Composition, form of production and packaging
Liofilizate for the preparation of a solution for infusions in the form of a compact mass or powder from white to almost white.
1 f.
oxaliplatin 50 mg
Excipients: lactose monohydrate - 450 mg.
Vials of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Oxaliplatin is 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 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
Distribution, metabolism, excretion
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 entire dose is found in the urine and less than 3% in the stool.
Pharmacokinetics in special clinical cases
With renal insufficiency, there is a significant decrease in clearance of oxaliplatin from 17.55 В± 2.18 l / h to 9.95 В± 1.91 l / h. The effect of severe renal failure on the clearance of platinum has not been studied.
INDICATIONS
- adjuvant therapy for colon cancer of stage III (Duke) after radical resection of the primary tumor, in combination with fluorouracil / calcium folinate;
- disseminated colorectal cancer (as monotherapy or combination therapy in combination with fluorouracil / calcium folinate);
- Ovarian cancer as a therapy for the 2nd line.
DOSING MODE
Oxaliplatin is prescribed only to adults in the form of intravenous infusion for 2-6 hours. When oxaliplatin is used, hyperhydration is not required. When used in combination with fluorouracil oxaliplatin should be administered earlier than fluorouracil.
Adjuvant therapy for colon cancer is 85 mg / m 2 once every 2 weeks for 12 cycles (6 months).
Treatment of disseminated colorectal cancer is 85 mg / m 2 once or twice a week as monotherapy or in combination with 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 is performed only with a neutrophil count of more than 1.5 Г— 10 9 / L and platelets greater than 50 Г— 10 9 / L.
Recommendations for dose adjustment and administration of oxaliplatin
When hematologic disorders (the number of neutrophils <1.5 Г— 10 9 / l and / or platelets <50 Г— 10 9 / L), the next course is postponed until normal laboratory parameters are restored.
With the development of diarrhea IV degree of toxicity (according to the WHO scale), neutropenia III-IV degree (the number of neutrophils <1 Г— 10 9 / l), thrombocytopenia III-IV degree (the amount of platelets is 50 Г— 10 9 / l) dose of oxaliplatin in subsequent injections should be reduced from 85 mg / m 2 to 65 mg / m2 in the treatment of disseminated colorectal cancer and ovarian cancer; up to 75 mg / m 2 with adjuvant therapy of colorectal cancer in addition to the usual dose reduction of 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 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 should be reduced by 25%. In case of paresthesia with functional impairments that persists until the next cycle, oxaliplatin should be canceled: if the symptoms of neurotoxicity decrease after the withdrawal of oxaliplatinum, the resumption of treatment can be considered.
In the development of stomatitis and / or mucositis II and more toxicity, treatment with oxaliplatin should be suspended until they stop or reduce toxicity to grade I.
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 for oxaliplatin is not required.
Changes in the dosing regimen in patients with mild to moderate liver failure are not required. Data on the use of oxaliplatin in patients with severe impairment of liver function are absent.
It is not necessary to correct the dosage regimen when oxaliplatin is prescribed to patients over 65 years of age (including when used in combination with fluorouracil).
Rules for the preparation and administration of a solution
Do not use materials containing aluminum when preparing and injecting the solution.
To prepare the infusion solution, the resulting solution is diluted with 5% dextrose solution to a volume of 250-500 ml. 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 / ml 2 .
To dissolve the drug the following solvents are used: water for injection or 5% dextrose solution. 10 mg or 20 mg of the solvent is added to the vial to produce an oxaliplatin solution at a concentration of 2.5 mg / ml or 5.0 mg / ml. The solution can not be used undiluted.
The solution should not be mixed with 0.9% sodium chloride solution and other saline (alkaline) solutions.
The solution can not be mixed and administered simultaneously in one infusion system with other drugs (especially fluorouracil, trometamol and folinate calcium preparations containing trometamol in its composition), alkaline solutions or solutions containing chlorides.
Oxaliplatin may be administered concomitantly 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.
The prepared 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.
In the case of extravasation, the drug should be discontinued immediately.
SIDE EFFECT
Gradation of the incidence of adverse reactions: very often (> 1/10), often (> 1/100,? 1/10); infrequently (> 1/1000,? 1/100); rarely (> 1/10 000,? 1/1000); very rarely (? 1/10 000), including single 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.
From the digestive system: very often - nausea, vomiting, diarrhea, stomatitis / mucositis, pain in the stomach, constipation, loss of appetite; often - dyspepsia, gastroesophageal reflex, intestinal bleeding, hiccups, metabolic acidosis, pancreatitis; infrequently - paralytic ileus, intestinal obstruction; rarely - colitis, including cases of pseudomembranous colitis.
From the hepatobiliary system: very rarely - sinusoidal obstruction of the portal blood flow, liver pelitis, nodular regenerative hyperplasia of the hepatic tissue, perisinusoidal fibrosis; Clinical complications are manifested by portal hypertension and / or increased activity of hepatic transaminases.
From the central nervous system and the peripheral nervous system: very often - peripheral sensory neuropathy, sensitivity disorders, headache, asthenia; often - dizziness, meningism, depression, insomnia; infrequent - increased nervousness; rarely - dysarthria, convulsions.
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 hypoesthesia, 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 infusion time during 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.
From the respiratory system: very often - cough, shortness of breath; often - rhinitis, infections of the upper respiratory tract, pain in the chest area; rarely - interstitial pneumonia, pulmonary fibrosis.
From the cardiovascular system: often - chest pain, thrombophlebitis of deep veins, thromboembolism of pulmonary arteries.
From the urinary system: often - hematuria, dysuria, hemolytic-uremic syndrome, 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, violations from the nails.
From the senses: very often - a violation of taste; often - conjunctivitis, visual impairment; rarely - transient reduction in visual acuity, loss of visual fields, optic neuritis, decreased hearing, neuritis of the auditory nerve.
Allergic reactions: rarely (with monotherapy) or often (in combination with 5-fluorouracil and calcium folinate) - bronchospasm, angioedema, lowering of blood pressure, anaphylactic shock. Often there have been cases of allergic manifestations, such 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 - hypokalemia, hyponatremia, hyperglycemia, increased level of alkaline phosphatase, activity of hepatic enzymes, bilirubin, LDH; often - an increase in serum creatinine.
Other: very often - increased body temperature, increased fatigue, weight gain, nosebleeds.
CONTRAINDICATIONS
- neutropenia (<2 Г— 10 9 / l) and / or thrombocytopenia (<100 Г— 10 9 / l), detected before the start of the first course of therapy;
- peripheral sensory neuropathy with functional impairment, revealed before the start of the first course of therapy;
- pronounced impairment of kidney function (QC less than 30 ml / min);
- Pregnancy;
- the period of lactation (breastfeeding);
- age up to 18 years;
- hypersensitivity to oxaliplatin and other components of the drug, as well as to other platinum derivatives.
With caution should apply the drug for violations of kidney function, severe violations of liver function.
PREGNANCY AND LACTATION
Oxaliplatin is contraindicated in pregnancy and during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
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 for oxaliplatin is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Changes in the dosing regimen in patients with mild to moderate liver failure are not required. Data on the use of oxaliplatin in patients with severe impairment of liver function are absent.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years.
APPLICATION IN ELDERLY PATIENTS
It is not necessary to correct the dosage regimen when oxaliplatin is prescribed to patients over 65 years of age (including when used in combination with fluorouracil).
SPECIAL INSTRUCTIONS
Oxaliplatin should be used only in specialized departments of oncology and under the supervision of a qualified clinical oncologist.
Caution should be given to oxaliplatin in patients with allergic reactions to other platinum compounds in the anamnesis. In case of development of anaphylactic reactions, infusion of the drug should be immediately interrupted and appropriate symptomatic treatment should be prescribed. Repeated use of oxaliplatinum is contraindicated.
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 treatment and during treatment, a neurological examination of patients should be performed to identify signs of neurotoxicity, especially when oxaliplatin is used with other drugs that have a specific toxic effect on the nervous system. Patients should be informed about the possibility of preserving the symptoms of peripheral sensory neuropathy after the end of the course of treatment. Localized mild paresthesias with functional disorders can persist up to 3 years after the end of the drug for adjuvant therapy.
If respiratory symptoms (dry cough, dyspnoea, wheezing or detection of pulmonary infiltrates during X-ray examination) appear, treatment with oxaliplatin 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 is used in combination with fluorouracil.
In the case of extravasation, the infusion should be stopped immediately and local symptomatic treatment started. The remaining dose of the drug should be injected into another vein.
Women of childbearing age and men during treatment with oxaliplatin should use reliable methods of contraception.
When administering the drug, medical personnel should use protective clothing, including conventional surgical gloves, a mask and glasses. If oxaliplatin concentrate, its solution or infusion solution hits the skin, mucous membranes should be washed off immediately and thoroughly with water. If the product is inhaled or if it gets into the mouth, immediately consult a doctor.
For all the items that were used to dissolve, dilute and administer oxaliplatin, standard methods for the destruction of cytotoxic substances should be followed.
Impact on the ability to drive vehicles and manage mechanisms
Special studies on the effect of oxaliplatin on the rate of psychomotor reactions have not been conducted. But since oxaliplatin may cause nausea, vomiting, dizziness and other neurological symptoms that affect the general condition, from driving the car and working with other mechanisms for this period it is recommended to abstain.
OVERDOSE
Symptoms: In case of overdose, the described side effects may be increased (myelosuppression, neurotoxicity, diarrhea, nausea, vomiting).
Treatment: hematological control; conduct symptomatic therapy. The antidote is unknown.
DRUG INTERACTION
In vitro, there was no evidence of oxaliplatin binding to plasma proteins when used concomitantly with erythromycin, salicylates, granisetron, paclitaxel, valproic acid.
In the application of oxaliplatin in combination with fluorouracil marked synergistic cytotoxic effect in vitro and in vivo.
By reaction with aluminum may precipitate and decrease the activity of oxaliplatin.
Oxaliplatin pharmaceutically incompatible with 0.9% sodium chloride and other sodium solutions containing chlorine, as well as alkaline solutions.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, protected from light at a temperature of no higher than 25 В° C. Shelf life - 2 years.
The prepared solution for infusion can be stored for 24 to 48 hours at a temperature of from 2 В° to 8 В° C.
