Doxorubicin Hydrochloride (Hospira)

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Doxorubicin hydrochloride 10 mg
Available from:
Pfizer New Zealand Limited
INN (International Name):
Doxorubicin hydrochloride 10 mg
Dosage:
10 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Doxorubicin hydrochloride 10 mg Excipient: Lactose monohydrate
Units in package:
Vial, 10 mg
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Microbiopharm Japan Co Ltd
Therapeutic indications:
Doxorubicin has produced significant therapeutic responses in a number of solid tumours and haematologic malignancies, and is commonly used in the treatment of the following tumours: · carcinoma of the breast · carcinoma of the lung · carcinoma of the ovary · transitional bladder cell cancer · neuroblastoma · Wilms' tumour · soft tissue sarcomas · osteosarcoma · acute lymphocytic - lymphoblastic leukaemia · acute myelogenous leukaemia · non-Hodgkin's lymphoma · Hodgkin's disease Doxorubicin has also shown antitumour activity in the following adult and paediatric malignancies: · carcinoma of the thyroid · carcinoma of the endometrium · carcinoma of the head and neck · carcinoma of the stomach · primary hepatocellular carcinoma · non-seminomatous carcinoma of the testis · carcinoma of the prostate · Ewing's sarcoma · rhabdomyosarcoma · multiple myeloma · chronic leukaemias
Product summary:
Package - Contents - Shelf Life: Vial, - 10 mg - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-4858/1
Authorization date:
1991-06-27

Version pfddoxoa10219

Page 1 of 16

NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

DBL™ Doxorubicin hydrochloride Injection

Doxorubicin Hydrochloride (Hospira) for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

DBL™ Doxorubicin hydrochloride Injection is supplied in solution form containing sodium

chloride.

Doxorubicin hydrochloride (Hospira) for Injection is supplied as a freeze dried product

containing Lactose as an excipient.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

DBL™ Doxorubicin hydrochloride Injection is a solution for injection

Doxorubicin Hydrochloride (Hospira) is a Powder for injection

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Doxorubicin has produced significant therapeutic responses in a number of solid tumours and

haematologic malignancies, and is commonly used in the treatment of the following tumours:

carcinoma of the breast

carcinoma of the lung

carcinoma of the ovary

transitional cell bladder cancer

neuroblastoma

Wilm's tumour

soft tissue sarcomas

osteosarcoma

Version pfddoxoa10219

Page 2 of 16

acute lymphocytic - lymphoblastic leukaemia

acute myelogenous leukaemia

non-Hodgkin's lymphoma

Hodgkin's disease

Doxorubicin

also

shown

antitumour

activity

following

adult

paediatric

malignancies:

carcinoma of the thyroid

carcinoma of the endometrium

carcinoma of the head and neck

carcinoma of the stomach

primary hepatocellular carcinoma

non-seminomatous carcinoma of the testis

carcinoma of the prostate

Ewing's sarcoma

rhabdomyosarcoma

multiple myeloma

chronic leukaemias

4.2 Dose and method of administration

Doxorubicin is a cytotoxic drug that is usually administered to cancer patients by the

intravenous and, whenever appropriate, intravesical and intra-arterial routes.

Intravenous (IV) Administration:

Dosage is usually calculated on the basis of body surface area (mg/m

). The doxorubicin

dose-schedule to be delivered may differ depending on the therapeutic indication (e.g. solid

tumours or acute leukaemias) as well as on its use within a specific regimen (e.g. as a single

agent or in combination with other cytotoxics or as a part of multidisciplinary approaches

which include combination with surgery and/or radiotherapy and/or hormonotherapy).

Intravenous

administration

doxorubicin

should

performed

with

caution.

recommended to administer doxorubicin into the tubing of a freely flowing IV infusion

(isotonic sodium chloride or 5% glucose solution) over a period of 3 to 5 minutes. This

technique is intended to minimize the risk of thrombosis or perivenous extravasation which

could lead to severe cellulitis, vesication and tissue necrosis. A direct push injection is not

Version pfddoxoa10219

Page 3 of 16

recommended due to the risk of extravasation, which may occur even in the presence of

adequate blood return upon needle aspiration.

Treatment of solid tumours: When doxorubicin is administered as a single

agent, the

recommended dose per cycle is 60-75mg/m

every three weeks. The drug is generally given

as a single dose per cycle; however, it is possible to give the drug dosage per cycle in divided

administrations (e.g. day 1 through 3, or days 1 and 8).

Administration of doxorubicin in a weekly regimen has been shown to be as effective as the

tri-weekly schedule. The recommended weekly dosage is 10-20mg/m

; this schedule of

administration might be accompanied by reduced toxicity, particularly on the heart.

doxorubicin

used

combination

with

other

antitumour

agents

with

potentially

overlapping toxicities, the recommended dose per cycle is in the 30-60mg/m

range.

As doxorubicin is a myelosuppressive agent, the interval between cycles may need to be

increased,

drug

dosage

reduced,

patients

whose

counts

(particularly

neutrophils) are below the range of normal values before any treatment cycle. Dosage may

also need to be reduced in children, in the elderly, and in pre-treated patients in whom the

marrow reserve might be low.

In the presence of impaired hepatic function it is suggested to reduce doxorubicin dosage (see

section 4.4).

Treatment of acute leukaemias: In the management of acute leukaemias, bone marrow aplasia

therapeutic

achievement

intensive

combination

chemotherapy

schedules

employed. In this situation the recommended dose of doxorubicin is 2.4mg/kg of body weight

(approximately

corresponding

75-90mg/m

administered

divided

over

three

consecutive days (one cycle). The time and dose of the second cycle should be dictated by

both the bone marrow and peripheral blood cells status. The interval between cycles should

be however at least 10 days.

Intravesical Administration:

Doxorubicin administered intravesically can be used for the treatment of superficial bladder

tumours

prophylaxis

reduce

recurrence

after

trans-urethral

resection.

recommended doxorubicin dose for topical intravesical treatment of superficial bladder

cancer is 30 to 50mg in 25 - 50mL of saline solution per instillation, with the optimal

concentration being in the 1.0mg/mL range. Once the instillation has been completed, the

patients should be rotated a quarter turn every fifteen minutes. Generally, the instillate should

be retained in the bladder for 1-2 hours. To avoid undue dilution with urine, the patients

should be instructed not to drink any fluid in the twelve hours prior to instillation (this should

limit urine production to approximately 50mL/hour). Instillations can be repeated at intervals

which can vary from one week to one month, depending on whether the treatment is

therapeutic or prophylactic. The systemic absorption of doxorubicin following intravesical

instillation is very low.

Intra-arterial Administration:

Doxorubicin has been also used by the intra-arterial route in an attempt to produce intense

local activity with reduced general toxicity. Since this technique is potentially hazardous and

Version pfddoxoa10219

Page 4 of 16

can lead to widespread necrosis of the perfused tissue, intra-arterial administration should

only be attempted by those physicians fully trained with this technique.

Intravenous administration

Doxorubicin is usually administered intravenously. The solution should be injected over 3 to

5 minutes through the tubing of a freely-running infusion of physiological solution, after

confirmation that the needle is correctly inserted into the vein. This technique reduces the risk

of thrombosis and perivenous extravasation of the drug that can lead to severe cellulitis and

necrosis, and ensures the washing of the vein after administration. Injection in small veins

and repeated injection in the same vein can lead to venous sclerosis.

Preparation of Doxorubicin Hydrochloride for Injection

The contents of the vial for Doxorubicin Hydrochloride for Injection should be reconstituted

with Water for Injection, Sodium Chloride 0.9% or Dextrose 5% injection to a solution

concentration of 2 mg per mL.

The reconstituted solution is stable at room temperature, in the vial or in a polypropylene

(Terumo) syringe, in the presence or absence of light for a period of 48 hours. However, it is

recommended that the solution be stored at 2 to 8°C in a refrigerator, and used within 24 hours,

in line with good pharmaceutical practice.

4.3 Contraindications

Situations in which patients should not be treated with IV intravenous doxorubicin are:

persisting myelosuppression or severe stomatitis from previous cytotoxic treatments;

presence of generalized infections;

marked liver function impairment;

severe arrhythmias, myocardial insufficiency, previous myocardial infarction;

previous treatment with anthracyclines up to their maximum cumulative dose;

hypersensitivity to doxorubicin or to other anthracyclines; or anthracenediones

Contraindications for intravesical use are:

invasive tumours that have penetrated the bladder wall;

urinary infections;

inflammation of the bladder;

catheterization problems (e.g. due to massive intravesical tumours).

haematuria

Version pfddoxoa10219

Page 5 of 16

4.4 Special warnings and precautions for use

Treatment with doxorubicin should be carried out only by physicians experienced in cancer

treatment and must be conducted under strict supervision, with a number of body functions

being carefully monitored. Doxorubicin is not a microbial agent.

Complete blood cell counts: These have to be performed with particular attention to total and

differential

counts.

Doxorubicin-induced

bone

marrow

depression,

primarily

leucocytes,

requires

careful

haematologic

monitoring

since

persistent

severe

myelo-

suppression

result

superinfections

haemorrhages.

doses/

schedules

recommended for the treatment of solid tumours, a marked leucopenia may occur (WBC

counts

1000/mm

lower

expected

during

treatment

with

full

doses

doxorubicin), but such leucopenia is usually transient, reaching its nadir 10 to 14 days after

treatment and with recovery usually completed by the 21st day. Platelet and erythrocyte

levels should also be monitored. Haematologic toxicity may require dose reduction or

suspension or delay of doxorubicin therapy. When using doxorubicin as part of chemotherapy

regimens which combine drugs of similar pharmacological effects (i.e. cytotoxicity) additive

toxicity is likely to occur. Such additive toxicity has to be taken into consideration especially

with

regard

bone

marrow

function.

Doxorubicin

powerful

temporary

immunosuppressant agent. Appropriate measures should be taken to prevent secondary

infection. Persistent severe myelosuppression may result in superinfection or haemorrhage.

Assessment of liver function: Since doxorubicin is predominantly eliminated via the liver

and bile, a delayed elimination of the drug can occur in the case of reduced liver function or

difficult bile outflow and serious secondary effects can develop. Commonly used guidelines

for dose reduction under conditions of impaired liver function in adult patients are based on

serum bilirubin levels as follows:

Serum bilirubin levels

BSP retention

Recommended dose

20 to 50 micromoles/L

9 to 15 %

½ normal dose

Over 50 micromoles/L

Over 15 %

¼ normal dose

Changes in hepatic function induced by concomitant therapies, either given to achieve

optimal antitumour efficacy or given for the pharmacological management of concomitant

diseases, may

affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy or

toxicity.

Cardiac Function: Cardiotoxicity is a known risk of anthracycline treatment. The most

severe and typical form of such toxicity is represented by a delayed cardiomyopathy which

occurs with increased frequency with high cumulative doses of the drug and can result in

congestive heart failure (CHF). Cardiac function should be assessed before undergoing

treatment with doxorubicin and has to be monitored throughout therapy to minimize the risk

of incurring severe cardiac impairment. Although endomyocardial biopsy is recognized as the

most

appropriate

diagnostic

tool

detect

anthracycline-induced

cardiomyopathy,

this

invasive examination may not be easily carried out on a routine basis.

Version pfddoxoa10219

Page 6 of 16

routine

assessment

cardiac

function

during

doxorubicin

treatment

include

electrocardiogram (ECG) and the evaluation of the left ventricular ejection fraction (LVEF).

ECG changes are generally indicative of a transient toxicity, but a reduction of the QRS

voltage, or a prolongation beyond normal limits of the systolic time interval may be

indicative - as is a decrease of the LVEF - of typical anthracycline-induced cardiomyopathy.

The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of

300mg/m

, slowly increases up to the total cumulative dose of 450-550mg/m

; thereafter the

risk of developing CHF increases steeply, and it is recommended not to exceed the total

cumulative dose of 550mg/m

If any additional risk factor for cardiac toxicity is present, cardiac toxicity might occur at

lower cumulative doses and the monitoring of cardiac function must be particularly strict.

Risk

factors

cardiac

toxicity

include

previous

history

heart

disease,

prior

concomitant

radiotherapy

mediastinal/pericardial

area,

previous

treatments

with

anthracyclines or anthracenediones, concomitant use of other cardioactive compounds (e.g.

calcium channel blocking drugs) or concomitant use of other potentially cardiotoxic drugs

(e.g.

cyclophosphamide,

5-fluorouracil

trastuzumab).

Anthracyclines

including

doxorubicin should not be administered in combination with other cardiotoxic agents unless

the patient's cardiac function is closely monitored. Patients receiving anthracyclines after

stopping treatment with other cardiotoxic agents, especially those with long half-lives such as

trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of

trastuzumab is approximately 28.5 days and may persist in the circulation for up to 24 weeks.

Therefore, physicians should avoid anthracycline-based therapy for up to 24 weeks after

stopping trastuzumab when possible. If anthracyclines are used before this time, careful

monitoring of cardiac function is recommended.

Doxorubicin induced cardiotoxicity mostly develops during the course of therapy up to two

months

from

termination

late

events

(several

months

years

after

treatment

termination)

have

occurred.

Delayed

cardiomyopathy

manifested

reduced

left

ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure

(CHF)

such

dyspnea,

pulmonary

oedema,

dependent

oedema,

cardiomegaly

hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as

pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe

form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting

toxicity of the drug.

Extravasation and rate of administartion: Extravasation of doxorubicin during IV injection

may give ride to severe tissue lesions and necrosis. Venous sclerosis may result from

injection into a small vessel or from repeated injections into the same vein. To minimize the

risk of drug extravasation and make sure that the vein is properly flushed after drug

administration, it is advisable to give the drug via the tubing of a freely running saline

infusion after checking that the needle is properly placed in the vein.

The rate of administration is dependent on the size of the vein and the dosage. It is important

that the dose be administered in not less than 3-4 minutes. Local erythematous streaking

along the vein as well as facial flushing may be indicative of too rapid administration.

Should signs of symptoms of extravasation occur during intravenous administration of

doxorubicin, the drug infusion should be immediately terminated. To manage extravasation,

the interventions approved by the physician and/or the health care institution must be

immediately utilized.

Version pfddoxoa10219

Page 7 of 16

Tumour-Lysis

Syndrome:

Like

other

cytotoxic

drugs,

doxorubicin

induce

hyperuricaemia secondary to rapid lysis of neoplastic cells (tumour-lysis syndrome).The

clinician should monitor the patient's blood uric acid level, potassium, calcium phosphate and

creatinine, and be prepared to use such supportive and pharmacologic measures as might be

necessary to control this problem. Hydration, urine alkalinisation, and prophylaxis with

allopurinol to prevent hyperuricaemia may minimise potential complications of tumour-lysis

syndrome.

Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of

cyclophosphamide-induced

haemorrhagic

cystitis

enhanced

hepatotoxicity

mercaptopurine have been reported. Radiation-induced toxicities (myocardium, mucosae,

skin and liver) have also been reported to increase.

Administration

live

live-attenuated

vaccines

patients

immunocompromised

chemotherapeutic agents including doxorubicin, may result in serious or fatal infections.

Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed

or inactivated vaccines may be administered; however, the response to such vaccines may be

diminished.

Concurrent use of doxorubicin with live virus vaccines may potentiate the replication of the

vaccine virus, increase adverse effects of the vaccine, and /or may decrease the patient’s

antibody response to the vaccine. Doxorubicin may also decrease the patient’s antibody

response to killed virus vaccines. The interval between discontinuation of medications that

cause immunosuppression and restoration of the patient’s ability to respond to the vaccine

depends on many factors; estimates vary from three months to one year.

It has been reported that doxorubicin may enhance the severity of the toxicity of anticancer

therapies such as: cyclophosphamide induced haemorrhagic cystitis, mucositis induced by

radiotherapy,

hepatotoxicity

6-mercaptopurine.

Radiation-induced

toxicities

(myocardium, mucosae, skin and liver) have also been reported.

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including

pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of

doxorubicin.

The systemic clearance of doxorubicin has been found to be reduced in obese patients; such

patients have to be carefully monitored if undergoing treatment with full doses of the drug.

Doxorubicin may impart a red colour to the urine. Patients should be advised that such an

event should not be cause for alarm.

Other

Dental Work: Patients should not undergo dental work during treatment with Doxorubicin.

4.5 Interaction with other medicines and other forms of interaction

Doxorubicin is mainly used in combination with other cytotoxic drugs and additive toxicity

may occur especially with regard to bone marrow/haematologic and gastro-intestinal effects.

In addition, the concomitant use of doxorubicin and other antitumour drugs which have been

reported as potentially cardiotoxic (e.g. 5-fluorouracil, cyclophosphamide, cisplatin, taxanes),

Version pfddoxoa10219

Page 8 of 16

as well as the concomitant use of other cardioactive compounds (e.g. calcium channel

blockers), requires a close monitoring of cardiac function throughout treatment.

Doxorubicin is extensively metabolized by the liver. Changes in hepatic function induced by

concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic

efficacy and/or toxicity.

Sorafenib: both increases (21% - 47%) and no change in the AUC of doxorubicin were

observed

with concomitant treatment

with sorafenib 400 mg twice

daily. The

clinical

significance of these findings is unknown.

4.6 Fertility, pregnancy and lactation

Fertility

Doxorubicin

cause

infertility

during

time

drug

administration.

women,

doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return

after termination of therapy, premature menopause can occur.

Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular

atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia.

Pregnancy

safe

doxorubicin

pregnancy

been

established.

Doxorubicin

embryotoxic and teratogenic in rats; it is embryotoxic and may induce abortion in rabbits.

Women

child-bearing

potential

undergo

doxorubicin

therapy

should

appraised of the potential hazard to the foetus and should be advised to avoid becoming

pregnant during treatment. If doxorubicin has to be used during pregnancy, the potential

benefits of the treatment must be carefully weighed against the possible risks to the foetus.

Given the mutagenic potential of doxorubicin, the drug could induce chromosomal damage in

human spermatozoa; therefore, males undergoing doxorubicin treatment should employ

contraceptive measures.

Lactation

Doxorubicin is secreted into breast milk, therefore doxorubicin-treated women should be

instructed not to breast-feed due to the potential for serious harm to nursing infants.

4.7 Effects on ability to drive and use machinery

There have been no reports of particular adverse events relating to effects of doxorubicin

treatment on the ability to drive or use machines.

4.8 Undesirable effects

Bone

Marrow/Haematologic

Toxicity:

dose-dependent,

reversible

leucopenia

and/or

granulocytopenia

(neutropenia)

predominant

manifestation

doxorubicin

bone

marrow/ haematologic toxicity and represents the acute dose-limiting toxicity of this drug.

Version pfddoxoa10219

Page 9 of 16

During

most

commonly

used

week

administration

schedule

nadir

leucocytes/granulocytes is generally reached 10 to 14 days following drug administration. In

patients with normal bone marrow regenerative capacity, white blood cell counts usually

recover by the end of the third week. If severe myelosuppression occurs, bone marrow

support (e.g. peripheral blood progenitor cells and/or colony-stimulating factors) may be

used. Thrombocytopenia and anaemia may also occur.

Clinical consequences of doxorubicin bone marrow/haematologic toxicity may be fever,

infections,

sepsis/septicemia,

septic

shock,

haemorrhages,

tissue

hypoxia

death.

Intravenous antibiotics should be given in the presence of febrile neutropenia. The occurrence

of secondary acute myelogenous leukaemia, with or without a pre-leukaemic phase, has been

reported rarely in patients concurrently treated with doxorubicin in combination with DNA-

damaging antineoplastic agents. These leukaemias can have a short (1-3 years) latency

period.

Cardiac Toxicity: Anthracycline-induced cardiac toxicity may be manifested by early (or

acute) or late (delayed) events. The early cardiac toxicity of doxorubicin mainly consists of

sinus tachycardia and/or ECG abnormalities, e.g. non-specific ST-T wave changes, but

tachyarrhythmias

such

premature

ventricular

contractions,

ventricular

tachycardia,

bradycardia as well as atrioventricular and bundle-branch block have also been reported.

With the exception of malignant cardiac dysrhythmias, these effects are usually not predictive

of subsequent development of delayed cardiotoxicity, are rarely of clinical importance and

are generally not considered an indication for the suspension of doxorubicin treatment. The

delayed cardiac toxicity is represented by a characteristic cardiomyopathy which clinically is

manifested by symptoms/signs of ventricular dysfunction/CHF (such as dyspnoea, pulmonary

oedema, dependent [e.g. ankle] oedema, hepato-megaly, ascites, pleural effusion, gallop

rhythm). This toxicity appears to be dependent on the cumulative dose of doxorubicin and

represents the cumulative dose-limiting toxicity of the drug. A number of studies have

assessed that the risk of developing CHF increases steeply, in absence of other cardiac risk

factors, after having reached a doxorubicin cumulative dose of 550mg/m

; however, if any

additional risk factor for cardiac toxicity is present (e.g. active or dormant cardiovascular

disease, previous mediastinal radiotherapy, previous/concomitant use of other cardiotoxic

drugs) cardiac toxicity might occur at lower cumulative doses. Delayed cardiotoxicity mainly

develops

during

course

therapy

with

doxorubicin

two-three

months

afterwards,

late

events

(several

months

years

after

treatment

termination)

have

occurred. Serious cardiac impairment may be prevented through regular surveillance during

course

treatment

(see

also

section

4.4).

Subacute

effects

such

pericarditis/myocarditis have also been reported.

Gastrointestinal Toxicity: Mucositis (mainly stomatitis, less often esophagitis) may occur in

patients undergoing doxorubicin therapy. Clinical manifestations of mucositis include pain or

burning sensation, erythema, erosions-ulcerations, bleeding, infections. Stomatitis generally

appears early after drug administration and, if severe, may progress over a few days to

mucosal ulcerations; however, most patients recover from this adverse event by the third

week of therapy. Nausea, vomiting and, occasionally, diarrhoea and abdominal pain can also

occur. Severe vomiting and diarrhoea may produce dehydration. Nausea and vomiting may

prevented

alleviated

administration

appropriate

antiemetic

therapy.

combination of doxorubicin and cytarabine has given rise to bleeding, ulceration and necrosis

of the colonic mucosa in patients with acute myelogenous leukaemia.

Version pfddoxoa10219

Page 10 of 16

Cutaneous and Hypersensitivity Reactions: Alopecia, including the interruption of beard

growth, occurs frequently. This side effect is usually reversible, with regrowth of all hair

occurring within two-three months from the termination of therapy. Flushes, skin and nail

hyperpigmentation and hypersensitivity to irradiated skin ('radiation recall reaction') may also

occur.

Urticaria

anaphylaxis

have

been

reported

doxorubicin-treated

patients;

signs/symptoms of these reactions may vary from skin rash and pruritus to fever, chills and

shock. The 'hand-foot syndrome' ('palmar-plantar erythrodysaesthesia', or 'acral erythema')

has also been reported.

Effects at Site of Injection: Erythematous streaking along the infused vein is not uncommon

and may precede local phlebitis or thrombophlebitis. The risk of phlebitis/thrombophlebitis at

injection

site

minimised

following

procedure

administration

recommended in Warnings and Precautions. Phlebosclerosis might also occur, particularly if

doxorubicin is repeatedly infused into a small vein.

In the case of perivenous drug extravasation, local pain, severe cellulitis and tissue necrosis

will occur (see section 4.4).

Other Adverse Reactions: Other adverse events include malaise/ asthenia, ocular toxicity

(conjunctivitis, lacrimation) and hyperuricemia, which may occur as a consequence of the

extensive

purine

catabolism

which

accompanies

drug-induced

rapid

cell

kill

highly

chemosensitive neoplasms ('tumour lysis syndrome'); hydration, urine alkalinization and

allopurinol

administration

will

help

prevent

minimize

adverse

effects

hyperuricemia.

Amenorrhoea may also occur and doxorubicin treatment may result in azoospermia in the

seminal fluid.

Administration of doxorubicin by the intravesical route may give rise to chemical cystitis and

bladder constriction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Acute

overdosage

with

doxorubicin

will

result

severe

myelosuppression

(mainly

leucopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute

cardiac alterations.

Treatment

acute

overdosage

consists

hospitalization,

intravenous

antibiotics,

granulocyte and platelet transfusions and treatment of the gastrointestinal and cardiac toxic

manifestations. The use of haematopoietic

growth factors may be considered. Chronic

overdosage, when total cumulative doses exceed 550mg/m

, increases the risk of cardio-

myopathy and could result in CHF. For such an occurrence, treatment is that for CHF,

consisting of digitalis preparations, diuretics, peripheral vasodilators and ACE inhibitors.

Version pfddoxoa10219

Page 11 of 16

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The chemical structure is shown below.

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic isolated from cultures of

Streptomyces peucetius var. caesius. The chemical structure of doxorubicin consists of a

tetracyclic ring, with the sugar daunosamine attached by a glycosidic linkage. Structurally,

doxorubicin is related to daunomycin (daunorubicin) and differs only in hydroxyl group

substitution (instead of hydrogen) at the alkyl side chain, at position ‘9' of the ‘A' ring.

Mechanism of action

Although it is known that anthracyclines are able to interfere with a number of biochemical

and biological functions within eukaryotic cells, the precise mechanisms of doxorubicin

cytotoxic and/or antiproliferative properties have not been completely elucidated. The drug,

once penetrated into a cell, mostly binds to chromatin. Experimental evidence indicates that

doxorubicin forms a complex with the DNA by intercalation of its planar rings between

nucleotide base pairs. The consequences of this intercalation are serious disturbances of DNA

synthesis, DNA-dependent RNA synthesis and protein synthesis. However, the doxorubicin

concentrations required to exert antiproliferative effects through these mechanisms appear

somewhat greater than those achievable at the tumour site in the clinical setting. More recent

experimental evidence seems to indicate that DNA intercalation triggers DNA cleavage by

topoisomerase-II, yielding serious disturbances in the tertiary structure of DNA. This effect is

seen with drug concentrations which have been found within the clinically therapeutic range.

Doxorubicin is also known to be involved in oxidation/reduction reactions: a number of

NADPH-dependent cellular reductases are able to reduce doxorubicin to semiquinone free

radicals, which can in turn react with molecular oxygen to generate highly reactive cytotoxic

compounds such as superoxide, hydroxyl radicals and hydrogen peroxide. Free radical

formation has been implicated in doxorubicin cardiotoxicity. A further site of action for

doxorubicin may be at the cell membrane level: the drug can bind to cell membrane lipids

COCH

R = H

R = OH

Daunorubicin

Doxorubicin

Version pfddoxoa10219

Page 12 of 16

and affect a variety of functions. Cytotoxicity and/or antiproliferative activity of doxorubicin

may result as a consequence of any mentioned mechanisms and there may be others.

Cell kinetic studies have shown that doxorubicin is active throughout the cell cycle, including

the interphase. Rapidly proliferating tissues such as tumour tissues (but also bone marrow,

gastrointestinal and oral mucosa, hair follicles) are therefore the most sensitive to the

antiproliferative effects of doxorubicin.

5.2 Pharmacokinetic properties

Absorption

Doxorubicin is not absorbed by the gastrointestinal tract. Since the drug is extremely

irritating to tissues, it has to be administered by intravascular routes (intravenous or intra-

arterial).

Intravesical

administration

been

demonstrated

feasible;

following

such

administration, drug passage to the systemic circulation is minimal.

Distribution

Doxorubicin is quickly and widely distributed into the extravascular compartments, as

indicated by a rapid (5 to 10 min) initial plasma half-life and by a steady-state distribution

volume in excess of 20 to 30 L/kg. However, doxorubicin does not cross the blood-brain

barrier in detectable amounts. Binding of doxorubicin to plasma protein is about 75%, and is

not dependent on plasma concentrations up to 2microM.

Biotransformation

Doxorubicin is metabolized to a significant extent, mainly by the liver. The major metabolite

of doxorubicin is 13-OH-doxorubicinol, produced by aldo-keto reductases, which possess a

certain degree of antitumour activity. Doxorubicin and 13-OH-doxorubicinol predominate

also in urine and in the bile. Other metabolites present in detectable amounts in plasma are

the aglycones of doxorubicin and 13-OH-doxorubicinol.

Elimination

Following IV administration, plasma levels of doxorubicin follow a multiphasic decline, with

a terminal half-life reported in the 20 to 48 hour range. The terminal half-life of 13-OH-

doxorubicinol is similar to that of doxorubicin. Plasma clearance is in the range of 8 to 20

ml/min/kg, and is mainly due to metabolism and biliary excretion. This slow elimination

from plasma might be further prolonged in patients with impaired liver function. The

clearance of doxorubicin occurs to a substantial extent by metabolic conversion to a number

of less active or inactive products. Forty to fifty percent of the administered dosage is

recovered in the bile or in the faeces in seven days. Renal excretion is modest, accounting for

only 5% to 10% of the administered dose in 5 days.

5.3 Preclinical safety data

Genotoxicity

The LD

of doxorubicin was 21.9 and 12.5mg/kg for mice and rats, respectively, and about

2.0mg/kg for dogs. The main targets after a single drug dose were the haemolymphopoietic

Version pfddoxoa10219

Page 13 of 16

system and, especially in dogs, the gastrointestinal tract. The toxic effects after repeated

administration were investigated in rats, rabbits and dogs. The main targets of doxorubicin in

the above mentioned species were the haemolymphoietic system, the gastro-intestinal tract,

the kidneys, the liver and both male and female reproductive organs. Concerning the heart,

acute, subacute and cardiotoxicity studies have indicated that doxorubicin was cardiotoxic in

all the laboratory animals tested. Doxorubicin was genotoxic in most of the in vitro or in vivo

mutagenicity tests performed, toxic to the reproductive organs, embryotoxic in rats and

rabbits, and teratogenic in rats. There is no information available on the administration of

doxorubicin in animals during the peri- and post-natal periods.

Doxorubicin was genotoxic in a battery of in vitro or in vivo tests. An increase in the

incidence of mammary tumours was reported in rats, and a trend for delay or arrest of

follicular maturation was seen in female dogs.

Carcinogenicity

Doxorubicin and related compounds have been shown to have mutagenic and carcinogenic

properties when tested in experimental models.

Doxorubicin, like other anthracyclines and many cytotoxic drugs, was carcinogenic in rats. A

local safety study in dogs has shown that extravasation of the drug causes tissue necrosis.

Reproductive and developmental toxicity

Doxorubicin

cause

infertility

during

time

drug

administration.

women,

doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return

after termination of therapy, premature menopause can occur.

Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular

atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia.

Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa.

Oligospermia or azoospermia may be permanent; however, sperm counts have been reported

to return to normospermic levels in some instances. This may occur several years after the

end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive

measures.

6.

PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Doxorubicin hydrochloride Injection

Sodium chloride

Hydrochloric acid

Sodium hydroxide

Water for injections

Version pfddoxoa10219

Page 14 of 16

Doxorubicin hydrochloride for Injection

Lactose monohydrate

6.2 Incompatibilities

Doxorubicin should not be mixed with heparin, dexamethasone, fluorouracil, hydrocortisone

sodium succinate, aminophylline, diazepam, frusemide or cephalothin, since it has been

reported that these medicines are incompatible to the extent that a precipitate may form.

Doxorubicin solution may darken in colour from red to purple if mixed with fluorouracil or

aminophylline. Doxorubicin is reported to be incompatible with allopurinol, cefepime and

ganciclovir.

Until specific compatibility data are available, it is not recommended that doxorubicin be

mixed with other medicines.

6.3 Shelf life

24 Months

6.4 Special precautions for storage

Store at 2 to 8

C (Refrigerate. Do not freeze). Protect from light.

6.5 Nature and contents of container

Doxorubicin Hydrochloride Injection is presented in vials containing doxorubicin as

a sterile solution.

Strength

Pack Size

10 milligrams/5 mL vial

20 milligrams/10 mL vial

50 milligrams/25 mL vial

Doxorubicin

Hydrochloride

(Hospira)

Injection

presented

vials

containing

doxorubicin as a freeze dried product.

Strength

Pack Size

10 milligrams in ONCO-TAIN™ vial

50 milligrams in ONCO-TAIN™ vial

Version pfddoxoa10219

Page 15 of 16

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

As with all antineoplastic agents, trained personnel should prepare Doxorubicin. This should be

performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown,

mask, gloves and appropriate eye protection should be worn when handling doxorubicin. Where

solution accidentally contacts skin or mucosa, the affected area should be immediately washed,

thoroughly with soap and water. It is recommended that pregnant personnel not handle

cytotoxic agents such as doxorubicin.

Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise

pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting

needle during preparation.

Items used to prepare Doxorubicin, or articles associated with body waste should be disposed of

by placing in a double sealed polythene bag and incinerated at 1100

Accidental contact with the skin or eyes should be treated immediately by copious lavage

with water, or soap and water, or sodium bicarbonate solution; medical attention should be

sought.

Spills and Disposal

If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a

suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering

with a suitable material such as absorbent towels or adsorbent granules. Spills may also be

treated with 5% sodium hypochlorite. Collect the absorbent/adsorbent and other debris from the

spill and place in a leakproof plastic container and label accordingly. Cytotoxic waste should be

regarded

toxic

hazardous

clearly

labelled

‘CYTOTOXIC

WASTE

INCINERATION AT 1100

C’. Waste material should be incinerated at 1100

C for at least 1

second. Clean the remaining spill area with copious amounts of water.

7.

MEDICINE SCHEDULE

Prescription Medicine.

8.

SPONSOR

Pfizer New Zealand Limited

P O Box 3998

Auckland, New Zealand

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

DBL™ Doxorubicin hydrochloride Injection

4 August 1986

Version pfddoxoa10219

Page 16 of 16

Doxorubicin Hydrochloride (Hospira)

16 April 1992

10. DATE OF REVISION OF THE TEXT

14 January 2019

Summary table of changes

Section changed

Summary of new information

Reformatting according to new Medsafe datasheet guidance

Similar products

Search alerts related to this product

Share this information