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Template version: 2017-04-21

Public Assessment ReportScientific discussion

Kolkicin Orifarm(colchicine)

Asp no: 2017-1043

This module reflects the scientific discussion for the approval of Kolkicin Orifarm. The procedure was finalised on 2018-09-25. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Orifarm Generics has applied for a marketing authorisation for Kolkicin Orifarm, 0.25 mg, tablet. The active substance is colchicine,(tillhör en grupp läkemedel som kallas giktmedel).

For approved indications, see the Summary of Product Characteristics.

The marketing authorisation has been granted pursuant to Article 10a of Directive 2001/83/EC.

For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to the marketing authorisation, please see section VI.

II. QUALITY ASPECTS

II.1 Drug Substance

The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described.

The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents.

The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated.

Stability studies confirm the retest period.

II.2 Medicinal Product

The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics.

The manufacturing process has been sufficiently described and critical steps identified.

The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose.

Stability studies have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4.

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III. NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of colchicine are well known. No further studies are required for this type of application and the applicant provides none. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology provided by the applicant is adequate. No new data have been presented that alter or give reason for re-evaluation of the non-clinical profile for these products.

Environmental Risk Assessment (ERA)Since Kolkicin Orifarm is expected to replace other products on the market, it will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

IV. CLINICAL ASPECTS

IV.1 IntroductionThe application for Kolkicin Orifarm, 0.25 mg, tablet, is submitted according to Article 10a of Directive 2001/83/EC.

For an application according to Article 10a, WEU (bibliographic application), the Applicant needs to demonstrate that the active substance of the medicinal product has been in well-established medicinal use for the claimed therapeutic indication within the Union for at least ten years, with recognised efficacy and an acceptable level of safety which need to be supported by means of bibliographic data. Each indication has to be applied for and supported separately. Strategy used for the search of published literature and justification for inclusion of references need to be described in detail, which is however not provided by the Applicant. The Applicant should provide detailed description of the strategy used for the search of published literature and justification for inclusion of references in the application. The Applicant has provided response as requested, which is considered adequate.

All clinical information supporting this application is provided in the Applicant's clinical overview dated Jun 2017. The Clinical Overview has been updated and dated April 2018 respective July 2018.

IV.2 Pharmacokinetics

AbsorptionData from several sources suggests an absolute bioavailability around 40-50%. Dose- proportional PK between 0.5 and 1.5 mg has been demonstrated.

No data on the effect of food on the PK of colchicine was supplied. In the SmPC colchicine should be administered with water, this is considered acceptable.

Both colchicine and its metabolites are excreted in high concentrations in urine and bile. The elimination half-life is approximately 30 hours.

Distribution

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The volume of distribution (7–10 l/kg) is considerably larger than the extracellular compartment, indicating widespread uptake by tissues. Plasma protein binding is approximately 30-50%.

EliminationThe terminal half-life of colchicine is 3 to 10 hours. No human mass-balance data are available for colchicine. Based on in vitro data CYP3A is involved in the metabolism of colchicine .This is confirmed with in vivo data using strong CYP3A inhibitors. Enterohepatic recirculation and biliary excretion occur and here is P-gp and possibly also MRP2 (Multidrug resistance-associated protein 2) involved (Dahan et al (2009)).

The major colchicine metabolites [Colchicine, 2-demethyl colchicine (2-DMC), 3-demethyl colchicine (3- DMC)] account for 5 % of circulating parent concentrations in plasma.

Special populationComparison of single-dose colchicine pharmacokinetic profiles in young (n = 20) versus elderly (n = 18) volunteers (mean creatinine clearance [CLCR] 132.6 vs. 87.0 mL/min, respectively) revealed a trend for increasing systemic exposure of colchicine with decreasing renal function. [Wason et al 2014].

In patients with cirrhosis the clearance of colchicine was half compared to normal subjects, the half-life was increased (Leighton et al 1991).

The pharmacokinetics of oral colchicine 1 mg tablet in elderly women (range 75 – 93) was compared to young healthy males (38 – 61 kg). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males.

Drug Interactions

Colchicine is a substrate for CYP3A4 and P-gp and concomitant administration with inhibitors of 3A4 or P-gp leads to increased colchicine plasma concentrations. The SPC contain relevant dosing information for such scenarios.

IV.3 Pharmacodynamics

GoutGout is one of the most common inflammatory arthritis conditions. It is the consequence of deposition of monosodium urate crystals in joints and other tissues, as a result of persistent hyperuricaemia.

Colchicine binds to both α- and β-tubulin to create a tubulin–colchicine complex that prevents the formation of microtubules and thereby interacting in several locations in the inflammatory cascade induces by the deposition of urate crystal; which is the basis for the use of colchicine for Gout.

FMFFMF is an inflammatory disease caused by mutation in the MEFV gene which encodes the protein pyrin. FMF is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis or erysipelas-like skin lesion. The most notorious aspect of FMF is amyloidosis which deposits in the kidneys leading to proteinuria and end stage renal failure.

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The basis for the use of colchicine for FMF is that even when used at low doses, colchicine can be found in white blood cells, blocking tubulin polymerization and subsequently microtubule generation and stability, thus interfering with migration and degranulation of white blood cells.

IV.4 Clinical efficacy

Introduction No efficacy data is available with colchicine 250 micrograms tablets. Hence, the Applicant has submitted data on the basis of the clinical studies on marketed colchicine (500 micrograms) to support this application.Provided that quality and pharmacokinetic issues had been satisfactorily addressed, the submitted efficacy data on the basis of the clinical studies on marketed colchicine (500 micrograms) could be considered acceptable.

This assessment report represents an evaluation of the key elements of the Applicant’s provided information (those relevant to the applied indications); for more details please refer to the Applicant's clinical overview.

Acute goutThe Applicant provided results from two published randomised and placebo-controlled trials (see a short summary below).

Terkeltaub et al. 2010Title: High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.

This study is a randomised, double-blind, placebo-controlled clinical trial, included 184 patients (18 years of age or above) with gout flare; compared self-administered low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total]) and high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]) with placebo. The study design including the primary endpoint is considered adequate.

The primary endpoint was the portion of patients who responded to treatment. Responders were defined as having a pre-treatment pain score within 12 hours of flare onset and a ≥50% reduction in pain within 24 hours of the first dose of study medication without the use of rescue medication.

Significant effects were observed in both groups of low-dose and high-dose colchicine regiments as compared with placebo in terms of proportions of responders. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7 %) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (p = 0.005 for low-dose group vs. placebo; p = 0.034 for high-dose group vs. placebo).

Secondary endpoints in terms of at least a 2-unit reduction in target joint pain score 32 h after the first dose support the results of primary endpoint.

The author concluded that the results of this trial provided the first evidence basis, after centuries of colchicine use, for low-dose colchicine therapy in the treatment of early acute gout flare. The low-dose colchicine regiment maintained efficacy equivalent to that of high-dose colchicine. The results are considered clinically relevant.

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Ahern et al. 1987 Title: Does colchicine work? The results of the first controlled study in acute gout.

In this study, 43 patients (40 males, 3 females, 55–91 years of age) who met the diagnostic criteria of acute gout flares were randomized to receive either placebo (n=21) or oral colchicine (n=22) with initial dose of 1 mg, followed by 0.5 mg every two hours until complete response or toxicity (nausea, vomiting, or diarrhea) occurred.

The primary endpoints were a 50 % improvement (decrease) from baseline pain and clinical scores. Pain was measured using a visual analogue scale. Clinical score of the target joint consisted of a compounded score based on pain, tenderness on palpation, swelling, and redness graded on a four-point scale (none 0, mild 1, moderate 2, severe 3) which were added together to generate a final score. The maximum score for any one joint was 12 (range 0-12). The baseline for clinical score, mean (SD), was 9.5 (2.8) for colchicine treated patients and 10.3 (2.4) for placebo patients; and for pain score it was 56 (21) in colchicine treated patients and 68 (21) in placebo patients. The duration of observation was 48 hours.

The study design is considered adequate. The visual analogue scales and clinical scores are widely used and the primary endpoints were judged appropriated.

Statistically significant responder difference was presented for both pain and clinical score at 36 and 48 hours after starting treatment and the difference sizes were roughly 40 to 50 % (Ahern et al. 1987).

In the figures from the study by Ahern et al., it is noted that a therapeutic response occur earlier in the colchicine treated patients as compared to the placebo treated patients.

There is a possible risk of unblinding due to AEs as colchicine toxicity (diarrhea and /or vomiting) occurred before there had been a major improvement in the clinical score in 91 % of the patients randomized to this treatment; however, the results are considered clinically relevant and support the effect of colchicine on acute gout, although it is a small study.

Prophylaxis (Prevention) of gout attacksThe Applicant provided data from published literature including one randomised, placebo-controlled clinical trial, and one additional open-label trial (see a short summary below).

Paulus et al. 1974Title: Prophylactic colchicine therapy of intercritical gout. A placebo-controlled study of probenecid-treated patients.

This study is a randomised, double-blind, placebo-controlled trial of colchicine, aimed to evaluate the usefulness of prophylactic colchicine in patients initiated with urate-lowering treatment of probenecid.

Male patients with confirmed gout were admitted to a parallel study for 6 months of therapy. Independently 28 patients were studied in Los Angeles, and 23 were studied in Kansas City, i.e. in total 51 patients; using essentially the same protocol. Diagnosis of gout was based on the presence of hyperuricemia (serum urate > 7.5 mg/100 ml) and a history of typical attacks of acute arthritis that responded promptly to intensive colchicine therapy.

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Patients were given identical-appearing tablets containing either 500 mg of probenecid or 500 mg of probenecid with 0.5 mg of colchicine, three times daily.

The primary endpoint was the number of gout attacks per month of treatment in each patient.

The study by Paulus et al. showed statistical significant lower rate of gout flares per month in patients in the colchicine-probenecid group as compared to patients in the placebo-probenecid group.

The study results support prophylactic effectiveness of colchicine in patients with gout initiated with urate-lowering treatment of probenecid, although it is a small study.

There is a number of limitations in study design, such as differences regarding the study conduct between the two study sites, for instance in the Los Angeles study, all urate lowering agents were withdrawn 2 weeks before therapy began, while in the Kansas City study, subjects were stabilized on probenecid (1.5 gm daily) for 2 weeks before start of therapy. But this study can still be considered as a supportive trial.

Yu et al. 1982Title: The Efficacy of Colchicine Prophylaxis in Articular Gout - A Reappraisal After 20 Years.

This study reviewed the experience of 540 patients, 518 males and 22 females over a period of more than 20 years. The study was mainly to assess the reappraisal of the efficacy of colchicine in the prevention of acute attacks of gouty arthritis.The duration of prophylaxis in this group of 540 patients varied from 2 yr to more than 20 yr. Patients received colchicine 0.5 or 1.0 mg (only one patient required 2.0 mg/day and then dose was reduced to 1.0 mg/day 2 yr later).

The results of this open-label study presented by the Applicant support the conclusions of the randomised, placebo-controlled trial.

The following is additional published data provided in the response document.

Borstad et al. 2004Title: Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis.

This study is a randomised, placebo-controlled trial of colchicine. Subjects with crystal-proven gouty arthritis were included based on accepted criteria for allopurinol administration: presence of tophi, uric acid overproduction, frequent attacks of gout (3 attacks/year), elevated serum urate in the setting of chronic renal insufficiency (CRI), and nephrolithiasis. Forty-three patients starting allopurinol for crystal-proven chronic gouty arthritis were randomised to receive either colchicine 0.6 mg twice daily (n=21) or placebo (n=22); once-daily dosing was utilized for subjects with chronic renal insufficiency (creatinine clearance of 20-50 ml/min). The patients initiated allopurinol treatment at 100 mg po QD. The dose of allopurinol was increased in 100 mg increments until a serum urate level of < 6.5 mg/dl was attained (in the renal insufficiency, dose escalated in 50 mg increment); the patients were on the study drug for 3 months beyond attaining a serum urate level of < 6.5 mg/dl. Treatment arms were analysed regarding frequency of flares, likelihood of any flare or multiple flares, severity of flares on the visual analogue scale (VAS), and length of flares in days.

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Patients were evaluated at 3 and 6-month time-points for evidence of acute gout flares.

It is noted that the figures from the study by Borstad et al. showed statistical significant fewer acute gout flares experienced in patients treated with colchicine as compared to placebo-treated patients, in both 0-3 and 3-6 month time period; and overall statistical significant fewer acute gout flares were observed in the colchicine group than in the placebo group.

Furthermore, the study results showed that multiple gout flares occurred in 14% of the colchicine subjects and 63% of the placebo subjects (p = 0.004), severity of acute gout flares measured by VAS averaged 3.64 in the colchicine group versus 5.08 in the placebo group (p = 0.018); and fewer recurrent gout flares occurred (p = 0.001).

The study results support treating patients with colchicine during initiation of allopurinol therapy for 6 months, although it is a small study with a number of limitations in the study design such as that the acute gout flares were recorded retrospectively. This study can be considered as a supportive trial.

In summary:Based on initial application and additional published data provided in the response document; there are evidence from two randomised, placebo-controlled trials (Paulus at al.1974 and Borstad et al. 2004), which clearly suggests the efficacy of lower dose colchicine for the prophylaxis of recurrent gout and for prevent of acute attacks during the initial treatment with allopurinol or uricosuric drug. Furthermore based on international guidelines including the 2016 updated EULAR evidence-based recommendations for the management of gout (Richette et al. Ann Rheum Dis 2017), prophylaxis is recommended during the first 6 months of ULT (urate-lowering therapy) and recommended prophylactic treatment is colchicine, 0.5–1 mg/day, a dose that should be reduced in patients with renal impairment.

In the current SmPC section 4.1, the proposed wording for this indication is “Profylaktisk behandling av gikt hos vuxna.” The added wording “Adults” is endorsed. However, the Applicant should update the indication to: profylax mot återkommande gikt och förebyggande av akuta attacker under inledande behandling med allopurinol eller urinsyrasänkande läkemedel. Furthermore, the wording “Adults” should be placed above the indications of both the acute gout and the prophylaxis.The Applicant has updated the SmPC section 4.1 as requested (see overall conclusions on clinical efficacy). Colchicine in Familial Mediterranean fever (FMF)The Applicant provided data from published literature including 3 published clinical trials and one of them is a randomised, placebo-controlled trial (Zemer et al. 1974). See a short summary below.

Zemer et al. 1974Title: A controlled trial of colchicine in preventing attacks of familial Mediterranean fever.

Citation Design Treatment No. of patients

Results

Zemer et al. 1974

A four-month, double-blinded, placebo-

Colchicine 0.5 mg or placebo twice daily, for two

N=22Table 2. Two-Month Study of Independent Samples – Mean Number of Attacks

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controlled, crossover study

month followed by additional two months of other treatment

Mo of Study

Mean No. of Attacks

p Value

COLCHICINE PLACEBO

1st 0.70 2.50 <0.012d 0.45 2.83 <0.01Both 1.15 5.25 <0.01

The study design is considered adequate for the randomised double-blinded and placebo-controlled studies. The crossover design has advantage that patients serve as their own controls. The primary endpoint for the study was the difference in the number of FMF attacks between the colchicine and the placebo treatment periods. The dosage regimen is 1 mg daily. Despite the small number of patients (n=22) and the questionable statistical analysis, the results support the effect of colchicine on FMF.

Zemer et al. 1986Title: Colchicine in the prevention and treatment of the amyloidosis of Familial Mediterranean Fever.

This is a study of colchicine in the prevention and treatment of the amyloidosis of FMF.A total of 1070 patients with FMF were advised to begin taking colchicine (1 to 2 mg daily) during 1973 to 1980 and they were followed for 4 to 11 years.

The authors concluded that colchicine prevented amyloidosis in this high-risk population and that it can prevent additional deterioration of renal function in patients with amyloidosis who have proteinuria but not a nephrotic syndrome.

Ben-Chetrit and Levy et al. 1991 Title: Colchicine Prophylaxis in Familial Mediterranean Fever: Reappraisal After 15 Years.

Forty-five patients with FMF (23 men and 22 women, aged 2 to 67 years (mean 39) and the age at diagnosis ranged from 4 to 50 years with mean 18), were included in the study and all of the patients were on colchicine treatment for a minimum of 15 years. Seventeen patients received 1.0 mg, 17 required 1.5 mg, while 11 received 2.0 to 3.0 mg colchicine daily.

Thirty-two patients (72%) responded well; the frequency of attacks was less than one per 6 months. In this group, 20 patients were completely disease free. Seven patients (15%) had less than one attack per 3 months, while six patients (13%) responded poorly and suffered from one or more episodes per month. This group included three women who had premenstrual attacks, despite a relatively high dosage of colchicine (2.0 to 3.0 mg/d). Nevertheless, it was noted that attacks under colchicine treatment were milder and of shorter duration compared with those before colchicine therapy. Discontinuation of the drug was accompanied, in most of the patients, by a relapse within a few days. Articular involvement is less responsive to colchicine (in four patients in whom arthralgia or arthritis were the major manifestation of the disease); and may require therapy with NSAID.

The followings are additional published data provided in the response document.

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Zemer et al. 1991Title: Long-term colchicine treatment in children with familial Mediterranean fever.

This study is an open-label study of long-term colchicine treatment in children with familial Mediterranean fever. A total of 350 children (<16 years of age) were included. The initial dosage was set at 0.5 mg/day, which soon proved insufficient for most of them. The dosage was increased to 1 mg/day. If remission from attacks of FMF was not achieved, the dosage was increased to 1.5 mg/day and, subsequently, to a maximum dosage of 2 mg/day, in 2 divided doses.

There was complete remission of attacks in 64% of treated paediatric patients. Partial remission, which was defined as either a significant decrease in the frequency and severity of all forms of attacks or a remission of one form (usually, abdominal) but not of another (usually, arthritic), was experienced by an additional 31% of the patients.

No deviation from normal growth or development was observed in the treated patients.

Polat et al. 2016 Title: Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever – a randomized controlled noninferiority trial.

This study is a multicenter, randomized controlled noninferiority trial of two parallel groups with 24-week colchicine treatment, to examine the efficacy and safety of a once-daily dosage schema of colchicine compared with a twice-daily dosage schema in pediatric patients with familial Mediterranean fever.

The required colchicine dosage was calculated as a total of 1 mg daily according to an internationally accepted advisory i.e. patients between 5 and 10 years of age should receive colchicine 1 mg/day, which was the age range of the study patients in both groups (7.90 ± 1.96 years in once-daily dosage group; 7.78 ± 2.00 years in twice-daily dosage group). All patients were prescribed 0.5-mg colchicine tablets. Patients in the once-daily dosage group were given two colchicine tablets at 8:00 a.m. The twice-daily dosage group received one 0.5-mg colchicine tablet at 8:00 a.m. and one 0.5-mg colchicine tablet at 8:00 p.m. Thus, the total dosage was given in either one dose or two divided doses. The primary objectives of this study were to compare the effectiveness of once- and twice-daily colchicine dosage regimens regarding control of disease symptoms, reducing disease severity assessed using the modified Mor scoring system, and laboratory findings indicative of inflammation, such as ESR, CRP, and SAA.

A total of 92 patients were selected, and 79 patients completed the study (42 patients in the once-daily dosage group and 37 in the twice-daily dosage group). The results indicated that the once-daily dosage was not inferior to the twice-daily dosage regarding decrease in attack frequency and duration as well as improvement in clinical findings and Mor severity scores. Alterations in laboratory findings indicating inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A, were similar in both groups. The rates of drug side effects were similar between the once- and twice-daily dosage groups, implying comparable safety of colchicine, with the exception of diarrhea, which was slightly higher in the once-daily dosage group.

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The authors concluded that using colchicine with either a once- or twice-daily dosage provides similar clinical and laboratory improvements; considering both efficacy and safety, colchicine can be prescribed with a once-daily dosage.

Ozkaya and Yalcinkaya 2003 Title: Colchicine treatment in children with familial Mediterranean fever.

This study is an open-label study of colchicine treatment in children with familial Mediterranean fever (FMF), aimed to find an 'Optimal effective colchicine dosage' for children in terms of body weight and surface area. A total of 62 children with FMF were included (mean age 12.16 ± 8.87 years). And colchicine treatment was initiated by giving 0.5 - 1 mg/day to each patient. The dose was gradually increased up to a maximum 2 mg/day in unresponsive patients; and mean duration of therapy was 45.6 ± 35.5 months.

The results showed that 50% of the patient attacks were controlled by 0.01-0.03 mg/kg/day colchicine (Group 1). However, 26% of the patients needed 0.04-0.05 mg/kg/day (Group 2) and 24% 0.06-0.08 mg/kg/day colchicine (Group 3) in order to reach similar attack control rates. When the optimal effective dose was calculated according to body surface area, it was observed that 29% of the patients received 0.7-0.9 mg/m2/day colchicine therapy (Group A), whereas 48% needed 1.0-1.5 mg/m2/day (Group B) and 23% 1.6-2.0 mg/m2/day colchicine (Group C) in order to control the attacks.

Response to colchicine therapy was favourable and the frequency of attacks reduced remarkably in all groups (P <0.001).

Koşan C and Ozkan B 2004This study is a randomized trial. Thirty-nine patients with the diagnosis of familial Mediterranean fever (FMF) were randomly divided into two groups; group I consisted of 20 patients who continued taking colchicine in 2 or 3 divided doses daily as they did before the study, group II comprised 19 patients who were given the total daily dose of colchicine once a day. Patients were re-examined at 30-day intervals and both groups maintained this regimen for an average duration of 8 months. Five (13%), 31 (79%), and 3 (8%) of the patients were taking 0.5 mg, 1 mg, and 1.5 mg of colchicine daily, respectively. The age range of the study patients was 10.2 ± 4.0 years in group I and 9.8 ± 4.3 years in group II.

The results indicates that prophylactic use of once-daily colchicine causes neither an increase in the incidence of FMF attacks nor acute phase response; there was no difference between these 2 groups with respect to frequency of side effects, number of attacks, and acute phase response. Therefore, the authors concluded that the daily colchicine dose can be given to children with FMF once daily.

In summary: The Applicant initially provided evidence from one randomised, placebo-controlled clinical trial, together with supportive results from two additional studies. Colchicine is commonly used in paediatric FMF patients with long-term treatment. This has, however, not been reflected in the documentation submitted by the Applicant. The Applicant was asked to provide more published efficacy data including randomised, placebo-controlled clinical trials, long-term studies and studies in paediatric population; in order to further justify the effect of colchicine on the treatment of FMF for prophylaxis of attacks and prevention of amyloidosis in both adult and paediatric population. The Applicant has provided response as requested. However, there was limited data provided for children with FMF younger than 4 years treated

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by oral colchicine. The Applicant was asked to add to an age limit in the proposed FMF indication i.e. in children aged 4 years and above; or to further justify. The applicant has addressed the issued and updated the SmPC section 4.1 (Familial Mediterranean fever) as requested (see also overall conclusions on clinical efficacy).

Neutrofila dermatoser Behçet’s diseaseDavatchi et al. 2009The study is a double-blind, placebo-controlled cross-over clinical trial; included 169 Behçet’s disease patients without major organ involvement. Patients were randomly assigned to colchicine (1 mg daily taken at night) or placebo. At 4 months, they were swapped over (colchicine to placebo, placebo to colchicine) for another 4 months. Thus, each patient tried both colchicine and placebo during the study.

The primary outcome was the overall disease activity index (IBDDAM) and the secondary outcome was the responses of the individual symptoms. The use of colchicine improved overall disease activity, oral and genital ulcers, skin lesions and joint manifestations.

However, there are limitations with regard to the cross-over design when studying efficacy, e.g. as discussed by the authors for the patients who dropped out (one of the reasons for this could be inefficacy of the treatment, as the patients knew that they could be on placebo instead of colchicine, they could have bought colchicine over the counter instead).

Yurdakul et al. 2001The study is a 2-year randomised, double-blind, placebo-controlled clinical trial of colchicine in Behcet’s Syndrome, included 116 patients with Behcet’s syndrome (60 male and 56 female), who had active mucocutaneous disease without eye or major organ involvement, to receive either placebo or colchicine (1–2 mg/day, adjusted to body weight) for 2 years.

All patients were required to meet the inclusion criteria, which meant that they had to 1) be consecutive patients (male or female), 2) be 18–35 years of age, 3) have active disease, 4) have a disease duration of 2 years, and 5) live at a reasonable traveling distance from our center. Active disease was defined as the minimum presence of oral or genital ulceration or erythema nodosum occurring at least 3 times within the preceding 6 months. The disease duration was defined as the time that had elapsed since the diagnostic criteria had been fulfilled.

The primary outcome measure was the sustained absence of any lesions during treatment (complete response). The secondary outcome measure was the difference in the number of mucocutaneous lesions or arthritic joints between the active drug and placebo arms. Women and men were analyzed separately.

Colchicine use significantly reduced the incidence of genital ulcers, erythema nodosum and arthritis, in the women; and significantly reduced the incidence of arthritis, in the men. No significant difference was noted on the outcome of oral ulcers. The authors concluded that colchicine may be useful for treating some of the manifestations of Behcet’s syndrome, especially among women. This might be a reflection of less severe disease among the women.

The patients included in this trial were relatively young and had short disease duration at entry to the study and thus the results would not be applicable to those with extended disease.

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Miyachi et al. 1981The authors reported 5 cases of Behcet's disease patients (Age/Sex: 45/M, 40/M, 59/F, 50/F, 33/M) treated with oral colchicine 1 mg daily. The authors concluded that colchicine may be considered the treatment of choice in the management of the skin manifestations of Behcet's disease.However, efficacy information from these case reports was very limited.

Masuda et al. 1989The study is a randomised double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporine in Behcet's disease. The study included 96 patients with 92 evaluated, compared cyclosporin (10 mg/kg per day) to colchicine (1 mg daily) for 16 weeks for the management of ocular manifestations of Behcet's disease.

This double-masked study showed that cyclosporin was effective in treating not only the ocular manifestations of Behcet’s disease but also oral aphthous ulcer, dermal lesions, and genital ulceration.The cyclosporine alleviated oral aphthous ulceration in 70 % compared to 20 % in the colchicine group (p<0.001). Dermal lesions were alleviated in 40% of the cyclosporin group and in 15% of the colchicine group (p < 0.01).

Mizushima et al. 1977The authors in a letter published in the Lancet 1977 reported that they have collected information about colchicine therapy on 131 patients with Behcet's disease treated in their hospitals and on 26 cases treated elsewhere.

All patients had had typical and frequent ocular attacks for more than a year. One tablet of colchicine (0.5 mg) was given twice daily for more than a year. In some cases, however, patients were given one or three tablets daily according to the severity of symptoms. Most of the other treatments were not changed. The effects of colchicine were estimated by comparing the frequency and severity of ocular attacks in one year before and after starting the colchicine therapy. The criteria were "much improved" (reduced in more than 80%), "improved" (definitely reduced, about 50% on average), "no change", or "worse". 46 patients were much improved, 58 were improved, in 42 there was no change, and 11 got worse. However, information provided from the publication was very limited.

The following is additional published data provided in the response document.

Al-Waiz et al. 2005 This study is a case-comparative study to evaluate efficacy of combined colchicine and benzathine penicillin in the treatment and prophylaxis of Behçet disease. The study included 66 patients fulfilled diagnosis of Behçet disease with the mucocutaneous manifestations, eye involvement and joint involvement; who were divided into three groups: group 1 (20 patients) received 1.2 Mu benzathine penicillin injection monthly; group 2 (21 patients) received two tablets of colchicine daily (each tablet contained 0.5 mg); and group 3 (25 patients) received both 1.2 Mu benzathine penicillin injection monthly and two tablets of colchicine daily. Each patient was followed up monthly for 5 months (4 months on treatment and 1 additional month follow-up). The clinical manifestation index (CMI), the numerical sum of the clinical features, was calculated for each patient initially and then monthly. When each colchicine and benzathine penicillin are used alone the CMI is reduced significantly, but this reduction is much less than when both drugs are used together and there is also rapid and earlier relapse. The authors concluded that the combination of colchicine and benzathine penicillin appears to be of greater efficacy in the treatment of Behçet disease than the use of either drug alone.

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In summary, for Behcet’s disease, colchicine could be effective in certain symptoms/signs in selected patients but there is no evidence to support the claimed manifestation neutrophil dermatosis in Behcet’s disease in the provided publications. See further discussions under overall conclusions on clinical efficacy. The Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Behçet’s disease.

Colchicine for Sweet’s syndrome (acute febrile neutrophilic dermatosis)Suehisa and Tagami 1981Suehisa and Tagami, in a correspondence to British Journal of Dermatology, reported one case regarding one 29-year-old male patient with diagnosis of Sweet's disease made on the basis of the clinical and histopathological features of the skin lesions and did not respond to oral potassium iodide 0.5 mg 3 times daily for 5 days but improved gradually with oral prednisone 10 mg daily for 4 week. Five months later, the patient had a 5-day history of dusky-red, tender, swollen plaques on the left forehead and the right upper eyelid associated with aphthous stomatitis and this time he was treated with 0.5 mg of oral colchicine three times daily. Within 2 days the tender erythematous plaques and aphthae began to recede and they disappeared within one week without the development of arthralgia.

Suehisa et al. 1983Suehisa et al. reported three cases of Sweet's syndrome treated with colchicine. All three cases had typical skin lesions; dusky-red, tender, swollen plaques or nodules histologically showing massive infiltration with a variable mixture of polymorphonuclear leukocytes and mononuclear cells. In addition to the typical signs, oral aphthosis was noted in two cases, and in case 3 an erythema nodosum-like lesion was found on the left lower leg which histologically showed the features of thrombophlebitis. In case 2, a skin biopsy specimen from the dusky-red plaque on the dorsum of the right hand showed the features of 'vasculitis', i.e. fibrinoid degeneration of the dermal vessels with peripheral polymorphonuclear leukocyte infiltration and nuclear debris.

Treatment with oral colchicine was started with 1.5 mg daily and clinical improvement appeared within 2-5 days in all patients. Cases 2 and 3 were able to stop taking the drug after 7 days, and in case 1 the dosage of colchicine was gradually reduced to 0.5 mg daily over 3 weeks to prevent recurrence. In case 2 the effectiveness of colchicine was confirmed in two different attacks.

Maillard et al. 1999Maillard et al. reviewed retrospectively cases in patients with a diagnosis of Sweet’s syndrome from 1984 to 1996 in the author’s department who were treated with colchicine. The diagnostic inclusion criteria were: the presence of typical skin lesions, i.e. painful, raised erythematous plaques; and of characteristic histopathological changes, e.g. a predominantly neutrophilic infiltration in the dermis without a leucocytoclastic vasculitis. All patients had a pyrexia > 38 °C, a raised white cell count composed of > 70% segmented nucleated neutrophils and an erythrocyte sedimentation rate of > 30mm in the first hour (normal < 10). Twenty patients were identified (12 women, eight men), aged between 29 and 93 years (median 59). Aside from clinical signs required as inclusion criteria, seven patients had arthritic arthralgia, three conjunctivitis and two myalgia. Colchicine was introduced 2–8 days after the first cutaneous signs at a dose of 1.5 mg/day (16 patients) or 1 mg/day (four patients). The dose of 1 mg/day was given to the first patients and was subsequently increased to 1.5 mg/day. The mean period of the treatment was 15 days (range 10–21).

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The Sweet’s syndrome responded to colchicine in 18 cases (apyrexia was obtained in 24–72 h, the cutaneous lesions were attenuated in 2–5 days and the arthralgia disappeared in 2–4 days). Colchicine was ineffective in two patients.

The following is additional published data provided in the response document.

Youn et al. 2000This article described a case of a 67-year-old female patient with an 8-month history of dusky-red, tender, swollen plaques and nodules with superimposed vesicles and bullae on the buttocks, hands, and ankles associated with rheumatoid arthritis. She was diagnosed with Neutrophilic dermatoses (ND) on the basis of the clinical and histopathological features of the skin lesions. She was treated by 0.6 mg of oral colchicine twice daily and within one week the erythematous plaques and arthralgia began to recede and disappeared within four weeks. The authors concluded that colchicine seemed to improve the signs and symptoms of ND and appeared to be more effective than the other drugs we had used.

In summary, the information available on the Sweet's syndrome as summarised by the Applicant included in total 25 cases, reported by Suehisa and Tagami (1 case), Suehisa et al. (3 cases), Maillard et al. (20 cases retrospectively reviewed) and Youn et al. (1 case). However, robust evidence of the effect of oral colchicine for the treatment of Sweet's syndrome is not considered being provided, based on the information from the cases identified in the literature. See further discussions under overall conclusions on clinical efficacy. The Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Sweet’s syndrome. Colchicine for leukocytoclastic vasculitisCallen 1985The author reported a prospective analysis of an open trial of colchicine. Thirteen patients with cutaneous leukocytoclastic vasculitis were treated with oral colchicine together with corticosteroids. All patients received oral colchicine 0.6 mg twice daily. This dose was then varied according to clinical response or the development of side effects. Evaluation of effectiveness was based on control of disease expression and/or the ability to withdraw concomitant therapy. Complete control of disease occurred in nine patients, partial control (as evidenced by the author’s ability to lower the corticosteroid dosage) was obtained in three patients, and one patient had no demonstrable effects during a one-month period of colchicine therapy. The support for efficacy from the open uncontrolled study is considered limited.

Werni et al. 1986The authors reported a patient with clinically and histologically typical urticarial vasculitis being treated with 0.5 mg of colchicine three times per day. This treatment resulted in both disappearance of urticarial skin lesions and amelioration of severe systemic symptoms such as abdominal pain, fever and arthralgia.

The followings are additional published data provided in the response document.

Plotnick et al. 1989The authors, in a letter to the Editor: reported a case of a 41-year-old white woman with a 5-year history of multiple, intermittent episodes of severe arthralgias involving the knees, elbows, shoulders, and hands, presented with painful, palpable, purpuric lesions, especially over the palms, soles, and buttocks. The patient was treated as an outpatient for several months with oral prednisone, 60 mg/day. Prior to her last hospitalization, hydroxychloroquine and

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weekly oral methotrexate were added to the treatment regimen. Biopsy of a buttock lesion revealed marked perivascular accumulation of neutrophils and nuclear debris (nuclear dust) in the subepidermal papillae. Direct immunofluorescence testing for immune complex deposition gave negative results. At this time, treatment with colchicine, 0.6 mg orally, twice daily, was initiated. By the fourth day of colchicine treatment, lesions were regressing and the patient's joint symptoms had abated. The authors experienced were consistent with Callen's report of the effectiveness of colchicine therapy in patients with leukocytoclastic vasculitis.

Callen JP and af Ekenstam E 1987The authors studied 44 patients (19 – 86 years) with leukocytoclastic vasculitis who had chronic or recurrent disease of more than three months' duration; while 16 cases were classified as urticarial vasculitis (UV) based on the major clinical manifestations and the remaining 28 cases represented various patterns (nonurticarial leukocytoclastic vasculitis (LV) (chronic or relapsing LV)). The patients were treated with several types of drugs singly or in combination, and most combinations included systemic corticosteroids. The analysis was partly retrospective, but also included same prospective (open) evaluation. Effectiveness of treatment was graded according to resolution of lesions, return to normal of abnormal laboratory findings, or the ability to lower the dosage of a second therapeutic agent (usually a corticosteroid). Systemic corticosteroids, azathioprine, and colchicine appeared to be effective in most patients. Nonsteroidal anti-inflammatory agents, sulfones, antihistamines, and antimalarials were effective only in sporadic cases.

In summary, based on initial application and additional published data provided in the response document; apart from a prospective analysis of one open trial, two case reports and one partly retrospective/partly prospective (open) trial with multiple drugs, there is no data provided on patients with leukocytoclastic vasculitis and thus the documentation submitted by the applicant is considered too limited to support the effect of colchicine in this condition. The Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Leukocytoclastic vasculitis.

Assessor’s overall conclusions on clinical efficacyDiscussion on clinical efficacyColchicine has been used for centuries and it has been approved as an anti-gout therapy since 1947 in Europe. Colchicine was also approved by the FDA in 2009 for treatment of acute gout flares and for use in the prevention of acute gout flares in adults; and for treatment of Familial Mediterranean Fever.There are several oral colchicine products approved in Sweden for indications of gout (acute gout and prophylaxis of gout attacks) and FMF, including Colchimex, 500 mikrogram, Tablett, which was approved through WEU with SE as RMS and BG, IS, PL as CMS (SE/H/1427/01/DC).

This application is submitted according to Article 10a of Directive 2001/83/EC.The proposed indications include:Akut behandling av gikt som alternativ vid kontraindikation mot t.ex. NSAID.Profylaktisk behandling av gikt.Neutrofila dermatoser, t.ex. vid Behcets sjukdom, leukocytoklastisk vaskulit och Sweets syndrom.Familjär Medelhavsfeber.

GoutGout is one of the most common inflammatory arthritis conditions, with acute flares and chronic manifestations.

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First-line options for treatment of acute gout are nonsteroidal antiinflammatory drugs (NSAIDs), oral colchicine or corticosteroids, based on recommendations and guidelines (the European League Against Rheumatism (EULAR) guidelines, 2006 and 2016; the American College of Rheumatology Guidelines, 2012; the multinational evidence-based recommendation, 2014).

Chronic gout, manifested as recurrent episodes of acute gout as well as deposition of uric acid crystals in tissues (tophi), is treated with therapies to reduce uric acid levels aimed to reduce the risk of gout flares and the resolution of tophi. Oral colchicine, along with NSAIDs, is an appropriate first-line gout attack prophylaxis therapy, recommended by Guidelines of the American College of Rheumatology (2012) and the multinational recommendation on the diagnosis and management of gout which are evidence-based and supported by a panel of rheumatologists from 14 countries (Sivera et al. 2014).

Recently Ilaris (canakinumab) was approved to treat the symptoms in adults with frequent attacks of gouty arthritis when NSAIDs and colchicine are contraindicated, not tolerated or do not work adequately, and when repeated treatment with corticosteroids is not appropriate.

Acute goutThe results from the two randomised and placebo-controlled trials (Terkeltaub et al. 2010 and Ahern et al. 1987) are considered clinically relevant and support the effect of colchicine on acute gout, although the Ahern trial was a small study. It is especially noted that the study by Terkeltaub et al. (2010) concluded that the low-dose colchicine regiment (1.8 mg total over 1 hour) maintained efficacy equivalent to that of high-dose colchicine (4.8 mg total over 6 hours) in the treatment of early acute gout flare. Furthermore, no treatment arm of NSAIDs was included in the two studies and the patients studied in the Terkeltaub trial did not have contraindication for NSAIDs. Please also see discussion on clinical safety (under dosing).

The American College of Rheumatology has updated theirs Guidelines for Management of Gout (Khanna et al. Arthritis Care & Research Vol. 64, No. 10, October 2012, Part 1 and Part 2). They conclude that nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are appropriate first-line options for treatment of acute gout, and certain combinations can be employed for severe or refractory attacks.

This is in accordance with the EULAR, European League Against Rheumatism, report by the Standing Committee for International Clinical Studies Including Therapeutics (Zhang et al. Ann Rheum Dis 2006), and 2016 updated EULAR evidence-based recommendations for the management of gout (Richette et al. Ann Rheum Dis 2017). The 2016 updates EULAR recommended first-line options for acute flare are colchicine at a loading dose of 1 mg followed 1 hour later by 0.5 mg on day 1 and/or a NSAID, oral corticosteroids or articular aspiration and injection of corticosteroids.

This is also supported by a multinational recommendation for the diagnosis and management of gout which is evidence-based and supported by a panel of rheumatologists from 14 countries (Sivera et al. 2014). The recommendation for acute gout concluded that there was consensus that NSAIDs, colchicine and glucocorticoids (given as intra-articular, oral or intramuscular therapy) are all effective in the treatment of acute gout flares and that there was insufficient evidence to prioritise them. Individual treatment decisions should be based on consideration of an individual’s characteristics and each drug’s safety profile.

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The Applicant was asked to justify the proposed indication wording for acute gout, i.e. why currently it states that colchicine is an alternative when NSAIDs are contraindicated; or remove this restriction for the NSAIDs. The Applicant has removed the restriction for NSAIDs. The proposed SmPC 4.1 is currently updated as “akut behandling av gikt”; however, this should be reworded as: Behandling av akut gikt. Furthermore, wording “Adults” should also be added and the wording “Adults” should be placed above the indications of both the acute gout and the prophylaxis. The Applicant has updated the SmPC section 4.1 indication to ”Behandling av akut gikt”. Furthermore, the wording “Adults” has been added and placed above the indications of both the acute gout and the prophylaxis.

Prophylaxis (Prevention) of gout attacksThe Applicant initially provided data from published literature including one randomised, placebo-controlled clinical trial, and one additional open-label trial, which is not considered sufficient for support the effect of colchicine on prophylaxis of gout attacks. Additional confirmatory randomised study of colchicine has not been submitted.

The American College of Rheumatology has updated theirs Guidelines for Management of Gout (Khanna et al. Arthritis Care & Research Vol. 64, No. 10, October 2012, Part 1 and Part 2). They conclude that oral colchicine is an appropriate first-line gout attack prophylaxis therapy, including with appropriate dose adjustment in chronic kidney disease and for drug interactions, unless there is a lack of tolerance or medical contraindication.

This is in accordance with the EULAR, European League Against Rheumatism, report by the Standing Committee for International Clinical Studies Including Therapeutics (Zhang et al. Ann Rheum Dis 2006), and 2016 updated EULAR evidence-based recommendations for the management of gout (Richette et al. Ann Rheum Dis 2017). In the 2016 updates EULAR, prophylaxis is recommended during the first 6 months of ULT (urate-lowering therapy) and recommended prophylactic treatment is colchicine, 0.5–1 mg/day, a dose that should be reduced in patients with renal impairment.

This is also supported by a recent multinational recommendation for the diagnosis and management of gout which is evidence-based and supported by a panel of rheumatologists from 14 countries (Sivera et al. 2014).

The Applicant was asked to provide more efficacy data/published data with regard to clinical trials especially randomised, placebo-controlled clinical trial together with additional supportive trials including long-term study and treatment recommendation (s); to further justify the efficacy of lower dose colchicine for the prophylaxis of recurrent gout and for prevent of acute attacks during the initial treatment with allopurinol or uricosuric drug. Furthermore, wording “Adults” should be added to the proposed indication of the prophylaxis. The Applicant has provided response as requested. Based on initial application and additional published data provided in the response document; there are evidence from two randomised, placebo-controlled trials (Paulus at al.1974 and Borstad et al. 2004), which clearly suggests the efficacy of lower dose colchicine for the prophylaxis of recurrent gout and for prevent of acute attacks during the initial treatment with allopurinol or uricosuric drug.

In the current SmPC section 4.1, the proposed wording for this indication is “Profylaktisk behandling av gikt hos vuxna.” The added wording “Adults” is endorsed. However, the Applicant should update the indication to: profylax mot återkommande gikt och förebyggande av akuta attacker under inledande behandling med allopurinol eller urinsyrasänkande läkemedel. Furthermore, the wording “Adults” should be placed above the indications of both the acute gout and the prophylaxis.

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The Applicant has updated the SmPC section 4.1 indication to ”profylax mot återkommande gikt och förebyggande av akuta attacker under inledande behandling med allopurinol eller urinsyrasänkande läkemedel.” And the wording “Adults” has been placed above the indications of both the acute gout and the prophylaxis.

Additionally, in this application, the proposed posology of colchicine for prophylaxis of gout is:“Vuxna:Mindre än en akut giktattack per år: 0,5 mg (2 tabletter) 3-4 dagar per vecka.Mer än en akut giktattack per år: 0,5 mg per dag. I svårare fall 0,5 mg 2 eller 3 gånger per dag.Förebyggande av giktattack i samband med kirurgi: 0,5 mg 3 gånger dagligen, med början 3 dagar före operation, tom tredje dygnet efter operationen.”The posology proposed, however, is not considered justified based on the current submitted data. The Applicant was asked to discussed/justify the proposed posology of oral colchicine for prophylaxis of gout attacks, supported by published clinical studies / data. The Applicant has provided published articles which supported/justified the updated posology proposed in the SmPC section 4.2, and the updated posology is accepted. However, the subheading should be reworded to: Profylax mot giktattack under insättande av behandling med allopurinol och medel mot utsöndring av urinsyra. The Applicant has updated the SmPC section 4.2 – subtitle to “Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs.”

FMFFamilial Mediterranean fever (FMF) is an inflammatory disease caused by mutation in the MEFV gene which encodes the protein pyrin and pyrin plays a role in the natural control of inflammation. It is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis or erysipelas-like skin lesion. The most notorious aspect of FMF is amyloidosis which deposits in the kidneys leading to proteinuria and end stage renal failure.

Colchicine has been used for treatment of FMF since 1972 and the aim of colchicine therapy is twofold: decreasing the frequency and severity of clinical attacks and preventing the risk of developing AA (amyloid A) amyloidosis. There are no established alternatives for the small number of patients who do not respond to colchicine or cannot tolerate therapeutic doses of colchicine; however use of interferon-alpha; the tumor necrosis factor–blocking drug etanercept; the interleukin-1 receptor antagonist anakinra (Kineret), rilonacept (Arcalyst) and canakinumab (Ilaris) may be effective (Grattagliano et al. Clin Pharmacol. & Ther. 95 (1), 2014).

Colchicine is commonly used in paediatric FMF patients with long-term treatment. This has, however, not been reflected in the documentation submitted by the Applicant (3 published clinical trials submitted and one of them is randomised, placebo-controlled trial). The Applicant was asked to provide more published efficacy data including randomised, placebo-controlled clinical trials, long-term studies and studies in paediatric population; in order to further justify the effect of colchicine on the treatment of FMF for prophylaxis of attacks and prevention of amyloidosis in both adult and paediatric population. The Applicant has provided response as requested.

Based on initial application and additional published data provided, the evidence from randomised, placebo-controlled trials and supportive results from open-label trials; including long-term studies in paediatric population, are considered adequate for support the effect of colchicine on FMF for prophylaxis of attacks and prevention of amyloidosis including

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paediatric population. The proposed SmPC 4.1 has been updated as “Familjär Medelhavsfeber som profylax mot attacker och förebyggande av amyloidos.”; which is endorsed.

However, there was limited data provided for children with FMF younger than 4 years treated by oral colchicine. The Applicant was asked to add to an age limit in the proposed FMF indication i.e. in children aged 4 years and above; or to justify by 1). Providing results and discussions focusing on number of patients (paediatric population) treated with oral colchicine for the proposed indication (FMF), by each age subgroup (year), together with relevant information such as dose, treatment duration, type of AE and corresponding literature references. 2). Discussing how tablet (recommended “Tabletten ska sväljas hela med ett glas vatten”) could be administered to children younger than 4 years, and in the case if the proposed administration would be crushing tablets, the discussion should be based on tests made on the applicant’s product (a general reference to the literature is not considered sufficient with regard to support the ability to crush tablets i.e. if the applicant’s product can be crushed for dosing to paediatric populations). The applicant responded and referred to a number of publications including Padeh et al (2012), Ozcakar et al (2010), Yalcinkaya et al (2011), Barut et al (2015), Isikay et al (2013), and Kallinich et al (2007). In summary, the referred publications provided limited safety information regarding oral colchicine treated children with FMF aged below 4 years (no individual data presented in the published studies except the study by Padeh et al 2012 which included 14 patients <2 years of age, but without individual dose or AE data reported). Furthermore, there are no results/discussions provided regarding the request of “focusing on number of patients (paediatric population) treated with oral colchicine for the proposed indication (FMF), by each age subgroup (year), …”; and no tests performed to verify that the applicant’s product can be crushed for dosing to paediatric populations.There are several oral colchicine products approved for treatment of FMF in children aged 4 years and above, including Colchimex. The Colchimex (500 mikrogram) was approved in Sweden through WEU with SE as RMS and BG, IS, PL as CMS (SE/H/1427/01/DC).Taken together, the Applicant was requested to add to an age limit in the proposed FMF indication i.e. in children aged 4 years and above. The applicant has updated the SmPC section 4.1 by adding an age (Familial Mediterranean fever) as requested.

Neutrofila dermatoser Behçet’s disease Behçet’s disease is a chronic inflammatory vasculitis that can affect multiple systems such as eye / refractory eye involvement, vascular disease, gastrointestinal, joint, neurological and mucocutaneous involvement. Oral and genital ulcerations, skin lesions, uveitis, and inflammatory vascular involvement of the central nervous system and gastrointestinal tract are common. Neutrophil dermatosis has been described in patients with Behcet´s disease, and it is for this manifestation the Applicant seeks marketing approval.

In summary, for Behcet’s disease, colchicine could be effective in certain symptoms/signs in selected patients but there is no evidence to support the claimed manifestation neutrophil dermatosis in Behcet’s disease in the provided publications. The Applicant was asked to justify the treatment of this manifestation by oral colchicine with more supportive evidence or remove this indication. The only new data provided in the response document is a publication by Al-Waiz et al. (2005), which is a case-comparative study to evaluate efficacy of combined colchicine and benzathine penicillin in the treatment and prophylaxis of Behçet disease. Based on the provided publications, there is no evidence to support the claimed manifestation neutrophil dermatosis in Behcet’s disease and the Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Behçet’s disease.

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Sweet’s syndrome (acute febrile neutrophilic dermatosis)Sweet’s syndrome is characterised by a constellation of clinical symptoms, physical features, and pathological findings which include pyrexia, elevated neutrophil count, painful red papules, nodules, plagues (may be recurrent) and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis; and additionally the syndrome can also present with extra-cutaneous manifestations. Sweet’s syndrome can be classified as classical or idiopathic, malignancy- associated and drug-induced. Sweet’s syndrome is treated by trying to identify and cure any underlying or associated disorders. In the cases no cause or underlying medical association is found, the condition is treated with corticosteroid tablets (prednisone o prednisolone). Corticosteroids can also be applied as a cream or injected into areas of Sweet’s syndrome in mild localised cases. Alternative treatment may be used where corticosteroid are not effective or tolerable, e.g. use of indomethicin, colchicine or potassium iodide were reported.

The information identified in the literature on the Sweet's syndrome (acute febrile neutrophilic dermatosis) as summarised by the Applicant included in total 24 cases and reported by Suehisa and Tagami (1 case), Suehisa et al. (3 cases) and Maillard et al. (20 cases retrospectively reviewed). The submitted information (in total 24 cases) cannot be regarded as robust evidence. Thus robust evidence of the effect of oral colchicine for the treatment of Sweet's syndrome is not considered being provided. The Applicant was asked to justify for the treatment of Sweet’s syndrome by oral colchicine or remove this indication. The only new data provided in the response document is a publication by Youn et al. 2000 which described a case of a 67-year-old female patient diagnosed with Neutrophilic dermatoses and treated by 0.6 mg of oral colchicine.

In summary, the information available on the Sweet's syndrome provided by the Applicant included in total 25 cases, reported by Suehisa and Tagami (1 case), Suehisa et al. (3 cases), Maillard et al. (20 cases retrospectively reviewed) and Youn et al. (1 case). There is no convincing evidence of the effect of oral colchicine for the treatment of Sweet's syndrome (acute febrile neutrophilic dermatosis). The Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Sweet’s syndrome.

Leukocytoclastic vasculitisLeukocytoclastic vasculitis (also known as hypersensitivity vasculitis and cutaneous necrotizing vasculitis) is a small-vessel vasculitis and the skin is the organ most commonly involved. Typical presentation is a painful, burning rash predominantly in the lower extremities, with also patients presenting with trunk and upper extremity involvement. The most common skin manifestation is palpable purpura and patients may also present with arthralgias or arthritis involving the knees or ankles. Multiple etiologic factors associated with leukocytoclastic vasculitis include drugs, infections, foods, autoimmune diseases, collagen vascular diseases, and malignancies. The leukocytoclastic vasculitis usually results from deposition of immune complexes at the vessel wall; systemic involvement is likely when IgA is the dominant immunoglobulin in immune complexes, and systemic involvement is less when due to IgG- or IgM-containing immune complexes. Therapy of immune complex leukocytoclastic vasculitis includes avoidance or treatment of eliciting agents and use of compression stockings to reduce purpura. Corticosteroids are indicated when there are signs of incipient skin necrosis. Colchicine has also been used in patients with skin and joint symptoms. Severe systemic vasculitis requires immunosuppressive strategies.

The Applicant provided the following publications.

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Callen (1985)The author reported a prospective analysis of an open trial of colchicine Including 13 patients with cutaneous leukocytoclastic vasculitis. Complete control of disease occurred in nine patients, partial control (as evidenced by the author’s ability to lower the corticosteroid dosage) was obtained in three patients, and one patient had no demonstrable effects during a one-month period of colchicine therapy. However, efficacy information from this open uncontrolled study in 13 patients was limited.

Werni et al. (1986)The authors reported a patient with clinically and histologically typical urticarial vasculitis being treated with 0.5 mg of colchicine three times per day. This treatment resulted in both disappearance of urticarial skin lesions and amelioration of severe systemic symptoms such as abdominal pain, fever and arthralgia.

In summary, apart from a prospective analysis of one open trial and a case report, there is no data provided on patients with leukocytoclastic vasculitis and thus the documentation submitted by the applicant is considered too limited to support the effect of colchicine in this condition. The Applicant was asked to justify for the treatment of leukocytoclastic vasculitis by oral colchicine or remove this indication. The only new data provided in the response document is articles by Plotnick et al. (1989) which is a letter to the Editor and reported a case of 41-year-old female outpatient; and Callen JP and af Ekenstam E (1987) which is a partly retrospective/partly prospective (open) trial with multiple drugs given.

Based on initial application and additional published data provided in the response document; apart from a prospective analysis of one open trial, two case reports and one partly retrospective/partly prospective (open) trial with multiple drugs, there is no convincing evidence of the effect of oral colchicine for the treatment of leukocytoclastic vasculiti. The Applicant is requested to remove this indication. The Applicant has updated the SmPC section 4.1 by removing the indication concerning leukocytoclastic vasculitis.

Conclusions on clinical efficacyThe Applicant has provided support for the efficacy of colchicine in the following indications:

VuxnaBehandling av akut gikt.Profylax mot återkommande gikt och förebyggande av akuta attacker under inledande behandling med allopurinol eller urinsyrasänkande läkemedel.

Vuxna och pediatriska patienter från 4 års ålderFamiljär Medelhavsfeber som profylax mot attacker och förebyggande av amyloidos.

There are no remaining issues.

IV.5 Clinical safety

Introduction

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No safety data is available with colchicine 250 micrograms tablets. Hence, the Applicant has submitted data on the basis of the clinical studies on marketed colchicine (500 micrograms) to support this application. Provided that quality and pharmacokinetic issues had been satisfactorily addressed, the submitted safety data on the basis of the clinical studies on marketed colchicine (500 micrograms) could be considered acceptable.

Patient exposureN/A

Adverse eventsTerkeltaub et al. 2010The study is a randomised, double-blind, placebo-controlled clinical trial, included 184 patients with gout flare; compared self-administered low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total]) and high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]) with placebo.

The results of this trial provided the first evidence basis, after centuries of colchicine use, for low-dose colchicine therapy in the treatment of early acute gout flare. The low-dose colchicine regiment maintained efficacy equivalent to that of high-dose colchicine and the results are considered clinically relevant. Further, the AEs occurred in a greater proportion of patients taking high-dose colchicine compared with low-dose colchicine or placebo.

Incidence of AEs was 76.9%, 36.5%, and 27.1% for the high-dose, low-dose, and placebo groups, respectively. In the low-dose group, all AEs were mild to moderate in nature; while 19.2% of high-dose group had severe AEs. The most common AE was diarrhea in all three groups, higher for the colchicine treatment (76.9% and 23% patients with diarrhoea in high-dose group and low-dose group, respectively), as compared with the placebo (13.6% patients with diarrhoea in placebo group). Nausea was occurred in high-dose, low-dose, and placebo groups with 17.3%, 4.1%, and 5.1%, respectively. Vomiting was only reported in the high-dose group (17.3% of patients); while no occurred in low-dose or placebo group.

There were no deaths, serious AEs, or patient withdrawals due to AEs noted from this study (AGREE trial).

Cochrane review (August 2014) compared high-dose versus low-dose colchicine, for all adverse events and gastrointestinal adverse events (diarrhoea, vomiting or nausea) respectively, based on data from the study by Terkeltaub et al. 2010; and concluded that compared with placebo, high-dose but not low-dose colchicine result in a statistically significantly greater number of adverse events, and therefore low-dose colchicine may be the preferred treatment option.

Schlesinger et al. 2011The study is a double-blind, double-dummy, active- controlled study, included 432 patients; to compare safety between canakinumab and colchicine for prophylaxis against acute gouty arthritis flares in the patients initiating urate-lowering treatment.

There was no placebo control group in this study, which is a shortcoming.

This study provided information regarding AEs following oral daily colchicine 0.5 mg for 16 weeks for prophylaxis against acute gouty arthritis flares in patients initiating treatment with allopurinol; including one death (a possible myocardial infarction) not regarded by the

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investigator as being related to study medication, infectious AEs reported in 13 (12.0%) patients receiving colchicine 0.5 mg, and further infections (more than 1% of patients) e.g. upper respiratory tract infections (3.7%) and cystitis (1.9%); no serious infections were reported in the patients receiving therapy of colchicine.

Feng et al. 2015The study is a retrospective study to evaluated the efficacy and safety associated with treatment available to prevent an acute attack of gout when initiating a urate-lowering therapy (ULT). The authors retrospectively reviewed patients who were diagnosed with gout and treated with ULT during the period from January 2000 to January 2014; and the patients were divided into three groups, 75 without prophylaxis treatment, 103 treated with etoricoxib, and 129 with colchicine treatment. In terms of AEs, patients who treated with colchicine had higher rates of gastrointestinal AEs than those who received etoricoxib; diarrhea was the most frequently reported and in 12 (10.7%) patients, also nausea and vomiting reported in 11 (9.8%) patients, furthermore gastrointestinal and abdominal pain reported in 7 (6.2%) patients and abnormal liver function reported in 8 (7.1%) patients in the colchicine group.

However, dosage of colchicine treatment in this study appears not available, and safety information from the uncontrolled study was limited although there were no additional safety concerns revealed as compared to those already established.

Yu et al. 1982The study reviewed the experience of 540 patients, 518 males and 22 females over a period of more than 20 years. The study was mainly to assess the reappraisal of the efficacy of colchicine in the prevention of acute attacks of gouty arthritis. Safety information from this uncontrolled study was very limited.

Ben-Chetrit and Levy 1991The study is a study of colchicine prophylaxis in Familial Mediterranean Fever. The authors reviewed FMF patients who had been followed in their clinic and treated with colchicine for at least 15 years. The study included 45 patients with FMF and all of the patients were on colchicine treatment for a minimum of 15 years. Out of the 45 patients, 17 received 1.0 mg, 17 received 1.5 mg, and 11 received 2.0 to 3.0 mg colchicine daily.

Adverse effects due to colchicine throughout the 15 years of observation were relatively mild and the most common side effects were gastrointestinal symptoms i.e., nausea and diarrhea (4 patients had nausea and 3 had diarrhea, which improved on dosage reduction); one patient had transient leukopenia of 3500/µL, and one had azoospermia. None of the side effects necessitated drug discontinuation.

Safety information from this uncontrolled study was limited and there was also risk of underreporting.

Naalt et al. 1992, Babu et al. 1982 and Uri and Biavis 1996Four case reports regarding colchicine neuromyopathy were provided.

- Naalt et al. (1992) reported severe colchicine neuromyopathy occurred within a few weeks of treatment by using electromyography, in a 66 year old male patient.

- Babu et al. (1982) reported that needle electromyography (EMG) showed probable colchicine neuromyopathy, in a 83-year-old male patient.

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- Uri and Biavis (1996) reported two cases of colchicine neuromyopathy which can complicate standard gout treatment especially in these two patients with underlying renal impairment (a 57-year old man and a 43-year old man).Following discontinuation of colchicine therapy, colchicine neuromyopathy were reversed.

Myopati is a known AE following colchicine treatment, which has been reflected in the proposed SmPC. The case reports included one case of positive dechallenge. Salem et al. 2010The authors provided one case report regarding colchicine-Induced rhabdomyolysis, in a 65-year-old female patient with chronic atrial fibrillation who was treated with amiodarone and acenocoumarol. Two weeks after administration of conventional dosage of colchicine (1 mg daily) for pericarditis, the patient developed rhabdomyolysis. Colchicine-induced rhabdomyolysis was suspected. Colchicine was stopped and the patient underwent supportive therapy. Clinical symptoms improved rapidly.

This case report discussed that concomitant colchicine and amiodarone which inhibits P-glycoprotein may increase colchicine toxicity. See also comments under Drug-Drug Interactions.

Eleftheriou et al. 2008The authors provided one case report regarding colchicine-induced toxicity in a heart transplanted 60-year old patient with chronic renal failure. This case report indicated that life-threatening colchicine toxicity in patients with renal compromise due to high blood concentrations of colchicine by co-administration of therapeutic doses of colchicine with cyclosporine which inhibits P-glycoprotein and CYP3A4 thus further decreasing hepatic and renal elimination of colchicine. See also comments under Hepatic and Renal Impairment; and Drug-Drug Interactions.

Rollot et al. 2004 and Velden et al. 2008Two case reports, with regard to acute colchicine intoxication and macrolides (Clarithromycin), were provided.

Other informationThe Applicant has provided published SmPCs to support safety profile/ADRs of oral colchicine.

However, for an application according to Article 10a, WEU, the applicant needs to demonstrate that the active substance of the medicinal product has been in well-established medicinal use for the claimed therapeutic indication within the Union for at least ten years, with recognised efficacy and an acceptable level of safety which need to be supported by means of bibliographic data. There are information about ADRs for oral colchicine and their frequencies available in published clinical trials. The frequencies of ADRs based on long-term high-dose data are regarded as a worst case scenario and thus could be acceptable if submitted. The Applicant has updated the SmPC section 4.8 with regard to the proposed ADRs and/or their frequency categories; supported by published safety data together with source they have been derived. This is considered acceptable. The Applicant has also updated the SmPC section 4.8 by adding a summary of safety profile of colchicine in accordance with the SmPC Guideline.

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Safety in special populationsPaediatric UseFMF is a chronic, lifelong inflammatory disease. Colchicine is commonly used in paediatric patients for treatment of FMF. There was very limited information with regard to paediatric patients provided in this application. The Applicant should provide safety data / published data to justify safe use of colchicine in the paediatric patient population, especially under long-term treatment.

The Applicant has proposed a starting dose between 0.5 mg and 1.5 mg based on age for paediatric use in treatment of FMF and the dosage should be increased in a stepwise fashion up to a maximum of 2 mg/day to control disease in patients who do not clinically respond to the standard dosage. However, if a patient 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. This aspect has not been reflected in the proposed SmPC. The Applicant is asked to discuss how this should be addressed in the proposed SmPC to ensure safe use of oral colchicine in paediatric patient population for treatment of FMF.

The Applicant has addressed concern to ensure safe use of oral colchicine in paediatric patient population for treatment of FMF; and text in the SmPC section 4.2 was updated, concerning concomitant therapy with a moderated or potent CYP3A4 inhibitor or with a P-glycoprotein inhibitor.

Geriatric UseConsidering limited data on clinical use of colchicine in elderly patients with gout and safety aspects such as comorbid conditions, concomitant medications, and longer term use for prophylactic treatment of recurrent gout flares in this patient population, careful monitoring is needed for elderly patients with gout especially who are >65 years of age. This information (careful monitoring) should be added in appropriate SmPC sections. The Applicant has addressed concern regarding clinical use of colchicine in elderly patients with gout; and the updated text in the SmPC section 4.4 is accepted. However, in the section 4.2, it is recommended to replace “Det är nödvändigt med noggrann övervakning av äldre patienter med gikt och i synnerhet patienter > 65 år.” with a reference to the section 4.4 i.e. (see section 4.4). The Applicant has updated the SmPC section 4.2 as requested.

Hepatic and Renal ImpairmentUse of colchicine in combination with a potent CYP3A4 inhibitor or with an inhibitor of the P-glycoprotein transport system in patients with renal impairment should be contraindicated, which has been reflected in the proposed SmPC.

Use of colchicine in combination with a potent CYP3A4 inhibitor or with an inhibitor of the P-glycoprotein transport system in patients with hepatic impairment should be contraindicated, which has been reflected in the proposed SmPC.

Use in Pregnancy, Reproduction and LactationSee section Non-clinical aspects.

Over-dosageFor oral colchicine, poisoning usually start with gastrointestinal phase mimicking gastroenteritis (10-24 h after ingestion), followed by multi-organ dysfunction (24 h to 7 days after ingestion). Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis.

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Colchicine has a narrow therapeutic window. Serious AEs including death associated with colchicine therapy have been reported in patients with underlying increased risks for colchicine toxicity e.g. patients with renal or hepatic impairment, or patients with concomitant therapy of P-glycoprotein or CYP3A4 inhibitors.

Both physicians and patients should be aware of the significant potential for, and the various stages of, toxicity of oral colchicine. The text for section 4.9 of the proposed SmPC has been updated in accordance with the SmPC of recently approved product Colchimex.

Drug-Drug InteractionsSerious AEs including death associated with colchicine therapy have been reported in patients with concomitant therapy of P-glycoprotein or CYP3A4 inhibitors. Use of colchicine in combination with a potent CYP3A4 inhibitor or with an inhibitor of the P-glycoprotein transport system in patients with renal or hepatic impairment should be contraindicated, which has been reflected in the proposed SmPC. Oral colchicine dose should be reduced or treatment of colchicine interrupted in patients with normal renal or hepatic function if concomitant therapy of P-glycoprotein or potent CYP3A4 inhibitor is required.

For details, see separate Clinical Pharmacokinetic Assessment Report.

Assessor’s overall conclusions on clinical safetyDiscussion on clinical safetyThere is a long history of colchicine use in Europe (EURD 30/07/1947) and its safety profile in the gout indications is well-known over decades of clinical practice.

DosingAcute GoutThe low dose regimen is regarded as a better option considering potential serious AEs/death occurred. A daily dose of lower than 2 mg is generally recommended.This recommended posology was based on the following considerations:- Efficacy of lower doses of oral colchicine for treatment of acute gout is considered

sufficiently supported by the published literature.- Oral administration of colchicine is mostly well tolerated at therapeutic dose range for

treatment of gout; overall low-dose oral colchicine appeared better tolerated than the high-dose colchicine.

- Colchicine has a narrow therapeutic window and serious AEs including death associated with colchicine therapy have been reported and it has usually occurred in patients with underlying increased risks for colchicine toxicity e.g. in patients with renal or hepatic impairment, or drug-drug interactions especially patients with concomitant therapy of P-glycoprotein or CYP3A4 inhibitors, or in the context of overdosing.

In this application, the proposed posology of colchicine for treatment of acute gout for adult included 1 mg (4 tablets) to be taken initially followed by 0.5 mg (2 tablets) with a dosing interval about 2-3 hours until symptom is free or AEs in form of vomiting or diarrhea occurs; and an alternative proposed is 0.25 mg (1 tablet) with dosing 2+2+2 tablets.

The posology proposed, however, is not considered justified based on the current submitted data. The Applicant was asked to discussed/justify the proposed posology of oral colchicine for treatment of acute gout, supported by published clinical studies / data. The Applicant has

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provided published articles which supported/justified the updated posology proposed in the SmPC section 4.2, and the updated posology is accepted.

However, regarding the proposed posology of oral colchicine for treatment of prophylaxis of gout attacks in the proposed SmPC section 4.2, the subheading should be reworded to: Profylax mot giktattack under insättande av behandling med allopurinol och medel mot utsöndring av urinsyra. The Applicant has updated the SmPC section 4.2 – subtitle to “Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs.”

FMFThe Applicant has proposed a starting dose between 0.5 mg and 1.5 mg based on age for paediatric use in treatment of FMF and the dosage should be increased in a stepwise fashion up to a maximum of 2 mg/day to control disease in patients who do not clinically respond to the standard dosage.

However, if a patient 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. This aspect has not been reflected in the proposed SmPC. The Applicant was asked to discuss how this should be addressed in the proposed SmPC to ensure safe use of oral colchicine in paediatric patient population for treatment of FMF. The Applicant has updated text in the SmPC section 4.2, regarding concomitant therapy with a moderated or potent CYP3A4 inhibitor or with a P-glycoprotein inhibitor, which is accepted.

Adverse eventsSafety profile of colchicine in the gout indications is well-established. The most important safety issue is colchicine has a narrow therapeutic window. Serious AEs including death associated with colchicine therapy have been reported and it has usually occurred in patients with underlying increased risks for colchicine toxicity e.g. in patients with renal or hepatic impairment, or drug-drug interactions especially patients with concomitant therapy of P-glycoprotein or CYP3A4 inhibitors, or in the context of overdosing. The most common AEs are related to GI symptoms (diarrhea, abdominal pain, nausea and vomiting) which occur frequently and can become severe and thus dose limiting.

Based on the study by Terkeltaub et al. (2010) which is a randomised, double-blind, placebo-controlled clinical trial and included 184 patients with gout flare, incidence of AEs was 76.9%, 36.5%, and 27.1% for the high-dose, low-dose, and placebo groups, respectively. The most common AE was diarrhea in all three groups, 76.9% and 23% patients with diarrhoea in high-dose group and low-dose group, respectively for colchicine treatment and 13.6% patients with diarrhoea in placebo group. Nausea was occurred in high-dose, low-dose, and placebo groups with 17.3%, 4.1%, and 5.1%, respectively. Vomiting was only reported in the high-dose group (17.3% of patients); while no occurred in low-dose or placebo group. In the low-dose group, all AEs were mild to moderate in nature; while 19.2% of high-dose group had severe AEs. There were no deaths, serious AEs, or patient withdrawals due to AEs noted from this study.

Other safety data submitted in this application include one controlled study (Schlesinger et al.) to compare safety between canakinumab and colchicine for prophylaxis against acute gouty arthritis flares and one retrospective study (Feng et al.) to evaluated safety between etoricoxib and colchicine to prevent an acute attack of gout (the both were in patients initiating urate-lowering treatment); one study (Ben-Chetrit and Levy) in FMF patients treated with colchicine for at least 15 years in their clinic; and also some case reports including colchicine

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neuromyopathy, colchicine-induced rhabdomyolysis or toxicity / polyneuropathy and multiple organ failure.

Considering limited data on clinical use of colchicine in elderly patients with gout and safety aspects such as comorbid conditions, concomitant medications, and longer term use for prophylactic treatment of recurrent gout flares in this patient population, careful monitoring is needed for elderly patients with gout especially who are >65 years of age. This information (careful monitoring) should be added in appropriate SmPC sections. The Applicant has addressed concern regarding clinical use of colchicine in elderly patients with gout; and the updated text in the SmPC section 4.4 is accepted. However, in the section 4.2, it is recommended to replace “Det är nödvändigt med noggrann övervakning av äldre patienter med gikt och i synnerhet patienter > 65 år.” with a reference to the section 4.4 i.e. (see section 4.4). The Applicant has updated the SmPC section 4.2 as requested.

FMF is a chronic, lifelong inflammatory disease. Colchicine is commonly used in paediatric patients for treatment of FMF. There was very limited information with regard to paediatric patients provided in this application. The Applicant should provide safety data / published data to justify safe use of colchicine in the paediatric patient population, especially under long-term treatment. The Applicant has addressed concern regarding safe use of oral colchicine in paediatric patient population for treatment of FMF.

The reported AEs from published studies and case reports did not reveal additional safety concerns as compared to those already established.The Applicant has provided published SmPCs to support safety profile/ADRs of oral colchicine. However, this is an application submitted according to Article 10a of Directive 2001/83/EC. The applicant therefore needs to demonstrate that the active substance of the medicinal product has been in well-established medicinal use for the claimed therapeutic indication within the Union for at least ten years, with recognised efficacy and an acceptable level of safety which need to be supported by means of bibliographic data. There is information about ADRs for oral colchicine and their frequencies available in published clinical trials that have not been provided in this submission.

At present, the submitted safety data is not sufficient to support the majority of the safety profile /ADRs of colchicine in the proposed SmPC. The Applicant was asked to provide published clinical studies/safety data to support and justify the safety profile of oral colchicine and the proposed ADRs and/or their frequency categories, including from which source they have been derived. The Applicant has updated the SmPC section 4.8 with regard to the proposed ADRs and/or their frequency categories; supported by published safety data together with source they have been derived. This is considered acceptable. The Applicant has also updated the SmPC section 4.8 by adding a summary of safety profile of colchicine in accordance with the SmPC Guideline.

Conclusions on clinical safetyThere are no remaining issues.

IV.6 Risk Management Plans

The MAH has submitted a Risk Management Plan (RMP), in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance

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activities and interventions designed to identify, characterise, prevent or minimise risks relating to Kolkicin Orifarm.

The RMP for the Kolkicin Orifarm Tablet, 0.25 mg (version 1.0) was valid from 01-September-2017 with data lock point 01-September-2017. The Applicant updated the RMP; version 1.1 dated 25 April 2018 and version 1.2 dated 9 August 2018, respectively. The RMP has been further updated and the current RMP is version 1.3 and dated 5 September 2018.

Safety specificationThe following safety concerns in RMP version 1.3 have been proposed by the Applicant.

Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMPThe RMP is approvable.

V. USER CONSULTATION

A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Colchimex, SE/H/1427/01/DC, and Diclofenac Orifarm, SE/H/1142/01/DC. The bridging report submitted by the applicant has been found acceptable.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Importance of favourable effectsGoutGout is one of the most common inflammatory arthritis conditions, with acute flares and chronic manifestations. Colchicine has been approved as an anti-gout therapy in Europe since 1947.

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- Existing treatment guidelines recommend that first-line options for treatment of acute gout are NSAIDs, oral colchicine or corticosteroids; this is supported by a multinational recommendation for acute gout which also concluded that there was insufficient evidence to prioritise among them and individual treatment decisions should be made based on consideration of an individual’s characteristics and each drug’s safety profile. The results from two submitted randomised and placebo-controlled trials (Terkeltaub et al. 2010 and Ahern et al. 1987) are considered clinically relevant and support the effect of colchicine on acute gout. The Applicant has updated the SmPC section 4.1 indication to ”Behandling av akut gikt”. Furthermore, the wording “Adults” has been added and placed above the indications of both the acute gout and the prophylaxis, as requested.

- For chronic gout, which is manifested as recurrent episodes of acute gout as well as deposition of uric acid crystals in tissues (tophi), the major treatment goal is to reduce uric acid levels aimed to reduce the risk of gout flares and the resolution of tophi. Oral colchicine, along with NSAIDs, is an appropriate first-line gout attack prophylaxis therapy, as recommended by existing guidelines including the EULAR (2016) in which prophylaxis is recommended during the first 6 months of ULT (urate-lowering therapy). Based on the Applicant’s initial application and additional published data provided in the response document; there are evidence from two randomised, placebo-controlled trials (Paulus at al.1974 and Borstad et al. 2004), which clearly suggests the efficacy of lower dose colchicine for the prophylaxis of recurrent gout and for prevent of acute attacks during the initial treatment with allopurinol or uricosuric drug. Furthermore, the Applicant has updated the SmPC section 4.1 indication wording to ”profylax mot återkommande gikt och förebyggande av akuta attacker under inledande behandling med allopurinol eller urinsyrasänkande läkemedel.”

Familial Mediterranean Fever (FMF)FMF is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis or erysipelas-like skin lesion. The most notorious aspect of FMF is amyloidosis which deposits in the kidneys leading to proteinuria and end stage renal failure. Colchicine has been used for treatment of FMF since 1972. The aim of colchicine therapy is twofold: decreasing the frequency and severity of clinical attacks and preventing the risk of developing AA (amyloid A) amyloidosis. There are no established alternatives for the small number of patients who do not respond to colchicine or cannot tolerate therapeutic doses of colchicine.Colchicine is commonly used in paediatric FMF patients with long-term treatment. Based on the Applicant’s initial application and additional published data provided, the evidence from randomised, placebo-controlled trials and supportive results from open-label trials; including long-term studies in paediatric population, are considered adequate for support the effect of colchicine on FMF for prophylaxis of attacks and prevention of amyloidosis including paediatric population. The proposed SmPC 4.1 has been updated as “Familjär Medelhavsfeber som profylax mot attacker och förebyggande av amyloidos.”. The applicant has further updated the SmPC section 4.1 by adding an age limit (children aged 4 years and above) for treatment of Familial Mediterranean fever.

Neutrofila dermatoser - Behçet’s disease is a chronic inflammatory vasculitis that can affect multiple systems. Oral

and genital ulcerations, skin lesions, uveitis, and inflammatory vascular involvement of the central nervous system and gastrointestinal tract are common. Neutrophil dermatosis has been described in patients with Behcet´s disease, and it is for this manifestation the marketing approval is sought. Based on the provided publications, there is no evidence to support the claimed manifestation neutrophil dermatosis in Behcet’s disease. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Behçet’s disease.

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- Sweet's syndrome (acute febrile neutrophilic dermatosis) is characterised by a constellation of clinical symptoms, physical features, and pathological findings; which can be classified as classical or idiopathic, malignancy- associated and drug-induced. The information available on the Sweet's syndrome provided by the Applicant included in total 25 cases. There is no convincing evidence of the effect of oral colchicine for the treatment of Sweet's syndrome (acute febrile neutrophilic dermatosis). The Applicant has updated the SmPC section 4.1 by removing the indication concerning Sweet’s syndrome.

- Leukocytoclastic vasculitis is a small-vessel vasculitis and the skin is the organ most commonly involved. The most common skin manifestation is palpable purpura and patients may also present with arthralgias or arthritis involving the knees or ankles. Based on the Applicant’s initial application and additional published data provided in the response document; apart from a prospective analysis of one open trial, two case reports and one partly retrospective/partly prospective (open) trial with multiple drugs, there is no convincing evidence of the effect of oral colchicine for the treatment of leukocytoclastic vasculiti. The Applicant has updated the SmPC section 4.1 by removing the indication concerning Leukocytoclastic vasculitis.

Importance of unfavourable effectsThere is a long history of colchicine use in Euroupe (EURD 30/07/1947) and its safety profile in the gout indications is well-known over decades of clinical practice.

Evidence from the published literature suggests the efficacy of lower doses of oral colchicine in acute gout. A publication from the Cochrane collaboration 2014 concludes that compared with placebo, high-dose but not low dose colchicine resulted in a statistically significantly greater number of adverse events. Oral administration of colchicine is mostly well tolerated at therapeutic dose range for treatment of gout. The most common AEs are related to GI symptoms (diarrhea, abdominal pain, nausea and vomiting) which occur frequently and can become severe and thus dose limiting. However, colchicine has a narrow therapeutic window. Serious AEs including death associated with colchicine therapy have been reported and have usually occurred in patients with underlying increased risks for colchicine toxicity e.g. in patients with renal or hepatic impairment, or drug-drug interactions especially patients with concomitant therapy of P-glycoprotein or CYP3A4 inhibitors, or in the context of overdosing.

The reported AEs from submitted published studies and case reports did not reveal additional safety concerns as compared to those already established.

Balance of benefits and risksThe overall benefit /risk balance of Kolkicin Orifarm is considered positive.

List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment

N/A

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List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC

N/A

VII. APPROVAL

Kolkicin Orifarm 0.25 mg, Tablet, was approved in the national procedure on 2018-09-25.

Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDENBesöksadress/Visiting address: Dag Hammarskjölds väg 42, UppsalaTelefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66Internet: www.mpa.se E-mail: registrator@mpa.se

Template version: 2017-04-21

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