Oxaliplatin medac, lyophilizate 150 mg

Pharmacodynamics

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

The study of the mechanism of action of oxaliplatin supports the hypothesis that biotransformed, aqueous derivatives of oxaliplatin interact with DNA by formation of inter- and intrathecal bridges suppresses DNA synthesis, which leads to cytotoxicity and antitumor 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/sq.m, with 15% of the administered platinum being in the blood and the remaining 85% rapidly distributed to the tissues or excreted by the kidneys. Platinum is bound to plasma albumin and excreted in the urine within the first 48 hours.

By day 5, about 54% of the total dose is found in the urine and less than 3% in the feces. In renal insufficiency there is a significant decrease in clearance of oxaliplatin from 17.6 l/hour to 9.95 l/hour. The effect of severe renal failure on platinum clearance has not been studied.

Indications

Active ingredient

Composition

1 vial contains:

Active substances:

oxaliplatin 150 mg.

Excipients:

Lactose monohydrate.

In a vial of 150 mg of lyophilizate.

There is 1 vial in the carton.

How to take, the dosage

Intravenously as a 2-6 h infusion. Hyperhydration is not required when using oxaliplatin.

The drug is used only in adults.

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

Adjuvant therapy for colorectal cancer: 85 mg/m 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.

Recurrent administration of oxaliplatin is done only if the neutrophil count is more than 1500/μL and the platelet count is more than 50000/μL.

Recommendations for adjusting the dose and regimen of oxaliplatin.

In case of hematologic abnormalities (neutrophil count < 1500/μL and/or platelet count < 50000/μL) the administration of the next course is postponed until the laboratory values are restored.

In case of development of grade 4 toxicity diarrhea (WHO scale), grade 3-4 neutropenia (neutrophil count < 1000/μL), grade 3-4 thrombocytopenia (platelet count < 50000/μL) the dose of oxaliplatin in subsequent administrations should be decreased 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 5-fluorouracil dose reduction when they are combined.

Patients who develop acute laryngeopharyngeal paresthesia during the infusion or within hours of a 2-hour infusion should have their next oxaliplatin infusion within 6 h.

Recommendations for dosage adjustment of oxaliplatin if neurotoxicity develops:

Patients with renal impairment

There are no data on the use of oxaliplatin in patients with severe renal impairment. Due to the limited data regarding 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 may be started from the recommended dose, under close monitoring of renal function. In mild renal dysfunction no dose adjustment of oxaliplatin is required.

Patients with impaired liver function

Dose adjustments are not required in patients with mild to moderate hepatic impairment. 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 seen in patients younger than 65 years.

Instructions for preparing the drug solution

Ingredients for preparing solutions and administering oxaliplatin must not use needles or other equipment containing aluminum.

The drug is dissolved before use in water for injection or in 5% dextrose solution, obtaining a solution with a concentration of 5 mg/ml of oxaliplatin (a 50 mg vial takes 10 ml of solvent, a 100 mg vial takes 20 ml, a 150 mg vial takes 30 ml of solvent). The drug thus reconstituted is immediately diluted with 250 to 500 ml of 5% dextrose solution. The concentration of the resulting oxaliplatin solution should be 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 should not be used undiluted.

Do not use saline solutions (sodium chloride solution) to dissolve or dilute the drug solution (to prepare 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 may be administered together with folinic acid infusions. In this case, the drugs should not be mixed in the same container for infusion. 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 should be clear and should not contain undissolved particles. Otherwise the drug solution should not be used. The drug solution shall be used immediately after preparation.

The drug is intended for single use only. Unused solution of the drug shall be destroyed.

The drug should be administered in the central venous line or in the peripheral vein within 2-6 hours.

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

The materials used to prepare the solution and to administer it must be disposed of in accordance with the rules for the use of cytotoxic drugs.

Interaction

Pharmaceutically incompatible with alkaline solutions and solutions containing chlorine.

In cases where patients were given a single dose of 85 mg/m2 oxaliplatin immediately prior to administration of 5-fluorouracil, no change in 5-fluorouracil levels was observed.

There was no detectable change in the binding of oxaliplatin to plasma proteins in joint in vitro experiments with erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.

Incompatibilities

Special Instructions

Treatment with Oxaliplatin Medac should be performed under the supervision of a physician experienced in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects during oxaliplatin therapy is mandatory.

Peripheral blood cells and renal and hepatic function parameters should be monitored regularly (once a week) and before each administration of Oxaliplatin Medac.

Ahead of each cycle of therapy with Oxaliplatin medac a neurological examination should be performed to detect signs of neurotoxicity.

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

If symptoms such as dry cough, dyspnea, rales, or pulmonary infiltrates are detected on radiologic examination, Oxliplatin medac should be suspended until interstitial pneumonitis is excluded.

Symptoms such as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be due to severe diarrhea or vomiting, especially when Oxaliplatin medac is used 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 should be prescribed. Further use of Oxaliplatin medac is contraindicated in case of allergic reactions. If hepatic dysfunction or portal hypertension not caused by liver metastases occurs, the possible presence of drug-induced hepato-vascular disorders should be considered, which are very rare.

In case of extravasation, the infusion should be stopped immediately and local symptomatic treatment initiated. The remaining dose of the drug should be administered in another vein. Women and men should use reliable contraceptive methods during treatment and for 6 months after the end of therapy with oxaliplatin. When using Oxaliplatin Medac all the usual instructions for using cytotoxic drugs should be followed. If Oxaliplatin medac lyophilisate or solution comes into contact with the skin or mucous membranes, they should be immediately and thoroughly rinsed with water.

The effect on the ability to drive vehicles and other mechanisms requiring increased concentration

I have not studied. However, use of oxaliplatin increases the risk of dizziness, nausea, vomiting, and the occurrence of other neurologic symptoms that affect reaction speed and thus impair the ability to drive and use machinery.

Contraindications

Side effects

The most frequent adverse effects observed with 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 side effects were more frequent and severe when oxaliplatin was combined with 5-fluorouracil/folinic acid compared with 5-fluorouracil and folinic acid alone.

The frequency of adverse reactions listed below is outlined according to the following gradation:

In the hematopoietic system: very often – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often – febrile neutropenia (including degree 3-4), sepsis with neutropenia; rarely – hemolytic anemia, immune thrombocytopenia.

Gastrointestinal system: very frequently – nausea, vomiting, diarrhea, stomatitis, mucositis, stomach pain, constipation, loss of appetite; frequently – dyspepsia, gastro-oesophageal reflux, hiccups; infrequently – bowel obstruction; rarely – colitis, including cases of pseudomembranous colitis.

The central and peripheral nervous system: very common – peripheral sensorineural neuropathy, sensory disorders, headache, asthenia; common – dizziness, meningism, depression, insomnia; infrequent – increased nervousness; rare – dysarthria.

Neurotoxicity is a dose-limiting side effect. Often symptoms of sensory neuropathy are provoked by cold. The duration of these symptoms, which usually resolve between courses, increases with the total dose of oxaliplatin. Functional impairment, which is expressed by difficulty in performing precise movements, is a possible consequence of sensory damage.

The risk of functional impairment for a total dose of about 850 mg/m2 (10 cycles) is about 10%, reaching 20% for a total dose of 1020 mg/m2 (12 cycles). In most cases, neurological symptoms improve or disappear altogether after discontinuation of treatment. However, 3% of patients had either persistent localized paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%) 3 years after treatment termination.

In the background of oxaliplatin treatment, acute neurosensory manifestations were observed, which usually occurred within a few hours after the drug administration and were most often provoked by cold. They were characterized by transient paresthesia, dysesthesia or hyposthesia, rarely (1-2%) acute laryngeopharyngeal dysesthesia syndrome.

The latter was manifested by a subjective sense of dysphagia and dyspnea without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm or bronchospasm (without stridor or wheezing). Jaw spasm, tongue dysesthesia, dysarthria, and a feeling of pressure in the chest have also been observed. Usually these symptoms were quickly resolved both without the use of drug therapy and with the administration of antihistamines and bronchodilators. Increased infusion times in subsequent cycles of oxaliplatin therapy reduce the incidence of this syndrome.

Muscular system disorders: very common – back pain; common – arthralgia, bone pain.

Respiratory system: very common – cough, shortness of breath; common – rhinitis, upper respiratory tract infections; rarely – pulmonary fibrosis.

Cardiovascular system: frequently – pain in the sternum, deep vein thrombophlebitis, pulmonary embolism.

Urinary system disorders: often – hematuria, dysuria.

Skin and skin appendages: very common – alopecia, skin rashes; common – skin peeling of the palms and feet, erythematous rashes, increased sweating, nail disorders.

Associations of vision and hearing: often – conjunctivitis, visual disturbances; rarely – transient decrease in visual acuity, loss of visual fields, decreased hearing, neuritis of the auditory nerve.

Allergic reactions: rarely (when using monotherapy) or frequently (in combination with 5-fluorouracil +/- calcium folinate) bronchospasm, angioneurotic edema, hypotension and anaphylactic shock may be observed. Allergic manifestations such as rash (especially urticaria), conjunctivitis or rhinitis have often been reported.

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

Laboratory parameters: very often – increased levels of alkaline phosphatase, activity of “liver” enzymes, bilirubin, lactate dehydrogenase, hypokalemia, disorders of serum sodium and glucose; often – increased serum creatinine.

Others: very common – increase in body temperature, increased fatigue, weight gain, taste disorders.

Overdose

Symptoms: aggravation of the described side effects. The antidote is not known.

Treatment: hematological control and symptomatic therapy.

Pregnancy use

It is contraindicated in pregnancy and during lactation.