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4.3 Contraindications

4.3 Contraindications

 

 

            Hypersensitivity to hydroxybenzoatesdoxorubicin or any of the excipients.

 

Dosage should not be repeated in cases of bone marrow depression or buccal ulceration or buccal burning sensation, which can precede ulceration.

 

 

 

4.4             Special warnings and special precautions for use

 

WARNINGS

 

Experienced Physician:         Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

 

 

           Special warnings and special precautions for use

 

WARNINGS

 

            Cardiac Toxicity:       Special attention must be given to the cardiac toxicity exhibited by doxorubicin.  This may present as tachycardia or ECG changes including supraventricular tachycardia.  Severe cardiac failure may occur suddenly, without premonitory ECG changes.

 

            It is recommended that the cumulative total lifetime dose of doxorubicin (including related drugs such as daunorubicin) should not exceed 450 – 550 mg/m² body surface area.  Above this dosage, the risk of irreversible congestive cardiac failure increases greatly.  Total dose should also take account of any previous or concomitant mediastinal irradiation, other anthracycline chemotherapy or concurrent high dose cyclophosphamide, which may also exhibit cardiotoxic effects.

 

            Congestive heart failure and/or cardiomyopathy may be encountered several weeksoccur even years after discontinuation of doxorubicin therapy and for. For this reason extreme care should be taken in patients with existing associated heart disease.

 

            Cardiac failure is often not favourably affected by presently known medical or physical therapy for cardiac support.  Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest.  Severe cardiac toxicity may occur precipitously without antecedent ECG changes.  Base line ECG and periodic  follow up ECG during and immediately after active drug therapy is an advisable precaution.  Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias are not considered indications for suspension of doxorubicin therapy.  A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity.  If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.

 

            The best non-invasive predictor of cardiomyopathy is a reduction in the left ventricular ejection fraction (LVEF), determined by ultra-sound or heart scintigraphy. LVEF–investigations are highly recommended before treatment and should be repeated after an accumulated dose of about 350-400 mg/m² in patients with normal cardiac function at baseline. Also repeat if there are clinical signs of heart failure at any cumulative dose. As a rule, an absolute decrease of ≥ 10% or a decrease to below 50% in patients with normal initial LVEF values, is a sign of impairment of cardiac function. Continued treatment with doxorubicin must be carefully evaluated in these cases.

 

            Bone Marrow Depression:    There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring.  With the recommended dosage schedule, leucopenia is usually transient, reaching its nadir at 10 – 14 days after treatment, with recovery usually occurring by the 21^st day.  White blood cell counts as low as 1000/mm³ are to be expected during treatment with appropriate doses of doxorubicin.  Red blood cell and platelet levels should also be monitored, since they may also be depressed.

 

            Haematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy.

 

            Immunosuppression:  Doxorubicin is a powerful but temporary immunosuppressant agent.  Appropriate measures should be taken to prevent secondary infection.

 

            Severe Myelosuppression:   Persistent severe myelosuppression may result in superinfection or haemorrhage.

 

            Enhanced Toxicity:    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 and hepatotoxicity of 6-mercaptopurine.

 

            Infertility:       Doxorubicin may cause infertility during the time of drug administration.  Although ovulation and menstruation appear to return after termination of therapy, there is no information about the restoration of male fertility.

 

            Hepatic Impairment:  Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment.  It is recommended that an evaluation of hepatic function be carried out prior to individual dosing, using conventional clinical laboratory tests such as AST, ALT, alkaline phosphatase, bilirubin and BSP.  If required, dosage schedules should be reduced accordingly.  (See DOSAGE and ADMINISTRATION (see section 4.2).

 

            Extravasation:            On intravenous administration of doxorubicin, a stinging or burning sensation signifies extravasation and, even if blood return from aspiration of the infusion needle is good, the injection or infusion should be immediately terminated and restarted in another vein.

 

            Should extravasation occur, stop the infusion immediately and apply ice packs to the injection site.  Local injection of dexamethasone or hydrocortisone may be used to minimise local tissue necrosis.  Hydrocortisone cream 1% may also be applied locally.

 

            PRECAUTIONS

 

            Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring.

 

            It is strongly recommended therefore, that patients be hospitalised at least during the first phase of treatment.  Blood count and liver function tests should be carried out prior to each doxorubicin treatment.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4.7 Effect on ability to drive and use machines

 

            Not known.

Doxorubicin may cause drowsiness.  If affected, patients should not drive or carry out other activities that may put themselves or others at risk.

 

 

 

4.8  Undesirable effects

 

            ADVERSE REACTIONS

 

            More Common Reactions

 

            Cardiovascular:          Cardiotoxicity i.e. cardiomyopathy, congestive heart failure, supraventricular tachycardia and ECG changes.

 

            Dermatological:         Doxorubicin extravasation, skin necrosis, cellulitis, vesication, phlebitis, reversible alopecia, including the interruption of beard growth, erythematous streaking along the vein proximal to the site of injection, phlebosclerosis.  Hair growth returns to normal after cessation of treatment.

 

            Gastrointestinal:        Nausea and vomiting, mucositis (stomatitis and oesophagitis), diarrhoea.  Mucositis is a frequent and painful complication of doxorubicin treatment.  Mucositis most commonly develops 5 to 10 days after treatment, and typically begins as a burning sensation in the mouth and pharynx.  It may involve the vagina, rectum and oesophagus, and progress to ulceration with risk of secondary infection and usually subsides in 10 days.  Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase.  Mucositis may be severe in patients who have had previous irradiation to the mucosae.

 

            General:         Dehydration, facial flushing (if an injection has been given too rapidly).  Administration of doxorubicin may cause red colouration of the urine.  Patients should be advised that this is no cause for alarm.

 

            Haematological:         Myelosuppression, leucopenia, thrombocytopenia, anaemia.  Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function (when appropriate dosage reduction has not been adopted, see section 4.2) and simultaneous treatment with other myelosuppressive agents.  The nadir (time from treatment to peripheral blood evidence of maximal myelosuppression) of leucopenia and thrombocytopenia is 10 to 15 days after treatment, and counts return to normal before day 21.

 

             The clinical consequences of doxorubicin bone marrow/ haematological toxicity may be fever, infections, sepsis/ septicaemia, septic shock, haemorrhages, tissue hypoxia or death.

 

            Less Common Reactions

 

            Dermatological:         Urticarial rash, hyperpigmentation of nailbeds and dermal increases (primarily in children in a few cases), recall of skin reaction due to prior radiotherapy.

 

            General:         Chills and fever, anorexia, anaphylaxis

 

            Haematological:    Leucopenia, thrombocytopenia, anaemia.  Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function (when appropriate dosage reductionNeoplasms benign, malignant and unspecified :    Secondary leukaemia has not been adopted.  See DOSAGE: WITH IMPAIRED HEPATIC FUNCTION) and simultaneous treatment rarely reported with other myelosuppressiveconcurrent treatment of doxorubicin and alkylating agents.  The nadir (time from treatment to peripheral blood evidence of maximal myelosuppression) of leucopenia and thrombocytopenia is 10 to 15 days after treatment, and counts return to normal before day 21.

 

            Nervous System:       Drowsiness

 

            Ocular:            Conjunctivitis.

 

            Renal: Renal damage.

 

 

 

 

 

 

 

 

 

 

 

5.2    Pharmacokinetic propertiesPharmacokinetic properties

 

Pharmacokinetic studies show the intravenous administration of normal or radiolabelled doxorubicin for injection is followed by rapid plasma clearance and significant tissue binding.  No information on plasma-protein binding of doxorubicin is available.

 

The metabolism and disposition of doxorubicin is still to be defined.  The drug is metabolised predominantly by the liver to doxorubicinol and several aglycone metabolites.  It should be noted that several of the metabolites are cytotoxic.  However, it is not certain whether any are more cytotoxic than the parent compound.  High levels of metabolites appear rapidly in plasma and undergo a distribution phase with a measurable short initial half-life.  Metabolism may be impaired in patients with abnormal liver function.

6.         PHARMACEUTICAL PARTICULARS

 

 

 

 

6.1              List of excipients

 

Lactose monohydrate

            Lactose monohydrate

 

 

 

 

7.                  Marketing Authorisation Holder

 

            Faulding Pharmaceuticals Plc

Hospira UK Limited

            Queensway

            Royal Leamington Spa

            Warwickshire CV31 3RW

            United Kingdom

 

8.                  MARKETING AUTHORISATION NUMBER

 

PL 4515/0073

 

9.                  DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

26^th July, 2001

 

10.              DATE OF REVISION OF THE TEXT

 

23^rd August, 2002

2^nd January 2008