Amifostin - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Included in the formulation

АТХ:

D.02 Preparations with softening and protective action

Pharmacodynamics:

A prodrug is metabolized to 3 active thiol metabolites, reducing cytotoxicity. It binds to the reactive metabolites of cisplatin, mitomycin and alkylating agents and neutralizes them, acting as a scavenger of free radicals. These effects are more pronounced in normal tissues than in the tumor, due to higher phosphatase activity, pH and better vascularization of normal tissues, which leads to their selective protection, reduces the risk of hemato-, nephro-, neuro- and ototoxic reactions observed during chemotherapy and radiotherapy.

Pharmacological effects

Cytoprotective.

Pharmacokinetics:

VD - 0,1 l / kg. After intravenous administration, they are detected in the cells of the bone marrow after 5-8 minutes. Under the action of AF, biotransformation of up to three active thiol metabolites, which are degraded to inactive disulphide metabolites, undergoes biotransformation. T1 / 2 (distribution) - less than 1 minute, T1 / 2 (elimination) - 8 minutes (after 6 minutes after injection, less than 10% of the administered dose remains in the plasma). Cmax - 200 μmol / l, Cmax of active metabolite WR-1065 (free thiol) - 35 μmol / l. Within 1 hour after infusion at a dose of 740-910 mg / m2 for 15 minutes and jet intravenous administration at a dose of 150 mg / m2, the release of unchanged substance,its disulfide and thiol metabolites in the urine are 0.69%, 2.22% and 2.64% of the administered dose, respectively. Cl - 2 l / min. Elimination is carried out mainly through rapid metabolism in tissues and kidneys.

Indications:

Prevention of hematotoxic action caused by DNA-binding chemotherapeutic agents; prevention of nephrotoxic, neurotoxic and ototoxic action associated with basic therapy with platinum drugs.

ICD-10

XIX.T51-T65.T56 Toxicity of metals

Contraindications:

Hypersensitivity (including to the compounds of aminothiol). Dehydration (correction before treatment with amifostin is necessary). Arterial hypotension (correction before treatment with amifostin is necessary). Pregnancy, lactation.

Carefully:

It is not recommended to apply amifostine with severe violations of the liver and kidneys.

It is not recommended to apply amifostine in children and patients older than 70 years, since the experience with the use of these groups of patients is not enough.

Pregnancy and lactation:

Pregnancy

Recommendations FDA category C. Controlled studies on humans were not conducted.It is also necessary to take into account the potential risk caused by the appointment of antitumor agents. Amifostine embryotoxic when used in rabbits at a dose corresponding to 60% of the recommended human. In rats, dose-dependent embryotoxic and teratogenic in doses exceeding 200 mg / kg. It is recommended to avoid the use of antitumor, especially combined chemotherapy in pregnancy, especially in the first trimester. In the presence of indications, it is necessary to relate the risk and benefit and take into account the mutagenic and carcinogenic potential of these agents.

Lactation

There is no information on the penetration into breast milk. Due to the excretion of other antitumor drugs with milk and the potential risk of adverse effects on the child during treatment with amifostine, breast-feeding is recommended to be discontinued.

Dosing and Administration:

Prophylaxis of nephrotoxicity (cisplatinum-induced, in the treatment of advanced ovarian cancer, non-small cell lung cancer, non-germogenic tumors).

Intravenously drip (for 15 minutes) to 910 mg / m2 once a day for 30 minutes before the introduction of cisplatin.

Intravenous drip on 740 mg / m2 once a day with a dose of cisplatin less than 100 mg / m2.

With a significant reduction in blood pressure, it is recommended to stop the infusion of amifostine. When the blood pressure is restored to the baseline within 5 minutes, and in the absence of clinical symptoms, it is possible to continue the infusion in a full dose. Otherwise, the dose of amifostine in subsequent courses of treatment should be reduced to 740 mg / m2.

With chemotherapy based on cisplatin, the addition of amifostine as compared to the control (chemotherapy alone) allows to maintain the original GFR (and not to reduce it by 30% or more - from 108 to 80 ml / min), reduce the incidence of hypomagnesemia to 17% (vs. 69 %), reduce the difference in microalbuminuria before and on the 2nd, 4th, 6th, 10th and 14th days after the course of treatment and the concentration of N-acetyl-β-D-glucase in the urine on the 4th, The 6th, 10th and 14th days after the first cycle of therapy (regardless of the type of tumor), the severity of hypercreatininaemia and increase the clearance of creatinine ( and ≥40%), without affecting the efficacy of chemotherapy.

Prevention of Xerostomia, induced by radiation therapy.

Intravenously drip (for 3 minutes) at 200 mg / m2 once a day for 15-30 minutes before the session of radiation therapy.

Amifostin reduces the incidence of moderate and severe xerostomia in adjuvant radiation therapy for head and neck tumors, when the irradiation field captures a significant portion of the parotid salivary glands.

When radiation therapy of tumors of the head and neck organs (the total focal dose of 50-70 Gy) amifostine reduces the incidence of chronic xerostomia of grade II and above during 2 years of observation from 70 to 57.5% (without affecting the effectiveness of treatment), acute xerostomia of grade III - from 45 to 39.3%, any degree - from 100 to 93, 9%.

Prevention of myelotoxicity induced by antitumor agents in the treatment of common non-germogenic tumors with the combination of cyclophosphamide and cisplatin, as well as with high doses of cisplatin in head and neck tumors, carboplatin in non-small cell lung cancer, combining carboplatin with radiotherapy for head and neck tumors.

Intravenous drip (for 15 minutes) at a dose of 910 mg / m2 once a day for 30 minutes before the introduction of cisplatin.

With a significant reduction in blood pressure, it is recommended to stop the infusion of amifostine. When blood pressure is restored to the baseline within 5 minutes, and in the absence of clinical symptoms, infusion in a full dose can be continued.Otherwise, the dose of amifostine in subsequent courses of treatment should be reduced to 740 mg / m2.

When chemotherapy with cisplatin (75 mg / m2 per week) amifostine reduces the incidence of grade III-IV thrombocytopenia (from 2.9 to 0.5%), grade IV neutropenia and / or infections requiring antibiotic therapy, the length of stay in the hospital and the duration of antibiotic therapy, without affecting the effectiveness of chemotherapy.

Amifostin does not have a significant effect on the severity of hematological toxicity in monotherapy with carboplatin.

Amifostin, which is used to prevent hematologic toxicity caused by the combination of paclitaxel and carboplatin in the treatment of ovarian cancer, reduces the incidence of thrombocytopenia of grade III to IV from 3.3 to 0.6%, grade III-IV neutropenia from 37.9 to 31 , 3%, heavy mucositis - from 15.4 to 4.7% and neurotoxicity of III-IV degree - from 7.2 to 3.7% (without affecting the incidence of leukopenia, anemia and median time to progression).

With combined chemoradiation (combination of paclitaxel and carboplatin), non-small-cell lung cancer amifostine reduces the number of new casesdevelopment of esophagitis III-IV degree from 84.4 to 38.9% and acute pulmonary toxicity of III-IV degree - from 56.3 to 19.4% (without affecting the frequency of responses).

Prevention of cisplatinum-induced neurotoxicity.

Intravenous drip (for 15 minutes) at a dose of 910 mg / m2 once a day for 30 minutes before the introduction of cisplatin.

With a significant reduction in blood pressure, it is recommended to stop the infusion of amifostine. When blood pressure is restored to the baseline within 5 minutes, and in the absence of clinical symptoms, infusion in a full dose can be continued. Otherwise, the dose of amifostine in subsequent courses of treatment should be reduced to 740 mg / m2.

According to experimental data, amifostine can influence the antitumor activity of cisplatin, and therefore it is not recommended to use it for potentially curable tumors (except for clinical studies). In the same time cisplatin in combination with cyclophosphamide does not affect the effectiveness in ovarian cancer, and in combination with vinblastine - with non-small cell lung cancer.

Amifostin prevents the development of severe cisplatinum-induced neuropathy (including subclinical neurotoxicity), reduces its severity and ototoxicity when treated with cisplatin.

Prevention of mucositis in combination chemoradiotherapy.

Intravenously drip (within 15 minutes) at a dose of 300 mg / m2 once a day (one day before radiotherapy).

In the treatment of malignant tumors amifostine (in comparison with placebo) slightly reduces the development of severe and mild mucositis and approximately comparable in effectiveness with pastes or pastilles with antibiotics, hydrolytic enzymes and ice slices.

Myelodysplastic syndrome (treatment in combination with other agents, eg with erythropoietin, topotecan, etoposide, cytarabine).

Intravenous bolus (for 15 minutes) at a dose of 200 mg / m2 3 times a week for 3 weeks with a subsequent break 2 weeks (in combination with other agents).

Use in children

Efficiency and safety have not been studied.

Side effects:

From the cardiovascular system: arterial hypotension, atrial fibrillation (flutter), supraventricular tachycardia, transient hypertension. It is possible to reduce both systolic and diastolic blood pressure, which can be accompanied by apnea, dyspnoea, hypoxia, tachycardia, bradycardia, extrasystole, chest pain, myocardial ischemia and seizures.In rare cases, during and after hypotension arises OPN, myocardial infarction, stopping breathing and heart. With a significant decrease in SBP (by 20 mm Hg with an initial arterial pressure of less than 100 mm Hg, 25 at 100-119 mm Hg, 30 at 120-139 mm Hg, 40 for 140-179 mm Hg, 50 for initial arterial pressure more than 180 mm Hg), it is recommended to stop infusion of amifostine, place the patient in the Trendelenburg position and intravenously drop 0.9% solution of sodium chloride in another vein). When the pressure is normalized for 5 minutes and there are no clinical symptoms, you can resume the infusion and enter the full dose. Otherwise, it is necessary to reduce the dose, and then introduce up to 740 mg / m2.

From the gastrointestinal tract: nausea, vomiting, metallic taste in the mouth, hiccough. From the nervous system: loss of consciousness, convulsions, fainting, pronounced drowsiness, dizziness. Dermatological: skin rashes. Hypersensitivity (patients hypersensitive to other aminothiol agents, may be hypersensitive to amifostin): allergic, anaphylactoid, severe skin reactions.

It is necessary to examine the skin of the patient before each administration of amifostine, differentiating skin reactions induced by the drug, from such other etiology and radiation dermatitis.In unclear cases (if erythematous, bullous or edematic lesions occur outside the irradiation or infusion site, on the palms of the hands or soles of the feet), treatment with amifostine should be discontinued. Skin biopsy and dermatologist consultation are recommended. Renewal treatment with amifostin can be done only after a thorough clinical and dermatological examination. Treatment of skin reactions is symptomatic.

Carcinogenicity: no protracted animal tests have been performed, but in vitro and in vivo studies suggest that the drug may protect against genotoxic effects of antitumor agents and the carcinogenic effects of radiation therapy. Amifostine is not mutagenic in the Ames test and micronucleus test in mice, but free thiol metabolites are mutagenic in the Ames test and in vitro mouse tests, do not show a mutagenic effect in the micronucleus test in mice and are not clastogenous for human lymphocytes. In vitro and in vivo studies suggest that amifostine can protect against the mutagenic effect of antitumor agents.

Other: hypocalcemia, fever, sneezing, unusual sensations of heat or cold, redness of the face or neck, hiccough, decreased calcium concentration in the blood plasma.

Overdose:

Not described.The most likely clinical sign is hypotension. When using high doses, anxiety and reversible urinary retention can develop.

Treatment: infusion (0.9% sodium chloride solution) and maintenance therapy.

Interaction:

Antihypertensive drugs or drugs that reduce blood pressure, β-blockers, aldesleukin, alprostadil, amantadine, general anesthetics, antidepressants, MAO inhibitors, tricyclic antidepressants, antihypertensives, benzodiazepines used for premedication, slow calcium channel blockers, brethil tosylate, bromocriptine, haloperidol, hydralazine, deferoxamine (with intravenous administration at a dose of more than 15 mg / kg per day), diuretics, droperidol, ACE inhibitors, cabergoline, calcium-containing infusion solutions, carbidopa, quetiapine, gadopentetic acid, clozapine, contrasting paramagnetic and contrast superparamagnetic means, levodopa, lidocaine (for systemic use), loxapine, magnesium sulfate (for parenteral administration), mirtazapine, molindone, narcotic analgesics, sodium calcium edetate, nitrates, nitrites, olanzapine, paclitaxel, pentamidine, pentoxifylline, pimozide, pramipexole, procainamide, propofol, Protamine sulfate (with very rapid introduction), ranitidine, bismuth tricalcium dicitrate, radiocontrast water-soluble drugs, organic iodides (with intravascular application), risperidone, rituximab, ropinirol, thioxanthenes, tizanidine, tokainid, tolcapone, thrombolytic agents, phenothiazines, quinidine, ethanol ρ - amifostine can cause hypotension. It is necessary to cancel antihypertensive or blood pressure lowering agents 24 hours before the administration of amifostine. If cancellation is not possible, do not enter amifostine.

Amifostine can not be diluted with other solvents, with the exception of 0.9% sodium chloride solution.

Amifostine is pharmaceutically incompatible with amphotericin, acyclovir, ganciclovir, hydroxyzine, miconazole, minocycline, prochlorperazine, chlorpromazine, cefoperazone and cisplatin when infused through the Y-splitter.

Amifostin lowers the kidney clearance of carboplatin, increases its AUC and T1 / 2 (by 64%).

Special instructions:

Monitoring of blood pressure (every 5 minutes in the prevention of nephrotoxicity,before and after infusion in the prevention of post-radiation xerostomia), the concentration of calcium in the blood (in patients prone to hypocalcemia, for example, in nephrotic syndrome or repeated administration of amifostine), water balance (when amifostine is combined with chemotherapy that causes severe vomiting), hypersensitivity reactions before, during and after infusion).

The use of the drug in doses exceeding 1300 mg / m2 per day has not been investigated. Efficiency and safety have not been studied.

Before intravenous administration, 9.7 ml of 0.9% sodium chloride solution is added to the contents of the vial and a solution with a concentration of 50 mg / ml is prepared, which is diluted with 0.9% sodium chloride solution before infusion.

Amifostin is administered intravenously drip (for 15 min) 30 minutes before chemotherapy. With longer infusions, side effects occur more often.

Before radiotherapy of malignant tumors of the head and neck organs amifostine injected in a jet (for 3 minutes) for 15-20 minutes before the session.

Before the infusion of amifostine, a complete hydration of the patient is necessary.

Because the amifostine can cause severe nausea and vomiting, prophylaxis with antiemetics is necessary(eg, combining intravenous administration of dexamethasone at a dose of 20 mg and a serotonin antagonist or other agents, depending on the chemotherapy regimen).

Because the amifostine can cause transient hypotension, before its introduction it is necessary to fully hydrate the patient. During infusion, it should be in the supine position. The arterial pressure is measured every 5 minutes (especially carefully in patients receiving antihypertensive treatment, since its cancellation and intravenous hydration can cause an increase in blood pressure). Possible development of hypotension both during and immediately after infusion.

The department should have equipment and medicines (epinephrine, oxygen), necessary for the relief of severe hypersensitivity reactions.

It is necessary to examine the skin of the patient before each injection of amifostine, during and after infusion - a thorough examination for the detection of skin reactions.

The potential risk and benefit of amifostine in cardiovascular pathology in an anamnesis (arrhythmia, CHF, CHD), stroke or transient ischemic attacks in the anamnesis should be correlated (safety of amifostine use in thisthe category of patients is not defined), with predisposition to hypocalcemia, for example, in nephrotic syndrome (careful monitoring of Ca2 + concentration is necessary), predisposition to nausea or vomiting (premedication with antiemetic, especially when combined with vomiting agents and careful monitoring of water balance ), with renal or hepatic insufficiency, age over 70 years.

Experience with amifostine in patients older than 70 years is limited: no studies have been conducted, efficacy and safety have not been determined. It should be used with caution, consider that cardiovascular pathology is not uncommon at this age.

A solution with a concentration of 50 mg / ml is stable for 5 hours at room temperature (25 ° C) and 24 hours in a refrigerator (2-8 ° C). After further dilution during storage in polyvinylchloride capacity, the preparation is stable for 5 hours at room temperature and 24 hours in the refrigerator. Do not use in case of turbidity or sedimentation!

Instructions

Amifostine (Amifostinum)