Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Treatment with doxorubicin often causes undesirable effects, and some of these effects are serious enough to entail careful monitoring of the patient. The frequency and kind of undesirable effects are influenced by the speed of administration and the dosage. Bone marrow suppression is an acute dose limiting adverse effect, but is mostly transient. Clinical consequences of doxorubicin bone marrow/haematological toxicity may be fever, infections, sepsis/septicaemia, septic shock, haemorrhages, tissue hypoxia or death. Nausea and vomiting as well as alopecia are seen in almost all patients.
Intravesical administration may cause the following adverse reactions: haematuria, vesical and urethral irritation, stranguria and pollakisuria. These reactions are usually of moderate severity and of short duration.
Intravesical administration of doxorubicin may sometimes cause haemorrhagic cystitis; this may cause a decrease in bladder capacity.
Extravasation can lead to severe cellulitis, vesication, thrombophlebitis, lymphangitis and local tissue necrosis which may require surgical measures (including skin grafts).
Adverse reactions are listed below by system organ class and absolute frequency (all reported events).
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).


Infections and infestations
Very common:             Infection.
Common:                  Sepsis/septicaemia.
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon:             Acute lymphocytic leukaemia.
Acute myeloid leukaemia.

Secondary leukaemia (sometimes) with or without a preleukaemic phase was observed in patients who were treated with anthracyclines (including doxorubicin). Secondary leukaemia occurs more frequently if the drug is given in combination with DNA-altering cytostatics (see section 4.4).
Blood and lymphatic system disorders
Very common:           Myelosuppression including leukopenia, neutropenia, thrombocytopenia, anaemia.

Myelosuppression is one of the dose-limiting side-effects and may be serious. It manifests mainly in the decrease of the leukocyte count. Leukopenia was observed in almost 75% of the patients with an adequate bone marrow reserve who were treated with 60 mg/m² BSA every 21 days. Although less frequently, thrombocytopenia, neutropenia, and anaemia were also reported. Superinfections (very frequent) and haemorrhage were likewise observed in a connection with the appearance of bone marrow suppression. Myelosuppression usually culminates 10 to 14 days after the administration of doxorubicin and subsides between the 21st and 28th days in most cases. If appearing, thrombocytopenia or anaemia occurs in the same period, but is usually less severe. (see section 4.4).
Immune system disorders
Rare:                 Anaphylactic reactions.
Endocrine disorders
Very rare:                Hot flashes.

Metabolism and nutrition disorders
Very common:           Decreased appetite.
Very rare:             Hyperuricaemia.
Eye disorders
Common:                   Conjunctivitis.
Not known:                Keratitis, increased lachrymation.
Cardiac disorders
Very common:             Cardiotoxicity.
Common:                  Life-threatening congestive (dilatative) cardiomyopathy (after cumulative dose of 550 mg/m²).
Sinus tachycardia, ventricular tachycardia, tachyarrhythmia,
supraventricular and ventricular extrasystoles, bradycardia, arrhythmia.
Asymptomatic reduction of the left ventricular ejection fraction.
Very rare:               Unspecific ECG changes (ST changes, low voltage, long QT intervals).
Isolated cases of life-threatening arrhythmias, acute left ventricular failure, pericarditis, fatal pericarditis-myocarditis syndrome.
Atrioventricular block, bundle branch block.

Doxorubicin is cardiotoxic. The risk that the cardiotoxic side-effects become manifest is elevated during and after radiation therapy of the mediastinal region, after pre-treatment with potentially cardiotoxic agents (e.g., anthracyclines, cyclophosphamide), and in elderly patients (over 70 years) and patients with manifest arterial hypertension. (see section 4.4).


The cardiotoxic effect of doxorubicin can manifest in two types:
Acute type
The acute-type side-effects occur mostly within the first 24 to 48 hours after initiation of therapy, are not dose-dependent and are characterized by the following symptoms: temporary arrhythmia (frequent), especially sinus tachycardia (frequent), and supraventricular and ventricular extrasystoles.
They are (very rarely) characterized by unspecific ECG changes (ST changes, low voltage, and long QT intervals).
These changes are generally reversible, and their appearance is no contraindication for the repeated use of doxorubicin. However life-threatening arrhythmias may occur during, or few hours after the use of doxorubicin; in isolated cases, acute left ventricular failure, pericarditis or fatal pericarditis- myocarditis syndrome was reported.

Delayed type
The delayed-type side-effects are manifestations of dose-dependent cumulative organ toxicity, which is generally irreversible and often life-threatening. They often manifest as congestive (dilatative) cardiomyopathy with signs of left ventricular failure within few months of the termination of therapy.
Cardiotoxicity may, however, become manifest for the first time as late as several years after the termination of the therapy; its incidence increases with the total cumulative dose. (see section 4.4).

Vascular disorders
Common:                   Haemorrhage.
Uncommon:                 Thromboembolism.
Not known:                Shock.
Thrombophlebitis.
Phlebitis.

Respiratory, thoracic and mediastinal disorders
Not known:              Bronchospasm.
Gastrointestinal disorders
Very common:            Gastrointestinal disturbance.
Diarrhoea.
Nausea and vomiting.
Mucositis, stomatitis, oesophagitis, colitis.
Common:                 Abdominal pain.
Uncommon:               Gastrointestinal haemorrhage.
Necrosis of the large intestine with massive haemorrhage and severe infections in combination therapies with cytarabine.
Very rare:              Gastric erosions/ulcers.
Ulceration of the mucous membranes (mouth, pharynx, oesophagus,
gastrointestinal tract).
Hyperpigmentation of the oral mucous membrane.

The emetogenic potential of doxorubicin is high; relatively severe nausea and vomiting occur in about 80% of the patients on the first day of therapy, but also later, when no prophylactic medication is provided (see section 4.4).

Hepatobiliary disorders
Not known:              Hepatotoxicity (sometimes progressing to cirrhosis).
Transient increase of liver enzymes.

Skin and subcutaneous tissue disorders
Very common:           Alopecia (dose-dependent and in most cases reversible).
                          Reddening.
Photosensitization.
Palmar-plantar erythrodysaesthesia syndrome.
Common:                   Local hypersensitivity reactions in the field of radiation (“radiation recall reaction”).
Pruritus.
Urticaria.
Rash (exanthema).
Hyperpigmentation of skin and nails.
Rare:                     Onycholysis.
Extravasation (may lead to severe cellulitis, vesication, thrombophlebitis, lymphangitis, and local tissue necrosis).
Very rare:                Acral erythemas.
Blistering.
Not known:                Actinic keratosis

Musculoskeletal and connective tissue disorders
Not known:             Arthralgia.

Renal and urinary disorders
Very common:           Red coloration to the urine.
Common:                Dysuria.
Chemical cystitis following intravesical administration (with dysuric complaints such as vesical irritation, urethral irritation, dysuria, stranguria, pollakisuria, haematuria, vesicular spasms, hemorrhagic cystitis).
Very rare:             Acute renal failure (isolated cases).
Hyperuricaemia and subsequent uric acid nephropathy as a consequence of massive tumour lysis.

Reproductive system and breast disorder
Very rare:            Amenorrhoea.
Oligospermia.
Azoospermia.

General disorders and administration site conditions
Very common:           Pyrexia.
Asthenia.
Chills.
Uncommon:              Dehydration.
Rare:                  Dizziness.
Injection site reactions (local erythematous reactions along the vein, pain, phlebitis, phlebosclerosis).
Not known:             Malaise.

Investigations
Very common:              Ejection fraction decreased, ECG abnormal, transaminases abnormal, weight increased (reported in patients with early breast cancer receiving doxorubicin- containing adjuvant therapy (NSABP B-15 trial)).

Surgical and medical procedures
Not known:             Radiation damage (skin, lungs, oesophagus, gastrointestinal mucosa, heart) that is already healing may reappear following doxorubicin administration.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.