Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a mass or powder of white or almost white color.
1 f.
oxaliplatin 100 mg
Excipients: lactose monohydrate.
Vials of colorless glass (1) - packs cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a mass or powder of white or almost white color.
1 f.
oxaliplatin 150 mg
Excipients: lactose monohydrate.
Vials of colorless glass (1) - packs cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a mass or powder of white or almost white color.
1 f.
oxaliplatin 50 mg
Excipients: lactose monohydrate.
Vials of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
Oxaliplatin is an antitumor drug related to a new class of platinum derivatives in which a platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane.Oxaliplatin shows a wide range of cytotoxic effects. It also exhibits in vitro and in vivo activity on various models of tumors resistant to cisplatin. In combination with 5-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 formation of inter- and interstitial bridges inhibit DNA synthesis, which leads to cytotoxicity and antitumor effect.
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 being injected in the blood, and the remaining 85% are rapidly distributed into tissues or excreted by the kidneys. Platinum binds to plasma albumin and is excreted in the urine for the first 48 hours.
By day 5, about 54% of the total dose is found in urine and less than 3% in feces. With renal insufficiency, there is a significant decrease in clearance of oxaliplatin from 17.6 l / h to 9.95 l / h. The effect of severe renal failure on the clearance of platinum has not been studied.
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 folinic acid;
- disseminated colorectal cancer (as monotherapy or combination therapy in combination with 5-fluorouracil and folinic acid).
DOSING MODE
Intravenously in the form of 2-6 h infusions. Hyperhydration with oxaliplatin is not required.
Applicable only in adults.
The drug should be used immediately after the preparation of the solution. When combined with 5-fluorouracil, oxaliplatinin infusion should precede the administration of 5-fluorouracil.
Adjuvant therapy for colorectal cancer: 85 mg / m 1 every 2 weeks for 12 cycles (6 months).
Disseminated colorectal cancer: 85 mg / m 2 once or twice a week as monotherapy or in combination with 5-fluorouracil.
Repeated administration of oxaliplatin is performed only with neutrophil counts over 1500 / ОјL and platelets more than 50,000 / ОјL.
Recommendations for dose adjustment and administration of oxaliplatin.
AT If hematological disorders (neutrophil count <1500 / ОјL and / or platelets <50000 / ОјL), the next course is delayed until the laboratory parameters are restored.
With the development of diarrhea 4 degrees of toxicity (according to the WHO scale), neutropenia 3-4 degrees (neutrophil count <1000 / Ојl), thrombocytopenia 3-4 degrees (platelet count <50000 / ОјL) dose of oxaliplatin in subsequent injections should be reduced from 85 mg / m 2 to 65 mg / m 2 in the treatment of disseminated colorectal cancer and up to 75 mg / m 2 with adjuvant therapy in addition to the usual dose reduction of 5-fluorouracil in the case of their combined use.
Patients who, during infusions or within a few hours after a 2-hour infusion develop acute laryngeal-pharyngeal paresthesia, the next infusion of oxaliplatin should be performed within 6 hours.
Recommendations for adjusting the dose of oxaliplatin in the development of neurotoxicity:
- with symptoms of neurotoxicity causing pain lasting 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 up to 75 mg / m 2 with adjuvant therapy.
- with paresthesia without functional impairment that persists until the next cycle, the subsequent dose of oxaliplatin should be reduced from 85 mg / m "to 65
mg / m with metastatic colorectal cancer and up to 75 mg / m with adjuvant therapy;
- with paresthesia with functional disorders that persists until the next cycle, oxaliplatin should be discontinued;
- with a decrease in the severity of neurotoxicity symptoms after the abolition of oxaliplatinum, one may consider resuming treatment. With the development of stomatitis and / or mucositis of the 2nd or more toxicity level, treatment with oxaliplatinum should be suspended until they stop or reduce toxicity to 1 degree.
Patients with renal insufficiency. Data on the use of oxaliplatin in patients with severe renal impairment are not present. Due to the limited data on safety and tolerability of the drug in patients with moderate renal impairment, the benefit / risk relationship for the patient 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 insufficient liver function. Dosage adjustment in patients with a mild or moderate form of liver failure is not required. Data on the use of oxaliplatin in patients with severe impairment of liver function are absent.
Elderly patients. The safety profile of oxaliplatin as a monotherapy or in combination with 5-fluorouracil in patients older than 65 years is similar to that observed in patients under 65 years of age.
Instructions for preparing the drug solution.
When preparing solutions and administering oxaliplatin, needles and other equipment containing aluminum can 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, 50 ml of 30 ml of solvent into a bottle of 50 mg) . The reconstituted drug is immediately diluted with 250-500 ml of a 5% dextrose solution. The concentration of the resulting solution of oxaliplatin should be from 0.2 to 0.7 mg / ml; with 0.7 mg / ml - the highest concentration used in clinical practice at a dose of 85 mg / m 2 .
To prepare the drug solution, only the recommended solvents should be used.
Do not apply the drug undiluted.
Saline solutions (sodium chloride solution) should 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, do not prescribe simultaneously in one infusion system with other drugs (especially with 5-fluorouracil, basic solutions, trometamol and folic acid preparations containing trometamol in its composition).
Oxaliplatin may be administered concomitantly with infusions of folic acid. In this case, the preparations should not be mixed in the same infusion container. Folinic acid for infusion should be diluted using 5% glucose solution, but in no case should use solutions containing sodium chloride, or alkaline solutions.
The prepared solution of the preparation should be transparent and should not contain undissolved particles. Otherwise, the drug solution can not be used. The solution of the drug is used immediately after preparation.
The drug is intended for single use only. Unused solution of the drug should be destroyed.
The drug should be injected into the central venous line or into the peripheral vein for 2-6 hours.
In the case of extravasation, the drug should be discontinued immediately.
The materials used to prepare the solution and its administration must be destroyed in accordance with the rules for the use of cytotoxic drugs.
SIDE EFFECT
The most common side effects observed with oxaliplatin, including in combination with 5-fluorouracil / folinic acid, were gastrointestinal reactions (diarrhea, nausea, vomiting, mucositis), hematologic reactions (neutropenia, thrombocytopenia), and neurologic reaction (acute and cumulative dose-dependent peripheral sensory neuropathy). In general, these side effects were more frequent and severe with the combination of oxaliplatin with 5-fluorouracil / folinic acid, compared with the use of only 5-fluorouracil and folinic acid.
The incidence of adverse reactions listed below is described in accordance with the following gradation: very often (> 1/10), often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000), including individual messages.
From the hemopoietic system: very often - anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often - febrile neutropenia (including grade 3-4), sepsis against neutropenia; rarely - hemolytic anemia, immune thrombocytopenia.
On the part of the digestive system: very often - nausea, vomiting, diarrhea, stomatitis, mucositis, pain in the stomach, constipation, loss of appetite; often - dyspepsia, gastro-esophageal reflux, hiccough; infrequently - intestinal obstruction; rarely - colitis, including cases of pseudomembranous colitis.
From the central and peripheral nervous system: very often - peripheral neurosensory neuropathy, sensitivity disorders, headache, asthenia; often - dizziness, meningism, depression, insomnia; infrequent - increased nervousness; rarely - dysarthria.
Neurotoxicity is a dose-limiting side effect. 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, which are expressed by the difficulty of performing precise movements, are possible consequences of sensory damage. The risk of functional disorders for 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, neurologic symptoms improve or completely disappear after discontinuation of treatment. However, in 3% of patients 3 years after the end of treatment, either stable localized paresthesias of moderate intensity (2.3%) or paresthesia, affecting functional activity (0.5%) were observed. On the background of treatment with oxaliplatin, there were acute neurosensory manifestations, which usually occurred within a few hours after the administration of the drug and were most often provoked by cold. They were characterized by transient paresthesia, dysesthesia or hypostasis, rarely (1-2%) with an acute syndrome of laryngeal dysaesthesia. 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, dysesthesia of the tongue, dysarthria and a feeling of pressure in the chest. Usually, these symptoms quickly stopped as without the use of drug therapy, and with the introduction of antihistamine and bronchodilators. Increasing the time of infusions in subsequent cycles of oxaliplatin therapy can reduce the incidence of this syndrome.
From the musculoskeletal system: very often - pain in the back; often - arthralgia, pain in the bones.
On the part of the respiratory system: very often - cough, shortness of breath; often - rhinitis, infections of the upper respiratory tract; rarely - pulmonary fibrosis.
From the cardiovascular system: often - chest pain, thrombophlebitis of deep veins, thromboembolism of pulmonary arteries.
From the urinary system: often - hematuria, dysuria .
From the skin and skin appendages: very often - alopecia, skin rashes; often - peeling of the skin of the palms and feet, erythematous rashes, excessive sweating, violations from the nails.
On the part of the organs of sight and hearing: often - conjunctivitis, visual impairment; rarely - transient reduction in visual acuity, loss of visual fields, decreased hearing, neuritis of the auditory nerve
Allergic reactions: rarely (with monotherapy) or often (in combination with 5-fluorouracil +/- calcium folinate), bronchospasm, angioedema, hypotension and anaphylactic shock may occur. Frequent cases of such allergic manifestations as a rash (especially hives) , conjunctivitis or rhinitis.
Local reactions: with extravasation of the drug - pain and inflammatory reactions at the site of administration.
On the part of laboratory indicators: very often - an increase in the level of alkaline phosphatase, the activity of "hepatic" enzymes, bilirubin, lactate dehydrogenase, hypokalemia, violation of sodium and glucose in the blood serum; often - increasing the level of creatinine.
Other: very often - increased body temperature, increased fatigue, weight gain, impaired taste.
CONTRAINDICATIONS
- hypersensitivity to oxaliplatinum or other constituents of the drug;
- myelosuppression (neutrophil count less than 2000 / ОјL and / or platelets less than 100,000 / ОјL) before the start of the first course of treatment;
- peripheral sensory neuropathy with functional disorders before the start of the first course of treatment;
- severe renal dysfunction (creatinine clearance less than 30 ml / min);
- Pregnancy;
- the period of breastfeeding.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and during lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in severe violations of kidney function (creatinine clearance less than 30 ml / min).
Patients with renal insufficiency. Data on the use of oxaliplatin in patients with severe renal impairment are not present. Due to the limited data on safety and tolerability of the drug in patients with moderate renal impairment, the benefit / risk relationship for the patient should be weighed before using the drug. Therapy in this category of patients can be initiated 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
Patients with insufficient liver function. Dosage adjustment in patients with a mild or moderate form of liver failure is not required. Data on the use of oxaliplatin in patients with severe impairment of liver function are absent.
APPLICATION FOR CHILDREN
The drug is used only in adults.
APPLICATION IN ELDERLY PATIENTS
The safety profile of oxaliplatin as a monotherapy or in combination with 5-fluorouracil in patients older than 65 years is similar to that observed in patients under 65 years of age.
SPECIAL INSTRUCTIONS
Treatment with oxaliplatinum medaka should be carried out under the supervision of a doctor who has experience in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects during oxaliplatin therapy is mandatory.
Regularly (once a week), as well as before each injection of Oxaliplatinum medak should monitor the elements of peripheral blood and indicators of kidney and liver function.
Before the beginning of each cycle of therapy with Oxaliplatinum medak, a neurologic examination should be performed to determine signs of neurotoxicity.
Patients should be informed about the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the course of treatment. Localized mild paresthesias with functional disorders can last up to 3 years after the end of treatment according to the adjuvant treatment regimen.
If symptoms such as dry cough, dyspnoea, wheezing or the detection of pulmonary infiltrates are found in an X-ray study, treatment with Oxliplatin medication should be suspended until the presence of interstitial pneumonitis is excluded.
Symptoms such as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and kidney failure may be due to severe diarrhea or vomiting, especially when Oxaliplatin medak is used in combination with 5-fluorouracil.
Patients with allergic reactions to other platinum compounds in the anamnesis should be monitored for allergic symptoms. In the case of a reaction to oxaliplatin, anaphylactic, infusion should be immediately discontinued and appropriate symptomatic treatment should be prescribed. Further use of the drug Oxaliplatinum medak in the case of development of allergic reactions is contraindicated. If there is a violation of the liver function or portal hypertension, not caused by metastases to the liver, the issue of the possible presence of hepato-vascular disorders caused by the drug, which are very rare, should be considered.
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 treatment with oxaliplatin should use reliable methods of contraception. When using the drug Oxaliplatin Medak must comply with all the usual regulations adopted for the application of cytotoxic drugs. After contact with the drug solution or lyophilizate Oxaliplatin Medac to the skin or mucous membranes, they should be rinsed immediately and thoroughly with water.
Impact on the ability to drive vehicles and manage mechanisms
It has not been studied. However, the use of oxaliplatin increases the risk of dizziness, nausea, vomiting, and other neurological manifestations of symptoms affecting the reaction speed value and thus reduce the ability to drive and use the mechanisms.
OVERDOSE
Symptoms amplification described side effects. The antidote is not known.
Treatment: hematology control and symptomatic therapy.
DRUG INTERACTION
Pharmaceutically compatible with alkaline solutions and solutions containing chlorine.
In cases of administration to patients a single dose of 85 mg / m 2 oxaliplatin immediately before administration of 5-FU were observed changes in the level of 5-fluorouracil.
There was no noticeable change in oxaliplatin binding to plasma proteins in in vitro experiments erythromycin joint, salicylates, granisetron, paclitaxel and sodium valproate.
Incompatibilities
- not used together with alkaline agents or solutions (eg, 5-fluorouracil, alkaline solutions, trometamol and folinic acid preparations containing trometamol as auxiliary substances);
- do not use for drug dissolution or dilution of the drug solution (for preparation of infusion solution) salt solutions, not mixed with other drugs in a single container or in the infusion system;
- did not use the equipment for administration comprising aluminum (possibly fouling and reduced activity of oxaliplatin).
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Keep out of reach of children and in the dark place at a temperature not higher than 25 В° C.
Shelf life - 2.5 years.
Do not use after the expiration date printed on the package.
