Doxorubicin encapsulated in liposomes parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Concentrate for solution for infusion of doxorubicin hydrochloride in a pegylated liposomal formulation
Drugs List
Therapeutic Indications
Uses
Advanced ovarian cancer - second line treatment
Kaposi's sarcoma (AIDS related) with CD4 <200/mm3 + extensive disease
Metastatic breast cancer
Treatment of multiple myeloma in combination with bortezomib
Monotherapy treatment for metastatic breast cancer where there is an increased cardiac risk
Advanced ovarian carcinoma in women who have failed a first-line platinum-based chemotherapy regimen
AIDS related Kaposi's sarcoma in patients with CD4 less than 200/cubic millimetre and extensive mucocutaneous or visceral disease
First line systemic chemotherapy or second line chemotherapy in AIDS related Kaposi's sarcoma patients with disease that has progressed with, or in patients intolerant to prior combination systemic chemotherapy comprising at least 2 of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline)
Progressive multiple myeloma in combination with bortezomib, in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant.
Dosage
Liposomal doxorubicin should not be used interchangeably with other formulations of doxorubicin hydrochloride.
The risk of delayed cardiomyopathy rises with increasing exposure to doxorubicin. Cumulative lifetime doses of 450 mg/square metre should not be exceeded (some sources quote a limit of 450 to 550 mg/square metre).
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
Breast cancer/ovarian cancer:
50 mg/square metre body surface area should be administered intravenously once every 4 weeks until disease progression or unacceptable toxicity.
Multiple myeloma:
30 mg/square metre on day 4 of the bortezomib 3 week regimen, as a 1 hour intravenous infusion administered immediately after the bortezomib infusion, until disease progression or unacceptable toxicity.
The bortezomib regimen is 1.3 mg/square metre on days 1, 4, 8 and 11 every 3 weeks.
Day 4 dosing of both products may be delayed up to 48 hours as medically necessary.
AIDS-related Kaposi's sarcoma:
20 mg/square metre should be administered intravenously every 2 to 3 weeks for 2 to 3 months to achieve a therapeutic response. Dose intervals should be more than 10 days to avoid accumulation.
Treatment should be continued as needed to maintain a therapeutic response.
Patients with Hepatic Impairment
Bilirubin between 1.2 to 3.0 mg/dl: Reduce first dose by 25%.
Bilirubin greater than 3.0 mg/dl: Reduce first dose by 50%.
If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e. if reduced by 25% for the first dose, increase to full dose for cycle 2. If reduced by 50% for the first dose, increase to 75% of the full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated.
Liposomal doxorubicin can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 times the upper limit of normal.
Additional Dosage Information
Suspend infusion immediately if the patient experiences early symptoms or signs of infusion reaction and treat appropriately with antihistamines and/or short acting corticosteroid. Restart the infusion once symptoms have resolved at a slower rate.
The guidelines for PPE and stomatitis provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle).
If these toxicities occur in patients with AIDS related Kaposi's sarcoma the recommended 2 to 3 week treatment cycle can be modified in a similar manner.
Dose modification guidelines in palmar-plantar erythrodysaesthesia (PPE)
Grade 1 (mild erythema, swelling or desquamation not interfering with daily activities)
Week 4 or 5: Redose unless the patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week.
Week 6: Decrease dose by 25% and return to 4 week interval.
Grade 2 (erythema, desquamation or swelling interfering with but not precluding normal physical activities; small blisters or ulcerations less than 2cm in diameter)
Week 4 or 5: Wait an additional week.
Week 6: Decrease dose by 25% and return to 4 week interval.
Grade 3 (blistering, ulceration or swelling interfering with walking or normal daily activities; cannot wear regular clothing)
Week 4 or 5: Wait an additional week.
Week 6: Discontinue treatment.
Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalisation)
Week 4 or 5: Wait an additional week.
Week 6: Discontinue treatment.
Dose modification guidelines in stomatitis
Grade 1 (painless ulcers, erythema or mild soreness)
Week 4 or 5: Redose unless the patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week.
Week 6: Decrease dose by 25% and return to 4 week interval or discontinue treatment based on clinical judgement.
Grade 2 (painful erythema, oedema or ulcers but can eat)
Week 4 or 5: Wait an additional week
Week 6: Decrease dose by 25% and return to 4 week interval or discontinue treatment based on clinical judgement.
Grade 3 (painful erythema, oedema or ulcers and cannot eat)
Week 4 or 5: Wait an additional week
Week 6: Discontinue treatment.
Grade 4 (requires parenteral or enteral support)
Week 4 to 5: Wait an additional week
Week 6: Discontinue treatment.
Dose modifications in haematological toxicity
The guidelines for haematologic toxicity provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only.
Grade 1 (ANC 1,500 to 1,900 and/or platelets 75,000 to 150,000)
Resume treatment at normal dose.
Grade 2 (ANC 1,000 to 1,500 and/or platelets 50,000 to 75,000)
Wait until ANC greater than or equal to 1,500 and platelets greater than or equal to 75,000, redose at normal dose.
Grade 3 (ANC 500 to 1,000 and/or platelets 25,000 to 50,000)
Wait until ANC greater than or equal to 1,500 and platelets greater than or equal to 75,000, redose at normal dose.
Grade 4 (ANC less than 500 and/or platelets less than 25,000)
Wait until ANC greater than or equal to 1,500 and platelets greater than or equal to 75,000, decrease dose by 25% or continue full dose with growth factor support.
In the treatment of AIDS-related KS patients, treatment should be suspended when ANC less than 1,000 and platelets less than 50,000 and G-CSF should be administered.
Dose modifications in the treatment of multiple myeloma in combination with bortezomib
For details on bortezomib dosing and dosage adjustments see the SPC for bortezomib.
Fever 38 degrees C and above, and ANC less than 1,000/cubic millimetre
Do not dose this cycle if before day 4; if after day 4, reduce next dose by 25%. Reduce next bortezomib dose by 25%
On any day of medicine administration after Day 1 of each cycle if platelet count less than 25,000/cubic millimetre, haemoglobin less than 8 g/dl, ANC less than 500/cubic millimetre
Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for haematological toxicity.
Grade 3 or 4 non-haematological medicine related toxicity
Suspend treatment until symptoms resolve to grade 2 or less, reduce dose by 25% for all subsequent doses.
Neuropathic pain or peripheral neuropathy
No dosage adjustment for doxorubicin; see information on bortezomib.
Administration
For intravenous infusion only.
It is recommended that the infusion line is connected through the side port of an intravenous infusion of 5% glucose, into a peripheral vein.
Breast/ovarian cancer and multiple myeloma
To minimise the risk of infusion reactions, the initial dose should be administered at a maximum rate of 1 mg/minute. If no infusion reaction is noted, subsequent infusions may be administered over a 60 minute period.
For patients that do experience an infusion reaction, the method of infusion should be modified as follows:
5% of the total dose should be infused slowly over the first 15 minutes. If tolerated, the infusion rate may be doubled for the next 15 minutes. If this is tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.
AIDS - related Kaposi's sarcoma
The dose of liposomal doxorubicin should be diluted in 250 ml of glucose 5% solution for infusion and administered over 30 minutes.
Contraindications
Children under 18 years
Breastfeeding
Pregnancy
Severe hepatic impairment
Splenectomy - AIDS related Kaposi's sarcoma patients
Precautions and Warnings
Elderly
History of mediastinal radiotherapy
History of treatment with anthracyclines
Within 7 months of discontinuing trastuzumab
Cardiac impairment
Diabetes mellitus
Hepatic impairment
Hypertension
Severe myelosuppression
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Consider premedication for patients with history of infusion reactions
Consider previous/concomitant cardiotoxic therapy in total doxorubicin dose
Treatment to be prescribed under the supervision of a specialist
Contains soya or soya derivative
Different formulations are not bioequivalent
Consult local policy on the safe use of anti-cancer drugs
Interrupt treatment if infusion reaction occurs & monitor until resolution
Resuscitation facilities must be immediately available
Staff: Not to be handled by pregnant staff
Measurement of LV ejection fraction recommended before and during treatment
Monitor hepatic function before treatment and regularly during treatment
Consider endomyocardial biopsy if anthracycline myocardial injury suspected
ECG reduction of QRS wave is considered indicative of cardiotoxicity
Evaluate benefit of continued therapy if LVEF has decreased from baseline
Monitor ECG
Monitor haematological parameters regularly throughout treatment
Severe cardiac failure may occur, without premonitory ECG changes
Advise patient to report oral ulceration and/or discomfort
Cardiac failure may occur weeks after administration & may resist treatment
Consider dose reduction if severe haematological events occur
Interrupt therapy/reduce dose if grade 3 or worse skin reaction occurs
Interrupt therapy/reduce dose if palmar-plantar erythrodysaesthesia occurs
Lifetime cumulative dose should be limited to 550mg/m squared
Male & female: Contraception required during & for 6 months after treatment
Secondary acute myeloid leukaemias and myelodysplasia have been reported in patients having received combined therapy with doxorubicin. Patients treated with doxorubicin should be kept under haematological supervision.
Cardiotoxicity
Before and periodically during treatment, a measurement of left ventricular ejection fraction by echocardiography or preferably by multigated angiography should be taken. An evaluation of left ventricular ejection fraction is considered mandatory before any administration of liposomal doxorubicin that exceeds a lifetime cumulative anthracycline dose of 450 mg/square metre.
Evaluation tests and methods concerning the monitoring of cardiac performance should occur in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy.
If test results indicate possible cardiac injury associated with therapy, the benefit of continued therapy must be weighed against the risk of myocardial injury.
Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also occur several weeks after discontinuation of treatment.
The total dose of doxorubicin should take into account any previous or concomitant therapy with cardiotoxic compounds (e.g. 5-fluorouracil) and other anthracyclines/anthraquinones.
Cardiac toxicity may occur at cumulative doses lower than 450 mg/square metre in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.
Pregnancy and Lactation
Pregnancy
Liposomal doxorubicin is contraindicated during pregnancy.
Doxorubicin is suspected to cause serious birth defects in human pregnancy. Animal studies have shown structural anomalies and foetal death when used during pregnancy.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Liposomal doxorubicin is contraindicated in breastfeeding.
Doxorubicin is excreted in human breast milk. As doxorubicin may interfere with the cellular metabolism of the nursing infant, breastfeeding is not recommended. Schaefer recommends withholding breastfeeding for at least 7 days after maternal dosing.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Acne
Acute myeloid leukaemia
Alopecia
Anaemia
Anaphylactic reaction
Anorexia
Anxiety
Asthma
Blurred vision
Breast pain
Bullous eruption
Cachexia
Chest pain
Chills
Confusion
Congestive cardiac failure
Conjunctivitis
Constipation
Convulsions
Cough increased
Dehydration
Depression
Dermatitis
Diarrhoea
Dizziness
Dry mouth
Dry skin
Dyspepsia
Dysphagia
Dyspnoea
Dysuria
ECG changes
Electrolyte disturbances
Elevation of liver enzymes
Epistaxis
Erythema
Erythema multiforme
Extravasation necrosis
Fatigue
Fever
Flushing
Folliculitis
Gastritis
Gastro-intestinal symptoms
Gingivitis
Glossitis
Headache
Hypertension
Hypertonia
Hypotension
Injection site reactions
Insomnia
Lacrimation
Leg cramps
Leucopenia
Maculopapular rash
Malaise
Mucositis
Musculoskeletal pain
Myalgia
Myelosuppression
Nail disorders
Nausea
Neuropathy
Oedema
Oesophagitis
Opportunistic infections
Palmar-plantar erythrodysaesthesia
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Pharyngitis
Pneumonia
Pruritus
Radiation recall dermatitis
Rash
Retinitis
Sepsis
Serum creatinine increased
Shortness of breath
Skin pigmentation changes
Skin ulcer
Stevens-Johnson syndrome
Stomatitis
Sweating
Tachycardia
Taste disturbances
Thrombocytopenia
Tightness of chest and/or throat
Toxic epidermal necrolysis
Upper respiratory tract infection
Urinary tract infections
Urticaria
Vaginitis
Vasodilatation
Ventricular arrhythmias
Vesiculo-bullous reactions
Vomiting
Weakness
Weight loss
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).
Further Information
Last Full Review Date: April 2015
Reference Sources
Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 26 March 2015.
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8th edition (2008) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Summary of Product Characteristics: Caelyx 2mg/ml Concentrate for Solution for Infusion. Janssen-Cilag. Revised May 2018.
The Renal Drug Handbook. 2nd edition. (2004) ed. Ashley, C and Currie, A. Radcliffe Medical Press, Abingdon.
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