Oxaliplatin-Teva, 5 mg/ml 20 ml

Code ATX: L01XA03

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. Oxaliplatin exhibits a wide spectrum of cytotoxic action. It also exhibits activity in vitro and in vivo in various cisplatin-resistant tumor models. A synergistic cytotoxic effect has been observed in combination with fluorouracil.

The study of the mechanism of action of oxaliplatin supports the hypothesis that biotransformed aqueous derivatives of oxaliplatin, interacting with DNA by formation of inter- and intrathecal bridges, inhibit DNA synthesis, which leads to cytotoxicity and anti-tumor effect.

Metastatic colorectal cancer (combination of oxaliplatin with fluorouracil/calcium folinate and bevacizumab)

The efficacy of oxaliplatin in combination with fluorouracil/calcium folinate (FOLFOX) and bevacizumab in metastatic colorectal cancer has been evaluated in two clinical trials, as first-line chemotherapy (the TREE trial) and second-line chemotherapy (the ECOG trial).

Pharmacokinetics

Invivo oxaliplatin undergoes active biotransformation and is not detectable in plasma by the end of its 2-hour administration at a dose of 85 mg/m², with 15% of the administered platinum in the blood and the remaining 85% rapidly distributed to the tissues or excreted by the kidneys. Platinum binds with blood plasma albumin and is excreted by the kidneys within the first 48 hours.

By the fifth day, about 54% of the total dose is found in the urine and less than 3% in the feces.

Elevation of oxaliplatin in patients with renal dysfunction of varying severity

The excretion of oxaliplatin correlates significantly with creatinine clearance (CK). Total plasma clearance of ultrafilterable platinum decreases by 34% at CK of 50-80 mL/min, by 57% at CK of 30-49 mL/min, and by 79% at CK less than 30 mL/min compared with that at CK greater than 80 mL/min. Renal clearance of ultrafilterable platinum and renal excretion of platinum are also reduced with decreased renal function.

Indications

Active ingredient

Composition

How to take, the dosage

Oxaliplatin is used in adults only.

Dosing regimen

Adjuvant therapy for colorectal cancer: intravenous 85 mg/m2 once every 2 weeks in combination with fluorouracil and calcium folinate for 12 cycles (6 months).

Treatment of metastatic colorectal cancer: intravenous 85 mg/m2 once every 2 weeks in combination with fluorouracil and calcium folinate or fluorouracil/calcium folinate and bevacizumab (until disease progression or development of unacceptable toxicity).

Fluorouracil, calcium folinate and bevacizumab dosing regimens when combined with oxaliplatin can be found in the dosing instructions for these drugs.

In this combination, oxaliplatin infusion should always be given after bevacizumab but before fluorouracil.

Treatment of ovarian cancer: Intravenously 85 mg/m2 once every 2 weeks in monotherapy or in combination with other chemotherapeutic agents.

The dosing regimens of fluorouracil, calcium folinate in combination with oxaliplatin can be found in the instructions for use of these drugs.

Method of administration

The infusion of oxaliplatin must always precede the administration of fluorouracil.

The intravenous infusion of the drug is given via an infusion system into the peripheral veins or via a central venous catheter simultaneously with an intravenous infusion of calcium folinate in 5% dextrose solution for 2-6 hours using a Y-shaped intravenous system connected immediately before the site of administration. The two drugs should not be mixed in the same infusion container. Calcium folinate must not contain trometamol as an excipient and must only be diluted with 5% dextrose solution and must never be diluted with alkaline solutions or sodium chloride and chloride containing solutions.

The oxaliplatin solution should not be mixed in the same infusion container with other drugs.

In case of extravasation (ingestion of the infusion solution with the drug into the surrounding tissues of the vein) its administration should be stopped immediately and the usual local symptomatic treatment should be initiated.

Hyperhydration is not required when using oxaliplatin. Repeated infusions of oxaliplatin are only given when neutrophil counts > 1500/μL and platelet counts > 75000/μL.

Recommendations for adjustment of the oxaliplatin administration regimen

The administered dose should be adjusted according to tolerability.

In case of hematologic abnormalities (neutrophil count < 1500/μL and/or platelet count < 75000/μL) after a cycle of chemotherapy or before the start of treatment (before the first cycle of treatment) the next cycle or first cycle is delayed until blood cell count is restored to acceptable values (to neutrophil count ≥ 1500/μL and/or platelet count ≥ 75000/μL). Before the start of treatment and before each subsequent cycle, a general blood count, leukocyte count, leukocyte formula and platelet count should be performed.

In the development of severe/life-threatening diarrhea, severe neutropenia (neutrophil count < 1000/μl), febrile neutropenia (fever of unknown genesis without clinically or microbiologically confirmed infection; defined as a combination of neutropenia [absolute leukocyte count < 1000/μl] with a single increase in body temperature <38.3 ºC or sustained elevation of body temperature >38 ºC for more than 1 hour), severe thrombocytopenia (platelet count < 50000/μl), oxaliplatin administration should be stopped until improvement or recovery of these parameters and the dose of oxaliplatin in subsequent administrations should be reduced by 25% in addition to each required reduction in the dose of fluorouracil in this case.

If neurologic symptoms (paresthesias, dysesthesias – manifestations of peripheral sensory neuropathy) occur, the following dosing regimen changes are recommended based on their duration and severity:

Interaction

No significant changes in the binding of oxaliplatin to plasma proteins inin vitro when concomitant use with erythromycin, salicylates, granisetron, paclitaxel and sodium valproate were observed.

In interaction with aluminum, precipitate formation and decreased activity of oxaliplatin may occur. It is recommended to exercise caution when using oxaliplatin together with other drugs prolonging the QT interval (because of the risk of severe ventricular arrhythmias, including ventricular tachycardia of the type “pirouette”). In case of combination with such drugs it is necessary to monitor QT interval carefully during ECG (see sect. “Indications”).

We recommend caution when using oxaliplatin with other drugs that may cause rhabdomyolysis (because of the increased risk of rhabdomyolysis, see section “Special Precautions”).

The drug Oxaliplatin-Teva is pharmaceutically incompatible with 0.9% sodium chloride solution and other saline (alkaline) solutions or solutions containing chlorides.

In patients receiving oxaliplatin at a dose of 85 mg/m2 immediately prior to administration of fluorouracil, no changes in blood fluorouracil concentrations were observed.

Special Instructions

Oxaliplatin should be used only in specialized oncology departments, and its administration should be carried out under the supervision of an oncologist experienced in working with antitumor drugs. Continuous monitoring of possible toxic effects during oxaliplatin treatment is mandatory. Regularly (once a week), as well as before each drug administration, monitoring of peripheral blood platelets and renal and hepatic function parameters should be performed.

In connection with the limited data regarding the safety of oxaliplatin use in patients with severe renal impairment, it is recommended to carefully balance risk and benefit before using the drug. Renal function should be closely monitored, and the initial dose of oxaliplatin in patients with severe renal impairment should be 65 mg/m2.

When using oxaliplatin, allergic reactions may occur during any cycle. If such anaphylactic reactions to the drug develop, its infusion should be stopped immediately and appropriate symptomatic therapy should be initiated immediately. In this case, re-injection of oxaliplatin is contraindicated. Before each infusion and periodically after administration of oxaliplatin a neurological examination should be performed to detect signs of neurotoxicity (peripheral sensory neuropathy), especially if the drug is combined with other drugs with neurotoxicity.

Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy after treatment completion. Local moderate paresthesias with functional impairment may persist for up to 3 years after completion of the adjuvant drug regimen.

Patients who develop acute pharyngeal dysesthesia during the infusion or within hours of a 2-hour infusion should have their next oxaliplatin infusion within 6 hours. To prevent the development of dysesthesia, the patient is advised to avoid hypothermia and the ingestion of excessively cold food and beverages during the infusion and for several hours after oxaliplatin infusion.

In the event of unexplained respiratory symptoms (dry cough, dyspnea, rales, or pulmonary infiltration seen on radiologic examination), treatment with oxaliplatin should be stopped until interstitial lung disease is excluded with additional studies.

Gastrointestinal toxicity, which is manifested by nausea and vomiting, may be significantly reduced or eliminated with the use of antiemetic medications. Severe diarrhea and/or vomiting may be associated with the development of dehydration, hypokalemia, metabolic acidosis, paralytic intestinal obstruction, small bowel obstruction and even renal dysfunction, especially when using a combination of oxaliplatin and fluorouracil.

Patients should be informed in detail about the possibility of diarrhea/vomiting and neutropenia after using oxaliplatin in combination with fluorouracil, with the recommendation that if they occur, they immediately contact their physician for urgent treatment for the development of these symptoms.

Cases of intestinal ischemia, including death, have been reported with oxaliplatin. If intestinal ischemia develops, oxaliplatin should be discontinued and appropriate treatment measures should be taken.

If oxaliplatin is combined with fluorouracil (with or without calcium folinate), the usual fluorouracil-related dose adjustment should be used in these cases if fluorouracil-associated toxicity develops (see

The signs and symptoms of posterior reversible leukoencephalopathy syndrome may include headache, intellectual disability, seizures, visual disturbances (from blurry vision to blindness), combined or not with elevated blood pressure (see side effects).

The diagnosis of posterior reversible leukoencephalopathy syndrome is confirmed with an MRI or CT scan of the brain.

The development of side effects such as: sepsis, neutropenic sepsis or septic shock (including deaths) has been reported during treatment with oxaliplatin (see section “Side effects”). The drug should be discontinued if any of these conditions develop. Cases of disseminated intravascular clotting, including death, have been reported with oxaliplatin.

If this condition develops, oxaliplatin should be discontinued and appropriate treatment measures should be taken.

Hemolytic-uremic syndrome is a life-threatening side effect. Oxaliplatin should be discontinued when the first symptoms of microangiopathic hemolytic anemia appear, such as: rapid decrease of hemoglobin with accompanying thrombocytopenia, increased concentrations of bilirubin, creatinine, urea nitrogen, serum lactate dehydrogenase (LDH) activity. Renal failure occurring with this may be irreversible after discontinuation of therapy and may require dialysis.

If abnormal laboratory values of liver function or portal hypertension are not clearly due to liver metastases, the patient should be evaluated for the very rare hepatic vascular lesion caused by oxaliplatin.

The development of QT interval prolongation is possible with oxaliplatin (see section “Adverse effects”), which can lead to severe ventricular arrhythmias, including ventricular pirouette tachycardia, possibly fatal. The drug should be used with caution in patients with a history of prolongation of the QT interval, or in patients with predisposing factors to prolongation of the QT interval (e.g., concomitant use with drugs that prolong the QT interval; in electrolyte disorders, such as hypokalemia, hypocalcemia or hypomagnesemia). If QT interval prolongation develops, treatment with oxaliplatin should be discontinued.

The development of rhabdomyolysis, including death, has been reported with oxaliplatin use. 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. Caution is recommended when concomitantly prescribing with oxaliplatin drugs that may cause rhabdomyolysis (see sections “Side effects”, “Interaction with other medicinal products”). When using oxaliplatin it is possible to develop duodenal ulcer and its potential complications such as ulcer bleeding and perforation of the ulcer, which may be fatal. If duodenal ulcer develops, treatment with the drug should be stopped and appropriate treatment measures should be taken.

The drug should not be administered intraperitoneally, since bleeding into the abdominal cavity may occur with such administration.

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

Women and men should use reliable contraceptive methods during treatment with oxaliplatin and after completion of treatment for 4 months for women and 6 months for men. When handling oxaliplatin, all the usual recommendations for handling cytotoxic drugs should be followed. If oxaliplatin comes into contact with the skin or mucous membranes, they should be washed immediately and thoroughly with water.

Influence on driving and operating machinery

Sight impairment, particularly transient vision loss (reversible after discontinuation of therapy), may pose a risk to patients when driving vehicles and engaging in other potentially hazardous activities. Therefore, patients should be warned about the possible influence of these phenomena on their ability to drive vehicles and engage in other potentially dangerous activities. In case of occurrence of the described adverse events, patients should refrain from performing the specified activities.

Synopsis

Contraindications

Cautious

Severe renal function impairment (creatinine clearance <30 ml/min) (renal function monitoring and dosing adjustment required). In patients with a history of QT interval prolongation or in patients with predisposing factors to QT interval prolongation (e.g., concomitant use with drugs that prolong the QT interval; in electrolyte disturbances such as hypokalemia, hypocalcemia or hypomagnesemia). Concomitant use with drugs that may cause rhabdomyolysis.

Side effects

The frequency of side effects below was defined according to the following criteria: very common (>1/10); common (>1/100, ≤1/10); infrequent (>1/1000, ≤1/100); rare (>1/10000, ≤1/1000); very rare (≤1/10000); frequency unknown (the frequency cannot be determined from available data).

Combination therapy with oxaliplatin and fluorouracil/calcium folinate

Laboratory and instrumental findings: very common – increased activity of “hepatic” transaminases, alkaline phosphatase, hyperbilirubinemia, increased lactate dehydrogenase activity, increased body weight; often – hypercreatininemia, reduced body weight.

Infectious and parasitic diseases:very often – infections; often – upper respiratory tract infections, neutropenic sepsis (including fatal outcomes); infrequently – sepsis (including fatal outcomes).

Blood and lymphatic system disorders:very frequently – 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, 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 < 50000/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 greater frequency when oxaliplatin was used in combination with fluorouracil compared to oxaliplatin monotherapy (40% vs < 3% of patients); often – febrile neutropenia (including grade 3-4); rarely – immune-allergic hemolytic anemia and thrombocytopenia, disseminated intravascular coagulation, including lethal outcomes (see. See section “Special Indications”).

Disorders of the digestive system: very frequently – nausea, vomiting, diarrhea, constipation (the development of dehydration, hypokalemia, metabolic acidosis, paralytic intestinal obstruction, small bowel obstruction, renal function disorders, especially when using a combination of oxaliplatin and fluorouracil), stomatitis or mucositis (mucous membrane inflammation), abdominal pain may be associated with severe diarrhea and/or vomiting; frequently, dyspepsia, gastroesophageal reflux disease, gastrointestinal bleeding, rectal bleeding; rarely, colitis, including pseudomembranous colitis caused by Clostridium difficile, pancreatitis.

Liver and urinary tract disorders: very rare – hepatic sinusoidal obstruction syndrome, also known as “venoocclusive liver disease” or pathological manifestations associated with this liver disease, including peliosis hepatitis, nodular regenerative hyperplasia, perisinusoidal fibrosis – whose clinical manifestations may include portal hypertension and/or increased serum “liver” transaminase activity.

Nervous system disorders:

very often:

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, either associated with the above adverse events or occurring in isolation: Ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness of the voice, sometimes described as vocal cord paralysis; impaired tongue sensitivity or dysarthria, sometimes described as aphasia; trigeminal neuralgia, facial pain, eye pain, decreased visual acuity, narrowed visual fields. In addition, the following symptoms have been observed: masticatory muscle spasm, muscle spasms, involuntary muscle contractions, muscle twitching, myoclonus; coordination disorders, gait disturbances, ataxia, balance disorders; feeling of pressure/discomfort/ pain in the 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%-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 disorders, as well as their duration, are indications for dosage adjustment or even withdrawal of treatment (see section “Dosage and administration”). These functional impairments, including difficulty in performing precise movements, are consequences of sensory disturbances. 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 diminish after discontinuation of treatment.

Frequently:dizziness, meningism.

Rarely:dysarthria, disappearance of deep tendon reflexes, Lhermitte’s symptom, posterior reversible leukoencephalopathy syndrome (see section “Special Precautions”).

Mental disorders: frequently – depression, insomnia; infrequently – nervousness.

Muscular and connective tissue disorders:very often – back pain (if this adverse reaction occurs, the patient should be examined to rule out hemolysis, because there have been rare reports of its development); often – arthralgia, bone pain.

Disorders of the respiratory system, thorax and mediastinum: very common – dyspnea, cough; often – hiccups, pulmonary embolism; rarely – acute interstitial lung injury, sometimes with fatal outcome; pulmonary fibrosis (see. section “Special Indications”).

Vascular disorders:very often – nasal bleeding; often – “hot flashes”, 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 common – skin lesions; frequent – alopecia (less than 5% of patients on monotherapy), erythematous rash, palmar and plantar erythrodysesthesia, increased sweating, nail changes.

VIight organ disorders: not infrequently, transient decrease in visual acuity; narrowing of visual fields, optic neuritis, transient loss of vision, reversible after discontinuation of treatment.

Hearing and labyrinth disorders: infrequent ototoxicity; rarely, deafness.

Disorders of the immune system: very common – allergic reactions, such as: skin rash (particularly urticaria), conjunctivitis, rhinitis; often – anaphylactic reactions, including bronchospasm, angioedema, decreased blood pressure, sensation of chest pain and anaphylactic shock.

General disorders and disorders at the site of administration: very often, increased fatigue, fever, chills (shivering) either due to the development of infections (with or without febrile neutropenia) or possibly due to immunologic mechanisms, asthenia, and injection site reactions.

The development of injection site reactions has been reported, including pain, hyperemia, edema and thrombosis.

Extravation (injection of the infusion solution with the drug into the surrounding tissues of the vein) can also result in local pain and inflammation that can be severe and lead to complications, including necrosis, especially when the drug is injected through a peripheral vein.

Metabolic and nutritional disorders: very frequently, anorexia, hyperglycemia, hypernatriemia; frequently, hypocalcemia.

Postmarketing experience

Infectious and parasitic diseases: frequency unknown – septic shock (including fatalities).

Disorders of the blood and lymphatic system: frequency unknown – hemolytic-uremic syndrome, secondary leukemia, pancytopenia.

Nervous system disorders: frequency unknown – seizures, cerebrovascular disorders of ischemic and hemorrhagic type.

Cardiac disorders: frequency unknown – QT interval prolongation, which may lead to severe ventricular arrhythmias, including ventricular tachycardia of the “pirouette” type, possibly with fatal outcome, acute coronary syndrome, including myocardial infarction.including myocardial infarction, coronary artery spasm and angina pectoris in patients treated with oxaliplatin in combination with 5-FU and bevacizumab.

Disorders of the respiratory system, thorax and mediastinum: frequency unknown – laryngospasm, pneumonia, and bronchopneumonia, including fatalities.

Gastrointestinal tract disorders: frequency unknown – intestinal ischemia (including lethal outcomes) (see section “Indications). Special indications, duodenal ulcer and its potential complications, such as ulcer bleeding and ulcer perforation (including lethal outcomes) (see section “Special indications”), esophagitis.

Musculoskeletal and connective tissue disorders: frequency unknown – rhabdomyolysis (including lethal outcomes) (see section “Special Instructions”).

Injuries, intoxications and complications of manipulation: frequent falls and fall-related injuries.

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 evaluated in 71 patients with metastatic colorectal cancer (TREE study).

In addition to the adverse reactions expected with the FOLFOX regimen, adverse reactions when combining FOLFOX with bevacizumab included: bleeding, proteinuria, impaired wound healing, gastrointestinal perforations and arterial hypertension.

For more information regarding the safety of bevacizumab, see the relevant instructions for use of this drug.

Overdose

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

Treatment: hematologic control and symptomatic therapy. An antidote to oxaliplatin is not known.

Pregnancy use

Pregnancy

There is currently no information on the safety of oxaliplatin in pregnant women. Based on the results of preclinical studies, it is assumed that oxaliplatin when used in therapeutic doses in humans will lead to fetal death and/or have teratogenic effects, and therefore the use of Oxaliplatin-Teva is contraindicated in pregnancy.

Effective methods of contraception should be used during treatment and should continue after the end of treatment for 4 months for women and 6 months for men.

Breastfeeding period

The release of oxaliplatin into breast milk has not been studied. Breastfeeding should be discontinued during treatment with Oxaliplatin-Teva.