GESSEDIL - instructions for use, dose, side effects, contraindications

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, oxaliplatinum forms inter- and intracerebral bonds with DNA, thereby inhibiting the phases of its replication and transcription.

Pharmacokinetics:

In vivo oxaliplatinum is subject to active biotransformation and is not detected in the plasma by the end of the second hour after administration at a dose of 130 mg /m², with 15% of the platinum introduced in the blood, and the remaining 85% quickly distributed to the tissues or excreted by the kidneys.

Platinum binds to plasma albumin and is excreted in the urine for the first 48 hours. By the fifth day, 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 ± 2.18 l / h to 9.95 ± 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 stage III (C according to Duke) after radical resection of the primary tumor in combination with calcium fluorouracil folinate;

- disseminated colorectal cancer in the form of monotherapy or combination therapy in combination with fluorouracil / calcium folinate;

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

Contraindications:

- Hypersensitivity to the active substance and / or components of the drug;

- myelosuppression (neutrophil count <2000 / μL and / or platelets <100,000 / μL) before the start of the first course of therapy;

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

- severe renal dysfunction (creatinine clearance less than 30 ml / min);

- Pregnancy and lactation (breastfeeding);

- Children's age (due to lack of sufficient clinical data).

Carefully:With violations of kidney function, severe violations of the liver.

Pregnancy and lactation:Contraindicated apply oxaliplatinum during pregnancy and during lactation, as well as women of childbearing age who do not use effective methods of contraception.

Dosing and Administration:

The drug is prescribed only adults - intravenously, drip for 2-6 hours. The introduction of oxaliplatin does not require pre-hydration. If oxaliplatinum is used in combination with fluorouracil, oxaliplatin infusion should precede the administration of fluorouracil.

Adjuvant therapy for colorectal cancer - 85 mg /m²1 every 2 weeks for 12 cycles (6 months).

Treatment of disseminated colorectal cancer - 85 mg /m²1 every 2 weeks as a monotherapy or in combination with fluorouracil.

Treatment of ovarian cancer - 85 mg /m²1 every 2 weeks as a monotherapy or in combination with other chemotherapeutic drugs.

Repeated administration of oxaliplatin is performed only with neutrophil counts over 1500 / μL and platelets more than 50,000 / μL.

Recommendations for dose adjustment and administration of oxaliplatin

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

With the development of grade IV diarrhea, III-IV grade neutropenia (neutrophil count <1000 / μl), thrombocytopenia III-IV degree (platelet count <50000 / μL), the dose of oxaliplatin in subsequent injections should be reduced from 85 mg /m²up to 65 mg /m²when treating disseminated colorectal cancer and ovarian cancer; up to 75 mg /m²with adjuvant therapy of colorectal cancer in addition to the usual reduction in the dose of fluorouracil in the case of their combined use.

Patients who, during infusion or after several hours after 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%.

When paresthesia with functional impairment persists until the next cycle, oxaliplatinum must be canceled; with a decrease in the severity of neurotoxicity symptoms after the abolition of oxaliplatinum, the resumption of treatment may 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 oxaliplatinum y patients with severe renal impairment no.Due to the limited data on safety and tolerability of the drug in patients with a moderate degree of impaired renal function, before using the drug should weigh the benefit / risk ratio for the patient.

Therapy in this category of patients can be initiated with the recommended dose, under careful control of kidney function. When mild renal impairment correction of oxaliplatin dose is not required.

Changes in the dosing regimen patients with mild to moderate liver function disorder not required. Data on the use of oxaliplatinum y patients with severe hepatic impairment no.

There is no need to correct the dosage regimen for oxaliplatin administration elderly patients over the age of 65 (including when used in combination with 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.

For the preparation of infusion solution oxaliplatinum diluted with 250-500 ml of a 5% solution of dextrose. 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 /m².

To prepare the drug solution, only the recommended solvents should be used.

Do not apply the drug undiluted.

Do not use 0.9% sodium chloride solution, other saline solutions 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 fluorouracil, trometamol and calcium folinate preparations containing trometamol in its composition), alkaline solutions or solutions containing chlorides.

Oxaliplatin should always be administered prior to the administration of fluorouracil.

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 should not contain trometamol as an auxiliary substance and for the infusion it should be diluted with 5% dextrose solution, but in no case should you 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. In case the solution is not used immediately after preparation, the storage time and storage conditions of the solution prior to its use are determined at the discretion of the user and should not exceed 24 hours at a temperature of 2 ° C-8 ° C under controlled aseptic conditions.

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 effects:

The incidence of adverse reactions listed below was determined according to the following criteria: very often (> 1/10); often (> 1/100, ≤ 1/10); infrequently (> 1/1000, ≤1/100); rarely (> 1/10 000, ≤1/1000); rarely (≤1/10 000), including individual messages.

On the part of the hematopoiesis 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 digestive system: very often - nausea, vomiting, diarrhea, stomatitis / mucositis, abdominal pain, constipation, loss of appetite; often - dyspepsia, gastroesophageal reflux, 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 pelosis, nodular regenerative hyperplasia of the hepatic tissue, perisinusoidal fibrosis; Clinically complications are manifested by portal hypertension and / or increased activity of hepatic transaminases.

From the 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 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 /m² (10 cycles) is about 10%, reaching 20% in the case of a total dose of 1020 mg /m² (12 cycles). After cessation of treatment 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 in subsequent cycles of therapy with oxaliplatin can reduce the incidence of this syndrome.

From the musculoskeletal system: very often - back pain; 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 side of 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, changes 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, optic neuritis, decreased hearing, neuritis of the auditory nerve.

Allergic reactions: rarely (when used as monotherapy) or often (in combination with fluorouracil and calcium folinate), bronchospasm, angioedema, lowering of blood pressure, anaphylactic shock can be observed. Often there have been cases of allergic manifestations, such as a rash (especially hives), conjunctivitis or rhinitis.

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

From the laboratory indicators: very often - hypokalemia, hyponatremia, hyperglycemia, increased activity of alkaline phosphatase, activity of hepatic enzymes, bilirubin, lactate dehydrogenase; often - increasing the concentration of creatinine.

Other: very often - increased body temperature, increased fatigue, weight gain, taste disorders, nosebleeds.

Overdose:

Symptoms: myelosuppression, neurotoxicity, diarrhea, nausea, vomiting.

Treatment: hematological control and symptomatic therapy. Antidote to oxaliplatinum is unknown.

Interaction:

There was no significant change in the binding of oxaliplatin to plasma proteins when used concomitantly with erythromycin, salicylates, granisetron, paclitaxel, and valproic acid.

When interacting with aluminum, it is possible to form a precipitate and reduce the activity of oxaliplatin.

Oxaliplatin is not pharmaceutically compatible with 0.9% sodium chloride solution and other solutions containing chlorides, as well as alkaline solutions.

Do not mix with alkaline medicines or solutions, especially with fluorouracil and folinate calcium preparations containing trometamol as an auxiliary substance, and with other active substances in the form of salts of trometamol. Alkaline solutions and drugs adversely affect the stability of oxaliplatin.

Special instructions:

Oxaliplatin therapy can be performed only in specialized oncology units and under the supervision of an experienced oncologist.

In view of the limited information on the safety of the drug in patients with impaired renal function of moderate severity,The drug should be administered only after an adequate assessment of the benefit / risk ratio for a particular patient. In such situations it is necessary to carry out careful monitoring of kidney function and selection of the dose of the drug taking into account the possible toxic effects.

Patients with an allergic reaction to platinum components in a history should be monitored, taking into account the possible occurrence of symptoms of an allergic reaction in them.

In case of anaphylactoid reaction to oxaliplatinum the infusion of the drug should be stopped immediately and the appropriate symptomatic treatment started. The resumption of oxaliplatin in this case is contraindicated.

In the case of extravasation (the outlet of the solution beyond the vein into the extravascular space), the drug should be discontinued immediately, and standard local symptomatic treatment should be initiated.

When oxaliplatin is used, careful monitoring should be carried out with regard to toxic effects on the nervous system, especially when drugs with known neurotoxicity are used concomitantly.A neurologic examination should be performed before each injection and periodically after the cycle of therapy.

Patients who have acute laryngopharyngeal dysesthesia during or for several hours after a 2-hour infusion of the drug, the next infusion of oxaliplatin should be performed for more than 6 hours.

When neurologic symptoms (paresthesia, dysesthesia) appear, the choice of dose based on the duration and severity of these symptoms is recommended according to the following principles:

- if the symptoms last longer than seven days and are significantly expressed, the dose of oxaliplatinum with subsequent administration should be reduced from 85 to 65 mg /m²(with metastatic therapy) or up to 75 mg /m² (with adjuvant therapy);

- if paresthesia in the absence of functional disorders persists until the next cycle, the dose of oxaliplatin with subsequent administration should be reduced from 85 to 65 mg /m² (with metastatic therapy) or up to 75 mg /m² (with adjuvant therapy);

- if paresthesia, accompanied by functional disorders, is retained until the next cycle, oxaliplatinum should be discarded;

- If after the abolition of oxaliplatin there is an improvement in the condition and a decrease in symptoms, therapy can be resumed.

Patients should be aware of the possibility that after the end of therapy the symptoms of peripheral sensory neuropathy may persist. Localized paresthesias of moderate severity or paresthesia, accompanied by a change in functional activity, may persist for up to 3 years after discontinuation of treatment (in the case of adjuvant therapy).

The toxic effect of the drug on the gastrointestinal tract, which is accompanied by nausea and vomiting, requires preventive and / or therapeutic use, antiemetic drugs.

Severe diarrhea / vomiting, especially as a result of combined use of oxaliplatin and fluorouracil, can cause dehydration, functional (paralytic) and obstructive bowel obstruction, hypokalemia, metabolic acidosis and renal failure.

If there are signs of toxic effects on the hematological level (neutrophil count <1500 / μL or platelet count <50 / μL), the next course of therapy should be postponed until the hematologic parameters are restored to acceptable values.Before the start of therapy and after each subsequent course, it is necessary to obtain a detailed blood test with counting blood cells and a leukocyte formula.

Patients should be informed of the risk of developing diarrhea / vomiting, mucositis / stomatitis, and neutropenia after oxaliplatin plus fluorouracil and the need for immediate contact with their health care provider for observation and treatment. In the case of inflammation of the mucous membranes / stomatitis in combination with neutropenia or without neutropenia, the next cycle of therapy should be postponed until the signs of inflammation of the stomatitis mucous membranes are reduced to 1 degree or less and / or before the concentration of neutrophils is> 1500 / μl. In combined use of oxaliplatin with fluorouracil (in combination with calcium folinate or without) requires the selection of a usual dose of fluorouracil taking into account toxicity.

In the case of development of diarrhea 4 degrees, neutropenia 3-4 degrees (neutrophil count <1000 / μl), thrombocytopenia 3-4 degrees (platelet count <50000 / μl) dose of oxaliplatin should be reduced from 85 to 65 mg /m² (with metastatic therapy) or up to 75 mg /m² (with adjuvant therapy), together with a decrease in the dose of fluorouracil to the required concentration.

In the case of unexplained symptoms on the part of the respiratory system, such as non-productive cough, shortness of breath, the appearance of wet wheezes or lung infiltrates in an X-ray examination, oxaliplatinum it is necessary to cancel until the moment when the next examination will exclude the development of interstitial lung injury or pulmonary fibrosis.

In the case of changes in liver status or the appearance of signs of portal hypertension, which are not a consequence of the formation of metastases in the liver, we should assume the development of a very rare complication in the form of drug-induced vascular damage of the liver.

Special precautions for the use and disposal of the drug

Care should be taken when applying and preparing oxaliplatin solutions, as with all potentially toxic substances.

Preparation of solutions for injection of cytotoxic drugs should be carried out by specially trained personnel,who know the rules for handling the drugs used, in conditions of guaranteed drug integrity, environmental protection and special personnel protection in accordance with the principles of the practice of this medical institution. To this end, preparation should be carried out in a specially designated room or in a specially designated place. This room is prohibited from smoking, eating and drinking beverages.

Personnel must use all protection means for use in the treatment of such drugs, in particular medical gown long-mask, headgear, eyewear, sterile disposable gloves, protective coating to the working surface, containers and bags for waste collection.

It is necessary to handle with caution the feces and vomit masses of the patient taking the drug.

Pregnant women should be excluded from working with cytotoxic drugs.

Any broken packaging should be treated with precautionary measures and regarded as contaminated waste.

Disposal of contaminated waste is carried out by incineration in rigid containers labeled for this purpose (see. Below "Recycling" section).

If the powder, reconstituted solution or infusion solution is on the skin or mucous membranes, immediately remove the drug immediately and wash it off with water.

Recycling

Any unused preparation, as well as the materials used for the reconstitution, dilution and administration of the drug, must be destroyed in accordance with the standard procedures for handling the cytotoxic substances provided in the treatment facility and in accordance with the legal provisions for the disposal of toxic waste, on that moment.

Effect on the ability to drive transp. cf. and fur:

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.

Form release / dosage:

Lyophilizate for solution for infusion, 50 mg, 100 mg (5 mg / 1 ml).

Packaging:

1 bottle of colorless glass type I, sealed with a rubber stopper made of chlorobutyl rubber and an aluminum cap in a cardboard pack together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep the drug out of the reach of children.

Shelf life:

3 years.

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

The reconstituted solution in the original bottle: the reconstituted solution should be immediately diluted.

Preparation of infusion: the solution when diluted in a 5% solution of dextrose remains chemically and physically stable for 12 hours at a temperature of 5 ° C ± 3 ° C. From a microbiological point of view, the solution prepared for infusion should be used immediately. In case the solution is not used immediately after preparation, the storage time and storage conditions of the solution prior to its use are determined at the discretion of the user and should not exceed 24 hours at a temperature of 2 ° C-8 ° C under controlled aseptic conditions.

Terms of leave from pharmacies:On prescription

Registration number:LP-001435

Date of registration:16.01.2012 / 20.10.2014

Expiration Date:16.01.2017

Date of cancellation:2016-10-17

The owner of the registration certificate:Egis Pharmaceutical Plant OJSCEgis Pharmaceutical Plant OJSC Hungary

Manufacturer: & nbsp

EGIS PHARMACEUTICALS, Plc Hungary

ONCOTEC PHARMA PRODUKTION, GmbH Germany

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp02.04.2017

Illustrated instructions

Instructions

GESSEDYL (Gessedil)