Endoxan, 200mg vial, 1pc

Composition

1 bottle contains:

Active ingredients:

cyclophosphamide monohydrate is 213.8 mg, which corresponds to a cyclophosphamide content of 200 mg.

In a 20 ml bottle.

In a cardboard box 1 bottle.

Pharmacological action

Framakodynamics

Cyclophosphamide is an alkylating cytostatic drug that is chemically close to the nitrogen analogues of mustard gas.

It is assumed that the mechanism of action involves the formation of cross-links between DNA and RNA strands, as well as inhibition of protein synthesis.

Pharmacokinetics

The content of the drug in the blood after intravenous use and oral use are the same. It is mainly metabolized in the liver under the action of the microsomal oxidase system, forming active alkylating metabolites (4-OH cyclophosphamide and aldophosphamide), some of which undergo further transformation to inactive metabolites, and some are transported to cells, where they are converted into cytotoxic metabolites under the influence of phosphatases. Cmax of metabolites is reached in plasma 2-3 hours after intravenous use.

The binding of the unchanged drug to plasma proteins is insignificant (12-14%), but some metabolites bind more than 60%. It penetrates the BBB to a limited extent.

Cyclophosphamide is mainly excreted by the kidneys in the form of metabolites, but 5-25% of the administered dose is excreted unchanged in the urine, as well as with bile. T1 / 2 is 7 hours for adults and 4 hours for children.

Indications

• Acute lymphoblastic and chronic lymphocytic leukemia;
• lymphogranulomatosis;
• non-Hodgkin’s lymphoma;
• multiple myeloma;
• breast cancer;
• ovarian cancer;
• neuroblastoma;
• retinoblastoma;
• fungal mycosis.

Endoxane is also used in combination with other antitumor drugs for the treatment of lung cancer, germinogenic tumors, cervical cancer, bladder cancer, soft tissue sarcoma, reticulosarcoma, Ewing’s sarcoma, Wilms ‘ tumor, and prostate cancer.

As an immunosuppressive agent, Endoxane is used in progressive autoimmune diseases (rheumatoid arthritis, psoriatic arthritis, collagenosis, autoimmune hemolytic anemia, nephrotic syndrome) and to suppress the graft rejection reaction.

Use during pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

The drug can cause sterility in both men and women, which in some cases can be irreversible.

A significant proportion of women develop amenorrhea, and regular menstruation usually recovers within a few months of stopping treatment. In girls treated with cyclophosphamide during the prepubertal period, secondary sexual characteristics developed normally and menstruation was normal; subsequently, they were able to conceive.

In men, as a result of treatment with the drug, oligospermia or azoospermia may develop, associated with an increase in the level of gonadotropins with normal testosterone secretion.

Sexual desire and potency in such patients is not disturbed, In boys, during treatment with the drug in the prepubertal period, secondary sexual characteristics develop normally, however, oligospermia or azoospermia and increased secretion of gonadotropins may occur.

Testicular atrophy of varying degrees may occur. In some patients, azoospermia caused by the drug is reversible, but recovery of impaired function may occur only a few years after discontinuation of treatment.

Contraindications

• Severe bone marrow dysfunction;
• cystitis;
• urinary retention;
• active infections;
• pregnancy;
• lactation;
• hypersensitivity to cyclophosphamide or other excipients included in the dosage form.

With caution: for severe heart, liver and kidney diseases, adrenalectomy, gout (in the anamnesis), nephrourolithiasis, suppression of bone marrow function, infiltration of bone marrow with tumor cells, previous radiation or chemotherapy.

Side effects

From the hematopoietic system: leukopenia, neutropenia; rarely-thrombocytopenia, anemia. The greatest decrease in the number of white blood cells and platelets is usually observed on days 7-14 of treatment. Recovery of blood counts in leukopenia usually begins 7-10 days after discontinuation of treatment.

From the digestive system: nausea, vomiting, anorexia, rarely stomatitis, abdominal discomfort or pain, diarrhea or constipation. There are separate reports of the development of hemorrhagic colitis, jaundice.

There are rare cases of liver dysfunction, manifested by an increase in the activity of hepatic transaminases, the level of alkaline phosphatase, and the content of bilirubin in the blood serum. 15-50% of patients receiving high doses of cyclophosphamide in combination with busulfan and total irradiation during allogeneic bone marrow transplantation develop obliterating endophlebitis of the hepatic veins.

A similar reaction is also observed in very rare cases in patients receiving high doses of cyclophosphamide alone in patients with aplastic anemia. This syndrome usually develops 1-3 weeks after bone marrow transplantation and is characterized by a sharp increase in body weight, hepatomegaly, ascites, and hyperbilirubinemia. Hepatic encephalopathy may also occur.

From the skin and skin appendages: often develops alopecia. Hair regrowth begins after the drug treatment is completed or even during prolonged treatment; hair may differ in its structure and color. Sometimes during treatment, a rash appears on the skin, pigmentation of the skin and changes in the nails are observed.

From the urinary system: hemorrhagic urethritis, cystitis, necrosis of the renal tubules. In rare cases, this condition can be severe and even fatal. Bladder fibrosis can also develop, sometimes with a widespread nature, in combination with or without cystitis. Atypical epithelial cells of the bladder can be found in the urine. These side effects depend on the dose of Endoxane and the duration of treatment. Prevention of cystitis is promoted by hydration and the use of mesna. Usually, in severe forms of hemorrhagic cystitis, it is necessary to stop treatment with the drug. When prescribing high doses of cyclophosphamide, in rare cases, impaired renal function, hyperuricemia, and nephropathy associated with increased uric acid formation may occur.

Infections: Patients with severe forms of immunosuppression may develop serious infections.

From the cardiovascular system: cardiotoxicity was observed when high doses of 4.5-10 g / m2 (120 to 270 mg / kg) of the drug were administered for several days, usually as part of intensive combined antitumor or drug therapy for organ transplantation. At the same time, there were severe and sometimes fatal episodes of congestive heart failure caused by hemorrhagic myocarditis.

From the respiratory system: interstitial pulmonary fibrosis (when high doses of the drug are administered for a long time).

From the reproductive system: violation of oogenesis and spermatogenesis. The drug can cause sterility in both men and women, which in some cases can be irreversible.

A significant proportion of women develop amenorrhea, and regular menstruation usually recovers within a few months of stopping treatment. In girls treated with cyclophosphamide during the prepubertal period, secondary sexual characteristics developed normally and menstruation was normal; subsequently, they were able to conceive.

In men, as a result of treatment with the drug, oligospermia or azoospermia may develop, associated with an increase in the level of gonadotropins with normal testosterone secretion. Sexual desire and potency in such patients is not violated. In boys, during treatment with the drug in the prepubertal period, secondary sexual characteristics develop normally, however, oligospermia or azoospermia and increased secretion of gonadotropins may occur. Testicular atrophy of varying degrees may occur. In some patients, azoospermia caused by the drug is reversible, but recovery of impaired function may occur only a few years after discontinuation of treatment.

Carcinogenicity: some patients who were previously treated with the drug in monotherapy or in combination with other antitumor drugs and/or other treatment methods developed secondary malignant tumors. Most often, these were bladder tumors (usually in patients who had previously suffered from hemorrhagic cystitis), myeloproliferative or lymphoproliferative diseases. Secondary tumors most often developed in patients as a result of treatment of primary myeloproliferative malignant tumors or non-malignant diseases, with impaired immune processes. In some cases, a secondary tumor developed several years after discontinuation of treatment with the drug.

When evaluating the ratio of expected positive results and the possible risk of using the drug, you should always keep in mind the probability of induction of a malignant tumor by the drug.

Allergic reactions: skin rash, urticaria or pruritus; rarely-anaphylactic reactions.

Other: One case of possible cross-sensitivity with other alkylating agents is described. Cyclophosphamide may interfere with normal wound healing.It is possible to develop a syndrome similar to the syndrome of inadequate ADH secretion. Redness, swelling, or pain at the injection site. Flushing of the face or redness of the face, headache, excessive sweating.

Interaction

Inducers of microsomal oxidation in the liver can induce microsomal cyclophosphamide metabolism, which leads to increased formation of aliquilating metabolites, thereby reducing the half-life of cyclophosphamide and increasing its activity.

The use of cyclophosphamide, which causes a noticeable and prolonged suppression of cholinesterase activity, increases the effect of suxamethonium, and also reduces or slows down the metabolism of cocaine, thereby increasing and/or increasing the duration of its effect and increasing the risk of toxic effects.

When used concomitantly with allopurinol, in addition, the toxic effect on the bone marrow may increase.

Concomitant use of cyclophosphamide, allopurinol, colchicine, probenecid, and sulfinpyrazone may require dose adjustment of anti-gouty medications. The use of uricosuric anti-gouty medications may increase the risk of nephropathy associated with increased uric acid formation when using cyclophosphamide.

Cyclophosphamide may increase anticoagulant activity by reducing the synthesis of blood clotting factors in the liver and disrupting platelet formation, but it may also reduce the activity of anticoagulants by an unknown mechanism.

Since grapefruit contains a compound that can interfere with cyclophosphamide activation and thus its effect, patients are advised not to eat grapefruit or drink grapefruit juice.

Cyclophosphamide enhances the cardiotoxic effects of doxorubicin and daunorubicin.

Other immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclosporine, mercaptopurine) they increase the risk of developing infections and secondary tumors.

Concomitant use of lovastatin in patients undergoing heart transplantation may increase the risk of acute skeletal muscle necrosis and acute renal failure.

Drugs that cause myelosuppression, as well as radiation therapy, may cause additive suppression of bone marrow function.

The concomitant use of cytarabine in high doses with cyclophosphamide in preparation for bone marrow transplantation led to an increase in the frequency of cardiomyopathy with a subsequent fatal outcome.

How to take, course of use and dosage

Endoxane is part of many chemotherapeutic treatment regimens, and therefore, when choosing the dosage regimen in each individual case, you should be guided by the data of the specialized literature.

The most commonly used doses and regimens for adults and children with parenteral use:

• 50-100 mg / m2 daily for 2-3 weeks;
• 100-200 2 mg / m2 or 3 times a week for 3-4 weeks, orally or iv;
• 600-750 mg / m2 1 time in 2 weeks iv;
• 1500-2000 mg / m2 1 time in 3-4 weeks up to a total dose of 6-14 g.

When using the drug in combination with other antitumor drugs, it may be necessary to reduce the dose of both Endoxane and other drugs.

Before intravenous use, the drug is dissolved in water for injection or 0.9% sodium chloride solution to a concentration of 20 mg / ml.

Overdose

The specific antidote for overdose of the drug is unknown.

In cases of overdose, supportive measures should be used, including appropriate treatment of infections, manifestations of myelosuppression or cardiotoxicity.

Special instructions

During treatment with the drug, it is necessary to regularly conduct a blood test (especially paying attention to the content of neutrophils and platelets) to assess the degree of myelosuppression, as well as regularly conduct a urine test for the presence of red blood cells, the appearance of which may precede the development of hemorrhagic cystitis.

If signs of cystitis with micro – or macrohematuria appear, Endoxan treatment should be discontinued.

If the number of white blood cells decreases to 2500/µl and/or platelets to 100,000/µl, Endoxan treatment should be discontinued.

If infections occur during Endoxan therapy, treatment should either be interrupted or the dose of the drug should be reduced.

When using high doses of Endoxane to prevent the development of hemorrhagic cystitis, Mesna is prescribed.

During the treatment period, you should refrain from taking alcoholic beverages.

If the patient is prescribed Endoxan during the first 10 days after surgery under general anesthesia, the anesthesiologist should be informed about this.

After adrenalectomy, the patient needs to adjust the doses of both corticosteroids used for replacement therapy and the drug Endoxan.

Women and men should use reliable methods of contraception during Endoxan treatment.

Form of production

Powder for preparation of solution for intravenous use

Storage conditions

Store at a temperature not exceeding 25°C out of the reach of children.

Shelf

life is 3 years.

Active ingredient

Cyclophosphamide

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Cancer