Oxaliplatin "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OXALIPLATIN „EBEWE” (OXALIPLATIN „EBEWE”)

Composition:

Active substance: oxaliplatin;

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

Excipients: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear, colorless to pale yellow solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds.

ATC code L01XA03.

Pharmacological properties.

Pharmacodynamics.

Oxaliplatin (cis-[oxalato(trans-1,2-diaminocyclohexane)platinum]) 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 an enantiomer.

Oxaliplatin exerts cytotoxic effects in vitro and antitumor effects in vivo against a broad spectrum of test systems, including human colorectal cancer models. In vitro and in vivo activity of oxaliplatin has been demonstrated in various tumor models resistant to cisplatin.

When oxaliplatin is used in combination with 5-fluorouracil, a synergistic cytotoxic effect is observed both in vitro and in vivo.

The mechanism of action of oxaliplatin has not been fully elucidated; however, studies have shown that aqueous derivatives formed during the biotransformation of oxaliplatin interact with DNA, leading to the formation of interstrand and intrastrand cross-links in DNA. This results in disruption of DNA synthesis and produces cytotoxic and antitumor effects.

Pharmacokinetics.

The pharmacokinetics of individual active metabolites has not been studied. Pharmacokinetic parameters (PKPs) for ultrafiltered platinum (a mixture of all unbound, active and inactive platinum compounds) after 2-hour infusions of oxaliplatin at a dose of 130 mg/m² body surface area every 3 weeks (1–5 cycles) or at a dose of 85 mg/m² body surface area every 2 weeks (1–3 cycles) are presented in the table below.

Dose	Cmax (μg/mL)	AUC0-48 (μg·h/mL)	AUC (μg·h/mL)	t½ α (h)	t½ ß (h)	t½ γ (h)	Vss (L)	CL (L/h)
85 mg/m²
Mean values	0.814	4.19	4.68	0.43	16.8	391	440	17.4
Standard deviation	0.193	0.647	1.40	0.35	5.74	406	199	6.35
130 mg/m²
Mean values	1.21	8.20	11.9	0.28	16.3	273	582	10.1
Standard deviation	0.10	2.40	4.60	0.06	2.90	19.0	261	3.07

At the end of a two-hour infusion, 15% of the administered platinum remains in the systemic circulation, while 85% is rapidly distributed into tissues or excreted in urine. Due to irreversible binding to erythrocytes and plasma albumin, the elimination half-lives of platinum in these compounds are close to the natural turnover times of erythrocytes and plasma albumin. When oxaliplatin is administered every 2 weeks at a dose of 85 mg/m² body surface area or every 3 weeks at a dose of 130 mg/m² body surface area, no accumulation of platinum in plasma ultrafiltrate is observed, and steady-state is achieved already after the first treatment cycle. Inter- and intrasubject variability of pharmacokinetic parameters is generally low.

In vitro biotransformation is considered to result from non-enzymatic degradation. There is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane ring.

In humans, oxaliplatin undergoes extensive biotransformation. After completion of the two-hour infusion, unchanged oxaliplatin is no longer detectable in plasma ultrafiltrate. Several cytotoxic biotransformation products of oxaliplatin have been identified in the systemic circulation, including mono-chloro, di-chloro, and di-aquo DACH-platinum species. Later, inactive platinum conjugates are also detected. Platinum is excreted predominantly in urine (within 5 days, 54% of the dose is excreted in urine and < 3% in feces). Most of the platinum is eliminated within 48 hours after drug administration. In patients with impaired renal function, platinum clearance is significantly lower compared to patients without such impairment (9.95 ± 1.91 L/h versus 17.6 ± 2.18 L/h). In addition, the volume of distribution is statistically significantly lower in these patients (241 ± 36.1 L versus 330 ± 40.9 L). Platinum clearance in patients with severe renal impairment has not been studied.

Clinical characteristics.

Indications.

Used in combination with 5-fluorouracil (5-FU) and folinic acid for:

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

Contraindications.

• Hypersensitivity to oxaliplatin in the medical history or to excipients.
• Bone marrow suppression prior to the first cycle of therapy (neutrophil count < 2 × 10^9/L and/or platelet count < 100 × 10^9/L).
• Breastfeeding period.
• Peripheral sensory neuropathy with functional impairment prior to the first treatment cycle.
• Severe renal impairment (creatinine clearance < 30 mL/min).

Safety precautions

Instructions for personnel

Due to the toxicity of oxaliplatin, the following precautions are recommended:

• Personnel must be adequately trained and informed about proper handling techniques.
• Standard procedures for handling cytotoxic agents must be followed.
• Pregnant healthcare workers must not handle the drug.
• Personnel must wear protective clothing, including gowns, caps, masks, goggles, and disposable gloves when handling the drug.
• A designated area must be established for handling the drug, where eating, drinking, and smoking are strictly prohibited. Work surfaces must be covered with disposable absorbent paper with a protective film backing.
• Residual drug, all materials and items used during reconstitution, dilution, and administration of oxaliplatin solutions, as well as cleaning materials (including gloves), must be collected in special containers or bags for toxic waste and disposed of according to standard hospital procedures for cytotoxic waste, in compliance with current regulations for hazardous waste disposal.
• Vomitus and patient excreta must be handled with caution.
• In case of accidental contact of the concentrate or oxaliplatin solutions with skin or mucous membranes, immediately rinse thoroughly with large amounts of water.

Interaction with other medicinal products and other types of interactions.

Single-dose administration of oxaliplatin at 85 mg/m^2 body surface area immediately before 5-fluorouracil does not affect the exposure of 5-fluorouracil.

In vitro studies have shown no significant displacement of plasma protein-bound oxaliplatin when co-administered with drugs such as erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Particular caution is required if the patient is receiving oxaliplatin together with other medicinal products known to prolong the QT interval. In cases of concomitant use of such drugs, careful monitoring of the QT interval is necessary (see section "Special precautions for use"). Concomitant use of medicinal products associated with rhabdomyolysis should be administered with particular caution when used with oxaliplatin (see section "Special precautions for use").

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

Special precautions for use.

Treatment with oxaliplatin should only be carried out in specialized oncology departments under the supervision of experienced oncologists.

Renal impairment

Due to limited data on the use of oxaliplatin in patients with moderate renal impairment, the drug should be administered only after careful assessment of benefit versus risk. Regular monitoring of renal function and dose adjustments based on toxic effects are required when treating patients with renal dysfunction.

Hypersensitivity reactions

Patients with a history of allergic reactions to platinum compounds should be closely monitored. In case of an anaphylactic/anaphylactoid reaction to oxaliplatin, the infusion must be stopped immediately and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin is contraindicated in such cases. Cases of cross-reactivity with all platinum compounds have been reported, sometimes resulting in fatal outcomes.

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

Neurological symptoms

Neurological toxicity of oxaliplatin should be carefully monitored, especially when used in combination with medicinal products known to have specific neurotoxic effects. A neurological examination should be performed before each administration and periodically thereafter.

If a patient develops laryngo-pharyngeal dysesthesia during or within several hours after the 2-hour oxaliplatin infusion, the next dose should be administered no sooner than 6 hours later. To prevent such dysesthesia, patients should be informed about the necessity to avoid cold exposure and refrain from ingesting cold food and/or drinks for several hours after drug administration.

Peripheral neuropathy

In case of symptoms of neurotoxic effects (paresthesia, dysesthesia), subsequent doses of oxaliplatin should be reduced depending on the duration and severity of symptoms:

• If symptoms last longer than 7 days and are bothersome to the patient, the next dose of oxaliplatin should be reduced from 85 to 65 mg/m² body surface area (in the treatment of metastatic colorectal cancer) or to 75 mg/m² body surface area (in adjuvant therapy of colon cancer).
• If paresthesia without functional impairment is present at the start of the next treatment cycle, the next dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² body surface area (in the treatment of metastatic colorectal cancer) or to 75 mg/m² body surface area (in adjuvant therapy of colon cancer).
• If paresthesia with functional impairment is present at the start of the next treatment cycle, oxaliplatin should be discontinued.
• If neurotoxic symptoms resolve after discontinuation of the drug, re-evaluation of the possibility of resuming therapy may be considered.

Patients should be informed that symptoms of peripheral sensory neuropathy may persist after completion of oxaliplatin treatment (moderate localized paresthesia or paresthesia interfering with functional activity may last up to three years after completion of adjuvant oxaliplatin therapy).

Reversible posterior leukoencephalopathy syndrome (RPLS)

Cases of reversible posterior leukoencephalopathy syndrome (RPLS, also known as posterior reversible encephalopathy syndrome – PRES) have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, rapidly developing, reversible neurological disorder that may present with seizures, hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section "Adverse reactions"). The diagnosis of RPLS is confirmed by brain imaging techniques, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration and hematological changes

Prophylactic and/or therapeutic use of antiemetics may help alleviate gastrointestinal toxic effects (nausea and vomiting). Severe diarrhea/vomiting may lead to dehydration, paralytic ileus, gastrointestinal obstruction, hypokalemia, metabolic acidosis, and renal dysfunction, especially when oxaliplatin is used in combination with 5-fluorouracil.

Cases of intestinal ischemia, sometimes fatal, have been reported in patients treated with oxaliplatin. In case of intestinal ischemia, treatment should be discontinued and appropriate measures taken (see section "Adverse reactions").

In case of hematological toxic effects (neutrophil count < 1.5 × 10⁹/L and/or platelet count < 50 × 10⁹/L), the next treatment cycle with oxaliplatin should be delayed until hematological parameters recover. A complete blood count with differential leukocyte count should be performed before initiation of treatment and prior to each treatment cycle.

If a patient develops mucositis/stomatitis with or without neutropenia, the next treatment cycle should be delayed until mucositis/stomatitis severity decreases to grade 1 or lower and/or neutrophil count increases to ≥ 1.5 × 10⁹/L.

In addition to effects observed during concomitant chemotherapy, myelosuppressive effects may also occur. Patients with severe and persistent myelosuppression are at high risk of developing infectious complications. Sepsis, neutropenic sepsis, and septic shock have been observed in patients receiving oxaliplatin, including fatal cases (see section "Adverse reactions"). In case of these symptoms, oxaliplatin should be discontinued.

Patients should be informed about the risk of developing diarrhea/vomiting, mucositis/stomatitis, and neutropenia, and advised to seek immediate medical attention if such symptoms occur.

When oxaliplatin is used in combination with 5-fluorouracil (with or without folinic acid), 5-fluorouracil doses should be adjusted according to toxicity using standard guidelines.

In case of grade IV diarrhea, grade III–IV neutropenia (neutrophil count < 1.0 × 10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically confirmed infection, absolute neutrophil count < 1.0 × 10⁹/L, single temperature rise > 38.3°C or persistent temperature > 38°C for more than one hour), or grade III–IV thrombocytopenia (platelet count < 50 × 10⁹/L), oxaliplatin doses should be reduced from 85 mg/m² to 65 mg/m² body surface area (in the treatment of metastatic colorectal cancer) or to 75 mg/m² body surface area (in adjuvant therapy of colon cancer), and 5-fluorouracil doses should also be reduced.

Pulmonary manifestations

In case of unexplained respiratory symptoms (such as non-productive cough, dyspnea, crackles, or infiltrates on chest X-ray), oxaliplatin should be discontinued until a pulmonological evaluation is performed to rule out interstitial lung disease or pulmonary fibrosis.

Immunosuppressive effect/increased susceptibility to infections: Administration of live or attenuated vaccines to patients whose immune system is compromised by chemotherapy, including oxaliplatin, may lead to serious or fatal infections. Live vaccines should not be administered during oxaliplatin therapy. Inactivated or killed vaccines may be administered, but the immune response may be weaker.

Hematological system disorders

Hemolytic uremic syndrome (HUS) is a life-threatening adverse reaction (frequency unknown). Oxaliplatin should be discontinued at the first signs of microangiopathic hemolytic anemia, as well as sudden drop in hemoglobin accompanied by thrombocytopenia, elevated bilirubin, creatinine, blood urea nitrogen, and serum lactate dehydrogenase levels. Renal failure may persist after discontinuation of the drug; in such cases, hemodialysis should be considered.

Cases of disseminated intravascular coagulation (DIC), including fatal cases, have been reported in patients treated with oxaliplatin. In case of DIC diagnosis, treatment should be discontinued and appropriate therapy initiated (see section "Adverse reactions"). Particular attention should be paid to patients with conditions associated with DIC, such as infections, sepsis, etc.

QT interval prolongation

Prolongation of the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes, potentially leading to fatal outcomes (see section "Adverse reactions"). The QT interval should be closely monitored continuously before and after oxaliplatin administration. Particular attention should be paid to patients with a history of QT interval prolongation, those predisposed to QT prolongation, patients taking medicinal products that may prolong the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia. In case of QT interval prolongation, oxaliplatin treatment should be discontinued (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rhabdomyolysis

Cases of rhabdomyolysis, including fatal cases, have been reported in patients treated with oxaliplatin. In case of muscle pain and swelling accompanied by weakness, fever, or dark urine, oxaliplatin treatment should be discontinued. Appropriate measures should be taken upon confirmation of rhabdomyolysis diagnosis. Concomitant use of medicinal products associated with rhabdomyolysis should be performed with particular caution during oxaliplatin therapy (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Gastric ulcer/gastrointestinal hemorrhage and perforation

Oxaliplatin may cause gastric ulceration and potentially life-threatening complications such as gastrointestinal hemorrhage and perforation. In case of gastric ulcer, oxaliplatin treatment should be discontinued and appropriate measures taken (see section "Adverse reactions").

Hepatic manifestations

In case of abnormal liver function tests or portal hypertension not attributable to liver metastases, the possibility of rare drug-induced hepatic vascular disorders should be considered.

Intraperitoneal hemorrhage may occur when oxaliplatin is administered intraperitoneally (a route of administration not approved by the manufacturer).

Pregnancy.

For use during pregnancy, see section "Use during pregnancy or breastfeeding".

Fertility.

Genotoxic effects of oxaliplatin have been observed in preclinical studies. Men are advised to use effective contraception throughout the entire period of oxaliplatin treatment and for at least 6 months after discontinuation of therapy, and to consider sperm cryopreservation prior to starting treatment, as oxaliplatin may cause infertility, including irreversible infertility. Women should avoid pregnancy during treatment and use reliable contraception (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Pregnancy. The safety of oxaliplatin use during pregnancy has not been studied. Preclinical data indicate that oxaliplatin at therapeutic doses may have embryolethal and/or teratogenic effects on the fetus; therefore, the drug is not recommended during pregnancy and in women of childbearing potential who are not using contraception.

Fertility. The drug may be administered only after careful benefit-risk assessment, patient counseling regarding fetal risk, and patient consent. Effective contraception should be used during therapy and for 4 months after completion in women and for 6 months in men. Oxaliplatin may cause infertility.

Breastfeeding. Excretion of oxaliplatin into human milk has not been studied; therefore, breastfeeding must be discontinued during oxaliplatin treatment.

Ability to affect driving and use of machines.

The effect of oxaliplatin on the ability to drive or operate machinery has not been studied; however, potential adverse effects (such as dizziness, nausea, vomiting, neurological symptoms, visual disturbances) may impair such abilities to some extent, and patients should be warned accordingly.

Method of Administration and Dosage

The medication is intended for use in adults only!

Dosage for Adults

The recommended dose of oxaliplatin for adjuvant therapy is 85 mg/m² of body surface area, administered as an intravenous infusion every 2 weeks, for a total of 12 cycles (overall treatment duration of 6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg/m² of body surface area, administered as an intravenous infusion every 2 weeks until disease progression or until signs of intolerable toxicity appear.

Dosage adjustments should be made based on treatment tolerability.

Oxaliplatin must always be administered before fluoropyrimidines (e.g., 5-fluorouracil).

Oxaliplatin is administered as a 2- or 6-hour intravenous infusion, in volumes of 250 or 500 ml, diluted in 5% (50 mg/ml) glucose solution, to achieve a concentration between 0.2 and 0.7 mg/ml; the concentration of 0.7 mg/ml is the maximum used in clinical practice when administering oxaliplatin at a dose of 85 mg/m² of body surface area.

Oxaliplatin is typically used in combination with 5-fluorouracil, which is administered as a prolonged infusion. When using a regimen with 2-week intervals, 5-fluorouracil may be given as bolus or prolonged infusions. Pre-treatment hyperhydration of the patient is not required when administering oxaliplatin.

Dosage in Patients with Renal Impairment

Oxaliplatin is contraindicated in patients with severe renal impairment (see section "Contraindications"). In cases of mild or moderate renal impairment, treatment may be initiated at the standard recommended doses, with subsequent dose adjustments based on the severity of toxic effects (see "Special Warnings and Precautions for Use").

Dosage in Patients with Hepatic Impairment

The effect of oxaliplatin in patients with severe hepatic impairment has not been sufficiently studied.

No increase in acute toxicity has been observed when treating patients with oxaliplatin who have abnormal liver function test results prior to the start of therapy; therefore, dose adjustments are generally not required in such cases.

Dosage in Elderly Patients

No increase in the frequency of severe toxic effects has been observed in patients aged 65 years and older receiving oxaliplatin monotherapy or combination therapy with oxaliplatin and 5-fluorouracil; therefore, dose adjustments are generally not required in these cases.

Method of Administration

• Oxaliplatin must not be administered using infusion systems containing aluminum components or through needles containing aluminum.
• The oxaliplatin concentrate with a concentration of 5 mg/ml must not be administered undiluted.
• Oxaliplatin must not be dissolved or diluted in sodium chloride solution.
• Oxaliplatin must not be mixed with any other medicinal products in the same infusion bag/bottle or administered simultaneously through the same infusion line (especially 5-fluorouracil, alkaline medicinal products, tromethamine, or folinic acid preparations containing tromethamine). Oxaliplatin should always be administered before fluoropyrimidines, for example, before 5-fluorouracil. After oxaliplatin administration, the infusion system must be flushed before administering 5-fluorouracil.
• Oxaliplatin may be administered simultaneously with folinic acid through a Y-type connector placed immediately before the injection site. However, oxaliplatin and folinic acid must not be mixed in the same infusion bag/bottle. Folinic acid must be diluted in 5% glucose solution.
• After oxaliplatin administration, the infusion line and vein must be flushed with 5% glucose solution.

Preparation of Infusion Solution

Oxaliplatin must be diluted prior to administration. For dilution of the concentrate to prepare the infusion solution, only 5% glucose solution should be used.

The required volume of oxaliplatin concentrate (5 mg/ml) should be diluted in 250–500 ml of 5% glucose solution. The final concentration of the infusion solution should not be less than 0.2 mg/ml. The prepared solution should be inspected visually. Only clear solutions without particulate matter should be used.

Children

The safety and efficacy of oxaliplatin have been studied only in adult patients; specific information regarding use in pediatric patients is lacking. The medicinal product is intended for use in adults only.

Overdose

There is no known specific antidote for oxaliplatin. In cases of overdose, more severe adverse effects may be expected. Regular monitoring of hematological parameters is required. Management of other intoxication symptoms should be symptomatic.

Adverse Reactions

During combination therapy with oxaliplatin and 5-fluorouracil/folinic acid (5-FU/FA), the most commonly observed adverse effects involve the gastrointestinal tract (diarrhea, nausea, vomiting, and mucositis), the hematologic system (neutropenia, thrombocytopenia), and the nervous system (acute and cumulative peripheral sensory neuropathy). Overall, the frequency and severity of adverse effects are higher with combination therapy using oxaliplatin and 5-FU/FA than with 5-FU/FA alone.

The adverse reactions listed below were observed during clinical trials and from post-marketing experience.

The frequency of the adverse reactions listed below is defined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

Infections and infestations
Very common – infections; common – rhinitis, upper respiratory tract infections, neutropenic sepsis+; uncommon – sepsis+.

Blood and lymphatic system disorders
Very common – anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia; common – febrile neutropenia; rare – hemolytic anemia, immune-mediated thrombocytopenia; frequency not known – autoimmune pancytopenia.

Immune system disorders
Very common – allergy/allergic reactions++.

Metabolism and nutrition disorders
Very common – anorexia, hyperglycemia, hypokalemia, hypernatremia; common – dehydration, hypocalcemia; uncommon – metabolic acidosis.

Psychiatric disorders
Common – depression, insomnia; uncommon – restlessness.

Nervous system disorders
Very common – peripheral sensory neuropathy, sensory disturbances, taste disturbances, headache; common – dizziness, motor nerve neuritis, meningeal irritation; rare – dysarthria, reversible posterior leukoencephalopathy syndrome (RPLS), and Lhermitte's sign (see section "Special precautions"); frequency not known – loss of deep tendon reflexes and Lhermitte's sign.

Eye disorders
Common – conjunctivitis, visual disturbances; rare – transient decrease in visual acuity, visual field defects; temporary vision loss resolving after discontinuation of treatment, optic neuritis.

Ear and labyrinth disorders
Uncommon – ototoxic effects, deafness.

Vascular disorders
Common – hemorrhage, hyperemia, arterial hypertension, deep vein thrombophlebitis, pulmonary embolism.

Respiratory, thoracic and mediastinal disorders
Very common – dyspnea, cough, epistaxis; common – hiccups, pulmonary embolism; rare – interstitial lung disease, sometimes fatal; pulmonary fibrosis**.

Gastrointestinal disorders
Very common – diarrhea, nausea, vomiting, stomatitis/mucositis, abdominal pain, constipation; common – dyspepsia, gastroesophageal reflux, gastrointestinal bleeding, rectal bleeding; uncommon – intestinal paresis, intestinal obstruction; rare – colitis (including colitis and diarrhea caused by Clostridium difficile), pancreatitis; frequency not known – esophagitis.

Skin and subcutaneous tissue disorders
Very common – dermatologic reactions, alopecia; common – skin exfoliation (hand-foot syndrome), erythematous rash, skin rash, increased sweating, nail changes; frequency not known – hypersensitivity vasculitis.

Musculoskeletal and connective tissue disorders
Very common – back pain; common – arthralgia, bone pain.

Renal and urinary disorders
Common – dysuria, hematuria, painful and frequent urination.

General disorders and administration site conditions
Very common – pyrexia+++, fatigue, asthenia, pain, injection site reactions++++.

Investigations
Very common – increased liver enzymes, increased alkaline phosphatase in blood, increased bilirubin in blood, increased lactate dehydrogenase in blood, weight gain (in adjuvant therapy); common – increased creatinine levels, weight loss (in metastatic cancer treatment).

Injury, poisoning and procedural complications
Common – falls.

* See details below.
** See section "Special precautions".

• Septic neutropenia, including fatal cases, is frequently observed.
  ++ Very common: allergic/allergic-type reactions, mostly occurring during infusion and sometimes resulting in death. Common allergic reactions include skin rash (especially urticaria), conjunctivitis, and rhinitis. Anaphylactic reactions, including bronchospasm, angioedema, arterial hypotension, chest pain, and anaphylactic shock or anaphylactoid reactions, have also been reported.

Hypersensitivity reactions of delayed type have also been reported, occurring several hours or even days after infusion.

+++ Very common: increased body temperature, chills (shivering), either of infectious origin (with or without febrile neutropenia) or possibly of immunologic origin.

++++ Injection site reactions observed include 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 infused into a peripheral vein (see section "Special precautions").

Description of selected adverse reactions

Disorders of the blood and lymphatic system

Frequency as a percentage of affected patients (%) and severity grade

Oxaliplatin and 5-FU/FA, 85 mg/m2, every 2 weeks	Treatment of metastases			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Anemia	82.2	3	< 1	75.6	0.7	0.1
Neutropenia	71.4	28	14	78.9	28.8	12.3
Thrombocytopenia	71.6	4	< 1	77.4	1.5	0.2
Febrile neutropenia	5.0	3.6	1.4	0.7	0.7	0.0
Neutropenic sepsis	1.1	0.7	0.4	1.1	0.6	0.4

Single cases:

Disseminated intravascular coagulation (DIC), including fatal cases (see section "Special precautions for use").

Post-marketing data (frequency unknown):

Hemolytic uremic syndrome, autoimmune pancytopenia, secondary leukopenia.

Infections and infestations

Adverse reaction frequency in patients (%)

Oxaliplatin and 5-FU/FA 85 mg/m2 Every 2 weeks	Metastatic treatment All grades	Adjuvant therapy All grades
Sepsis (including sepsis and neutropenic sepsis)	1.5	1.7

Post-marketing surveillance data (frequency unknown):

Septic shock, including fatal outcomes.

Immune system disorders.

Oxaliplatin in combination with 5-FU/FA 85 mg/m2 every 2 weeks	Treatment of metastases			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Allergic reactions/allergies	9.1	1	< 1	10.3	2.3	0.6

Adverse reactions observed during the post-marketing period (frequency unknown): delayed-type hypersensitivity reactions.

Nervous system disorders

The dose-limiting factor in oxaliplatin treatment is neurotoxicity. Sensory peripheral neuropathy develops, characterized by paresthesia and/or dysesthesia of the extremities with or without spasms, often triggered by cold. These symptoms occur in nearly 95% of patients. The duration of these symptoms, which usually regress between treatment cycles, increases with the number of treatment cycles.

The onset of pain and/or functional impairment, depending on the duration of symptoms, indicates the need for dose adjustment or even discontinuation of the drug.

Functional impairments, particularly difficulty in performing fine motor movements, may result from sensory disturbances. The risk of developing persistent symptoms is approximately 10% at a cumulative dose of 850 mg/m² body surface area (10 cycles) and approximately 20% at a cumulative dose of 1020 mg/m² body surface area (12 cycles).

In most cases, neurological symptoms regress or completely resolve after treatment is discontinued. Six months after completion of adjuvant therapy for colorectal cancer, 87% of patients had no or only mild neurological symptoms. After 3 years, approximately 3% of patients had persistent localized paresthesia of moderate severity (2.3%) or paresthesia interfering with functional activity (0.5%). Acute neurosensory symptoms occurring within several hours after oxaliplatin infusion, often triggered by cold, have been reported. These may include transient paresthesia, dysesthesia and hypesthesia, or acute laryngopharyngeal dysesthesia syndrome. This syndrome, with a frequency of 1–2%, is characterized by subjective sensations of dysphagia or dyspnea without objective clinical signs of respiratory distress (no cyanosis or hypoxia), or laryngospasm, or bronchospasm (without stridorous breathing). Other possible manifestations include spasm of masticatory muscles, tongue dysesthesia, dysarthria, and chest pressure sensation. Although antihistamines and bronchodilators have been used in such cases, symptoms resolve rapidly even without intervention. Prolonging the infusion duration helps reduce the frequency of this syndrome. Other occasionally observed symptoms include jaw muscle spasm, muscle spasms, muscle contractions, involuntary muscle twitching, myoclonus, impaired motor coordination, gait disturbances, ataxia, loss of balance, and sensations of throat or chest tightness/pressure/discomfort/pain.

Neurological symptoms involving cranial nerve dysfunction may also occur, either in isolation or in combination: eyelid ptosis, diplopia, aphonia, dystonia, hoarseness sometimes described 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 disorders observed during oxaliplatin therapy include dysarthria, loss of deep tendon reflexes, and Lhermitte's sign. Isolated cases of optic neuritis have been reported.

Post-marketing experience with the drug, frequency of events unknown:

Seizures. Ischemic and hemorrhagic cerebrovascular events, falls.

Cardiac disorders

Post-marketing experience with unknown frequency of occurrence:

QT interval prolongation, which may lead to ventricular arrhythmias including torsades de pointes, potentially fatal (see section "Special precautions").

Acute coronary syndrome (including myocardial infarction, coronary arteriospasm, and angina pectoris in patients receiving oxaliplatin in combination with 5-FU and bevacizumab).

Respiratory, thoracic and mediastinal disorders

Post-marketing data with unknown frequency of occurrence:

Laryngospasm. Pneumonia and bronchopneumonia, including cases with fatal outcomes.

Gastrointestinal disorders

Frequency according to number of affected patients (%) and severity degree

Oxaliplatin and 5-FU/FA, 85 mg/m2 every 2 weeks	Metastatic disease			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Nausea	69.9	8	< 1	73.7	4.8	0.3
Diarrhea	60.8	9	2	56.3	8.3	2.5
Vomiting	49.0	6	1	47.2	5.3	0.5
Mucositis/stomatitis	39.9	4	< 1	42.1	2.8	0.1

Indicated for the prevention or treatment of highly emetogenic antiemetic agents.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal impairment may result from severe diarrhea/vomiting, particularly when oxaliplatin is used in combination with 5-fluorouracil.

Post-marketing experience with unknown frequency of occurrence:

Intestinal ischemia, including fatal cases (see section "Special warnings and precautions for use").

Gastric ulceration and perforation, including fatal cases (see section "Special warnings and precautions for use"). Esophagitis.

Hepatobiliary disorders

Uncommon: sinusoidal obstruction syndrome of the liver, also known as veno-occlusive liver disease or pathological manifestations of such liver disorders, including hepatic purpura, regenerative lymph node hyperplasia, perisinusoidal fibrosis. Clinical manifestations may include portal hypertension and/or elevated liver transaminase activity.

Musculoskeletal and connective tissue disorders

Post-marketing experience with unknown frequency of occurrence:

Rhabdomyolysis, including fatal cases (see section "Special warnings and precautions for use").

Renal and urinary disorders

Uncommon: acute tubular necrosis. Acute interstitial nephritis and acute renal failure.

Skin and subcutaneous tissue disorders

Post-marketing experience with unknown frequency of occurrence:

Allergic vasculitis.

Shelf life. 2 years.

From a microbiological standpoint, the prepared infusion solution should be used immediately. If not used immediately, responsibility for the duration and conditions of storage prior to use lies with the medical personnel. Generally, storage time should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Incompatibilities.

• Oxaliplatin must not be administered together with alkaline medicinal products (in particular 5-fluorouracil, trometamol, and folinic acid preparations containing trometamol).
• Oxaliplatin must not be dissolved in sodium chloride solution or diluted with sodium chloride solution.
• Oxaliplatin must not be mixed with other medicinal products in the same infusion bag/bottle or administered through the same infusion line (instructions for concomitant administration of folinic acid are provided in the section "Dosage and administration").

Oxaliplatin must not be administered using infusion systems containing aluminum components or through needles containing aluminum.

Packaging.

Vial stoppered and sealed with an aluminum crimp cap containing 10 ml, 20 ml, 30 ml, or 40 ml of concentrate for solution for infusion, packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

FAREVA Unterach GmbH

EBEWE Pharma Ges.m.b.H. Nfg. KG

Manufacturer's address and place of business.

Mondeesee Strasse 11, 4866 Unterach am Attersee, Austria

Mondeesee Strasse 11, 4866 Unterach am Attersee, Austria