Goutrelefe 0,5 Mg/1 Mg Film-Coated Tablets

GOUTRELEFE is indicated for relief of acute attacks of gout in cases of emergency.

Posology
In acute gout the initial dose is 0.5 mg to 1.0 mg (one 1 mg or two 0.5 mg tablets) by mouth immediately, followed by 0.5 mg (1 tablet) every 2 hours until pain relief is obtained or gastrointestinal symptoms like vomiting or diarrhoea occur. A maximum total treatment course of 6 mg must not be exceeded. The course should not be repeated within 3 days, but preferably 7 days should elapse between courses of gout treatment with GOUTRELEFE to avoid cumulative toxicity. GOUTRELEFE is not an analgesic medicine and should not be used to treat pain from other causes.
Special populations
Elderly
GOUTRELEFE should be given with caution to the elderly (see section 4.3).
Paediatric population
There are no data available.
Method of administration
For oral use.

GOUTRELEFE is contraindicated in:
- Patients with hypersensitivity to colchicine or to any of the excipients in GOUTRELEFE (see section 6.1).
- Pregnancy and lactation (see section 4.6).
- Patients with blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anaemia.
- Women of childbearing potential unless they are using effective contraceptive measures.
- Patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.4).
- Patients with severe hepatic impairment.
- Patients undergoing haemodialysis since it cannot be removed by dialysis or exchange transfusion.
- Patients with renal or hepatic impairment who are taking a P-glycoprotein (P-gp) inhibitor or a strong CYP3A4 inhibitor (see section 4.5). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine in therapeutic doses (see section 4.8).
- Combination with macrolide antibiotics and pristinamycin.
- Patients with serious gastrointestinal, renal, hepatic or cardiac disorders (see section 4.4)

Fatal overdoses
GOUTRELEFE is potentially toxic so it is important not to exceed the recommended dose as prescribed by a healthcare provider with the necessary knowledge and experience (see section 4.2). Colchicine, as contained in GOUTRELEFE, has a narrow therapeutic window. The administration should be discontinued if toxic symptoms such as nausea, vomiting, abdominal pain, diarrhoea occur (see sections 4.2 and 4.8). GOUTRELEFE should be withdrawn or the dose reduced if adverse gastrointestinal effects occur. Fatal overdoses have been reported with colchicine, as contained in GOUTRELEFE, in adults and children. Keep GOUTRELEFE away from children. GOUTRELEFE should be given with great care to elderly or debilitated patients who may be particularly susceptible to cumulative toxicity and to those patients with cardiovascular, hepatic, renal or gastrointestinal disease. Patients with liver or renal impairment should be carefully monitored for adverse effects of colchicine.
Blood dyscrasias
Colchicine, as contained in GOUTRELEFE, may cause severe bone marrow depression (agranulocytosis, aplastic anaemia, thrombocytopenia). The change in blood counts may be gradual or very sudden. Aplastic anaemia in particular has a high mortality rate. Periodic checks of the blood picture are essential (see section 4.3). If patients develop signs or symptoms that could indicate a blood cell dyscrasia, such as fever, stomatitis, sore throat, prolonged bleeding, bruising or skin disorders, treatment with GOUTRELEFE should be immediately discontinued and a full haematological investigation should be conducted straight away.
Hepatic and renal impairment
Patients with liver or renal impairment should be carefully monitored for adverse effects of GOUTRELEFE (see sections 4.2, 4.3 and 4.8). Co-administration with P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors will increase the exposure to colchicine, as contained in GOUTRELEFE, which may lead to colchicine induced toxicity including fatalities. If treatment with a P-gp inhibitor or a moderate or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, a reduction in GOUTRELEFE dosage or interruption of GOUTRELEFE treatment is recommended (see sections 4.3 and 4.5).
Elderly population
GOUTRELEFE should be given with care to old and debilitated patients and to those with cardiac, hepatic, renal or gastrointestinal disease.
Co-administration with P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors
Co-administration with P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors will increase the exposure to GOUTRELEFE, which may lead to GOUTRELEFE induced toxicity including fatalities. If treatment with a P-gp inhibitor or a moderate or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, a reduction in GOUTRELEFE dosage or interruption of GOUTRELEFE treatment is recommended (see sections 4.3 and 4.8).
Paediatric population
Safety and efficacy of GOUTRELEFE have not been established in paediatric populations.

GOUTRELEFE 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 ketoconazole) (see section 4.3). Colchicine, as contained in GOUTRELEFE, 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, telithromycin, erythromycin), ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors (ritonavir, atazanavir), calcium channel blockers (verapamil and diltiazem) and disulfiram (see sections 4.3 and 4.4). A reduction in GOUTRELEFE dosage or an interruption of treatment is recommended in patients with normal renal or hepatic function if treatment with a P-gp inhibitor or strong CYP3A4 inhibitor is required. A 4-fold reduction in colchicine dosage is recommended when co-administered with a P-gp inhibitor (e.g. ciclosporin) and/or a strong CYP3A4 inhibitor (e.g. clarithromycin, ketoconazole, ritonavir). A 2-fold reduction in colchicine, as contained in GOUTRELEFE dosage is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g. verapamil, diltiazem, grapefruit juice (see sections 4.3 and 4.4). Such combinations should be avoided in patients with renal and hepatic impairment (see sections 4.3 and 4.4). Given the nature of the side effects, caution is advised with concomitant administration of medicine that can affect the blood count or have a negative effect on hepatic and/or renal function.
Pristinamycin
Concomitant administration of pristinamycin and GOUTRELEFE can increase the undesirable effects of colchicine with potentially fatal consequences (see section 4.3).
Oral anticoagulants
Concomitant administration of GOUTRELEFE and oral anticoagulants may increase the effect of the oral anticoagulant and increase the risk of haemorrhage. More frequent INR checks are required. Possible modification of the dosage of the oral anticoagulant during treatment with GOUTRELEFE and for 8 days after its cessation may be required.
Thiazide diuretics
May increase serum uric levels and interfere with the activity of GOUTRELEFE.
Cimetidine and tolbutamide
Reduce metabolism of colchicine and thus plasma levels of GOUTRELEFE increase.
Grapefruit juice
May increase plasma levels of GOUTRELEFE as grapefruit juice is a moderate inhibitor of CYP3A4. Grapefruit juice should therefore not be taken together with GOUTRELEFE.
Vitamin B12 (cyanocobalamin)
Reversible malabsorption of cyanocobalamin (vitamin B12) may be induced by an altered function of the intestinal mucosa.
Statins (HMG-CoA reductase inhibitors), fibrates, ciclosporin, digoxin
The risk of myopathy and rhabdomyolysis is increased by a combination of colchicine with statins, fibrates, ciclosporin or digoxin. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors and co-administration with GOUTRELEFE, and caution should be exercised when given concomitantly. There may be an increased risk if renal function is impaired. Patients should be advised to report muscle pain or weakness.
Alcohol
Concomitant use of GOUTRELEFE increases the risk of gastrointestinal disorders. Alcohol increases blood uric acid concentrations.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Concomitant use may increase the risk of gastrointestinal symptoms.
Antineoplastic medicines
Cytolytic medicines may increase the serum uric acid concentrations.
Bone marrow depressants or radiation therapy
Additive bone marrow depression may occur and dosage reduction of GOUTRELEFE may be required.
Medicines affecting the blood count, hepatic function or renal function
Given the nature of the side effects, caution is advised with concomitant administration of medicines that can affect the blood count or have a negative effect on hepatic and/or renal function.

Women of childbearing potential
Women of childbearing have to use effective contraception during treatment (see section 4.3).
Pregnancy
Use of GOUTRELEFE is contraindicated during pregnancy (see section 4.3).
Breastfeeding
Colchicine, as contained in GOUTRELEFE is excreted in breast milk. Therefore, use of GOUTRELEFE is contraindicated in women who are breastfeeding (see section 4.3).
Fertility
No data is available.

GOUTRELEFE is not expected to have an influence; however patients should not drive, use machinery or perform any tasks that require concentration until they are certain that GOUTRELEFE does not adversely affect their ability to do so safely (see section 4.8).

GOUTRELEFE frequently causes nausea, vomiting, abdominal pain and diarrhoea.
Table 1: Tabulated summary of adverse reactions
System organ class
Frequent
Less frequent
Frequency unknown
Blood and the lymphatic system disorders
Bone marrow suppression with, agranulocytosis, thrombocytopenia, aplastic anaemia, leukopenia, neutropenia*
Immune system disorders
Hypersensitivity reactions
Nervous system disorders
Peripheral neuritis, peripheral neuropathy
Vascular disorders
Hypotension (with large doses), General vascular damage
Gastrointestinal disorders
Nausea, vomiting, abdominal pain and diarrhoea.**
Burning of the throat
Profuse diarrhoea, gastrointestinal haemorrhage
Hepatobiliary disorders
Hepatotoxicity, hepatic damage
Skin and subcutaneous tissue disorders
Urticaria, morbilliform eruptions
Burning of the skin, skin rashes, alopecia
Musculoskeletal and connective tissue disorders
Myopathy, rhabdomyolysis
Renal and urinary disorders
Renal damage, dehydration, Anuria, haematuria, oliguria
Reproductive system and breast disorders
Amenorrhoea, dysmenorrhoea, oligospermia, reversible azoospermia
Description of selected adverse reactions
* Larger doses may cause profuse diarrhoea, gastrointestinal haemorrhage, skin rashes and renal damage. Bone marrow depression with agranulocytosis, thrombocytopenia and aplastic anaemia have occurred on prolonged treatment, as well as peripheral neuritis, myopathy, rashes and alopecia.
** GOUTRELEFE should be withdrawn or the dose reduced if gastrointestinal side effects occur. Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website or to Macleods Pharmaceuticals SA (Pty) Ltd. at [email protected]

Symptoms
Colchicine, as contained in GOUTRELEFE, has a narrow therapeutic window and is extremely toxic in overdose, it has been associated with serious and fatal toxicity. Patients at particular risk of toxicity are those with renal or hepatic impairment, gastrointestinal or cardiac disease, and patients at extremes of age (very young and very old). Following colchicine overdose, all patients, even in the absence of early symptoms, should be referred for immediate medical assessment (see section 4.4).
Clinical:
There is often a delay of up to 6 hours before toxicity is apparent; some features may be delayed up to 1 week or longer. Early symptoms of acute overdosage may be delayed (which occur up to 1 day after ingestion but 3 hours on average): nausea, vomiting, abdominal pain, haemorrhagic gastroenteritis, volume depletion, electrolyte abnormalities, diarrhoea, electrolyte disturbances, hypovolaemic shock, leukocytosis, hypotension in severe cases. The second phase with life threatening complications develops 24 to 72 hours (7 days or longer) after medicine administration: hepatic impairment, hyperpyrexia, bone marrow depression with leukopenia followed by rebound leukocytosis, multisystem organ dysfunction, acute renal failure, confusion, coma, ascending peripheral motor and sensory neuropathy, myocardial depression (decreased cardiac output), pancytopenia, cardiac dysrhythmias, respiratory failure (respiratory distress), consumption coagulopathy. A toxic epidermal necrolysis-like reaction has also been reported. These can progress in severe cases to multiple organ damage with bone marrow aplasia, convulsions, coma, delirium, rhabdomyolysis, neuropathy, hepatocellular damage and ascending paralysis of the central nervous system, disseminated intravascular coagulation and death. 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. The lethal dose varies widely (7 mg to 65 mg single dose) for adults but is generally about 20 mg.
Treatment
No antidote is available. Consider oral activated charcoal 50 g in adults who have ingested more than 0,1 mg/kg bodyweight within 1 hour of presentation and children who have ingested any amount of GOUTRELEFE within 1 hour may be given activated charcoal 1 g/kg. Doses may be repeated every 4 hours in both adults and children, for those who have ingested more than 300 u03bcg/kg, provided they are not vomiting. Haemodialysis and haemoperfusion has no efficacy (high apparent distribution volume) as they do not enhance GOUTRELEFE elimination; blood and urine concentrations are of no use diagnostically (see section 4.3). Close clinical and biological monitoring in hospital environment. Management is mainly symptomatic and supportive, with attention given to respiration, pulse, blood pressure and circulation, and cardiac rhythm; fluid and electrolyte imbalances should be corrected. In cases of overdosage or acute poisoning patients should be carefully monitored. Patients are monitored for at least 6 hours after ingestion, or 12 hours if they have taken more than 300 u03bcg/kg. Asymptomatic patients may then be discharged, with advice to return if gastrointestinal symptoms appear.