Universal reference book for medicines
Product name: OXALIPLATIN-EBEVE (OXALIPLATIN-EBEWE)

Active substance: oxaliplatin

Type: Antitumor preparation

Manufacturer: EBEWE PHARMA (Austria)
Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions
(powder or compact mass) of white color.

1 f.

oxaliplatin 50 mg

Excipients: lactose monohydrate - 450 mg.

50 mg - bottles of colorless glass with a capacity of 32 ml (1) - packs of cardboard.

Lyophilizate for the preparation of a solution for infusions (powder or compact mass) of white color.

1 f.

oxaliplatin 100 mg

Excipients: lactose monohydrate - 900 mg.

100 mg - bottles of colorless glass with a capacity of 60 ml (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

An antitumor drug belonging to a new class of compounds based on platinum, in which the platinum atom forms a complex bond with 1,2-diaminocyclohexane (DACG) and an oxalate group.

Oxaliplatin has antitumor activity in various types of tumors, including colorectal cancer.
It is also effective in the treatment of tumors resistant to cisplatin. The effect manifests itself regardless of the phase of the cell cycle. When used with 5-fluorouracil synergism of cytotoxic effects is observed. The mechanism of the antitumor effect of oxaliplatin is based on the cytotoxic effect and has not been fully studied. Presumably, oxaliplatin forms inter- and intracerebral bonds with DNA, thereby inhibiting the phases of its replication and transcription.
PHARMACOKINETICS

In vivo, oxaliplatin undergoes active biotransformation and is not detected in the plasma by the end of 2 hours after administration at a dose of 130 mg / m 2 , with 15% of platinum introduced in the blood, and the remaining 85% quickly distributed in tissues or excreted by the kidneys.

Biotransformation in vitro is the result of nonenzymatic decay, and there is no evidence that oxaliplatin is metabolized by cytochrome P450.
Oxaliplatin is extensively metabolized, and the drug is not detected in the ultrafiltrate plasma after 2 hours of infusion. Some cytotoxic products of oxaliplatin disintegration, incl. monochloro-, dichloro- and quartro-diaminocyclohexane platinum are found in the blood plasma together with inactive conjugates at later periods of the study.
Platinum binds to plasma albumin and is excreted in the urine for the first 48 hours. By day 5, about 54% of the entire dose is found in urine and less than 3% in feces.

Pharmacokinetics in special clinical cases

Influence of renal dysfunction
on the distribution of oxaliplatin was studied in patients with varying degrees of renal function impairment. Oxaliplatin was administered at a dose of 85 mg / m 2 in the control group with normal renal function (KC more than 80 ml / min), in patients with insignificant (KK from 50 to 80 ml / min) and moderate renal dysfunction (KCOT 30 to 49 ml / min); and in a dose of 65 mg / m 2 in patients with severe renal insufficiency (CC less than 30 ml / min). It was found that excretion of oxaliplatin significantly correlates with QC. Renal clearance of platinum has been reduced in patients by 30%, 65% and 84% with mild, moderate and severe renal impairment, respectively, compared with patients with normal renal function.
INDICATIONS

- adjuvant therapy of colorectal cancer of the III stage (C according to Duke) after radical resection of the primary tumor in combination with 5-fluorouracil and calcium folinate;

- disseminated colorectal cancer (as monotherapy or combination therapy in combination with 5-fluorouracil / calcium folinate);

- Ovarian cancer (as a second line of therapy).

DOSING MODE

Oxaliplatin-Ebewe is prescribed only to adults in the form of intravenous infusion for 2-6 hours.

Hyperhydration with the use of the drug is not required.
If oxaliplatin is used in combination with 5-fluorouracil, oxaliplatin infusion should precede the administration of 5-fluorouracil.
Adjuvant therapy for colorectal cancer is 85 mg / m 2 once every 2 weeks for 12 cycles (6 months).

Treatment of metastatic colorectal cancer is 85 mg / m 2 once or twice a week as monotherapy or in combination with 5-fluorouracil.

Treatment of ovarian cancer - 85 mg / m 2 1 every 2 weeks as a monotherapy or in combination with other chemotherapeutic drugs.

Repeated administration of oxaliplatin-ebewe is performed only with neutrophil count> 1500 / μL and platelets> 50,000 / μl.

Recommendations for dose adjustment and administration of oxaliplatin

With hematological disorders (neutrophil count <1500 / μL and / or platelet count <50000 / μL), the next course is postponed until normal laboratory parameters are restored.

With the development of diarrhea 4 degrees of toxicity (according to the WHO scale), neutropenia 3-4 (neutrophil count <1000 / μl), thrombocytopenia 3-4 degrees (platelet count <50000 / μL), the dose of Oxaliplatin-Ebweve in subsequent administrations should be reduced from 85 mg / m 2 to 65 mg / m 2 for the treatment of disseminated colorectal cancer and ovarian cancer;
up to 75 mg / m 2 with adjuvant therapy for colorectal cancer in addition to the usual dose reduction of 5-fluorouracil in the case of their combined use.
Patients who, during infusion or within a few hours after a 2-hour infusion, develop acute laryngeal-pharyngeal dysesthesia, the next infusion of oxaliplatin-ebewe should be performed within 6 hours.

When pain (as a sign of neurotoxicity) lasts more than 7 days or when paresthesia without functional impairment persists until the next cycle, the subsequent dose of Oxaliplatin-Ebweve should be reduced from 85 mg / m 2 to 65 mg / m 2 (in the treatment of metastatic cancer ) or up to 75 mg / m 2 (with adjuvant therapy).
With paresthesia with functional impairment, which persists until the next cycle, the Oxaliplatin-Ebweave preparation should be withdrawn; with a decrease in the severity of the symptoms of neurotoxicity after the withdrawal of oxaliplatin, one may consider resuming treatment.
With the development of stomatitis and / or mucositis of the 2nd or more toxicity level, treatment with Oxaliplatin-Ebevé should be suspended until they stop or reduce toxicity to 1 degree.

Patients with impaired renal function

Do not use the drug in patients with severe renal dysfunction.
Due to the limited data on safety and tolerability of the drug in patients with moderate renal impairment, the patient's benefit / risk ratio should be weighed before using the drug. Therapy in this category of patients can be started with the recommended dose, under careful control of kidney function. With a mild degree of impaired renal function, dosage adjustment of oxaliplatin is not required.
Patients with impaired hepatic function

Changing the dosing regimen in patients with mild or moderate liver dysfunction is not required.
Data on the use of oxaliplatin in patients with severe impairment of liver function are absent.
Elderly patients

It is not necessary to correct the dosage regimen when oxaliplatin is used in patients over the age of 65 (including when used in combination with 5-fluorouracil).

Rules for the preparation and administration of a solution

When preparing and administering oxaliplatin, needles and other equipment containing aluminum should not be used.

The preparation is dissolved in water for injection or in a 5% solution of dextrose before use to obtain a solution with a concentration of 5 mg / ml of oxaliplatin (10 ml of solvent, 100 ml of 20 ml of solvent are added to the 50 mg bottle).
The reconstituted drug is immediately diluted with 250-500 ml of a 5% dextrose solution. The concentration of the resulting oxaliplatin solution should be from 200 μg / ml to 700 μg / ml; with 700 μg / ml - the highest concentration used in clinical practice at a dose of 85 mg / m 2 .
For the preparation of the drug solution, only the recommended solvents should be used.

Do not apply the drug undiluted.

0.9% solution of sodium chloride and other saline solutions can not be used to dissolve the drug or dilute the drug solution (for the preparation of the infusion solution).

Do not mix in the same container and prescribe simultaneously in one infusion system with other drugs (especially with 5-fluorouracil, alkaline solutions, trometamol and calcium folinate preparations containing trometamol in its composition).

Oxaliplatinum can be prescribed together with calcium folinate infusions.
In this case, the preparations should not be mixed in the same infusion container. Calcium folinate for infusion should be diluted with a 5% solution of dextrose, but in no case should use solutions containing sodium chloride, or alkaline solutions.
A solution of the drug for infusions is recommended to be applied immediately after preparation.
The reconstituted infusion solution remains stable for 24 hours at room temperature (not above 25 ° C).
The prepared solution of the preparation should be transparent and should not contain undissolved particles.
A solution with signs of precipitation is subject to destruction.
In the case of extravasation, the drug should be discontinued immediately.

SIDE EFFECT

According to WHO, unwanted reactions are classified according to their frequency of development as follows: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10000, <1/1000) and very rarely (<1/10000);
frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.
From the hemopoietic system: very often - anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia;
often - febrile neutropenia (including grade 3-4), sepsis against neutropenia; rarely - granulocytopenia, hemolytic anemia, immune thrombocytopenia.
From the side of the nervous system: very often - peripheral sensory neuropathy, sensitivity disorders, headache, asthenia, taste disorder;
often - dizziness, meningism, depression, insomnia; infrequent - increased nervousness; rarely - dysarthria, a syndrome of posterior reversible leukoencephalopathy.
Neurotoxicity is a dose-limiting factor.
Often the symptoms of sensory neuropathy are provoked by cold. The duration of these symptoms, which are usually docked in the interval between courses, increases depending on the total dose of oxaliplatin. Functional disorders in the form of difficulty in performing accurate 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). In most cases, the severity of neurologic symptoms decreases or they completely stop. In 3% of patients 3 years after the end of treatment, either stable local paresthesias of moderate intensity (2.3%) or paresthesia affecting functional activity (0.5%) were observed.
On the background of treatment with oxaliplatin, acute neurosensory manifestations were noted, which usually occurred within a few hours after the administration of the drug and were most often provoked by exposure to cold.
They were characterized by transient paresthesia, dysesthesia or hypoesthesia, rarely (1-2%) - an acute syndrome of laryngeal pharyngeal dysesthesia. The latter manifested itself as a subjective feeling of dysphagia and dyspnea without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or spasm of the larynx, or bronchospasm (without stridor or wheezing). Also observed were such phenomena as spasm of the jaw muscles, dysesthesia of the tongue, dysarthria and a feeling of pressure in the chest. Usually, these symptoms were quickly stopped both without the use of drug therapy, and with the administration of antihistamines and bronchodilators. Increasing the duration of infusion during subsequent cycles of oxaliplatin therapy can reduce the incidence of this syndrome.
From the senses: often - conjunctivitis, visual impairment;
infrequently - ototoxicity; rarely - transient reduction in visual acuity, loss of visual fields, decreased hearing, neuritis of the auditory nerve, optic neuritis, deafness.
From the respiratory system: very often - cough, shortness of breath;
often - rhinitis, infections of the upper respiratory tract, pain in the chest area; rarely - pulmonary fibrosis, intestinal lung diseases, sometimes with the development of lethal outcome.
On the part of the digestive system: very often - nausea, vomiting, diarrhea, stomatitis, mucositis, abdominal pain, constipation, loss of appetite, increased level of alkaline phosphatase, activity of liver enzymes, bilirubin, LDH;
often - dyspepsia, hiccups, gastro-esophageal reflux, bleeding from the gastrointestinal tract (including from the rectum); infrequent - intestinal obstruction, paralytic ileus; rarely - colitis, including cases of pseudomembranous colitis, pancreatitis; very rarely - obliterating endophlebitis of hepatic veins, incl. hepatic purpura, nodal regenerative hyperplasia, perisinusoidal fibrosis, which can clinically manifest itself as signs of portal hypertension and / or an increase in the activity of "hepatic" transaminases.
From the side of the urinary system: often - hematuria, dysuria, changes in frequency of urination, increase in the concentration of creatinine in the blood plasma;
very rarely - hemolytic-uremic syndrome, acute tubular (tubular) necrosis, acute interstitial nephritis, acute renal failure.
From the skin and subcutaneous tissues: very often - alopecia, skin rashes;
often - peeling of the skin of the palms and feet, erythematous rashes, excessive sweating, changes from the nails.
From the musculoskeletal system: very often - pain in the back;
often - arthralgia, pain in the bones.
From the metabolism: very often - anorexia, hyperglycemia, hypokalemia, hyponatremia;
often - dehydration; infrequently - metabolic acidosis.
From the cardiovascular system: often - chest pain, deep vein thrombophlebitis, pulmonary embolism, bleeding, increased blood pressure, "tides" of blood to the face.

Allergic reactions: rarely (when used as monotherapy) or often (in combination with 5-fluorouracil +/- calcium folinate), bronchospasm, angioedema, hypotension and anaphylactic shock can occur.
Often there have been cases of allergic manifestations, such as a skin rash (especially urticaria), conjunctivitis or rhinitis.
Local reactions: with extravasation of the drug - pain and inflammatory reactions at the site of administration.

Other: very often - increased body temperature, increased fatigue, weight gain, asthenia.

CONTRAINDICATIONS

- myelosuppression before the first course of therapy with a neutrophil count less than 2000 / μL and / or platelets less than 100,000 / μL;

- peripheral sensory neuropathy with functional disorders before the start of the first course of therapy;

- pronounced impairment of kidney function (QC less than 30 ml / min);

- Pregnancy;

- lactation period (breastfeeding);

- childhood;

- hypersensitivity to oxaliplatinum, other derivatives of platinum or other components of the drug.

Caution should be given to the drug for violations of kidney function, rare hereditary forms of lactose intolerance, lactase deficiency or impaired absorption of glucose / galactose (because the composition contains lactose).

PREGNANCY AND LACTATION

Do not use Oxaliplatin-Ebove during pregnancy.

Controlled studies of doxorubicin in pregnant women have not been conducted.
Studies in animals have shown embryotoxic, teratogenic and mutagenic effects of oxaliplatin. Therefore, oxaliplatin should not be given to pregnant women.
It is not known whether oxaliplatin penetrates into breast milk, therefore, in order to avoid the potential toxic effect of the drug on the baby, breastfeeding should be stopped during the treatment period.

APPLICATION FOR FUNCTIONS OF THE LIVER

Do not use the drug in patients with severe renal dysfunction.
Due to the limited data on safety and tolerability of the drug in patients with moderate renal impairment, the patient's benefit / risk ratio should be weighed before using the drug. Therapy in this category of patients can be started with the recommended dose, under careful control of kidney function. With a mild degree of impaired renal function, dosage adjustment of oxaliplatin is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Changes in the dosing regimen in patients with mild to moderate liver function impairment are not required.
Data on the use of oxaliplatin in patients with severe impairment of liver function


APPLICATION FOR CHILDREN

Contraindicated in childhood.

APPLICATION IN ELDERLY PATIENTS

It is not necessary to correct the dosage regimen when oxaliplatin is prescribed to patients over the age of 65 (including when used in combination with 5-fluorouracil).

SPECIAL INSTRUCTIONS

Oxaliplatin-Ebeva should be used only under the supervision of an oncologist who has experience with antitumor drugs.

Regularly (once a week), as well as before each injection of the drug, it is necessary to monitor the peripheral blood elements and the renal and hepatic function.

Before the beginning of each cycle of therapy with the drug Oksaliplatin-Ebeva, a neurologic examination should be performed to determine signs of neurotoxicity.Patients should be informed about the possibility of preserving the symptoms of peripheral sensory neuropathy after the end of the course of treatment.
Localized moderate paraesthesia with functional impairment may persist for up to 3 years after the end of the drug according to the scheme of adjuvant therapy.
Syndrome reversing back leukoencephalopathy (SZOL) was reported in patients receiving oxaliplatin in combination with other chemotherapy drugs. SZOL is a rare, reversible, rapidly evolving neurological complications. The main clinical manifestations SZOL are headache, dizziness, nausea, vomiting, seizures, behavioral disorders, disorders of consciousness (from somnolence to coma) and visual disturbances in the form of hemianopsia, scotoma, cortical blindness. Since SZOL is a potentially life-threatening neurological syndrome in the absence of timely treatment may be complicated by the development of a massive cerebral infarction, it is particularly important early diagnosis, determining the correct treatment of patients.Diagnosis SZOL based on brain imaging by means of a computer or magnetic resonance tomography.
When the respiratory symptoms (dry cough, dyspnea, wheezing or detection of pulmonary infiltrates X-ray examination), the treatment of oxaliplatin-Ebewe should be suspended to preclude the presence of interstitial pneumonitis.
For the prevention and treatment of symptoms from the gastrointestinal tract such as nausea and vomiting, shows the use of antiemetics. Symptoms such as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be due to severe diarrhea or vomiting, especially when using the drug-Ebewe Oxaliplatin in combination with 5-fluorouracil.
Patients must be adequately informed of the risk of diarrhea / vomiting, mucositis / stomatitis and neutropenia when using oxaliplatin and 5-fluorouracil, and the need to refer to the attending physician in the event of adverse effects to said treatment of the corresponding correction.
In identifying the human liver and portal hypertension occurs, which is not related to the presence of metastases in the liver in very rare cases may cause drug-induced disorders of the vascular bed of the liver, namely the development obliterans endoflebita hepatic veins.
Patients with allergic reactions to other platinum compounds in history should be monitored for the presence of allergic symptoms. In the case of drug reaction Oxaliplatin-Ebewe similar anaphylactic, infusion should immediately be interrupted and assign appropriate symptomatic treatment. Further application of oxaliplatin-Ebewe in the case of allergic reactions is contraindicated.
In the event of extravasation, the infusion should be discontinued immediately and symptomatic treatment is to start local. The remaining dose should be introduced into another vein.
Women and men during treatment and for 6 months after the end of therapy with oxaliplatin-Ebewe should use reliable methods of contraception. Because oxaliplatin has a genotoxic effect that may be irreversible, men who want to have children, it is recommended to consider the preservation of sperm prior to treatment.
When using the drug Oxaliplatin-Ebewe must comply with all the usual regulations adopted for the application of cytotoxic drugs. If the product enters the skin - immediately produce copious water washing the skin with soap or sodium hydrogen carbonate; After eye - to pull eyelids and producing lavage eye (s) with water for 15 minutes.
Remains of the drug and all the tools and materials that were used for solution for / in infusion Oxaliplatin-Ebewe, must be disposed of in accordance with standard procedure, hospital waste disposal cytotoxic substances, with the existing regulations destruction of hazardous waste.
Effects on ability to drive a car and operate machinery
is not carried out studies of the effect of the drug Oxaliplatin Ebewe-on ability to drive and use machines.
Of side effects such as dizziness, nausea, vomiting, transient loss of vision, other neurological symptoms that may, to varying degrees affect the ability to engage in potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE

Symptoms: myelosuppression, neurotoxicity, diarrhea, nausea, vomiting.
Treatment: hematology control and symptomatic therapy. The antidote to oxaliplatin is not known.
DRUG INTERACTION

Significant changes oxaliplatin binding to plasma proteins, while the use erythromycin, salicylates, granisetron, paclitaxel and valproic acid were reported.
By reaction with aluminum may precipitate and decrease the activity of oxaliplatin.
For a single I / oxaliplatin administered at a dose of 85 mg / m 2 , immediately before the administration of 5-fluorouracil, no change in serum concentrations of 5-fluorouracil was observed.
Pharmaceutical interaction
preparation pharmaceutically incompatible with alkali solutions and solutions containing chlorides.
Do not mix with alkaline solutions or drugs, especially drugs with fluorouracil and calcium folinate containing trometamol as auxiliary substances and other active substances in the form of salts of trometamol.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of the reach of children at a temperature of no higher than 25 ° C.
Shelf life - 3 years.
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