Plaxate, lyophilizate 100 mg

Pharmacotherapeutic group: antitumor agent – alkylating compound

ATX code: L01XA03

Pharmacological properties

Pharmacodynamics

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

Oxaliplatin is represented by a single enantiomer, cis-[oxalato(trans-I-1,2-DACG)platinum].

Oxaliplatin exhibits a broad spectrum of both cytotoxic in vitro, and antitumor activity in vivo in various tumor models, including a human colorectal cancer model. It also exhibits in vitro and in vivo activity on various cisplatin-resistant cell cultures.

In combination with fluorouracil, synergistic cytotoxic effects of in vitro and in vivo.

Mechanism of Action

. The study of the mechanism of action of oxaliplatin supports the hypothesis that biotransformed aqueous derivatives of oxaliplatin, interacting with deoxyribonucleic acid (DNA) by forming inter- and intrathecal bridges, suppress DNA synthesis, which accounts for cytotoxicity and antitumor effect.

Pharmacokinetics

Extraction

Pharmacokinetics of individual active derivatives have not been determined. The following are pharmacokinetic values for ultrafiltered platinum, which is a mixture of all unbound, active and inactive platinum compounds after a two-hour infusion of oxaliplatin at a dose of 130 mg/m² body surface every 3 weeks for 1-5 cycles or at a dose of 85 mg/m² body surface every 2 weeks for 1-3 cycles.

Summarized results of platinum pharmacokinetic parameters in ultrafiltrate after multiple administrations of oxaliplatin at a dose of 85 mg/m² body surface every two weeks or at a dose of 130 mg/m² body surface every three weeks

The mean values of AUC_0-48 and C_max were determined at cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

The mean AUC, V_ss, CL values were determined at cycle 1.

The final concentration values of C_max, AUC, AUC_0-48, V_ss, and CL were performed by noncompartmental analysis.

The determination of t_1/2α, t_1/2β, t_1/2γ were performed by compartmental analysis (combination of cycles 1-3).

Distribution

At the end of a 2-hour administration of oxaliplatin, 15% of the platinum is in the systemic bloodstream, and the remaining 85% is rapidly distributed to the tissues or excreted through the kidneys. Due to irreversible binding with erythrocytes and blood plasma albumin half-lives of platinum in these compounds are close to natural renewal time of erythrocytes and blood plasma albumin. When oxaliplatin is administered every 2 weeks at a dose of 85 mg/m² body surface and every 3 weeks at a dose of 130 mg/m² body surface platinum cumulation in blood plasma ultrafiltrate (BPU) is not observed and an equilibrium state is reached already after the first course of therapy.

Individual and interindividual variability of pharmacokinetic parameters is usually small.

Metabolism

Biotransformation in vitro is thought to result from enzyme-free degradation. There is no evidence of cytochrome P450-mediated metabolism of the DATG ring. In humans, oxaliplatin is intensively biotransformed, and unchanged oxaliplatin is not detected in the USP after completion of a 2-hour infusion of the drug. Several cytotoxic biotransformation products of oxaliplatin, in particular monochloro-, dichloro- and diacvo-DACG platinum compounds, have been indentified in the systemic circulation.

Evacuation

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

Special patient groups

Renal impairment

. The effect of impaired renal function on the distribution of oxaliplatin has been studied in patients with various degrees of renal failure. Oxaliplatin was administered at a dose of 85 mg/m² in control patients with normal renal function (CLcr (creatinine clearance) > 80 mL/min, n=12) and in patients with mild (CLcr = 50 to 80 mL/min, n=13) and moderate (CLcr = 30 to 49 mL/min, n=11) renal function impairment, and at a dose of 65 mg/m² in patients with severe renal function impairment (CLcr < 30 mL/min, n=5). The median number of cycles of therapy was 9, 4, 6, and 3, respectively, and pharmacokinetic data on 1 cycle of therapy were obtained in 11, 13, 10, and 4 patients, respectively.

There was an increase in platinum AUC, AUC/dose in UFP and a decrease in total and renal CL and V_ss with increasing severity of renal impairment, particularly in the small group of patients with severe renal impairment: The point estimate (90% CI (confidence interval)) of the estimated mean ratios according to renal function status compared with normal renal 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 renal function impairment, respectively.

The excretion of oxaliplatin correlated significantly with creatinine clearance. Total platinum clearance in UFP was 0.74 (0.59; 0.92), 0.43 (0.33; 0.55), and 0.21 (0.15; 0.29), and V_ss 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 renal failure, respectively. Total platinum clearance in UFP was thus reduced by 26% for mild, 57% for moderate, and 79% for severe renal impairment compared with patients with normal function, respectively.

The renal clearance of platinum in UFP was reduced in patients with renal impairment by 30% for mild, 65% for moderate, and 84% for severe renal impairment compared with patients with normal function.

There was an increase in t_1/2β platinum in UFP with increasing degree of renal impairment, mainly in the severe renal failure group. Despite the small number of patients with severe renal impairment, these data are of interest and should be considered when prescribing oxaliplatin to this group of patients.

Indications

Active ingredient

Composition

How to take, the dosage

The drug Plaksat is used only in adults.

Dosing regimen

Adjuvant therapy for colorectal cancer III

Interaction

In patients who received a single dose of 85 mg/m2 of oxaliplatin immediately prior to fluorouracil administration, no changes in fluorouracil exposure were detected.
In vitro there was no significant displacement of oxaliplatin from plasma protein binding when used concomitantly with erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.
Pharmaceutical incompatibility
– Do not mix the drug solution with other drugs in the same container, dropper or infusion system.
– Do not mix the drug solution with alkaline drugs or solutions, particularly fluorouracil, calcium folinate preparations containing trometamol as an excipient, and other active substances in the form of trometamol salts. Alkaline drugs and solutions adversely affect the stability of oxaliplatin.
– Do not dilute oxaliplatin with 0.9% sodium chloride solution or other solutions containing chloride ion (including calcium, potassium and sodium chlorides).
– Do not use injection equipment containing aluminum.

Special Instructions

Oxaliplatin should be used only in specialized oncology departments, administration of Plaxat should be performed under the supervision of a physician experienced in the use of cytotoxic drugs.

Plaxat should not be administered intraperitoneally as this may cause bleeding into the abdominal cavity.

In cases of intestinal ischemia, including fatal outcomes, sepsis, neutropenic sepsis, septic shock, disseminated intravascular coagulation, duodenal ulcer and its potential complications (ulcerative bleeding, ulcer perforation) have been reported when using oxaliplatin. In this case the use of the drug Plaksat should be stopped and appropriate treatment measures should be taken.

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome is a life-threatening side effect. The use of the drug Plaksat should be stopped when the first symptoms of microangiopathic hemolytic anemia appear (rapid decrease of hemoglobin with accompanying thrombocytopenia, increased concentration of bilirubin, creatinine, nitrogen, urea, lactate dehydrogenase activity in blood serum).

The resulting renal failure may be irreversible after discontinuation of therapy and may require dialysis.

Longening of the interval QT

.When oxaliplatin is used, QT interval prolongation may develop, which can lead to severe ventricular arrhythmias, including pirouette-type ventricular tachycardia, possibly with a fatal outcome. In patients with a history of prolongation of the QT interval or patients with predisposing factors to QT interval prolongation (e.g., concomitant use with drugs that prolong the QT interval, electrolyte disorders such as hypokalemia, hypocalcemia, hypomagnesemia) Plaksat should be used with caution. If QT interval prolongation occurs, treatment with Plaxat should be discontinued.

Rhabdomyolysis

When using oxaliplatin, rhabdomyolysis, including death, has been reported. In case of muscle pain and swelling combined with weakness, fever or darkened urine, treatment should be discontinued. If the diagnosis of rhabdomyolysis is confirmed, appropriate treatment measures should be taken. However, caution is recommended when concomitantly prescribing medications that may cause rhabdomyolysis with the drug Plaxat.

Renal dysfunction

In patients with impaired renal function, careful monitoring for adverse reactions should be performed and the dose adjusted according to the toxicity and degree of impairment (see

High sensitivity reactions

In the event of an anaphylactic reaction to oxaliplatin, the infusion should be stopped immediately and appropriate symptomatic therapy initiated. Repeated administration of oxaliplatin is contraindicated in such patients. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

In case of oxaliplatin extravasation, the infusion should be stopped immediately and standard local symptomatic treatment administered.

Neurologic toxicity

The neurologic toxicity of oxaliplatin should be closely monitored, especially if it is administered with other drugs that have specific neurologic toxicity.

Neurologic evaluation should be performed before each administration and at intervals thereafter.

Laryngopharyngeal dysesthesia

If a patient has acute laryngopharyngeal dysesthesia during or within hours of a 2-hour infusion, the duration of the next oxaliplatin infusion should be 6 hours.

Neurologic symptoms (paresthesia, dysesthesia)

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

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

Posterior reversible leukoencephalopathy syndrome (RLOS)

.Posterior reversible leukoencephalopathy syndrome (RLS, also known as posterior reversible encephalopathy syndrome (PRESE)) has been described in patients receiving oxaliplatin during combination chemotherapy.

SZOL is a rare, reversible, rapidly developing neurologic condition that may include seizures, elevated blood pressure, headache, confusion, blindness, and other visual and neurologic disturbances. The diagnosis of SLE is based on imaging studies of the brain, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, hematologic changes

Gastrointestinal obstruction manifested by nausea and vomiting requires prophylactic and/or antiemetic therapy to treat adverse events.

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

If hematologic toxicity occurs (neutrophil count < 1.5*109/l or platelets < 50*109/L) the next course of therapy should be postponed until hematologic values return to acceptable values. General blood counts and leukocyte counts should be performed before starting treatment and before each subsequent course.

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 that they can contact the treating physician immediately to begin appropriate treatment.

If mucositis and/or stomatitis with or without neutropenia occurs, the next course of treatment should be delayed until mucositis and/or stomatitis has recovered to stage 1 or less and/or until neutrophil count > 1.5*109/l.

When combining oxaliplatin with fluorouracil (and calcium folinate or not), the usual dose adjustment regimens for fluorouracil-associated toxicity should be used.

For grade 4 diarrhea, grade 3-4 neutropenia (neutrophil count < 1.0*109/l), grade 3-4 thrombocytopenia (neutrophil count < 50*109/l), the oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic treatment regimen) or to 75 mg/m2 (adjuvant therapy), in addition to any necessary fluorouracil dose reductions.

Respiratory system disorders

.If respiratory symptoms of unknown etiology occur, such as non-productive cough, dyspnea, wheezing, or pulmonary infiltrates visible on radiographs, treatment with oxaliplatin should be suspended until interstitial pneumonitis is excluded.

Hepatitis

In case of altered hepatic function test results or portal hypertension not obviously associated with hepatic metastases, consider the possibility of very rare cases of hepatic vascular disorders caused by oxaliplatin.

Effects on fertility

In preclinical studies of oxaliplatin, genotoxic effects have been observed. Therefore, male patients receiving oxaliplatin are advised to use reliable methods of contraception during and at least 6 months after treatment, and are advised to obtain sperm preservation counseling before starting treatment, as oxaliplatin may have a depressing, sometimes irreversible effect on the gonads. Women of reproductive age should use reliable contraception during treatment.

Influence on driving and operating ability

The effect on driving and other activities requiring increased concentration and quick psychomotor reactions has not been studied.

But use of oxaliplatin does increase the risk of dizziness, nausea and vomiting, and other neurological symptoms affecting gait and balance, which affects the ability to drive or operate moving machinery.

Visual impairments, particularly short-term vision loss (reversible after discontinuation of treatment), may affect the patient’s ability to drive and operate machinery. Therefore, patients should be advised of the potential effect of these complications on their ability to drive or operate moving machinery.

Synopsis

Contraindications

With caution

In patients with severe renal dysfunction (creatinine clearance
< 30 ml/min); In patients with a history of history of QT interval prolongation or in patients with predisposing factors for QT interval prolongation; when used concomitantly with drugs that may cause rhabdomyolysis.

Side effects

The frequency of side effects listed below was determined according to the following gradation: veryfrequent (>1/10), frequent (>1/100, < 1/10); not often (>1/1000, < 1/100); not often (>1/10000, <1/1000); very rarely (<1/10000), including individual reports; frequency unknown (it is not possible to determine the frequency from the available data).

Combination therapy with oxaliplatin and fluorouracil/calcium folinate

Laboratory and instrumental data

p> Very common

Frequently

Infectious and parasitic diseases

Very common

Frequently

Infrequent

Disorders of the blood and lymphatic system

Very common

The incidence of these side effects is increased when treated with oxaliplatin (85 mg/m2 every 2 weeks) in combination with fluorouracil +/- calcium folinate compared with oxaliplatin monotherapy at a dose of 130 mg/m2 every 3 weeks, such as anemia rate (80% versus 60%), neutropenia rate (70% versus 15%), and thrombocytopenia rate (80% versus 40%).

– Severe anemia (hemoglobin < 8 g/dL) or severe thrombocytopenia (platelet count < 50,000/μL) occurred with equal frequency (< 5% of patients) when oxaliplatin was used as monotherapy or in combination with fluorouracil).

– Severe neutropenia (neutrophil count < 1000/μL) occurred with a higher frequency when oxaliplatin was used in combination with fluorouracil compared with oxaliplatin monotherapy (40% compared with < 3% of patients).

Frequently

Rarely

Disorders of the digestive system

very often

The development of dehydration, hypokalemia, metabolic acidosis, paralytic intestinal obstruction, small bowel obstruction, and renal dysfunction may be associated with severe diarrhea and/or vomiting, especially when using a combination of oxaliplatin and fluorouracil.

Frequently

Rarely

Liver and biliary tract disorders

Very rare

Nervous system disorders

./p>

Very common

These symptoms usually occur at the end of a 2-hour oxaliplatin infusion or within hours of administration and decrease on their own over the next few hours or days and often reappear in subsequent cycles. They may occur or be exacerbated by exposure to low temperatures or cold objects. They usually manifest as the appearance of transient paresthesia, dysesthesia and hypoesthesia. Acute laryngeopharyngeal dysesthesia syndrome occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or dyspnea/feeling of choking without any objective respiratory disturbances (no cyanosis or hypoxia), or laryngospasm or bronchospasm (no stridor or wheezing). Other occasional symptoms, particularly cranial nerve dysfunction, both associated with the above adverse events and occurring in isolation: ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness of voice, sometimes described as vocal cord paralysis; tongue sensitivity or dysarthria, sometimes described as aphasia; trigeminal neuralgia, facial pain, eye pain, reduced visual acuity, narrowed visual fields. Other symptoms were: masseter spasm, muscle cramps, involuntary muscle contractions, muscle twitching, myoclonus; coordination problems, gait disturbances, ataxia, balance problems; feeling of tightness/pressure/discomfort/ pain in throat or chest.

The limiting toxicity of oxaliplatin is neurologic toxicity. It manifests as peripheral sensory neuropathy, characterized by peripheral dysesthesia and/or paresthesia with or without the development of convulsive muscle contractions, often provoked by cold (85% to 95% of patients).

The duration of these symptoms (the severity of which usually decreases between treatment cycles) increases with the number of therapy cycles. The occurrence of pain or functional abnormalities and their duration are indications for adjusting the dosing regimen or even withdrawing treatment (see Term of Use and Dosage, recommendations for adjusting the dosing regimen of oxaliplatin). These functional impairments, including difficulty performing precise movements, are consequences of sensory impairments. The risk of functional impairment for a cumulative dose of approximately 800 mg/m2 (e.g., 10 cycles) is < 15%. In most cases, neurological manifestations and symptoms decrease after discontinuation of treatment.

Frequently

Rarely

Mental disorders

Frequently

Infrequent

Musculoskeletal and connective tissue disorders

Very common

If this adverse reaction occurs, the patient should be examined to rule out hemolysis, as there have been rare reports of it developing.

Frequently

Disorders of the respiratory system, thoracic and mediastinal organs

Very common

Frequently

Rarely

vascular disorders.

very often

Frequently

Kidney and urinary tract disorders

Frequently

Very rare

Skin and subcutaneous tissue disorders

Very common

Frequently

Visual disturbances

Rarely

Overdose

Symptoms
In overdose, dose-dependent side effects increase. Allergic reactions described in the section Side effects do not depend on the dose of the drug Plaksat.
Treatment
An antidote to oxaliplatin is unknown. Close monitoring of the patient and strict control of hematologic parameters is recommended. Treatment is symptomatic.

Pregnancy use

Pregnancy

There is currently no available information on the safety of oxaliplatin in pregnant women. Reproductive toxicity has been observed in animal studies. The use of the drug Plaxat is contraindicated in women during pregnancy.

Trustworthy contraception must be used during treatment and after discontinuation for 4 months for women and 6 months for men.

Breast-feeding period

The excretion in the breast milk of women has not been studied. Breast-feeding is contraindicated during treatment with Plaxat.

Fertility

Plaxat has the property of inhibiting fertility.