Cyclophosphamide

Cyclophosphamide is a cytostatic agent that belongs to the chemical category of oxazaphosphorins. The process of activation of cyclophosphamide is carried out by microsomal enzymes inside the liver cells, in which it is converted into the metabolic element 4-hydroxy-cyclophosphamide.

The cytotoxic effect of the drug is mainly based on the interaction of deoxyribonucleic acid with its alkylating metabolic components. As a result, chemical cross-links between DNA strands are disrupted. This slows down the G2 stage of the cell cycle.[1]

Indications Cyclophosphamide

It is used in case of the following disorders and pathologies:

• lung , ovarian or breast carcinoma, lymphosarcoma, NHL and lymphogranulomatosis, osteogenic sarcoma , reticulosarcoma, multiple myeloma, ALL, chronic lymphocytic leukemia, endothelial myeloma, nephroblastoma and testicular seminoma;
• preventing the development of graft rejection;
• SLE, rheumatoid arthritis, multiple sclerosis and nephrotic syndrome (as an immunosuppressant).

Release form

The release of the drug substance is made in the form of a lyophilisate for injections - inside bottles with a volume of 0.2 g. Inside the box contains 1 such bottle.

Pharmacokinetics

Cyclophosphamide is almost completely absorbed inside the intestine. With a 1-time use of the drug, during the period of the day, a significant decrease in its indicators and the values of its derivatives inside the blood is carried out.[2]

The average half-life is 7 hours (in an adult) and 4 hours (in a child). Excretion of cyclophosphamide with its metabolic elements is carried out mainly through the kidneys.

Dosing and administration

Cyclophosphamide therapy can only be carried out under the supervision of an experienced oncologist. The portion size is selected personally, the medicine is injected at a low speed by the attending doctor - in / in the way through a dropper.

The following dosage regimens are used in monotherapy. In the case of combination with other cytostatics, a dosage reduction or prolongation of the interval between treatment procedures is required.

Dosage sizes for monotherapy:

• with intermittent therapy, it is required to inject 10-15 mg / kg of the drug at 2-5-day intervals;
• in the case of continuous treatment, the medication is used daily at a dosage of 3-6 mg / kg;
• in a treatment course with breaks, when high dosages are used, portions of 20-40 mg / kg are used at 3-4 week intervals.

Use Cyclophosphamide during pregnancy

It is forbidden to use Cyclophosphamide during pregnancy. If there are strict indications in the 1st trimester, an abortion may be prescribed.

The drug is excreted in breast milk, which is why breastfeeding must be abandoned for the duration of treatment.

Contraindications

Among the contraindications:

• severe intolerance associated with cyclophosphamide;
• severe bone marrow dysfunction (especially in people who have received radiation therapy or used cytotoxic drugs);
• cystitis;
• delay in urination processes;
• infection in an active form.

Side effects Cyclophosphamide

The main side symptoms:

• infections of an infectious type: often with severe suppression of bone marrow activity, an agranulocytic fever develops, and infections of a secondary nature appear, similar to pneumonia, then progressing to sepsis. Occasionally, such defeats result in death;
• immune disorders: occasionally there are symptoms of intolerance, in which there is a rash, bronchial spasm, chills, tachycardia, fever, hot flashes, dyspnea, swelling and a sharp decrease in blood pressure. Single anaphylactoid manifestations may progress to the development of anaphylaxis;
• problems with the work of lymph and hematopoiesis: taking into account the size of the portion, different types of bone marrow suppression can develop: leuko-, neutro- and thrombocytopenia with an increased likelihood of anemia and bleeding. It should be taken into account that with severe suppression of bone marrow function, secondary infections and fever of the agranulocytic type occur. During the 1st and 2nd week of treatment, the minimum number of platelets with leukocytes is observed. Bone marrow regeneration occurs fairly quickly, and the blood composition usually stabilizes within 20 days. The development of anemia is noted only after several consecutive therapeutic courses. The most severe depression of bone marrow activity is expected in persons who underwent courses of chemotherapy or radiation therapy immediately before the use of Cyclophosphamide, and in addition, in people with insufficient renal function;
• disorders in the work of the NS: neurotoxic symptoms, paresthesias, polyneuropathy, taste disturbances, neuropathic pain and convulsions appear;
• lesions of the digestive system: most often there is nausea with vomiting (these are dose-dependent signs). Sometimes the occurrence of diarrhea, anorexia, constipation and inflammation in the mucous membrane (from the development of stomatitis to the formation of ulcers) is noted. The appearance of an active form of pancreatitis, hemorrhagic colitis, as well as bleeding in the gastrointestinal tract is possible. Occasionally, hepatic dysfunctions appear (an increase in the level of alkaline phosphatase, transaminases, GGT and bilirubin). Obliterating endophlebitis affecting the liver vessels was observed in some patients who used large portions of cyclophosphamide in combination with busulfan or body radiation during allogeneic bone marrow transplantation. Contributing factors include hepatic dysfunction and the use of hepatotoxic agents in combination with chemotherapy courses in large portions. Liver encephalopathy is observed singly;
• disorders in the area of the urogenital system: the metabolic elements of drugs trapped in the urine lead to changes associated with the bladder. Hemorrhagic cystitis and microhematuria depend on the size of the dosage and most often develop with the use of this medication (in these cases, you need to stop using it). Cystitis often appears. Sometimes there are bleeding, sclerosis or swelling of the walls of the urea and interstitial inflammation. Large doses sometimes cause renal dysfunction. The use of uromitexan or drinking large quantities of liquid can significantly reduce the frequency and intensity of urotoxic negative signs. There is information about the appearance of hemorrhagic cystitis, leading to death. Nephropathy of a toxic type and failure of renal function in active or chronic form may develop. Disorders of spermatogenesis (oligo- and azoospermia) or ovulation, a decrease in estrogen levels and the development of amenorrhea are rarely observed;
• lesions associated with blood flow: cardiotoxicity develops with the following symptoms: the appearance of weak fluctuations in blood pressure, changes in ECG readings, arrhythmia and cardiomyopathy of the secondary type with deterioration of left ventricular function and the development of heart failure. Among the clinical manifestations of cardiotoxicity are angina attacks or thoracalgia. A single injection of drugs causes atrial fibrillation or ventricular fibrillation, pericarditis, myocarditis, heart attack, or even cardiac arrest;
• disorders of the respiratory function: cough, bronchospasm and dyspnea develop most often. Pulmonary endophlebitis of the obliterating type, pulmonary embolism, edema or hypertension, pneumonitis, or an interstitial form of pneumonia occurs singly. There is evidence of the development of RDS syndrome and severe respiratory failure leading to death;
• tumors of a benign and malignant nature: there is an increased likelihood of the appearance of secondary neoplasms, as well as their precursors. The risk of developing carcinoma of the organs of the urogenital system and myelodysplastic disorders, which sometimes progress to active leukemia, increases. In animal tests, it was found that the use of uromitexan significantly reduces the likelihood of developing bladder carcinoma;
• lesions in the epidermis and signs of allergies: alopecia areata of the focal type (complete baldness can be observed) is reversible and occurs quite often. There are reports of dermatitis, a violation of epidermal pigmentation on the feet and hands, as well as erythrodysis. Occasionally there is SJS, TEN, shock and fever;
• problems affecting metabolic processes and the hormonal system: dehydration, Parkhon's syndrome, hyponatremia and normotensive hyperaldosteronism are noted;
• visual disturbances: conjunctivitis, blurred vision and swelling of the eyelids may develop;
• lesions affecting blood vessels: thromboembolism, peripheral ischemia, hemolytic syndrome and disseminated intravascular coagulation (chemotherapy with a drug increases the incidence of these disorders);
• systemic manifestations: fever, malaise and asthenia very often develop in people with oncology. Occasionally, erythema, inflammation or phlebitis appear in the injection area.

Administration in combination with other medicines that suppress hematopoiesis often requires dosage adjustment. It is necessary to use the appropriate tables for changing portions of cytotoxic drugs.

Overdose

There are no antidotes for cyclophosphamide, which is why it must be used with extreme caution. The drug is excreted during dialysis. Intoxication leads to dose-dependent bone marrow suppression and leukopenia. It is required to carefully monitor the values of blood tests, as well as the general condition of the patient. If thrombocytopenia develops, the loss of platelets must be replenished.

Interactions with other drugs

Use in combination with antidiabetic drugs potentiates their therapeutic effect.

Combination with indirect anticoagulants causes impairment of anticoagulant blood activity.

The introduction of Cyclophosphamide together with allopurinol potentiates myelotoxicity.

The use in combination with cytarabine, daunorubicin and doxorubicin can lead to the appearance of cardiotoxic effects.

Prescribing a medication along with immunosuppressants increases the likelihood of developing secondary neoplasms and infections.

The combination of a medication with lovastatin increases the likelihood of muscle necrosis, as well as acute renal failure.

Storage conditions

Cyclophosphamide must be kept in a place closed from the penetration of children. Temperature indicators are not higher than 10 ° C.

Shelf life

Cyclophosphamide can be used for 36 months from the date of manufacture of the therapeutic substance.

Analogs

Analogs of the drug are the drugs Ribomustin, Endoxan and Leukeran with Alkeran, and besides this, Holoxan and Ifosfamide.

Reviews

Cyclophosphamide generally receives positive reviews as a drug that is effective in the treatment of systemic vasculitis.