Doxorubicin

Serious side effects have been reported with doxorubicin. See "Doxorubicin Precautions."

Infusion site reactions. Serious infusion site reactions can happen with doxorubicin. Symptoms of infusion reaction may include:

• pain at injection site
• skin redness or swelling
• burning or stinging
• open skin sores at injection site

Your doctor will watch you closely while you are receiving doxorubicin and after your infusion for signs of a reaction. You may experience these reactions immediately or within 2 hours of infusion.

Change in the color of your urine. You may have red colored urine for 1 to 2 days after your infusion of doxorubicin. This is normal. Tell your doctor if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine.

Infection. Call your doctor right away if you get any of the following signs of infection:

• fever (temperature of 100.4 F or greater) chills or shivering
• cough that brings up mucus
• burning or pain with urination

Doxorubicin may cause lower sperm counts and sperm problems in men. This could affect your ability to father a child and cause birth defects. Men should use effective birth control (contraception) while receiving doxorubicin. Do not have unprotected sexual contact with a female who could become pregnant. Tell your doctor if you do have unprotected sexual contact with a female who could become pregnant. Talk to your doctor if this is a concern for you.

Irreversible amenorrhea or early menopause. Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return after you complete your treatment of Doxorubicin.

The most common side effects of Doxorubicin include:

• hair loss (alopecia). Your hair may re-grow after your treatment.
• darkening of your nails or separation of your nails from your nailbed
• nausea
• vomiting
• lack of appetite or increased thirst
• bruise or bleed more easily
• abnormal heart beat
• a secondary cancer may occur when Doxorubicin is combined with other chemotherapy agents.
• mouth sores
• weight changes
• stomach (abdominal) pain
• diarrhea
• eye problems
• allergic reactions. Call your doctor right away if you have any of the following symptoms of an allergic reaction:
• rash
• flushed face
• fever
• hives
• dizziness or feel faint
• itching
• shortness of breath or trouble breathing
• swelling of your lips or tongue

Tell your doctor or nurse if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of doxorubicin. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• Paclitaxel
• progesterone (Provera, Depo-Provera)
• Verapamil
• cyclosporine (Neoral, Sandimmune)
• cytarabine (DepoCyt)
• cyclophosphamide (Cytoxan)
• phenobarbital
• phenytoin (Dilantin)
• streptozocin (Zanosar)
• saquinavir

This is not a complete list of doxorubicin drug interactions. Ask your doctor or pharmacist for more information.

Liposomal formulation (Lipodox):

• Breast Cancer/Ovarian cancer: 50 mg/m2 once every 4 weeks
• AIDS-KS patients: 20 mg/m2 once every 3 weeks

Liposomal formulation (Doxil):

• Ovarian Cancer: 50 mg/m2 once every 4 weeks. A minimum of 4 courses is recommended.

• AIDS-Related Kaposi's Sarcoma: 20 mg/m2 once every three weeks

• Multiple Myeloma: 30 mg/m2 on day 4 following bortezomib therapy. You may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.

Adriamycin (doxorubicin) formulation:

• The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single injection. It is given at 21-day intervals.
•  When used in combination with other chemotherapy drugs, the most commonly used dosage is 40 to 60 mg/m2 every 21 to 28 days.
• The NSABP B-15 study: the combination dosage regimen of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 was done on day 1 of each 21-day treatment cycle. Four cycles of treatment were completed.

WARNINGS

1. Severe local tissue necrosis will occur if there is extravasation during administration. Doxorubicin must not be given by the intramuscular or subcutaneous route.
2. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. Pediatric patients are at increased risk for developing delayed cardiotoxicity.
3. Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with anthracyclines, including doxorubicin. The occurrence of refractory secondary AML or MDS is more common when anthracyclines are given in combination with DNA-damaging anti-neoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The rate of developing secondary AML or MDS has been estimated in an analysis of 8563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1000 patient years (95% CI, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% CI, 0.11 to 0.41%). In another analysis of 1474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center,the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS. Pediatric patients are also at risk of developing secondary AML.
4. Dosage should be reduced in patients with impaired hepatic function.
5. Severe myelosuppression may occur.
6. Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agent.

Call your doctor for instructions if you miss an appointment for your doxorubicin injection.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, chest tightness, back pain, trouble breathing, or swelling in your face.

Call your doctor at once if you have:

• pain, blisters, or skin sores where the injection was given;

• missed menstrual periods;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• low white blood cell counts--fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing; or

• signs of heart problems--fast heartbeats, shortness of breath (even with mild exertion), swelling in your ankles or feet.

Doxorubicin may cause your urine to turn a reddish-orange color. This side effect by itself is usually not harmful. However, call your doctor if you also have upper stomach pain, clay-colored stools, or jaundice (yellowing of your skin or the whites of your eyes).

Common side effects may include:

• nausea, vomiting; or

• hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Effect of CYP3A4 Inhibitors, Inducers and P-gp

Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of Doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may decrease the concentration of Doxorubicin. Avoid concurrent use of Doxorubicin HCl with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.

Trastuzumab

Concurrent use of trastuzumab and Doxorubicin HCl results in an increased risk of cardiac dysfunction. Avoid concurrent administration of Doxorubicin and trastuzumab. The appropriate interval for administering Doxorubicin following trastuzumab therapy has not been determined [see Warnings and Precautions (5.1)].

Paclitaxel

Paclitaxel, when given prior to Doxorubicin HCl, increases the plasma-concentrations of Doxorubicin and its metabolites. Administer Doxorubicin HCl prior to paclitaxel if used concomitantly.

Dexrazoxane

Do not administer dexrazoxane as a cardioprotectant at the initiation of Doxorubicin HCl-containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with Doxorubicin HCl-based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p=0.007) and shorter time to progression than in women who received Doxorubicin HCl-based chemotherapy alone.

 6-Mercaptopurine

Doxorubicin HCl may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for 5 days per cycle every 2-3 weeks) and Doxorubicin HCl (50 mg/m2 intravenous once per cycle every 2-3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of Doxorubicin HCl (300 mg/m2) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. A 17-year-old girl with osteogenic sarcoma received 150 mg of Doxorubicin HCl daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4-7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose.

1.  "Hazardous Drugs". OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. It is indicated for the treatment of metastatic carcinoma of the ovary, metastatic breast cancer and AIDS related Kaposis Sarcoma (KS).

Mechanism Of Action

The exact mechanism of the antitumor activity of doxorubicin is not known. It is generally believed that inhibition of synthesis of DNA, RNA and protein is responsible for the majority of the cytotoxic effects. Liposomal doxorubicin penetrates the cells rapidly, binds to chromatin and inhibits nucleic acid synthesis by intercalation between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.

Pharmacokinetics

Liposomal doxorubicin displayed linear pharmacokinetics over the dose range of 10 to 20 mg/m². Disposition occurred in two phases after doxorubicin administration with a relatively short phase (approximately 5 hours) and a prolonged second phase (approximately 55 hours) that accounted for the majority of the area under the curve (AUC).

The pharmacokinetics of liposomal doxorubicin at a dose of 50 mg/m² is reported to be nonlinear. At this dose, the elimination half life of liposomal doxorubicin is expected to be longer and the clearance lower compared to a 20 mg/m² dose. The exposure (AUC) is thus expected to be more than proportional at a 50 mg/m² dose when compared with the lower doses.

The plasma protein binding of liposomal doxorubicin has not been determined; the plasma protein binding of doxorubicin is approximately 70%. Unlike conventional doxorubicin which displays a large volume of distribution, ranging from 700 to 1100 L/m², a small steady state volume of distribution of liposomal doxorubicin shows that liposomal doxorubicin is confined mostly to the vascular fluid volume and the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment.

The plasma clearance of liposomal doxorubicin was slow with a mean clearance of 0.041 L/h/m² at a dose of 20 mg/m². Because of the slow clearance, the AUC of liposome-encapsulated doxorubicin is approximately two to three orders of magnitude larger than the AUC for a similar dose of the conventional form of doxorubicin. Doxorubicinol, the main metabolite was detected at very low levels (0.8 to 26.2 ng/ml) in the plasma of patients who received liposomal doxorubicin at the dose of 10 to 20 mg/m².

No pharmacokinetic study has been done in individuals with renal or hepatic insufficiency.