ENDOXAN TABLETS 50MG

Indications

• Cytotoxic responsive malignancy
• Acute lymphoblastic leukaemia
• Non-Hodgkin's lymphoma
• Severe systemic rheumatoid arthritis with systemic manifestations
• Other connective tissue diseases with active vasculitis

Dosage

Adults: Adult: 1–1.5 mg/kg daily or 0.5–1 g every month, adjusted according to clinical response and haematological monitoring. Increase fluid intake for 24–48 hours after intravenous injection to prevent cystitis.

Mechanism of action

Cyclophosphamide acts as an alkylating agent by attaching alkyl groups to DNA bases, resulting in DNA fragmentation and cross-linking. This prevents DNA replication and transcription, leading to cell death. Its effects are achieved through three primary mechanisms: alkylation that induces DNA damage, formation of cross-links in DNA, and mispairing of nucleotides which causes mutations. The drug preferentially interacts with the nitrogen atom of guanine, impacting the integrity of the DNA double helix.

Pharmacodynamics

As an antineoplastic agent, cyclophosphamide is classified among alkylating agents. It disrupts tumor growth by cross-linking guanine bases in DNA strands, hindering the uncoiling necessary for DNA replication. This cell cycle-nonspecific action results in the inhibition of cell division and promotes apoptosis in rapidly dividing cells, characteristic of malignant tumors.

Pharmacokinetics

Cyclophosphamide is administered either orally or intravenously and is well absorbed. It is metabolized in the liver to active metabolites, including phosphoramide mustard, which is responsible for its cytotoxic effects. The drug has a half-life that varies based on dosage and route of administration, and its clearance can be affected by renal and hepatic function. The presence of acrolein, a urinary metabolite, is associated with potential toxicity such as hemorrhagic cystitis.

Contra-indications

• Acute porphyrias
• Severe renal impairment
• Pregnancy

Adverse effects

• Agranulocytosis
• Alopecia
• Anaemia
• Asthenia
• Bone marrow disorders
• Cystitis
• Decreased leucocytes
• Fever
• Hemolytic uremic syndrome
• Hemorrhage
• Hepatic disorders
• Immunosuppression
• Mucosal abnormalities
• Neutropenia
• Progressive multifocal leukoencephalopathy (PML)
• Reactivation of infections
• Sperm abnormalities
• Thrombocytopenia
• Secondary malignancies

Interactions

• cyclophosphamide + pentostatin: Severe (increases risk of toxicity)
• cyclophosphamide + suxamethonium: Unknown (increases risk of prolonged neuromuscular blockade)
• isavuconazole + cyclophosphamide: Unknown (increases exposure)
• netupitant + cyclophosphamide: Unknown (increases exposure)
• pemigatinib + cyclophosphamide: Unknown (increases exposure)

Precautions

• Caution in hepatic impairment
• Consider dose adjustments in renal impairment
• Monitor for signs of infection due to immunosuppression
• Effective contraception advised during treatment and for at least 3 months after

Pregnancy

Avoid during pregnancy due to potential harm to the fetus.

Breast-feeding

Discontinue breastfeeding during and for 36 hours after stopping treatment.

Storage

Store in a cool, dry place away from light.

Formulations

• Cyclophosphamide 50 mg tablets
• Cyclophosphamide injection

Mechanism of action

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, & imidazole groups. The chemotherapeutic & cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents & may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine & pyrimidine bases of DNA- particularly, the 1 & 3 nitrogens of adenine, the 3 nitrogen of cytosine, & the 6 oxygen of guanine- also may be alkylated, as will be the phosphate atoms of the DNA chains & amino & sulfhydryl groups of proteins. /Alkylating agents/ Cyclophosphamide can be used to cause immunologically mediated regression of the immunogenic, cyclophosphamide-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice (B6D2F1 (C57BL/6 x DBA/2) females). In order to cause tumor regression it was necessary to give cyclophosphamide (125-200 mg/kg of body wt, iv shortly before or shortly after tumor implantation. Regardless of whether cyclophosphamide was given before or after tumor implantation, tumor regression was associated with the presence in the spleen of an incr number of Lyt-2+ T-cells capable of passively transferring immunity to tumor bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after day 12 of tumor growth. Because the therapeutic effect of cyclophosphamide could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of cyclophosphamide is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by cyclophosphamide. These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has long latency of onset (8-13 hr) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors. The most likely mechanism by which cyclophosphamide augments immune responses relates to preferential elimination of suppressor and relative sparing of effector and helper cells. Thus, precursors and mature murine suppressor cells are very sensitive to cyclophosphamide whereas the mature effector cells are relatively insensitive ... . Cyclophosphamide induced immunological regression of murine leukemia is reversed by the infusion of normal spleen cells as a source of precursors of suppressor c

Pharmacodynamics

Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.