Exorum, lyophilizate 50 mg

Antitumor drug, platinum derivative, in the molecular structure of which platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane. Exorum exhibits a broad spectrum of cytotoxic action and is also active in vitro and in vivo in various cisplatin-resistant tumor models.

The mechanism of action of the drug is caused by interaction of biotransformed aqueous derivatives of oxaliplatin with DNA by formation of inter- and intraspiral bridges and suppression of DNA synthesis.

Indications

Disseminated colorectal cancer (as monotherapy or combination therapy in combination with fluoropyrimidines).

Active ingredient

Composition

1 vial – oxaliplatin 50 mg.

Excipients: lactose monohydrate.

How to take, the dosage

Eksorum is administered only in adults as an IV infusion for 2-6 h.

Hyperhydration is not required when using oxaliplatin. If oxaliplatin is used in combination with 5-fluorouracil, the infusion of oxaliplatin should precede the administration of 5-fluorouracil.

The drug is given at a dose of 85 mg/m2 once every 2 weeks as monotherapy or in combination with 5-fluorouracil.

Recurrent infusions of oxaliplatin are only given when neutrophil counts >1500/μL and platelet counts >50,000/μL.

Recommendations for adjusting the dose and regimen of oxaliplatin.

If hematologic abnormalities (neutrophil count <1500/μL and/or platelet count <50,000/μL) the next course is delayed until the laboratory values have returned.

In case of development of diarrhea of 4th degree of toxicity (according to WHO scale), neutropenia of 3rd-4th degree (neutrophil count <1000/μl), thrombocytopenia of 3rd-4th degree (platelet count <50,000/μL), the dose of oxaliplatin for subsequent administrations should be reduced from 85 mg/m2 to 65 mg/m2 for therapy of disseminated colorectal cancer and ovarian cancer; and to 75 mg/m2 for adjuvant therapy of colorectal cancer, in addition to the usual reduction in the dose of 5-fluorouracil 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.

If pain (as a sign of neurotoxicity) persists for more than 7 days or if paresthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced by 25%.

If paresthesia with functional impairment persists until the next cycle, oxaliplatin should be withdrawn.

If symptoms of neurotoxicity decrease after withdrawal of oxaliplatin, resumption of treatment may be considered.

If stomatitis and/or mucositis of grade 2 or greater toxicity develops, treatment with oxaliplatin should be suspended until they resolve or toxicity is reduced to grade 1.

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

There is no need to change the dosing regimen in patients with mild to moderate hepatic impairment. There are no data on the use of oxaliplatin in patients with severe hepatic impairment.

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

Rules for preparation and administration of the solution

Do not use needles or other equipment containing aluminum when preparing and administering Exorum.

Do not dissolve or dilute with 09% sodium chloride solution and do not mix with other saline (alkaline) solutions or solutions containing chlorides.

Injection water or 5% dextrose solution should be used to dissolve lyophilized powder. In this case, 10 ml of the solvent is added to a bottle with 50 mg of Exorum, and 20 ml to a bottle with 100 mg to obtain a solution with a concentration of 5 mg/ml.

Mostly after dissolution of lyophilized powder the infusion solution should be prepared.

To prepare the infusion solution, the dissolved drug Exorum is diluted in 250-500 ml of 5% dextrose solution to obtain a concentration of at least 0.2 mg/ml. It is recommended to use the solution for infusion immediately after preparation. Infusion solution is stable for 24 hours at the temperature from 2° to 8°C.

The solution with signs of precipitation should be destroyed. Only clear solution may be used.

The oxaliplatin solution should not be mixed in the same infusion system with other drugs especially 5-fluorouracil and calcium folinate. The drug should not be administered undiluted.

Interaction

Significant changes in the binding of oxaliplatin to plasma proteins when concomitant use with erythromycin, salicylates, granisetron, paclitaxel, sodium valproate were not observed.

Pharmaceutical interactions

The drug is incompatible with alkaline solutions or solutions containing chloride.

In interaction with aluminum, precipitate formation and decreased activity of oxaliplatin are possible.

The drug is incompatible with alkaline solutions or solutions containing chloride.

Special Instructions

Exorum should only be used in specialized oncology departments and under the supervision of a qualified oncologist. Constant monitoring of possible toxic effects during treatment with Exorum is mandatory.

Peripheral blood, liver and kidney function tests should be performed regularly (once a week) and before each administration of Exorum.

A neurological examination should be performed before each administration and during treatment. Patients should be informed about the possibility of persistent symptoms of peripheral sensory neuropathy after the end of treatment. Localized moderate paresthesias with functional impairment may persist for up to 3 years after the end of treatment with the adjuvant drug regimen.

In case of respiratory symptoms (dry cough, dyspnea, rales or revealing pulmonary infiltrates at radiological examination), treatment with Exorum should be suspended until exclusion of interstitial pneumonitis.

Symptoms such as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal failure may be due to severe diarrhea or vomiting, especially when using Exorum 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 administered. Further use of oxaliplatin in case of allergic reactions is contraindicated.

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 in another vein.

When using the drug, all the usual instructions for the use of cytotoxic drugs should be followed. If the lyophilizate or solution of Exorum comes into contact with the skin or mucous membranes, they should be immediately and thoroughly rinsed with water.

Contraindications

– myelosuppression before the first course of therapy with neutrophil <2000/μl and/or platelet <100,000/μl;

– peripheral sensory neuropathy with functional impairment before the first course of therapy;

– significant renal dysfunction (CK <30 ml/min);

-pregnancy;

– lactation (breastfeeding);

– hypersensitivity to oxaliplatin or other components of the drug.

Side effects

The frequency of adverse reactions listed below was determined according to the following criteria: very frequently (>1/10), frequently (>1/100, <1/10); sometimes (>1/1000, <1/100); rarely (>1/10 000, <1/1000); very rarely (<1/10 000), including individual reports.

Hematopoietic system: very common – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; common – febrile neutropenia (including degree 3-4), sepsis against neutropenia; rare – hemolytic anemia, immune thrombocytopenia.

Digestive system disorders: very common – nausea, vomiting, diarrhea, stomatitis, mucositis, gastric pain, constipation, loss of appetite, increased levels of alkaline phosphate, liver enzyme activity, bilirubin, LDH; common – dyspepsia, gastro-oesophageal reflux, hiccups; sometimes – bowel obstruction; rare – colitis, including cases of pseudomembranous colitis.

CNS and peripheral nervous system: very common – peripheral sensorineural neuropathy, sensitivity disorders, headache, asthenia; common – dizziness, meningism, depression, insomnia; sometimes – increased nervousness; rarely – dysarthria. Neurotoxicity is a dose-limiting factor. Often the symptoms of sensory neuropathy are provoked by cold. The duration of these symptoms, which usually subside between courses, increases depending on the total dose of oxaliplatin. Functional impairment in the form of difficulty performing precise movements is a possible consequence of sensory damage. The risk of functional impairment at 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). After discontinuation of treatment, in most cases the severity of neurological symptoms decreases or they completely resolve.

In 3% of patients 3 years after treatment termination, either persistent local paresthesias of moderate intensity were observed (2.3%), or paresthesias affecting functional activity (0.5%).

In the background of oxaliplatin treatment, acute neurosensory manifestations were noted, which usually occurred within hours after drug administration and were most often provoked by exposure to cold. They were characterized by transient paresthesia, dysesthesia or hypoesthesia, rarely (1-2%) – acute laryngeopharyngeal dysesthesia syndrome. The latter was manifested by a subjective feeling of dysphagia and dyspnea without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm, or bronchospasm (without stridor or wheezing). There were also phenomena such as jaw muscle spasm, tongue dysesthesia, dysarthria, and a feeling of pressure in the chest. Usually these symptoms quickly subsided both without drug therapy and with the administration of antihistamines and bronchodilators. Increasing the duration of infusion in subsequent cycles of oxaliplatin therapy can reduce the frequency of this syndrome.

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

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

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

Urinary system: often – hematuria, dysuria.

Dermatological reactions: very common – alopecia, skin rash; common – skin peeling of palms and feet, erythematous rash, increased sweating, nail disorders.

Sight and hearing: often – conjunctivitis, visual impairment; rarely – transient decrease of visual acuity, loss of visual fields, decreased hearing, neuritis of the auditory nerve.

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

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

In laboratory parameters: very often – hypokalemia, disorders of sodium and serum glucose; often – increase in creatinine.

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

Overdose

Symptoms: in case of overdose, the described side effects may worsen.

Treatment: close monitoring of the patient (including hematological control); symptomatic therapy is carried out. The antidote is unknown.

The antidote is unknown.

Pregnancy use

Eksorum is contraindicated in pregnancy and during lactation (breast-feeding).

Women and men of childbearing age should use reliable methods of contraception while using the drug.