SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Colchimex 500 microgram tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One tablet contains 500 micrograms colchicine Excipient with known effect: 56.4mg of lactose per tablet For the full list of excipients, see section PHARMACEUTICAL FORM Tablet White or faintly yellow biconvex uncoated tablets, diameter 5.5 mm, engraved Evans 126 on one side, plain on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults: Colchimex is used for the treatment of acute gout. They are also used for the prophylaxis of recurrent gout and to prevent acute attacks during the initial treatment with allopurinol or uricosuric drugs. Paediatric population: Colchimex is indicated in Familial Mediterranean Fever for prophylaxis of attacks and prevention of amyloidosis in children aged 4 years and above. 4.2 Posology and method of administration Posology Adults Treatment for acute gout: 1 mg (2 tablets of 500 micrograms) to be taken initially followed by 500 micrograms 1 hour later, and then followed, as needed, after 12 hours, by continued colchicine (up to 500 micrograms 3 times daily) until the acute attack resolves. A total dose of 6 mg should not be exceeded. After completion of a course, another course should not be started for at least three days. Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs: 500 micrograms twice daily. The treatment duration should be decided after factors such as flare frequency, gout duration and the presence and size of tophi have been assessed. Elderly Use with caution. 1

2 Paediatric population Familial Mediterranean fever For paediatric use, colchicine should only be prescribed under the supervision of a medical specialist with the necessary knowledge and experience. A starting dose should be administered orally based on age: 0.5mg/day in children less than 5 years of age 1mg/day in children from 5 to 10 years of age 1.5mg/ day in children over 10 years, The dose could be given as a single dose or doses higher than 1mg/day could be divided and given twice daily. Colchicine dosage should be increased in a stepwise fashion (e.g. 0.25mg/step) up to a maximum of 2mg/day to control disease in patients who do not clinically respond to the standard dosage. Any increase of the daily dose should be monitored closely for adverse effects. In children with amyloid nephropathy, higher daily doses up to 2mg/day might be needed. Concomitant treatment of colchicine with several drugs, mostly inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein have been shown to increase the risk for colchicine toxicity. If a patient has received concomitant therapy with a moderated or potent CYP3A4 inhibitor or with a P-glycoprotein inhibitor, the maximum recommended dosage of oral colchicine should be reduced. Patients with renal impairment Use with caution in patients with mild and moderate renal impairment. For patients with severe renal impairment, reduce dose or increase interval between doses. Patients with renal impairment should be carefully monitored for adverse effects of colchicine. Patients with hepatic impairment Use with caution in patients with mild/moderate hepatic impairment. For patients with severe hepatic impairment, reduce dose or increase interval between doses. Patients with hepatic impairment should be carefully monitored for adverse effects of colchicine. Method of administration For oral administration: Tablet should be swallowed whole with a glass of water. 4.3 Contraindications Hypersensitivity to colchicine or to any of the excipients listed in section 6.1. Colchicine is contraindicated in patients with blood dysfunction. Colchicine is contraindicated in patients with severe renal impairment Colchicine is contraindicated in patients with severe hepatic impairment Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a P-glycoprotein (P-gp) inhibitor or a strong CYP3A4 inhibitor (see section 4.5). 4.4 Special warnings and precautions for use Colchicine is potentially toxic so it is important not to exceed the dose prescribed by a medical specialist with the necessary knowledge and experience. 2

3 Patients with liver or renal impairment should be carefully monitored for adverse effects of colchicine. Co-administration with P-gp inhibitors and/or strong CYP3A4 inhibitors will increase the exposure to colchicine, which may lead to colchicine-induced toxicity including fatalities. If treatment with a P-gp inhibitor or a strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, a reduction in colchicine dosage or interruption of colchicine treatment is recommended (see section 4.5). For oral colchicine, poisoning usually start with gastrointestinal phase mimicking gastroenteritis, followed by multi-organ dysfunction. (See section 4.9) Colchicine should be given with great care to elderly or debilitated patients and those with cardiac, hepatic, renal or gastro-intestinal disease. Overdose and high-dose therapy of oral colchicine leads to bone marrow suppression with agranulocytosis. Periodic blood counts should be done in patients receiving long term therapy. The elderly, even those with normal renal and hepatic function, may be more susceptible to cumulative toxicity with colchicine. As the elderly are more likely to have age related renal function impairment, the risk of myopathy and other toxic effects increases in patients receiving colchicine. Hence careful monitoring is needed for elderly patients with gout especially who are >65 years of age. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Colchicine may impair the absorption of fat, sodium, potassium, nitrogen, xylose and other actively transported sugars. This may lead to decreased serum cholesterol and carotene concentrations. Colchicine may increase sensitivity to CNS depressants and enhance the response to sympathomimetic agents. Colchicine may cause false-positive results when testing urine for RBC or haemoglobin. Colchicine may react with cyclosporin leading to an increased risk of nephrotoxicity and increased plasmacyclosporin concentration. Colchicine has been reported to interfere with urinary determinations of 17-hydroxycorticoids using the Reddy, Jenkins and Thorn procedure. Concomitant use with clarithromycin may lead to colchicine toxicity. Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant use with erythromycin may also lead to colchicine toxicity. Colchicine is a substrate for both CYP3A4 and the transport protein P-gp. In the presence of CYP3A4 or P- gp inhibitors, the concentrations of colchicine in the blood increase. Toxicity, including fatal cases, have been reported during concurrent use of CYP3A4 or P-gp inhibitors such as macrolides (clarithromycin and erythromycin), cyclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors, calcium channel blockers (verapamil and diltiazem) (see section 4.4). 3

4 Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a P-gp inhibitor (e.g. ciclosporin, verapamil or quinidine) or a strong CYP3A4 inhibitor (e.g. ritonavir, atazanavir, indinavir, clarithromycin, telithromycin, itraconazole or ketaconazole) (see section 4.3). A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with a P-gp inhibitor or strong CYP3A4 inhibitor is required (see section 4.4) Antibacterials: Increased risk of colchicine toxicity when given with clarithromycin or erythromycin, particularly in patients with pre-existing renal impairment. Rare reports of fatalities (see section 4.3 Contraindications). AS CYP3A4 inhibitors, macrolides should not be used to treat patients with renal or hepatic impairment who are taking colchicine (see section 4.3, Contraindications). P-glycoprotein or strong CYP3A4 inhibitors: Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a P-glycoprotein inhibitor (e.g. ciclosporin, verapamil or quinidine) or a strong CYP3A4 inhibitor (e.g. ritonavir, atazanavir, indinavir, clarithromycin, telithromycin, itraconazole or ketaconazole). For moderate CYP 450 3A4 inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil), colchicine should be given at the usual dose for gout flares, but the treatment should not be repeated for at least three days. Higher colchicine levels have been observed therefore, dose reduction of colchicine is recommended. CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported. Concurrent therapy with strong CYP450 3A4 inhibitors: For concurrent therapy with strong CYP450 3A4 inhibitors including (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), colchicine requires a dose reduction due to the significantly higher colchicine levels. Moderate CYP 450 3A4 inhibitors: For moderate CYP 450 3A4 inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil), colchicine should be given at the usual dose for gout flares, but the treatment should not be repeated for at least three days. Higher colchicine levels have been observed therefore, dose reduction of colchicine is recommended. 4

5 4.6 Fertility, pregnancy and lactation Fertility Animal research has shown that administration of colchicine may adversely affect spermatogenesis (see section 5.3). Rare cases of reversible oligospermia and azoospermia in men are found in literature. If colchicine is used to treat FMF Since the course of FMF without treatment can also lead to infertility, the use of colchicine should be weighed against the potential risks and treatment may be considered if there is a clinical need. If colchicine is used for the treatment of acute gout or recurrent gout and to prevent acute attacks during the initial treatment with allopurinol or uricosuric drugs Male patients should not have children during treatment and at least 6 months after completion of colchicine treatment. However, if pregnancy should occur during this period, genetic counselling is required. Pregnancy Animal studies have shown reproductive toxicity effects (see section 5.3). If colchicine is used to treat FMF A moderate amount of data on pregnant women with FMF shows no malformations or fetal / neonatal toxicity due to colchicine. Since the course of FMF without treatment may also have a negative effect on pregnancy, the use of colchicine during pregnancy should be weighed against the potential risks and may be considered if there is a clinical need. If colchicine is used for the treatment of acute gout or recurrent gout and to prevent acute attacks during the initial treatment with allopurinol or uricosuric drugs There is limited amount of data from the use of colchicine in pregnant women with gout. As a precaution, the use of colchicine should be avoided in this patient group and for fertile women who do not use effective 5

6 contraceptives.female patients must use effective contraception during and for at least 3 months after completion of colchicine treatment. However, if pregnancy should occur during this period, genetic counselling is required. Breast-feeding Colchicine / metabolites are found in breastfeeding new-borns / infants of treated women. There is insufficient information on the effects of colchicine on new-borns / infants. Colchicine should not be used by nursing women with gout. In lactating mothers with FMF, a decision must be made to discontinue / abstain from breastfeeding or discontinue treatment with colchimex after taking into account the benefit of breast-feeding for the child and the benefit of treatment for the woman. 4.7 Effects on ability to drive and use machines Colchicine has no known influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions in patients taking colchicine were nausea, vomiting, diarrhoea, abdominal cramping and abdominal pain. Rare adverse effects include thrombocytosis, epistaxis, multiple organ failure and bone marrow alteration (haemolytic or aplastic anemia, pancytopenia, neutropenia, thrombocytopenia), urticaria, maculopapular rash, purpura, erythema, oedema, azoospermia and oligospermia. Tabulated summary of adverse reactions Frequency convention: (very common ( 1/10) common ( 1/100 to <1/10) uncommon ( 1/1,000 to <1/100) rare ( 1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data) System Organ Class (SOC) Blood and lymphatic system disorders Frequency category uncommon rare rare rare Adverse Drug Reactions leukopenia thrombocytosis epistaxis bone marrow alteration (haemolytic or aplastic anemia, pancytopenia, neutropenia, thrombocytopenia) Nervous system disorders very rare sensory motor neuropathy Gastrointestinal disorders common nausea, vomiting, diarrhoea, abdominal cramping, abdominal pain Hepatobiliary disorders not known elevated AST, elevated ALT Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Reproductive system and breast disorders uncommon rare uncommon rare alopecia urticaria, maculopapular rash, purpura, erythema, oedema myopathy, myotonia, muscle weakness, muscle pain, rhabdomyolysis azoospermia, oligospermia Reporting of suspected adverse reactions 6

7 Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Colchicine has a narrow therapeutic window and is extremely toxic in overdose. Patients at particular risk of toxicity are those with renal or hepatic impairment, gastrointestinal or cardiac disease, and patients at extremes of age. Colchicine overdose is complex and specialist advice should be promptly obtained. There is often a delay of up to 6 hours before toxicity is apparent, and some features of toxicity may be delayed by 1 week or longer. Following colchicine overdose, all patients, even in the absence of early symptoms, should be referred for immediate medical assessment. Symptoms Symptoms of acute overdosage may be delayed (3 hours on average): nausea, vomiting, abdominal pain, hemorrhagic gastroenteritis, volume depletion, electrolyte abnormalities, leukocytosis, hypotension in severe cases. The second phase with life threatening complications develops 24 to 72 hours after drug administration: multisystem organ dysfunction, acute renal failure, confusion, coma, ascending peripheral motor and sensory neuropathy, myocardial depression, pancytopenia, dysrhythmias, respiratory failure, consumption coagulopathy. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery may be accompanied by rebound leukocytosis and reversible alopecia starting about one week after the initial ingestion. Treatment No antidote is available. Elimination of toxins by gastric lavage within one hour of acute poisoning. Consider oral activated charcoal in adults who have ingested more than 0.1mg/kg bodyweight within 1 hour of presentation and in children who have ingested any amount within 1 hour of presentation. Haemodialysis has no efficacy (high apparent distribution volume) Close clinical and biological monitoring in hospital environment. Symptomatic and supportive treatment: control of respiration, maintenance of blood pressure and circulation, correction of fluid and electrolytes imbalance. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antigout preparations, preparations with no effect on uric acid metabolism, ATC code: M04AC01 Mechanism of action The exact mechanism of action of colchicine in gout is not completely known. It is involved in leukocyte migration inhibition; reduction of lactic acid production by leukocytes which results in a decreased deposition of uric acid; interference with kinin formation and reduction of phagocytosis with inflammatory response abatement. The mechanism by which colchicine exerts its beneficial effect in patients with FMF has not been fully elucidated; however, the evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin1β. Pharmacodynamic effects Colchicine apparently exerts its effect by reducing the inflammatory response to the deposited crystals and also by diminishing phagocytosis. 7

8 Colchicine diminishes lactic acid production by leukocytes directly and by diminishing phagocytosis and thereby interrupts the cycle of urate crystal deposition and inflammatory response that sustains the acute attack. The oxidation of glucose in phagocytizing as well as in nonphagocytizing leukocytes in vitro is suppressed by colchicine. Colchicine is not an analgesic, although it relieves pain in acute attacks. It is not a uricosuric agent and will not prevent the progression of gout to chronic gouty arthritis. It has a prophylactic, suppressive effect which helps reduce the incidence of acute attacks and relieve the patient s occasional residual pain and mild discomfort. Colchicine can produce a temporary leukopenia which is followed by leukocytosis. 5.2 Pharmacokinetic properties Paediatric population No pharmacokinetics data are available in children. Absorption Readily absorbed after oral administration, peak concentrations in plasma after 2 hours. Distribution Colchicine does not appear to be specifically localised in any tissues except the liver leucocytes, spleen and kidneys; it undergoes enterohepatic circulation. Biotransformation Deacetylated in the liver. Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-Odemethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug). Measurement of colchicine metabolites (2-demethylcolchicine, 3-demethylcolchicine, and 10- demethylcolchicine) following colchicine administration revealed that this pathway contributes very little to the overall degradation and removal of colchicine from the body. The plasma concentrations of the colchicine metabolites identify the importance of the excretion pattern of colchicine from the body. Several pharmacokinetics studies previously conducted with various single-dose and multiple-dose colchicine regimens measured plasma concentrations of colchicine and its metabolites in order to assess the predominant uptake and metabolic pathways of colchicine. Elimination Colchicine is mainly excreted in the faeces, with 10-20% in the urine. The percentage excreted in the urine rises in patients with hepatic disease. Plasma half-life about 1 hour, but 60 hours in leucocytes, which is increased in renal function impairment and decreased in hepatic function impairment. Renal and hepatic impairment are also important factors to consider when using colchicine in an elderly patient because reduced colchicine clearance may leads to accumulation of colchicine increases risk of gastrointestinal upset or more severe adverse effects. 8

9 Colchicine is predominantly eliminated by the liver, through biliary excretion and metabolism by the hepatic cytochrome CYP3A4, to colchicine into 2- and 3-DMC with about 10% to 20% of the drug secreted unchanged in urine. Pharmacokinetic drug interactions Colchicine with nephrotoxic drugs: Increases the risk of adverse effects Colchicine with macrolides: carries a risk of lifethreatening pancytopenia Colchicine with Ciclosporins: aggravate the neuromuscular adverse effects Colchicine with lipid lowering drugs (statins and fibrates): Cause myopathy Drug food interaction: Study data of potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate suggests that GFJ may augment colchicine oral bioavailability. Special population Paediatric population No pharmacokinetics data are available in children. Effect of age, race and gender There were no clinically meaningful differences in colchicine pharmacokinetic parameters (i.e., C max, AUC, T 1/2, and C L/F ) between young and elderly healthy subjects, including those with mild renal impairment. There were no statistically significant differences observed in the comparisons of the pharmacokinetic parameters by race or gender. 5.3 Preclinical safety data Reproductive toxicity Colchicine has been shown to be teratogenic in animals at clinically relevant doses. A risk of teratogenicity in humans cannot be excluded. In rabbits, colchicine was found to arrest spermatogenesis and to produce atrophy of the testicles at a clinically relevant dose. Offspring of pregnant rats injected with colchicine at 0.4 mg/kg bw on gestation days 18, 19 and 20 showed a reduction in brain size, a reduction of neocortical cells, and a reduction in the width of the corpus callosum. These anatomical changes were correlated with behavioural alterations. Genotoxicity Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. Colchicine tested positive in a chromosomal aberration assay in cultured Chinese hamster ovary cells, as well as in a mouse lymphoma assay and an in vivo mouse micronucleus test. These results are related to colchicine s effects on the mitotic spindle. Carcinogenicity Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine to produce aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of malignancy. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Starch maize 9

10 Magnesium stearate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store below 25 C. 6.5 Nature and contents of container Polypropylene bottle with child resistant tamper-evident closure of low density polyethylene. Pack sizes 20, 28, 30, 50, 60, 100 and 120 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION <Date of first authorisation: {DD month YYYY}> 10. DATE OF REVISION OF THE TEXT 27 November