Cyclophosphamide (Endoxan): FDA Approval, Licensing in Türkiye, and Reimbursement Status

• FDA Approval: Yes (first approval: 1959)
• Trade Names: Cytoxan®, Endoxan®
• Active Ingredient: Cyclophosphamide
• Administration: Oral tablet, intravenous injection
• Class: Alkylating agent (nitrogen mustard derivative)
• Category: Antineoplastic, immunosuppressant
• Manufacturers: Baxter, Amneal, and Roxane in the United States; Baxter İlaç in Türkiye
• Distribution in Türkiye: By Baxter İlaç San. ve Tic. Ltd. Şti. under the name Endoxan®
• Cancers for Which It Is Approved: Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, breast cancer, ovarian cancer, retinoblastoma, neuroblastoma, soft tissue sarcomas (Ewing sarcoma, rhabdomyosarcoma), and mycosis fungoides (advanced cutaneous T-cell lymphoma)

What Is Endoxan and How Does It Work?

Endoxan contains cyclophosphamide, a chemotherapy and immunosuppressive medicine used in cancer and some immune system diseases. Its uses include many malignancies, such as leukemias, lymphomas, and breast and ovarian cancers. It is also used in autoimmune diseases, including systemic lupus erythematosus and nephrotic syndrome.

How Does It Work?

• Endoxan is an alkylating agent that acts by damaging cellular DNA.
• It is a prodrug: After administration, the liver converts it into an active form. Its active metabolite, phosphoramide mustard, targets cancer cell DNA.
• It adds alkyl groups to DNA, disrupting its structure and forming crosslinks between DNA strands. This prevents cell division (mitosis).
• It triggers programmed cell death (apoptosis): If cells cannot repair DNA damage, they destroy themselves. This is particularly effective in rapidly dividing cancer cells.

FDA (United States Food and Drug Administration) Approval History

• November 16, 1959: The FDA approved Cytoxan® (cyclophosphamide) to treat various malignancies.
• August 17, 1999: The FDA approved cyclophosphamide manufactured by Roxane Laboratories under Abbreviated New Drug Application (ANDA) number 040032.
• May 30, 2018: Amneal Pharmaceuticals received FDA approval for Cyclophosphamide for Injection USP. A generic equivalent of Cytoxan®, it is supplied in 500 mg, 1 g, and 2 g single-dose vials.
• July 5, 2023: Nevakar Injectables received FDA approval for a ready-to-use diluted cyclophosphamide injection at a concentration of 200 mg/mL. This formulation was developed for use in combination therapy for various cancers.

Licensing in Türkiye

The conditions/therapeutic indications for which Endoxan is licensed in Türkiye are listed as follows:

Therapeutic Indications

• Leukemias
• Lymphomas
• Solid Tumors
• Progressive Autoimmune Diseases
• Immunosuppressive Treatment in Organ Transplantation
• Conditioning Before Allogeneic Bone Marrow Transplantation

Is Endoxan Reimbursed?

It is on the list of medicines for which an indication requirement is not applied to a cancer diagnosis. SGK reimburses it for all cancer diagnoses.

Price: Endoxan 50 mg coated tablets: 731. 70 TL.

Mechanisms of Resistance

• Impaired Drug Activation: Cyclophosphamide is a prodrug requiring conversion to its active form in the liver. If hepatic CYP450 activity decreases, activation may be inadequate. Less active substance then reaches cancer cells, making treatment ineffective.
• Drug Detoxification: Cancer cells may increase substances such as glutathione to inactivate the drug. Glutathione S-transferase (GST) binds and neutralizes the active form, preventing its DNA-damaging effects.
• Increased DNA Repair: Endoxan works by forming DNA crosslinks. Cancer cells may increase DNA repair enzymes (such as MGMT) capable of repairing these links. When damage is repaired rapidly, cells continue dividing rather than dying. Damaged cells should undergo apoptosis, but some cancer cells ignore these signals through p53 mutations or increased Bcl-2. Cells then fail to destroy themselves despite damage, rendering the drug ineffective.
• Some cells increase pump proteins such as P-glycoprotein, which expel the drug from the cell. This lowers intracellular drug concentrations and causes resistance.

Absorption

• Endoxan tablets are rapidly absorbed after oral administration.
• Absorption is generally high, with bioavailability of 75–90%.
• Peak blood levels (maximum plasma concentration) are reached within 0. 5–1. 5 hours.
• Food does not substantially affect absorption.

Distribution

• Plasma protein binding: 20–50%
• Widely distributed throughout the body, reaching organs including the liver, kidneys, lungs, bone marrow, and tumor tissues.
• Partially crosses the blood–brain barrier and is therefore also used for some brain tumors.
• Crosses the placenta and may enter breast milk.

Metabolism

• Cyclophosphamide is a prodrug converted into an active form in the liver.
• Activation involves cytochrome P450 enzymes, particularly CYP2B6 and CYP3A4.
• Active metabolites: 4-hydroxycyclophosphamide and aldophosphamide, the DNA-damaging forms.
• The toxic metabolite acrolein is also produced. It can damage the bladder, which is why drinking plenty of water is recommended.

Elimination

• Eliminated in urine through the kidneys: 50–70% is excreted within the first 24 hours.
• Most is eliminated as metabolites, but 10–20% may be excreted unchanged.
• Half-life in adults: approximately 3–12 hours
• This may be prolonged in liver or kidney impairment, requiring dose adjustment.

Dose Range

• Breast Cancer: Dose: 100–150 mg/m²/day, usually for 14 days (in the CMF protocol: cyclophosphamide + methotrexate + 5-FU). Repeated every 28 days.
• Lymphoma (Hodgkin/Non-Hodgkin): 100 mg/m²/day for 7–14 days, generally in combination treatment, such as CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone.
• Multiple Myeloma: 50–100 mg/m²/day for 5–14 days. Used in combination protocols, such as Cyclo-VMP: cyclophosphamide + bortezomib + prednisone.
• Leukemia (ALL/AML): 2–3 mg/kg/day, usually for 5–7 days. Oral use is uncommon and IV administration is generally preferred, although oral doses may be used for support.
• Ovarian and Testicular Cancer: 100–150 mg/m²/day for 5–10 days, in combination chemotherapy, such as with cisplatin and etoposide.
• Neuroblastoma, Ewing Sarcoma, and Rhabdomyosarcoma (Pediatric): 2–5 mg/kg/day for 5–7 days. Used in combination chemotherapy, such as VAC: vincristine, actinomycin-D, and cyclophosphamide.
• Maintenance Treatment (Particularly in ALL): 50 mg/m²/day or a fixed 50 mg/day, for long-term maintenance.

Drug Interactions

• Medicines affecting liver enzymes (CYP450): Phenytoin, carbamazepine, and rifampicin cause faster breakdown in the liver; St. John's wort may also reduce effectiveness.
• Enzyme inhibitors (may increase Endoxan levels and toxicity risk): Azole antifungals (ketoconazole, voriconazole), macrolide antibiotics (erythromycin, clarithromycin), and grapefruit juice.
• Toxicity may increase when combined with medicines such as doxorubicin, etoposide, vincristine, or bleomycin. Bone marrow suppression, particularly leukopenia and thrombocytopenia, becomes more likely.
• Combining it with cardiotoxic medicines such as trastuzumab may increase cardiac adverse reactions.
• Combining it with immunosuppressants such as azathioprine, methotrexate, or tacrolimus may excessively suppress immunity and increase infection risk.
• It must not be combined with live vaccines, such as chickenpox, measles, or yellow fever vaccines, because of the risk of serious or fatal infection. Inactivated vaccines may be given, but the immune response may be weak.
• Combining it with warfarin (Coumadin) may increase bleeding risk. INR should be monitored closely.
• Endoxan carries a risk of bladder toxicity, including bloody urine and cystitis. Combining it with medicines that irritate the urinary tract may increase this risk.
• Allopurinol: Combining it with high-dose Endoxan may increase bone marrow suppression.

Precautions

• Endoxan may suppress bone marrow, causing leukopenia, thrombocytopenia, and anemia. Blood counts and liver/kidney function tests should be monitored regularly.
• Immune suppression increases susceptibility to infection. Seek medical attention immediately for fever, sore throat, cough, or burning urination. Avoid crowds and people who are ill, and maintain good hygiene.
• Acrolein, a toxic byproduct, may damage the bladder and cause hemorrhagic cystitis (bloody urine). Drinking at least 2-3 liters of water daily reduces this risk. A protective agent such as Mesna may also be used if recommended by the physician.
• Endoxan can harm the fetus and cause birth defects. Pregnancy must be prevented using effective contraception. It must not be used during breastfeeding because it may pass into breast milk.
• Live vaccines, including measles, chickenpox, and BCG, must not be administered during treatment. Immune suppression may allow them to cause serious infection. If vaccination is needed, it should be planned under medical supervision.
• Tell the physician about all medicines, including prescription, nonprescription, and herbal products. Antibiotics, antiepileptic medicines, antifungals, anticoagulants such as warfarin, and herbal products, especially St. John's wort, may interact.
• Mouth sores may develop. Use a soft toothbrush and maintain good oral hygiene. Any necessary dental treatment should be planned before chemotherapy.
• Temporary hair loss may occur. Hair usually regrows after treatment.
• Nausea, vomiting, and loss of appetite may occur; the physician may provide supportive treatment.
• Dose adjustment may be necessary in kidney or liver impairment.
• Older patients and children require individualized dosing and monitoring.
• Long-term use may carry a risk of secondary leukemia; medical monitoring is important.

Adverse Reactions

• Leukopenia: 60–90%
• Thrombocytopenia: 20–40%
• Anemia: 20–30%
• Nausea and vomiting: 30–60%
• Loss of appetite (anorexia): 20–30%
• Hair loss (alopecia): 30–65%
• Weakness/fatigue: 15–25%
• Mouth sores/mucositis: 5–10%
• Diarrhea: 5–10%
• Dizziness/headache: 3–5%
• Transient elevation of liver enzymes: approximately 5%
• Skin rash/itching: 2–5%
• Temporary reduction in sperm/egg cells: 1–10%
• Hemorrhagic cystitis (bloody urine): 0. 5–1%
• Pulmonary toxicity (fibrosis, etc.): 0%. 
• Abnormal heart rhythms: <1%
• Allergic reactions: 0%
• Taste changes: 0%. 
• Secondary leukemia or MDS: less than 0. 1%
• Bladder cancer: less than 0. 1%
• Severe immunosuppression: less than 0. 1%
• Infertility (permanent inability to conceive): less than 0. 1%
• Anaphylaxis/severe allergic reaction: less than 0. 1%