Doxorubicin

Doxorubicin is an antineoplastic agent belonging to the pharmacological class of anthracycline antibiotics.

Doxorubicin is chiefly derived from the Streptomyces peucetius bacterium. It is approved by the FDA to be used alone or with other drugs to treat various cancers, including blood and breast cancers.

When administered intravenously, Doxorubicin rapidly exits the circulation, widely distributing into different tissues and binding to proteins to a 75% extent. Drug metabolism occurs quickly in the liver due to the aldo-keto reductases. About 40% is eliminated from the body as unchanged drugs are primarily excreted in the faeces.

The most common side effects of Doxorubicin include nausea, vomiting, abdominal pain and rash.

Doxorubicin is available as an injectable solution and powder for injections.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Doxorubicin is an antineoplastic agent belonging to the pharmacological class of anthracycline antibiotics.

Doxorubicin's ability to intercalate within DNA base pairs, breaking DNA strands and inhibiting DNA and RNA synthesis is its primary mode of action. Doxorubicin damages DNA and induces apoptosis by inhibiting the enzyme topoisomerase II. Doxorubicin further inhibits DNA synthesis by oxidatively damaging DNA through free radical-mediated damage when combined with iron. By reducing the amount of iron that Doxorubicin binds to, iron chelators like dexrazoxane may inhibit the production of free radicals.

Injectable solutions: To be administered parenterally as applicable.

The physician recommends taking this medication once daily, with or without food.

• Doxorubicin effectively induces regression in diverse neoplastic conditions such as acute leukaemia, Wilms' tumour, sarcomas, breast, ovarian, bladder, thyroid, and gastric carcinomas, Hodgkin's disease, lymphomas, and bronchogenic carcinoma, with higher responsiveness in small cell histologic types.
• It is also indicated for adjuvant therapy in women with axillary lymph node involvement in post-resected primary breast cancer.

Parenterally: Doxorubicin is administered intravenous infusion for quick and efficient bloodstream delivery; a central venous line is usually preferred to reduce the risk of tissue irritation. Adjust dosage based on patient condition, ongoing therapies, and the particular cancer type. Gradually increase the infusion time per the patient's tolerance and the recommended dosage. Monitor closely for any indications of extravasation, such as injection site pain or swelling. Adhere to strict aseptic procedures to avoid infections and modify dosage following hematologic parameters.

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

• Injectable solution: 2mg/mL
• Powder for injection: 10mg, 20mg, 50mg

Doxorubicin is available as an injectable solution and powder for injections.

Dose Adjustment in Adult Patients:

Cancers of the head and neck, small cell lung and liver cancer, Hodgkin's disease, lymphomas, ALL, and AML; breast, ovarian, prostate, stomach, and thyroid cancer;

IV q21 days at 60–75 mg/m² OR

Every 14 days, 60 mg/m² IV OR

Every 21–28 days, 40–60 mg/m² IV OR

20 mg/m³/dose every week.

Increase the effectiveness of the doxorubicin treatment by including foods high in energy, such as fruits, vegetables, lean meats, whole grains, and healthy fats. Drink lots of water to stay well-hydrated and combat the common dehydration associated with cancer. Avoid drinking alcohol and smoking. To improve overall wellness, reduce intake of processed meats, added sugars, refined carbohydrates, and fast and fried.

The dietary restriction should be individualized as per patient requirements.

• Baseline neutrophil count <1500 cells/mm3;
• severe hepatic impairment;
• IM/SC administration;
• recent myocardial infarction or severe myocardial insufficiency; severe arrhythmias;
• active infection;
• previous treatment with complete cumulative doses of daunorubicin, doxorubicin, idarubicin, and/or other anthracyclines and anthracenediones;
• Hypersensitivity to Doxorubicin, its excipients, or other anthracyclines or anthracenediones.

• Cardiotoxicity: Because Doxorubicin can cause congestive heart failure, it is essential to check for cardiotoxicity routinely. To reduce this risk, carefully monitor the cumulative dosage.
• Hematologic Effects: Monitor the blood cell counts because Doxorubicin may cause severe myelosuppression. If necessary, alter the dosage or consider hematopoietic growth factors to reduce the risk of bleeding, anaemia, or infection.
• Prevent Extravasation: When administering Doxorubicin, use a central venous line to prevent extravasation. Observe for any signs and act quickly to stop any leaks if detected.
• Assess Secondary Leukemia Risk: Determine whether long-term doxorubicin use increases the risk of secondary leukaemia. For each patient, consider different treatments to reduce this possible long-term risk.
• As the liver is where doxorubicin metabolism occurs, evaluate liver function regularly. To maximize safety, modify dosage as per hepatic impairment.
• Prevent Tumor Lysis Syndrome: Use prophylactic measures to ensure patients with rapidly growing tumours are correctly hydrated to prevent tumour lysis syndrome. Optimizing the safety profile of Doxorubicin requires timely intervention and routine monitoring.
• Advise on the possibility of fetal harm and infertility when using Doxorubicin during pregnancy. To lower reproductive risks, use the proper contraceptive methods.
• Treat hypersensitivity reactions quickly by stopping doxorubicin usage immediately. When needed, control reactions with corticosteroids or antihistamines.

The adverse reactions related to Doxorubicin can be categorized as:

• Common Adverse Effects: Neutropenia, anaemia, leukopenia, pruritus, nausea, stomatitis, fatigue, congestive heart failure (CHF), thrombocytopenia, vomiting, rash, alopecia, anorexia, constipation, and diarrhoea.
• Less Common Adverse Effects: Cardiomyopathy
• Rare Adverse Effects: Severe myelosuppression (e.g. neutropenia, leucopenia, thrombocytopenia, anaemia), arrhythmias, CHF, pulmonary embolism, infusion-related reactions (liposomal formulations).

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

• Drug-Drug Interactions: Phenytoin, phenobarbital, rifampicin, CYP3A4 inducers, CYP2D6 inhibitors, bupropion, fluoxetine, paroxetine, CYP2D6 inducers, and clarithromycin, voriconazole, cyclosporine, and chloramphenicol may interact with Doxorubicin.

Potentially Fatal: Vaccines containing live viruses may cause life-threatening infections in immunocompromised individuals.

• Drug-Food Interactions: Abstain from drinking alcohol and smoking.
• Interactions Between Drugs and Diseases: Let the physician know in case of kidney, liver, or cardiovascular problems.

• 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.

When given to a pregnant woman, the drug may cause fetal harm based on research done on animals and its mode of action; use should be avoided during the first trimester. Existing human data does not prove the existence or non-existence of significant congenital disabilities and miscarriages associated with use in the second and third trimesters. When given during organogenesis at doses roughly 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2, the drug was teratogenic, embryotoxic, and embryotoxic in rats and embryotoxic in rabbits. Inform expectant mothers of any possible fetal risk.

Before starting treatment, confirm the pregnancy status of all females who are capable of bearing children are pregnant.

Drug use may result in amenorrhea and infertility in females who are fertile; it may also cause premature menopause; the age at which ovulation and menstruation resume is correlated with these side effects.

Contraception

Female: Women who have the potential to become pregnant should be advised to use highly effective contraception both during and for six months after treatment, as it may cause harm to the fetus.

Males: Due to the potential for genotoxicity, advise males with female partners who are capable of reproduction to use effective contraception during treatment and for three months after treatment; males who are pregnant should use condoms during treatment and for at least ten days after the final dose.

Males: Treatment may damage spermatozoa and testicular tissue, potentially resulting in genetic fetal abnormalities.

• Nursing Mothers

There is no data on breastfed infants' effects or the amount of milk produced.

Advise women not to breastfeed during treatment and for ten days following the last dose because there is a possibility that breastfed children may experience severe adverse reactions.

• Pediatric Use

Doxorubicin's safety and effectiveness are determined in pediatric patients to ensure appropriate therapeutic outcomes while considering potential risks.

Dose Adjustments

Cancers

Cancers of the stomach, thyroid, liver, multiple myeloma, Hodgkin's disease, lymphomas, ALL, and AML; squamous cell cancer of the head and neck

35–75 mg/m³ IV every 21 days OR

20–30 mg/m³/dose every week

Every 3–4 weeks, 60–90 mg/m² IV over 96 hours

Dose Adjustment in Kidney Impairment Patients:

Dose adjustment not necessary

Dose Adjustment in Hepatic Impairment Patients:

No dose adjustment is required if serum bilirubin is less than 1.2 mg/dL.

1.2–3 mg/dL [20.5–51.3 micromoles/L] of serum bilirubin: Administer 50% of the dose.

3.1–5 mg/dL [53–85.5 micromoles/L] of serum bilirubin: Administer a dose of 25%.

Severe liver impairment: Not recommended

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

Signs and Symptoms

Overconsumption of Doxorubicin could lead to an increased risk of severe mucositis, acute myocardial degeneration, and severe myelosuppression (leucopenia and thrombocytopenia).

Management

Overdosing on Doxorubicin has no known antidote. Take immediate action to stop taking Doxorubicin and immediately begin receiving supportive and symptomatic care if an overdose occurs. To treat acute overdosage, hospitalize patients who are severely myelosuppressed and treat them with antimicrobials, platelet transfusions, and symptomatic treatment for mucositis. Consider about utilizing hematopoietic growth factors (G-CSF, GM-CSF).

Pharmacodynamics

In general, Doxorubicin has been suggested to produce DNA strand breaks and damages by intercalating DNA structures to destabilize them and cause cancer. Apoptotic pathways can be triggered in addition to changing the transcriptomes of the cells when DNA damage cannot be repaired. Furthermore, as essential enzymes like DNA polymerase, RNA polymerase, and topoisomerase II are involved in cell cycle arrest, doxorubicin intercalation can disrupt their activity. Again, Doxorubicin can cause cellular damage by producing cytotoxic reactive oxygen species.

Pharmacokinetics

• Absorption: After intravenously administered, Doxorubicin is rapidly eliminated from the bloodstream.
• Distribution: When injected intravenously, Doxorubicin, particularly in its conventional formulation, spreads to the kidneys, lungs, liver, heart, and spleen. But when incused in pegylated liposome formulations, it remains mainly in the vascular fluid. Additionally, Doxorubicin penetrates breast milk and crosses the placenta barrier. The volume of distribution (Vd) in the conventional formulation is between 20-30 L/kg (700-1214 L/m³) and roughly 2.7-2.8 L/m².About 75% of Doxorubicin binds to plasma proteins in its standard formulation.
• Metabolism: With the help of Aldo-keto reductases, Doxorubicin is rapidly metabolized, mainly in the liver. In addition to various inactive aglycones, conjugated sulfates, and glucuronides, this metabolic process produces the active metabolite doxorubicinol, also known as adriamycin.
• Excretion: Doxorubicin is mainly eliminated through the stools, constituting 40% of the drug's total excretion. Only 3% of the drug doxorubicinol is excreted in urine, with the remaining 5-12% being unchanged drug and its metabolites. Doxorubicin has a half-life of just 1-3 hours, which is comparatively short. A rate of 8–20 mL/min/kg has been reported for clearance.

• Almajidi YQ, Kadhim MM, Alsaikhan F, Turki Jalil A, Hassan Sayyid N, Alexis Ramírez-Coronel A, Hassan Jawhar Z, Gupta J, Nabavi N, Yu W, Ertas YN. Doxorubicin-loaded micelles in tumor cell-specific chemotherapy. Environ Res. 2023 Jun 15;227:115722. doi: 10.1016/j.envres.2023.115722. Epub 2023 Mar 21. PMID: 36948284.
• D'Angelo NA, Noronha MA, Câmara MCC, Kurnik IS, Feng C, Araujo VHS, Santos JHPM, Feitosa V, Molino JVD, Rangel-Yagui CO, Chorilli M, Ho EA, Lopes AM. Doxorubicin nanoformulations on therapy against cancer: An overview from the last 10 years. Biomater Adv. 2022 Feb;133:112623. doi: 10.1016/j.msec.2021.112623. Epub 2021 Dec 23. PMID: 35525766.
• Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, Dehpour AR. Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-clinical Therapeutic Approaches. Cardiovasc Toxicol. 2022 Apr;22(4):292-310. doi: 10.1007/s12012-022-09721-1. Epub 2022 Jan 21. PMID: 35061218.
• Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S, et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82. doi: 10.1200/JCO.1989.7.5.572. PMID: 2651576.

• KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 867
• https://www.ncbi.nlm.nih.gov/books/NBK459232/
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Adriamycin (doxorubicin hydrochloride)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/062921s022lbl.pdf