Rx Prescription information

OXALIPLATIN - BELMED

(User’s information)

Trade name: Oxaliplatin - Belmed

International nonproprietary name: Oxaliplatin

Appearance: white or almost white powder or porous mass

Composition: one bottle/vial contains: active substance: oxaliplatin - 50 mg; excipients: lactose monohydrate

Pharmaceutical form: lyophilized powder for infusion

Pharmaceutical group. Antineoplastic agents. Alkylating agent

ATC code: L01XA03

 

Pharmacological action

Oxaliplatin is an antineoplastic drug product of a new class of platinum derivatives wherein the platinum atom forms a complex with oxalate and 1.2-diaminocyclohexane. Oxaliplatin demonstrates a wide spectrum of cytotoxic effect. It is also as active in vitro as in vivo in various tumor models resistant to cisplatin. Synergetic cytotoxic effect has been observed in combination with 5-fluorouracil. The study of oxaliplatin mechanism of action supports the hypothesis of DNA synthesis inhibition due to cross-chain and intra-chain bands formation during oxaliplatin biotransformed derivatives and DNA interaction, which cause cytotoxicity and antitumor effect.

Indications for use

·      III stage colorectal cancer (Dukes’ stage C) adjuvant therapy after the primary tumor radical resection in combination with 5-fluorouracil and folic acid;

·      disseminated colorectal cancer (monotherapy or combined therapy with 5-fluorouracil and folic acid).

Route of administration and doses

Intravenous infusion within 2-6 hrs. Hyperhydration is not required for oxaliplatin administration. Use only in adults. Drug product should be used immediately after preparation. At concomitant administration with 5-fluorouracil oxaliplatin infusion must precede 5-fluorouracil intake.

Colorectal cancer adjuvant therapy: a single dose of 85 mg/m2 every 2 weeks during 12 cycles (6 months).

Disseminated colorectal cancer: a single dose of 85 mg/m2 every 2 weeks as monotherapy or together with 5-fluorouracil. Oxaliplatin re-administration is recommended only when the number of neutrophils is more than 1500/µl and platelets are more than 50000/µl.

Recommendations for dose adjustment and oxaliplatin administration mode.

In case of hematological disorders (neutrophil count <1500/ µl and/or platelets <50000/ µl) the next treatment course has to be postponed until the laboratory parameter recovery.

In case of grade 4 toxicity diarrhea (WHO scale), grade 3-4 neutropenia (neutrophil count <1000/ µl), grade 3-4 thrombocytopenia (platelet count <50000/ µl) during the following administrations oxaliplatin dose should be reduced from 85 mg/m2 to 65 mg/m2 in case of disseminated colorectal cancer treatment and to 75 mg/m2 for adjuvant therapy in addition to common 5-fluorouracil dose reduction in case of combined use.

Patients who develop acute laryngo-pharyngeal paresthesia during the infusion or within a few hours after 2 hrs infusion should have the next treatment within 6 hrs.

Recommendations for oxaliplatin dose adjustment in case of neurotoxicity development:

-       in case of neurotoxicity symptoms causing pain for more than 7 days the next oxaliplatin dose should be reduced from 85 mg/m2 to 65 mg/m2 in disseminated colorectal cancer and to 75 mg/m2 in adjuvant therapy;

-       in paresthesia without functional disturbances continued until the next cycle, the following dose of oxaliplatin should be reduced from 85 mg/m2 to 65 mg/m2 in metastatic colorectal cancer and 75 mg/m2 in adjuvant therapy;

-       in paresthesia with functional impairment persisting until the next cycle, oxaliplatin administration should be declined;

-       in case of neurotoxicity symptoms reduction (after oxaliplatin discontinuation) it is possible to consider the drug reinstitution.

In case of stomatitis and/or mucositis of the 2nd or higher toxicity degree, oxaliplatin treatment should be interrupted until their eradication or toxicity reduction to the 1st degree.

Patients with renal impairment.

There is no data on oxaliplatin administration in patients with severe renal impairment. Due to the limited data on the drug safety and tolerance in patients with moderate degree renal impairment, the benefit/risk ratio for the patient should be taken into account before the drug administration. Therapy in these patients group can be started with the recommended dose under strict renal function control. Oxaliplatin dosage adjustment is not required in mild renal dysfunction.

Patients with liver failure. The dosage change is not required in patients with mild or moderate form of liver failure. There are no data on oxaliplatin administration in patients with severe hepatic impairment.

Elderly patients. Oxaliplatin safety profile in a mode of monotherapy or combined with 5-fluorouracil in patients over 65 years is similar to that observed in patients up to 65 years old.

Instructions for the drug solution preparation.

Needles and other equipment containing aluminum cannot be used for oxaliplatin solution preparation and administration. Do not use sodium chloride and other salt (alkaline) solutions, solutions containing chlorides for drug reconstitution or dilution (for infusion solution preparation).

Prior to administration the drug should be dissolved in water for injection or 5% dextrose. 20 ml of the solvent should be added into 50 ml bottle, and 10 ml of the solvent should be added into 20 ml vial.

Reestablished in such a way solution should be diluted immediately in 250-500 ml of 5% dextrose. Concentration of the resulting oxaliplatin solution should not be less than 0.2 mg/ml. Only recommended solvents should be used to prepare the drug solution. Do not use undiluted product. The resulting solution of the drug should be transparent and contain no undissolved particles. Otherwise, the drug solution cannot be used. The drug solution should be used immediately after preparation. The drug is intended for single use only. Unused drug solution should be discarded. The drug should be administered into a central venous line or peripheral vein within 2-6 hours. In case of extravasation, the drug infusion should be stopped immediately. Materials used for solution preparation and administration must be destroyed in accordance with the rules of cytotoxic drugs handling.

Oxaliplatin should not be mixed in one container and should not be administered in the same infusion system together with other drug products (especially with 5-fluorouracil, alkaline solutions, trometamol and folic acid medicine containing trometamol). Oxaliplatin can be administered together with folic acid infusions. In this case, the drugs should not be mixed in one container for infusion. Folic acid for infusion should be diluted with 5% dextrose, but in no case can be used the solutions containing sodium chloride or alkalies.

Side effect

The most common side effects observed with oxaliplatin administration, including combinations with 5-ftoruratsilom/folic acid, were the gastrointestinal tract disorders (diarrhea, nausea, vomiting, mucositis), hematological reactions (neutropenia, thrombocytopenia) and neurological reactions (acute and cumulative dose-related peripheral sensory neuropathy). In general, these side effects were more frequent and severe with oxaliplatin combined with 5-fluorouracil/folic acid, compared with only 5-fluorouracil and folic acid administration. The frequency of side effects listed below is presented in accordance with the following gradation: very often (> 1/10), often (> 1/100, <1/10), uncommon (> 1/1000, <1/100), rare > 1/10000, <1/1000), very rare (<1/10000), including special reports.

Hematopoietic system: very often – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often – febrile neutropenia (including grade 3-4), sepsis in the presence of neutropenia, rare – hemolytic anemia, immune thrombocytopenia.

Digestive system: very often – nausea, vomiting, diarrhea, stomatitis, mucositis, stomach ache, constipation, loss of appetite; often – dyspepsia, gastro-esophageal reflux, hiccups, uncommon – intestinal obstruction, rare – colitis, including pseudomembranous colitis.

Central and peripheral nervous system: very often – peripheral sensorineural neuropathy, sensory disturbances, headache, asthenia; often – dizziness, meningism, depression, insomnia; uncommon – hyper nervosity, rare – dysarthria.

Neurotoxicity is a dose-limiting side effect. Often sensory neuropathy symptoms are provoked by cold. The duration of these symptoms usually cropped between courses increases with the cumulative dose of oxaliplatin. Functional disorders, expressing difficulty in performing precise movements are the possible consequences of sensory deprivation. The risk of functional disorders for a total dose of 850 mg/m2 (10 cycles) is about 10%, reaching 20% at the total dose of 1020 mg/m2 (12 cycles). In most cases, neurological symptoms improve or completely disappear after the treatment cessation. However, stable localized paresthesias of moderate intensity (2.3%) and paresthesias affecting functional activity (0.5%) were observed in 3% of patients 3 years after the treatment.

Acute neurosensory manifestations have been observed during the treatment with oxaliplatin, usually occurred within a few hours after the drug administration and were mostly provoked by cold. They were characterized by transient paresthesia, dysesthesia or hypesthesia, rare (1-2%) – acute syndrome of laryngo-pharyngeal dysesthesia. The latter is manifested in a subjective feeling of dyspnea and dysphagia without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm or bronchospasm (without stridor or wheezing). Some phenomena such as jaw stiffness, tongue dysesthesia, dysarthria and sense of pressure in the chest have also been observed. Usually these symptoms were stopped quickly either without drug therapy or with antihistamines and bronchodilators administration.  The infusion time prolongation during the next cycles of oxaliplatin therapy can reduce the incidence of this syndrome.

Musculoskeletal system: very often – back pain; often – arthralgia, bone pain.

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

Cardiovascular system: often – pain behind the breastbone, deep vein thrombophlebitis, pulmonary embolism.

Urinary system: often – hematuria, dysuria.

Skin and skin appendages: very often – alopecia, skin rash, often –hands and feet peeling, erythematous rash, increased sweating, nails disorders.

Organs of vision and hearing: often – conjunctivitis, blurred vision; rarely – transient decrease in vision, visual field loss, hearing loss, cochlear neuritis.

Allergic reactions: rare (in monotherapy) or often (in combination with 5-fluorouracil +/- calcium folinate) bronchospasm, angioedema, hypotension and anaphylactic shock may be observed. Such allergic reactions as rash (particularly urticaria), conjunctivitis, or rhinitis were the most often reported cases.

Local reactions: pain and inflammatory reactions at the injection site during the drug extravasation.

Laboratory parameters: very often –alkaline phosphatase activity, liver enzymes, bilirubin, lactate dehydrogenase increase, hypokalemia, serum sodium and glucose abnormality; often – increased serum creatinine.

Others: very often –body temperature increase, tiredness, weight gain, impaired taste.

Contraindications

• oxaliplatin or other components of the drug hypersensitivity

• myelosuppression (neutrophil count less than 2000/µl and/or platelet count less than 100000/ µl) prior to the first course of treatment;

• peripheral sensory neuropathy with functional impairment prior to the first course of treatment;

• severe renal dysfunction (creatinine clearance below 30 ml/min);

• pregnancy;

• breast-feeding.

Overdose

Symptoms: described side effectsenhancement.

Treatment: No specific antidote. Hematologic control and symptomatic therapy.

Interaction with other medicinal products

Pharmaceutically incompatible with alkaline and chlorine contained solutions. In case of single-dose 85 mg/m2 oxaliplatin administration in patients immediately prior to 5-fluorouracil intake there were no changes in 5-fluorouracil level. There was no significant change in plasma proteins oxaliplatin binding capacity in co-experiments with erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate in vitro.

Incompatibilities

• Do not use together with alkaline drugs or solutions (such as 5-fluorouracil, alkaline solutions, trometamol and folic acid preparations containing trometamol as an excipient),

• Do not use for drug reconstitution or dilution of the drug solution (for infusion preparation), saline solutions, not to be mixed with other drugs in the same container or infusion system

• Do not use equipment with aluminum for the drug administration (may cause sediment formation and decrease oxaliplatin activity).

Application special characteristics

Oxaliplatin treatment should be carried out under the doctor supervision experienced with cytotoxic drugs. Possible oxaliplatin toxic effects permanent control is required during the treatment. Regularly (once a week), and prior to each dose of oxaliplatin the formed elements of peripheral blood and kidney and liver function parameters should be tested. Prior to each cycle of therapy with oxaliplatin neurological examinations for neurotoxicity signs detection should be performed.

Patients should be informed of possible persistent peripheral sensory neuropathy symptoms occurrence after the treatment. Localized moderate paresthesias with functional impairment can be presented up to 3 years after the adjuvant drug treatment scheme completion. If such symptoms as dry cough, dyspnea, wheezing, or detection of pulmonary infiltrates in the X-ray examination have occurred, the oxaliplatin treatment should be suspended to the exclusion of interstitial pneumonia.

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

Patients with allergic reactions to other platinum compounds in past medical history should be monitored for allergic symptoms. In case of reaction to oxaliplatin, like anaphylactic, the infusion should be stopped immediately and appropriate symptomatic treatment should be ordered. Further use of oxaliplatin is contraindicated in case of allergic reactions. If abnormal liver function or portal hypertension not caused by liver metastases has occurred the possible drug-related hepato-vascular impairments which are very rare should be considered.

In case of extravasation the infusion should be stopped immediately and local symptomatic treatment should be started. The remaining dose of the drug should be injected into another vein.

Precautions

Reliable methods of contraception should be used by women and men during the treatment and 6 months after oxaliplatin therapy discontinuation.

All the common instructionsdesigned for dealing with cytotoxic drugs should be applied for oxaliplatin. In case of lyophilizate or oxaliplatin solution contact to the skin or mucous membranes, they should be washed out immediately and thoroughly with water.

Ability to drive and use mechanisms: not studied. However, the use of oxaliplatin increases risk of dizziness, nausea, vomiting, and other neurologic symptoms that affect the adequacy and reaction rate thus reducing the ability to drive and use machinery.

Storage conditions

Store in protected from light place at temperatures below 30°С.

Keep out of reach of children.

Shelf life

2 years.

Do not use after expiration of a shelf life.

Package

50 mg in bottle/vial. One bottle/vial together with leaflet is placed in a cardboard pack.

Pharmacy purchasing terms

On prescription.

Manufacturer

Belmedpreparaty RUE

30 Fabritsius St., 220007 Minsk, Republic of Belarus

Tel./fax (+ 375 17) 220 37 16

e- mail: medic@belmedpreparaty.com

http://www.belmedpreparaty.com