NAB-XELPAC INJECTION (LYOPHILIZED POWDER)

Indications

• Adjuvant treatment of operable node-positive and node-negative breast cancer
• Treatment of hormone-refractory metastatic prostate cancer
• Initial chemotherapy for metastatic breast cancer
• Treatment of advanced ovarian cancer in combination with cisplatin
• Initial chemotherapy of non-small cell lung cancer with cisplatin
• Treatment of metastatic gastric adenocarcinoma
• Treatment of locally advanced squamous cell carcinoma of the head and neck

Dosage

Children: Refer to the BNF for Children for detailed paediatric dosing guidelines.

Adults: Refer to product literature or local protocols for specific dosing information.

Mechanism of action

Paclitaxel interferes with the normal function of microtubule growth by hyper-stabilizing their structure. It binds to the beta subunit of tubulin, locking the microtubule structure in place and preventing disassembly. This disrupts the dynamic instability necessary for essential cellular functions, including mitosis, and promotes apoptosis in cancer cells by inhibiting the function of the apoptosis regulator Bcl-2.

Pharmacodynamics

Paclitaxel acts as an antineoplastic agent by promoting the assembly of microtubules and preventing their depolymerization. This results in the formation of abnormal microtubule structures and inhibits cellular processes essential for cell division and function. It is indicated for first-line and subsequent therapy in advanced ovarian carcinoma and other malignancies, demonstrating a significant ability to induce programmed cell death in cancer cells.

Pharmacokinetics

Paclitaxel is administered intravenously and exhibits a multi-compartment pharmacokinetic profile. It is extensively metabolized by the liver, primarily through cytochrome P450 enzymes. Its half-life can vary widely due to extensive protein binding and distribution in tissues. The drug's clearance is affected by hepatic function, necessitating monitoring in patients with liver impairment.

Contra-indications

• Severe hypersensitivity to paclitaxel or any excipients
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Abdominal pain
• Alopecia
• Anaemia
• Appetite decreased
• Arrhythmia
• Arthralgia
• Asthenia
• Constipation
• Diarrhoea
• Dyspnoea
• Fluid imbalance
• Haemorrhage
• Hypersensitivity
• Hypertension
• Hypotension
• Increased risk of infection
• Myalgia
• Nausea
• Neutropenia
• Pain
• Peripheral neuropathy
• Sepsis
• Skin reactions
• Stomatitis
• Taste altered
• Thrombocytopenia
• Vomiting

Interactions

• Dabrafenib (severe - decreases exposure)
• Bosentan (severe - decreases exposure)
• Mitotane (severe - decreases exposure)
• Rifampicin (severe - decreases exposure)
• Selpercatinib (severe - increases exposure)
• St John's Wort (severe - decreases exposure)
• Berotralstat (moderate - increases concentration)
• Eliglustat (moderate - increases exposure)
• Sotorasib (moderate - increases exposure)
• Tucatinib (moderate - increases exposure)

Precautions

• Monitor liver function in hepatic impairment
• Caution in patients with acute porphyrias
• Caution in patients with pre-existing heart conditions

Pregnancy

Paclitaxel is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Breastfeeding is not recommended during treatment with paclitaxel due to potential adverse effects on the infant.

Storage

Store in a refrigerator (2°C to 8°C). Protect from light. Do not freeze.

Formulations

• Paclitaxel 80mg/8ml concentrate for solution for infusion

Dosage

Children: Refer to specific formulations for dosing guidance.

Adults: Refer to specific formulations for dosing guidance.

Mechanism of action

Nanoparticles can enhance drug solubility and stability, allowing for more effective delivery to target cells. They can be engineered to release their therapeutic payload in response to specific stimuli (e.g., pH changes, temperature variations) or through passive or active targeting mechanisms. Active targeting involves modifying the surface of nanoparticles with ligands that bind to receptors on target cells, facilitating cellular uptake.

Pharmacodynamics

The pharmacodynamics of nano formulations can vary widely depending on the specific drug, its formulation, and the characteristics of the nanoparticles used. Generally, nanoparticles can alter the distribution of drugs within the body, leading to enhanced accumulation at target sites, prolonged circulation time in the bloodstream, and improved therapeutic outcomes.

Pharmacokinetics

Pharmacokinetics of nano drugs can also differ from conventional drugs. Factors such as particle size, surface charge, and coating can influence absorption, distribution, metabolism, and excretion (ADME) processes. Nanoparticles may exhibit altered absorption rates, prolonged half-lives, and may be metabolized and excreted differently than their non-nanoparticle counterparts.

Pregnancy

The safety of nano formulations during pregnancy has not been established. Use with caution and consult a healthcare provider.

Breast-feeding

The effects of nano formulations during breastfeeding are unknown. Consult a healthcare provider before use.

Storage

Store in a cool, dry place away from direct sunlight and moisture. Follow specific storage instructions if provided by the manufacturer.

Dosage

Children: Refer to specific formulation guidelines or literature for dosage recommendations, as this varies widely depending on the drug and its formulation.

Adults: Refer to specific formulation guidelines or literature for dosage recommendations, as this varies widely depending on the drug and its formulation.

Mechanism of action

The mechanism of action of particles in drug formulations often involves enhancing solubility, stability, and absorption of the active pharmaceutical ingredient. Nanoparticles can facilitate cellular uptake through endocytosis, allowing for targeted delivery to specific tissues or cells, which can improve therapeutic efficacy and reduce side effects.

Pharmacodynamics

Pharmacodynamics of particle-based drug delivery systems can vary widely depending on the size, surface properties, and composition of the particles. Generally, smaller particles may have increased surface area leading to enhanced interaction with biological membranes. This can result in improved drug release profiles, increased cellular uptake, and sustained drug action.

Pharmacokinetics

Pharmacokinetics of drug particles is influenced by their size, shape, and surface characteristics. Smaller particles may exhibit faster absorption rates and higher bioavailability compared to larger particles. The distribution of drug particles in the body can be affected by their ability to evade the immune system, their clearance rates, and their interaction with plasma proteins. Metabolism and excretion pathways can also differ based on the formulation of the drug particle.

Pregnancy

The safety of particle administration during pregnancy has not been established. Consultation with a healthcare professional is advised.

Breast-feeding

It is unclear whether particles are excreted in breast milk. A healthcare professional should be consulted.

Storage

Store in a cool, dry place away from direct sunlight and moisture.

Mechanism of action

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive. Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication. ... Taxol induces tubulin polymerization and forms extremely stable and nonfunctional microtubules. Taxol has demonstrated broad activity in preclinical screening studies, and antineoplastic activity has been observed in several classically refractory tumors. These tumors include cisplatin resistant ovarian carcinoma in phase II trials and malignant melanoma and non-small cell lung carcinoma in phase I studies.

Pharmacodynamics

Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.