DaunoXome Injection (liposomal daunorubicin)

Daunorubicin hydrochloride, Ph.Eur., present as citrate salt, equivalent to daunorubicin 2.0 mg/ml, (50 mg) encapsulated in liposomes. The liposomes are small unilamellar vesicles with mean diameter of about 45 nm. The active ingredient is daunorubicin, an anthracycline antibiotic with antineoplastic activity originally obtained from Streptomyces peucetius. Daunorubicin has a four ring anthracycline moiety linked by a glycosidic bond to daunosamin, an amino sugar. Daunorubicin is currently isolated from Streptomyces coeruleorubidus and is described by the following chemical name:

(8S,10S)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione.

Daunorubicin has a molecular weight of 527.5 and is represented by the formula C₂₇H₂₉NO₁₀.

Each vial contains a sterile, pyrogen free, preservative-free liposomal emulsion. This emulsion is red and clear to slightly opalescent in appearance. The product is an injectable intended to be administered by intravenous infusion.

DaunoXome is indicated for the treatment of advanced HIV-related Kaposi's Sarcoma.

DaunoXome should be administered by intravenous infusion. The recommended initial dose of DaunoXome in patients with AIDS-related Kaposi's sarcoma is 40 mg/m² every two weeks. The dosage of DaunoXome must be adjusted for each patient. Therapy should be continued as long as disease control can be maintained.

DaunoXome should be diluted with 5% dextrose for infusion before administration. The recommended concentration after dilution is between 0.2 mg and 1 mg daunorubicin/ml of solution. DaunoXome should be administered intravenously over a minimum period of 30-60 minutes (See also Sections 6.2, 6.3 and 6.6).

DaunoXome must not be given by the intramuscular or subcutaneous route or as a bolus injection.

DaunoXome is a liposomal preparation and should not be used interchangeably with conventional daunorubicin.

Pediatric patients: DaunoXome is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

Elderly: The safety and effectiveness of DaunoXome in patients over 65 years of age have not been established. Cardiotoxicity may be more frequent in the elderly (see Section 4.4).

Hepatic impairment: Limited clinical experience exists in treating hepatically impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if bilirubin is elevated as follows:

- Serum bilirubin 1.2 to 3 mg/dl (20.3 to 50.8 μmol/l), give 75% of the normal dose

- Serum bilirubin (> 3 mg/dl >50.8 μmol/l), give 50% of the normal dose.

Renal impairment: Limited clinical experience exists in treating renally impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if creatinine is elevated as follows:

Serum creatinine > 3 mg/dl (>265 μmol/l), give 50% of the normal dose.

Hypersensitivity to DaunoXome, any of its excipients or other anthracyclines/anthracenediones.

Pregnancy and breast feeding.

Cardiotoxicity

DaunoXome and other anthracyclines can cause cardiotoxicity, notably congestive heart failure due to cardiomyopathy. The onset of symptoms can be sudden and may not occur until weeks or months after discontinuation of therapy. Cardiac damage may be irreversible and there have been rare reports of fatalities, usually in patients with risk factors.

The risk of cardiotoxicity increases with total cumulative dosage of anthracyclines. Caution must therefore be exercised in patients previously treated with anthracyclines, or those with previous (or concomitant) therapy with other cardiotoxic compounds such as 5-fluorouracil (5-FU).

The risk of cardiotoxicity appears to be higher in those with pre-existing cardiovascular disease, a history of mediastinal radiation and the elderly. Caution must therefore be exercised when DaunoXome is given to these patients. DaunoXome should only be given to patients with cardiovascular disease when the benefit outweighs the risks.

Experience in patients treated with high dose DaunoXome (above 60mg/m²) for malignancies other than Kaposi's sarcoma indicates that the risk of cardiotoxicity may be higher in these patients.

Cardiac monitoring

Careful monitoring of cardiac function is essential in patients treated with DaunoXome.

Cardiomyopathy induced by anthracyclines is usually associated with a decreased left ventricular ejection fraction (LVEF) measured by echocardiography or by MUGA (Multiple Gated Acquisition). Measurement of LVEF provides a more specific method for monitoring cardiac function than ECG.

All patients should undergo baseline ECGs, echocardiography and measurement of LVEF prior to starting DaunoXome. These tests should be repeated regularly during treatment. Furthermore, in all patients, LVEF must be determined when a cumulative dose of 320mg/m² has been reached, then every 160mg/m² thereafter, in order to identify at an early stage any changes in LVEF that may be a precursor to cardiomyopathy if DaunoXome therapy is continued.

In patients with risk factors for cardiotoxicity with DaunoXome, or those receiving high dose DaunoXome per cycle (e.g. 120mg/m² or above), decreases in cardiac function may occur at lower cumulative doses of DaunoXome, therefore consideration should be given to determination of LVEF after each treatment cycle and before any additional DaunoXome is administered.

Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for cessation of DaunoXome. A reduction of the QRS wave is considered more indicative of cardiac toxicity.

Whenever cardiomyopathy is suspected, and/or LVEF has decreased significantly as compared to pre-treatment values (e.g. 20% decline) and/or if the LVEF is lower than would be expected (e.g. <45%), the benefit of continued therapy must be carefully weighed against the risk of producing irreversible cardiac damage.

It is recommended that DaunoXome is stopped if signs or symptoms of heart failure occur.

Haematological toxicity

DaunoXome is a bone marrow suppressant. The most significant effect is usually neutropenia, which may be severe and result in fever and infection. Anemia and thrombocytopenia may also occur, but are usually less marked. Persistent severe myelosuppression may result in sepsis, or haemorrhage. Complete blood counts must be performed prior to each dose and frequently during the course of DaunoXome therapy.

Patients with malignancies or with HIV infection, whose immune system is already compromised, must be monitored carefully for evidence of intercurrent or opportunistic infections.

Anti-infective therapy should be employed in the presence of suspected or confirmed infection and during febrile neutropenia.

Haematological toxicity may require dose reduction of DaunoXome or suspension or delay of therapy. The colony stimulating factor GCSF has been used to manage patients with neutropenia.

Caution is warranted when combining DaunoXome with other agents which suppress bone marrow function.

Injection site reactions

Care should be taken to ensure that there is no extravasation of DaunoXome during administration. Paravenous administration has resulted in erythema, pain and swelling around the site of tissue infiltration. These changes are generally transitory, resolving within 6 months. However, localised tissue necrosis must still be regarded as a possible consequence of extravasation.

If any signs or symptoms of extravasation occur (e.g. stinging, erythema), the infusion should be stopped immediately and re-started in another vein. The affected limb should be elevated. It may be inappropriate to provide any measure that might cause release of the drug from the liposome (such as application of ice or corticosteroids, instillation of local antidotes, local compression, etc.)

Acute infusion associated reactions

Acute infusion-related reactions have been reported in patients treated with DaunoXome. Symptoms typically include back pain, flushing, chest tightness and dyspnoea. These infusion reactions may occur during the patient's first exposure to DaunoXome, or during re-exposure in a patient who had previously received DaunoXome without incident. Infusion-related reactions generally occur within the first 10 minutes of the infusion and subside when the infusion is slowed or halted. Acute allergic/anaphylactic reactions, sometimes associated with hypotension, have also been reported.

Birth defects

Daunorubicin may cause serious birth defects when used during pregnancy (see Section 4.6). DaunoXome is contra-indicated in pregnancy (see Section 4.3).

Protease Inhibitors and Non Nucleoside Reverse Transcriptase Inhibitors are known inhibitors of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction between DaunoXome and these two groups of antiviral therapy. To date however, a single study has indicated that there is no effect of PI's or NNRTI's on DaunoXome's pharmacokinetic properties. Limited data from one small study where patients were treated with and without protease inhibitors indicate that there were no major changes in DaunoXome associated toxicity.

Caution should be exercised when DaunoXome is used concomitantly with other myelosuppressive or cardiotoxic agents.

DaunoXome may cause serious birth defects when administered during pregnancy. DaunoXome is contraindicated during pregnancy and in women who are breastfeeding (see Section 4.3).

Women of childbearing potential must use effective contraception while they or their male partner is receiving DaunoXome, and for 24 weeks following discontinuation of treatment with DaunoXome. The active ingredient of DaunoXome, daunorubicin, has been shown to be mutagenic, teratogenic and carcinogenic in in vitro and in vivo experiments.

No studies have been performed on the effects of DaunoXome on the ability to drive and use machines. However, patients should be informed that dizziness, nausea and vomiting have been reported with DaunoXome and may affect the ability to drive and operate machinery.

The adverse reactions considered at least possibly related to treatment with DaunoXome are listed below, by body system organ class and absolute frequency. Frequencies are defined as follows: very common 10%; common 1% and < 10%; uncommon 0.1% and < 1%; rare 0.01% and < 0.1%, very rare < 0.01%.

INFECTIONS AND INFESTATIONS

Very common: infections

Uncommon: sepsis, septic shock (see Section 4.4)

BLOOD AND LYMPHATIC SYSTEM DISORDERS

Very common: bone marrow suppression, agranulocytosis, neutropenia, febrile neutropenia, leucopenia, pancytopenia, thrombocytopenia and anemia (see Section 4.4)

IMMUNE SYSTEM DISORDERS

Very common: infusion-associated reactions (including back pain, flushing, chest tightness, dyspnoea, allergic reactions) (See Section 4.4)

Rare: anaphylactic reaction

METABOLISM AND NUTRITIONAL DISORDERS

Common: dehydration

PSYCHIATRIC DISORDERS

Common: depression

NERVOUS SYSTEM DISORDERS

Very common: headache

Common: dizziness

CARDIAC DISORDERS (see Section 4.4):

Common: decreased left ventricular ejection fraction

Uncommon: congestive heart failure, cardiomyopathy

Rare: atrial fibrillation, myocardial infarction

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Very common: dyspnoea

GASTROINTESTINAL DISORDERS:

Very common: stomatitis, mucous ulcerations, nausea, vomiting, diarrhoea, abdominal pain

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Very common: alopecia

Rare: palmar-plantar erythrodysaesthesia syndrome (see below)

Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been reported rarely in patients treated with high dose DaunoXome and cytarabine for leukaemia. The condition is characterised by swelling, pain, tingling and erythema of the palms and soles, which may lead to desquamation of the skin in some patients. Dose reduction or delayed dosing may be required to manage the condition.

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:

Very common: asthenia, fatigue, fever, chills

Common: extravasation at the injection site may result in erythema, pain and swelling (see Section 4.4)

From experience with non-liposomal anthracycline preparations, the primary anticipated toxicity from overdose would be myelosuppression. Other side effects may occur in more pronounced form, like cardiomyopathy. In the event of overdose, bone marrow function and cardiac function should be carefully monitored with appropriate therapy for any severe side-effects.

DaunoXome is a liposomal preparation of daunorubicin formulated to maximise the selectivity of daunorubicin for solid tumours in situ. This tumour selectivity has been demonstrated for transplanted tumours in animal models. While in the circulation, the DaunoXome formulation protects the entrapped daunorubicin from chemical and enzymatic degradation, minimises protein binding, and generally decreases uptake by normal tissues, as well as by the non-reticuloendothelial system. The specific mechanism by which DaunoXome is able to deliver daunorubicin to solid tumours in situ is not known. However, it is believed to be a function of increased permeability of the tumour neovasculature to some particulates in the size range of DaunoXome. Thus, by a decrease in distribution and uptake of normal tissues and binding to plasma proteins and by selective extravasation in tumour neovasculature, the pharmacokinetics of daunorubicin are favourably shifted towards an accumulation of DaunoXome in tumour tissue. Once within the tumour environment, DaunoXome vesicles enter the tumour cells intact. Daunorubicin is then released over time in the cytoplasm, where it is able to exert its antineoplastic activity over a longer period.

DaunoXome has a pharmacokinetic profile significantly different from that of conventional daunorubicin. DaunoXome was administered intravenously over approximately 30 minutes as a single dose of 10, 20, 40, 60, or 80 mg/m². Plasma pharmacokinetic profiles for most patients demonstrated monoexponential declines, although biexponential or Michaelis-Menton (saturation) kinetics occurred in some instances. Peak plasma levels at 40 mg/m² ranged from 14.8 to 22.0 μg/ml with a mean peak plasma level of 18.0 μg/ml. The mean terminal half-life at this dose was 4.0 hours and mean total body clearance was 10.5 ml/minute. This resulted in a mean area under the plasma curve of 120 μg·hr/ml. Metabolism of DaunoXome appeared not to be significant at lower doses. At 60 mg/m² and above, three metabolites were observed, although they have not yet been identified.

DaunoXome pharmacokinetic parameters were also compared to published values for conventional daunorubicin. At 80 mg/m², peak plasma levels ranged from 33.4 to 52.3 μg/ml for DaunoXome compared to 0.40 μg/ml for conventional drug. At this dose, DaunoXome plasma levels decline monoexponentially with a terminal half-life of 5.2 hours versus an initial half-life of 0.77 hours and a final half-life of 55.4 hours for conventional daunorubicin. Mean clearance for DaunoXome is 6.6 ml/min versus 223 ml/minute for daunorubicin. When combined, these parameters indicate that DaunoXome produces a 36-fold increase in mean area under the plasma curve compared to conventional drug (375.3 versus 10.33 μg·hr/ml).

Animal studies with tumour models in mice have demonstrated that DaunoXome can increase daunorubicin tumour exposure ten-fold (in terms of area under the tumour concentration vs. time curve, AUC) when compared with equivalent doses of conventional (free) drug. The rate of drug accumulation in tumour tissues, however, appears to be slower for DaunoXome than for conventional daunorubicin. This difference is thought to be due to a slow diffusion process by which DaunoXome extravasates through the tumour neovasculature into the extracellular space while free drug, in contrast, is able to rapidly equilibrate from the circulation to both normal and neoplastic tissues. Since tumour accumulation of DaunoXome-delivered daunorubicin is a gradual process, it is important that DaunoXome remains in the circulation at high levels for prolonged periods. This has been shown to occur in animal studies where plasma AUC values for daunorubicin were approximately 200-fold greater for DaunoXome than for conventional drug. In contrast to tumour tissue, however, AUC values for normal tissues were only moderately elevated in DaunoXome-treated animals, relative to conventional daunorubicin. Exclusive of reticuloendothelial tissues (liver and spleen, AUC values increased by 110% and 60%, respectively) and brain tissue (AUC value increased by 3.5 fold) AUC increases ranged from 10% for heart and lungs to 30% for kidney and small intestines.

Liposome:

Distearoylphosphatidylcholine

Cholesterol, USNF

Citric acid, Ph.Eur.

Buffer:

Sucrose, Ph.Eur.

Glycine, B.P.

Calcium chloride, Ph.Eur.

q.s. to approximately 25 ml with Water for Injection, Ph.Eur.

To date, no incompatibilities of DaunoXome with other drugs have been reported. However, it is known that the active component daunorubicin is physically incompatible with heparin sodium and with dexamethasone phosphate when directly admixed. A precipitate is produced with either drug. Additionally, because of the chemical instability of the glycosidic bond of daunorubicin, admixture into a highly alkaline media (pH > 8.0) is not recommended. DaunoXome should not be mixed with saline; aggregation of the liposomes may result.

Admixtures containing bacteriostatic agents such as benzyl alcohol or other detergent like molecules should be avoided because such compounds can rupture the bilayer wall of the liposomes causing premature leakage of the active drug.

The shelf-life is 52 weeks when stored at 2° - 8°C.

Chemical and physical in-use stability has been demonstrated for DaunoXome diluted with 5% dextrose, see table below for details.

From a microbial point of view, diluted DaunoXome should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2-8°C for the 5% dextrose dilutions. This recommendation is made on the assumption that dilution has taken place in controlled and validated aseptic conditions.

Store at 2° - 8°C. Do not freeze. Protect against exposure to light. Do not store partially used vials for future patient use. Vials are for single use only.

DaunoXome is presented in 50 ml, sterile, Type I glass vials. The closure consists of a butyl rubber stopper and aluminium ring seal fitted with a removable plastic cap. Each single dose vial is packed in a white chipboard carton. Included in each carton are directions for use.

Use Aseptic Technique. Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in DaunoXome or in the materials recommended for dilution.

Withdraw the calculated volume of DaunoXome into a sterile syringe. Instill the DaunoXome preparation into a sterile container with the correct amount of 5% Dextrose Injection. The recommended concentration after dilution is between 0.2 mg and 1 mg daunorubicin/ml of solution. Infuse over a 30-60 minute period. As with all parenteral drug products, inspect the solution visually for particulate matter prior to administration.

Caution: The only fluid which may be mixed with DaunoXome is 5% Dextrose Injection; DaunoXome should not be mixed with saline, bacteriostatic agents such as benzyl alcohol, or any other solution.

An in-line filter is not recommended for the intravenous infusion of DaunoXome. However, if such a filter is used, the mean pore diameter of the filter should not be less than 5 μm.

Procedures for proper handling and disposal of anticancer drugs should be followed.

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK

PL 27827/0007

12 October 1995

30 October 2011