cannot be mixed in the same vial.

These two drugs should not be combined in the same infusion bag. Folinic acid should not contain trometamol as an excipient and should only be diluted with isotonic 5% glucose solution. Do not dilute folinic acid with alkaline or sodium chloride solutions or other chlorine-containing solutions.

After the introduction of oxaliplatin, the system should be flushed.

Concentrate for solution preparation for intravenous administration

Breeding before intravenous administration

The required amount of concentrate is taken from the vial and diluted with 5% glucose solution to 250 - 500 ml to obtain a concentration of at least 0.2 mg / ml. Enter in intravenous infusion.

Visual inspection is carried out before use. Use only

clear solution without particles.

Single use drug. Unused solution must be destroyed.

NEVER use sodium chloride solution to dissolve or dilute the drug.

Infusion

The use of oxaliplatin does not require prior hydration.

Oxaliplatin, diluted in 250-500 ml of 5% glucose solution, to obtain a concentration of at least 0.2 mg / ml, must be infused either into a peripheral vein or into the central venous system for 2-6 hours. If oxaliplatin is used in combination with 5-fluorouracil, the infusion of oxaliplatin should precede the administration of 5-fluorouracil. After administration of oxaliplatin, flush the line and then inject 5-fluorouracil.

Precautionary measures

Studies to evaluate the effect of oxaliplatin on the ability to drive vehicles and mechanisms have not been conducted. However, treatment with oxaliplatin may lead to an increased risk of dizziness, nausea and vomiting, and other neurological symptoms that affect reaction time and sense of balance, and therefore may have a minor or moderate effect on the ability to drive and use machines.

Visual impairment, in particular, temporary loss of vision (reversible after discontinuation of therapy) may affect the patient's ability to drive a car and other mechanisms. Therefore, patients should be warned about the potential impact of these adverse reactions on the ability to drive or use machines.

Release form

10 ml of concentrate in a clear glass vial, type I, with a nominal volume of 15 ml, stoppered with a 20 mm dark gray bromobutyl elastomer stopper with a 20 mm aluminum rim, green flip-off®. The bottle is placed in a cell package, sealed with a LDPE film. Cell packaging is placed in a cardboard box along with instructions for the medical use of the drug.

20 ml of concentrate in a clear glass vial, type I, with a nominal volume of 20 ml, stoppered with a 20 mm dark gray bromobutyl elastomer stopper with a 20 mm blue aluminum rim. The bottle is placed in a cell package, sealed with a LDPE film. Cell packaging is placed in a cardboard box along with instructions for the medical use of the drug.

Storage conditions

List B.

Store in a place protected from light at a temperature not exceeding 25°C. Keep out of the reach of children. Do not freeze!

Shelf life

Do not use after the expiry date!

The physico-chemical stability of the infusion solution diluted with 5% glucose solution is maintained for 48 hours at a temperature of 2-8°C or 24 hours at a temperature of 25°C.

From a microbiological point of view, the solution should be used immediately. If the solution is not used immediately, storage conditions and shelf life prior to use are the responsibility of the person using it, but storage should not exceed 24 hours at 2-8°C unless dilution has taken place under aseptic, controlled and validated conditions.

Instructions for the drug Eloxatin, contraindications and methods of use, side effects and reviews about this drug. The opinions of doctors and the opportunity to discuss on the forum.

Instructions for use

Method of application and dosage Eloxatin

• ELOXATIN

Eloxatin ® is prescribed only adults in the form of intravenous infusions for 2-6 hours.

Hyperhydration when using oxaliplatin is not required. If oxaliplatin is used in combination with 5-fluorouracil, the infusion of oxaliplatin should precede the administration of 5-fluorouracil.

For adjuvant therapy for colon cancer the drug is administered at a dose of 85 mg/m 2 once every 2 weeks for 12 cycles (6 months).

For treatment of disseminated colorectal cancer at the rate of 85 mg / m 2 1 time in 2 weeks as monotherapy or in combination with 5-fluorouracil.

For ovarian cancer treatment - 85 mg / m 2 1 time in 2 weeks as monotherapy or in combination with other chemotherapeutic drugs.

Repeated injections of oxaliplatin are performed only when the number of neutrophils> 1500 / μl and platelets > 50,000 / μl.

With hematological disorders (the number of neutrophils<1500/мкл и/или тромбоцитов <50 000/мкл) проведение следующего курса откладывают до восстановления лабораторных показателей.

With the development of diarrhea of ​​4 degrees of toxicity (according to the WHO scale), neutropenia of 3-4 degrees (the number of neutrophils<1000/мкл), тромбоцитопении 3-4 степени (количество тромбоцитов <50 000/мкл) доза оксалиплатина при последующих введениях должна быть снижена с 85 мг/м 2 до 65 мг/м 2 при терапии диссеминированного колоректального рака и рака яичников; и до 75 мг/м 2 при адъювантной терапии колоректального рака в дополнение к обычному снижению дозы 5-фторурацила в случае их комбинированного применения.

Patients who develop acute laryngeal-pharyngeal dysesthesia during infusions or within a few hours after a 2-hour infusion should receive the next infusion of oxaliplatin within 6 hours.

If pain occurs (as a sign of neurotoxicity) for more than 7 days, the subsequent dose of oxaliplatin should be reduced from 85 mg/m 2 to 65 mg/m 2 in the treatment of disseminated colorectal cancer and ovarian cancer; and up to 75 mg/m 2 in adjuvant therapy for colorectal cancer.

With paresthesia without functional impairment, which persists until the next cycle, the subsequent dose of oxaliplatin should be reduced from 85 mg / m 2 to 65 mg / m 2 in the treatment of disseminated colorectal cancer and ovarian cancer; and up to 75 mg/m 2 in adjuvant therapy for colorectal cancer.

With paresthesia with functional impairment, which persists until the next cycle, oxaliplatin should be canceled; with a decrease in the severity of symptoms of neurotoxicity after discontinuation of oxaliplatin, consideration may be given to resuming treatment.

With the development of stomatitis and / or mucositis of 2 or more degrees of toxicity, treatment with oxaliplatin should be suspended until they stop or reduce the manifestations of toxicity to 1 degree.

Data on the use of the drug in patients with severe impairment of kidney function no. Due to limited data on the safety and tolerability of the drug in patients with moderate kidney dysfunction, before using oxaliplatin, the benefit-risk ratio for the patient should be weighed. Therapy in this category of patients can be started with the recommended dose, under close monitoring of renal function. At mild impairment of kidney function dose adjustment of oxaliplatin is not required.

Changes in dosing regimen patients with mild or moderate hepatic insufficiency not required. Data on the use of oxaliplatin in patients with severe hepatic impairment no.

The safety profile of oxaliplatin alone or in combination with 5-fluorouracil patients over the age of 65 similar to that seen in younger patients.

Rules for the preparation and administration of the solution

In the preparation and administration of Eloxatin, needles and other equipment containing aluminum should not be used.

Do not dissolve or dilute with 0.9% sodium chloride solution and do not mix with other saline (alkaline) solutions or solutions containing chlorides.

To prepare an infusion solution, Eloxatin concentrate is diluted in 250-500 ml of a 5% dextrose solution to obtain a concentration of at least 0.2 mg / ml. The solution for infusion is recommended to be used immediately after preparation. The infusion solution remains stable for 24 hours at 2° to 8°C.

Solution with signs of precipitation must be destroyed. Only clear solutions can be used.

Oxaliplatin solution should not be mixed in the same infusion system with other drugs, especially 5-fluorouracil and calcium folinate. The drug should not be administered undiluted.

Side effects of Eloxatin

• ELOXATIN Concentrate for solution for infusion

Determining the frequency of adverse reactions: very often (> 1/10), often (> 1/100,<1/10); иногда (>1/1000, <1/100); редко (>1/10 000, <1/1000); очень редко (< 1/10 000), включая отдельные сообщения.

From the hematopoietic system: very often - anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often - febrile neutropenia (including 3-4 degree), sepsis on the background of neutropenia; rarely - hemolytic anemia, immune thrombocytopenia, hemolytic uremic syndrome.

From the digestive system: very often - nausea, vomiting, diarrhea, stomatitis, mucositis, pain in the stomach, constipation, loss of appetite, increased levels of alkaline phosphatase, liver enzymes, bilirubin, LDH; often - dyspepsia, gastroesophageal reflux, hiccups, gastrointestinal bleeding; sometimes - intestinal obstruction; rarely - colitis, including cases of pseudomembranous colitis.

From the side of the central nervous system and peripheral nervous system: very often - peripheral sensory neuropathy, sensitivity disorders, headache, asthenia; often - dizziness, meningism, depression, insomnia; sometimes - increased nervousness; rarely - dysarthria. Neurotoxicity is a dose-limiting factor. Often the symptoms of sensory neuropathy are triggered by cold. The duration of these symptoms, which usually resolve between courses, increases with the total dose of oxaliplatin. Functional impairments in the form of difficulty performing precise movements are possible consequences of sensory damage. The risk of functional disorders at a total dose of about 850 mg/m 2 (10 cycles) is about 10%, reaching 20% ​​in the case of a total dose of 1020 mg/m 2 (12 cycles). After discontinuation of treatment, in most cases, the severity of neurological symptoms decreases or they are completely stopped. In 3% of patients, 3 years after the end of treatment, either persistent local paresthesias of moderate intensity (2.3%), or paresthesias affecting functional activity (0.5%) were observed.

During treatment with oxaliplatin, acute neurosensory manifestations were noted, which usually occurred within a few hours after administration of the drug and were most often provoked by exposure to cold. They were characterized by transient paresthesia, dysesthesia or hypesthesia, rarely (1-2%) - acute syndrome of laryngeal-pharyngeal dysesthesia. The latter was manifested by a subjective feeling of dysphagia and shortness of breath without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm, or bronchospasm (without stridor or wheezing). Jaw muscle spasm, tongue dysesthesia, dysarthria, and a feeling of pressure in the chest have also been observed. Usually, these symptoms quickly stopped both without the use of drug therapy, and with the introduction of antihistamines and bronchodilators. Increasing the duration of infusion during subsequent cycles of oxaliplatin therapy can reduce the incidence of this syndrome.

From the musculoskeletal system: very often - back pain; often - arthralgia, bone pain.

From the respiratory system: very often - cough, shortness of breath; often - rhinitis, infections of the upper respiratory tract; rarely - pulmonary fibrosis.

From the side of the cardiovascular system: often - chest pain, nosebleeds, deep vein thrombophlebitis, pulmonary embolism, arterial hypertension.

From the urinary system: often - hematuria, dysuria; very rarely - acute tubular necrosis, acute interstitial nephritis, acute renal failure.

Dermatological reactions: very often - alopecia, skin rashes; often - peeling of the skin of the palms and feet, erythematous rashes, excessive sweating, disorders of the nails.

From the organs of vision and hearing: often - conjunctivitis, visual impairment; rarely - a transient decrease in visual acuity, loss of visual fields, hearing loss, neuritis of the auditory nerve, deafness.

allergic reactions: rarely (when used as monotherapy) or often (in combination with 5-fluorouracil +/- calcium folinate), bronchospasm, angioedema, arterial hypotension, anaphylactic shock can be observed. Often there have been cases of allergic manifestations such as rash (especially urticaria), conjunctivitis or rhinitis.

Local reactions: with extravasation of the drug - pain and inflammatory reactions at the injection site.

From the side of laboratory indicators: very often - hypokalemia, violations of the content of sodium and glucose in the blood serum; often - an increase in the level of creatinine.

Others: very often - fever, increased fatigue, weight gain, taste disturbances.

Almost all drugs cause side effects. As a rule, this happens when taking drugs at maximum doses, when using the drug for a long time, when taking several drugs at once. Individual intolerance to a particular substance is also possible. This can lead to serious consequences, so if the drug causes you side effects, you should stop taking it and consult a doctor.

Overdose

• ELOXATIN Concentrate for solution for infusion

Symptoms: in case of overdose, the described side effects may increase.

Treatment: careful monitoring of the patient's condition (including hematological control); carry out symptomatic therapy. The antidote is unknown.

drug interaction

• ELOXATIN Concentrate for solution for infusion

Significant changes in the binding of oxaliplatin to plasma proteins in vitro with simultaneous use with erythromycin, salicylates, granisetron, paclitaxel, sodium valproate were not observed.

Pharmaceutical interaction

The drug is incompatible with 0.9% sodium chloride solution and other saline (alkaline) solutions or solutions containing chlorides.

When interacting with aluminum, the formation of a precipitate and a decrease in the activity of oxaliplatin are possible.

Very significant information, which is not always paid due attention when taking medications. If you are taking two or more drugs, they can either weaken or enhance the effect of each other. In the first case, you will not get the expected effect from the medicine, and in the second, you run the risk of overdose or even poisoning.

Oxaliplatin (cis-[oxalato (trans-1-1-1,2-diaminocyclohexano)-platinum]) is an anticancer drug belonging to a new class of platinum derivatives in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane (DACH ). Oxaliplatin is the enantiomer of cis-[oxalo(trans-1-1-1.2-DACH)platinum].
Oxaliplatin has a broad spectrum of both cytotoxicity in vitro, and antitumor activity in vivo in various tumor models, including human colorectal cancer models. He is also active in vitro and in vivo in various cisplatin-resistant models. In combination with fluorouracil (5-fluorouracil), a synergistic cytotoxic effect was observed. in vitro and in vivo.
The mechanism of action of oxaliplatin, even if it is not fully understood, supports the hypothesis that biotransformed aqueous oxaliplatin derivatives interact with DNA by forming inter- and intra-strand bridges and thus inhibit DNA synthesis, which leads to cytotoxicity and an antitumor effect.
The pharmacokinetics of individual active metabolites has not been established. The pharmacokinetics of ultrafilterable platinum, that is, all forms of non-conjugated active and inactive platinum in blood plasma after a two-hour infusion of the drug at a dose of 130 mg / m2 every 3 weeks for 1-5 courses, is as follows:

Note: Average values ​​of AUC0-48 and Cmax are calculated for the 5th cycle.
Mean values ​​of AUC0-∞, volume of distribution at steady state and clearance were calculated for the 1st cycle.
Elimination half-lives are calculated as averages for all cycles using compartmental analysis.
At the end of a two-hour infusion, 15% of the injected platinum is in the systemic circulation, and the remaining 85% is rapidly distributed to the tissues or excreted in the urine. Irreversible binding to erythrocytes and plasma proteins leads to half-lives of platinum in these matrices, close to the duration of the natural turnover of erythrocytes and serum albumin. Do not note the accumulation of the drug in the ultrafiltrate of blood plasma, both when using 85 mg / m2 every 2 weeks, and when using 130 mg / m2 every 3 weeks; the equilibrium state is reached in this matrix during the first course. Indicators in different patients and in the same patient differ slightly.
Biotransformation in vitro is the result of non-enzymatic degradation and no cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring is observed.
Oxaliplatin undergoes significant biotransformation in the body of patients and the unchanged drug is not detected in the plasma ultrafiltrate by the end of the two-hour infusion. In a later period, individual cytotoxic biotransformation products were detected in the systemic circulation, including monochloro-, dichloro-, and diaquo derivatives of DACH-platinum, along with some inactive conjugates.
Platinum is excreted primarily in the urine during the first 48 hours after administration. By day 5, about 54% of the total dose is recovered in the urine and less than 3% in the feces. A significant decrease in clearance (from 17.6 ± 2.18 l / h to 9.95 ± 1.91 l / h) is observed in renal failure, along with a statistically significant decrease in the volume of distribution (from 330 ± 40.9 to 241 ± 36, 1 l). The effect of severe renal impairment on platinum clearance has not been studied.
In preclinical studies, it was found that oxaliplatin is a mutagenic and clastogenic substance in mammalian test systems and exhibits embryotoxic effects in rats. Possibly oxaliplatin is carcinogenic, but studies on carcinogenesis have not been conducted.

Indications for use of the drug Eloxatin

In combination with 5-fluorouracil and folinic acid, it is recommended for:

• adjuvant therapy for stage III colorectal cancer (Dukes C) after complete removal of the primary tumor;
• treatment of metastatic colorectal cancer.

The use of the drug Eloxatin

Eloxatin is recommended for the treatment of adults only. The recommended dose of oxaliplatin for adjuvant therapy is 85 mg/m2 IV, the same dose is repeated every 2 weeks for 12 cycles (6 months).
The recommended dose of oxaliplatin in the treatment of metastatic colorectal cancer is 85 mg/m2 IV, repeated every 2 weeks.
The dose of Eloxatin should be adjusted according to individual patient tolerance (see).
Eloxatin should be given earlier than fluoropyrimidines.
Eloxatin is usually used as a 2-6-hour IV infusion in 250-500 ml of 5% glucose solution in such a dilution as to obtain a concentration of the drug above 0.2 mg / ml. Eloxatin is most commonly used in combination with 5-fluorouracil by continuous IV infusion. For treatment that is repeated every 2 weeks, a dosing regimen of 5-fluorouracil bolus and continuous infusion is recommended.
Patients at risk
Patients with impaired renal function
The use of Eloxatin in the treatment of patients with severe renal insufficiency has not been studied (see).
In patients with moderate renal insufficiency, treatment can be started with the usual recommended dose (see). There is no need for dose adjustment in patients with mild renal impairment.
Patients with impaired liver function
The use of Eloxatin in the treatment of patients with severe hepatic impairment has not been studied. There was no increase in acute toxicity of Eloxatin in subjects with abnormal baseline liver function tests. In clinical studies, no dose adjustments have been made in patients with abnormal liver function tests.
The elderly
There was no increase in the toxicity of Eloxatin when used as monotherapy or in combination with 5-fluorouracil in patients over the age of 65 years. Special dosage adjustment in the elderly is not required.
Mode of application
Eloxatin is administered as an IV infusion. The use of Eloxatin does not require prehydration. Eloxatin, diluted in 250-500 ml of 5% glucose solution to obtain a concentration above 0.2 mg / ml, is injected into a peripheral or central vein for 2-6 hours, always before the introduction of 5-fluorouracil. In case of extravasation, the administration of Eloxatin should be stopped immediately.
Special Instructions
Do not use injection materials containing aluminum. Do not use the drug undiluted. Do not mix with other solutions containing chlorides. Do not mix or use simultaneously with other drugs in the same infusion system (especially with 5-fluorouracil, alkaline solutions, trometamol and products that contain folinic acid and trometamol as an excipient). Eloxatin can be used simultaneously with folinic acid using a Y-shaped infusion set, with a fork just before the injection site. Drugs must not be mixed in the same vial. Folinic acid should be diluted with isotonic infusion solutions such as 5% glucose solution. Never dilute folinic acid with isotonic sodium chloride or alkaline solutions. After the introduction of Eloxatin, the system must be flushed. Use only recommended solvents (see below). Do not use the prepared solution with a precipitate; it must be destroyed in accordance with the requirements for the disposal of toxic waste (see below).
Dissolution of the drug
To dissolve the drug, use water for injection or 5% glucose solution.
For a 50 mg vial: 10 ml of diluent is added to the vial to obtain a solution of oxaliplatin at a concentration of 5 mg/ml.
For a 100 mg vial: 20 ml of diluent is added to the vial to obtain a solution of oxaliplatin at a concentration of 5 mg/ml.
For reasons of microbiological purity and chemical stability, freshly prepared solution must be immediately diluted in 5% glucose solution. Before using the solution, its visual control is carried out. Only transparent solution without particles can be used. Unused solution is subject to destruction.
Dilution before infusion
The required amount of the newly prepared solution is taken from the vial and diluted with 5% glucose solution to 250-500 ml to obtain a concentration of more than 0.2 mg / ml. Administered as an intravenous infusion. The physico-chemical stability of the solution for infusion is maintained for 24 hours at a temperature of 2-8 °C. From a microbiological point of view, the prepared solution should be used immediately. If the solution is not introduced immediately after preparation, the specialist using it is responsible for compliance with the storage conditions and time. The shelf life should not exceed 24 hours at a temperature of 2-8 ° C, if the dilution was carried out in compliance with the rules of asepsis, under controlled and standardized conditions. Unused solution must be destroyed.
Infusion
The use of Eloxatin does not require prehydration. Eloxatin, diluted in 250-500 ml of 5% glucose solution to obtain a concentration of more than 0.2 mg / ml, should be injected into a peripheral or central vein for 2-6 hours. If signs of extravasation of the solution appear, the drug should be administered stop immediately. When using Eloxatin in combination with 5-fluorouracil, the infusion of Eloxatin should precede the administration of 5-fluorouracil.
Disposal
Residues of the drug and all items used to dissolve, dilute and administer Eloxatin must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic waste, taking into account current regulations regarding the disposal of hazardous waste.

Contraindications to the use of the drug Eloxatin

Eloxatin is contraindicated in patients with a history of hypersensitivity to oxaliplatin, with myelosuppression before the start of the first course (initial level of neutrophilic granulocytes ≤2.109/l and/or platelets ≤100.109/l), peripheral sensory neuropathy accompanied by functional impairment before the start of the first course; in severe renal failure (creatinine clearance less than 30 ml / min); During pregnancy and breastfeeding.

Side effects of Eloxatin

Hematopoietic system
Eloxatin, which was administered as monotherapy at a dose of 85 mg/m2 every 2 weeks, caused the most cases of hemotoxicity. Anemia, neutropenia, thrombocytopenia have been observed; cases of hematological toxicity of the 3rd or 4th degree of severity were rarely noted.
When Eloxatin is combined with 5-fluorouracil and folinic acid, the incidence of neutropenia and thrombocytopenia is higher compared with the use of 5-fluorouracil and folinic acid alone.
Digestive system
When used as a monotherapy (85 mg / m2 every 2 weeks), oxaliplatin causes moderate nausea, vomiting, anorexia, diarrhea and abdominal pain, usually not severe.
Prophylactic or therapeutic use of antiemetics is recommended. With the combined use of Eloxatin with 5-fluorouracil (in combination with folinic acid or without it), the frequency and severity of diarrhea and mucositis are significantly increased compared with the use of 5-fluorouracil / folinic acid.
In isolated cases, colitis developed, including diarrhea caused by Clostridium difficile.
Severe diarrhea and/or vomiting can cause dehydration, hypokalemia, metabolic acidosis, and kidney damage, especially when Eloxatin is combined with 5-fluorouracil.
In the treatment with Eloxatin, an increase in the activity of liver enzymes of the 1st-2nd degree is often noted. In randomized trials comparing the combination of 5-fluorouracil and folinic acid with the combination of 5-fluorouracil, folinic acid and Eloxatin, the incidence of grade 3-4 elevations in liver enzymes was comparable in both groups.
Nervous system
The neurotoxicity of Eloxatin is dose-limiting and is mainly manifested by the development of peripheral sensory neuropathies, characterized by dysesthesia and / or paresthesia of the extremities, with or without convulsions, often caused by cold. These symptoms are noted in 85-95% of patients receiving treatment. The duration of these symptoms, which usually regress or disappear between courses of treatment, increases with the number of courses.
The appearance of pain and / or functional impairment is an indication for dose adjustment depending on the duration of symptoms or even drug withdrawal (depending on their duration).
Functional impairment (difficulty performing precise movements) is a possible consequence of sensory impairment. The risk of functional impairment for a cumulative dose of about 800 mg/m2 (i.e. 10 cycles) is 10-20% or less. Usually, neurological symptoms regress after stopping treatment.
In the course of treatment with Eloxatin, the development of acute neurosensory symptoms was noted, which usually occurred within a few hours after the administration of the drug, often under the influence of cold. These included transient paresthesia, dysesthesia, hypesthesia, or acute laryngo-pharyngeal dysesthesia syndrome. The frequency of the latter is 1-2%. This syndrome is characterized by subjective sensations of dysphagia and dyspnea without objective clinical signs of respiratory distress (cyanosis and hypoxia) or laryngeal spasm or bronchospasm (no stridor breathing). Spasm of masticatory muscles, dysesthesia of the tongue, dysarthria, and a feeling of pressure in the chest are also possible. Although antihistamines and bronchodilators were used in such cases, the symptoms quickly disappeared even without any intervention. Prolonging the infusion in subsequent courses of treatment helps to reduce the incidence of this syndrome.
Neurological symptoms such as dysarthria, loss of the deep tendon reflex, and Lhermitte's sign have been reported during treatment with Eloxatin. In isolated cases, optic neuritis developed.
allergic reactions
Bronchospasm, angioedema, hypotension and anaphylactic shock have rarely been observed with Eloxatin monotherapy and often with its use in combination with 5-fluorouracil and folinic acid.
Other
Clinically significant ototoxic effects were observed in less than 1% of patients treated with Eloxatin; cases of deafness are seldom described. Impaired renal function was noted in approximately 3% of patients, while the 3rd-4th degree of such disorders was observed in 1% of patients.
Very often cases of fever were observed - both isolated fever of the immunological type, and fever of infectious genesis (with or without neutropenia).
Isolated cases of immunoallergic hemolytic anemia and thrombocytopenia have been noted.
Rarely, acute interstitial pneumonia and pulmonary fibrosis have been reported.
Moderately severe alopecia was noted in 2% of patients treated with Eloxatin as monotherapy; the combination of Eloxatin with fluorouracil did not increase the incidence of alopecia observed with 5-fluorouracil alone.
Extravasation can cause local pain and inflammation, sometimes severe, and complications, especially when Eloxatin is infused through a peripheral vein.
A decrease in visual acuity after the use of Eloxatin was noted in less than 1% of patients.

Special instructions for the use of the drug Eloxatin

Eloxatin should only be used in specialized oncology departments under the supervision of a qualified oncologist experienced in chemotherapy.
Eloxatin is not a nephrotoxic agent, however, due to limited information regarding the safety and tolerability of the drug in patients with moderate renal impairment, the drug should be used only after carefully weighing the benefit / risk ratio for the patient. In this case, renal function should be regularly monitored, and doses of the drug, if necessary, adjusted.
Patients with a history of allergic reactions to other platinum compounds should be monitored for allergic manifestations. In the event of an anaphylactic-like reaction to Eloxatin, the drug infusion should be stopped immediately and appropriate symptomatic treatment prescribed. Repeated use of Eloxatin in such patients is contraindicated.
In case of extravasation of the drug, the infusion should be stopped immediately and local symptomatic treatment prescribed.
The manifestations of neurological toxicity of Eloxatin should be regularly monitored, especially if used in combination with drugs that have neurotoxicity. Before the start of each injection, and then periodically, a neurological examination should be performed.
Patients who develop acute laryngeal-pharyngeal paresthesia during the infusion or for several hours after it (see), the next administration of Eloxatin should be carried out after 6 hours.
Depending on the duration and severity of neurological symptoms (paresthesia, dysesthesia), recommendations for dose adjustment of Eloxatin are as follows: if symptoms persist for more than 7 days and are accompanied by pain, the next dose of Eloxatin should be reduced from 85 to 65 mg / m2; if paresthesia without functional impairment persists until the next cycle, the dose of Eloxatin should be reduced from 85 to 65 mg / m2; if paresthesia with functional impairment persists until the next cycle, Eloxatin should be discontinued; if these symptoms disappear after discontinuation of Eloxatin, consideration may be given to resuming treatment.
The gastrointestinal toxicity of Eloxatin, which is manifested by nausea and vomiting, requires the use of antiemetics for prophylactic and / or therapeutic purposes (see).
Severe diarrhea/vomiting can lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and impaired renal function, especially when Eloxatin is used in combination with 5-fluorouracil.
In case of development of hematological disorders (≤1.5.109/l and/or platelet count ≤50.109/l), do not prescribe the next course until laboratory parameters normalize. A blood test should be performed before starting treatment and before each subsequent course.
The patient should be informed about the possibility of developing diarrhea, vomiting, and neutropenia after the use of Eloxatin and 5-fluorouracil, so that he can immediately consult a doctor.
If Eloxatin is combined with 5-fluorouracil (with or without folinic acid), due to the toxicity of 5-fluorouracil, dose adjustment is usually recommended.
With diarrhea of ​​the 4th degree (according to the WHO classification), neutropenia of the 3rd-4th degree (the number of neutrophilic granulocytes ≤1 . 109/l) or thrombocytopenia 3-4th degree (platelet count ≤50 . 109/l), the dose of Eloxatin should be reduced from 85 to 65 mg/m2, in addition to the dose reduction of 5-fluorouracil.
If respiratory symptoms such as non-productive cough, dyspnea, wheezing, pulmonary infiltrates on x-ray occur, treatment with Eloxatin should be discontinued until interstitial pneumonitis is ruled out using additional examinations (see).
The handling and preparation of Eloxatin by medical personnel requires the necessary precautions to be taken when using potentially toxic substances. The preparation of injectable solutions for cytotoxic preparations should be carried out only by specially trained personnel familiar with the substance used, under conditions that guarantee its protection and protection of the environment. Preparation of solutions should be carried out in a room specially designated for this purpose. Smoking, drinking or eating is prohibited in this room. Personnel must use protective clothing, including a long-sleeved gown, face shield, cap, as well as goggles, sterile disposable gloves, work surface covers, waste containers and bags. The feces and vomit of patients should be handled with caution. Do not allow pregnant women to work with the drug. Contaminated waste is collected in suitably labeled rigid containers and disposed of by incineration. If Eloxatin concentrate, its solution or infusion solution comes into contact with the skin or mucous membrane, it should be washed off immediately and thoroughly with water.
There are currently no data on the safety of using Eloxatin during pregnancy. Based on experimental data, Eloxatin at the recommended therapeutic dose is likely to cause death or impaired development of the fetus, therefore, the use of Eloxatin during pregnancy is not recommended. The appointment of the drug is possible only after informing the patient in detail about the risk to the fetus and upon obtaining her consent. The penetration of the drug into breast milk has not been studied. During treatment with Eloxatin, breastfeeding is contraindicated.

Eloxatin drug interactions

Patients who received a single dose of 85 mg/m2 of Eloxatin immediately prior to the use of 5-fluorouracil showed no change in the pharmacological effects of 5-fluorouracil.
When Eloxatin binds to proteins in vitro no significant substitution was observed with the following drugs: erythromycin, salicylates, granisetron, paclitaxel, sodium valproate.

Eloxatin overdose, symptoms and treatment

There is no specific antidote. In case of an overdose, an increase in the severity of side effects can be expected. Hematological control should be carried out simultaneously with symptomatic treatment of other manifestations of intoxication.

Storage conditions of the drug Eloxatin

In original packaging at temperatures up to 30 °C. The dissolved drug in the original vial should be stored for no more than 24 hours at a temperature of 2-8 °C.

List of pharmacies where you can buy Eloxatin:

• St. Petersburg