Medaxa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEDAXA (MEDAXA)

Composition:

Active substance: oxaliplatin;

1 ml of concentrate for infusion solution contains 5 mg of oxaliplatin;

10 ml of concentrate for infusion solution contains 50 mg of oxaliplatin;

20 ml of concentrate for infusion solution contains 100 mg of oxaliplatin;

40 ml of concentrate for infusion solution contains 200 mg of oxaliplatin;

Excipient: water for injections.

Pharmaceutical form. Concentrate for infusion solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds. Oxaliplatin.

ATC code L01XA03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Oxaliplatin is an antineoplastic agent belonging to a new class of platinum compounds in which the platinum atom forms a complex with 1,2-diaminocyclohexane (DACH) and an oxalate group. Oxaliplatin is the single enantiomer (SP-4-2)-[(1R,2R)-cyclohexane-1,2-diamine-kN,kN’] [ethanedioato(2-)-kO1,kO2] platinum. Oxaliplatin exhibits a broad spectrum of both in vitro cytotoxicity and in vivo antitumor activity in various tumor models, including human colorectal cancer models. Oxaliplatin also demonstrates in vitro and in vivo activity in various tumor models resistant to cisplatin. When combined with 5-fluorouracil (5-FU), synergistic cytotoxic effects have been observed both in vitro and in vivo.

Studies on the mechanism of action, although not yet fully elucidated, indicate that aqueous derivatives formed as a result of oxaliplatin biotransformation interact with DNA by forming intra- and interstrand cross-links. This disrupts DNA synthesis, leading to cytotoxic and antitumor effects.

Clinical Efficacy and Safety

The efficacy of oxaliplatin (85 mg/m² every 2 weeks) in combination with 5-fluorouracil/folinic acid (5-FU/FA) in patients with metastatic colorectal cancer has been demonstrated in three clinical trials:

− In the EFCT2962 study, a comparative (Phase III) first-line therapy trial was conducted in which 420 patients were randomized into two groups: those receiving 5-fluorouracil/folinic acid alone (5-FU/FA) (LV5FU2, N = 210), and those receiving the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N = 210);

− In the EFCT4584 study, a comparative (Phase III) trial involving 821 patients previously treated with the combination of irinotecan (CPT-11) and 5-FU/FA and who were refractory to this regimen, patients were randomized into three groups: 5-FU/FA alone (LV5FU2, N = 275), oxaliplatin alone (N = 275), and the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N = 271);

− In the EFCT2964 study, a single-arm (Phase II) trial without a control group was conducted in patients previously treated with 5-FU/FA alone and who were refractory to this regimen, in which they received combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4, N = 57).

Two randomized clinical trials, EFCT2962 in first-line therapy patients and EFCT4584 in previously treated patients, demonstrated higher response rates and longer progression-free survival (PFS) / time to progression (TTP) compared to monotherapy with 5-FU/FA.

In the EFCT4584 study involving previously treated and refractory patients, median overall survival (OS) did not reach statistical significance between the oxaliplatin plus 5-FU/FA combination and control groups.

Table 1

Therapeutic response rates with the FOLFOX4 regimen compared to the LV5FU2 regimen

* NA — not applicable.

Table 2

Median progression-free survival (PFS) / median time to progression (TTP): FOLFOX4 regimen compared with LV5FU2 regimen

* NR — not applicable.

Table 3

Median overall survival (OS) of the FOLFOX4 regimen compared to the LV5FU2 regimen

* N/A — not applicable.

Among patients who had disease symptoms at the beginning of the study and who had previously received anticancer therapy (EF34584), significantly greater improvement in symptoms was observed in the group receiving oxaliplatin with 5-FU/FA, compared to the group receiving 5-FU/FA alone (27.7% vs. 14.6%, p = 0.0033).

In patients who had not received prior treatment (EFC2962), no statistically significant differences between the two groups were observed for any of the quality-of-life parameters. However, quality-of-life scores reflecting general health status and presence or absence of pain were generally better in the control group, whereas scores related to nausea and vomiting were worse in the group receiving oxaliplatin.

In the adjuvant setting, during the phase III comparative MOSAIC study (EFC3313), 2246 patients [899 patients with stage II disease (Duke's B2 stage) and 1347 patients with stage III disease (Duke's C stage)] were randomized into groups undergoing complete resection of the primary colorectal cancer tumor followed by treatment with 5-FU/FA (LV5FU2, N = 1123 (B2/C = 448/675)) or treatment with a combination of oxaliplatin and 5-FU/FA (FOLFOX4, N = 1123 (B2/C) = 451/672).

Table 4

EFC3313: 3-year disease-free survival (ITT analysis)* for the overall patient population

* The median follow-up after completion of treatment was 44.2 months (all patients were observed for at least 3 years after completion of treatment).

The study demonstrated a statistically significant overall benefit in 3-year disease-free survival for the combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4) compared to 5-FU/FA (LV5FU2) therapy.

Table 5

EFC3313: 3-year disease-free survival (ITT analysis)* by disease stage

* The median follow-up after completion of treatment was 44.2 months (all patients were observed for at least 3 years after completion of treatment).

Overall survival (ITT analysis)

At the time of analysis of 3-year disease-free survival, the primary endpoint of the MOSAIC study, 85.1% of patients remained alive in the FOLFOX4 treatment group compared to 83.8% in the LV5FU2 treatment group. This represented an overall 10% reduction in the risk of death in favor of FOLFOX4, which did not reach statistical significance (hazard ratio — 0.90).

Numerical values were 92.2% versus 92.4% in the subgroup of patients with stage II disease (Duke's stage B2) (hazard ratio = 1.01) and 80.4% versus 78.1% in the subgroup of patients with stage III disease (Duke's stage C) (hazard ratio — 0.87) for the FOLFOX4 and LV5FU2 treatment regimens, respectively.

Pediatric population

Monotherapy with oxaliplatin was evaluated in children during two phase I studies (69 patients) and two phase II studies (166 patients). A total of 235 children (aged from 7 months to 22 years) with solid tumors received treatment. The efficacy of oxaliplatin monotherapy in the treated pediatric population was not established. Enrollment in both phase II studies was discontinued due to lack of tumor response.

Pharmacokinetics

The pharmacokinetics of individual active compounds has not been defined. The pharmacokinetics of ultrafilterable platinum, representing a mixture of all free, active, and inactive platinum molecules in blood plasma, after 2-hour infusions of oxaliplatin at a dose of 130 mg/m² every 3 weeks for 1–5 cycles and oxaliplatin at a dose of 85 mg/m² every 2 weeks for 1–3 cycles is presented in Table 6.

Table 6

Summary of results from the assessment of pharmacokinetic parameters of platinum in plasma ultrafiltrate following repeated administration of oxaliplatin at a dose of 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks

Mean AUC0–48 and Cmax values were determined during cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

Mean values of AUC, Vss, and clearance were determined during cycle 1. Cmax, AUC, AUC0–48, Vss, and clearance values were determined using non-compartmental analysis. t1/2α, t1/2β, and t1/2γ values were determined using compartmental analysis (combined cycles 1–3).

Distribution

At the end of the 2-hour infusion, 15% of the administered platinum remains in systemic circulation, while the remaining 85% is rapidly distributed into tissues or excreted in urine. Irreversible binding to erythrocytes and plasma proteins results in half-lives of these matrices being close to the natural lifespan of erythrocytes and serum albumin. No accumulation of the drug was observed in plasma ultrafiltrate when administered either as 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks, with steady-state being achieved in this matrix during the first treatment cycle. Pharmacokinetic parameters generally show little variation between different patients and within the same patient.

Biological transformation

In vitro, biotransformation is believed to result from non-enzymatic degradation, and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation and is not detectable in unchanged form in plasma ultrafiltrate at the end of the 2-hour infusion. Subsequently, several cytotoxic metabolites were detected in systemic circulation, including monochloro-, dichloro-, and diaqua derivatives of DACH-platinum, along with some inactive conjugates.

Elimination

Platinum is predominantly excreted in urine within the first 48 hours after administration. By day 5, approximately 54% of the total dose is excreted in urine and less than 3% in feces.

Renal impairment

In patients with renal impairment, a statistically significant decrease in clearance was observed, from 17.6 ± 2.18 L/h to 9.95 ± 1.91 L/h, together with a statistically significant reduction in volume of distribution from 330 ± 40.9 to 241 ± 36.1 L. The impact of severe renal impairment on platinum clearance has not been adequately evaluated.

The effect of renal impairment on oxaliplatin distribution was studied in patients with varying degrees of renal dysfunction. Oxaliplatin was administered at a dose of 85 mg/m² to control group patients with normal renal function (creatinine clearance [CrCl] >80 mL/min, N=12), and to patients with mild (CrCl 50–80 mL/min, N=13) and moderate (CrCl 30–49 mL/min, N=11) renal impairment, and at a dose of 65 mg/m² to patients with severe renal impairment (CrCl <30 mL/min, N=5). Median drug exposure was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data during cycle 1 were obtained from 11, 13, 10, and 4 patients, respectively. An increase in platinum AUC in plasma ultrafiltrate (UF) and a decrease in total and renal clearance and Vss were observed with increasing severity of renal impairment, particularly in the small group of patients with severe renal impairment: point estimate (90% CI) of calculated mean ratio relative to normal renal function for AUC was 1.36 (1.08; 1.71), 2.34 (1.82; 3.01), and 4.81 (3.49; 6.64) in patients with mild, moderate, and severe renal impairment, respectively.

Oxaliplatin elimination correlates significantly with creatinine clearance. Total clearance of platinum in UF 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) in patients with mild, moderate, and severe renal impairment, respectively. Thus, total clearance of platinum in UF decreased by 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal renal function.

Renal clearance of platinum in UF decreased by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal renal function.

An increase in the beta-phase elimination half-life of platinum in UF was observed with increasing severity of renal impairment, particularly in the group with severe renal impairment. Although the number of patients with severe renal dysfunction was small, these data raise concerns regarding patients with severe renal impairment and should be carefully considered when prescribing oxaliplatin to patients with renal impairment (see sections “Dosage and administration”, “Contraindications”, and “Special precautions”).

Preclinical safety data

Target organs identified in preclinical species (mice, rats, dogs, and monkeys) in single- and multiple-dose studies included bone marrow, gastrointestinal tract, kidneys, testes, nervous system, and heart. Toxicity to target organs observed in animals is similar to that of other platinum-containing and DNA-damaging cytotoxic agents used in human cancer therapy, except for the effect on the heart. Cardiac effects were observed only in dogs and included electrophysiological disturbances leading to fatal ventricular fibrillation. Cardiotoxicity is considered specific to dogs not only because it was observed only in this species, but also because doses similar to those causing fatal cardiotoxicity in dogs (150 mg/m²) were well tolerated in humans. Preclinical studies using rat sensory neurons suggest that acute neurosensory symptoms associated with oxaliplatin may involve interaction with voltage-dependent Na⁺ channels.

Oxaliplatin shows mutagenic and clastogenic activity in mammalian test systems and causes embryofetal toxicity in rats. Oxaliplatin is likely to be a carcinogen, although carcinogenicity studies have not been conducted.

Clinical Characteristics

Indications. Medaxa should be used in combination with 5-fluorouracil (5-FU) and folinic acid (FA):

• for adjuvant treatment of stage III colorectal cancer (stage C according to Dukes' classification) following complete resection of the primary tumor;
• for treatment of metastatic colorectal cancer.

Contraindications. Medaxa is contraindicated in patients:

• with a history of hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• during breastfeeding;
• with myelosuppression prior to the first treatment cycle, evidenced by baseline neutrophil count < 2 × 10⁹/L and/or platelet count < 100 × 10⁹/L;
• with pre-existing peripheral sensory neuropathy causing functional impairment prior to the first treatment cycle;
• with severe renal impairment (creatinine clearance < 30 mL/min).

Special safety precautions

As with other potentially toxic substances, caution must be exercised when handling and preparing oxaliplatin solutions.

Handling this cytotoxic agent requires healthcare personnel to take all necessary precautions to ensure protection of the worker and the surrounding environment.

Solutions of cytotoxic agents for injection should be prepared by experienced personnel familiar with the specific characteristics of these medicinal products, under conditions ensuring protection of the environment and, above all, of the personnel handling these agents. A specifically designated area for preparation is required. Smoking, eating, or drinking are prohibited in this designated area.

Personnel must be provided with appropriate materials for handling the medicinal product, including medical gowns with long sleeves, protective masks, head covers, protective eyewear, sterile disposable gloves, protective coverings for work surfaces, and containers and bags for waste collection.

Special caution is required when handling patient excreta and vomitus.

Pregnant women should not handle cytotoxic drugs.

Any damaged packaging must be handled with adherence to these precautions and considered as contaminated waste. Contaminated waste must be incinerated in rigid, sealed containers with appropriate labeling.

If the oxaliplatin concentrate or infusion solution comes into contact with the skin, it should be immediately and thoroughly rinsed with water.

If the oxaliplatin concentrate or infusion solution comes into contact with mucous membranes, they should be immediately and thoroughly rinsed with water.

Any residual medicinal product, as well as all materials used for dissolving and administering oxaliplatin, must be disposed of according to standard procedures for cytotoxic waste disposal, in compliance with current regulations on the destruction of toxic waste.

Interaction with other medicinal products and other types of interactions

In patients who received a single dose of oxaliplatin 85 mg/m² immediately before administration of 5-fluorouracil, no alteration in the pharmacological effect of 5-fluorouracil was observed.

In vitro studies showed no significant displacement of plasma protein-bound oxaliplatin by the following medicinal products: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Caution and careful monitoring of the QT interval are required when oxaliplatin is administered concomitantly with other medicinal products known to prolong the QT interval (see section "Special precautions for use"). Caution is also recommended when oxaliplatin is used concomitantly with other medicinal products that may be associated with the development of rhabdomyolysis.

Patients receiving oxaliplatin should avoid vaccination with live or live attenuated vaccines (see section "Special precautions for use").

Special precautions for use

Oxaliplatin should be administered only in specialized oncology departments and under the supervision of an experienced oncologist.

Renal impairment. Patients with mild to moderate renal impairment should be closely monitored for adverse reactions, and the dose should be adjusted according to the level of toxicity.

Hypersensitivity reactions. Particular caution is required in patients with a history of allergic reactions to other platinum-containing agents. If anaphylactic reactions occur during infusion, administration of oxaliplatin must be immediately discontinued and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin to such patients is contraindicated. Cases of cross-reactivity with all platinum compounds have been reported, sometimes resulting in fatal outcomes.

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

Neurological symptoms. Neurological toxicity of oxaliplatin should be closely monitored, especially when used in combination with medicinal products characterized by specific neurotoxicity. A neurological examination should be performed before each administration and periodically thereafter. In patients who develop acute laryngopharyngeal dysesthesia during or within several hours after the 2-hour infusion, the next dose should not be administered earlier than 6 hours after the previous infusion. To prevent such dysesthesia, patients should be advised to avoid cold exposure and swallowing cold or fresh food and/or drinks for several hours after drug administration.

Peripheral neuropathy. If neurological symptoms (paresthesia, dysesthesia) occur, dose adjustment of oxaliplatin should be based on the duration and severity of these symptoms:

− if symptoms persist for more than 7 days and are bothersome to the patient, the next dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² (metastatic regimen) or 75 mg/m² (adjuvant regimen);

− if paresthesia without functional impairment persists until the next treatment cycle, the next dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² (metastatic regimen) or 75 mg/m² (adjuvant regimen);

− if paresthesia with functional impairment persists until the next cycle, oxaliplatin treatment should be discontinued;

− if these symptoms resolve after discontinuation of oxaliplatin, re-initiation of treatment may be considered.

Patients should be informed that symptoms of sensory peripheral neuropathy may persist after discontinuation of treatment. Mild localized paresthesia or paresthesia that may interfere with functional activity may be observed for more than 3 years after completion of adjuvant therapy.

Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of reversible posterior leukoencephalopathy syndrome (RPLS, also known as reversible posterior encephalopathy syndrome) have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, reversible neurological disorder that develops rapidly and may be associated with seizures, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. The diagnosis of RPLS is confirmed by brain imaging, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, and hematological changes. Gastrointestinal toxicity of oxaliplatin, manifested as nausea and vomiting, requires the use of antiemetic agents for prophylactic and/or therapeutic purposes.

Severe diarrhea and/or vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal dysfunction, particularly when oxaliplatin is used in combination with 5-fluorouracil.

Cases of intestinal ischemia, including fatal outcomes, have been reported with oxaliplatin use. In case of intestinal ischemia, oxaliplatin should be discontinued and appropriate treatment initiated.

In case of hematological toxicity (neutrophil count <1.5×10⁹/L or platelet count <50×10⁹/L), the next treatment cycle should be delayed until acceptable hematological parameters are restored. A complete blood count with differential should be performed before the start of oxaliplatin therapy and prior to each subsequent cycle. Myelosuppressive effects of the drug may be additive to those of concomitantly administered chemotherapeutic agents. Patients with severe and persistent myelosuppression are at high risk of infectious complications. Cases of sepsis, neutropenic sepsis, and septic shock, including fatal outcomes, have been observed in patients receiving oxaliplatin. If any of these events occur, oxaliplatin administration should be discontinued.

Patients should be informed that in case of diarrhea/vomiting, mucositis/stomatitis, or neutropenia following oxaliplatin and 5-fluorouracil administration, they should seek immediate medical attention for appropriate management of these symptoms.

In case of mucositis/stomatitis, with or without neutropenia, the next administration of the drug should be delayed until symptoms of mucositis/stomatitis decrease to Grade 1 or lower and/or until neutrophil count exceeds 1.5×10⁹/L. When oxaliplatin is combined with 5-fluorouracil (with or without folinic acid), dose adjustment of 5-fluorouracil is usually recommended due to its toxicity.

In case of Grade 4 diarrhea (WHO classification), Grade 3–4 neutropenia (neutrophil count <1×10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with absolute neutrophil count <1.0×10⁹/L), single temperature elevation >38.3°C or persistent temperature elevation >38°C for more than 1 hour, or Grade 3–4 thrombocytopenia (platelet count <50×10⁹/L), the dose of 5-fluorouracil should be reduced, and the dose of oxaliplatin should also be reduced from 85 mg/m² to 65 mg/m² (metastatic regimen) or 75 mg/m² (adjuvant regimen).

Pulmonary manifestations. In case of respiratory symptoms of unknown etiology, such as non-productive cough, dyspnea, crackles, or pulmonary infiltrates on X-ray, oxaliplatin treatment should be discontinued until interstitial pneumonitis or pulmonary fibrosis is ruled out by additional lung investigations.

Blood disorders. Hemolytic uremic syndrome (HUS) is a life-threatening adverse reaction (frequency not known). Oxaliplatin should be discontinued at the first signs suggestive of microangiopathic hemolytic anemia, such as rapid decline in hemoglobin levels accompanied by thrombocytopenia or elevated levels of bilirubin, creatinine, blood urea, or lactate dehydrogenase (LDH). Renal failure may be irreversible after drug discontinuation and may require dialysis.

Cases of disseminated intravascular coagulation (DIC), including fatal cases, have been reported with oxaliplatin treatment. In case of DIC, oxaliplatin should be discontinued and appropriate treatment initiated. Patients with conditions associated with DIC development, such as infections, sepsis, etc., require particularly close monitoring.

QT interval prolongation increases the risk of ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), which may be fatal. Careful periodic monitoring of the QT interval before and after oxaliplatin administration is required. Particular monitoring is indicated in patients with a history of QT prolongation or predisposition to QT prolongation, patients taking medicinal products known to prolong the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia.

Rhabdomyolysis. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving oxaliplatin. In case of muscle pain and swelling combined with weakness, fever, or dark urine, oxaliplatin should be discontinued. Appropriate treatment should be initiated upon confirmation of rhabdomyolysis diagnosis. Particular close monitoring is recommended when oxaliplatin is used concomitantly with medicinal products associated with rhabdomyolysis (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Gastrointestinal ulcers / bleeding and gastrointestinal ulcer perforation. Oxaliplatin treatment may lead to gastrointestinal ulceration and potential complications such as gastrointestinal bleeding and perforation, which may be fatal. In case of gastrointestinal ulcer development, oxaliplatin administration should be discontinued and appropriate treatment initiated.

Hepatic manifestations. In case of liver function abnormalities in laboratory tests, splenomegaly, or portal hypertension not caused by liver metastases, the possibility of rare vascular liver disorders induced by the drug should be considered.

Other warnings. Peritoneal hemorrhage may occur if oxaliplatin is administered intraperitoneally (which is not a recommended route of administration).

Immunosuppressive effect / increased susceptibility to infections

Administration of live or live attenuated vaccines to patients with immunosuppression due to chemotherapy may lead to serious or fatal infections.

Use during pregnancy or breastfeeding

Pregnancy. Currently, there are no data on the safety of oxaliplatin use in pregnant women. Reproductive toxicity was observed in animal studies (see section "Pharmacological properties"). Therefore, oxaliplatin is not recommended for use in pregnant women or women of childbearing potential who are not using contraception. Oxaliplatin use may be considered only after proper assessment of risk to the fetus and with patient consent.

Fertility / contraception in men and women. Oxaliplatin may adversely affect fertility. Genotoxic effects of oxaliplatin were observed in preclinical studies.

Men are advised to use reliable contraception during the entire period of oxaliplatin treatment and for 6 months after treatment discontinuation, and to consider sperm cryopreservation before starting therapy, as oxaliplatin may cause irreversible infertility.

Women of childbearing potential should use appropriate contraceptive methods during treatment and for 9 months after treatment completion.

Breastfeeding. It is unknown whether oxaliplatin or its metabolites are excreted in human breast milk. Breastfeeding is contraindicated during oxaliplatin treatment (see section "Contraindications").

Ability to influence the speed of reactions while driving or operating machinery

The effect of the medicinal product on the ability to drive or operate machinery has not been studied. However, since oxaliplatin administration increases the risk of dizziness, nausea, vomiting, and other neurological symptoms affecting gait and balance, treatment may have a minor or moderate effect on the ability to drive and operate machinery.

Additionally, visual disturbances, including temporary vision loss (which resolves after treatment discontinuation), may affect patients' ability to drive or operate machinery. Therefore, patients should be warned about the potential impact of these manifestations on their ability to drive and operate machinery.

Method of Administration and Dosage

The medicinal product is intended only for adult patients.

The recommended dose of oxaliplatin for adjuvant therapy is 85 mg/m² body surface area administered intravenously every two weeks for 12 cycles (total duration of treatment is 6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg/m² body surface area administered intravenously every two weeks until disease progression or until signs of intolerable toxicity occur.

The dose should be adjusted according to individual tolerance of the drug (see section "Special Warnings").

Oxaliplatin should always be administered before fluoropyrimidines, for example before 5-fluorouracil (5-FU).

Oxaliplatin is administered as a 2–6 hour intravenous infusion, diluted in 250–500 mL of 5 % glucose solution (50 mg/mL) to achieve a concentration between 0.2 mg/mL and 0.7 mg/mL; 0.7 mg/mL corresponds to the highest concentration used in clinical practice at an oxaliplatin dose of 85 mg/m².

Oxaliplatin is preferably administered in combination with continuous infusion of 5-fluorouracil.

For a treatment regimen repeated every two weeks, bolus administration combined with continuous infusion of 5-fluorouracil is recommended.

Special Patient Groups
Renal Impairment. Oxaliplatin is contraindicated in patients with severe renal insufficiency.

For patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m².

Hepatic Impairment. In a phase I study involving patients with varying degrees of hepatic insufficiency, the frequency and severity of hepatobiliary disorders were related to disease progression and pre-existing liver function abnormalities.

No specific dose adjustment has been performed in clinical trials for patients with hepatic impairment.

Elderly Patients. No increase in oxaliplatin toxicity has been observed when administered as monotherapy or in combination with 5-fluorouracil in patients aged over 65 years. Therefore, no special dose adjustment is required for elderly patients.

Method of Administration

Oxaliplatin is administered as an intravenous infusion. Administration of the drug does not require hyperhydration.

Oxaliplatin, diluted in 250–500 mL of 5 % glucose solution (50 mg/mL) to achieve a concentration of at least 0.2 mg/mL, should be infused over 2–6 hours into a central or peripheral vein. Infusion of oxaliplatin must always precede infusion of 5-fluorouracil. If hematoma develops at the injection site, administration of the drug should be immediately discontinued.

Special Warnings

Oxaliplatin must be diluted before administration. Only the recommended diluent — 5 % glucose solution — should be used for reconstitution of the concentrate for infusion solution.

When preparing oxaliplatin solutions, safety precautions must be followed, as with handling other potentially toxic substances.

Handling this cytotoxic agent requires healthcare personnel to take all necessary precautions to ensure protection of the worker and the surrounding environment.

Special Warnings Regarding Administration

• DO NOT use injection equipment containing aluminum.
• DO NOT administer the drug undiluted.
• Only 5 % glucose infusion solution should be used as diluent. DO NOT dilute with sodium chloride or chloride-containing solutions.
• DO NOT mix with other medicinal products in the same infusion bag or administer simultaneously through the same infusion line.
• DO NOT mix with alkaline drugs or solutions, including 5-fluorouracil, folinic acid preparations containing tromethamine as an excipient, or tromethamine salts of other substances. Alkaline drugs or solutions may adversely affect the stability of oxaliplatin.

Administration with Folinic Acid (sodium folinate or calcium folinate)

Intravenous infusion of oxaliplatin 85 mg/m² in 250–500 mL of 5 % glucose solution is administered simultaneously with intravenous infusion of folinic acid in 5 % glucose solution. The infusion lasts from 2 to 6 hours and is administered via a Y-type infusion system with a side port immediately before the infusion site.

These two medicinal products must not be mixed in the same infusion bag. Folinic acid must not contain tromethamine as an excipient. It should be diluted only with 5 % glucose solution and never with alkaline solutions, sodium chloride, or chloride-containing solutions.

Administration with 5-Fluorouracil

Oxaliplatin should always be administered before fluoropyrimidines, for example before 5-fluorouracil.

After oxaliplatin infusion, the infusion line must be flushed before administering 5-fluorouracil.

For additional information on medicinal products that can be combined with oxaliplatin, refer to the summary of product characteristics provided by the respective manufacturer.

Visual inspection of the concentrate for infusion solution should be performed before administration. Only clear solutions free from particulate matter should be used.

The vial is intended for single use only. Any unused solution must be discarded.

Dilution Prior to Infusion

Withdraw the required amount of concentrate from the vial and dilute in 250–500 mL of 5 % glucose solution to obtain an oxaliplatin concentration between 0.2 mg/mL and 0.7 mg/mL. Physical and chemical stability of oxaliplatin has been demonstrated at concentrations between 0.2 mg/mL and 2 mg/mL. Administer as an intravenous infusion.

After dilution with 5 % glucose solution, physicochemical stability of the solution is maintained for 48 hours at 2–8 °C or 6 hours at 25 °C.

However, from a microbiological standpoint, the prepared solution should be used immediately.

If the solution is not administered immediately after preparation, the responsibility for storage conditions and duration lies solely with the healthcare professional administering the solution. The storage period must not exceed 24 hours at 2–8 °C, provided dilution was performed under aseptic conditions in controlled and standardized environments.

Visual inspection of the solution should be performed before administration. Only clear solutions free from mechanical particles should be used.

NEVER use sodium chloride solution or chloride-containing solutions for dilution.

Compatibility of oxaliplatin infusion solution has been tested with standard PVC administration sets.

Infusion

Administration of oxaliplatin does not require prehydration. Oxaliplatin, diluted in 250–500 mL of 5 % glucose solution to achieve a concentration of at least 0.2 mg/mL, should be infused over 2–6 hours into a peripheral or central vein. When oxaliplatin is used in combination with 5-fluorouracil, oxaliplatin infusion must precede 5-fluorouracil administration.

Disposal

Any unused medicinal product and all materials used for dissolving and administering oxaliplatin must be disposed of according to standard procedures for cytotoxic waste disposal, in compliance with current regulations on toxic waste management.

Children. The medicinal product is intended for use in adults only. There are no established indications for the use of oxaliplatin in children. The efficacy of oxaliplatin as monotherapy in children with solid tumors has not been established.

Overdose. There is no known antidote for oxaliplatin. In case of overdose, an increase in the severity of adverse effects may be expected. Hematological monitoring should be performed along with symptomatic treatment of other signs of intoxication.

Adverse Reactions

During combination therapy with oxaliplatin and 5-fluorouracil/folinic acid (5-FU/FA), the most frequently observed adverse events were gastrointestinal disorders (diarrhea, nausea, vomiting, and mucositis), hematological disorders (neutropenia, thrombocytopenia), and neurological syndromes (acute and cumulative sensory peripheral neuropathy). Overall, these adverse effects were observed more frequently and were more severe with the combination of oxaliplatin and 5-FU/FA compared to monotherapy with 5-FU/FA.

The adverse reactions listed in Table 7 were observed during clinical trials of metastatic and adjuvant treatment (which included 416 and 1108 patients, respectively, in the oxaliplatin + 5-FU/FA treatment groups) and during post-marketing use.

The frequency of adverse effects is defined according to the following criteria: 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), unknown (cannot be estimated based on available data).

Table 7

* See details in the section "Description of selected adverse reactions" below.

** See section "Special precautions".

*** Microangiopathic hemolytic anemia associated with hemolytic-uremic syndrome (HUS), or hemolytic anemia with positive Coombs test (see section "Special precautions").

• Septic neutropenia is frequently observed, including cases with fatal outcome.

++ Very common allergic / hypersensitivity reactions, predominantly occurring during infusion and sometimes resulting in death. Common allergic reactions include skin rash (particularly urticaria), conjunctivitis, and rhinitis. Anaphylactic reactions, including bronchospasm, angioedema, arterial hypotension, chest pain, and anaphylactic shock, or anaphylactoid reactions have been reported. Hypersensitivity reactions of delayed type have also been reported, occurring several hours or even days after infusion.

+++ Fever and chills (shivering) are very commonly observed, either of infectious origin (with or without febrile neutropenia) or possibly of immunological origin.

++++ Injection site reactions have been observed, including localized pain, erythema, swelling, and thrombosis. Extravasation may also cause local pain and inflammation, which can be severe and lead to complications, including necrosis, particularly when oxaliplatin is administered via peripheral vein infusion (see section "Special safety measures").

Description of selected adverse reactions

Infections and infestations

Table 8

Incidence in patients (%)

Post-marketing experience (frequency unknown): septic shock, including fatal outcomes.

Blood and lymphatic system disorders

Table 9

Incidence of adverse reactions in patients (%), by grades

Rare (>1/10,000, <1/1,000): disseminated intravascular coagulation (DIC), including fatal cases (see section "Special precautions").

Adverse reactions observed during the post-marketing period (frequency unknown): hemolytic uremic syndrome; autoimmune pancytopenia; pancytopenia; secondary leukemia.

Immune system disorders

Table 10

Frequency of allergic reactions in patients (%), by severity

Disorders of the nervous system

Neurological toxicity of oxaliplatin is dose-dependent. It is mainly manifested as sensory peripheral neuropathies characterized by paresthesia and/or dysesthesia of the extremities, with or without spasms, often triggered by cold. These symptoms are observed in approximately 95 % of patients undergoing treatment. The duration of these symptoms, which usually regress between treatment cycles, increases with the number of treatment cycles. Depending on the duration of symptoms such as pain and/or functional impairment (see section "Special precautions for use"), dose adjustment or even discontinuation of treatment may be required. Functional impairment, such as difficulty in performing fine motor tasks, may result from sensory dysfunction. The risk of developing persistent symptoms at a cumulative dose of approximately 850 mg/m² (i.e., 10 cycles) is about 10 %, and at a cumulative dose of 1020 mg/m² (i.e., 12 cycles) is about 20 %. In most cases, neurological symptoms show improvement or complete resolution at the time of treatment discontinuation. Six months after completion of adjuvant therapy for colorectal cancer, 87 % of patients had no symptoms or only mild symptoms. After 3 years or more, approximately 3 % of patients had either persistent localized moderate paresthesia (2.3 %) or paresthesia that may interfere with functional activity (0.5 %). Acute neurosensory disturbances have been reported. These symptoms occur within several hours after drug administration, often triggered by exposure to cold. They are characterized by transient paresthesia, dysesthesia, and hypoesthesia. This acute pharyngolaryngeal dysesthesia syndrome, estimated to occur in 1 to 2 % of cases, is characterized by subjective sensations of dysphagia or dyspnea/choking without objective signs of respiratory distress syndrome (not accompanied by cyanosis or hypoxia), laryngospasm, or bronchospasm (without stridor or wheezing).

Although antihistamines and bronchodilators have been administered in such cases, these symptoms resolve rapidly even without treatment. Prolonging the infusion duration in subsequent cycles reduces the frequency of this syndrome (see section "Special precautions for use").

Other observed symptoms include jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorders, gait disturbances, ataxia, balance disorders, throat or chest tightness, depression, discomfort, and pain. Additionally, cranial nerve involvement may occur, presenting as ptosis, diplopia, aphonia, dysphonia, hoarseness (sometimes referred to as vocal cord paralysis), tongue dysesthesia, or dysarthria (sometimes referred to as aphasia), trigeminal neuralgia, facial or ocular pain, decreased visual acuity, and visual field disturbances.

Other neurological symptoms such as dysarthria, loss of deep tendon reflexes, and Lhermitte's sign have been reported during oxaliplatin treatment. Isolated cases of optic neuritis have also been observed.

Adverse reactions reported in the post-marketing period (frequency unknown): seizures, ischemic and hemorrhagic cerebrovascular events.

Cardiac disorders

Adverse reactions reported in the post-marketing period (frequency unknown): QT interval prolongation, which may lead to ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), potentially resulting in fatal outcomes (see section "Special precautions for use"), acute coronary syndrome, including myocardial infarction, coronary artery spasm, and angina in patients receiving oxaliplatin in combination with 5-FU or bevacizumab.

Respiratory, thoracic and mediastinal disorders

Adverse reactions reported in the post-marketing period (frequency unknown): laryngospasm; pneumonia and bronchopneumonia, including fatal cases.

Gastrointestinal disorders

Table 11

Frequency of adverse reactions in patients (%), by grade

Treatment or prophylactic administration of potent antiemetic agents is indicated.

Severe diarrhoea/vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal failure, particularly when oxaliplatin is used in combination with 5-fluorouracil. Adverse reactions observed in the post-marketing period (frequency unknown): intestinal ischaemia, including fatal cases (see section "Special precautions"), oesophagitis. Gastrointestinal ulcers and perforations, which may be fatal (see section "Special precautions").

Hepatobiliary disorders

Very rare (≤ 1/10,000): sinusoidal obstruction syndrome of the liver, also known as veno-occlusive liver disease, or related pathological changes including hepatic peliosis, nodular regenerative hyperplasia and perisinusoidal fibrosis. Clinical manifestations may include portal hypertension and/or elevated transaminase levels.

Post-marketing experience (frequency unknown): focal nodular hyperplasia.

Skin and subcutaneous tissue disorders

Adverse reactions observed in the post-marketing period (frequency unknown): leukocytoclastic vasculitis.

Musculoskeletal and connective tissue disorders

Adverse reactions observed in the post-marketing period (frequency unknown): rhabdomyolysis, including fatal cases (see section "Special precautions").

Renal and urinary disorders

Very rare (≤ 1/10,000): acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Shelf life. 3 years.

After dilution in 5% glucose, chemical and physical stability has been demonstrated for 48 hours at a temperature of +2°C to +8°C and for 6 hours at 25°C.

From a microbiological standpoint, the infusion preparation should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage, which generally should not exceed 24 hours at a temperature of 2°C to 8°C, provided that dilution was carried out under controlled and validated aseptic conditions.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Do not freeze. Keep out of reach of children.

Incompatibilities. The diluted medicinal product must not be mixed with other medicinal products in the same infusion bottle or infusion system. Oxaliplatin may be administered together with folic acid through a Y-line.

DO NOT MIX with alkaline drugs or solutions, including 5-fluorouracil, folic acid preparations containing tromethamine as an excipient, and tromethamine salts of other substances. Alkaline drugs or solutions may adversely affect the stability of oxaliplatin.

DO NOT DILUTE with saline solutions containing chlorides (including calcium, potassium and sodium chloride).

DO NOT MIX with other medicinal products in the same infusion vial or intravenous infusion system (see section "Method of administration and dosage" regarding concomitant administration with folic acid).

DO NOT USE injectable preparations containing aluminium.

Packaging. 10 ml (50 mg) or 20 ml (100 mg) or 40 ml (200 mg) in a vial; 1 vial in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Medac Gesellschaft für klinische Spezialpräparate mbH, Germany

Manufacturer's address and place of business

Theaterstrasse 6, 22880 Wedel, Germany