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Drug Details

DAUNOXOME

• Drug Class Description
  Cytotoxics (anthracycline antibiotics).
• Generic Name
  Daunorubicin
• Presentation
  Infusion, daunorubicin (in liposomes) 50 mg .
• Description
  Red, clear to slightly opalescent emulsion in vials.
• Indications
  Treatment of advanced HIV-related Kaposi's sarcoma.
• Adult Dosage
  

  DaunoXome should be administered by intravenous infusion. The recommended initial dose of DaunoXome in patients with AIDS-related Kaposi's sarcoma is 40 mg/m² every two weeks. The dosage of DaunoXome must be adjusted for each patient. Therapy should be continued as long as disease control can be maintained.

  DaunoXome should be diluted with 5% dextrose for infusion before administration. The recommended concentration after dilution is between 0.2 mg and 1 mg daunorubicin/ml of solution. DaunoXome should be administered intravenously over a minimum period of 30-60 minutes.

  DaunoXome must not be given by the intramuscular or subcutaneous route or as a bolus injection.

  DaunoXome is a liposomal preparation and should not be used interchangeably with conventional daunorubicin.

  Pediatric patients: DaunoXome is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

  Elderly: The safety and effectiveness of DaunoXome in patients over 65 years of age have not been established. Cardiotoxicity may be more frequent in the elderly.

  Hepatic impairment: Limited clinical experience exists in treating hepatically impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if bilirubin is elevated as follows:

  - Serum bilirubin 1.2 to 3 mg/dl (20.3 to 50.8 μmol/l), give 75% of the normal dose

  - Serum bilirubin > 3 mg/dl (>50.8 μmol/l), give 50% of the normal dose.

  Renal impairment: Limited clinical experience exists in treating renally impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if creatinine is elevated as follows:

  Serum creatinine > 3 mg/dl (>265 μmol/l), give 50% of the normal dose.

• Child Dosage
  Not recommended.
• Contra Indications
  

  Hypersensitivity to DaunoXome, any of its excipients or other anthracyclines/anthracendions.

  Pregnancy and breast feeding.

• Special Precautions
  

  Cardiotoxicity

  DaunoXome and other anthracyclines can cause cardiotoxicity, notably congestive heart failure due to cardiomyopathy. The onset of symptoms can be sudden and may not occur until weeks or months after discontinuation of therapy. Cardiac damage may be irreversible and there have been rare reports of fatalities, usually in patients with risk factors.

  The risk of cardiotoxicity increases with total cumulative dosage of anthracyclines. Caution must therefore be exercised in patients previously treated with anthracyclines, or those with previous (or concomitant) therapy with other cardiotoxic compounds such as 5-fluorouracil (5-FU).

  The risk of cardiotoxicity appears to be higher in those with pre-existing cardiovascular disease, a history of mediastinal radiation and the elderly. Caution must therefore be exercised when DaunoXome is given to these patients. DaunoXome should only be given to patients with cardiovascular disease when the benefit outweighs the risks.

  Experience in patients treated with high dose DaunoXome (above 60mg/m²) for malignancies other than Kaposi's sarcoma indicates that the risk of cardiotoxicity may be higher in these patients.

   

  Cardiac monitoring

  Careful monitoring of cardiac function is essential in patients treated with DaunoXome.

  Cardiomyopathy induced by anthracyclines is usually associated with a decreased left ventricular ejection fraction (LVEF) measured by echocardiography or by MUGA (Multiple Gated Acquisition). Measurement of LVEF provides a more specific method for monitoring cardiac function than ECG.

  All patients should undergo baseline ECGs, echocardiography and measurement of LVEF prior to starting DaunoXome. These tests should be repeated regularly during treatment. Furthermore, in all patients, LVEF must be determined when a cumulative dose of 320mg/m² has been reached, then every 160mg/m² thereafter, in order to identify at an early stage any changes in LVEF that may be a precursor to cardiomyopathy if DaunoXome therapy is continued.

  In patients with risk factors for cardiotoxicity with DaunoXome, or those receiving high dose DaunoXome per cycle (e.g. 120mg/m² or above), decreases in cardiac function may occur at lower cumulative doses of DaunoXome, therefore consideration should be given to determination of LVEF after each treatment cycle and before any additional DaunoXome is administered.

  Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for cessation of DaunoXome. A reduction of the QRS wave is considered more indicative of cardiac toxicity.

  Whenever cardiomyopathy is suspected, and/or LVEF has decreased significantly as compared to pre-treatment values (e.g. 20% decline) and/or if the LVEF is lower than would be expected (e.g. <45%), the benefit of continued therapy must be carefully weighed against the risk of producing irreversible cardiac damage.

  It is recommended that DaunoXome is stopped if signs or symptoms of heart failure occur.

   

  Haematological toxicity

  DaunoXome is a bone marrow suppressant. The most significant effect is usually neutropenia, which may be severe and result in fever and infection. Anemia and thrombocytopenia may also occur, but are usually less marked. Persistent severe myelosuppression may result in sepsis, or haemorrhage. Complete blood counts must be performed prior to each dose and frequently during the course of DaunoXome therapy.

  Patients with malignancies or with HIV infection, whose immune system is already compromised, must be monitored carefully for evidence of intercurrent or opportunistic infections.

  Anti-infective therapy should be employed in the presence of suspected or confirmed infection and during febrile neutropenia.

  Haematological toxicity may require dose reduction of DaunoXome or suspension or delay of therapy. The colony stimulating factor GCSF has been used to manage patients with neutropenia.

  Caution is warranted when combining DaunoXome with other agents which suppress bone marrow function.

   

  Injection site reactions

  Care should be taken to ensure that there is no extravasation of DaunoXome during administration. Paravenous administration has resulted in erythema, pain and swelling around the site of tissue infiltration. These changes are generally transitory, resolving within 6 months. However, localised tissue necrosis must still be regarded as a possible consequence of extravasation.

  If any signs or symptoms of extravasation occur (e.g. stinging, erythema), the infusion should be stopped immediately and re-started in another vein. The affected limb should be elevated. It may be inappropriate to provide any measure that might cause release of the drug from the liposome (such as application of ice or corticosteroids, instillation of local antidotes, local compression, etc.)

   

  Acute infusion associated reactions

  Acute infusion-related reactions have been reported in patients treated with DaunoXome. Symptoms typically include back pain, flushing, chest tightness and dyspnoea. These infusion reactions may occur during the patient's first exposure to DaunoXome, or during re-exposure in a patient who had previously received DaunoXome without incident. Infusion-related reactions generally occur within the first 10 minutes of the infusion and subside when the infusion is slowed or halted. Acute allergic/anaphylactic reactions, sometimes associated with hypotension, have also been reported.

   

  Birth defects

  Daunorubicin may cause serious birth defects when used during pregnancy. DaunoXome is contra-indicated in pregnancy.

• Interactions
  

  Protease Inhibitors and Non Nucleoside Reverse Transcriptase Inhibitors are known inhibitors of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction between DaunoXome and these two groups of antiviral therapy. To date however, a single study has indicated that there is no effect of PI's or NNRTI's on DaunoXome's pharmacokinetic properties. Limited data from one small study where patients were treated with and without protease inhibitors indicate that there were no major changes in DaunoXome associated toxicity.

  Caution should be exercised when DaunoXome is used concomitantly with other myelosuppressive or cardiotoxic agents.

• Adverse Drug Reactions
  

  The adverse reactions considered at least possibly related to treatment with DaunoXome are listed below, by body system organ class and absolute frequency. Frequencies are defined as follows: very common 10%; common 1% and < 10%; uncommon 0.1% and < 1%; rare 0.01% and < 0.1%, very rare <0.01%.

  INFECTIONS AND INFESTATIONS

  Very common: infections

  Uncommon: sepsis, septic shock

  BLOOD AND LYMPHATIC SYSTEM DISORDERS

  Very common: bone marrow suppression, agranulocytosis, neutropenia, febrile neutropenia, leucopenia, pancytopenia, thrombocytopenia and anemia

  IMMUNE SYSTEM DISORDERS

  Very common: infusion-associated reactions (including back pain, flushing, chest tightness, dyspnoea, allergic reactions) 

  Rare: anaphylactic reaction

  METABOLISM AND NUTRITIONAL DISORDERS

  Common: dehydration

  PSYCHIATRIC DISORDERS

  Common: depression

  NERVOUS SYSTEM DISORDERS

  Very common: headache

  Common: dizziness

  CARDIAC DISORDERS:

  Common: decreased left ventricular ejection fraction

  Uncommon: congestive heart failure, cardiomyopathy

  Rare: atrial fibrillation, myocardial infarction

  RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

  Very common: dyspnoea

  GASTROINTESTINAL DISORDERS:

  Very common: stomatitis, mucous ulcerations, nausea, vomiting, diarrhoea, abdominal pain

  SKIN AND SUBCUTANEOUS TISSUE DISORDERS

  Very common: alopecia

  Rare: palmar-plantar erythrodysaesthesia syndrome (see below)

  Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been reported rarely in patients treated with high dose DaunoXome and cytarabine for leukaemia. The condition is characterised by swelling, pain, tingling and erythema of the palms and soles, which may lead to desquamation of the skin in some patients. Dose reduction or delayed dosing may be required to manage the condition.

  GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:

  Very common: asthenia, fatigue, fever, chills

  Common: extravasation at the injection site may result in erythema, pain and swelling