Ftoruratsil-Darnitsa

General characteristics. Structure:

Active ingredient: fluorouracil;

1 ml of solution contains 50 mg of a ftoruratsil (in terms of 100% dry matter);

excipients: sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics. Ftoruratsil treats structural analogs of a pyrimidine and shows antineoplastic activity as an antimetabolite of nucleinic exchange.

Ftoruratsil suppresses growth of epithelial new growths and in a smaller measure influences tumors of a ferruterous origin. Drug is inactivated in a liver and reveals the expressed hepatotoxic. Suppresses immunological activity of an organism.

Pharmacokinetics. Easily passes through gistogematichesky barriers, including a blood-brain barrier, and it is distributed in fabrics (tumors, marrow, a liver) and organism liquids (spinal, extracellular). At intravenous administration the elimination half-life of a ftoruratsil makes about 16 minutes of plasma (in             the range of 8-20 minutes), depends on the entered dose. It is removed through respiratory tracts (60-80% in the form of carbon dioxide) and kidneys (about 7-20% in not changed look, 90% – for the first hour). For 6 hours in not changed look less than 20% of a single dose are removed with urine (intravenous administration). A small amount of a ftoruratsil is removed with bile.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent colourless or slightly yellowish liquid.

 

Incompatibility.

It is incompatible from calcium folinaty, karboplatiny, Cisplatinum, Cytarabinum, diazepam, doxorubicine, Droperidolum, gallium nitrate, a methotrexate, Metoclopramidum, morphine, ondansetrony, with products for parenteral food, vinorelbiny, other anthracyclines.

Indications to use:

Palliative mono - or the therapy of a number of malignant tumors combined with other cytostatics, especially a colon cancer and a mammary gland.

Route of administration and doses:

Ftoruratsil-Darnits is entered by intravenous injections or intravenous infusions, or intra-arterial infusions.

Adults

Selection of the corresponding dose and the scheme of therapy are defined individually depending on a condition of the patient (for example, cancer which it is necessary to treat), and also depending on that, apply Ftoruratsil-Darnits as monotherapy or in a combination with other types of therapy.

It is necessary to begin treatment in the conditions of a hospital. The general daily dose should not exceed 1 g.

Usually doses determine at the rate on 1 kg of body weight of the patient, however by the patient with the considerable excessive body weight, hypostases, determine by ascites and other forms of an abnormal delay of liquid in an organism of a dose at the rate on 1 kg of ideal body weight.

The dose decline is recommended to patients in the following cases:

1. Cachexia.

2. Heavy surgery in the last 30 days.

3. Deterioration in function of marrow.

4. Existence of abnormal liver functions or kidneys.

Doses for adults

Such mode for Ftoruratsila-Darnits's use in the form of monotherapy is recommended.

Initiation of treatment.

During an initial course of therapy means can be entered by infusion or an injection. It is better than infusion as at such way of introduction there are less toxic effects.

Intravenous infusion

15 mg on 1 kg of body weight, but is no more than 1 g on infusion, part 500 ml of 5% of solution of glucose or 0,9% of solution of sodium of chloride and enter by intravenous infusion 40 drops in a minute for 4 hours.

Alternatively daily dose can be entered by infusion for 30-60 minutes or by continuous 24-hour intravenous infusion. In the next days the drug is administered in the same dose before emergence of toxic effects or still general dose will not reach 12-15 g.

Intravenous injection

 Ftoruratsil-Darnitsa it is necessary to part only 0,9% with solution of sodium of chloride or    5% glucose solution.

Ftoruratsil-Darnits cannot be mixed with other drugs in one infusion solution. On 12 mg on 1 kg of body weight it is possible to enter every day for 3 days. In the absence of signs of toxic effects it is alternatively possible to continue introduction in a dose of 6 mg on 1 kg of body weight in three following doses on an extent of 3 days.

The alternative mode – 15 mg on 1 kg of body weight as one-time intravenous administration       2 times a week.

Intra-arterial infusion

The daily dose of 5-7,5 mg on 1 kg of body weight is entered by continuous 24-hour intra-arterial infusion.

Maintenance therapy

The initial intensive course can be followed by a maintenance therapy if there are no considerable toxic effects. In such cases toxic side effects have to disappear before the supported therapy.

The initial course of treatment of Ftoruratsilom-Darnits can be repeated in 4-6 weeks after receiving the last dose or alternatively treatment it is possible to continue with further intravenous administration 5-15 mg/kg of body weight a week.

This sequence makes a course of treatment. Some patients received up to 30 g of drug on a course, on 1 g a day (the maximum daily dose). More modern alternative method is in applying doses of 15 mg on 1 kg of body weight intravenously once a week throughout all course of treatment. It eliminates need to use drug daily

In a combination with radiotheraphy

Standard doses of drug can be applied in a combination with radiotheraphy in the presence at patients of some types a metastasis in lungs and to pain relief, caused by a recurrent inoperable new growth.

Elderly patients

Dose adjustment is not necessary.

Features of use:

Use during pregnancy or feeding by a breast.

Use of drug is categorically contraindicated during pregnancy. For the period of treatment it is necessary to stop feeding by a breast.

 

Children.

There are no recommendations concerning treatment of children therefore it is not necessary to use drug in pediatric practice.

Ftoruratsilom-Darnits's treatment has to be performed under the supervision of the qualified oncologist who has experience of use of antimetabolites.

Patients have to be in hospital conditions.

At adequate treatment of Ftoruratsilom-Darnits the leukopenia usually develops. The minimum quantity of leukocytes is usually noted during the period between the 7th and 14th day of the first course of treatment, but the minimum can sometimes be observed also in 20 days. The quantity of leukocytes is, as a rule, normalized by 30th day.

It is recommended to control every day quantity of thrombocytes and leukocytes and to stop treatment in case of reduction of quantity of thrombocytes to the level less than 100'109/l, and leukocytes – less than 3'109/l. At reduction of quantity of leukocytes less than 2'109/l, especially in the presence of a granulocytopenia, it is recommended to hospitalize patients to the hospital isolation center and to take measures for prevention of development of system infections.

Treatment needs also to be stopped at emergence of the first symptoms of stomatitis or ulcers of a mucous membrane of an oral cavity, heavy diarrhea, ulcers of a digestive tract, bleeding from digestive tract, and also at bleedings and hemorrhages of any localization. Distinction between therapeutic and toxic doses small. It is improbable that it is possible to reach therapeutic effect without some toxic action therefore it is necessary to select carefully patients for therapy and to select doses.

It is necessary to appoint Ftoruratsil-Darnits with care the patient with renal failures or a liver, and also with jaundice. At treatment quinsy, changes on an ECG arose drug, it is rare – a myocardial infarction. Care is also necessary at therapy of patients who during the previous courses of therapy had a stethalgia, and also the patient with cardiological diseases in the anamnesis.

Patients had messages on increase in toxic effects with deficit of enzyme of a degidropirimidindegidrogenaza (DPD).

DPD enzyme plays an important role in Ftoruratsila-Darnits's disintegration. Nukleozidny analogs, such as бривудин and соривудин, can serve as the reason of acute increase in concentration of a 5-fluorouratsil or any fluoropirimidin in plasma which is followed by toxic effects. For this reason the interval between Ftoruratsila-Darnits's use and use of a brivudin and a sorivudin, and also their analogs has to make 4 weeks.

In case of accidental use of a brivudin patients who are treated Ftoruratsilom-Darnitsa need to take effective measures to reduce Ftoruratsila-Darnits's toxicity. Immediate hospitalization is recommended. All measures have to be directed to prevention of system infections and dehydration.

For patients who accept Phenytoinum along with Ftoruratsilom-Darnitsa it is necessary to establish regular observation as there is a possibility of increase in Phenytoinum in plasma.

Ability to influence speed of response at control of motor transport or work with other mechanisms.

During treatment it is necessary to abstain from control of motor transport and occupations other potentially dangerous types of activity which demand the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The most frequent side effects are diarrhea, nausea. The leukopenia is also very often observed. Below undesirable effects are described.

Frequency assessment: very widespread (³ 1/10), extended (³ 1/100, <1/10), not widespread (³ 1/1000, <1/100), seldom widespread (³ 1/10 000, <1/1000), very seldom widespread (<1/10 000).

Infections and invasions: very widespread – infections; not widespread – sepsis.

Blood and lymphatic system: very widespread – a leukopenia, a miyelosupressiya, a neutropenia, a granulocytopenia, thrombocytopenia, anemia, a pancytopenia; seldom widespread – an agranulocytosis.

Immune system: very widespread – immunosuppression, development of conditionally pathogenic infections, sepsis; very seldom widespread – anaphylactic reactions, an acute anaphylaxis.

Endocrine disturbances: seldom widespread – increase in total quantity of thyroxine (T4), increase in total quantity of triiodothyronine (T3).

Metabolism: not widespread – a hyperuricemia.

Mental disturbances: seldom widespread – confusion of consciousness.

Disturbances from a nervous system: seldom widespread – an ataxy, extrapyramidal disturbances, cerebellar frustration, cerebral disturbances, cortical disturbances, a nystagmus, a headache, вертиго, a parkinsonopodobny syndrome, pyramidal symptoms, euphoria, a leukoencephalopathy, disturbances of the speech, aphasia, spasms, a coma, damage of an optic nerve, peripheral neuropathy.

Organ of sight: extended – conjunctivitis; not widespread – the raised dacryagogue, a dacryostenosis (narrowing of a nasal duct), vision disorders, photophobia, a diplopia, decrease in sight, a blepharitis, ectropion (an ectropion of a century), an optic neuritis.

Cardiovascular frustration: extended – a stethalgia, tachycardia, changes on an ECG, stenocardia; seldom widespread – arrhythmia, a myocardial infarction, myocarditis, heart failure, a cardiomyopathy, an acute heart failure, a heart consciousness, a cardiac standstill, a sudden cardiac death; vasculitis, Reynaud's syndrome, brain ischemia, ventricular ischemia, peripheral ischemia, thromboembolism.

Respiratory organs: not widespread – nasal bleeding, диспноэ, a bronchospasm, a necrosis of nasal bones.

Gastrointestinal frustration: very widespread – diarrhea, nausea, vomiting, an inflammation of a mucous membrane, stomatitis; not widespread – stomach ulcer, gastrointestinal bleedings and perforation.

Liver: not widespread – an abnormal liver function; seldom widespread – a liver necrosis.

Skin and hypodermic fabrics: very widespread – an alopecia, a palmar and bottom eritrodizesteziya; not widespread – dermatitis, a hyperpegmentation, hypopigmentation, change of nail plates, a depigmentation and a hyperpegmentation of nails, dystrophy of nails, an inflammation of a nail bed, a nail degeneration, pain of a nail bed, partial loss of nails, онихолизис, a dieback, a small tortoiseshell, photosensitivity, dryness, cracks, erosion and an itch of skin.

Others: very widespread – fever, fatigue; not widespread – thrombophlebitis, dehydration, a phlebectasia.

Interaction with other medicines:

Other antineoplastic drugs, calcium фолинат, chlordiazepoxide, Disulfiramum, griseofulvin, an isoniazid – at simultaneous use raises efficiency and toxicity of a ftoruratsil.

Mitomitsin – simultaneous prolonged use exponentiates risk of development of a gemolitiko-uraemic syndrome.

Antimicrobic and antiulcerous drugs – at simultaneous use inhibit metabolism and increase plasmatic concentration, duration of action and toxicity ftoruratsit.

The methotrexate, metronidazole, лейковорин, Allopyrinolum, алонуринен, Cimetidinum – at simultaneous use biochemical modulate antineoplastic effect and toxicity of a ftoruratsil.

Cimetidinum – can increase concentration of a ftoruratsil in a blood plasma.

Calcium фолинат – can strengthen antineoplastic and toxic action of a ftoruratsil, especially on digestive tract.

Warfarin – at simultaneous use with ftoruratsily is noted increase in a prothrombin time and the international normalized ratio (INR).

Phenytoinum – at simultaneous use with ftoruratsily raises toxicity of Phenytoinum.

Fluorakril – it is not necessary to apply with ftoruratsily in view of increase in risk of development of an agranulocytosis.

The antiviral drug "sorivudin" and its chemical analogs – as a result of interaction with ftoruratsily DPD inhibition sorivudiny or its chemical analogs is possible.

Levamisole – can strengthen a hepatotoxic of a ftoruratsil.

Tiazida – can strengthen a miyelotoksichnost of antineoplastic drugs.

Gemcitabine – can increase system exposure of a ftoruratsil.

Efficiency and toxicity of therapy increases in case of use of a ftoruratsil in combination with other cytotoxic drugs (cyclophosphamide, Vincristinum, Cisplatinum, doxorubicine), интерфероном-α or folinovy acid.

Before or during treatment ftoruratsily it is impossible to accept Aminophenazonum, phenylbutazone and sulfonamides.

During Ftoruratsilom-Darnits's treatment it is impossible to carry out vaccination by a live virus vaccine of both the most sick, and the persons which are with it in contact owing to possible activation of a virus in the conditions of immunosuppression.

Contraindications:

Hypersensitivity to a ftoruratsil or to other components of drug. Exhaustion or oppression of marrow after radiation therapy or after treatment by other antineoplastic means. The expressed changes of composition of peripheral blood: level of leukocytes is lower 4Õ109/l, thrombocytes – lower than 150Õ109/l).

The expressed abnormal liver functions and kidneys, a sprue, serious infectious diseases, ulcerations of a mucous membrane of an oral cavity and digestive tract, pseudomembranous colitis, heavy diarrhea, severe exhaustion, bilirubin level in a blood plasma more than 85 µmol/l.

Active vaccination during treatment ftoruratsily.

Drug is absolutely contraindicated during pregnancy, at bleedings of any localization, during feeding by a breast. It is forbidden to use drug to children.

Do not apply to treatment of benign tumors. It is impossible to accept along with brivudiny, sorivudiny or with their analogs. Brivudin, соривудин and analogs – powerful inhibitors of enzyme of a dihydropyrimidindehydrogenase which destroys ftoruratsit.

Overdose:

Symptoms: nausea, vomiting, diarrhea, stomach ulcer and bleeding, oppression of activity of marrow (including thrombocytopenia, a leukopenia and an agranulocytosis).

Treatment: the specific antidote is not known. Patients who underwent overdose need to carry out blood test for 4 weeks. If symptoms of overdose are still shown, it is necessary to carry out the corresponding therapy.

Storage conditions:

Period of validity. 2 years. To store in the place, unavailable to children, in original packaging at a temperature from 15 °C to 25 °C.

At storage of drug at lower temperatures loss of a deposit is possible. In this case the ampoule should be heated to temperature of 60 °C at vigorous stirring then drug needs to be cooled up to the temperature of 35 °C. If the deposit is dissolved and solution will become transparent, drug is good for use.

Issue conditions:

According to the recipe

Packaging:

On 5 ml in an ampoule; on 10 ampoules in a box; on 5 ampoules in a blister strip packaging; on the 2nd blister strip packagings in a pack.