Adrim

Doxorubicin hydrochloride.

Each mL contains Doxorubicin hydrochloride 2 mg.
ADRIM (Doxorubicin hydrochloride Injection) is a sterile clear, red coloured solution for Injection. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from the culture of Streptomyces peucetius var caesius.
Chemical name of Doxorubicin hydrochloride is (8S, 10S)-10-[(3-Amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7, 8, 9, 10-tetrahydro-6, 8,11-trihydroxy-1-methoxy-5, 12-naphthacenedione hydrochloride.
It has a molecular formula of C₂₇H₂₉NO₁₁. HCl and molecular weight 579.98.

Pharmacology: Mechanism of Action: Doxorubicin binds directly to DNA via intercalation between base pairs on the DNA helix. Doxorubicin also inhibits DNA repair by inhibiting topoisomerase II. These actions result in the blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin is also a powerful iron-chelator. The iron-doxorubicin complex can bind DNA and cell membranes producing free radicals that immediately cleave DNA and cell membranes. Although maximally cytotoxic in S phase, doxorubicin is not cell cycle-specific.
Pharmacokinetics: Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours.
Distribution: Steady-state distribution volume ranges from 809 to 1214 L/m². Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75%.
Doxorubicin does not cross the blood brain barrier.
Metabolism: It undergoes rapid metabolism in the liver to metabolites including the active metabolite doxorubicinol (adriamycinol).
Excretion: Plasma clearance is in the range 324 to 809 mL/min/m² and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days. Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.
Pediatric patients: Clearance in children older than 2 years was increased compared with adults.
Patient Gender: Clearance appears to be higher in men than women; however, the half-life was longer in men compared with women.
Patients with hepatic impairment: The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin.

Doxorubicin hydrochloride is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.
Doxorubicin hydrochloride is indicated for the treatment of: acute lymphoblastic leukemia; acute myeloid leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); metastatic breast cancer; metastatic Wilms tumor; metastatic neuroblastoma; metastatic soft tissue sarcoma; metastatic bone sarcoma; metastatic ovarian carcinoma; metastatic transitional cell bladder carcinoma; metastatic thyroid carcinoma; metastatic gastric carcinoma; metastatic bronchogenic carcinoma.

Recommended Dose: Adjuvant Breast Cancer: The recommended dose of doxorubicin is 60 mg/m² administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.
Metastatic Disease, Leukemia, or Lymphoma: The recommended dose of doxorubicin when used as a single agent is 60 to 75 mg/m² intravenously every 21 days.
The recommended dose of doxorubicin, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m² intravenously every 21 to 28 days.
Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
Cumulative doses above 550 mg/m² are associated with an increased risk of cardiomyopathy.
Dose Modifications: Cardiac Impairment: Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.
Hepatic Impairment: Doxorubicin hydrochloride is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL).
Decrease the dose of doxorubicin hydrochloride in patients with elevated serum total bilirubin concentrations as follows: (See Table 1.)

Click on icon to see table/diagram/image

Preparation and Administration: Do not administer IM or subcutaneously.
A direct push injection is not recommended due to the risk of extravasation.
Administration: Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.
Administration by Intravenous Injection: Administer doxorubicin hydrochloride as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
Administer doxorubicin hydrochloride intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
Administration by Continuous Intravenous Infusion: Preparation for Continuous Intravenous Infusion: Dilute doxorubicin hydrochloride solution in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.
Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
Protect from light from preparation for infusion until completion of infusion.
Management of Suspected Extravasation: Discontinue doxorubicin hydrochloride for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows: Do not remove the needle until attempts are made to aspirate extravasated fluid.
Do not flush the line.
Avoid applying pressure to the site.
Apply ice to the site intermittently for 15 min 4 times a day for 3 days.
If the extravasation is in an extremity, elevate the extremity.
In adults, consider administration of dexrazoxane.

Single doses of 250 mg and 500 mg of doxorubicin have proved fatal. Such doses may cause acute myocardial degeneration within 24 hours and severe myelosuppression (mainly leucopenia and thrombocytopenia), the effects of which are greatest between 10 and 15 days after administration. Treatment should aim to support the patient during this period and should utilise such measures as blood transfusions and reverse barrier nursing.
Acute overdose with doxorubicin will result in gastrointestinal toxic effects (mainly mucositis). This generally appears early after drug administration, but most patients recover from this within three weeks.
Delayed cardiac failure may occur up to six months after the overdosage. Patients should be observed carefully and should signs of cardiac failure arise, be treated along conventional lines.

Doxorubicin hydrochloride is contraindicated in patients with: Severe myocardial insufficiency; recent (occurring within the past 4-6 weeks) myocardial infarction; severe persistent drug-induced myelosuppression, severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL); severe hypersensitivity reaction to doxorubicin hydrochloride including anaphylaxis; any component of the formulation, or to other anthracyclines or anthracenediones.

Cardiomyopathy, secondary malignancies, extravasation and tissue necrosis, and severe myelosuppression.
Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin hydrochloride. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1%-20% for cumulative doses ranging from 300 mg/m² to 500 mg/m² when doxorubicin hydrochloride is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess LVEF (Left Ventricular Ejection Fraction) before and regularly during and after treatment with doxorubicin hydrochloride.
Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin hydrochloride.
Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area.
Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur.

Cardiomyopathy and Arrhythmias: Cardiomyopathy: Doxorubicin hydrochloride can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride. Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin hydrochloride, 3 to 5% at a dose of 400 mg/m², 5 to 8% at a dose of 450 mg/m², and 6 to 20% at a dose of 500 mg/m², when doxorubicin hydrochloride is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab.
Pericarditis and myocarditis have also been reported during or following doxorubicin hydrochloride treatment.
Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m². Use the same method of assessment of LVEF at all time points. Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m² and who will continue to receive doxorubicin hydrochloride.
Arrhythmias: Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia may occur. Electrocardiographic changes including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require dose-modifications of doxorubicin hydrochloride.
Secondary Malignancies: The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride. These leukemias generally occur within 1 to 3 years of treatment.
Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride can result in severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. When given via a peripheral venous line, infuse doxorubicin over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation. If signs or symptoms of extravasation occur, immediately terminate the injection or infusion. Extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle. If extravasation is suspected, apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.
Severe Myelosuppression: Doxorubicin may cause severe myelosuppression, which may result in serious infection, septic shock, transfusion requirements, hospitalization, and death. Myelosuppression may be dose-limiting and primarily manifests as leukopenia and neutropenia; anemia and thrombocytopenia may also occur. The nadir typically occurs 10 to 14 days after administration with cell count recovery around day 21. Monitor blood cell counts at baseline and regularly during therapy.
Obtain baseline assessment of blood counts and carefully monitor patients during treatment for possible clinical complications due to myelosuppression.
Use in Patients with Hepatic Impairment: The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity. Reduce the dose of doxorubicin hydrochloride in patients with serum bilirubin levels of 1.2-5.0 mg/dL. Doxorubicin is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL). Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during doxorubicin hydrochloride therapy.
Tumor Lysis Syndrome: Doxorubicin hydrochloride may induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.
Radiation Sensitization and Radiation Recall: Doxorubicin hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin hydrochloride after prior radiation therapy.
Embryofetal Toxicity: Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin.
Females and Males of Reproductive Potential: Contraception: Females Doxorubicin hydrochloride can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin hydrochloride and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin hydrochloride.
Males: Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment.
Infertility: Females: In females of reproductive potential, doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment.
Males: Doxorubicin hydrochloride may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Doxorubicin was genotoxic and mutagenic in vitro and in vivo tests. In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhoea. Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.
Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.
Use in Children: Based on observations, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially <5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary. There are no recommended dose adjustments based on age. Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in children less than 2 years as compared to adults.
Use in the Elderly: Elderly patients may need a reduced dose.

Pregnancy Category: D.
Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Doxorubicin has been detected in the milk of at least one lactating patient. Because of the potential for serious adverse reactions in nursing infants from doxorubicin hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The following adverse reactions are discussed in more detail in the Precautions and Warnings section: Cardiomyopathy and arrhythmias; secondary malignancies; extravasation and tissue necrosis; severe myelosuppression; tumor lysis syndrome; radiation sensitization and radiation recall.
Clinical Trial Experience in Breast Cancer: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety data below were collected from women who received doxorubicin hydrochloride at a of 60 mg/m² and cyclophosphamide at a dose of 600 mg/m² every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in the table as follows. No treatment-related deaths were reported in patients on either arm of the study. (See Table 2.)

Click on icon to see table/diagram/image

Other Adverse Reactions: Cardiac: Cardiogenic shock.
Cutaneous: Skin and nail hyperpigmentation, onycholysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia.
Gastrointestinal: Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa.
Hypersensitivity: Anaphylaxis.
Laboratory Abnormalities: Increased alanine aminotransferase, increased aspartate aminotransferase.
Neurological: Peripheral sensory and motor neuropathy, seizures, coma.
Ocular: Conjunctivitis, keratitis, lacrimation.
Vascular: Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism.
Other: Malaise/asthenia, fever, chills, weight gain.

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 hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.
Trastuzumab: Concurrent use of trastuzumab and doxorubicin hydrochloride 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.
Paclitaxel: Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma- concentrations of doxorubicin and its metabolites. Administer doxorubicin hydrochloride prior to paclitaxel if used concomitantly.
Dexrazoxane: Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin hydrochloride containing chemotherapy regimens. Dexrazoxane may diminish the therapeutic effect of Doxorubicin. This recommendation does not apply to the use of dexrazoxane for other indications (e.g., extravasation), or to the use of dexrazoxane later in treatment.
Mercaptopurine: Doxorubicin may enhance the hepatotoxicity of mercaptopurine.

Incompatibilities: Do not admix doxorubicin hydrochloride with other drugs. If doxorubicin hydrochloride is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride. Admixture of doxorubicin hydrochloride with cefalotin sodium, dexamethasone, diazepam, or hydrocortisone sodium succinate is reported to result in immediate precipitation. Similarly precipitation has occurred when doxorubicin hydrochloride was mixed with furosemide.
Handling and Disposal: Handle and dispose of doxorubicin hydrochloride consistent with recommendations for the handling and disposal of hazardous drugs.
In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush.
In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store under refrigeration 2-8 °C. Protect from light.

Cytotoxic Chemotherapy

L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.

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