About Pharmacology

• Cyclophosphamide is an alkylating agent commonly used in cancer chemotherapy and
  immunosuppressive therapy. It exerts its therapeutic effects by undergoing bioactivation in the
  liver, where it is converted to its active metabolites, such as phosphoramide mustard, which
  cross-links DNA strands, leading to DNA damage and inhibition of DNA replication and
  transcription. This results in cell cycle arrest and eventual apoptosis, particularly in rapidly
  dividing cells like those in tumors.
• Cyclophosphamide exhibits an elimination half-life of 3 to 12 hours and total body clearance
  (CL) values of 4 to 5.6 L/h. Following IV administration, its distribution is approximately 30 to 50
  L, reflecting the volume of total body water, and about 20% of the drug is protein-bound. The
  liver is the primary site of cyclophosphamide activation, involving cytochrome P450 enzymes
  (CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19), with CYP2B6 exhibiting the highest
  4-hydroxylase activity. Cyclophosphamide is metabolized to 4-hydroxycyclophosphamide, which
  is in equilibrium with aldophosphamide. These can further metabolize to inactive metabolites or
  undergo β-elimination to form active metabolites, phosphoramide mustard and acrolein. At high
  doses, the 4-hydroxylation process decreases, leading to non-linear elimination.
  Cyclophosphamide also induces its own metabolism, enhancing clearance and shortening the
  half-life with repeated dosing. About 10 to 20% of the drug is excreted unchanged in the urine,
  with 4% excreted in the bile.

Drug Interaction:

• Cyclophosphamide can interact with various medications, leading to enhanced toxicities.
  Protease inhibitors may increase cytotoxic metabolites, raising the risk of infections and
  neutropenia, while ACE inhibitors, natalizumab, paclitaxel, and others can exacerbate
  hematotoxicity and immunosuppression. It can also increase cardiotoxicity when combined with
  anthracyclines or trastuzumab, pulmonary toxicity with amiodarone or G-CSF, and
  nephrotoxicity with amphotericin B or indomethacin. Other significant interactions include
  increased hepatotoxicity with azathioprine, mucositis with protease inhibitors, and the risk of
  thromboembolic events with tamoxifen. Cyclophosphamide may also lower cyclosporine levels,
  increasing graft-versus-host disease risk, and its use with depolarizing muscle relaxants can
  cause prolonged apnea. Careful monitoring is required when cyclophosphamide is used with
  these agents.

Important:

• Before starting the treatment dose of cyclophosphamide, complete blood count of the
  patient is essential to observe as it can help for dose adjustment can be done if required.
• Patients who develop serious infection, cyclophosphamide treatment is not
  recommended to such patients.
  If a patient is having active urinary tract infection, use of cyclophosphamide should be
  avoided.
  Risk of cardiotoxicity can be increased with high doses of cyclophosphamide with a
  previous or concomitant treatment with other cardiotoxic agents.
  Monitoring of patients is required in case of pulmonary toxicity.

Use in specific population:

•  Pediatric
•  Geriatric
• Pregnancy and lactation
• Girls in late pre-pubescence are observed to develop ovarian fibrosis with complete loss of
  germ cells; also there is a high risk of developing premature menopause after prolonged
  cyclophosphamide treatment. While in pre-pubescent boys may have an increase in
  gonadotropin secretion and may develop oligospermia (low sperm count) or azoospermia (a
  condition in which there is no sperm in ejaculation).
• Dose selection in case of elderly patients should be cautious.
  There is a potential risk for pregnant women who are on treatment of cyclophosphamide as it
  can cause fetal abnormalities and also can cause miscarriage issues. Lactating women are
  advised not to breast feed during the cyclophosphamide treatment till 1st week of last dose.

Contraindications:

•  In patients with a history of severe hypersensitivity reactions, cyclophosphamide is
  contraindicated in them. Severe anaphylactic reactions may even cause death has been
  reported. Cross-sensitivity with other alkylating agents can also occur.
• Use of cyclophosphamide is contraindicated in patients suffering from urinary outflow
  obstruction.