Cyclophosphamide

Cyclophosphamide is an alkylating agent that has an effective anticancer activity. It introduces alkyl radicals into  DNA strands  of cells and stops cancer cells from growing. It has also an immunosuppressive effect – suppress the body’s natural immune response, and used to treat some autoimmune diseases.

General pharmacology:

Cyclophosphamide is a synthetic anticancer drug. The chemical name is 2-[Bis (2-chloroethyl) amino] tetrahydro-2H-1, 3, 2-oxazaphosphorine 2-oxide monohydrate, molecular formula is C7H15Cl2N2O2P and molecular weight is 261.1. It is rapidly absorbed from the gastrointestinal tract after oral administration and distribute widely throughout the body. Onset of action is 2-3 hours. Metabolized mainly in the liver and is excreted exclusively through the urine. Learn more.

Mechanism of action:

Cyclophosphamide is an inactive drug. With the help of cytochrome P-450 oxidase system in the liver, the inactive drug is converted into phosphoramide mustard and acrolein which are very active compounds. Phosphoramide mustard has an ability to introduces alkyl radicals into DNA strands with interferes DNA replication by forming DNA cross-linkage. Cross-linked cancer cell DNA is unable to complete normal cell division. Thus, it stops cancer cells from growing, causing them to die. Cyclophosphamide also produces immunosuppressive effects possibly through a cytotoxic effect on lymphocytes.

Uses:

Cyclophosphamide is used to treat in different types of cancer including Non Hodgkin lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia (CLL), Breast cancer, Bronchial cancer, Prostate cancer, Testicular cancer, malignant pheochromocytoma and Ewing’s sarcoma.

 It is also used to treat autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis, myasthenia gravis, Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa, autoimmune hemolytic anemia, polymyositis, dermatomyositis, mononeuritis multiplex, pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, Goodpasture’s syndrome, minimal change disease and membranous nephropathy.

 Patients undergoing bone marrow transplantation is another indication of cyclophosphamide.

Contraindications:

Cyclophosphamide is contraindicated in patients with a history of severe hypersensitivity reactions to it, or any of its components. Anaphylactic reactions including death may occur due to hypersensitivity reactions. It is also contraindicated in patients with urinary tract outflow obstruction.

Use in pregnancy:

Cyclophosphamide is a pregnancy category D drug. It can cause fetal malformations, fetal growth retardation and miscarriage when administered to a pregnant mother particularly in the first trimester. Therefore, this drug is absolutely contraindicated in the first trimester of pregnancy and should be used during second and third trimester of pregnancy only if absolutely essential.

Use in lactation:

Cyclophosphamide is excreted through the breast milk. Because of its serious side effects in lactating infants, a decision should be taken whether to discontinue lactation or to discontinue the drug that depends on the importance of the drug to the lactating mother.

Preparations and dosage:

 It is available as tablets containing 25 mg and 50 mg cyclophosphamide for oral intake, and as 200mg, 500mg, 1gm and 2gm vial containing white powder for reconstitution for intravenous (IV) administration.

When cyclophosphamide is used orally, the usual dose for induction or maintenance therapy is 1 to 5 mg per kg body weight per day, depending on the tolerance of the patient.

When cyclophosphamide is administered intravenously, the usual dose is 40 to 50 mg per kg body weight in divided doses over a period of 2 to 5 days every 2-4 weeks or 10 to 15 mg per kg body weight every 7 to 10 days or 3 to 5 mg per kg body weight twice weekly.

 It may be given intramuscularly (IM), intraperitoneally or intrapleurally.

Click here to learn specific dosage of cyclophosphamide for specific diseases.

Side effects:

Cyclophosphamide may cause –

  • Nausea, vomiting, diarrhea.
  • Urinary bladder toxicity – The presentations of urinary bladder toxicity are dysuria (painful urination), hemorrhagic cystitis (blood in the urine with painful voiding) and increased urinary frequency.
  • Urinary bladder cancer.
  • Bone marrow suppression.
  • Gonadal suppression – It may suppress the gonad (testes or ovary)
  • Myelodysplasia – Ineffective blood cell production in the bone marrow.
  • Pulmonary fibrosis – Formation of fibrous tissue in the lung.
  • Hypogammaglobulinemia – Lowers the body’s antibody.
  • Opportunistic infection – Infection caused by opportunistic microorganisms that usually do not cause harm but do so when lowered body’s immune system.
  • Alopecia – Loss of hair from head.
  • Hyperpigmentation of the skin

Learn more.

Precautions:

Cyclophosphamide should be administered in the morning and encourage the patients to intake plenty of fluid at least 2-3 liter per day to reduce the risk of urinary bladder toxicity. It should be used cautiously in patients with abnormal kidney function, abnormal liver function, and in patients who taking doxorubicin, digoxin, cytochrome P-450 oxidase system stimulating drugs, anticoagulant drugs and depolarizing muscle relaxant drugs. Learn more.

Mechanism of resistance:

Cyclophosphamide is one of the most active chemotherapeutic drug used in the treatment of many cancerous conditions. Sometimes it may resistant and cannot act properly against cancer cells. As a result, treatment failure developed. Resistance to cyclophosphamide is multifactorial with a diverse spectrum of mechanisms. Learn more.