Endoxan® [Cyclophosphamide]

Brand Baxter

In stock 1285 Items

Available since: 2019-09-19

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Clinical Pharmacology

Fracodynamics

Cyclophosphamide is an cytostatic alkylating agent chemically close to nitrogen mustard analogs.

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

Pharmacokinetics

The content of the drug in the blood after the on / in the introduction and ingestion of the same. Metabolized mainly 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, the part is transported into cells, where, under the influence of phosphatases, they are converted to metabolites with cytotoxic effect. C_max Metabolites reach plasma 2-3 hours after i / v administration.

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

Cyclophosphamide is excreted by the kidneys mainly in the form of metabolites, but 5–25% of the administered dose is excreted in the urine unchanged, as well as in the bile. T_1/2 is 7 hours for adults and 4 hours for children.

Indications

Endoxan is also used in combination with other anticancer drugs for the treatment of lung cancer, germ cell tumors, cervical cancer, bladder cancer, soft tissue sarcoma, reticulosarcoma, Ewing sarcoma, Wilms tumor, prostate cancer.

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

Composition

1 bottle contains:

Active substances: cyclophosphamide monohydrate 534.5 mg, which corresponds to the content of cyclophosphamide 500 mg.

Cyclophosphamide is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Endoxan	Baxter	USA	vials
Endoxan	Baxter	USA	dragee
Endoxan	Baxter	USA	bottle

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Dosage and Administration

Endoxan is a part of many chemotherapy regimens, therefore, when choosing a dosing regimen in each individual case, you should be guided by the data of special literature.

The most commonly used doses and regimens for adults and children when administered parenterally:

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

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

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

Adverse reactions

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

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

There are rare cases of abnormal liver function, manifested by an increase in liver transaminase activity, alkaline phosphatase levels, and serum bilirubin levels. In 15-50% of patients receiving high doses of cyclophosphamide in combination with busulfan and total irradiation during allogeneic bone marrow transplantation, endoflebitis obliterans of the hepatic veins develops. A similar reaction in very rare cases is also observed in patients receiving high doses of one cyclophosphamide 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 be observed.

From the skin and skin appendages: alopecia often develops. Hair regrowth begins after completion of drug treatment or even during long-term treatment; hair may vary in structure and color. Sometimes during treatment a rash appears on the skin, skin pigmentation 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, sometimes widespread, may also develop in combination with or without cystitis. Atypical bladder epithelial cells can be detected in the urine. These side effects depend on the dose of Endoxan and the duration of treatment. Prevention of cystitis contributes to hydration and the use of the drug mesna. Usually, in severe forms of hemorrhagic cystitis, treatment with the drug should be stopped. With the appointment of high doses of cyclophosphamide in rare cases, there may be impaired renal function, hyperuricemia, nephropathy associated with increased formation of uric acid.

Infections: Patients with severe immunosuppression may develop serious infections.

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

On the part of the respiratory system: interstitial pulmonary fibrosis (with the introduction of high doses of the drug 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 may be irreversible.

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

In men, as a result of drug treatment, oligospermia or azoospermia may develop, associated with an increase in gonadotropins during normal testosterone secretion. Sexual attraction and potency in these patients is not disturbed. In boys, during drug treatment in the prepubertal period, secondary sexual characteristics develop normally, however, oligospermia or azoospermia and increased gonadotropin secretion may occur. There can be atrophy of the testes of varying degrees. In some patients, azoospermia caused by the drug is reversible, however, restoration of impaired function can occur only several years after stopping treatment.

Carcinogenicity: in some patients who had previously been treated with the drug in monotherapy or in combination with other anticancer drugs and / or other methods of treatment, secondary malignant tumors developed. 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 the treatment of primary myeloproliferative malignant tumors or non-malignant diseases, in violation of immune processes. In some cases, a secondary tumor developed several years after discontinuation of the drug treatment.

Assessing the ratio of expected positive results and the possible risk of using the drug, one should always keep in mind the probability of drug induction of a malignant tumor.

Allergic reactions: skin rash, hives or itching; rarely - anaphylactic reactions.

Other: One case of possible cross-sensitivity with other alkylating agents has been described. Cyclophosphamide may interfere with normal wound healing. Perhaps the development of the syndrome, similar to the syndrome of inadequate secretion of ADH. Redness, swelling, or pain at the injection site. A rush of blood to the face or redness of the face, headache, excessive sweating.

Carefully: in severe diseases of the heart, liver and kidneys, adrenalectomy, gout (history), nephrorolithiasis, bone marrow function suppression, bone marrow infiltration with tumor cells, prior radiotherapy or chemotherapy.

Drug interactions

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

The use of cyclophosphamide, which causes a marked and prolonged suppression of cholinesterase activity, enhances the action of suxametonium, and also reduces or slows down the metabolism of cocaine, thereby enhancing and / or increasing the duration of its effect and increasing the risk of toxic action.

With simultaneous use with allopurinol, in addition, the toxic effect on the bone marrow may be enhanced.

With the simultaneous use of cyclophosphamide, allopurinol, colchicine, probenecid, sulfinpyrazone, dosage adjustment of anti-gout preparations may be required. The use of uricosuric anti-gout agents may increase the risk of nephropathy associated with an increased formation of uric acid when using cyclophosphamide.

Cyclophosphamide may increase anticoagulant activity as a result of a decrease in the synthesis of blood clotting factors and impaired platelet formation in the liver, but it may also decrease the activity of anticoagulants through an unknown mechanism.

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

Cyclophosphamide enhances the cardiotoxic effect of doxorubicin and daunorubicin.

Other immunosuppressants (azathioprine, chlorambucil, GCS, cyclosporin, mercaptopurine) increase the risk of developing infections and secondary tumors.

With simultaneous use of lovastatin in patients with heart transplantation, an increased risk of acute necrosis of skeletal muscles and acute renal failure is possible.

Drugs that cause myelosuppression, as well as radiation therapy - possibly additive inhibition of bone marrow function.

The simultaneous use of cytarabine in high doses with cyclophosphamide in preparation for bone marrow transplantation resulted in an increase in the incidence of cardiomyopathy, followed by death.

Pregnancy and Lactation

The drug is contraindicated in pregnancy and lactation.

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

In men, as a result of drug treatment, oligospermia or azoospermia may develop, associated with an increase in gonadotropins during normal testosterone secretion. Sexual attraction and potency in such patients is not impaired. In boys, during prepubertal treatment, secondary sexual characteristics develop normally, however, oligospermia or azoospermia and increased gonadotropin secretion may occur. There can be atrophy of the testes of varying degrees. In some patients, azoospermia caused by the drug is reversible, however, restoration of impaired function can occur only several years after stopping treatment.

Special instructions

During drug treatment, it is necessary to perform a regular blood test (especially paying attention to neutrophil and platelet counts) to assess the degree of myelosuppression, and also to regularly conduct urinalysis for red blood cells, the appearance of which may precede the development of hemorrhagic cystitis.

If there are signs of cystitis with micro- or gross hematuria, treatment with Endoxan should be discontinued.

With a decrease in the number of leukocytes to 2500 / μl and / or platelets to 100 000 / μl, treatment with Endoxan should be stopped.

In the event of infections in the process of treatment with Endoxan, treatment should be either interrupted or the dose should be reduced.

When high doses of Endoxan are used to prevent the development of hemorrhagic cystitis, the drug Mesna is prescribed.

During the period of treatment should refrain from taking alcoholic beverages.

If the patient is prescribed Endoxan within the first 10 days after the operation performed under general anesthesia, it is necessary to inform the anesthesiologist 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 during treatment with Endoxan should use reliable methods of contraception.

Overdosage

The specific antidote for overdose is unknown. In cases of overdose, supportive measures should be used, including appropriate treatment of infections, manifestations of myelosuppression or cardiotoxicity.