Doxorubicin Kalbe

Each vial contains :

Doxorubicin HCl solution………………………………………………10 or 50 mg

Doxorubicin HCl is one of the of the anthracycline antibiotics, isolated from strains of  Streptomyces peucetius var caesius. It can penetrate through cell wall rapidly and intercalate with DNA in the nucleus. The presence of doxorubicin HCl in the nucleus freeze the enzyme DNA topoisomerase II and breaks protein associated DNA strand. This action causes inhibition of mitotic activity, nucleid acid synthesis, mutagenesis and chromosomal aberrations. Another action of Doxorubicin HCl is its reaction with cytochrome P₄₅₀ to produce hydrogen peroxide and hydroxyl radical that are highly destructive to cell.

Besides acting as cytotoxic, Doxorubicin Kalbe has another activity from animal studies. Its another activities like immunosuppression, induction of toxic effects including cardiac toxicity, myelosuppression in all species and testes athropy in rats and dogs. After i.v. administration, Doxorubicin Kalbe, shown rapid plasma clearance. Urinary excretion approximately 4-5 % of the dose administration excreted in the bile or feces in 7 days and 75 % of the drug present in plasma is bound to protein. Impairment of hepatic function increase retention and accumulation in plasma and tissue.

·        Myelosuppression induces by treatment of the antitumor agents or radiotherapy.

·        Patients with pre-existing heart disease.

·        Patients who received previous treatment with complete cumulative doses of doxorubicin or daunorubicin.

·        Patients who are hypersensitive to hydroxybenzoate.

·        Pregnancy.

• For intravenous use only. Severe local tissue necrosis will occur if there is extravasation during administration. Doxorubicin must not be given by the intramuscular or subcutaneous rate.

• Dosage should be reduced in patients with impaired hepatic function.

• Toxicity to recommended doses of Doxorubicin is enchaned by hepatic impairment; therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical.

• laboratory test (such as SGOT, SGPT, Alkaline phosphate and Bilirubine).

• Severe myelosuppression may occur.

• Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemoterapeutic agents.

• Doxorubicin may potentiate in toxicity of other anticancer therapies. Exacerbation of cyclophospamide induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-Mercaptopurine have been reported. Radiation induced toxicity to the myocardium, mucosal, skin, and liver have been reported to be increase by the administration of Doxorubicin.

• Doxorubicin Kalbe may cause heart failure even though the risk is very low at the recommended limit of 550 mg/m². The risks become higher when total dosages of the drug exceed the recommended limit. The recommended limit become lower, 400 mg/m², in patients who received radiotherapy to the mediastinal area or concomitant therapy with another cardiotoxic agent.

• Congestive heart failure may occur, several weeks after discontinuation of Doxorubicin Kalbe therapy, which is not favorable affected by presently known physical therapy for cardiac support.

• Monitoring ECG is advisable, before and after treatment, to predict cardiotoxicity that is indicated by reduction in the QRS wave.

• Since the incidence of bone marrow depression is high, careful hematological monitoring is recommended. Hematological toxicity may require dose reduction or delay of Doxorubicin Kalbe therapy.

• Evaluation or infusion should be terminated, when extravasation symptoms have occurred. Therapy should be restarted in another vein.

• Like another cytotoxic agents, Doxorubicin Kalbe have shown mutagenic and teratogenic properties in animal evaluation. Even though there is no adequate study in human, use of Doxorubicin Kalbe in pregnancy is avoided.

• Doxorubicin Kalbe may induce hyperuricemia secondary to rapid lysis of neoplastic cells. Therefore blood uric level should be monitored to control the problem.

• Doxorubicin Kalbe therapy causes red coloration to urine for 1-2 days after administration.

· Primarily adverse reactions of Doxorubicin Kalbe are myelosuppression and cardiotoxicity. The other adverse reactions are :

Drug Interaction

· Concurrent treatment with Cyclophospamide, Dactinomycin or Mytomycin may sensitize the heart to the cardiotoxic effect of Doxorubicin.

· Propanolol may increase the cardiotoxicity of Doxorubicin as both drugs have been shown to inhibit cardiac mitochondrial co- and 10-enzymes.

· Doxorubicin may raise the concentration of blood uric acid dosage adjustment of antigout agent (e.g. Allopurinol, Colchicine) may be necessary to control hyperuricaemia. The leucopenic, thrombocytopenic and bone marrow depressant effects of Doxorubicin may be increase with concurrent or recent therapy with other drugs causing these effects.

· Doxorubicin may decrease the patient’s antibody response to vaccines and/or may increase adverse effects of alive virus vaccine due to immunosuppression. These effect may persist from three months to one year.

· Hepatotoxic medications (e.g. high dose Methotrexate) may impair hepatic function and, therefore, increase the toxicity of subsequantly administered Doxorubicin.

·        The recommended doses are 60-75 mg/m² as a single i.v. administration for 21 days, the lower dose (60 mg/m²) should be given to patients with inadequate marrow reserves due to neoplastic marrow infiltration or old age or prior therapy.

·        An alternative doses are 20 mg/m² weekly or 30 mg/m² each successive days repeated every 4 weeks to decrease toxicity.

·        The dose of Doxorubicin Kalbe when used in combination with other myelosuppresive drugs is 30-40 mg/m² every 3 to 4 weeks and 60-75 mg/m² if used with drugs that are not myelosuppressive.

·        Dosage of Doxorubicin Kalbe should be reduced if the bilirubin increase as follow :

à        ½ normal dose of Doxorubicin Kalbe if serum bilirubin is 20-50 mmol/L and BSP retention is 9-15%.

à        ¼ normal dose of Doxorubicin Kalbe if serum bilirubin is > 50 mmol/L and BSP retention is > 5%.

·        The following procedure is recommended :

à        The bladder should be catheterized and emptied.

à        A solution containing 80 mg of Doxorubicin in 100 ml of normal Saline, should be instilled via catheter into the bladder.

à        The catheter should than be removed and the patient instructed to lie on side. At 15 minutes interval, the patient should be instructed to alternate to the other side over 1 hour period.

à        The patient should not urinate for 1 hour after which the bladder should emptied of solution.

à        The procedure is repeated at monthly intervals.

Notes :

·        Skin reaction may occur when Doxorubicin Kalbe contacts the skin. It is recommended to use protective gloves when administrated Doxorubicin Kalbe solution. If Doxorubicin Kalbe solution contacts the skin, immediately wash with soap and water.

·        It is not recommended to mix Doxorubicin Kalbe with heparin or 5-fluorouracil or other drugs.

Sometimes Doxorubicin Kalbe is administered concurrently with another chemotherapeutic agents for some types of neoplastic disease therapy.

Box containing 1 vial of Doxorubicin Kalbe solution 10 mg/5 ml       Reg No. DKI 0405400243A1

Box containing 1 vial of Doxorubicin Kalbe solution  50 mg/25 ml    Reg No. DKI 0405400243A1

Store between 2 – 8 ^oC