Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent, colorless liquid.
1 ml
oxaliplatinum 2 mg
Excipients: hydrochloric acid - qs to adjust the pH value, water q / and - qs to 1 ml.
25 ml - bottles of dark glass (1) - packs of cardboard.
50 ml - bottles of dark glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
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 that are 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
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 85 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 by the kidneys during the first 48 hours. By day 5, about 54% of the entire dose is found in urine and less than 3% in feces.
With renal insufficiency, there is a significant decrease in clearance of oxaliplatin from 17.55 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 of colorectal cancer of the III stage after radical resection of the primary tumor in combination with fluorouracil and calcium folinate;
- disseminated colorectal cancer (as monotherapy or combination therapy in combination with fluorouracil and calcium folinate);
- Ovarian cancer (as a second line of therapy).
DOSING MODE
The drug Oxitane is prescribed only to adults in the form of intravenous infusion for 2-6 hours.
Hyperhydration with the use of the drug Oxitane is not required. If the drug Oxitane is used in combination with fluorouracil, the infusion of the drug Oxitane should precede the administration of fluorouracil.
Adjuvant therapy for colorectal 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 the drug Oxitane is produced only when the number of neutrophils is more than 1.5 Г— 10 9 / L and platelets are more than 50 Г— 10 9 / L.
Recommendations for dose adjustment and administration of oxaliplatin
When hematological 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 4 degrees of toxicity (according to the WHO scale), neutropenia 3-4 degrees (the number of neutrophils <1 Г— 10 9 / l), thrombocytopenia 3-4 degrees (platelet count 50 Г— 10 9 / l) dose of the drug Oxitane in subsequent administrations should be reduced from 85 mg / m 2 to 65 mg / m 2in the treatment of disseminated colorectal cancer and ovarian cancer and up to 75 mg / m 2 with adjuvant therapy for 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 the drug Oxitane should be performed for 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 the drug Oxitane should be reduced by 25%.
In case of paresthesia with functional impairment, which persists until the next cycle, the preparation Oxitane must be canceled; with a decrease in the severity of neurotoxicity symptoms after the withdrawal of the drug Oxitane, the resumption of treatment can be considered.
With the development of stomatitis and / or mucositis of 2 or more toxicity levels, treatment with the drug Oxitane should be suspended until they stop or reduce toxicity to 1 degree.
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.
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.
No dosage adjustment is necessary for the administration of oxaliplatin to elderly patients over the age of 65 (including when used in combination with fluorouracil).
Rules for the preparation of a solution for infusion
When preparing and administering the Oxitane preparation, you should not use needles or other equipment containing aluminum.
Do not use 0.9% sodium chloride solution, other saline solutions and solutions containing chlorides for dilution of the preparation.
It should not be mixed in one container and should not be administered simultaneously in one infusion system with other drugs (especially fluorouracil, trometamol and folinate calcium preparations containing trometamol in its composition), with alkaline solutions or solutions containing chlorides.
The drug Oxitane can be administered 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.To prepare a solution for infusions, the drug Oxitane should be diluted in 250-500 ml of a 5% solution of dextrose. The concentration of the resulting solution of oxaliplatin should be at least 0.2 mg / ml (0.2 to 0.7 mg / ml, 0.7 mg / ml - the highest concentration used in clinical practice at a dose of 85 mg / m 2 ).
Shelf life of the infusion solution is 6 hours when stored at 25 В° C or up to 24 hours when stored in a refrigerator (at a temperature of 2 В° to 8 В° C).
A solution with signs of precipitation is subject to destruction. Use only a clear solution.
The drug should not be administered undiluted.
In the case of extravasation, the drug should be discontinued immediately.
SIDE EFFECT
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 (> 1/10 000,? 1/1000); very rarely (? 1/10 000), 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, hemolytic uremic syndrome.
From the digestive system: very often - nausea, vomiting, diarrhea, stomatitis, mucositis, abdominal pain, constipation, loss of appetite; increased activity of AP, activity of hepatic enzymes, bilirubin content, LDH activity; often - dyspepsia, gastroesophageal reflux, hiccough, gastrointestinal bleeding; infrequently - intestinal obstruction; rarely - colitis, including cases of pseudomembranous colitis.
From the side of the nervous system: very often - peripheral sensory neuropathy, sensitivity disorders, headache, asthenia; often - dizziness, meningism, depression, insomnia; infrequent - increased nervousness; rarely - dysarthria. 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 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 are weakened or completely stopped. 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, 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 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.
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, arterial hypertension.
From the urinary system: often - hematuria, dysuria; very rarely - acute 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 senses: often - conjunctivitis, visual impairment; rarely - transient reduction in visual acuity, loss of vision, hearing loss, neuritis of the auditory nerve, deafness.
Allergic reactions: rarely (with monotherapy) or often (in combination with fluorouracil В± calcium folinate), bronchospasm, angioedema, arterial hypotension and anaphylactic shock can occur. 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.
Laboratory indicators: very often - hypokalemia, hyponatremia, hyperglycemia; often - increasing the concentration of creatinine.
Other: very often - increased body temperature, increased fatigue, weight gain, taste disorders.
CONTRAINDICATIONS
- Myelosuppression before the first course of therapy with a neutrophil count of less than 2 Г— 10 9 / L and / or platelets of less than 100 Г— 10 9 / L;
- 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;
- the period of lactation (breastfeeding);
- childhood;
- Hypersensitivity to oxaliplatinum or other components of the drug.
With caution should appoint a drug for violations of kidney function (with QC more than 30 ml / min), severe violations of the liver.
PREGNANCY AND LACTATION
Contraindicated use of the drug Oxitane during pregnancy and during breastfeeding.
Women and men during treatment with the drug Oxitane and within 6 months after the end of therapy with the drug Oxitane should use reliable methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in marked violation of kidney function (creatinine clearance less than 30 ml / min). With caution: for violations of kidney function (with the clearance of creatinine more than 30 ml / min). Regularly (once a week), as well as before each administration of the drug should be monitored indicators of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: with severe violations of the liver.
The change in the dosage regimen 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.
Regularly (once a week), as well as before each administration of the drug should be monitored indicators of liver function.
APPLICATION FOR CHILDREN
Contraindicated in childhood.
APPLICATION IN ELDERLY PATIENTS
There is no need for correction of the dosing regimen in the appointment of oxaliplatin to patients over 65 years of age (including when used in combination with fluorouracil).
SPECIAL INSTRUCTIONS
The drug Oxitane 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 Oxitane, 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 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 pulmonary infiltrates are detected during X-ray examination), treatment with Oxitane should be stopped until the presence of interstitial pneumonitis is excluded.
Symptoms such as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be due to severe diarrhea or vomiting, especially with the use of the drug Oxitane in combination with 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 the preparation of Oxytane, similar to anaphylactic, infusion should be immediately interrupted and appropriate symptomatic treatment should be prescribed. Further use of the drug Oxitane in the case of development of allergic reactions is contraindicated.
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.
If the product gets into the eyes, they must be washed immediately with a large amount of water or a solution of sodium chloride. In case of contact with the skin and mucous membranes, immediately contact the preparation with plenty of water. If the product is inhaled or if it gets into the mouth, immediately consult a doctor.
OVERDOSE
Symptoms: myelosuppression, neurotoxicity, diarrhea, nausea, vomiting. Antidote to oxaliplatinum is not known.
Treatment: hematological control and symptomatic therapy.
DRUG INTERACTION
Significant changes in the binding of oxaliplatin to plasma proteins with simultaneous use with erythromycin, salicylates, granisetron, paclitaxel and valproic acid have not been observed.
When interacting with aluminum, it is possible to form a precipitate and reduce the activity of oxaliplatin.
The drug is not pharmaceutically compatible with 0.9% sodium chloride solution and other solutions containing chlorides, 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 in a place protected from light, inaccessible to children, at a temperature of no higher than 25 В° C. Do not freeze. Shelf life - 2 years.
