RUBEXET LIPOSOMAL 50 mg/25 ml

Indications

• Acute leukaemias
• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma
• Breast cancer
• Advanced soft-tissue sarcoma
• Recurrent superficial bladder tumours
• Transitional cell carcinoma
• AIDS-related Kaposi’s sarcoma
• Advanced ovarian cancer
• Progressive multiple myeloma

Dosage

Children: Dosing for children should be adjusted according to individual treatment protocols and based on serum bilirubin concentration. Refer to the BNF for

Adults: Dosing varies by indication and should be consulted with product literature. Generally, it is administered as an intravenous injection with careful monitoring due to potential toxicity.

Mechanism of action

Doxorubicin acts by intercalating between DNA base pairs, inhibiting topoisomerase II activity, which prevents DNA replication and transcription. This leads to the generation of free radicals, causing oxidative damage to cellular components and ultimately resulting in apoptosis of cancer cells.

Pharmacodynamics

Doxorubicin's pharmacodynamic profile is characterized by its ability to inhibit DNA and RNA synthesis, leading to the disruption of cellular proliferation. The drug demonstrates a dose-dependent relationship with its cytotoxic effects, and its efficacy is significantly influenced by the duration and schedule of administration. The therapeutic window is narrow due to its associated cardiotoxicity.

Pharmacokinetics

Doxorubicin is administered intravenously and exhibits a volume of distribution of approximately 20-30 L/m². It is highly bound to plasma proteins (approximately 95%) and is metabolized primarily in the liver via reductive metabolism to active and inactive metabolites. The elimination half-life ranges from 20 to 48 hours, with renal and biliary excretion of metabolites. Cardiac function should be monitored due to the risk of cumulative dose-dependent cardiotoxicity.

Contra-indications

• Severe renal impairment
• Cardiac disease
• Previous myocardial irradiation
• Hypersensitivity to doxorubicin or any component of the formulation

Adverse effects

• Alopecia
• Anaemia
• Anxiety
• Appetite decreased
• Arrhythmias
• Arthralgia
• Asthenia
• Bone marrow depression
• Breast pain
• Cachexia
• Chest discomfort
• Chills
• Constipation
• Cough
• Decreased leukocytes
• Dehydration
• Dizziness
• Fatigue
• Hyperthermia
• Hypotension
• Increased risk of infection
• Influenza-like illness
• Infusion-related reactions
• Insomnia
• Malaise
• Mucosal abnormalities
• Muscle complaints
• Muscle weakness
• Nail disorder
• Nausea
• Nerve disorders
• Neutropenia
• Oedema
• Oral disorders
• Pain
• Scrotal erythema
• Sepsis
• Skin reactions
• Skin ulcer
• Syncope
• Taste altered
• Thrombocytopenia
• Vasodilation
• Vision blurred
• Vomiting
• Weight decreased

Interactions

• Increased risk of cardiotoxicity with other anthracyclines
• Caution with other medications that may cause myelosuppression
• Potential interaction with CYP450 inducers or inhibitors

Precautions

• Monitor cardiac function regularly due to the risk of cardiotoxicity
• Caution in patients with congestive heart failure
• Ensure effective contraception during and for at least 6 months after treatment

Pregnancy

Doxorubicin is contraindicated in pregnancy due to potential harm to the fetus. It is classified as a Category D drug.

Breast-feeding

Breastfeeding is not recommended during treatment with doxorubicin due to the potential for serious adverse reactions in the nursing infant.

Indications

• Breast cancer
• Lung cancer
• Acute lymphoblastic leukemia

Mechanism of action

Doxorubicin exerts its antineoplastic activity primarily through two mechanisms: intercalation into DNA and disruption of topoisomerase II-mediated DNA repairs. By intercalating between DNA base pairs, doxorubicin induces torsional stress, destabilizing the DNA structure and leading to nucleosome eviction. It also inhibits topoisomerase II activity, preventing the relegation of DNA breaks, thereby inhibiting DNA replication and transcription, which ultimately induces apoptosis. Additionally, doxorubicin is metabolized into a semiquinone radical, leading to the generation of reactive oxygen species that cause cellular damage and apoptosis, particularly in tumor and myocardial cells.

Pharmacodynamics

Doxorubicin is a cytotoxic, cell-cycle non-specific agent that destabilizes DNA structures through intercalation, resulting in DNA strand breakages. This disruption alters cellular transcriptomes and triggers apoptotic pathways when DNA repair fails. Furthermore, doxorubicin interferes with the activity of vital enzymes, including topoisomerase II, DNA polymerase, and RNA polymerase, leading to cell cycle arrest. The generation of cytotoxic reactive oxygen species also contributes to its efficacy and associated toxicities.

Pharmacokinetics

Doxorubicin is administered intravenously and has a volume of distribution of approximately 16-20 L/m². It is highly protein-bound (approximately 95%) and is metabolized primarily in the liver. The elimination half-life ranges from 20 to 48 hours, depending on the dosing and individual patient factors. Its clearance can be affected by hepatic function, and it is excreted mainly in bile as metabolites, with less than 5% excreted unchanged in urine. Caution is advised in patients with hepatic impairment due to potential accumulation and increased toxicity.

Contra-indications

• Severe myocardial insufficiency
• Previous hypersensitivity to doxorubicin or other anthracyclines
• Pregnancy (unless the potential benefit justifies the risk to the fetus)

Adverse effects

• Cardiotoxicity
• Nausea and vomiting
• Bone marrow suppression
• Alopecia
• Mucositis
• Secondary malignancies

Interactions

• Ciclosporin: Unknown (increases concentration)
• Leflunomide: Unknown (increases exposure)
• Teriflunomide: Unknown (increases exposure)
• Verapamil: Unknown (increases exposure)

Precautions

• Monitor cardiac function during treatment
• Assess liver function prior to and during treatment
• Cautious use in patients with pre-existing cardiac disease
• Use with caution in patients with renal impairment

Pregnancy

Doxorubicin is classified as pregnancy category D. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether doxorubicin is excreted in human milk. Caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature (20-25°C), protected from light. Keep out of reach of children.

Formulations

• Doxorubicin hydrochloride injection

Dosage

Children: Refer to specific product information for paediatric dosing, as it varies widely based on the formulation and intended use.

Adults: Refer to specific product information for adult dosing, as it varies widely based on the formulation and intended use.

Mechanism of action

The mechanism of action of a drug is determined by its active ingredients and how they interact with biological systems. Formulations can be designed to target specific pathways, such as receptor binding, enzyme inhibition, or modulation of ion channels, depending on the therapeutic intent.

Pharmacodynamics

Pharmacodynamics involves the study of the effects of the drug formulation on the body and the relationship between drug concentration and effect. This can include the drug's efficacy, potency, and the duration of action, which are influenced by the formulation's properties such as release rate and route of administration.

Pharmacokinetics

Pharmacokinetics describes how the body absorbs, distributes, metabolizes, and excretes a drug formulation. Factors influencing pharmacokinetics include the formulation type, which can alter absorption rates (e.g., immediate vs extended release), distribution based on solubility and protein binding, metabolism primarily via the liver, and excretion through the kidneys or other routes.

Pregnancy

Consult healthcare provider for safety information regarding use during pregnancy.

Breast-feeding

Consult healthcare provider for safety information regarding use during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Cancer treatment (chemotherapy)
• Fungal infections (antifungal therapy)
• Pain management (analgesics)
• Inflammatory diseases

Dosage

Children: Refer to specific liposomal drug guidelines for paediatric dosing, as it varies by formulation and indication.

Adults: Refer to specific liposomal drug guidelines for dosing, as it varies by formulation and indication.

Mechanism of action

Liposomal drugs work by encapsulating the therapeutic agent within a lipid bilayer, which facilitates prolonged circulation time in the bloodstream. This can enhance the drug's accumulation at target sites, such as tumors or infected tissues, via passive or active targeting mechanisms. The liposomes can also modulate the release of the drug, allowing for controlled pharmacokinetics.

Pharmacodynamics

Once administered, liposomal drugs interact with cellular membranes through fusion or endocytosis, leading to the release of the encapsulated drug within the target cells. This localized release increases drug concentration at the site of action, potentially enhancing efficacy while minimizing side effects associated with systemic exposure. The pharmacodynamics depend on the specific drug encapsulated and its inherent properties.

Pharmacokinetics

Liposomal formulations often exhibit altered pharmacokinetics compared to their free drug counterparts. They typically have increased half-lives due to their lipid composition, which protects the drug from rapid metabolism and clearance. Distribution is influenced by the size and surface characteristics of the liposomes, affecting their uptake by various tissues. Excretion generally occurs through the reticuloendothelial system, primarily in the liver and spleen.

Adverse effects

• Infusion-related reactions
• Nausea
• Vomiting
• Fever
• Chills
• Fatigue
• Hypersensitivity reactions
• Thrombocytopenia

Precautions

• Monitor for infusion-related reactions
• Use with caution in patients with renal impairment
• Consider potential allergic reactions in patients with a history of hypersensitivity

Pregnancy

Liposomal formulations should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether liposomal formulations are excreted in human milk. Caution is advised.

Storage

Store at 2–8°C. Do not freeze. Protect from light.

Formulations

• Liposomal doxorubicin
• Liposomal amphotericin B
• Liposomal irinotecan

Indications

• Chronic kidney disease
• Certain cancers
• Hematologic disorders
• Viral infections

Dosage

Children: Refer to BNF for Children for appropriate dosing.

Adults: Refer to specific product guidelines and BNF for appropriate dosing.

Mechanism of action

The pegylation process alters the pharmacokinetics of the drug by increasing its molecular size, which reduces renal clearance and enzymatic degradation. This results in prolonged circulation time in the bloodstream, allowing for sustained therapeutic effects.

Pharmacodynamics

Pegylated drugs demonstrate improved efficacy due to enhanced distribution and prolonged action. The increased size and hydrophilicity reduce immunogenicity and can lead to a more favorable safety profile. Additionally, the modified drug's interaction with biological targets may be altered, potentially enhancing therapeutic effects.

Pharmacokinetics

Pegylated formulations typically exhibit altered absorption and distribution characteristics compared to their unmodified counterparts. The increased molecular weight leads to reduced glomerular filtration and extended half-life, allowing for less frequent administration. The metabolism of pegylated drugs may also be impacted, with certain enzymes being less effective at processing the larger molecules.

Pregnancy

There is limited data on the use of pegylated formulations during pregnancy. Caution is advised and benefits versus risks should be considered.

Breast-feeding

It is unknown whether pegylated formulations are excreted in human milk. Caution is recommended when administering to breastfeeding women.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Mechanism of action

Generally, doxorubicin is thought to exert its antineoplastic activity through 2 primary mechanisms: intercalation into DNA and disrupt topoisomerase-mediated repairs and free radicals-mediated cellular damages. Doxorubicin can intercalate into DNA through the anthraquinone ring, which stabilizes the complex by forming hydrogen bonds with DNA bases. Intercalation of doxorubicin can introduce torsional stress into the polynucleotide structure, thus destabilizing nucleosome structures and leading to nucleosome eviction and replacement. Additionally, the doxorubicin-DNA complex can interfere with topoisomerase II enzyme activity by preventing relegation of topoisomerase-mediated DNA breaks, thus inhibiting replication and transcription and inducing apoptosis. Moreover, doxorubicin can be metabolized by microsomal NADPH-cytochrome P-450 reductase into a semiquinone radical, which can be reoxidized in the presence of oxygen to form oxygen radicals. Reactive oxygen species have been known to cause cellular damage through various mechanisms, including lipid peroxidation and membrane damage, DNA damage, oxidative stress, and apoptosis. Although free radicals generated from this pathway can be deactivated by catalase and superoxide dismutase, tumor and myocardial cells tend to lack these enzymes, thus explaining doxorubicin's effectiveness against cancer cells and tendency to cause cardiotoxicity. Doxorubicin hydrochloride is an antineoplastic antibiotic with pharmacologic actions similar to those of daunorubicin. Although the drug has anti-infective properties, its cytotoxicity precludes its use as an anti-infective agent. The precise and/or principal mechanism(s) of the antineoplastic action of doxorubicin is not fully understood. It appears that the cytotoxic effect of the drug results from a complex system of multiple modes of action related to free radical formation secondary to metabolic activation of the doxorubicin by electron reduction, intercalation of the drug into DNA, induction of DNA breaks and chromosomal aberrations, and alterations in cell membranes induced by the drug. Evidence from in vitro studies in cells treated with doxorubicin suggests that apoptosis (programmed cell death) also may be involved in the drug's mechanism of action. These and other mechanisms (chelation of metal ions to produce drug-metal complexes) also may contribute to the cardiotoxic effects of the drug. Doxorubicin undergoes enzymatic 1- and 2-electron reduction to the corresponding semiquinone and dihydroquinone. 7-Deoxyaglycones are formed enzymatically by 1-electron reduction, and the resulting semiquinone free radical reacts with oxygen to produce the hydroxyl radical in a cascade of reactions; this radical may lead to cell death by reacting with DNA, RNA, cell membranes, and proteins. The dihydroquinone that results from 2-electron reduction of doxorubicin also can be formed by the reaction of 2 semiquinones. In the presence of oxygen, dihydroquinone reacts to form hydrogen peroxide, and in its absence, loses its sugar and gives rise to the quinone methide, a monofunctional alkylating agent with low affinity for DNA. The contribution of dihydroquinone and the quinone methide to the cytotoxicity of doxorubicin is unclear. Experimental evidence indicates that doxorubicin forms a complex with DNA by intercalation between base pairs, causing inhibition of DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering and steric obstruction. Doxorubicin also inhibits protein synthesis. Doxorubicin is active throughout the cell cycle including the interphase. Several anthracycline-induced effects may contribute to the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for ?-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase, which may result in myofibrillar loss associated with anthracycline-induced cardiotoxicity. Other potenti

Pharmacodynamics

Doxorubicin is a cytotoxic, cell-cycle non-specific anthracycline antibiotic. It is generally thought to exert its antitumor effect by destabilizing DNA structures through intercalation, thus introducing DNA strand breakages and damages. Not only does it alter the transcriptomes of the cells, failure in repairing DNA structures can also initiate the apoptotic pathways. Additionally, doxorubicin intercalation can also interfere with vital enzyme activity, such as topoisomerase II, DNA polymerase, and RNA polymerase, leading to cell cycle arrests. Finally, doxorubicin can also generate cytotoxic reactive oxygen species to exert cellular damages.