PEMETREXED 500 mg/20 ml FRESENIUS

Indications

• Sedation for surgical procedures
• Management of anxiety disorders
• Preoperative sedation

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Diacid is believed to exert its sedative effects primarily through the intact molecule, despite some decomposition to bromide ion. This suggests that its sedative action is not solely reliant on the breakdown products but rather on the overall structure and function of the diacid molecule.

Pharmacodynamics

Diacid has a sedative effect that is mediated through its interaction with neurotransmitter systems in the brain. The precise pathways involved are not fully elucidated, but the drug likely influences gamma-aminobutyric acid (GABA) receptors, which play a critical role in regulating neuronal excitability. This leads to a calming effect on the central nervous system, reducing anxiety and promoting sleep.

Pharmacokinetics

The pharmacokinetics of diacid, including its absorption, distribution, metabolism, and excretion, have not been extensively detailed. However, it is expected to be absorbed well following administration, with distribution throughout the body's tissues. The metabolism may involve hepatic pathways, while excretion is likely renal, similar to other sedative agents.

Pregnancy

Use with caution. Limited data on safety during pregnancy. Consult a healthcare professional before use.

Breast-feeding

Use with caution. Limited data on excretion in breast milk. Consult a healthcare professional before use.

Storage

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

Indications

• Malignant pleural mesothelioma (in combination with cisplatin)
• Locally advanced or metastatic non-small cell lung cancer (NSCLC) other than predominantly squamous cell histology (first-line therapy in combination with cisplatin)
• Second-line treatment of locally advanced or metastatic NSCLC (monotherapy)

Mechanism of action

Pemetrexed inhibits several folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). These enzymes are crucial for the de novo biosynthesis of thymidine and purine nucleotides. Upon entering the cell, pemetrexed is converted into polyglutamate forms by folylpolyglutamate synthetase, which are retained within the cell and act as potent inhibitors of TS and GARFT, prolonging the drug's action in tumor cells.

Pharmacodynamics

In vitro studies indicate that pemetrexed effectively inhibits the growth of mesothelioma cell lines, demonstrating synergistic effects when used in combination with cisplatin. The drug's pharmacodynamic effects correlate with systemic exposure, particularly the depth of the absolute neutrophil counts (ANC) nadir, which is influenced by the concurrent administration of folic acid and vitamin B12. Notably, there is no cumulative effect of pemetrexed on ANC nadir across multiple treatment cycles.

Pharmacokinetics

Pemetrexed is administered as a solution for infusion and is absorbed into cells via reduced folate carriers and membrane folate binding proteins. Once inside the cells, it undergoes polyglutamation, which enhances its retention and activity. The pharmacokinetic profile indicates that the drug has an extended intracellular half-life due to its polyglutamate forms, resulting in prolonged effects in malignant tissues. Its clearance and distribution are influenced by factors such as renal function and the use of folate supplementation.

Adverse effects

• Appetite decreased
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Anemia
• Neutropenia
• Thrombocytopenia
• Rash
• Stomatitis

Interactions

• Aspirin: Moderate (increases exposure)
• NSAIDs: Moderate (increases exposure)
• Pyrimethamine: Unknown (increases risk of adverse effects)
• Live vaccines: Unknown (increases risk of generalized infection, possibly life-threatening)

Precautions

• Prophylactic folic acid supplementation required
• History of diabetes
• History of cardiovascular disease

Pregnancy

Pemetrexed is not recommended during pregnancy due to potential harm to the fetus.

Breast-feeding

It is not known whether pemetrexed is excreted in human milk; caution is advised.

Storage

Store in the original container, protected from light. Once reconstituted, use immediately.

Formulations

• Pemetrexed 100 mg powder for concentrate for solution for infusion
• Pemetrexed 500 mg powder for concentrate for solution for infusion
• Pemetrexed 850 mg/34 ml concentrate for solution for infusion
• Pemetrexed 1 g/40 ml concentrate for solution for infusion

Mechanism of action

PARTIALLY DECOMP TO BROMIDE ION, BUT SEDATIVE ACTION IS PRESUMABLY DUE TO INTACT MOLECULE.

Mechanism of action

Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells. Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folyl polyglutamate synthase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells. ... Activity of the /pemetrexed/ may be partially preserved under conditions in which cells are highly resistant to other thymidylate synthase inhibitors, possibly because of premetrexed's secondary inhibitory effects on purine synthesis. ... Pemetrexed activity is modulated by natural folates within cells that compete for polyglutamation at the level of folylpolyglutamate synthetase. Cells resistant to methotrexate because of impaired transport via the reduced folate carrier may retain partial sensitivity to pemetrexed. This is due to concurrent diminished transport of physiologic reduced folates and contraction of the cellular folate pool, thereby relaxing the usual level of suppression of pemetrexed polyglutamation. The risk of pemetrexed toxicity is increased when cellular folates are suboptimal.

Pharmacodynamics

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.