What Is Doxorubicin? FDA Approval, Licensing and Reimbursement in Turkey

• FDA Approved: Yes (Initial approval date: 1974)
• Brand Names, Manufacturers and Distribution in Turkey: The original brand name is Adriamisin (Pfizer). It is also available under various generic brand names: Doxorubicin Koçak (Koçak Farma), Doxtu (Onko & Koçsel), Doxel (Nobel İlaç), Doxorubicin Sandoz (Sandoz) and Adrimisin (Saba İlaç).
• Active Ingredient: Doxorubicin
• Route of Administration: Intravenous (IV)
• Class: Anthracycline, antitumor antibiotic
• Category: Chemotherapy drug
• Approved Cancers: Used to treat many cancers, including breast cancer, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer and bladder cancer.

What Is Doxorubicin?

Doxorubicin is an anthracycline chemotherapy drug isolated from bacteria of the genus Streptomyces. It prevents cancer cells from proliferating by inhibiting DNA synthesis and repair.

How Does It Work?

Doxorubicin kills cancer cells by damaging their DNA and stopping them from dividing. It works through the following mechanisms:

1. Inserts into DNA (Intercalation): Doxorubicin inserts between the strands of a cell's DNA. This prevents DNA from functioning normally. DNA is essential for cells to renew themselves and proliferate. By damaging DNA, doxorubicin disrupts this process. DNA damage stops cells from growing and dividing uncontrollably.

2. Blocks RNA Production: Doxorubicin blocks enzymes that transfer information from DNA to RNA. RNA is needed for protein synthesis. When this process is blocked, the cell cannot produce essential proteins or perform vital functions.

3. Creates DNA Breaks: Doxorubicin inhibits an enzyme called topoisomerase II, which enables DNA to unwind and rejoin properly. Without this enzyme, breaks occur in DNA. This DNA damage makes it impossible for cells to divide normally and survive.

4. Generates Harmful Free Radicals: Doxorubicin leads to the formation of harmful molecules called free radicals inside the cell. These free radicals seriously damage the cell's DNA, proteins and membrane. This damage causes cell death. The damage caused by free radicals is one reason for doxorubicin's potent mechanism of action.

5. Damages the Cell Membrane: Free radicals damage the cell's outer protective membrane. The cell membrane is an important structure that protects the cell's internal environment from external influences. Damage to it causes the cell's contents to leak out uncontrollably, leading to cell death.

These mechanisms work together to stop cancer cells from growing and proliferating. However, they can also occur in healthy cells. Doxorubicin can therefore cause toxic effects, particularly in sensitive tissues such as heart cells. These effects must be monitored closely during treatment.

FDA (US Food and Drug Administration) Approval History

• August 7, 1974: Doxorubicin (Adriamycin) was approved by the FDA to treat advanced or metastatic solid tumors and hematologic malignancies.

• 1995: Liposomal doxorubicin (Doxil) received FDA approval for the treatment of AIDS-related Kaposi sarcoma.

• May 28, 1999: Liposomal doxorubicin (Doxil) was approved by the FDA to treat patients with advanced ovarian cancer unresponsive to platinum-based therapy.

• June 17, 2005: Liposomal doxorubicin (Doxil) received FDA approval for metastatic breast cancer, particularly in patients whose non-anthracycline treatments had failed.

• February 26, 2007: The FDA approved liposomal doxorubicin in combination with bortezomib for the treatment of multiple myeloma.

• 2020: Doxorubicin received expanded approval under the FDA label for use in various cancers (such as breast cancer, lung cancer and lymphoma) and additional indications with its liposomal formulations.

Licensing in Turkey

Doxorubicin is licensed in Turkey and is available under many generic brand names. It is approved for use in both solid tumors and hematologic malignancies.

Therapeutic Indications 

Doxorubicin is indicated for the regression of various neoplastic diseases, including cancers of the breast, lung, bladder, thyroid and ovary; bone and soft tissue sarcoma; Hodgkin and non-Hodgkin lymphomas; neuroblastoma; Wilms' tumor; acute lymphoblastic leukemia; and acute myeloid leukemia. Doxorubicin is indicated for superficial bladder tumors when administered intravesically, either after transurethral resection (preventive treatment) or for therapeutic purposes.

Is Doxorubicin Reimbursed in Turkey?

It is on the list of drugs for which an indication requirement is not sought in patients diagnosed with cancer. It is covered by SGK reimbursement for all cancer diagnoses.

Mechanisms of Resistance

Cancer cells may develop resistance to doxorubicin through the following mechanisms:

1. Increased P170 Glycoprotein (Multidrug Resistance Gene – MDR1): Cancer cells produce more of a protein called P170 in their membranes. This protein transports the drug out of the cell, preventing its accumulation inside. As a result, doxorubicin cannot accumulate to an adequate level within the cell and cannot exert its effect.

2. Reduced Topoisomerase II: Doxorubicin interacts with topoisomerase II to increase DNA damage. However, cancer cells reduce the production of this enzyme, weakening the drug's effect. When enzyme levels fall, the DNA strand breaks that doxorubicin should cause do not occur, and the cell continues to divide.

3. Changes in the Structure of Topoisomerase II: Cancer cells develop mutations that alter the structure of topoisomerase II. These mutations reduce doxorubicin's ability to bind to the enzyme, preventing the drug from damaging DNA.

4. Increased Production of Glutathione and Sulfhydryl Proteins: Cancer cells increase their production of protective molecules such as glutathione, which neutralize free radicals. These molecules prevent doxorubicin from damaging cells through free radicals, making the cancer cells more resistant to the drug.

These mechanisms reduce the efficacy of doxorubicin, causing cancer cells to resist treatment.

Absorption

Doxorubicin is administered only intravenously.

Distribution

Doxorubicin is widely distributed throughout body tissues but cannot cross the blood–brain barrier. Approximately 75% of the drug binds to plasma proteins. This binding determines its distribution between tissues and its effects. Doxorubicin and its metabolites circulate bound to plasma proteins, which influences their movement through the body.

Metabolism

Doxorubicin is extensively metabolized in the liver. It is converted to an active metabolite, doxorubicinol, and other inactive metabolites. Approximately 40-50% of the drug is excreted in feces via the bile, while less than 10% is eliminated through the kidneys. Only a small amount is excreted unchanged as the parent compound. Doxorubicin can remain in the body for a long time; its terminal half-life is approximately 20-48 hours. These properties make close monitoring of liver and kidney function important during treatment.

Dose Range

• Single agent: 60-75 mg/m² administered intravenously (IV) every 3 weeks.

• Single agent: 15-20 mg/m² administered intravenously (IV) weekly.

• Combination therapy: 45-60 mg/m² administered intravenously (IV) every 3 weeks.

• Continuous infusion: 60-90 mg/m² administered intravenously (IV) over 96 hours.

Drug Interactions

• Dexamethasone, 5-FU, Heparin: Doxorubicin is incompatible with dexamethasone, 5-fluorouracil (5-FU) and heparin because combining them may cause precipitation. This may reduce the drug's effectiveness and make administration more difficult.

• Dexrazoxane: Dexrazoxane is an iron-chelating agent used to reduce the cardiotoxic effects of doxorubicin. When given with doxorubicin, it may reduce the incidence of cardiac adverse effects.

• Cyclophosphamide: The risk of hemorrhagic cystitis and cardiotoxicity may increase when it is used with doxorubicin. Careful monitoring is necessary when these two drugs are combined.

• Phenobarbital, Phenytoin: Phenobarbital and phenytoin increase the plasma clearance of doxorubicin. This may reduce its efficacy and make it harder to achieve the desired therapeutic effect.

• Trastuzumab, Mitomycin-C: The risk of cardiotoxicity increases when doxorubicin is used with these drugs. Regular cardiac monitoring is necessary, particularly in patients receiving it in combination with trastuzumab.

• 6-Mercaptopurine: The risk of doxorubicin-associated hepatotoxicity increases when it is used with 6-mercaptopurine. Close monitoring of liver function is recommended.

Precautions

1. Hepatic Impairment: Caution is required in patients with abnormal liver function. A dose reduction is recommended in this situation.

2. Potent Vesicant Properties: Doxorubicin is a potent vesicant. It must therefore be administered carefully to prevent leakage outside the vein. Increased pressure on veins during infusion may raise the risk of leakage.

3. In the Event of Extravasation: If extravasation occurs, the infusion should be stopped immediately, fluid aspirated and ice applied to the affected area. A local steroid may be administered, and plastic surgery support is recommended in severe cases.

4. Cardiac Monitoring: Cardiac function should be monitored regularly before and during treatment by assessing left ventricular ejection fraction (LVEF). The risk of cardiotoxicity may be higher in older patients (>70 years), those with hypertension and those with pre-existing heart disease.

5. Interaction with Radiotherapy: Patients who have previously received radiation therapy may experience a "radiation recall reaction." This can cause skin reactions in irradiated areas. Concurrent doxorubicin and radiotherapy increase the risk of skin toxicity.

6. Sensitivity to Sunlight: Patients should be told to avoid sun exposure and to wear protective clothing or use sunscreen outdoors.

7. Red-Orange Urine: Red-orange discoloration of urine may occur after doxorubicin treatment. This generally appears within 1-2 days after treatment and is harmless.

8. Pregnancy and Breastfeeding: Doxorubicin is in pregnancy category D and carries a risk of fetal harm. Its use during pregnancy is therefore not recommended. It is also contraindicated during breastfeeding because it is thought to pass into breast milk.

Side Effects

1. Cardiotoxicity: It may damage the heart muscle. Acute effects (arrhythmias and conduction disturbances) are generally temporary. However, the risk of permanent heart failure increases when the cumulative dose is >450 mg/m².

2. Myelosuppression: Bone marrow suppression is common. A reduction in white blood cells (neutropenia) is frequently seen during treatment and may increase infection risk.

3. Gastrointestinal Side Effects: Nausea, vomiting, mucositis and diarrhea are commonly reported.

4. Skin and Nail Problems: Nail discoloration, skin rash and radiation recall reactions may occur.

5. Alopecia (Hair Loss): Occurs in almost all patients during treatment but is reversible after treatment.

6. Red-Orange Urine: Urine discoloration may occur within 1-2 days after treatment; this is a normal side effect.

7. Extravasation: If the drug leaks outside the vein, tissue damage and necrosis may develop at the injection site. This is a serious adverse effect requiring intervention.