Cytoxan

General information about the drug

Cytoxan is a powerful chemotherapeutic drug belonging to the class of alkylating agents. It is used to treat various types of malignant neoplasms and some autoimmune diseases by suppressing the growth of rapidly dividing cells. The drug has a pronounced cytotoxic effect and requires strict medical control when used.

Trade name

Cytoxan

International Nonproprietary Name (INN)

Cyclophosphamide

Form of release

The drug is available in the following forms:

• Covered tablets: 25 mg and 50 mg.
• Liophilizate for preparation of solution for injection: 200 mg, 500 mg, 1000 mg vials.

Constitution

Acting substance

Cyclophosphamide (in the form of monohydrate).

Auxiliary components

Composition depends on the form of release:

• Tablets: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose (shell), titanium dioxide.
• Liophilizate: sodium chloride, mannitol (stabilizer).

Pharmacological properties

Pharmacodynamics

Cyclophosphamide, the active substance of Cytoxan, refers to alkylating agents that exert cytotoxic effects by binding to the DNA of cells. The drug disrupts DNA replication and transcription by adding alkyl groups to guanine bases, resulting in the formation of inter- and intra-chain cross-links. This interferes with cell division, especially those in the active proliferation phase, such as tumor cells and some cells of the immune system.

Cyclophosphamide is a prodrug, meaning that its activity occurs after metabolic activation in the liver. Under the action of enzymes of the cytochrome P450 system, it is converted into the active metabolites 4-hydroxycyclophosphamide and aldophosphamide, which are further converted into phosphoramide mustard and acrolein. Phosphoramide mustard is responsible for the antitumor effect, whereas acrolein can cause toxicity, especially to the urinary tract.

The drug has immunosuppressive effects by inhibiting lymphocyte activity, making it effective in the treatment of autoimmune diseases. Its action is not selective, so it affects both pathological and healthy rapidly dividing cells, such as bone marrow and mucosal cells. The therapeutic effect depends on the dosage and duration of administration.

Pharmacokinetics

When taken orally, cyclophosphamide is well absorbed from the gastrointestinal tract, reaching maximum plasma concentrations in 1-2 hours. Bioavailability is about 75-90%. When administered intravenously, the drug immediately enters the systemic bloodstream, bypassing the first-pass effect. Binding to plasma proteins is minimal (about 20%), but active metabolites bind more strongly (up to 60%).

Metabolism occurs in the liver with the participation of the enzymes CYP2B6, CYP3A4 and other cytochrome P450 isoenzymes. The main active metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard, are rapidly distributed in tissues, including tumor cells. The volume of distribution is about 0.5-0.7 L/kg, which corresponds to the volume of total body water.

The elimination half-life of cyclophosphamide varies from 3 to 12 hours (average 7 hours), but metabolites are eliminated more slowly. Excretion is performed mainly by kidneys (70-80% as metabolites, of which 10-20% is unchanged). About 5-10% is excreted through bile with feces. In case of renal or hepatic dysfunction, elimination may be delayed, which requires dose adjustment.

Indications for use

Cytoxan is prescribed for the following diseases and conditions:

• Malignant neoplasms: Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia.
• Breast, ovarian, lung cancer (as part of combined chemotherapy).
• Autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, vasculitis, glomerulonephritis.
• Preparation for bone marrow transplantation (in high doses).

Contraindications

The use of Cytoxan is prohibited under the following conditions:

• Hypersensitivity to cyclophosphamide or the excipients.
• Severe myelosuppression (leukopenia less than 1000/μL, thrombocytopenia less than 50,000/μL).
• Active infections (bacterial, viral, fungal).
• Severe renal insufficiency (creatinine clearance less than 10 mL/min).
• Severe hepatic insufficiency.
• Pregnancy and period of breastfeeding (except in cases of extreme necessity).
• Hemorrhagic cystitis in the anamnesis (without prophylaxis).

Method of administration and dosage

How to take

The tablets are taken orally, preferably in the morning, drinking plenty of water (200-300 ml) to reduce the risk of bladder irritation. Injections are prepared by medical personnel and administered intravenously (trickle or drip) with preliminary dilution in 0.9% sodium chloride solution or 5% glucose. For the prevention of cystitis it is recommended to drink plenty of water (2-3 liters of water per day).

Dosages for adults and children

Adults

Dosage depends on the indication and treatment regimen:

• Oncology (orally): 1-3 mg/kg body weight per day (usually 50-200 mg).
• Oncology (w/v): 600-1500 mg/m² body surface area every 3-4 weeks as part of chemotherapy regimens.
• Autoimmune diseases: 1-2 mg/kg per day orally or 500-1000 mg/m² w/w monthly.

Children

Dosage is calculated individually: 1-3 mg/kg per day (orally) or 400-600 mg/m² (intravenously), taking into account body weight and indication.

Dose adjustment for certain conditions

In renal insufficiency (creatinine clearance 10-50 ml/min) the dose is reduced by 25-50%. In hepatic insufficiency (bilirubin >3 mg/dL), the dose is reduced by 30-50%. In elderly patients, the correction is carried out taking into account the general condition and organ function.

Side effects

The following adverse reactions are possible during the use of Cytoxan:

• From the side of the hematopoietic system: leukopenia, thrombocytopenia, anemia.
• Side of the urinary system: hemorrhagic cystitis, dysuria, nephrotoxicity.
• Side of the digestive system: nausea, vomiting, diarrhea, stomatitis.
• Skin and hair: alopecia, rash, hyperpigmentation.
• Reproductive system: infertility, amenorrhea, azoospermia.
• Other: fever, weakness, increased risk of infections.

Overdose

Symptoms of overdose

If the dose is exceeded, the following may be observed:

• Severe myelosuppression (pancytopenia).
• Hemorrhagic cystitis or acute renal failure.
• Nausea, vomiting, diarrhea.
• Cardiotoxicity (arrhythmias, heart failure).

First aid measures

In case of overdose it is necessary:

1. Stop administering or taking the drug.
2. Seek emergency medical attention.
3. Gastric lavage (in oral overdose, if less than 1 hour has elapsed).
4. Prescribe hydration and diuretics to protect the kidneys.
5. Control blood counts and organ function.

Interactions with other drugs

Influence on the effects of other drugs

Cytoxan may increase the effects of:

• Other myelosuppressive drugs (increased risk of leukopenia).
• Immunosuppressants (increased immunosuppression).

CYP3A4 inducers (rifampicin, phenytoin) accelerate metabolism, reducing efficacy, and inhibitors (ketoconazole) increase the concentration of active metabolites.

Compatibility with alcohol and food

Alcohol increases hepatotoxicity and bladder irritation, its use is contraindicated. Food does not affect absorption, but ingestion on an empty stomach may reduce nausea.

Special Instructions

Use in pregnancy and breastfeeding

Cytoxan has teratogenic effect and is contraindicated in pregnancy, especially in the first trimester, except in cases threatening the life of the mother. The drug is excreted with breast milk, therefore breastfeeding is prohibited.

Effects on driving and mechanisms

The drug causes weakness, nausea and confusion, which makes driving transportation or mechanisms dangerous during treatment.

Particularities of use in the elderly and children

Toxic effects (myelosuppression, infections) occur more often in elderly patients, monitoring and dose reduction are required. In children, the drug is used with caution, taking into account the risk of long-term effects on the reproductive system.