Teksalok - instructions for use, doses, side effects, contraindications

Oxaliplatin is an antitumor drug belonging to the class of platinum derivatives in which a platinum atom forms a complex with 1,2-diaminocyclohexane (DACG) and an oxalate group.

Oxaliplatin is the only enantiomer of cis- [oxalato (trans-1-1-1,2-DATG) -platinum].

Oxaliplatin displays a wide spectrum of both cytotoxicity in vitro, and antitumor activity in vivo on various models of tumors, including the model of colorectal cancer of man. Oxaliplatin also shows activity in vitro and in vivo on various cisplatin-resistant cell cultures.

In combination with fluorouracil, synergism of cytotoxic action was observed in vitro and in vivo.

Biotransformed aqueous oxaliplatin derivatives interact with DNA by forming inter- and interstitial bridges and suppress DNA synthesis, which causes cytotoxicity and antitumor effect.

Pharmacokinetics:

Suction

The pharmacokinetics of individual active derivatives are not defined. Below are the pharmacokinetic parameters for ultrafiltrated platinum, which is a mixture of all unbound, active and inactive platinum compounds after two hours of oxaliplatin infusion at a dose of 130 mg / m² body surface every 3 weeks for 1-5 cycles or at a dose of 85 mg / m body surface every 2 weeks for 1-3 cycles.

The generalized results of the pharmacokinetic parameters of platinum in the ultrafiltrate after several injections of oxaliplatin at a dose of 85 mg / m2 body surface every two weeks or at a dose of 130 mg / m body surface every three weeks

Dose	The maximum concentration in the blood plasma (C_m_Oh) μg / ml	Area under pharmacokinetic curve "concentration-time" (AUC _0-48), μgxh / ml	AUC, mcg_xh / ml	α-half-life (T_1/2) α, h	β-period half-generation (T_1/2) β, h	γ-the half-life period (T_1/2) γ, h	Volume of distribution (Vss), l	Clearance (CL), l / h
85 mg / m²
Medium indicators	0,814	4,190	4,68	0,43	16,80	391	440	17,40
Standard deviation	0,193	0,647	1,40	0,35	5,74	406	199	6,35
130 mg / m²
Medium indicators	1,210	8,200	11,90	0,28	16,30	273	582	10,10
Standard deviation	0,100	2,400	4,60	0,06	2,90	19	261	3,07

Mean values AUC_0-48and C_max were determined on the 3 cycle (85 mg / m²) or at 5 cycle (130 mg / m²). The mean values of AUC, V_ss, CL were determined on 1 cycle. Determination of final concentration C_max, AUC, AUC_0-48, V_ss and CL is performed by non-compartmental analysis. Definition of indicators t_1/2α, t_1/2βand t_1/2γ is performed by compartmental analysis (a combination of cycles 1-3).

Distribution

At the end of a 2-hour administration of oxaliplatin, 15% of platinum is in the systemic circulation, and the remaining 85% are rapidly distributed into tissues or are excreted through the kidneys. Due to irreversible binding to erythrocytes and albumin of blood plasma, the half-lives of platinum in these compounds are close to the time of natural renewal of red blood cells and albumin of blood plasma. When oxaliplatin is administered every 2 weeks at a dose of 85 mg / m body surface or every 3 weeks at a dose of 130 mg / m body surface, cumulation of platinum in the ultrafiltrate plasma (PFC) is not observed,and the equilibrium state is reached after the first course of therapy. Individual and interindividual variability of pharmacokinetic parameters is usually small.

Metabolism

Biotransformation in vitro is considered the result of nonenzymatic degradation. There were no signs of cytochrome P450-mediated metabolism of the DACG ring. In the human body oxaliplatinum intensively biotransformed, and after the end of the 2-hour infusion of the drug unchanged oxaliplatinum is not determined in the FPE. Several cytotoxic products of the biotransformation of oxaliplatin, in particular monochloro-, dichloro- and diaceto-DACH of a platinum compound, have been identified in the systemic circulation.

Excretion

Platinum derivatives are excreted mainly through the kidneys, mainly during the first 48 hours after the administration of the drug. By the 5th day, about 54% of the total dose is found in urine and <3% in feces.

Special patient groups

Renal insufficiency

The effect of renal dysfunction on the distribution of oxaliplatin was studied in patients with varying degrees of renal insufficiency. Oxaliplatin was administered at a dose of 85 mg / m in the control group to patients with normal renal functionCLcr (creatinine clearance)> 80 ml / min, n= 12) and patients with mild (CLcr = 50 to 80 ml / min, n= 13) and the mean (CLcr = 30 to 49 ml / min, n= 11) degrees of impaired renal function, as well as at a dose of 65 mg / m in patients with severe renal impairment (CLcr <30 ml / min, n = 5). The median number of cycles of therapy was 9, 4, 6 and 3, respectively, and pharmacokinetics data against the background of 1 cycle of therapy were obtained in 11, 13, 10 and 4 of patients, respectively.

An increase was noted AUC platinum, AUC/ dose in PF and reduction in total and renal CL and Vss with an increase in the severity of renal impairment, especially in a small group of patients with severe renal impairment: a point estimate (90% confidence interval) of the estimated average ratios, depending on the state of kidney function compared to normal kidney function for AUC/ dose was 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for patients with mild, moderate and severe degrees of impaired renal function, respectively.

Excretion of oxaliplatin significantly correlated with the clearance of creatinine. The total clearance of platinum in PFC was 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29), and Vss 0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27 (0.20, 0.36) for patients with mild, moderate and severe degrees of renal insufficiency, respectively. The total clearance of platinum in PFC was thus reduced by 26% in the case of mild, 57% in the case of moderate and 79% in cases of severe renal impairment compared to patients with normal function, respectively.

Renal clearance of platinum in PFC was reduced in patients with renal insufficiency by 30% in the case of mild, 65% in the case of middle and 84% in cases of severe renal impairment compared to patients with normal function.

There was an increase in t_1/2β platinum in PFC with increasing degree of renal dysfunction, mainly in the group of severe renal insufficiency. Despite the small number of patients with severe renal insufficiency, these data are of interest to this group of patients, they must be taken into account in the appointment of oxaliplatin to patients with impaired renal function.

Indications:

Oxaliplatin combined with fluorouracil and calcium folinate is indicated for:

- adjuvant therapy of the III stage (stage D according to Duke's classification) of colon cancer after complete resection of the primary tumor;

- treatment of metastatic colorectal cancer.

Contraindications:

- Hypersensitivity to oxaliplatinum, other derivatives of platinum or other components of the drug;

- pregnancy and the period of breastfeeding;

- Myelosuppression before the start of the first course of therapy (neutrophil count <2x10⁹/ l and / or platelets <100x10⁹/ l);

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

- severe renal impairment (creatinine clearance <30 mL / min);

- children's age till 18 years.

Carefully:

If the renal function is impaired, the drug should be used with caution.

Pregnancy and lactation:

Fertility

Teksalok has the property of inhibiting fertility.

Pregnancy

To date, there is no available information on the safety of the drug in pregnant women. In animal studies, reproductive toxicity was observed. Therefore, the use of texalok is contraindicated in women during pregnancy.

It is necessary to apply reliable contraceptive measures during treatment and after its termination for 4 months for women and for 6 months for men.

Breastfeeding period

Excretion into breast milk has not been studied. Breastfeeding is contraindicated during treatment with Texalkus.

Dosing and Administration:

The drug is used only in adults.

The recommended dose of Teksalok with adjuvant therapy is 85 mg / m²body surface infusion every 2 weeks for 12 cycles (6 months). The recommended dose of Teksalok in the treatment of metastatic colorectal cancer is 85 mg / m² body surface infusion every 2 weeks until the onset of disease progression or development of unacceptable toxicity.

The given doses should be adjusted depending on the tolerability. The use of Teksalok should always precede the administration of fluoropyrimidines - fluorouracil.

Texalok is administered in the form of 2-6-hour intravenous infusions in 250-500 ml of 5% dextrose solution, obtaining a concentration of 0.2 mg / ml to 0.70 mg / ml; 0.70 mg / ml is the highest concentration used in clinical practice for the dose of oxaliplatin 85 mg / m².

The drug Teksalok is mainly used in combination with a long infusion of fluorouracil.For a treatment regimen that involves the administration of drugs every 2 weeks, use a combination of bolus administration of fluorouracil and its long infusion.

Special patient groups

Children

Teksalok is not used in pediatrics. The drug should be used only in adults.

Elderly patients

No increase in severe toxicity was observed with the drug as a monotherapy or in combination with fluorouracil in patients older than 65 years. Therefore, no specific dose adjustment is necessary in the elderly.

Patients with impaired renal function

The drug texalok is contraindicated in patients with severe renal failure. For patients with mild to moderate renal impairment, the recommended dose of Texalok is 85 mg / m².

Patients with impaired hepatic function

In the Phase I study, which included patients with varying degrees of hepatic insufficiency, the degree and severity of liver and biliary tract disorders was apparently associated with disease progression and abnormal functional liver tests at baseline.Specific dose adjustment for patients with impaired liver function during clinical trials was not conducted.

Mode of application

The drug texalok is administered intravenously.

The introduction of Teksalok does not require pre-hydration.

Texalok is diluted in 250-500 ml of a 5% dextrose solution to a concentration of at least 0.2 mg / ml, and then administered through a central venous or peripheral venous catheter for 2-6 hours.

The solution of oxaliplatin should always be applied before the administration of fluorouracil.

In the case of extravasation, the administration should be stopped immediately.

Terms of use

Teksalok preparation must be diluted before use. To prepare a solution for infusion, only 5% dextrose or water for injection is used as the solvent.

As with other potentially toxic compounds, caution should be exercised when preparing solutions and working with solutions of oxaliplatin.

The treatment with this cytotoxic drug requires the medical personnel to follow all precautions to ensure their safety and environmental safety.

Preparation of solutions for cytotoxic drugs for injection should be carried out by trained personnel with knowledge of the drugs used in conditions that guarantee product integrity, safety for the environment and in particular safety for personnel working with the drug. This requires the presence of a special zone for the preparation of drug solutions.

It is necessary to allocate the zone intended for work with the drug. It is prohibited to smoke, eat food and drink in a designated area.

Staff should be provided with appropriate working material, in particular, medical gowns with long sleeves, protective masks, caps, goggles, sterile disposable gloves, protective suits for the work area, containers and bags for collecting waste.

Caution should be treated with secretions from the body and vomit masses of patients taking the drug Texalk.

Pregnant women are not allowed to work with cytotoxic drugs.

To the damaged vials should be treated with the same precautions and treat them as contaminated waste.Contaminated waste must be burned in rigid containers with the appropriate marking.

If oxaliplatin powder, reconstituted solution or ready-to-use infusion solution has got on the skin or mucous membrane, immediately and thoroughly rinse it with water.

The drug is intended for single use only. Any unused solution must be destroyed in accordance with the rules in force in the medical institution.

The use of oxaliplatin in combination with calcium folinate

Teksalok at a dose of 85 mg / m as an intravenous infusion, diluted in 250-500 ml of a 5% solution of dextrose is administered concomitantly with an intravenous infusion of calcium folinate in a 5% dextrose solution for 2-6 hours via Y-like system, installed immediately before the infusion. These medications can not be mixed in a single dropper. Calcium folinate preparations should not contain trometamol as an auxiliary substance. Dilution of the drug Texalko allowed only isotonic 5% solution of dextrose. Dilution with alkaline solutions, sodium chloride solution or solutions containing chloride is prohibited.

The use of oxaliplatin in combination with fluorouracil

The use of Teksalok should always precede the administration of fluoropyrimidines, namely fluorouracil.

After oxaliplatin administration, the system should be rinsed and then administered fluorouracil. The reconstituted solution

To reconstitute the solution, use water for injection or a 5% dextrose solution according to the table below.

Oxaliplatin dosage	50 mg	100 mg
Quantity of solvent	10 ml	20 ml
The concentration of the resulting solution	5 mg / ml	5 mg / ml

The reconstituted solution should be diluted immediately with a 5% solution of dextrose.

Ready-made infusion solution

The required amount of reconstituted solution should be diluted in 250-500 ml of 5% dextrose solution until the oxaliplatin concentration is reached from 0.2 mg / ml to 0.7 mg / ml. The concentration interval at which the physicochemical stability of Texalko was demonstrated was 0.2 mg / ml to 1.3 mg / ml.

The drug texalok is administered intravenously.

From the microbiological point of view, the prepared infusion solution should be used immediately.

Only transparent solutions without visible particles are used.

The drug is intended for single use only. Any unused solution must be destroyed.

Do not dilute Texalko with 0.9% sodium chloride solution or other solutions containing chloride ion.

Infusion

When oxaliplatin is used, no preliminary hydration is required.

Oxaliplatin is diluted in 250-500 ml of 5% dextrose solution to a concentration of at least 0.2 mg / ml and injected through a peripheral or central venous catheter for 2-6 hours. When using oxaliplatin together with fluorouracil, oxaliplatin infusion should precede the administration of fluorouracil. It is prohibited to use injection equipment containing aluminum, to apply Texalko preparation not diluted, to mix with other medicinal preparations in one dropper or to inject simultaneously with the help of one infusion system. It is forbidden to mix Texalok preparation with alkaline preparations and solutions, in particular with fluorouracil, calcium folinate preparations containing trometamol as an auxiliary substance, other active substances in the form of salts.Alkaline preparations and their solutions disrupt the stability of oxaliplatin.

Side effects:

The most frequent adverse reactions to the use of oxaliplatin in combination with fluorouracil and calcium folinate are gastrointestinal (diarrhea, nausea, vomiting and mucositis), blood (neutropenia, thrombocytopenia) and the nervous system (acute and dose-related peripheral sensory neuropathy). In general, these adverse reactions were more frequent and more severe with oxaliplatin combined with fluorouracil and calcium folinate than with fluorouracil and calcium folinate alone. The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence.

Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases), frequency unknown (can not be estimated from the available data). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Frequency of occurrence of undesirable reactions

Violations of the blood and lymphatic system⁴

very often: anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia;

often: febrile neutropenia;

rarely: immune thrombocytopenia, hemolytic anemia;

frequency unknown: hemolytic uremic syndrome.

Immune system disorders⁵

very often: allergies or allergic reactions¹.

Disorders from the metabolism and nutrition

very often: anorexia, hyperglycemia, hypokalemia, hypernatremia;

often: dehydration;

infrequently: metabolic acidosis.

Disturbances from the nervous system⁶

very often: peripheral sensory neuropathy sensory disorders, taste change, headache;

often: depression, insomnia, dizziness, polyneuropathy, meningism;

infrequently: nervousness; rarely: dysarthria, reversible leukoencephalopathic syndrome;

frequency unknown: convulsions.

Vascular disorders

often: bleeding, hyperemia, deep vein thrombosis, increased blood pressure; frequency is unknown: "hot flashes".

Disturbances from the respiratory system, chest and mediastinal organs

very often: shortness of breath, cough, nosebleeds;

often: hiccough, thromboembolism of the pulmonary artery;

rarely: interstitial pneumonia, sometimes fatal, pulmonary fibrosis;

frequency unknown: pain in the chest.

Disorders from the gastrointestinal tract⁷

very often: nausea, diarrhea, vomiting, stomatitis, inflammation of the mucous membrane of the mouth, abdominal pain, constipation;

often: dyspepsia, gastroesophageal reflux, gastrointestinal bleeding, rectal bleeding;

infrequently: intestinal obstruction, incl. paralytic;

rarely: colitis, incl. diarrhea caused by Clostridium difficile, pancreatitis.

Disturbances from the liver and bile ducts

very often: increased activity of "liver" enzymes, increased activity of alkaline phosphatase, increased bilirubin concentration, increased lactate dehydrogenase activity in the blood;

very rarely: a sinusoidal liver obstruction syndrome, also known as veno-occlusive disease of the liver, or pathological manifestations of the disease are associated with liver disorders such as hepatic purpura, nodular regenerative hyperplasia, perisinusoidal fibrosis.In clinical manifestations can be expressed in the form of portal hypertension and / or increased activity of "hepatic" transaminases.

Disturbances from the skin and subcutaneous tissues

very often: skin damage, alopecia; often: skin peeling (for example, palmar-plantar syndrome), erythematous rash, rash, excessive sweating, impaired nails.

Disorders from the kidneys and urinary tract

often: hematuria, dysuria, frequent urination, increased serum creatinine concentration;

very rarely: acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Disturbances from musculoskeletal and connective tissue

very often: back pain;

often: arthralgia, pain in the bones.

Disturbances on the part of the organ of sight

often: conjunctivitis, impaired vision;

rarely: temporary reduction of visual acuity, violation of visual fields, optic neuritis, transient loss of vision, reversible after discontinuation of treatment.

Hearing disorders and labyrinthine disorders

infrequently: ototoxicity;

rarely: hearing loss, deafness;

frequency unknown: neuritis of the auditory nerve.

Infectious and parasitic diseases

very often: an infectious disease;

often: rhinitis, upper respiratory tract infection, neutropenic sepsis.

General disorders and disorders at the site of administration

very often: increased fatigue, fever, asthenia, pain, reaction at the injection site³;

often: weight loss (treatment of metastatic cancer).

¹Very common allergies or allergic reactions, which mainly occur during infusion, are sometimes fatal. Frequent allergic reactions include skin rashes, especially hives, conjunctivitis and rhinitis. Frequent anaphylactic or anaphylactoid reactions include bronchospasm, angioedema, lowering of blood pressure, a feeling of chest pain and anaphylactic shock.

²fever, tremor (tremor) can occur either as a result of infection (with or without febrile neutropenia) or, possibly, as a consequence of the activity of the immunological mechanism.

³reactions at the injection site were described, including pain, redness, edema, and thrombosis. Extravasation can lead to local pain and inflammation,which can be severe and lead to the development of complications, including necrosis, especially when introducing oxaliplatin into the peripheral vein.

⁴ Violations of the blood and lymphatic system

The incidence of adverse reactions in patients (%), distributed by their severity

Oxaliplatin with fluorouracil and calcium folinate 85 mg / m² every 2 weeks	Treatment of Metastatic Cancer			Scheme of adjuvant therapy
	All degree	Power 3	Power 4	All degree	Power 3	Power 4
Anemia	82,2	3	<1	75,6	0,7	0,1
Neutropenia	71,4	28	14	78,9	28,8	12,3
Thrombocytopenia	71,6	4	<1	77,4	1,5	0,2
Febrile neutropenia	5,0	3,6	1,4	0,7	0,7	0,0
Neutropenic sepsis	1,1	0,7	0,4	1,1	0,6	0,4

⁵ Immune system disorders

The incidence of adverse reactions in patients (%), distributed according to their severity

Oxaliplatin with fluorouracil and calcium folinate 85 mg / m²

every 2 weeks

Treatment of Metastatic Cancer

Scheme of adjuvant therapy

All

degree

Power

All

degree

Power

Allergy or

Allergic

reactions

9,1

10,3

2,3

0,6

⁶ Disturbances from the nervous system

Neurotoxicity is dose-limiting for this drug. The dose restriction is the neurological toxicity of the drug.It is manifested by peripheral sensory neuropathy, characterized by dysesthesia and / or paresthesia of the extremities with or without seizures, and is often caused by low temperature. These symptoms occur in almost 95% of patients receiving treatment. The duration of symptoms, usually regressing between treatment courses, increases with the number of treatment cycles.

The appearance of pain and / or functional disorders indicates that, depending on the duration of the symptoms, dose adjustment or even drug cancellation is required.

Functional disorders include difficulty in performing accurate movements and are consequences of sensory damage. The risk of persistent symptoms at a total dose of 850 mg / m² (10 courses) is about 10% and reaches 20% in the case of a total dose of 1020 mg / m² (12 courses).

In most cases, neurological signs and symptoms decrease or completely disappear after discontinuation of treatment. In adjuvant therapy for colon cancer, after 6 months of discontinuation of treatment, 87% of patients had no symptoms or were mild. After three years of follow-up, approximately 3% of patients showed either persistent localized paresthesia of moderate intensity (2.3%) or paresthesia,which can interfere with daily activity (0.5%).

Acute neurosensory manifestations were recorded. They begin within a few hours after administration and are often provoked by exposure to low temperatures. They are usually represented by transient paresthesia, dysesthesia or hypoesthesia. Acute syndrome of pharyngeal-laryngeal dysesthesia occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia and dyspnea, a feeling of suffocation without any objective signs of respiratory depression (without cyanosis or hypoxia) or laryngospasm or bronchospasm (without stridor breathing or dyspnea). Although antihistamines and bronchodilators are used in such cases, the symptoms are quickly reversible even in the absence of treatment. Increasing the duration of the infusion helps to reduce the incidence of this syndrome.

Other symptoms are seldom observed: muscle spasms, including jaw spasms, involuntary muscle contractions, convulsions, including myoclonic ones, impaired coordination, gait, balance, a feeling of tightness in the throat or chest, pressure, discomfort, chest pain.In addition, symptoms that are characteristic of damage to the cranial nerves in the form of combined or isolated symptoms such as ptosis, diplopia, aphonia, dysphonia, hoarseness, sometimes described as paralysis of the vocal cords, a violation of the sensitivity of the tongue or dysarthria, sometimes described as aphasia ; neuralgia of the trigeminal nerve, facial pain, pain in the eyes, decreased visual acuity, loss of visual fields.

In the process of treatment with oxaliplatin, other neurologic symptoms such as dysarthria, loss of deep tendon reflex and the Lermitt symptom were reported. Single cases of optic neuritis were also noted.

⁷ Disorders from the gastrointestinal tract

The incidence of adverse reactions in patients (%), distributed according to their severity

Oxaliplatin with fluorouracil and calcium folinate 85 mg / m² every 2 weeks	Treatment of Metastatic Cancer			Scheme of adjuvant therapy
	All degree	Power 3	Power 4	All degree	Power 3	Power 4
Nausea	69,9	8	<1	73,7	4,8	0,3
Diarrhea	60,8	9	2	56,3	8,3	2,5
Vomiting	49,0	6	1	47,2	5,3	0,5
Mucositis and / or stomatitis	39,9	4	<1	42,1	2,8	0,1

Prophylactic and therapeutic use of powerful antiemetics is shown.Dehydration, paralytic intestinal obstruction, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be caused by severe diarrhea or vomiting when oxaliplatin is combined with fluorouracil.

Overdose:

Symptoms

In case of an overdose, dose-related side effects increase. Allergic reactions described in the section "Side effect" are of a dose-independent nature.

Treatment

The antidote for oxaliplatinum is unknown. It is recommended to closely monitor the patient, strict control of hematological parameters, and symptomatic treatment.

Interaction:

In patients receiving a single dose of 85 mg /m² oxaliplatin directly before the use of fluorouracil, there was no change in the exposure of fluorouracil. In vitro There was no significant displacement of oxaliplatin from the connection with plasma proteins when used with the following drugs: erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.

- Do not mix the drug solution with other drugs in a single dropper or infusion system.

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

- Do not breed oxaliplatinum 0,9% solution of sodium chloride or other solutions containing chloride ion (including chloride of calcium, potassium and sodium).

- Do not use injection equipment containing aluminum.

Special instructions:

Oxaliplatin should be used only in specialized oncology units, the drug should be administered under the supervision of an experienced oncologist.

Impaired renal function

In patients with mild to moderate renal impairment, careful monitoring should be performed to determine if adverse reactions occur and adjust the dose according to toxicity.

Hypersensitivity reactions

In the case of anaphylactic-type reaction, oxaliplatinum, the infusion should be stopped immediately and appropriate symptomatic therapy started.Repeated administration of oxaliplatin for such patients is contraindicated. Reports of cross reactions, sometimes deadly, have been reported with all platinum compounds.

With extravasation of oxaliplatin, administration should be immediately discontinued and standard local symptomatic treatment should be prescribed.

Neurological Toxicity

The neurologic toxicity of oxaliplatin should be carefully monitored, especially if it is administered with other drugs with specific neurological toxicity.

Neurological examination should be performed before each introduction and at certain intervals in the future.

Laryngopharyngeal dysesthesia

If patients develop acute laryngopharyngeal dysesthesia during a 2-hour infusion or for several hours afterwards, the duration of the next infusion of oxaliplatin should be 6 hours.

Neurological symptoms (paresthesia, dysesthesia)

In the case of manifestations of neurologic symptoms (paresthesia, dysesthesia), depending on the duration and severity of these symptoms, the following dose adjustment is recommended:

- if the symptoms last more than 7 days and cause anxiety, the next dose of oxaliplatin should be reduced from 85 to 65 mg / m² (in the treatment of metastatic cancer) or up to 75 mg / m (when used as adjuvant therapy);

- if paresthesia without functional impairment persists until the next cycle, the subsequent dose of oxaliplatin should be reduced from 85 to 65 mg /m² (in the treatment of metastatic cancer) or up to 75 mg /m² (when used in the form of adjuvant therapy);

- if paresthesia with functional impairment persists until the next cycle, oxaliplatinum should be discarded;

- if these symptoms are normalized after the cessation of treatment with oxaliplatin, resumption of treatment can be considered.

Patients should be informed of the possibility of developing persistent symptoms of peripheral sensory neuropathy after treatment. Moderate localized paresthesias or paresthesias that impede functional activity may persist for up to 3 years after discontinuation of adjuvant treatment.

The syndrome of posterior reversible leukoencephalopathy (SZOL)

Cases of the syndrome of posterior reversible leukoencephalopathy (SZOL, also known as SZOE, a syndrome of reverse reversible encephalopathy) have been described in patients receiving oxaliplatinum when carrying out combined chemotherapy. SZOL is a rare, reversible, rapidly developing neurological condition that can include convulsions, increased blood pressure, headache, confusion, blindness and other visual and neurological disorders. The diagnosis of SZOL is based on visualization studies of the brain, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, hematologic changes

Gastrointestinal toxicity, manifested as nausea and vomiting, requires preventive and / or therapeutic antiemetic therapy.

Dehydration, intestinal obstruction, vt paralytic, hypokalemia, metabolic acidosis and renal failure may be due to severe diarrhea or vomiting, especially when oxaliplatin is used in combination with fluorouracil.

If hematological toxicity occurs (neutrophil count <1.5 x 10⁹/ l or platelets <50 x 10⁹/ l) the next course of therapy should be postponed until the haematological indicators return to acceptable values.Before the beginning of treatment, as well as before each subsequent course, a general blood test should be performed with the definition of the leukocyte formula.

Patients should be informed in detail about the risk of diarrhea and / or vomiting, mucositis and / or stomatitis and neutropenia after using oxaliplatin and fluorouracil, so they can immediately contact the doctor in charge to begin appropriate treatment.

When mucositis and / or stomatitis occur with neutropenia or without it, the next course of treatment should be postponed until the recovery of mucositis and / or stomatitis to 1 stage or less and / or until the number of neutrophils is> 1.5 x 10⁹/ l.

When a combination of oxaliplatin with fluorouracil (and calcium folinate or without it), conventional dose adjustment regimens for the toxicity associated with the use of fluorouracil should be used.

With diarrhea 4 degrees, neutropenia 3-4 degree (the number of neutrophils <1.0 x 10⁹/ l), thrombocytopenia 3-4 degrees (platelet count <50 x 10⁹/ l) dose of oxaliplatin should be reduced from 85 to 65 mg / m² (scheme of treatment of metastatic form) or up to 75 mg / m² (adjuvant therapy), in addition to any necessary dose reduction of fluorouracil.

Disturbances from the respiratory system

If respiratory symptoms of an unknown etiology, such as a non-productive cough, dyspnoea, wheezing or visible pulmonary infiltrates on the radiograph, appear, suspend treatment with oxaliplatin until the interstitial pneumonitis is eliminated.

Hepatitis

In the case of altered results of hepatic functional tests or portal hypertension, which is not directly related to hepatic metastases, the probability of very rare cases of vascular disorders of the liver caused by oxaliplatin should be considered.

Impact on fertility

In preclinical studies of oxaliplatin, genotoxic effects were observed. Therefore, male patients receiving oxaliplatinum, it is recommended to use reliable methods of contraception during and for at least 6 months after treatment, and it is recommended to receive advice on the preservation of sperm before the start of treatment, since oxaliplatinum may have a depressing, sometimes irreversible effect on the gonads.

Women of reproductive age should use an effective contraceptive method during treatment.

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

Influence on the ability to drive vehicles and engage in other activities that require increased concentration and speed of psychomotor reactions, has not been studied.

However, the use of oxaliplatin increases the risk of dizziness, nausea and vomiting, as well as other neurological symptoms affecting gait and balance, which affects the ability to drive or move vehicles lightly or to medium degree.

Visual impairments, in particular short-term vision loss (reversible after discontinuation of treatment), can affect a patient's ability to drive and use mechanisms. Therefore, patients should be warned about the potential impact of these complications on the ability to drive or move vehicles.

Form release / dosage:

Lyophilizate for solution for infusion, 50 mg, 100 mg.

Packaging:

For 50 mg or 100 mg of oxaliplatin in a vial of clear, colorless glass (type 1, Hebrew F), sealed with a bromobutyl rubber stopper and crimped with an aluminum cap with a plastic disc.

For 1 bottle with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 30 ° C.

Ready to use the infusion solution immediately.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002582

Date of registration:14.08.2014

Date of cancellation:2017-07-06

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

Onco Therapies Limited India

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp06.07.2017

Illustrated instructions

Instructions

Texalko (Texaloc)