those who took 0.5 to 0.8 mg/kg had more severe adverse reactions, includingmyelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.
•The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includesgastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea and significant fluid loss,leading to volume depletion. Peripheral leukocytosis may also be seen.
•Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drugadministration, attributed to multiorgan failure and its consequences. Death is usually a result ofrespiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injurymay be accompanied by rebound leukocytosis and alopecia starting about one week after the initialingestion.
•Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock.
Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is noteffectively removed by hemodialysis [see Clinical Pharmacology (12.3)].
11 DESCRIPTION
Colchicine is an alkaloid obtained from various species of Colchicum. The chemical name for colchicine is(S)-N-(5,6,7,9- tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl) acetamide with a molecularformula of C22H25NO6 and a molecular weight of 399.4. The structural formula of colchicine is provided in
Figure 1.
Figure 1: Colchicine Structural Formula
Colchicine consists of pale yellow scales or powder; it darkens on exposure to light. Colchicine is soluble inwater, freely soluble in alcohol, and slightly soluble in ether.
GLOPERBA is supplied for oral administration as a slightly hazy, red liquid with a cherry odor, containing0.6 mg/5 mL of the active ingredient colchicine USP. Inactive ingredients: benzyl alcohol, FD&C Red No. 40,artificial cherry flavor, anhydrous citric acid, dibasic sodium phosphate, glycerin, propylene glycol, sucralose,xanthan gum and purified water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Colchicine’s effectiveness as a prophylactic treatment for gout has been postulated to be due to its ability toblock neutrophil-mediated inflammatory responses induced by monosodium urate crystals in synovial fluid.
Colchicine disrupts the polymerization of β-tubulin into microtubules, thereby preventing the activation,degranulation and migration of neutrophils to sites of inflammation. Colchicine also interferes with theinflammasome complex found in neutrophils and monocytes that mediates interleukin-1β (IL-1β) activation.
12.2 Pharmacodynamics
The pharmacodynamics of colchicine are unknown.
12.3 Pharmacokinetics
Absorption
In healthy adults, GLOPERBA reached a mean Cmax of 2.16 ± 0.87 ng/mL in 1 hour (range 0.5 to 2 hours)after a single dose administered under fasting conditions. A minimal food effect was observed whenGLOPERBA was administered following a high fat, high calorie meal. A slight decrease in Cmax wasobserved; however, the overall extent of absorption based on AUC0-t and AUC0-inf, was similar in the fedand fasted states. The absolute bioavailability of colchicine is reported to be approximately 45%. Meanpharmacokinetic parameter values for GLOPERBA in healthy adults are shown in Table 1.
Table 1: Mean Pharmacokinetic Parameter Estimates for GLOPE |
