Doxorubicin: Indications, Contraindications, Warnings, Interactions, Side Effects and Dosage

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 as well, but the study of these so far is too limited to justify specific indications.

Contraindications

Doxorubicin hydrochloride is contraindicated in patients with hypersensitivity to doxorubicin, other anthracyclines, anthracenediones or any component of the formula.

It is also contraindicated in patients with persistent or severe stomatitis myelosuppression and patients already treated with the recommended cumulative doses of doxorubicin, daunorubicin, idarubicin or 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, inflammation of the bladder, catheterization problems (for example, due to extensive intravesical tumors).

Warnings

Doxorubicin treatment should only be performed under the supervision of medical professionals experienced in cytotoxic therapy.

Cardiac function

Cardiotoxicity is a risk of anthracycline treatment that can manifest as early (ie 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).

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 dose 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.

Other effects

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 3 days and cytarabine given by infusion daily for 7 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).

Serum levels of uric acid, potassium, calcium, phosphate, and creatinine should be assessed after initial treatment. 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 up to 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.

Doxorubicin, as a component of intensive chemotherapy regimens for pediatric patients, may contribute to prepubertal growth failure. It can also contribute to damage to the gonads, which is 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 and embryotoxic and induces abortion in rabbits. There are no adequate and well-controlled studies in 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 have to undergo treatment 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 baby during treatment with doxorubicin hydrochloride.

Interactions with other medications

Doxorubicin can be combined with other antineoplastic drugs. When used as part of chemotherapy regimens combining drugs with similar pharmacological effects (eg, cytotoxicity), additive toxicity is likely to occur.

This additive toxicity must be taken into account especially in relation to bone marrow and gastrointestinal effects.

The concomitant use of doxorubicin and other drugs considered cardiotoxic (for example, fluorouracil and / or cyclophosphamide) as well as the concomitant use of other cardioactive components (for example blockers, calcium channels), require particularly close attention to cardiac function during therapy. .

Doxorubicin is extensively metabolized by the liver; Any concomitant medications that may affect liver function may also affect the metabolism, pharmacokinetics, efficacy, and / or 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, atrioventricular and atrioventricular bundle blocks have been observed.

With the exception of malignant cardiac dysrhythmias, these effects are not generally predictive of the development of subsequent late cardiotoxicity, are rarely clinically important, and are not considered indications for discontinuation of treatment.

Late cardiotoxicity is dose cumulative dependent and is represented by a characteristic cardiomyopathy that is clinically manifested by symptoms / signs of ventricular dysfunction such as dyspnea, pulmonary edema, gravitational edema (eg, ankle), hepatomegaly, ascites, pleural effusion, and gallop rhythm.

Skin and hypersensitivity reactions:  there is complete and reversible alopecia in most of the treated cases. Erythemas (with rapid administration), hyperpigmentation of the skin and nails and hypersensitivity to irradiated skin, dermal folds mainly in children and onycholysis can also occur.

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 for serious infections. Stomatitis generally appears immediately after administration and, if severe, 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 administration in small vessels or by repeated applications in the same vein. In the case of perivinal 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, hemorrhage, 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 the form of locoregional sensory disturbances have been reported in patients treated with intra-arterial doxorubicin, especially in combination with cisplatin.

Dizziness has been reported in patients who received too high a dose of doxorubicin (2 to 3 times the recommended dose) in combination with high doses of cyclophosphamide.

Other adverse reactions : conjunctivitis and lacrimation occur rarely. Other 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 of short duration.

Dosage

Intravenous use: the dose is usually calculated on the basis of 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 in combination with other antitumor agents, the dose of doxorubicin should be reduced to 25-50 mg / m² every three weeks.

The cumulative dose of intravenous doxorubicin, regardless of dose level, should not exceed 550 mg / m2 body surface area.

Despite low renal excretion, moderate impairment of renal function does not normally require a reduction in the recommended dose.

Intravesically: doxorubicin hydrochloride is used by intravesical administration in the treatment of monocytic carcinoma, papillary tumors of the bladder, and carcinoma in situ. However, this route is not used in the treatment of invasive tumors that have penetrated the bladder wall.

The recommended dose for topical intravesical treatment is 50 mg by instillation, to be 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 are at the medical discretion.

To avoid excessive dilution by urine, the patient should be instructed not to ingest any fluids in the 12 hours prior to instillation. This should limit urine output to approximately 50 ml per hour.

Pediatric patients and their relatives and / or caregivers should be advised to prevent contact with urine or other body fluids, using gloves, for at least 5 days after each treatment.

Protection measures

The following protective measures are necessary due to the toxic nature of this substance:

  • Personnel should be trained in good 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). The work surface should be protected by a disposable absorbent paper, 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 abundant 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.

Overdose

Doxorubicin overdose can cause gastrointestinal toxic effects (mainly mucositis), myelosuppression (mainly leukopenia and thrombocytopenia) and acute cardiac disturbances.

Its treatment consists of the hospitalization of myelosuppressed individuals, with administration of antimicrobials, platelet and granulocyte transfusion, and symptomatic treatment of mucositis.

The use of hematopoietic growth factor should be considered. Chronic doxorubicin overdose increases the risk of cardiomyopathy and HF; treatment consists of the administration of digitalis and diuretics.

Pharmacological characteristics

Doxorubicin hydrochloride is an anthracycline antibiotic isolated from antiblastic cultures Streptomyces peucetius. This product is soluble in water for injections and in physiological saline.

Pharmacodynamic properties

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 serious 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 loco-regional treatment of tumors, by slow intra-arterial infusion or by 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 infusion set, regardless of the drip, after verification 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, 4 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 introduction of 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 greatly reduce the unpleasant toxic effect represented by mucositis; on the other hand, dividing the dose 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 periurral regions should be thoroughly washed during instillation as well as immediately after removal of the solution from the bladder.

Pediatric patients and their relatives and / or 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 stored 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 that are beyond the expiration date, as the desired effect may not be obtained.