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

Adjuvant therapy for stage III colon cancer (stage C according to the Duke classification) after radical resection of the primary tumor in combination with fluorouracil/calcium folinate;
metastatic colorectal cancer (in combination with fluorouracil/calcium folinate);
metastatic colorectal cancer (as first-line therapy in combination with fluorouracil/calcium folinate and bevacizumab);
ovarian cancer (as 2nd line therapy).

Pharmacological effect

Pharmacotherapeutic group: antitumor agent – ​​alkylating compound

ATX code: L01ХА03

Pharmacological properties

Pharmacodynamics

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

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

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

In combination with fluorouracil, a synergistic cytotoxic effect is observed in vitro and in vivo.

Mechanism of action

A study of the mechanism of action of oxaliplatin confirms the hypothesis that biotransformed aqueous derivatives of oxaliplatin, interacting with deoxyribonucleic acid (DNA) through the formation of inter- and intrastrand bridges, suppress DNA synthesis, which causes cytotoxicity and antitumor effect.

Pharmacokinetics

Suction

The pharmacokinetics of the individual active derivatives have not been determined. The following are pharmacokinetic parameters 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 area every 3 weeks for 1-5 cycles or at a dose of 85 mg/m2 body surface area every 2 weeks for 1-3 cycles.

Generalized results of pharmacokinetic parameters of platinum in ultrafiltrate after several 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

Dose

Maximum concentration in blood plasma (Cmax), µg/ml

Area under the concentration-time pharmacokinetic curve (AUC0-48), mcg*h/ml

AUC, mcg*h/ml

α-half-life (t1/2α), h

β-half-life (t1/2β), h

γ-half-life (t1/2γ), h

Distribution volume (Vss), l

Clearance (CL), l/h

85 mg/m2

Averages

0.814

4,190

4.68

0.43

16.80

391

440

17.40

Standard Deviation

0.1936

0.647

1.40

0.35

5.74

406

199

6.35

130 mg/m2

Averages

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

Average AUC0-48 and Cmax values ​​were determined on the 3rd cycle (85 mg/m2) or on the 5th cycle (130 mg/m2).

The average values ​​of AUC, Vss, CL were determined on the 1st cycle.

Determination of the final concentration indicators Cmax, AUC, AUC0-48, Vss and CL was performed by non-compartmental analysis.

Determination of indicators t1/2α, t1/2β, t1/2γ was performed by compartment 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 circulation, and the remaining 85% is rapidly distributed to tissues or excreted through the kidneys. Due to irreversible binding to red blood cells and plasma albumin, the half-lives of platinum in these compounds are close to the time of natural turnover of red blood cells and blood plasma albumin. When oxaliplatin is administered every 2 weeks at a dose of 85 mg/m2 of body surface and every 3 weeks at a dose of 130 mg/m2 of body surface, no accumulation of platinum in the blood plasma ultrafiltrate (UPF) is observed, and an equilibrium state is achieved after the first course of therapy.

Individual and interindividual variability in pharmacokinetic parameters is usually small.

Metabolism

Biotransformation in vitro is considered to be the result of enzyme-free degradation. There were no signs of cytochrome P450-mediated metabolism of the DACG ring. In the human body, oxaliplatin is intensively biotransformed, and after the end of a 2-hour infusion of the drug, unchanged oxaliplatin is not detected in the UFP. Several cytotoxic products of oxaliplatin biotransformation have been identified in the systemic circulation, in particular monochloro-, dichloro- and diaqua-DACG platinum compounds.

Removal

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

Special patient groups

Kidney failure

The effect of renal impairment on the distribution of oxaliplatin has been studied in patients with varying degrees of renal impairment. Oxaliplatin was administered at a dose of 85 mg/m2 in the control group to patients with normal renal function (CLcr (creatinine clearance) > 80 ml/min, n=12) and patients with mild (CLcr = 50 to 80 ml/min, n=13) and moderate (CLcr = 30 to 49 ml/min, n=11) degrees of renal impairment, as well as at the dose 65 mg/m2 in patients with severe renal impairment (CLcr < 30 ml/min, n=5). The median number of treatment cycles was 9, 4, 6 and 3, respectively, and pharmacokinetic data during 1 treatment cycle 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 Vss with increasing severity of renal impairment, particularly in a small group of patients with severe renal impairment: the point estimate (90% CI (confidence interval)) of the estimated mean ratios by 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 impairment, respectively.

Oxaliplatin excretion was significantly correlated with creatinine clearance. The total clearance of platinum in the UFP was 0.74 (0.59; 0.92), 0.43 (0.33; 0.55) and 0.21 (0.15; 0.29), and Vss was 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. The total clearance of platinum in the UFP was therefore reduced by 26% in mild, 57% in moderate and 79% in severe renal impairment compared with patients with normal renal function, respectively.

Renal clearance of platinum in the 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 renal function.

An increase in t1/2β of platinum in the UFP was observed with an increase in the degree of renal dysfunction, mainly in the group of severe renal failure. Despite the small number of patients with severe renal impairment, these data are of interest and should be taken into account when prescribing oxaliplatin to this group of patients.

Special instructions

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

The drug Plaxat cannot be administered intraperitoneally, since such administration may cause bleeding into the abdominal cavity.

When using oxaliplatin, cases of intestinal ischemia, including deaths, sepsis, neutropenic sepsis, septic shock, disseminated intravascular coagulation, duodenal ulcer and its potential complications (ulcer bleeding, ulcer perforation) have been reported. In this case, you should stop using the drug Plaxat and take appropriate treatment measures.

Hemolytic-uremic syndrome

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

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

QT interval prolongation

When using oxaliplatin, QT prolongation may develop, which can lead to severe ventricular arrhythmias, including torsade de pointes (TdP), possibly fatal. In patients with a history of prolongation of the QT interval or patients with predisposing factors to prolongation of the QT interval (for example, when used simultaneously with drugs that prolong the QT interval, with electrolyte disturbances such as hypokalemia, hypocalcemia, hypomagnesemia), Plaxat should be used with caution. If prolongation of the QT interval develops, treatment with Plaxat should be discontinued.

Rhabdomyolysis

When using oxaliplatin, the development of rhabdomyolysis, including deaths, was observed. If muscle pain and swelling occur in combination with weakness, fever or dark urine, treatment with the drug should be discontinued. If the diagnosis of rhabdomyolysis is confirmed, then appropriate therapeutic measures should be taken. At the same time, it is recommended to exercise caution when simultaneously prescribing drugs that can cause the development of rhabdomyolysis with Plaxat.

Impaired kidney function

Patients with impaired renal function should be closely monitored for adverse reactions and the dose adjusted according to toxicity and degree of impairment (see Dosage and Administration).

Hypersensitivity reactions

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

If oxaliplatin is extravasated, administration should be stopped immediately and standard local symptomatic treatment should be prescribed.

Neurological toxicity

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

Neurological examination should be performed before each injection and at regular intervals thereafter.

Laryngopharyngeal dysesthesia

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

Neurological symptoms (paresthesia, dysesthesia)

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

If symptoms last more than 7 days and are bothersome, the next dose of oxaliplatin should be reduced from 85 to 65 mg/m2 (when treating metastatic cancer) or to 75 mg/m2 (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 (when treating metastatic cancer) or to 75 mg/m2 (when used as adjuvant therapy).
If paresthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.
If these symptoms return to normal after discontinuation of oxaliplatin treatment, reinitiation of treatment may be considered.

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

Posterior reversible leukoencephalopathy syndrome (RPLS)

Cases of posterior reversible leukoencephalopathy syndrome (PRL, also known as posterior reversible encephalopathy syndrome (PRES)) have been reported in patients receiving oxaliplatin during combination chemotherapy.

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

Nausea, vomiting, diarrhea, dehydration, hematological changes

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

Dehydration, intestinal obstruction, including paralytic, hypokalemia, metabolic acidosis and renal failure can be caused by severe diarrhea or vomiting, especially when using oxaliplatin in combination with fluorouracil.

If hematological toxicity occurs (neutrophil count <1.5*109/L or platelet count <50*109/L), the next course of therapy should be postponed until hematological parameters return to acceptable values. Before starting treatment, as well as before each subsequent course, it is necessary to conduct a general blood test with determination 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 the use of oxaliplatin and fluorouracil, so that they can immediately contact their doctor to initiate appropriate treatment.

If mucositis and/or stomatitis appears with or without neutropenia, the next course of treatment should be postponed until the mucositis and/or stomatitis is restored to stage 1 or less and/or until the neutrophil count is > 1.5*109/l.

When oxaliplatin is combined with fluorouracil (with or without calcium folinate), routine dose adjustment regimens should be used for fluorouracil-associated toxicity.

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

Respiratory system disorders

If respiratory symptoms of unknown etiology occur, such as nonproductive cough, dyspnea, wheezing, or pulmonary infiltrates visible on radiographs, oxaliplatin treatment should be withheld until interstitial pneumonitis is ruled out.

Hepatitis

In the case of abnormal liver function tests or portal hypertension not clearly associated with hepatic metastases, the possibility of very rare cases of oxaliplatin-induced hepatic vascular disease should be considered.

Impact on fertility

Genotoxic effects were observed in preclinical studies of oxaliplatin. Therefore, male patients treated with oxaliplatin are advised to use reliable methods of contraception during and for at least 6 months after treatment, and are also recommended to obtain advice on sperm conservation before starting treatment, as oxaliplatin may have a depressant, sometimes irreversible effect on the gonads. Women of reproductive age should use reliable methods of contraception during treatment.

Influence on the ability to drive vehicles and machinery

The effect 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 a car or use moving machines.

Visual disturbances, in particular short-term vision loss (reversible after stopping treatment), may affect the patient’s ability to drive and use machinery. Therefore, patients should be warned about the potential impact of these complications on the ability to drive a vehicle or operate machinery.

Active ingredient

Oxaliplatin

Composition

1 bottle with a dosage of 100 mg contains:
active ingredient: oxaliplatin 100.00 mg;
excipient: lactose monohydrate 900.00 mg.

Pregnancy

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 Plaxat is contraindicated in women during pregnancy.

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

Breastfeeding period

Excretion into breast milk of women has not been studied. During treatment with Plaxat, breastfeeding is contraindicated.

Fertility

The drug Plaxat has the property of inhibiting fertility.

Contraindications

Hypersensitivity to oxaliplatin or other components of the drug, as well as other platinum derivatives;
myelosuppression (neutrophil count < 2000/μl and/or platelets < 100,000/μl) before the start of the first course of treatment; peripheral sensory neuropathy with functional impairment before the start of the first course of treatment; pregnancy and breastfeeding; children under 18 years of age.

With caution

In patients with severe renal impairment (creatinine clearance
< 30 ml/min); in patients with a history of prolongation of the QT interval or in patients with factors predisposing to prolongation of the QT interval; when used simultaneously with drugs that can cause the development of rhabdomyolysis.

Side Effects

The frequency of side effects listed below was determined according to the following gradation: very often (>1/10), often (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including isolated reports; frequency is unknown (it is not possible to determine the frequency of occurrence based on available data).

Combination therapy with oxaliplatin and fluorouracil/calcium folinate

Laboratory and instrumental data

Very often

Increased activity of “liver” transaminases, alkaline phosphatase, hyperbilirubinemia, increased activity of lactate dehydrogenase, increased body weight.

Often

Hypercreatininemia, weight loss.

Infectious and parasitic diseases

Very often

Infections.

Often

Upper respiratory tract infections, neutropenic sepsis (including deaths).

Uncommon

Sepsis (including deaths).

Blood and lymphatic system disorders

Very often

Anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia.

– 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, for example, the incidence of anemia (80% compared with 60%), the incidence of neutropenia (70% compared with 15%), the incidence of thrombocytopenia (80% compared with from 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 alone or in combination with fluorouracil).

– Severe neutropenia (neutrophil count <1000/μL) occurred at a higher rate with oxaliplatin in combination with fluorouracil compared with oxaliplatin alone (40% versus <3% of patients).

Often

Febrile neutropenia (including grade 3-4).

Rarely

Immunoallergic thrombocytopenia and hemolytic anemia.
Disseminated intravascular coagulation, including deaths (see section Special instructions).

Digestive system disorders

Very often

Nausea, diarrhea, vomiting, constipation.

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

Stomatitis or mucositis (inflammation of the mucous membranes).
Stomach ache.

Often

Dyspepsia.
Gastroesophageal reflux disease.
Gastrointestinal bleeding.
Bleeding from the rectum.

Rarely

Colitis, including pseudomembranous colitis caused by Clostridium difficile.
Pancreatitis.

Disorders of the liver and biliary tract

Very rarely

Hepatic sinusoidal obstruction syndrome, also known as veno-occlusive liver disease or pathological manifestations associated with this liver disease, including peliosis hepatitis, nodular regenerative hyperplasia, perisinusoidal fibrosis, the clinical manifestations of which may be portal hypertension and/or increased liver transaminases in the blood serum.

Nervous system disorders

Very often

Acute neurosensory manifestations.

These symptoms usually occur at the end of a 2-hour oxaliplatin infusion or within a few hours after administration of the drug and improve spontaneously over the next few hours or days and often recur in subsequent cycles. They may occur or worsen when exposed to low temperatures or cold objects. They are usually expressed in the appearance of transient paresthesia, dysesthesia and hypoesthesia. Acute laryngopharyngeal dysesthesia syndrome occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or shortness of breath/suffocation without any objective respiratory distress (no cyanosis or hypoxia), or laryngospasm or bronchospasm (no stridor or wheezing). Other, sometimes occurring symptoms, in particular, dysfunction of the cranial nerves, both associated with the above adverse events and occurring in isolation: ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness, sometimes described as paralysis of the vocal cords; impaired sensitivity of the tongue or dysarthria, sometimes described as aphasia; trigeminal neuralgia, facial pain, eye pain, decreased visual acuity, narrowing of visual fields. In addition, the following symptoms were observed: spasm of the masticatory muscles, muscle spasms, involuntary muscle contractions, muscle twitching, myoclonus; loss of coordination, gait disturbance, ataxia, balance disorders; feeling of constriction/pressure/discomfort/pain in the throat or chest.

Dysesthesia or paresthesia of the limbs and peripheral sensory neuropathy.

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

– The duration of these symptoms (the severity of which usually decreases between treatment cycles) increases with the number of treatment cycles performed. The occurrence of pain or functional impairment, as well as their duration, are indications for adjusting the dosage regimen or even discontinuing treatment (see section Dosage and administration, recommendations for adjusting the dosage 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 (eg, 10 cycles) is <15%. In most cases, neurological signs and symptoms decrease after cessation of treatment.

Dysgeusia (impaired sense of taste).
Headache.

Often

Dizziness.
Meningism.

Rarely

Dysarthria.
Disappearance of deep tendon reflexes.
Lhermitte’s sign.
Posterior reversible leukoencephalopathy syndrome (see section Special instructions).

Mental disorders

Often

Depression.
Insomnia.

Uncommon

Nervousness.

Musculoskeletal and connective tissue disorders

Very often

Back pain.

If such an adverse reaction occurs, the patient should be examined to exclude hemolysis, as there have been rare reports of its development.

Often

Arthralgia.
Bone pain.

Respiratory, thoracic and mediastinal disorders

Very often

Dyspnea.
Cough.

Often

Hiccups.
Pulmonary embolism.

Rarely

Acute interstitial lung damage, sometimes fatal; pulmonary fibrosis (see section Special instructions).

Vascular disorders

Very often

Nosebleed.

Often

“Tides”.
Deep vein thrombosis.
Thromboembolism.
Increased blood pressure.

Renal and urinary tract disorders

Often

Hematuria.
Dysuria.

Very rarely

Acute tubular necrosis, acute interstitial nephritis, acute renal failure.

Skin and subcutaneous tissue disorders

Very often

Skin damage.

Often

Alopecia (less than 5% of patients with monotherapy).
Erythematous rash.
Palmoplantar erythrodysesthesia.
Increased sweating.
Changes in the nails.

Visual disorders

Rarely

Transient decrease in visual acuity; narrowing of visual fields, optic neuritis.
Transient vision loss, reversible after cessation of treatment.

Hearing and labyrinth disorders

Uncommon

Ototoxicity.

Rarely

Deafness.

Immune system disorders

Very often

Allergic reactions such as skin rash (in particular urticaria), conjunctivitis, rhinitis.

Often

Anaphylactic reactions, including bronchospasm, angioedema, decreased blood pressure, chest pain and anaphylactic shock.

General and administration site disorders

Very often

Increased fatigue.
Fever, chills (shivering), either due to the development of an infection (with or without febrile neutropenia), or possibly due to immunological mechanisms.
Asthenia.
Reactions at the injection site.

Administration site reactions including pain, pyrexia, swelling and thrombosis have been reported.

Extravasation (entry of the infusion solution with the drug into the tissue surrounding the vein) can also lead to local pain and inflammation, which can be severe and lead to complications, including necrosis, especially when oxaliplatin is administered through a peripheral vein.

Metabolic and nutritional disorders

Very often

Anorexia, hyperglycemia, hypernatremia.

Post-marketing experience

Infectious and parasitic diseases

Frequency unknown

Septic shock (including deaths).

Blood and lymphatic system disorders

Frequency unknown

Hemolytic-uremic syndrome.

Nervous system disorders

Frequency unknown

Cramps.

Heart disorders

Frequency unknown

Prolongation of the QT interval, which can lead to the development of severe ventricular arrhythmias, including torsade de pointes (TdP), which can be fatal.

Respiratory, thoracic and mediastinal disorders

Frequency unknown

Laryngospasm.

Gastrointestinal disorders

Frequency unknown

Intestinal ischemia (including deaths) (see section Special instructions).
Duodenal ulcer and its potential complications, such as ulcer bleeding and ulcer perforation (including deaths) (see Special Instructions).

Musculoskeletal and connective tissue disorders

Frequency unknown

Rhabdomyolysis (including deaths) (see section Special instructions).

Combination therapy of oxaliplatin with fluorouracil/calcium folinate (FOLFOX) and bevacizumab

The safety of the combination of oxaliplatin with fluorouracil/calcium folinate (FOLFOX) and bevacizumab as first-line therapy was assessed in 71 patients with metastatic colorectal cancer (TREE study). In addition to the adverse reactions expected from the FOLFOX regimen, adverse reactions with the combination of FOLFOX and bevacizumab included bleeding, proteinuria, impaired wound healing, gastrointestinal perforation, and hypertension. For more detailed information regarding the safety of bevacizumab, see the appropriate instructions for use of this drug.

Interaction

In patients receiving a single dose of 85 mg/m2 oxaliplatin immediately before fluorouracil administration, no changes in fluorouracil exposure were observed.
In vitro, no significant displacement of oxaliplatin from binding to plasma proteins was observed when used simultaneously with erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.
Pharmaceutical incompatibility
• Do not mix the drug solution with other medications in the same container, dropper or infusion system.
• Do not mix the drug solution with alkaline drugs or solutions, in particular fluorouracil, calcium folinate preparations containing trometamol as an excipient, and other active substances in the form of trometamol salts. Alkaline preparations and solutions negatively 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.

Overdose

Symptoms
In case of overdose, dose-dependent side effects increase. The allergic reactions described in the Side effects section do not depend on the dose of Plaxat.
Treatment
There is no known antidote to oxaliplatin. Close monitoring of the patient and strict monitoring of hematological parameters are recommended. Treatment is symptomatic.

Storage conditions

In a place protected from light at a temperature not exceeding 25 °C.
Keep out of the reach of children!

Shelf life

4 years.

Manufacturer

Actavis Italy S.p.A., Italy