Oxaliplatin Medak^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Medac, GmbH (Germany)

Labeled By

ONCOTEC PHARMA PRODUKTION, GmbH (Germany)

ATC Code

L01XA03 (Oxaliplatin)

Active Substance

Oxaliplatin (Rec.INN registered by WHO)

Dosage Forms

	Oxaliplatin Medak	Lyophilisate for solution for infusion 50 mg: vial 1 pc.
		Lyophilisate for solution for infusion 100 mg: vial 1 pc.
		Lyophilisate for solution for infusion 150 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for solution for infusion as a mass or powder of white or almost white color.

Excipients: lactose monohydrate.

Colorless glass vials (1) – cardboard packs.

Lyophilisate for solution for infusion as a mass or powder of white or almost white color.

Excipients: lactose monohydrate.

Colorless glass vials (1) – cardboard packs.

Lyophilisate for solution for infusion as a mass or powder of white or almost white color.

Excipients: lactose monohydrate.

Colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Oxaliplatin is an antineoplastic drug belonging to a new class of platinum derivatives in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane. Oxaliplatin exhibits a broad spectrum of cytotoxic activity. It also shows activity in vitro and in vivo in various tumor models resistant to cisplatin. Synergistic cytotoxic action is observed in combination with 5-fluorouracil.

Study of the mechanism of action of oxaliplatin confirms the hypothesis that biotransformed, aqueous derivatives of oxaliplatin interact with DNA by forming inter- and intrastrand cross-links, suppressing DNA synthesis, which leads to cytotoxicity and an antineoplastic effect.

Pharmacokinetics

In vivo, Oxaliplatin undergoes active biotransformation and is not detected in plasma by the end of 2 hours after administration at a dose of 130 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 in the urine within the first 48 hours.

By day 5, approximately 54% of the total dose is found in the urine and less than 3% in the feces. In renal impairment, a significant decrease in the clearance of oxaliplatin from 17.6 L/h to 9.95 L/h is observed. The effect of severe renal impairment on platinum clearance has not been studied.

Indications

• Adjuvant therapy of stage III colorectal cancer (Duke’s C) after radical resection of the primary tumor in combination with 5-fluorouracil and folinic acid;
• Disseminated colorectal cancer (as monotherapy or combination therapy in combination with 5-fluorouracil and folinic acid).

ICD codes

Dosage Regimen

Intravenously as 2-6 hour infusions. Hyperhydration is not required when using oxaliplatin.

Used in adults only.

The drug should be used immediately after solution preparation. When combined with 5-fluorouracil, the infusion of oxaliplatin should precede the administration of 5-fluorouracil.

Adjuvant therapy for colorectal cancer: 85 mg/m² once every 2 weeks for 12 cycles (6 months).

Disseminated colorectal cancer: 85 mg/m² once every 2 weeks as monotherapy or in combination with 5-fluorouracil.

Re-administration of oxaliplatin is performed only when the neutrophil count is greater than 1500/µL and platelets greater than 50000/µL.

Recommendations for dose adjustment and administration regimen of oxaliplatin.

In case of hematological disorders (neutrophil count <1500/µL and/or platelet count <50000/µL), the next course is postponed until laboratory parameters recover.

If grade 4 diarrhea toxicity (according to WHO scale), grade 3-4 neutropenia (neutrophil count <1000/µL), grade 3-4 thrombocytopenia (platelet count <50000/µL) develop, the dose of oxaliplatin in subsequent administrations should be reduced from 85 mg/m² to 65 mg/m² for therapy of disseminated colorectal cancer and to 75 mg/m² for adjuvant therapy, in addition to the usual dose reduction of 5-fluorouracil in case of their combined use.

In patients who develop acute laryngopharyngeal paresthesia during infusions or within several hours after a 2-hour infusion, the next infusion of oxaliplatin should be administered over 6 hours.

Recommendations for adjusting the dose of oxaliplatin in case of neurotoxicity

• For neurotoxicity symptoms causing pain, lasting more than 7 days, the subsequent dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² for therapy of disseminated colorectal cancer and to 75 mg/m² for adjuvant therapy.
• For paresthesia without functional impairment, persisting until the next cycle, the subsequent dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² for therapy of metastatic colorectal cancer and to 75 mg/m² for adjuvant therapy;

• For paresthesia with functional impairment, persisting until the next cycle, Oxaliplatin should be discontinued;
• If the severity of neurotoxicity symptoms decreases after discontinuation of oxaliplatin, resumption of treatment may be considered. If stomatitis and/or mucositis of grade 2 or higher toxicity develop, treatment with oxaliplatin should be suspended until they resolve or toxicity manifestations decrease to grade 1.

Patients with renal impairment. There are no data on the use of oxaliplatin in patients with severe renal impairment. Due to limited data regarding the safety and tolerability of the drug in patients with moderate renal impairment, the benefit/risk ratio for the patient should be weighed before using the drug. Therapy in this category of patients can be started with the recommended dose, under careful monitoring of renal function. In mild renal impairment, dose adjustment of oxaliplatin is not required.

Patients with hepatic impairment. Dose adjustment in patients with mild or 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 as monotherapy or in combination with 5-fluorouracil in patients older than 65 years is similar to that observed in patients under 65 years.

Instructions for preparation of the drug solution.

When preparing solutions and administering oxaliplatin, needles and other equipment containing aluminum must not be used.

The drug is dissolved before use in water for injections or in 5% dextrose solution, obtaining a solution with a concentration of 5 mg/ml of oxaliplatin (add 10 ml of solvent to a 50 mg vial, 20 ml to a 100 mg vial, 30 ml of solvent to a 150 mg vial). The reconstituted drug is then immediately diluted with 250 – 500 ml of 5% dextrose solution. The concentration of the resulting oxaliplatin solution should be from 0.2 to 0.7 mg/ml; with 0.7 mg/ml being the highest concentration used in clinical practice at a dose of 85 mg/m².

Only recommended solvents should be used to prepare the drug solution.

The drug must not be used undiluted.

Do not use saline solutions (sodium chloride solution) for dissolving the drug or diluting the drug solution (for preparing the infusion solution). Do not mix in the same container, do not administer simultaneously in the same infusion system with other drugs (especially with 5-fluorouracil, basic solutions, trometamol and folinic acid preparations containing trometamol in their composition).

Oxaliplatin can be administered together with folinic acid infusions. In this case, the drugs should not be mixed in the same infusion container. Folinic acid for infusion should be diluted using 5% glucose solution, but under no circumstances should solutions containing sodium chloride or alkaline solutions be used.

The prepared drug solution must be clear and must not contain undissolved particles. Otherwise, the drug solution must not be used. The drug solution is used immediately after preparation.

The drug is for single use only. Unused drug solution must be destroyed.

The drug should be administered into a central venous line or a peripheral vein over 2-6 hours.

In case of extravasation, administration of the drug must be stopped immediately.

Materials used for preparing the solution and its administration must be destroyed in accordance with the rules for the use of cytotoxic drugs.

Adverse Reactions

The most frequent adverse effects observed with the use of oxaliplatin, including in combination with 5-fluorouracil/folinic acid, were gastrointestinal reactions (diarrhea, nausea, vomiting, mucositis), hematological reactions (neutropenia, thrombocytopenia) and neurological reactions (acute and cumulative dose-dependent peripheral sensory neuropathy). In general, these adverse effects were more frequent and severe when oxaliplatin was combined with 5-fluorouracil/folinic acid compared to the use of 5-fluorouracil and folinic acid alone.

The frequency of adverse reactions listed below is presented according to the following gradation: very common (>1/10), common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (< 1/10000), including isolated reports.

From the hematopoietic system very common – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; common – febrile neutropenia (including grade 3-4), neutropenic sepsis; rare – hemolytic anemia, immune thrombocytopenia.

From the digestive system very common – nausea, vomiting, diarrhea, stomatitis, mucositis, stomach pain, constipation, loss of appetite; common – dyspepsia, gastroesophageal reflux, hiccups; uncommon – intestinal obstruction; rare – colitis, including cases of pseudomembranous colitis.

From the central and peripheral nervous system very common – peripheral neurosensory neuropathy, sensory disturbances, headache, asthenia; common – dizziness, meningism, depression, insomnia; uncommon – increased nervousness; rare – dysarthria.

Neurotoxicity is a dose-limiting adverse event. Often, symptoms of sensory neuropathy are triggered by cold. The duration of these symptoms, which usually resolve between cycles, increases depending on the cumulative dose of oxaliplatin. Functional impairments, which are expressed as difficulty in performing precise movements, are possible consequences of sensory damage. The risk of functional impairment for a cumulative dose of about 850 mg/m² (10 cycles) is about 10%, reaching 20% for a cumulative dose of 1020 mg/m² (12 cycles). In most cases, neurological symptoms improve or resolve completely after discontinuation of treatment. However, in 3% of patients, 3 years after the end of treatment, either persistent localized paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%) were observed. During treatment with oxaliplatin, acute neurosensory manifestations were noted, which usually occurred within a few hours after drug administration and were most often triggered by cold. They were characterized by transient paresthesia, dysesthesia or hypoesthesia, rarely (1-2%) by an acute syndrome of laryngopharyngeal dysesthesia. The latter manifested as a subjective feeling of dysphagia and dyspnea without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or as laryngeal spasm or bronchospasm (without stridor or wheezing). Also observed were phenomena such as jaw spasm, tongue dysesthesia, dysarthria and a feeling of pressure in the chest. Usually these symptoms resolved quickly both without drug therapy and with the administration of antihistamines and bronchodilators. Increasing the infusion time in subsequent cycles of oxaliplatin therapy can reduce the frequency of this syndrome.

From the musculoskeletal system very common – back pain; common – arthralgia, bone pain.

From the respiratory system very common – cough, dyspnea; common – rhinitis, upper respiratory tract infections; rare – pulmonary fibrosis.

From the cardiovascular system common – chest pain, deep vein thrombophlebitis, pulmonary embolism.

From the urinary system common – hematuria, dysuria.

From the skin and skin appendages very common — alopecia, skin rash; common – palmar-plantar erythrodysesthesia, erythematous rash, increased sweating, nail disorders.

From the organs of vision and hearing: common – conjunctivitis, visual disturbances; rare – transient decrease in visual acuity, visual field loss, hearing loss, acoustic neuritis

Allergic reactions rare (with monotherapy) or common (in combination with 5-fluorouracil +/- calcium folinate) may include bronchospasm, angioedema, hypotension and anaphylactic shock. Cases of such allergic manifestations as rash (especially urticaria), conjunctivitis or rhinitis were frequently noted.

Local reactions in case of drug extravasation – pain and inflammatory reactions at the injection site.

From laboratory parameters very common – increased level of alkaline phosphatase, activity of “liver” enzymes, bilirubin content, LDH, hypokalemia, disturbances in serum sodium and glucose levels; common – increased creatinine level.

Other very common – fever, increased fatigue, weight gain, taste disturbances.

Contraindications

• Hypersensitivity to oxaliplatin or other components of the drug;
• Myelosuppression (neutrophil count less than 2000/µL and/or platelet count less than 100000/µL) before the start of the first treatment cycle;
• Peripheral sensory neuropathy with functional impairment before the start of the first treatment cycle;
• Severe renal impairment (creatinine clearance less than 30 ml/min) ;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Patients with hepatic impairment. Dose adjustment in patients with mild or 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

Contraindicated in severe renal impairment (creatinine clearance less than 30 ml/min).

Patients with renal impairment. There are no data on the use of oxaliplatin in patients with severe renal impairment. Due to limited data regarding the safety and tolerability of the drug in patients with moderate renal impairment, the benefit/risk ratio for the patient should be weighed before using the drug. Therapy in this category of patients can be started with the recommended dose, under careful monitoring of renal function. In mild renal impairment, dose adjustment of oxaliplatin is not required.

Pediatric Use

The drug is used in adults only.

Geriatric Use

The safety profile of oxaliplatin as monotherapy or in combination with 5-fluorouracil in patients older than 65 years is similar to that observed in patients under 65 years.

Special Precautions

Treatment with Oxaliplatin Medak should be carried out under the supervision of a physician experienced in the use of cytotoxic drugs. Constant monitoring for possible toxic effects during therapy with oxaliplatin is mandatory.

Regularly (once a week), as well as before each administration of the drug Oxaliplatin Medak, peripheral blood cell counts and renal and liver function parameters should be monitored.

Before the start of each cycle of therapy with Oxaliplatin Medak, a neurological examination should be performed to identify signs of neurotoxicity.

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

If symptoms such as dry cough, dyspnea, wheezing or detection of pulmonary infiltrates on X-ray appear, treatment with Oxaliplatin Medak should be suspended until interstitial pneumonitis is ruled out.

Such symptoms as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be caused by severe diarrhea or vomiting, especially when using Oxaliplatin Medak in combination with 5-fluorouracil.

Patients with a history of allergic reactions to other platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to Oxaliplatin, the infusion should be immediately interrupted and appropriate symptomatic treatment prescribed. Further use of Oxaliplatin Medak in case of allergic reactions is contraindicated. If liver function impairment or portal hypertension occurs, not due to liver metastases, the possible presence of drug-induced hepatovascular disorders, which are observed very rarely, should be considered.

In case of extravasation, the infusion should be stopped immediately and local symptomatic treatment should be initiated. The remaining dose of the drug should be administered into another vein. Women and men during treatment and for 6 months after the end of oxaliplatin therapy should use reliable methods of contraception. When using the drug Oxaliplatin medak, all standard instructions adopted for the use of cytotoxic drugs must be observed. If the lyophilisate or solution of the drug Oxaliplatin medak gets on the skin or mucous membranes, they should be washed immediately and thoroughly with water.

Effect on the ability to drive vehicles and mechanisms

It has not been studied. However, the use of oxaliplatin increases the risk of dizziness, nausea, vomiting, and the manifestation of other neurological symptoms that affect the speed and adequacy of reaction and thus reduce the ability to drive a car and use mechanisms.

Overdose

Symptoms: intensification of the described side effects. An antidote is not known.

Treatment: hematological monitoring and symptomatic therapy.

Drug Interactions

Pharmaceutically incompatible with alkaline solutions and solutions containing chlorine.

When patients were administered a single dose of 85 mg/m² of oxaliplatin immediately before the administration of 5-fluorouracil, no change in the level of 5-fluorouracil was noted.

No noticeable change in the binding of oxaliplatin to plasma proteins was observed in joint in vitro experiments with erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Incompatibilities

• Do not use together with alkaline preparations or solutions (in particular, 5-fluorouracil, alkaline solutions, trometamol and folinic acid preparations containing trometamol as an auxiliary substance);
• Do not use saline solutions for dissolving the drug or diluting the drug solution (for preparing an infusion solution), do not mix with other drugs in one container or in an infusion system;
• Do not use administration equipment containing aluminum (precipitation may occur and the activity of oxaliplatin may decrease).

Storage Conditions

Store in a place inaccessible to children and protected from light at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2.5 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

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.