Doxorubicin Hydrochloride 50 mg Powder for Injection

Doxorubicin hydrochloride 50.0 mg per vial.

When reconstituted as recommended in section 6.6 each ml contains 2 mg doxorubicin hydrochloride.

For excipients, see 6.1

Powder for solution for injection.

Doxorubicin has been used successfully in the treatment of neoplastic conditions such as acute leukaemia, soft tissue and osteogenic sarcomas, breast carcinoma, lymphomas, bronchogenic (lung) carcinoma. It has also been used in the treatment of paediatric malignancy. Doxorubicin is frequently used in combination chemotherapy regimen involving other cytotoxic drugs. Doxorubicin can be used in the treatment of non-metastatic transitional cell carcinoma, carcinoma in situ and papillary tumours of the bladder, by intravesical administration.

Intravenous administration

When used as a single agent, the recommended dosage is 60-75 mg/m² body surface area, as a single intravenous injection administered at 21 day intervals. If it is used in combination with other antitumour agents having overlapping toxicity, the dosage for doxorubicin may need to be reduced to 30-40 mg/m² every three weeks. If using body weight to calculate the dose, then dosages of 1.2 – 2.4 mg/kg as a single dose every three weeks are recommended.

It has been shown that giving doxorubicin as a single dose every three weeks greatly reduces the distressing toxic effect, mucositis. However, there are some regimens which divide the dose over three successive days (20-25 mg/m² or 0.4-0.8 mg/kg). It is thought that this regimen has greater effectiveness although at a cost of higher toxicity.

Administration of doxorubicin in a weekly regimen has been shown to be as effective as the three weekly regimen. The recommended dosage is 20 mg/m² once a week although objective responses have been seen at 6-12 mg/m². This regimen of weekly dosing also reduces the incidence of cardiotoxicity.

It is particularly important to reduce the dose of doxorubicin if it is used in combination with other drugs with a similar toxicity profile. The recommended lifetime cumulative dose limit is 450-550 mg doxorubicin hydrochloride/m² body surface area.

It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection 0.9% or 5% Dextrose Injection. The tubing should be attached to a Butterfly needle inserted preferably into a large vein. The rate of administration is dependent on the size of the vein and the dosage. However the dose should be administered in not less than 3 to 5 minutes. This technique minimises the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis and vesication.

Intravenous infusion is not advised due to the tissue damage that may occur if the infusion infiltrates the tissues. If a central vein catheter is used then infusion of doxorubicin in Sodium Chloride 0.9% Injection is advised.

Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Please refer to section 6.2 for details on incompatibilities.

Intravesical administration

This technique may be used for the treatment of transitional cell carcinoma, papillary bladder tumours and carcinoma in situ. It should not be used for invasive tumours of the bladder which have penetrated the bladder wall.

Many regimens are in use, making interpretation difficult, but the following procedure may be a helpful guide:

1. Patient should be instructed not to drink fluids for 12 hours prior to the examination.

2. Dissolve 50 mg of doxorubicin in 50 ml of normal saline and instil via the catheter into the bladder.

3. The catheter should be removed and the patient instructed to be on one side. At 15 minute intervals the patient should make a quarter turn over a 1 hour period. At the end of this period, the patient may void.

4. The procedure may be repeated at monthly intervals.

Intraarterial administration

Doxorubicin hydrochloride has been administered as an intra-arterial infusion in an attempt to produce local intense activity and reduce systemic toxicity. However it must be recognised that this route of administration is potentially extremely hazardous and can lead to widespread necrosis of perfused tissue unless careful precautions are taken. Intraarterial administration should be undertaken only by experienced professionals.

Paediatric

Adult dosage regimens may be suitable for paediatric cases, but may need to be reduced.

Geriatric

It is recommended that the total cumulative dose of doxorubicin for adults aged 70 or older be restricted to 450 mg/m² body surface area. Adult doses may be suitable for geriatric patients, but may need to be reduced.

Impaired Hepatic Function

Doxorubicin is metabolised by the liver and excreted in bile. Impairment of liver function results in slower excretion of the drug and consequently increased retention and accumulation in the plasma and tissues, resulting in enhanced clinical toxicity.

Doxorubicin dosage must be reduced if hepatic function is impaired according to the following table:

Impaired Renal Function

Doxorubicin and metabolites are excreted in the urine to a minor degree and there are no clear indications that the pharmacokinetics or toxicity of doxorubicin are altered in patients with impaired renal function.

Hypersensitivity to doxorubicin 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.

WARNINGS

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

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 occur even years after discontinuation of doxorubicin therapy. 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 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.

Patients taking concurrent doxorubicin and cyclosporin should be carefully monitored for neurological side effects.

Use In Pregnancy

The drug is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits, and trace amounts of the drug have been found in mouse foetuses and in one aborted human foetus. Although there is no conclusive evidence, there is data which suggests that doxorubicin may harm the foetus. It is therefore recommended that doxorubicin is not administered to women who are pregnant.

Use In Lactation

Doxorubicin is distributed into milk. Experimental data suggests that doxorubicin may harm the infant and should therefore not be administered to mothers who are breast feeding.

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

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 creases (primarily in children in a few cases), recall of skin reaction due to prior radiotherapy.

General: Chills and fever, anorexia, anaphylaxis

Neoplasms benign, malignant and unspecified : Secondary leukaemia has been rarely reported with concurrent treatment of doxorubicin and alkylating agents.

Nervous System: Drowsiness

Ocular: Conjunctivitis.

Renal: Renal damage.

Clinical Features: The symptoms of overdosage are likely to be an extension of doxorubicin's pharmacological action. Single doses of 250 mg and 500 mg of doxorubicin have proved fatal. Such doses may cause acute myocardial degeneration within 24 hours, and severe myelosuppression, the greatest effects of which are seen between 10 and 15 days after administration.

Delayed cardiac failure may occur up to six months after the overdose. Patients should be monitored carefully and if symptoms appear, conventional treatment started.

Management: Symptomatic supportive measures should be instituted. Particular attention should be given to prevention and treatment of possible severe haemorrhage or infections secondary to severe, persistent bone marrow depression. Blood transfusion and reverse barrier nursing may be considered.

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic.

Although not completely elucidated, the mechanism of action of doxorubicin is related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations.

The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are the main normal tissues damaged.

Doxorubicin is not suitable for oral administration as less than 5% of the drug is absorbed.

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.

The disappearance of doxorubicin and its metabolites from the plasma follows a triphasic pharmacokinetic pattern with a mean half-life of the first phase of 12 minutes, of a second phase of 3.3 hours and a prolonged third phase of 29.6 hours.

Urinary excretion of doxorubicin hydrochloride and its metabolites is prolonged and accounts for only 5% of the drug excreted during the first 5 days. Approximately 50% of an administered dose is excreted in bile.

Impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Doxorubicin does not cross the blood brain barrier. However it is known to cross the placenta barrier.

There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Lactose monohydrate

Doxorubicin should not be mixed with heparin since it has been reported that these drugs are incompatible to the extent that a precipitate may form. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

Prior to first use: 36 months.

In use: 24 hours.

Prior to first use: Do not store above 25°C. Keep container in the outer carton.

In use: Chemical and physical in-use stability following reconstitution in either sodium chloride 0.9% or Water for Injections in glass or polypropylene containers has been demonstrated for up to 21 days at 2-8ºC. From a microbiological point of view, however, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours when stored at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions

30 ml clear, Type I glass vials and Onco-Tain^® vials, with rubber closures in packs of 1 vial.

Single use only. Discard any unused contents.

Doxorubicin is a potent cytotoxic agent which should only be prescribed, prepared and administered by professionals who have been trained in the safe use of the preparation. The following guidelines should be followed when handling, preparing and disposing of doxorubicin.

Preparation

1. Reconstitution of powder, transfer to syringes or infusion bags should be carried out in designated areas, preferably a laminar flow station.

2. Personnel must be adequately protected with suitable clothing, gloves, mask and eye shield.

3. Pregnant women should be excluded from handling cytotoxic agents.

Contamination

1. In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat transient stinging of skin. Medical advice should be sought if the eyes are affected.

2. In the event of spillage treat with 1% Sodium Hypochlorite solution using a cloth/sponge kept in the designate area. Rinse twice with water. Put all cloths into a plastic bag and seal for incineration.

Disposal

All items used during preparation or administration including syringes, containers, absorbent materials, residual solutions should all be placed in a thick plastic bag and incinerated at 700°C.

Preparation of the Injection

The contents of the vial should be reconstituted with Water for Injection BP, Sodium Chloride 0.9%, or Dextrose 5% Injection to a solution concentration of 2 mg per ml.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire CV31 3RW

United Kingdom

PL 4515/0073

26^th July 2001

2^nd January 2008