Cyclophosphamide

Cyclophosphamide is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

The FDA approves cyclophosphamide for treating various conditions of Malignant Diseases, autoimmune disorders (such as rheumatoid arthritis), and Minimal Change Nephrotic Syndrome (MCNS) in Pediatrics. Its immunosuppressive properties also make it valuable in organ transplantation to prevent rejection.

Cyclophosphamide is rapidly and almost completely absorbed in the gastrointestinal tract, achieving peak plasma concentration in about 1 hour orally and 2-3 hours intravenously. The drug extensively permeates tissues, crossing the placenta and blood-brain barrier and entering breast milk. Metabolism occurs in the liver, mainly through CYP450 isoenzymes like CYP2B6 and approximately 10-20% of the unchanged drug is eliminated via urine and 4% through faeces.

Cyclophosphamide's most common side effects include vomiting, nausea, hair loss, fever, and blood in urine.

Cyclophosphamide is available as a powder for injection (intravenous) and oral tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Belgium and Spain.

Cyclophosphamide is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

Three mechanisms are used by alkylating compounds to produce their effects: attaching alkyl groups to DNA bases, which prevents enzymes from repairing the base and impedes DNA and RNA processes;2) creating cross-links that damage DNA and prevent it from being separated for synthesis or transcription; and3) starting nucleotide mispairing, which leads to mutations. Additionally, it exerts a potent immunosuppressive effect.

The onset of cyclophosphamide occurs within 2-3 hours, with the peak plasma time for cyclophosphamide itself being approximately 1 hour, while the metabolites reach their peak concentration around 2-3 hours after administration.

Cyclophosphamide is available as a powder for injection and oral tablets

Powder for injection: To be administered parenterally as applicable.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking the medication with or without food as directed.

Cyclophosphamide can be used for the following health conditions:

• Treatment of Malignant Diseases: It is used in the treatment of various malignant lymphomas (Stages III and IV of the Ann Arbor staging system), lymphocytic lymphoma, Hodgkin’s disease, mixed-cell type lymphoma, histiocytic lymphoma and Burkitt’s lymphoma.
• Minimal Change Nephrotic Syndrome (MCNS) in Pediatric Patients: Cyclophosphamide treats biopsy-proven minimal change nephrotic syndrome in pediatric patients who fail to respond adequately or cannot tolerate adrenocorticosteroid therapy.
• Leukaemias: chronic lymphocytic leukaemia, chronic granulocytic leukaemia, acute myelogenous and monocytic leukaemia and acute lymphoblastic (stem-cell) leukaemia.
• Off-label uses: Induction therapy for lupus nephritis, Juvenile idiopathic arthritis/vasculitis.
• Other uses: It is also used for treating breast carcinoma, retinoblastoma and adenocarcinoma of the ovary.

In treatment of Malignant Diseases: Treatment for some types of cancer may involve the anti-cancer drug cyclophosphamide. For treating cancer in different body sections, it can be used either by itself or in conjunction with other medications. This alkylating chemical prevents cancer cells from growing and multiplying by causing damage to their genetic material, specifically their DNA and RNA.

Nephrotic syndrome: Nephrotic syndrome is a kidney disease characterized by high protein excretion in the urine and widespread oedema in the feet, ankles, and surrounding areas of the body, including the eyes. Cyclophosphamide reduces inflammation and swelling associated with nephrotic syndrome by inhibiting the immune system. It reduces the amount of protein in the urine and aids in eliminating excess fluid, which relieves swelling in various body areas. This stops additional kidney damage and aids in returning kidney function to normal.

Cyclophosphamide, an alkylating prodrug, indicated in the treatment of :

• malignant diseases,
• pediatric MCNS,
• leukaemia,
• mycosis fungoides (advanced disease),
• neuroblastoma (disseminated disease),
• carcinoma of the breast,
• Multiple myeloma
• retinoblastoma and
• adenocarcinoma of the ovary.

Orally: Cyclophosphamide is usually administered orally as a tablet, with or without food; adjust dosage according to patient response and severity of condition. It's advisable to swallow the tablets whole with a full glass of water. Patients should refrain from crushing or chewing the tablets. Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

Parenterally: Cyclophosphamide for injection is delivered intravenously (infusion) under the supervision of a healthcare professional, typically lasting 1-2 hours. For doses exceeding 500 mg up to around 1 g, the administration time may be shortened to 20-30 minutes. To mitigate bladder toxicity, patients are advised to increase fluid intake during and for 1-2 days after therapy, with most adults requiring at least 2 L/day. High-dose regimens should include robust hydration, with or without mesna therapy, as a precautionary measure.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Powder for injection: 500mg, 1g, 2g

Tablets: 25mg, 50mg

Cyclophosphamide is available in the form of oral tablets and powder for injection.

Dose Adjustment in Adult Patients:

Malignant Diseases IV (intermittent therapy): 40-50 mg/kg divided over 2 to 5 days; may be repeated at intervals of 2 to 4 weeks

IV (continuous daily treatment): 60-120 mg/m²/day (1-2.5 mg/kg/day)

Oral (intermittent treatment): 400-1000 mg/m² divided over 4 to 5 days

Oral (continuous daily treatment): 50-100 mg/m²/day or 1-5 mg/kg/day

Non-Hodgkin Lymphoma 600-1500 mg/m² IV with other antineoplastics (part of CHOP regimen); dose intensification possible.

Nephrotic Syndrome: 2-3 mg/kg/day for up to 12 weeks when corticosteroids unsuccessful

Breast Cancer 600 mg/m² IV with other antineoplastics; dose intensification possible.

Lupus Nephritis (Off-Label):Low-dose: corticosteroids + 500 mg IV every two weeks for six doses, followed by maintenance with azathioprine or mycophenolate mofetil

High-dose: six monthly injections of 500–1000 mg/m² IV in addition to corticosteroids

Off-label treatment for juvenile idiopathic arthritis/vasculitis: 10 mg/kg IV every two weeks.

Adhering to specific dietary restrictions and safety guidelines is crucial during cyclophosphamide treatment. Individuals should avoid consuming raw or undercooked meats, fish, and eggs to minimise the risk of infections due to compromised immunity. It is recommended to incorporate a diet rich in leafy vegetables, fruits, fatty fish, and legumes while avoiding fast food and processed meats. Limiting alcohol consumption is advised, as it may exacerbate the drug's liver-related side effects. Patients are encouraged to monitor their nutrition intake and stay hydrated closely. Adopting these practices actively contributes to managing chronic illnesses and promoting overall health.

The dietary restriction should be individualized as per patient requirements.

• Patients with diseases that have previously shown resistance to cyclophosphamide shouldn't be treated with it. The medication shouldn't be administered to patients who have shown signs of hypersensitivity to cyclophosphamide.
• Severe myelosuppression
• Urinary outflow obstruction

• Caution is advised when using cyclophosphamide in patients with hepatic or renal impairment, thrombocytopenia, leukopenia, recent radiation therapy, or chemotherapy. The alcohol content of cyclophosphamide Injection should be considered, especially in patients with hepatic impairment.
• Special attention is warranted when administering cyclophosphamide to pediatric patients due to its alcohol content.

• Pelvic irradiation has the potential to potentiate hemorrhagic cystitis, emphasizing the need for careful consideration and monitoring in individuals undergoing this treatment combination.

• The concurrent use of cyclophosphamide with radiation therapy raises the risk of radiation recall, necessitating vigilance and close monitoring for potential reactions.

• Prolonged use of cyclophosphamide carries the risk of potentially fatal and irreversible interstitial pulmonary fibrosis. Healthcare providers should carefully assess the benefits and risks of prolonged treatment, weighing potential therapeutic outcomes against this severe pulmonary complication.

• Male patients who received high doses of cyclophosphamide during childhood face a risk of infertility. This underscores the importance of discussing fertility preservation options before initiating treatment in this population.

• Additionally, vigilant monitoring for the development of secondary malignancies is imperative during and after cyclophosphamide therapy. Regular screening and follow-up assessments are essential to detect any potential complications promptly.

• Healthcare professionals should exercise caution and closely evaluate individual patient factors before prescribing cyclophosphamide, considering these warnings and precautions to ensure patient safety and optimize therapeutic outcomes.
• Heart Failure Risk: Cyclophosphamide therapy can cause potentially fatal cardiac complications, including reporting instances of myocarditis, myopericarditis, pericardial effusion, and congestive heart failure. Reports indicate the occurrence of arrhythmias, such as atrial fibrillation and ventricular tachyarrhythmia with severe QT prolongation, following regimens that included cyclophosphamide. The risk of cardiotoxicity may increase with high doses, advanced age, prior cardiac radiation, and concomitant use of other cardiotoxic agents. Healthcare providers should exercise caution, especially in patients with predisposing factors, requiring vigilant monitoring in those with pre-existing cardiac conditions or risk factors. Regular assessment is crucial to mitigate potential cardiac risks associated with the active use of cyclophosphamide.

Avoid alcohol consumption while taking Cyclophosphamide.

Avoid use during breastfeeding.

It is not recommended during pregnancy.

Avoid smoking. Increase intake of nutrient-rich foods.

The adverse reactions related to cyclophosphamide can be categorized as:

• Common Adverse Effects: Nausea, vomiting, hair loss, bone marrow suppression leading to low blood cell counts, and heightened susceptibility to infections.
• Less Common Adverse Effects: Gastrointestinal disturbances, skin rash, and liver toxicity.
• Rare Adverse Effects: Pulmonary and cardiac toxicity, neurological effects such as peripheral neuropathy, kidney damage, secondary malignancies, and reproductive toxicity leading to infertility.

The clinically relevant drug interactions of cyclophosphamide are briefly summarized here.

• Drug-Drug Interactions: Doxorubicin, paclitaxel, ace inhibitors, monoclonal antibodies, natalizumab, zidovudine, thiazide diuretics, anti-cancer drugs, and anti-emetic drugs may interact with cyclophosphamide.
• Drug-Food Interactions: None have been discovered or proven.
• Drug-Disease Interactions: Notify your physician if you have decreased bone marrow activity, a blocked urinary tract, or impairment of your heart, kidneys, liver, or lungs.

The most common side effects of cyclophosphamide include nausea, vomiting, loss of appetite, stomach ache, diarrhoea, hair loss, blood in urine, decreased white blood cell count (neutrophils) or darkening of the skin/nails may occur.

•Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

The administration of cyclophosphamide to a pregnant woman may result in fetal damage, as indicated by the medication's mechanism of action and documented side effects in animals or pregnant patients. Pregnancy exposure to cyclophosphamide may result in fetal abnormalities, miscarriage, fetal growth retardation, and harmful consequences on the unborn child. In mice, rats, rabbits, and monkeys, cyclophosphamide is detrimental to the developing embryo and teratogenic.

Inform the patient about the possible risk to a fetus if this medication is used during pregnancy or if the patient gets pregnant while taking this medication.

Human Data

There have been reports of miscarriages and abnormalities of the skeleton, palate, limbs, and eyes following first-trimester exposure to cyclophosphamide. Cyclophosphamide exposure has been linked to fetal development retardation and toxic consequences in the infant, such as leukopenia, anaemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.

Animal Data

Cyclophosphamide was administered at doses equal to or less than the patient's dose based on body surface area during the organogenesis period. This treatment caused a variety of malformations, such as reduced skeletal ossification, cleft lip and palate, neural tube defects, limb and digit defects, and other skeletal anomalies.

•Nursing Mothers

Breast milk contains cyclophosphamide. Breastfed newborns of cyclophosphamide-treated mothers have been seen to exhibit neutropenia, thrombocytopenia, poor haemoglobin, and diarrhoea. Given the possibility of severe side effects in nursing infants from cyclophosphamide, a choice should be made between stopping the medication or stopping nursing, with consideration for the mother's need for the drug.

•Pediatric Use

Cyclophosphamide typically induces normal development of secondary sexual characteristics and regular menses in pre-pubescent girls. However, prolonged treatment in late pre-pubescence can result in ovarian fibrosis and apparent loss of germ cells. Girls who retain ovarian function post-treatment face an elevated risk of premature menopause. Pre-pubescent boys treated with cyclophosphamide undergo normal development of secondary sexual characteristics but may experience oligospermia or azoospermia, along with increased gonadotropin secretion. Some may also experience reversible testicular atrophy, although this reversal may take several years after therapy cessation.

Dose Adjustment

Treatment for Malignant Diseases IV (Intermittent): 40–50 mg/kg (400–1800 mg/m2) given over 2–5 days; may be repeated every 2-4 weeks

IV (daily, continuing treatment): 60–120 mg/m²/day (1–2.5 mg/kg/day)

PO: 400–1000 mg/m² split over four to five days

PO (daily, continuous medication): 50–100 mg/m²/day

Vasculitis and Juvenile Idiopathic Arthritis: 10 mg/kg IV every two weeks

Nephrotic Syndrome

For up to 12 weeks, take 2-3 mg/kg/day if corticosteroids don't work.

Monthly IV dosage for systemic lupus erythematosus: 500–750 mg/m2; maximum dose: 1 g/m²

•Geriatric Use

For patients 65 years of age and above, there is not enough information from clinical trials using cyclophosphamide to ascertain whether their responses differ from those of younger people. Care should be taken when choosing a dose for an aged patient; typically, this means starting at the low end of the dosing range. This is because reduced hepatic, renal, or cardiac functioning and concurrent diseases or other medication therapies are more common.

Dose Adjustment in Kidney Impairment Patients:

Reduced renal excretion in patients with severe renal impairment may lead to elevated plasma levels of cyclophosphamide and its metabolites. This could lead to a rise in toxicity. Keep an eye out for toxicity signs and symptoms in individuals with severe renal impairment (CrCl = 10 mL/min to 24 mL/min).

Give 75% of the standard dose if the renal impairment is CrCl <10 mL/min;

Give the total amount if it is CrCl >10 mL/min.

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Cyclophosphamide tablets because the drug is extensively metabolized in the liver.

Hepatic impairment: If bilirubin is 3.1–5 mg/dL or transaminase values are more than three times the upper limit of normal, administer 75% of the recommended dosage.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of cyclophosphamide.

Overconsumption of Cyclophosphamide includes manifestations of dose-dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease and stomatitis.

Management

There is no known specific cyclophosphamide antidote. When an overdose occurs, supportive treatments should be implemented, such as the proper management of any concomitant infections, myelosuppression, or heart toxicity that may arise. Cyclophosphamide is dialyzable. Hence, in the event of an accidental overdose or intoxication, prompt hemodialysis is recommended.

Urotoxic symptoms from cyclophosphamide overdose may be avoided or reduced with cystitis prophylaxis with mesna.

In severe cases, consulting a poison control centre or a medical toxicologist can be beneficial for appropriate guidance and intervention.

Pharmacodynamics: The ability of alkylating agents to add alkyl groups to many electronegative groups under conditions found in cells gives them their name. By directly targeting DNA, they cross-link guanine bases in DNA double-helix strands, halting the formation of tumours. The strands are unable to uncoil and split as a result. Cell division is no longer possible because this is essential for DNA replication. Furthermore, these medications introduce methyl or other alkyl groups onto molecules that shouldn't be there. This prevents the right base pairing and miscodes DNA. Alkylating compounds do not exhibit cell cycle specificity. Three distinct processes are employed by alkylating chemicals to accomplish the same purpose: cell death and impairment of DNA function.

Pharmacokinetics:

• Absorption: The gastrointestinal tract efficiently absorbs cyclophosphamide. With a bioavailability exceeding 75%, it achieves peak plasma concentration in about 1 hour orally and 2-3 hours intravenously, with metabolites present.
• Distribution: Cyclophosphamide extensively permeates tissues, crossing the placenta and blood-brain barrier and entering breast milk. Its volume of distribution approximates total body water (30-50 L). While cyclophosphamide's plasma protein binding is around 20%, specific metabolites bind more than 60%.
• Metabolism: The liver metabolises cyclophosphamide mainly through various CYP450 isoenzymes like CYP2B6. Initial active metabolites, 4-hydroxy cyclophosphamide and aldophosphamide, are formed, potentially converting non-enzymatically into phosphoramide mustard (active metabolite) and acrolein (linked to bladder toxicity).
• Excretion: Approximately 10-20% of unchanged drug is eliminated via urine, and 4% through faeces. The elimination half-life ranges from 4 to 8 hours.

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