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

Clinical and pharmacological group: & nbsp

Included in the formulation

АТХ:

L.01.X.X.03 Altrethamine

Pharmacodynamics:

The exact mechanism of action is not known.Despite the fact that the chemical structure of altretamine resembles that of alkylating agents, it does not have an alkylating effect in vitro. Antitumor activity is caused by metabolites, which form covalent bonds with RNA and DNA (including tumor cells), preventing the incorporation of thymidine into the DNA. It disrupts vital activity and blocks mitosis of tumor cells, slows the growth and development of the tumor /

Pharmacological effects

Antineoplastic.

Pharmacokinetics:

Studies included a limited number of patients. The data given below is based on the analysis of pharmacokinetics in 11 patients. Absorption from the gastrointestinal tract is rapid. Due to its high solubility in fats it is distributed into tissues with a significant fat content (for example, in the gland and subcutaneous tissue). Connection with plasma proteins: altretamine - 6%; pentamethylmelamine and tetramethylmelamine (major metabolites) - 25% and 50%, respectively. Biotransformation in the liver by rapid and intensive demethylation catalyzed by cytochrome P450 to active metabolites. The final T1 / 2 is 4.7-10.2 parts. Cmax is variable due to rapid metabolism in the liver. TCmax 0.5-3 h.Elimination with feces, lungs and kidneys (less than 1% - unchanged, 60% - in the form of metabolites) for 24 hours; 90% within 72 hours. Decreased kidney function (including in old age) and liver, concurrent administration of nephrotoxic drugs (cisplatin etc.) can affect the clearance.

Indications:

Ovarian cancer (epithelial, recurrent, as second-line therapy after development of resistance to platinum drugs or alkylating agents).

ICD-10

II.C51-C58.C56 Malignant neoplasm of ovary

Contraindications:

Hypersensitivity, pregnancy, breast-feeding, children's age (safety and effectiveness of use in children are not defined).

Carefully:

Inhibition of hemopoiesis against the background of previous cytotoxic or radiotherapy, chicken pox or herpes zoster, bacterial and fungal infections, renal dysfunction, severe liver dysfunction, severe neurotoxicity, bone marrow infiltration, CNS dysfunction, cachexia, CHF, terminal stage of the tumor process .

Pregnancy and lactation:

Pregnancy

FDA recommendation category D.Controlled studies on humans were not conducted. Possible development of fetal side effects observed in adults. Altrethamine embryotoxic and teratogenic for rats and rabbits when administered at doses 2-10 times higher than those recommended for humans. It should 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. In view of the potential threat to the fetus for women of childbearing age, during the treatment with altretamine it is recommended to use contraceptives.

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 unwanted effects on the child (side effects, carcinogenicity, mutagenicity), it is recommended to stop breastfeeding during treatment with altretamine.

Dosing and Administration:

Ovarian cancer (epithelial, recurrent, as second-line therapy after development of resistance to platinum drugs or alkylating agents). Inside (after each meal and at bedtime) at a dose of 260 mg / m2 per day, divided into 4 doses, on the 1-14th (21st) every 4 weeks. In total - up to 12 cycles. Inside (after each meal and at bedtime) at a dose of 4-12 mg / kg per day, divided into 4 doses, for 21-90 days. Inside (after each meal and at bedtime) in a dose of 240-320 mg / m2 per day, divided into 4 doses, for 21 days every 6 weeks.

With ovarian cancer stage III and achieved complete remission altretamine (260 mg / m2 per day in the 1-14 days every 4 weeks in 6 cycles) provides a 2-year survival rate of 82% for tumors less than 1 cm in size, with a size of more than 1 cm - 64% with a frequency of toxicity of grade IV 4% , at a frequency of toxicity of the third degree - 22%.

Small cell lung cancer (in combination with other antitumour agents).

In advanced small cell lung cancer, the induction of remission by alternating combinations of cyclophosphamide, doxorubicin, vincristine (CAV), and altretamine, etoposide, methotrexate (HEM), compared with the combination of CAV only, increases the frequency of complete remissions from 16 to 23% (p = 0.03) with the overall response rate was 61-64%, the median survival rate was from 42.7 to 45.9 weeks (P = 0.002) and the two-year survival rate was from 4 to 10% with significantly higher toxicity (p = 0.01)

Side effects:

Hematologic: anemia, leukopenia, thrombocytopenia. On the part of the gastrointestinal tract: nausea and vomiting, diarrhea, loss of appetite, abdominal pain, stomatitis. From the urinary system: a moderate increase in the concentration of urea and creatinine in the blood, a violation of kidney function, cystitis.so the nervous system (more pronounced with the introduction of high doses , reversible after the abolition of altretamine): central and peripheral neurotoxicity. Dermatological: alopecia. Hypersensitivity: skin itching, skin rashes.

On the part of the reproductive system: gonadal suppression (amenorrhea or azoospermia), especially in combination with alkylating agents. Effects depend on the dose and duration of treatment and can be irreversible. With the introduction of altretamine to female rats before mating for 14 days, the effect on fertility is not established. When 120 mg / m2 per day is administered to male rats 60 days prior to mating, causes testicular atrophy, decreases fertility and, possibly, has a lethal dominant mutagenic effect; in a dose of 450 mg / m2 per day for 10 days reduces spermatogenesis, causes atrophy of the testicles, seminal vesicles and the ventral prostate.

Carcinogenicity (mutagenicity): secondary malignant tumors are a potential delayed side effect of many antitumor drugs. It is unclear whether this is due to their mutagenic or immunosuppressive effect. The effect of the dose and duration of treatment is unknown, but it is assumed that the risk increases with prolonged use. One case of development of acute myeloblastic leukemia is described in the treatment with altretamine. The preparation shows a weak mutagenicity for the strain TA100 Salmonella typhimurium.

Other: hepatotoxicity, influenza-like syndrome, fever, infections, increased activity of the alkaline phosphatase in the blood.

Overdose:

Strengthening of neuro- and myelotoxicity, complications from the gastrointestinal tract. Treatment: dose reduction or drug withdrawal, symptomatic therapy (antiemetics, pyridoxine and etc.).

Interaction:

MAO inhibitors (including furazolidone, procarbazine, selegiline) - it is possible to develop severe orthostatic hypotension with parallel application. The development of potentially life-threatening orthostatic hypotension in the combination of altretamine with amitriptyline, imipramine and phenelzine is described.A satisfactory tolerability of the combination of altretamine and nortriptyline has been reported.

NSAIDs - an increased risk of bleeding.

Pyridoxine - may decrease the activity of altretamine.

Cimetidine - oppression of cytochrome P450 can lead to inhibition of the metabolism of altretamine in the liver, to a slowing of its elimination and an increase in the concentration in the blood plasma.

Special instructions:

Monitoring of hematocrit or hemoglobin concentration, number of leukocytes, platelets (before and periodically during treatment, depending on the patient's condition, dose and other combination drugs), neurological status (regularly during treatment).

To reduce nausea and vomiting, it is recommended to take altretamine after eating.

Stop the treatment with altretamine for a period of at least 14 days and then resume therapy at a dose reduced to 200 mg / m2 per day, with the development of gastrointestinal intolerance refractory to symptomatic therapy, leukopenia (less than 2 × 109 / L), granulocytopenia ( less than 1 × 109 / L), thrombocytopenia (less than 75 × 109 / L), progressive neurotoxicity (with recurrence of neurotoxicity even after lowering the dose of treatment with altretamine is recommendedto cease).

Altrethamine has irritating properties. Avoid contact with mucous membranes and skin.

The factors limiting the use of altretamine in the elderly are not established, but in this category of patients the kidney function is more often violated, which may require a reduction in the dose of the drug and careful monitoring.

Store at a temperature of 15-30 ° C (less than 40 ° C), unless otherwise instructed by the manufacturer.

Instructions

Altrethamine (Altretaminum)