Eloxatin^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis France (France)

Manufactured By

Sanofi-Aventis Deutschland, GmbH (Germany)

Labeled By

Sanofi-Aventis Vostok, ZAO (Russia)

ATC Code

L01XA03 (Oxaliplatin)

Active Substance

Oxaliplatin

Dosage Form

Eloxatin®

Concentrate for solution for infusion 5 mg/1 ml: fl. 10 ml, 20 ml, or 40 ml, 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, colorless solution.

Excipients: water for injections.

10 ml – colorless glass vials (1) – plastic contour cell blisters (1) – cardboard boxes.
20 ml – colorless glass vials (1) – plastic contour cell blisters (1) – cardboard boxes.
40 ml – colorless glass vials (1) – plastic contour cell blisters (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antineoplastic drug, alkylating compound. Oxaliplatin belongs to a new class of platinum derivatives in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane. Oxaliplatin exhibits a broad spectrum of cytotoxic activity. It is also active in vitro and in vivo in various tumor models resistant to cisplatin. Synergistic cytotoxic action is observed in combination with fluorouracil.

Study of the mechanism of action of oxaliplatin confirms the hypothesis that biotransformed aqueous derivatives of oxaliplatin, interacting with DNA by forming inter- and intrastrand crosslinks, suppress DNA synthesis, leading to cytotoxicity and an antitumor effect.

Pharmacokinetics

Distribution and Metabolism

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

Excretion

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

Pharmacokinetics in Special Clinical Situations

Excretion of oxaliplatin in patients with varying degrees of renal impairment: oxaliplatin excretion significantly correlates with CrCl. The total plasma clearance of ultrafilterable platinum decreases by 34% for CrCl 50-80 ml/min, by 57% for CrCl 30-49 ml/min, and by 79% for CrCl less than 30 ml/min compared to CrCl greater than 80 ml/min. Decreased renal function also reduces the renal clearance of ultrafilterable platinum and the renal excretion of platinum.

Indications

• Adjuvant therapy of stage III colon cancer (Duke’s C) after radical resection of the primary tumor (in combination with fluorouracil/calcium folinate);
• Disseminated colorectal cancer (in combination with fluorouracil/calcium folinate);
• Ovarian cancer as a second-line therapy.

ICD codes

Dosage Regimen

Oxaliplatin is used only in adults.

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

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

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

For the dosing regimens of fluorouracil and calcium folinate when combined with oxaliplatin, refer to the prescribing information for those drugs.

Method of Administration

Infusion of oxaliplatin should always precede the administration of fluorouracil.

IV infusion of the drug is administered via an infusion system into peripheral veins or through a central venous catheter simultaneously with IV infusion of calcium folinate in 5% dextrose solution over 2-6 hours using a Y-type IV administration system connected directly before the injection site. These two drugs must not be mixed in the same infusion container. Calcium folinate must not contain trometamol as an excipient and must be diluted only with 5% dextrose solution and never with alkaline solutions or sodium chloride and chloride-containing solutions.

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

In case of extravasation (leakage of the infusion solution with the drug into the tissues surrounding the vein), its administration must be stopped immediately and standard local symptomatic treatment initiated.

Hyperhydration is not required when using oxaliplatin.

Repeated administrations of oxaliplatin are performed only when the neutrophil count is >1500/µl and platelet count is >75,000/µl.

Recommendations for Adjusting the Oxaliplatin Administration Regimen

The administered dose should be adjusted based on tolerance.

In case of hematological disorders (neutrophil count <1500/µl and/or platelet count <75,000/µl) after a treatment course or before treatment initiation (before the first treatment course), the next course or the first course is postponed until blood cell counts recover to acceptable values (to neutrophil count ≥1500/µl and/or platelet count ≥75,000/µl). A complete blood count with accurate determination of leukocyte and platelet counts should be performed before treatment initiation and before each subsequent cycle.

If severe/life-threatening diarrhea, severe neutropenia (neutrophil count <1000/µl), or severe thrombocytopenia (platelet count <50,000/µl) develops, administration of oxaliplatin should be discontinued until these parameters improve or recover, and the dose of oxaliplatin in subsequent administrations should be reduced by 25% in addition to any required dose reduction of fluorouracil in this case.

If neurological symptoms occur (paresthesia, dysesthesia – manifestations of peripheral sensory neuropathy), the following changes in the dosing regimen are recommended based on their duration and severity:

• For neurological symptoms that bother the patient, lasting more than 7 days, or if paresthesia persists until the next treatment cycle without functional impairment, the subsequent dose of oxaliplatin should be reduced by 25%;
• For paresthesia with functional impairment persisting until the next cycle, administration of oxaliplatin should be discontinued;
• If the severity of neurological symptoms decreases after discontinuation of oxaliplatin, resumption of treatment may be considered.

Patients with Renal Impairment

In patients with normal renal function or with mild to moderate renal impairment, the recommended dose of the drug is 85 mg/m². In patients with severe renal impairment, the initial dose of oxaliplatin should be reduced to 65 mg/m².

Patients with Hepatic Impairment

Dose adjustment in patients with mild to moderate hepatic impairment is not required. There are no data on the use of oxaliplatin in patients with severe hepatic impairment.

Elderly Patients

The safety profile of oxaliplatin in combination with fluorouracil in patients over 65 years of age is similar to that observed in patients under 65 years of age. No dose regimen adjustment is required for elderly patients.

Rules for Preparing the Drug Solution

When preparing and administering Eloxatin^®, needles and other equipment containing aluminum must not be used. Only recommended solvents should be used for diluting the drug.

Do not dissolve or dilute with 0.9% sodium chloride solution and do not mix with other alkaline solutions or sodium chloride and chloride-containing solutions.

To prepare the infusion solution, the Eloxatin^® concentrate is diluted in 250-500 ml of 5% dextrose solution to achieve a concentration of at least 0.2 mg/ml. The infusion solution is recommended for use immediately after preparation. If the solution is not administered immediately after preparation, it can be stored for 24 hours at a temperature of 2°C (35.6°F) to 8°C (46.4°F).

A solution showing signs of precipitate formation must be discarded.

Only a clear solution should be used.

The drug must not be administered undiluted.

Adverse Reactions

The frequency of adverse effects listed below was determined according to the following gradation: very common (>1/10), common (>1/100, ≤1/10), uncommon (>1/1000, ≤1/100), rare (>1/10,000, ≤1/1000), very rare (≤ 1/10,000), including isolated reports; frequency unknown – cannot be estimated from the available data.

Combination therapy with oxaliplatin and fluorouracil/calcium folinate

Blood and Lymphatic System Disorders

Very common anemia, neutropenia, thrombocytopenia.

The incidence of these adverse effects increases with treatment with Eloxatin^® (85 mg/m² every 2 weeks) in combination with fluorouracil +/- calcium folinate compared to monotherapy with Eloxatin^® at a dose of 130 mg/m² every 3 weeks, for example, the incidence of anemia (80% compared to 60%), the incidence of neutropenia (70% compared to 15%), the incidence of thrombocytopenia (80% compared to 40%).

Severe anemia (hemoglobin <8 g/dL) or severe thrombocytopenia (platelet count <50,000/µl) occurred with the same frequency (<5% of patients when Eloxatin^® was used as monotherapy or in combination with fluorouracil).

Severe neutropenia (neutrophil count <1000/µl) occurred more frequently with the use of Eloxatin^® in combination with fluorouracil compared to monotherapy with Eloxatin^® (40% compared to 15% of patients).

Common febrile neutropenia (including grade 3-4).

Rare autoimmune hemolytic anemia and thrombocytopenia.

Gastrointestinal Disorders

Very common: nausea, vomiting, diarrhea, stomatitis or mucositis (inflammation of mucous membranes), abdominal pain.

Severe diarrhea and/or vomiting may be associated with the development of dehydration, hypokalemia, metabolic acidosis, intestinal obstruction, renal function impairment, especially when using the combination of Eloxatin^® and fluorouracil.

Common gastrointestinal bleeding.

Rare colitis, including pseudomembranous colitis caused by Clostridium difficile, pancreatitis.

Hepatobiliary Disorders

Very rare: 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 or increased activity of liver transaminases, serum ALP.

Nervous System Disorders

Very common: acute neurosensory manifestations (these symptoms usually occur at the end of the 2-hour infusion of Eloxatin^® or within a few hours after drug administration and resolve on their own within the next few hours or days and often recur in subsequent cycles; they may occur or worsen upon exposure to low temperatures or cold objects; they are usually expressed as transient paresthesia, dysesthesia, and hypesthesia).

Acute laryngopharyngeal dysesthesia syndrome occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or shortness of breath/sensation of choking without any objective respiratory disorders (absence of cyanosis or hypoxia) or laryngospasm or bronchospasm (absence of stridor or wheezing). Other occasionally occurring symptoms, particularly cranial nerve function disorders, or associated with the above adverse events or occurring in isolation: ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness, sometimes described as vocal cord paralysis; tongue sensory impairment or dysarthria, sometimes described as aphasia; trigeminal neuralgia, facial pain, eye pain, decreased visual acuity, visual field constriction. Additionally, the following symptoms were observed: jaw muscle spasm, muscle cramps, involuntary muscle contractions, muscle twitching, myoclonus; coordination impairment, gait disturbance, ataxia, balance disorders; feeling of tightness/sensation of pressure/discomfort/pain in the pharynx or chest.

Dysesthesia or paresthesia of the extremities and peripheral sensory neuropathy. The dose-limiting toxicity of Eloxatin^® is neurological toxicity. It manifests as peripheral sensory neuropathy characterized by peripheral dysesthesia and/or paresthesia with or without the development of convulsive muscle contractions, often triggered by cold (85-95% of patients).

The duration of these symptoms, which usually decrease between treatment cycles, increases with the number of treatment cycles performed. The occurrence of pain or functional impairment and their duration are indications for dose regimen adjustment or even treatment discontinuation. These functional impairments, including difficulties 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 decrease after treatment cessation.

Dysgeusia (taste disturbance).

Rare dysarthria, loss of deep tendon reflexes, Lhermitte’s sign, reversible posterior leukoencephalopathy syndrome.

Musculoskeletal and Connective Tissue Disorders

Very common back pain (if such an adverse reaction occurs, the patient should be examined to rule out hemolysis, as there have been rare reports of its development).

Common arthralgia.

Respiratory, Thoracic and Mediastinal Disorders

Very common: cough.

Common hiccups.

Rare acute interstitial lung disease, sometimes fatal, pulmonary fibrosis.

Cardiac Disorders

Very common epistaxis.

Common deep vein thrombosis, thromboembolism, increased blood pressure.

Renal and Urinary Disorders

Very rare acute tubular necrosis, acute interstitial nephritis, acute renal failure.

Skin and Subcutaneous Tissue Disorders

Common alopecia (less than 5% of patients with monotherapy).

Eye Disorders

Rare transient decreased visual acuity, visual field constriction, optic neuritis, transient vision loss, reversible after treatment cessation.

Ear and Labyrinth Disorders

Rare deafness.

Immune System Disorders

Very common allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis.

Common: anaphylactic reactions, including bronchospasm, angioedema, decreased blood pressure, chest pain sensation, and anaphylactic shock.

Metabolism and Nutrition Disorders

Very common anorexia.

General Disorders and Administration Site Conditions

Very common weakness; fever, chills (shivering) either due to the development of infections (with or without febrile neutropenia) or due to a possible immune reaction, asthenia.

Administration Site Reactions

Very common reports of reactions at the injection site, including pain, redness, swelling, and thrombosis. Extravasation (leakage of the infusion solution with the drug into the tissues surrounding the vein) can also lead to local pain and inflammation, which can be severe and lead to complications, including necrosis, especially when Eloxatin^® is administered into a peripheral vein.

Postmarketing Experience

Blood and Lymphatic System Disorders frequency unknown – hemolytic-uremic syndrome.

Nervous System Disorders frequency unknown – seizures.

Contraindications

• Myelosuppression (neutrophil count < 2000/µl and/or platelet count < 100,000/µl) before the start of the first treatment course;
• Peripheral sensory neuropathy with functional impairment before the start of the first treatment course;
• Pregnancy;
• Lactation (breastfeeding);
• Children under 18 years of age;
• Hypersensitivity to oxaliplatin and other components of the drug, as well as other platinum derivatives.

Use with caution in patients with severe renal impairment (CrCl < 30 ml/min) (renal function monitoring and dose regimen adjustment are required).

Use in Pregnancy and Lactation

Eloxatin^® is contraindicated for use during pregnancy and lactation (breastfeeding).

Women and men of reproductive potential must use reliable methods of contraception during treatment with the drug.

Use in Hepatic Impairment

Liver function tests should be performed regularly (once a week) and before each administration of Eloxatin^®.

Dose adjustment in patients with mild to moderate hepatic impairment is not required. There are no data on the use of oxaliplatin in patients with severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in patients with severe renal impairment (CrCl < 30 ml/min) (monitoring of renal function and dose adjustment are required).

The recommended dose for patients with normal renal function or with mild to moderate renal impairment is 85 mg/m². In patients with severe renal impairment, the initial dose of oxaliplatin should be reduced to 65 mg/m².

Pediatric Use

The drug is prescribed only for adults.

Geriatric Use

The safety profile of oxaliplatin in combination with fluorouracil in patients over 65 years of age is similar to that observed in patients under 65 years of age. No dose adjustment is required in elderly patients.

Special Precautions

Eloxatin^® should be used only in specialized oncology departments, and its administration should be supervised by an oncologist experienced in the use of anticancer drugs.

Constant monitoring for the development of possible toxic effects during treatment with oxaliplatin is mandatory.

Peripheral blood cell counts and renal and liver function tests should be monitored regularly (once a week) and before each administration of Eloxatin^®.

Due to limited data on the safety of the drug in patients with severe renal impairment, the risk and benefit should be carefully weighed before use. Renal function must be strictly monitored. The initial dose of oxaliplatin in patients with severe renal impairment should be 65 mg/m².

A neurological examination should be performed before each administration and periodically after administration of oxaliplatin to detect signs of neurotoxicity (peripheral sensory neuropathy), especially if the drug is combined with other neurotoxic agents.

Patients should be informed about the possibility of persistent peripheral sensory neuropathy symptoms after the end of the treatment course. Mild local paresthesias with functional impairment may persist for up to 3 years after the end of treatment according to the adjuvant regimen.

In patients who develop acute laryngopharyngeal dysesthesia during the infusion or within several hours after a 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours. To prevent the development of dysesthesia, the patient is advised to avoid cooling and the consumption of very cold food and drinks during and for several hours after the administration of Eloxatin^®.

If unexplained respiratory symptoms occur (dry cough, dyspnea, wheezing, or evidence of pulmonary infiltration on X-ray), treatment with oxaliplatin should be discontinued until interstitial pneumonitis is ruled out by further lung investigations.

Gastrointestinal toxicity, manifested by nausea and vomiting, can be significantly reduced or eliminated by the use of antiemetics. Severe diarrhea and/or vomiting may be associated with the development of dehydration, hypokalemia, metabolic acidosis, paralytic ileus, intestinal obstruction, and even renal impairment, especially when using the combination of Eloxatin^® and fluorouracil.

Patients should be fully informed about the possibility of developing diarrhea/vomiting and neutropenia after using oxaliplatin in combination with fluorouracil, so that if they occur, the patient can immediately contact their doctor for urgent necessary treatment.

When oxaliplatin is combined with fluorouracil (with or without calcium folinate), in case of fluorouracil-related toxicity, the dose adjustment of fluorouracil usually recommended in such cases should be applied (see the prescribing information for fluorouracil).

Signs and symptoms of reversible posterior leukoencephalopathy syndrome may include headache, altered mental status, seizures, visual disturbances (from blurred vision to blindness), with or without elevated blood pressure. The diagnosis of reversible posterior leukoencephalopathy syndrome is confirmed by magnetic resonance imaging or computed tomography of the brain.

In case of abnormal liver function tests or development of portal hypertension, which are not clearly a consequence of liver metastases, the patient should be examined for the very rare occurrence of hepatic vascular injury.

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

All usual precautions for handling cytotoxic drugs should be observed when using oxaliplatin. If oxaliplatin comes into contact with the skin or mucous membranes, they should be washed immediately and thoroughly with water.

Effect on ability to drive and use machines

Visual disturbances, especially transient vision loss (reversible after discontinuation of therapy), may pose a risk to patients when driving or engaging in other potentially hazardous activities.

Overdose

Symptoms: more pronounced manifestation of side effects can be expected.

Treatment: there is no known antidote for oxaliplatin. Close monitoring of the patient and strict control of hematological parameters are recommended. Treatment is symptomatic.

Drug Interactions

No significant change in the plasma protein binding of oxaliplatin in vitro was observed when co-administered with erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Interaction with aluminum may lead to precipitation and reduced activity of oxaliplatin.

No changes in the plasma concentration of fluorouracil were observed in patients receiving Eloxatin^® at a dose of 85 mg/m² immediately before fluorouracil administration.

Pharmaceutical incompatibility

Eloxatin^® is pharmaceutically incompatible with 0.9% sodium chloride solution and other saline (alkaline) solutions or solutions containing chlorides.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 30°C (86°F); do not freeze.

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.