A drug commonly used for cancer chemotherapy.
Indications of Doxorubicin
Doxorubicin hydrochloride has been used successfully to regress various cancers, such as breast, lung, bladder, thyroid, and ovarian carcinoma; bone and soft tissue sarcomas; Hodgkin’s lymphomas; neuroblastoma; Wilms tumor; acute lymphoblastic leukemia and acute myeloblastic leukemia.
Doxorubicin hydrochloride has provided positive results in superficial bladder tumors by intravesical administration after transurethral resection. Other solid tumors have responded, but the study of these so far is too limited to justify specific indications.
Doxorubicin hydrochloride is contraindicated in patients with hypersensitivity to Doxorubicin, other anthracyclines, anthracenediones, or any formula component.
It is also contraindicated in patients with persistent or severe stomatitis myelosuppression and patients already treated with the recommended cumulative doses of doxorubicin, daunorubicin, and idarubicin, other anthracyclines and anthracenediones.
Doxorubicin is contraindicated in the presence of generalized infections in severe liver failure, current or previous history of severe arrhythmias or severe heart failure, and recent myocardial infarction.
Contraindications to intravesical use are invasive tumors that have penetrated the bladder wall, urinary tract infections, bladder inflammation, and catheterization problems (for example, due to extensive intravesical tumors).
Doxorubicin treatment should only be performed under the supervision of medical professionals experienced in cytotoxic therapy.
Cardiotoxicity is a risk of anthracycline treatment that can manifest as early (i.e., acute) or late (ie delayed) events.
Cardiac function should be assessed before the patient is treated with doxorubicin hydrochloride and should be monitored during treatment to minimize the risk of severe heart failure (HF).
The left ventricular function should be monitored via radionucleotide angiography or echocardiography, especially for patients with increased risk factors for cardiotoxicity.
The probability of loss of myocardial function is estimated to range from 1 to 20%, depending on the total cumulative dose of Doxorubicin (range 300 mg / m2 to 500 mg / m2). The probability of developing HF ranges from 3 to 21% and depends on the cumulative dose of Doxorubicin (430 to 728 mg / m2).
The cumulative incidence of HF was 2.2%. At cumulative doses of 300 mg / m2, the probability of IC is estimated to be 1 to 2% and slowly increases to 450 to 550 mg / m2. Above this dose, the risk of HF increases sharply, leading to the recommendation not to exceed the cumulative amount of 550 mg / m2.
Effects at the infusion site
Phlebosclerosis can result from infusion of the drug into a small vessel or repeated infusions from the same vein. Following recommended administration procedures can minimize the risk of phlebitis/thrombophlebitis at the infusion site.
Pediatric patients who received Doxorubicin concomitantly with actinomycin-D developed a recurrence of acute pneumonia at varying times after local irradiation.
Colitis manifested by inflammation of the cecum and severe amounts of blood in the stool, and sometimes fatal necrotizing infections have been associated with a combination of Doxorubicin given intravenously for three days and cytarabine given by infusion daily for seven days.
Other cytotoxic agents, thrombophlebitis, and thromboembolic phenomena, including pulmonary embolism (fatal in some cases), have been reported coincidentally with the use of Doxorubicin.
Doxorubicin can induce hyperuricemia by extensive purine catabolism that accompanies drug-induced rapid lysis of neoplastic cells (tumor lysis syndrome).
After initial treatment, serum levels of uric acid, potassium, calcium, phosphate, and creatinine should be assessed. Hydration, urinary alkalinization, and allopurinol prophylaxis to prevent hyperuricemia can minimize the potential complications of tumor lysis syndrome.
Patients should be advised that Doxorubicin can give urine a reddish tint for 1-2 days after administration.
Doxorubicin has no antimicrobial activity.
Use in children
Children are at increased risk of developing late cardiotoxicity. Follow-up with periodic evaluation of cardiac functions is recommended to monitor this cardiotoxicity.
As a component of intensive chemotherapy regimens for pediatric patients, Doxorubicin may contribute to prepubertal growth failure. It can also damage the gonads, which are usually temporary.
Use during pregnancy
The safety of the use of Doxorubicin has not been established during pregnancy. Doxorubicin is embryotoxic and teratogenic in rats, which induces abortion in rabbits. There are no adequate and well-controlled studies on pregnant women.
If Doxorubicin is administered during pregnancy, or if the patient becomes pregnant during treatment, the patient should be informed of the potential harm to the fetus. Women of childbearing potential who undergo therapy with Doxorubicin should be advised to avoid pregnancy during treatment.
Use during lactation
Doxorubicin is secreted in milk. Women should not breastfeed or feed their babies during treatment with doxorubicin hydrochloride.
Interactions with other medications
Doxorubicin can be combined with other antineoplastic drugs. Additive toxicity is likely to occur when used as part of chemotherapy regimens combining drugs with similar pharmacological effects (e.g., cytotoxicity).
This additive toxicity must be considered, especially regarding bone marrow and gastrointestinal effects.
The concomitant use of Doxorubicin and other drugs considered cardiotoxic (for example, fluorouracil and cyclophosphamide) and the simultaneous use of other cardioactive components (for example, blockers, calcium channels) require particularly close attention to cardiac function during therapy.
The liver extensively metabolizes Doxorubicin; Any concomitant medications that may affect liver function may also affect the metabolism, pharmacokinetics, efficacy, and toxicity of Doxorubicin.
Adverse reactions and side effects of Doxorubicin
Cardiotoxicity: induced anthracycline cardiotoxicity can manifest itself by acute or delayed events. The acute cardiotoxicity of Doxorubicin consists mainly of sinus tachycardia.
Premature ventricular contractions, ventricular tachycardia, bradycardia, and atrioventricular and atrioventricular bundle blocks have been observed.
Except for malignant cardiac dysrhythmias, these effects are not generally predictive of the development of subsequent late cardiotoxicity, are rarely clinically significant, and are not considered indications for discontinuation of treatment.
Late cardiotoxicity is cumulative dose-dependent and is represented by characteristic cardiomyopathy that is clinically manifested by symptoms/signs of ventricular dysfunction such as dyspnea, pulmonary edema, gravitational edema (leg, ankle), hepatomegaly, ascites, pleural effusion, and gallop rhythm.
Skin and hypersensitivity reactions: there is complete and reversible alopecia in most treated cases. Erythemas (with rapid administration), hyperpigmentation of the skin and nails, hypersensitivity to irradiated skin, dermal folds, mainly in children, and onycholysis.
Urticaria and anaphylaxis have been observed; The signs/symptoms of these reactions can range from skin rash and itching to fever, chills, and shock. A case of apparent cross hypersensitivity with lincomycin has also been reported.
Gastrointestinal Toxicity: Acute nausea and vomiting occur frequently, can be severe, leading to dehydration, and are attenuated by antiemetic therapy. Mucositis (stomatitis and esophagitis) can occur around 5-10 days after administration.
The clinical manifestations of mucositis include pain and burning sensation, erythema, ulcerative erosions, and bleeding.
The effects can be severe, leading to ulceration and necrosis of the colon, representing a site of origin of severe infections. Stomatitis generally appears immediately after administration and, if painful, can progress to mucosal ulceration, most patients recover from this adverse effect in the third week of treatment.
The dosing schedule in which Doxorubicin is administered on three consecutive days causes an increased incidence and severity of mucositis. Anorexia, diarrhea, and abdominal pain have been reported occasionally.
Injection site effects: Erythematosis from the infused vein is common and can cause local phlebitis or thrombophlebitis. Phlebosclerosis can occur by administering small vessels or by repeated applications in the same vein. In the case of original extravasation, local pain, severe cellulitis, gallbladder, severe tissue lesions, and necrosis occur.
Hematologic / Bone Marrow Effects: The predominant manifestation of doxorubicin toxicity is leukopenia and granulocytopenia (neutropenia), representing the acute dose-limiting toxicity of the drug.
Thrombocytopenia and anemia can also occur. The clinical consequences of hematologic and bone marrow toxicity in Doxorubicin can be fever, infection, sepsis, septic shock, bleeding, tissue hypoxia, or death.
Intravenous antibiotics should be given in the case of febrile neutropenia.
Secondary acute myeloid leukemia has been reported rarely. Phase rarely in patients treated concomitantly with Doxorubicin and anticancer agents and causing DNA damage. These leukemias can have a short latency period (1-3 years).
Neurological effects: peripheral neurotoxicity in locoregional sensory disturbances has been reported in patients treated with intra-arterial Doxorubicin, especially with cisplatin.
Dizziness has been reported in patients who received too high a dose of Doxorubicin (2 to 3 times the recommended dose) combined with high doses of cyclophosphamide.
Other adverse reactions: conjunctivitis and lacrimation, occur rarely. Different adverse reactions include malaise/asthenia and hyperuricemia. Amputation and azoospermia can also occur.
Administration of Doxorubicin intravesically can cause chemical cystitis and increased bladder constriction, and hematuria, itching, and pain in the bladder and urethra, dysuria, frequent urination. These reactions are usually of moderate intensity and short duration.
Intravenous use: the dose is usually calculated based on the body surface area.
When used as an isolated antitumor agent, the recommended dose in adults is 60-70 mg / m² every three weeks. On the other hand, when used with other antitumor agents, the amount of Doxorubicin should be reduced to 25-50 mg / m² every three weeks.
Regardless of dose level, the cumulative dose of intravenous Doxorubicin should not exceed 550 mg / m2 of body surface area.
Despite low renal excretion, moderate impairment of renal function does not usually require a reduction in the recommended dose.
Intravesically: doxorubicin hydrochloride is used by intravesical administration to treat monocytic carcinoma, papillary tumors of the bladder, and carcinoma in situ. However, this route is not used to treat invasive tumors that have penetrated the bladder wall.
The recommended dose for topical intravesical treatment is 50 mg by instillation, administered at variable intervals from 1 week to 1 month. Depending on whether the treatment is prophylactic or curative, the frequency of administration and the duration of the treatment area is at the medical discretion.
To avoid excessive dilution by urine, the patient should be instructed not to ingest any fluids 12 hours before installation. This should limit urine output to approximately 50 ml per hour.
Pediatric patients and their relatives and caregivers should be advised to prevent contact with urine or other body fluids, using gloves for at least five days after each treatment.
The following protective measures are necessary due to the toxic nature of this substance:
- Personnel should be trained in suitable dilution and handling techniques.
- Pregnant women should not be treated with this drug.
- Personnel handling doxorubicin hydrochloride should wear protective clothing such as glasses, aprons, gloves, and disposable masks.
- A designated area should be defined for reconstitution (preferably under the laminar flow system). A disposable absorbent paper should protect the work surface with a plastic base.
- All items used for reconstitution, administration, or cleaning, including gloves, should be placed in high-risk, disposable garbage bags for high-temperature incineration.
- Accidental contact with the skin should be treated immediately with much washing with soap and water or sodium bicarbonate solution; however, do not scrub the skin with brushes.
- In case of contact with the eyes, hold and lift the eyelid of the affected eye and flush with a large amount of water for at least 15 minutes.
Doxorubicin overdose can cause gastrointestinal toxic effects (mainly mucositis), myelosuppression (mainly leukopenia and thrombocytopenia), and acute cardiac disturbances.
Its treatment consists of hospitalized myelosuppression individuals, administering antimicrobials, platelet and granulocyte transfusion, and symptomatic treatment of mucositis.
The use of hematopoietic growth factors should be considered. Chronic doxorubicin overdose increases the risk of cardiomyopathy and HF; treatment consists of the administration of digitalis and diuretics.
Doxorubicin hydrochloride is an anthracycline antibiotic isolated from anticlastic cultures Streptomyces peucetius. This product is soluble in water for injections and in physiological saline.
The cytotoxic properties of Doxorubicin in malignant cells and the toxic effects on many organisms appear to be related to the fusion of its planar rings between nucleotide base pairs.
Intercalation to DNA inhibits nucleotide replication and can trigger DNA breakdown by topoisomerase II, causing severe disturbances in the tertiary structure of DNA. The ability of Doxorubicin to bind to the cell membrane can affect a variety of functions.
Doxorubicin also appears to be involved in oxidation/reduction reactions with the production of highly reactive and highly toxic free radicals.
Cells treated with Doxorubicin have shown changes in the morphological characteristics associated with apoptosis, which may be one of the mechanisms of action of Doxorubicin.
How to use
Doxorubicin is not administered orally and should not be done intramuscularly or intrathecally. Its administration should only be carried out by intravenous injection or, in the case of locoregional treatment of tumors, by slow intra-arterial infusion or topical intravesical administration through a catheter.
Doxorubicin hydrochloride must be dissolved in 0.9% sodium chloride solution or sterile water for injections.
The recommended concentration is 2 mg / ml. It is recommended that intravenous administration be done through the tube of a 0.9% sodium chloride set, regardless of the drip, after verifying that the needle is correctly in the vein.
This technique reduces the risk of perverse drug extravasation and allows flushing of the vein after administration.
If signs or symptoms of extravasation appear, the injection or infusion should be stopped immediately, and the skin should be washed with warm, soapy water.
If extravasation is suspected, intermittent application of ice to the site for 15 minutes, four times a day may be helpful. The use of gloves and proper clothing for protection is recommended during the preparation and administration of the drug.
For intravesical therapy, doxorubicin hydrochloride should be dissolved in water for injection at room temperature; the recommended concentration is 1 mg/ml. After introducing the solvent, the contents of the vial should be dissolved by gently shaking the vial, without inversion, within 30 seconds.
Administration of a single dose every three weeks has been shown to reduce significantly the unpleasant toxic effect represented by mucositis; on the other hand, by dividing the amount over three successive days (20-25 mg / m2 each day), greater efficacy is achieved even at a higher toxicity rate.
The dose should be reduced in patients who have previously been treated with other cytotoxic agents and in elderly patients. The perioral regions should be thoroughly washed during installation and immediately after removal of the solution from the bladder.
Pediatric patients and their relatives and caregivers should be advised to prevent contact with urine or other body fluids, using gloves, for at least 5 days after each treatment.
Stability of reconstituted solutions
The reconstituted solution is chemically stable when stored for up to 7 days at room temperature (15-30ºC) and in contact with normal artificial light. It is recommended that the reconstituted solution be held between 2 ° C and 8 ° C, protected from light, and used within 24 hours after reconstitution.
Storage precautions: keep the product in its original container, at room temperature (between 15 and 30 ºC), protected from light. Accidental contact with the skin or eyes should be treated immediately by abundant washing with soap and water.
Validity period: the validity period is 24 months, counted from the date of manufacture, and is printed on the outer packaging of the product, together with the batch number. Do not use medications beyond the expiration date, as the desired effect may not be obtained.