Interacting drugs- summary

+ Doxorubicin 

Barbiturates-                                                                                                                        total doxorubicin plasma clearance increased

Doxorubicin+

Cyclophosphamide/ Mercaptopurine-                                                                         exacerbation of cyclophosphamide -induced hemorrhagic cystitis and  enhancement of 6-mercaptopurine occured.

  Digoxin-                                                                                                                         serum levels decreased by combination chemotherapy (including doxorubicin ) .Digitoxin and digoxin capsules do not appear to be affected 

Radiation-                                                                                                                     radiation-induced toxicity to the myocardium , mucosa, skin and liver have been increased by doxorubicin administration

Regression following acute lymphoblastic leukemia, acute myleoblastic leukemia

Infusion reactions

acute infusion-associated reactionscharacterized by flushing, shortness of breath, facial swelling, headache, chills, back pain, thightness in the chest and throat, and hypotension have occurred in 6.8% of patients with liposomal doxorubicin

Dermatologic

reversible complete alopecia, hyperpigmentation of nailbeds, and dermal creases (primarily in children) ,onycholysis, recall of skin reaction prior to radiotherapy, palmer-planter erythrodysethesia Vascular- phlebosclerosis, especially when small vein is used for repeaeted aaadministration. Facial flushing may occur if injectionis too rapid.

GI- acute nausea and vomiting, may be severe andmay be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis ) anorexia, , diarrhea (occasionally) Local- severe cellulitis, vesicultion and tissue necrosis ocur ifdrug is extravasated . Erythematous streaking along the vein next to injection site has occurred.

Hypersensitivity

fever, chills, urticaria, anphylaxis, lincomycin cross-sensitivity Ophthalmic- conjuctivitis, and lacrimation (rare)

Cardiac disease,pregnancy,prior irradiation to mediasttenium. Special precautions: Elderly, jaundice, monitor blood counts. ECG. Monitoring- initial tratment requires close patient observation and extensivelaboratory monitoring. Hospitaalize patients at laest during the first phase of treatment.

Hyperuriemia- may be induced by doxorubicin secondary to rapid lysis of neoplastic cells. monitor patients blood uric acid levels. Urine discoloration- doxorubicin imparts a red clor to the urine for 1 to 2 days after administration, advise patients to expect this during active therapy.

Warnings- Myelosuppression- primarily to leukocytes requires careful monitoring. With the recommended dosage schedule. Leukopenia is usually transcient , reaching its nadir 10 to 14 days after treatment., with recovery usually by the 21st day. Necrotizing colitis- manifested by typhlitis , bloody stools, and severe and sometimes fatal infections have occurred with doxorubicin given by IV push daily for 3 days with cytarbine continuous daily infusion for > 7 days.

Cardiac toxicity mustbe given special attention. Although uncommon acute left ventricular failure has occurred paticularly in patients who have received total dosage exceeding the recommended dose of 550mg/m2. Extravastion at injection site- with or without stinging or burning sensation may occur even when blood returns on aspiration of the infusion needle. In most cases, these reactions resolve over the course of several hours to a day once the infusion is teminated. Infusion reactions- appear to occur with the first infusion and do not appaer to occur with later infusions if not present initially.

Palmar-plantar erythrodysethesia- The syndrome was generally seen after > 6 weeks of treatment but may occur earlier. The reaction may be severe and debilating in some patients, however and may require discontinuation of treatment. Mucositis- may occur 5 to 10 days after administration, leading to ulceration and represent a sit of origin for severe, Incidence and severity of mucositis is graeter with the 3 succesive daily dose regimen. Hepatic function impairment- doxorubicin is excreted primarily via the bile and toxicity is enhanced by hepatic impairment. Prior to dosing evaluate hepatic function using clinical laboratory tests such as AST,ALT,alkaline phosphatase and bilirubin. Reduction of dose is recommended.

Carcinogenesis/Mutagenesis- doxorubin and related compounds have mutagenic age group

Elderly- Patients > 65 years of age tolerate side effects as well as the younger age group

Pregnancy- use only when the potential benefits outweigh the potential hazards to the fetus.

Children- chidren treated with doxorubin during childhood are more lokely to have abnormal cardiac function. Females may be at more risk.

Indications:

Regression following acute lymphoblastic leukemia, acute myleoblastic leukemia

Dosage:

Recommended dose- 60 to 75mg/sqm as a single IV injection administered at 21 day intervals.

Overdosage- Symptoms Acute overdosage enhances the toxic effects of mucositis, leukopenia, pancytopenia, and thrombocytopenia.

Treatment

1. Treat the severity myleosuppressed patient by hospitalization, antibiotics, platelet and granulocyte tranfusions and give sympatimatic treatment of mucositis.

2.Chronic overdosage with doxorubin exceeding 550mg.m2 increases the risk of cardiomyopathy and resultant CHF.

3.Vigorously manage CHF digitalis preparations and diuretics.

4.Use of peripheral vasodilators is recommended.

Missed dose

1. If you miss a dose of this medicine, take it as soon as possible.

2. However, if it is almost time for next dose, skip the missed dose and go back to your regular dosing schedule.

3. Do not double doses.

1. Allergies- Tell your doctor if you have ever had any unusual or allergic reactions to doxorubicin or other related medicines. Also tell your doctor if your are allergic to any other substances such as foods, preservatives or dyes.

2. Pregnancy- there is a chance that yhis medicine may cause birth defects if either the male or female is receiving it at the time of conception or it is taken during pregnancy. Atthough sterilty is reported in animals and humans with this medicine, the effect is weaker inhumans than in animals

3. Breast feeding- before receiving doxorubicin make sure that your doctor knows if you are pregnant or if you may become pregnant

4. Children- heart problems are more likely to occur in under 2 years of age who are usually more sensitive to the effects of doxorubicin

5. Elderly- heart problems are more likely to occur in the elderly who are more sensitive to the effects of doxorubicin. Elderly may also be more likely to have blood pressure

6. Other medicines- tell your doctor if you are taking any of the following- Ampotericin B or Antithyroid drugs or Azathioprine or Chloramphenicol or Colchicine or Flucytosine or Ganciclovir or Interferon or Pilcamycin or Zidovudine or If you have been treated with radiation or cancer - doxorubicin may increase the efects of these medicines or radiation therapy on the blood Probenecid or Sulfinpyrazone - doxorubicin may raise the concentration ofuric acid in the blood. Since these medicines are used to lower uric acid levels they may not work as well in patients receiving doxorubicin

7. Other medical - Chicken pox or Herpes zoster -risk of severe disease affecting other parts of the body Gout or Kidney stones - doxorubicin may ioncrease blood levels of uric acid in the body, which can cause gout or kidney stones Heart disease -risk of heart problems caused by doxorubicin may be increased Liver disease - effects of doxorubicin may be increased because of slower removal from the body

8. Missed dose- If you miss a dose of this medicine take it as soon as possible. However if it is almost time for your next dose go back to your regular dosing schedule. Do not double doses.

Pharmacology:

Doxorubicin is a cytotoxic antibiotic isolated from cultures of strptomyces peucetius var caesius. Its mechanism is related to ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies studies have shown rapid cell penetration, perinucleolar chromantin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberarations.

Pharmacokinetics:

Doxorubin is metabolised by carbonyl reduction to the active alcohol, doxorubinol and inactive aglycones. Other inactive metabolites have been identified in urine and bile. Urinary excretion accounts for 4 to 5% of the dose in 5 days. Biliary excretion is the major excretion route 40 to 50% is reovered in bile or feces in 7 days.

Pregnancy:

Safety for use during pregnancy is not established. Use only when required.

Children:

Children treated with doxorubicin are more likely to have abnormal cardiac function. Females may be at more risk.