hydroxychloroquine - heads of medicines agencies

Hydroxychloroquine (Plaquenil). UK/WS/029/PdWS/001

Rapporteur’s

Public Assessment Report for paediatric studies submitted in accordance

with Article 45 of Regulation (EC) No1901/2006, as amended

Hydroxychloroquine UK/W/029/pdWS/001 Rapporteur:

UK

Start of the procedure (Day 0):

13th April 2011

Circulation of Rapporteur’s Preliminary Pd Assessment Report (D 70 )

20 July 2011

Circulation of Rapporteur’s final Pd Assessment Report (D 90 )

6th March 2012

Member states responses due (D115)

25 March 2012

Finalisation of procedure 19th April 2012

Hydroxychlorouine (Plaquenil). UK/WS/029/PdWS/001

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ADMINISTRATIVE INFORMATION

Invented name of the medicinal product: Plaquenil

INN (or common name) of the active substance(s):

hydroxychloroquine

MAH: Sanofi-Aventis

Currently approved Indication(s)

Pharmaco-therapeutic group (ATC Code):

Anti-malarial ATC code ATC:PA1BAO2

Pharmaceutical form(s) and strength(s): 200mg tablet

Rapporteur:

UK


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Table of contents Page I. EXECUTIVE SUMMARY AND RECOMMENDATION 4 I.1 Introduction 4 I.2 Rapporteur’s Recommendations 4 II. INTRODUCTION 5 III. REGULATORY ASPECTS 5 III.1 Regulatory History 5 III.2 Product Information 6 IV. SCIENTIFIC DISCUSSION 6 IV.1 Introduction 6 IV.2 Pharmaceutical aspects 8 IV.3 Non-clinical aspects 8 IV.4 Clinical aspects 9 IV.4.1 Submitted clinical studies 9 V. RAPPORTEUR’S OVERALL CONCLUSIONS 15 VI. RAPPORTEUR’S PRELIMINARY RECOMMENDATIONS 16 VII. MEMBER STATES COMMENTS AND COMPANY RESPONSE. 16 VIII. RAPPORTEUR’S FINAL RECOMMENDATIONS AFTER 24 DAY 115 COMMENTS References 25


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I. EXECUTIVE SUMMARY AND RECOMMENDATION I.1 Introduction This is an assessment of data for hydroxychloroquine, as part of the Article 45 EU work-sharing procedure for assessment of paediatric studies completed before the Paediatric Regulation entered into force (26 Jan 2007). The UK is Rapporteur for this product; the initial assessment report (day 70) is due to be circulated to concerned Member States on 20July 2011. On 10th January 2011 the MAH submitted a largely bibliographic application, in accordance with Article 45 of Regulation (EC) No1901/2006, as amended, on medicinal products for paediatric use. In addition, a short critical expert overview has been provided. The submitted studies are for the use of hydroxychloroquine for the treatment of juvenile idiopathic arthritis, systemic lupus erythematosus, cutaneous/discoid lupus erythematosus) and malaria in children. The MAH stated that the submitted paediatric studies do not influence the benefit risk for hydroxychloroquine and that there is no consequential regulatory action. Hydroxychloroquine and other 4-aminoquinolines are old drugs; they are used clinically used for their anti-inflammatory, immunosuppressive and antimalarial activities. The drug has well established use; however there are limited data regarding its use in children. Clinical data submitted The submission was entirely bibliographic; the studies were old and mainly concerned the use of the drug in children suffering from juvenile idiopathic arthritis. However, the post-marketing safety data did not reveal any unexpected findings. Preliminary Conclusions The submitted data were old, published studies and therefore provided limited information regarding the use of this well established drug in children. However, with regard to the post-marketing data, there were no unexpected findings or data to cause concern. In conclusion, the submitted data do not alter the risk-benefit of the product. Assessment of Member States questions and company response The questions posed by Member States are detailed in this report. All of the issues were resolved with the exception of the NL position with regard to the JIA indication and DE’s position with regard to the malaria indication. Summary of outcome No change Change New study data:

New safety information:

Paediatric information clarified: sections 4.1 and 4.2.


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I.2 Final Recommendation The Rapporteur recommends that the product information should be up-dated in keeping with current guidance and also to include the results of the JIA clinical trial in section 5.1. On receipt of D 115 comments, most of the outstanding issues have been resolved; however, the NL did not agree with the JIA indication or proposed wording in section 5.1. In addition, DE has provided comments requesting further information at a late stage in the procedure; the assessor considers that this is inappropriate. Also, DE does not support the malaria indications. As previously stated, the purpose of the Article 45 procedure is not to harmonise the SmPC. It is acknowledged that there are differences in MS with regard to clinical usage and with regard to the existing indications. However, the Rapporteur still considers that as in the UK hydroxychloroquine is used for the treatment of JIA and the treatment and prohylaxis of malaria, the UK position with regard to these indications and the SmPC wording still stands. Nevertheless, the assessor acknowledges the fact that the NL and DE may not wish to follow the proposed wording. However, although the MAH agreed that the indication for JIA should stand, they also did not agree to the inclusion of the clinical study data in section 5.1 for the JIA indication. On balance, the Rapporteur therefore considers that although the study information is useful, it should not be included in section 5.1 of the SmPC. The MAH is requested to submit a Type IB variation to change SmPC and PL according to the recommended wording .The following SmPC changes are recommended (in bold italics, underlined and strike through): Section 4.1 Therapeutic indications Adults Treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. Paediatric Population Treatment of juvenile chronic idiopathic arthritis (in combination with other therapies), discoid and systemic lupus erythematosus. Section 4.2. Posology and method of administration Children Paediatric Population The minimum effective dose should be employed and should not exceed 6.5mg/kg/day based on ideal body weight. The 200mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg. Section 4.4 Special warnings and special precautions for use Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Plaquenil out of the reach of children.


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Section 4.9 Overdosage Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2g having proved fatal. II. INTRODUCTION This is an assessment of data for hydroxychloroquine, as part of the Article 45 EU work-sharing procedure for assessment of paediatric studies completed before the Paediatric Regulation entered into force (26 Jan 2007). The UK is Rapporteur for this product; the initial assessment report (day 70) is due to be circulated to concerned Member States on 20 July 2011. On 10th January 2011 the MAH submitted a largely bibliographic application, in accordance with Article 45 of Regulation (EC) No1901/2006, as amended, on medicinal products for paediatric use. In addition, a short critical expert overview has been provided. The submitted studies are for the use of hydroxychloroquine for the treatment of juvenile idiopathic arthritis, systemic lupus erythematosus, cutaneous/discoid lupus erythematosus) and malaria in children. The MAH stated that the submitted paediatric studies do not influence the benefit risk for hydroxychloroquine and that there is no consequential regulatory action. III. REGULATORY ASPECTS III.1 Regulatory History Hydroxychloroquine, sulphate is available for oral administration as 200 mg film-coated tablets in Europe, Africa, Asia, Russia, Latin America, North America and the Middle East. It is also formulated in Latin America only as a 400 mg coated-tablet. In Europe, hydroxychloroquine sulphate 200 mg tablets were first registered in 1958 in Denmark. Today, it is registered in 21 European countries via national procedures. Hydroxychloroquine and other 4-aminoquinolines are clinically used for their anti-inflammatory, immunosuppressive and antimalarial activities. In adults, hydroxychloroquine is mainly approved for use in the treatment of rheumatoid disorders (rheumatoid arthritis), in the treatment of lupus (systemic lupus erythematosus, cutaneous/discoid lupus erythematosus) and in the treatment of photodermatitis (dermatological conditions caused by or aggravated by exposures to sunlight) and scleroderma morphea. It is also indicated in the treatment of and prophylaxis against malaria. In children in the UK, hydroxychloroquine is approved for use in children in juvenile idiopathic arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, dermatological conditions aggravated by sunlight and malaria. Although the approved indications and the specific age limits (and weight) may vary in each country, it is usually available for use in children 6-18 years of age (weighing > 35 Kg). No liquid formulation for hydroxychloroquine is available; extemporaneous solutions are usually used in younger children. Unfortunately, the drug has an extremely bitter taste. III.2 Product Information


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The following information is included in the UK SmPC: Section 4.1 Therapeutic indications Treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. Section 4.2 Posology and method of administration

Children The minimum effective dose should be employed and should not exceed 6.5mg/kg/day based on ideal body weight. The 200mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg. Section 4.4 Special warnings and special precautions for use Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Plaquenil out of the reach of children.

Section 4.9 Overdosage Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2g having proved fatal. IV. SCIENTIFIC DISCUSSION IV.1 Introduction IV.1.1 Clinical pharmacology Hydroxychloroquine and other 4-aminoquinolines are clinically used for their anti-inflammatory, immunosuppressive and antimalarial activities. The pharmacokinetic profile of hydroxychloroquine has been well established in healthy and adult patients with rheumatoid arthritis (RA). After oral administration, hydroxychloroquine is well absorbed with a mean absolute bioavailability of 74% in healthy subjects. In patients with RA, a large variability was observed. Hydroxychloroquine is widely distributed in organs such as kidneys liver, eyes and lungs and in erythrocytes (with concentrations 5 times higher than in plasma) After chronic oral administration of hydroxychloroquine, low levels of three metabolites, i.e.; desethylhydroxychloroquine, desethylchloroquine and bidesethyl hydroxychloroquine, were found in plasma and blood. In both healthy and RA patients, hydroxychloroquine has a long elimination half-life ranging between 40 and 50 days. Excretion is mostly renal with 16- 25% excreted as unchanged hydroxychloroquine. IV.1.2 Background information regarding the conditions to be treated.


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Juvenile idiopathic arthritis (JIA) Juvenile idiopathic arthritis (JIA) is defined as arthritis of unknown aetiology beginning before the 16th birthday and persisting for at least six weeks where other known conditions are excluded. In the United Kingdom, JIA has an incidence of 1 in 10 000 children and a prevalence of 1 in 1000, with a female predominance. The management of JIA is multidisciplinary. The medical treatment mainly includes non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and synthetic and biological disease modifying drugs (DMARDs). Among DMARDs, methotrexate is the first-line agent. Other synthetic DMARDs have been studied and are used in the management of JIA. Hydroxychloroquine 5-7 mg/kg/day has been proposed for children with polyarticular disease, especially in mildly active forms. It has modest benefit and is rarely used alone for JIA. Adding hydroxychloroquine, ciclosporin or sulfasalazine to methotrexate can confer benefit. Systemic and cutaneous lupus erythematosus Systemic lupus erythematosus (SLE) is a multisystem, autoimmune, connective-tissue disorder with a broad range of clinical presentations. There is a peak age of onset in young women between their late teens and early 40s and women to men ratio of 9:1. This disorder is a chronic illness that can be life threatening when major organs are affected, but more commonly results in chronic debilitating ill health. Lupus is a life-long disease of variable severity. Persistent activity or flares interspersed among periods of remission lead to accumulation in disease and treatment-related damage. Accordingly, therapeutic strategies with multiple targets should be aimed at reducing overall burden of systemic inflammation. Such approaches require the capacity for early diagnosis, precise definition of disease activity and flare, stratification according to severity of involvement, use of drugs to induce remission promptly and prevent flares, and prevention and management of comorbidities. Drugs that have demonstrated efficacy in lupus include hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide. As stated by the European League Against Rheumatism (EULAR) Task Force on SLE, glucocorticoids, antimalarials, NSAIDs and in severe, refractory cases, immunosuppressive agents are used in the treatment of SLE patients without major-organ involvement. Despite their widespread use, considering the few randomized controlled trials and the limited evidence, the panel recommends judicious use of these agents, taking into consideration the potential harms associated with each of these drugs, in particular with regard to ocular toxicity (see section IV.4.2). Among patients with SLE, 10–15% present in childhood. Paediatric patients with SLE have a more severe disease course compared with SLE in adults. In this population, long-term and high-dose corticosteroid therapy leads to safety concerns. Although there have been no studies of efficacy of antimalarial therapy in children or adolescents with SLE, hydroxychloroquine is recommended to be included in the therapy. Skin disease is a frequent manifestation of lupus erythematosus, and cutaneous lesions include both lupus-specific and lupus non specific-eruptions. The three main lupus-specific cutaneous presentations are acute cutaneous LE, subacute cutaneous LE, and chronic cutaneous LE which mainly consists of discoid LE but also includes hypertrophic LE, lupus profundus, lupus tumidus, and chilblain lupus. Antimalarials and especially hydroxychloroquine are used in the management of cutaneous LE despite the lack of controlled studies. Acute cutaneous LE lesions virtually always present in


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patients with SLE, and these patients are treated for the systemic disease. In patients with subacute cutaneous lesions, sun protection, local glucocorticoids and antimalarials are usually the first line of treatment; clinical observations indicate that the disease responds to a single antimalarial agent or combined antimalarial therapy. Chronic cutaneous LE lesions are similarly responsive to antimalarial therapy, but due to the potential of scarring associated with discoid LE, aggressive therapy is advocated. Antimalarials have also been effective in treating less common forms of chronic cutaneous LE . Hydroxychloroquine is also used in children with cutaneous LE, despite the lack of clinical studies. Malaria Malaria is still the most important parasitic disease in the world and is responsible for a high burden of morbidity and mortality. The current guidelines recommend the use of hydroxychloroquine for adults and children as a second line for the treatment of P. Falciparum and P. malariae infections acquired in areas without chloroquine-resistant strains. Its use is also recommended for prophylaxis in areas with chloroquine –sensitive malaria. . IV.2 Pharmaceutical aspects Hydroxychloroquine 200 mg tablets were used in all of these studies. IV.3 Non-clinical aspects No non- clinical information was submitted.


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IV.4 Clinical aspects

IV.4.1 Submitted clinical studies With regards to the efficacy data, the submission was entirely bibliographic. A literature search of the Medline and Embase databases was performed, using hydroxychloroquine as a keyword on clinical trials conducted with hydroxychloroquine in children, with 11-Oct-2010 as cut-off date. No unpublished Sanofi-Aventis clinical studies were found. The clinical expert provided a brief summary of each study as follows: IV.4.1.1 Clinical Pharmacology Study Laaksonen AL et al. 1974 The objective of this study was to establish a suitable daily dosage of antimalarial drugs for children with juvenile rheumatoid arthritis in order to reduce the number of complications, by using serum concentrations as a guideline in individual dosage. One hundred twenty three children aged between 1 and 15 years (119 with juvenile rheumatoid arthritis, and 4 with SLE) were treated with either chloroquine diphosphate (60 children) or hydroxychloroquine sulphate (63 children). The children came regularly at 2 to 3-month intervals to an outpatient examination. A check-up by an ophthalmologist was performed at each visit, including a slit lamp examination. The patients were treated for at least 6 weeks before the determinations of serum concentration. In the chloroquine group, complications were observed in 36 patients (60 %). In these patients, the mean duration of treatment was 4.3 months, versus 7.2 months in the 24 patients without complications. The mean dosage was 6.9 mg/kg and 6.4 mg/kg respectively. In the hydroxychloroquine group, complications were reported in 23 patients (36.5 %). In these patients, the mean duration of treatment was 7.8 months, versus 7.0 months in the 40 patients without complications. The mean dosage was 6.4 mg/kg and 5.7 mg/kg respectively. The main adverse effects were keratopathy (29 cases with chloroquine and 12 with hydrochloroquine), bleaching of hair (6 and 7), light sensitivity (4 and 5 cases), and anorexia (6 in both groups). No case of retinopathy occurred. A correlation between serum concentrations and the daily dose in mg/kg and mg/m² was observed, but with great individual variations. 5 mg/kg/day of chloroquine phosphate gave serum concentrations up to 300 μg/l. The dose of hydroxychloroquine sulphate 5 to 7 mg/kg/day gave serum concentrations up to 500 to 700 μg/l. The appearance of keratopathy correlated to high chloroquine and hydroxychloroquine serum concentration and was considered to be a sign of overdosage. Based on these results, the authors considered that the maximum safe dose of chloroquine diphosphate was 4 mg/kg/day. They considered that the maximum safe dose of hydroxychloroquine sulphate was 5 to 7 mg/kg/day, but that this dose could possibly be increased up to 10 mg/kg/day. The maximum safe serum concentrations were considered to be 250 to 280 μg/l for chloroquine sulphate and 370 to 470 μg/l for hydroxychloroquine. The authors also recommended a control of serum concentrations during therapy.

Assessor’s comments: This old study provides useful supportive dosage and safety data regarding the use of hydroxychloroquine in children.


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IV.4.1.2 Studies in juvenile idiopathic arthritis (JIA) Kvien TK et al. 1985 The aim of this study was to compare the efficacy and safety of hydroxychloroquine, gold sodium thiomalate, and D-penicillamine in patients with pauciarticular and polyarticular juvenile rheumatoid arthritis. This was a randomized, open, controlled, parallel group study with a duration of 50 weeks. The daily dose of hydroxychloroquine was 5 mg/kg, given bid during 9 months, followed by a withdrawal period of 3 months. Gold sodium thiomalate was administered parenterally with a dose of 0.7 mg/kg given weekly for 20 weeks, then monthly until 50 weeks. D-penicillamine was given orally with a daily dose increasing from 2.5 mg/kg during week 1 to 10 mg/kg after week 12. NSAID therapy was kept constant. The patients were assessed after 12, 24, and 50 weeks. Seventy-two consecutive patients were randomized. Median age was 120 months (range 43-191 months). Median disease duration was 16 months (range 3-164 months). Similar improvement of disease activity measurements and reduction of the erythrocyte sedimentation rate were seen in all groups. Adverse reactions were noted in 2 hydroxychloroquine treated patients: dermatitis (1 case) and gastrointestinal upset (1). No hydroxychloroquine treated patients were withdrawn because of adverse reactions. The authors concluded that this study indicate that hydroxychloroquine is better tolerated than gold sodium thiomalate and especially D-penicillamine, but that the drugs are comparable with regard to efficacy in patients with pauciarticular and polyarticular juvenile rheumatoid arthritis. Brewer EJ et al. 1986 The purpose of this study was to compare the efficacy and safety of penicillamine and hydroxychloroquine with those of placebo, in patients with juvenile rheumatoid arthritis who were considered to be candidate for therapy with slow-acting antirheumatic drugs. One hundred sixty-two children with severe juvenile rheumatoid arthritis were entered in a randomized, double-blind, placebo-controlled 12-month clinical trial. Age and duration of disease at entry averaged 9.7 and 3.2 years. One group of subjects received 10 mg/kg/day of penicillamine, another group received 6 mg/kg/day of hydroxychloroquine, and a third group received placebo. All three groups were allowed a single concurrent NSAID drug, but no other antirheumatic medications, including corticosteroids. All three groups had dramatic improvement in many of the clinical and laboratory outcome variables after one year of study. There were no significant differences in efficacy between the penicillamine and placebo groups. Pain on movement was the only index of articular disease that was alleviated more by hydroxychloroquine than by placebo. Adverse reactions with hydroxychloroquine were: hemoglobin or hematocrit decreased (6), leucopenia (4), hematuria (4), proteinuria (7), aspartate and alanine aminotransferases increased (9), aspirin-associated duodenal ulcer (1), rash (2), non clinically important deposits in corneal epithelium (1). From these adverse reactions, three led to the patient’s dropout from the study: hematuria (1), proteinuria (1) and aspirin-associated duodenal ulcer (1).


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The authors concluded that they were unable to demonstrate that, in the presence of a NSAID, either penicillamine or hydroxychloroquine is superior to placebo in the treatment of children with juvenile rheumatoid arthritis. Giannini EH et al. 1988 The authors performed a further analysis of the data obtained in the previous study, in order to investigate the possible existence of select subgroups of patients who have a higher likelihood of response to active drugs than to placebo. Using previously published criteria, each patient was classified as a responder or non-responder, and their demographic and disease characteristics at baseline were compared. The authors concluded that they were unable to identify a subgroup of individuals who were more likely to respond to D-penicillamine or hydroxychloroquine than to placebo. Van Kerckhove C et al. 1988 The authors performed a further analysis of the same study, and calculated the time required for therapeutic benefit to become apparent following initiation of treatment with D-penicillamine, hydroxychloroquine, or placebo. Using previously published criteria to classify the outcome, they found that 60% of the hydroxychloroquine group, 46% of the D-penicillamine group, and 39% of the placebo group responded favourably after 12 months of therapy. Data from examinations between the initial and final assessments were used to determine when the response first occurred. Approximately 50% of all patients who showed improvement at 12 months had already done so by 2 months. After 6 months, 96% of the D-penicillamine group, 88% of the hydroxychloroquine group, and 85% of the placebo group responders had met the criteria for response. The average time until response was attained was 105 days for the D-penicillamine group, 129 days for the hydroxychloroquine group, and 140 days for the placebo group. The authors concluded that a favourable response to these slow-acting antirheumatic drugs is unlikely if improvement has not occurred within the first 6 months of therapy.

Assessor’s comments: The above old studies provide supportive efficacy and safety data regarding the use of hydroxychloroquine in children in JIA. Grondin C et al. 1988 The authors conducted a retrospective study on children with juvenile rheumatoid arthritis or juvenile psoriatic arthritis receiving slow-acting antirheumatic drugs. Patients were included in the analysis if sufficient data were available for appropriate review and if they had been treated for at least 3 months or developed side-effects necessitating drug discontinuation before 3 months of treatment. Forty-three patients were included, 37 with juvenile rheumatoid arthritis and 6 with juvenile psoriatic arthritis; their mean age ranged from 9.4 years to 12.2 years according to the drugs received. Twenty-two received only one slow-acting antirheumatic drug (gold 14, penicillamine 3, hydroxychloroquine 5), and 21 received 2 or more drugs. Overall, 32 patients received gold 1 mg/kg/week, 12 penicillamine 4.4 to 21 mg/kg/day, 19 hydroxychloroquine 5 to 6 mg/kg/day, and 12 sulfasalazine 37 to 83 mg/kg/day.


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A remission was reported in 9/32 patients receiving gold, 0/12 patients receiving penicillamine, 1/19 patients receiving hydroxychloroquine, and 1/12 patients receiving sulfasalazine. An improvement was reported in respectively 6, 1, 3, and 4 patients. The number of patients who experienced adverse-effects was higher with gold (47 %) and sulfasalazine (42 %) than with penicillamine (33 %) and hydroxychloroquine (11 %) Two patients treated with hydroxychloroquine experienced adverse reactions: photosensitivity (1 case) and transient corneal deposits (1). All the adverse reactions subsided after stopping the drug and none resulted in death. From a literature review and from the data reported in the present study, the authors concluded that considerable uncertainty remains about the efficacy of the slow-acting antirheumatic drugs commonly used in chronic arthritis of childhood. They proposed to start the slow-acting antirheumatic drugs therapy with hydroxychloroquine and, if this fails after a maximum of 6 months of therapy, to introduce gold.

Assessor’s comments: The above old study provides limited retrospective efficacy and safety data regarding the use of hydroxychloroquine in children in JIA. Lomater C et al. 1994 The authors conducted a pilot prospective study on combination therapy in juvenile rheumatoid arthritis. Seven children with very active polyarthritis with a mean disease duration of 4 years received a combination of hydroxychloroquine, gold salts, and methotrexate for a mean duration of 15 months. The mean age at start of the therapy was 16 years (range 12 to 21 years). Hydroxychloroquine was given at a dosage of 400 mg daily for the first 2 months and then reduced to 200 mg daily. Gold salts were given intramuscularly at a dosage of 20-50 mg once a week and methotrexate was given intramuscularly at a dosage of 10-15 mg once a week. All patients were also treated with NSAIDs and 4 patients also received low-dose steroids. At last observation one patient went into remission, 4 had significant clinical improvement, one was still continuing without adverse-effects and one completed with good results. A very small number of adverse effects was observed during the combination therapy. The authors concluded that a combination therapy with DMARDs is feasible also in young patients and could be considered as a new choice in treating severe cases of juvenile rheumatoid arthritis.

Assessor’s comments: The above old study provides supportive efficacy and safety data regarding the use of hydroxychloroquine in combination with other drugs in children in polyarticular JIA. IV.4.1.3 Systemic and cutaneous lupus erythematosus Only efficacy data in cutaneous lupus erythematosus have been identified, in a published case report.


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Fox JN et al. 1987 The authors described two cases of lupus profundus in two young girls, one with onset at 3 ½ years of age, the other at 8 years of age. Unusual nodules of the face that ultimately healed with atrophy and hyperpigmentation showed histologic and immunofluorescent confirmation of lupus erythematosus. No systemic involvement was found. The patients received hydroxychloroquine 100 mg a day (200 mg/m²), topical corticosteroids and used sunscreens (intralesional and low-dose corticosteroids were added in one patient). They responded successfully to hydroxychloroquine, and the drug was well tolerated by one child for 1 year and the other for 4 years. One patient experienced 2 episodes of palpitations and chest pains that prompted the discontinuation of hydroxychloroquine. This patient had a history of similar symptoms prior to treatment.

Assessor’s comments: The above case reports provide very limited supportive efficacy and safety data regarding the use of hydroxychloroquine in children with cutaneous lupus erythematosus. IV.4.1.4 Malaria Two cases series published in the 1950s have been identified. Loughlin EH et al. 1952 The authors reported an unselected series of 75 cases of P. falciparum malaria treated with hydroxychloroquine in Haïti. The drug was given in single oral dose of 2 g in adults, 1.5 g in children 6-12 years of age, and 1 g to children under 6 years of age. Hydroxychloroquine was reported to be effective. A mild toxic effect (vertigo) was observed in only one of the 75 patients. Clark HC 1954 The authors described a series of 93 patients (42 adults and 51 children) living in a village in Panama who received suppressive treatments weekly with a fixed dose combination of primaquine and hydroxychloroquine for from 20 to 26 weeks. The weekly dose of each component was respectively 5 mg and 50 mg for patients weighting less than 15 pounds, 10 mg and 100 mg for patients weighting 15-45 pounds, 15 mg and 150 mg for patients weighting 45-90 pounds, and 30 mg and 300 mg for patients weighting 90 pounds and above. After the first 3 weeks, only 6 were found positive for malaria parasites on weekly examination of thick blood films, although the percentage of positives was 52.2 % at the start. No adverse effects were noted either in children or adults.

Assessor’s comments: The above case series provide supportive efficacy and safety data regarding the use of hydroxychloroquine in children with malaria.


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IV.4.1.5 Rapporteur’s conclusions regarding submitted efficacy studies

These old, published studies provide only limited efficacy and safety data regarding the use of hydroxychloroquine in children for the authorised indications. IV.4.2 Submitted Safety Data Systemic side effects of hydroxychloroquine include disturbances in hepatic and renal function, nausea & indigestion, visual, neurological, muscular and psychiatric adverse effects; it also can cause and skin changes. Hydroxychloroquine is highly toxic, especially to the heart if taken in overdose, especially in infants. Ocular side effects include retinal toxicity (which can lead to permanent visual impairment) and deposition of the drug in the cornea. The mechanism of retinal toxicity is not well understood, though it appears that the earliest changes occur in the cytoplasm of ganglion cells and photoreceptors with later involvement of the retinal pigment epithelium2, where it binds to melanin. Although hydroxychloroquine appears to be considerably less toxic to the retina than chloroquine, (possibly because chloroquine crosses the blood-retinal barrier more easily), a similar pattern of retinopathy has been observed with both drugs. The incidence of clinically significant hydroxychloroquine retinopathy appears to be very low, with only 50 cases identified in a literature review to May 2005. Maximum daily dosage based on lean body weight and duration of treatment appear to be more important determinants of the risk of toxicity than cumulative dosage. The Royal College of Ophthamologists & British Association of Dermatologists have published recommendations with regard to good clinical practice for adults. However, with regard to use in children, there are none. Generally, however, annual review by an opthalmologist is recommended by most rheumatologists for all children taking hydroxychloroquine. Data submitted The safety data from the literature search are detailed above in the efficacy section (IV.4.1). IV.4.2.1 Post-marketing data The Sanofi-aventis global pharmacovigilance database (Application for Worldwide Adverse Event Reporting and Evaluation [AWARE]) was searched for worldwide solicited cases and unsolicited medically-confirmed cases up to 31 August 2010 that had been reported in the paediatric population. Overall, 92 unsolicited medically-confirmed cases and 1 solicited case from unsponsored study (compassionate use) were reported; among these 93 cases involving 197 reactions, 47 cases were serious and 46 cases were non-serious.


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The search identified the following:

• A total of 81 cases: 80 unsolicited cases and 1 solicited case (41 serious cases and 40 nonserious cases) involving 174 reactions, in patients aged from 6 to 17 year-old.

• 1 non-serious unsolicited case involving 1 reaction, for which the patient’s age was

unspecified and was reported as child.

• 11 unsolicited cases (6 serious cases and 5 non-serious cases) involving 22 reactions, in Children under 6 years of age.

The adverse drug reactions (ADRs) most frequently reported were with respect to skin (34 cases), nervous system (19 including 3 cases of convulsions) and gastrointestinal disorders (17 cases). Patients aged 0 - 6 years Eleven cases (including 5 non- serious cases) were reported. The ADRs most frequently reported were with respect to skin. Overdose Among the 93 cases, an overdose of hydroxychloroquine was reported in 12 unsolicited medically- confirmed cases. In 5 cases, no adverse reactions were reported. In 3 cases, there was an accidental intake of hydroxychloroquine. In children less than 6 years of age, non-serious ADRs were observed in 2 cases and a fatal outcome in the youngest child aged 21 months. IV.4.2.2 Rapporteur’s conclusions regarding safety data Based on the analysed data including safety data from clinical trials, post-marketing data and publications, no differences in the safety profile in children and adolescents compared to that in adult population were identified. In addition, all of the reported ADRs are listed in the SmPC. In particular, there were no particular findings with respect to ocular toxicity, which is reassuring. With respect to overdose, the UK SmPC already includes a statement regarding young children in section 4.4. V. RAPPORTEUR’S OVERALL CONCLUSIONS Hydroxychloroquine is a well established drug for the treatment of juvenile idiopathic arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus and malaria, with a well documented efficacy and safety profile, although there are only limited data available with regard to its use in children. The submitted data were old, published studies and therefore provided limited additional information regarding the use of hydroxychloroquine in children. However, with regard to the post-marketing safety data, there were no unexpected findings or data to cause concern. In conclusion, the submitted data do not alter the risk-benefit of the product.


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VI. RAPPORTEUR’S PRELIMINARY RECOMMENDATIONS The Rapporteur recommends that the product information should be up-dated in keeping with current guidance

VII. MEMBER STATES COMMENTS AND COMPANY RESPONSE.

Comments were received from two Member States; Ireland agreed with the UK recommendations. The Netherlands agreed with the overall conclusions that the submitted data does not alter the benefit risk, but proposed to address the following additional questions for clarification to the MAH:

1. The indication “juvenile chronic arthritis” has never been accepted in the Netherlands as there is no evidence of a benefit of hydroxychloroquine in this indication. Of note: the PRINTO guidelines on “juvenile chronic arthritis” do not mention hydroxychloroquine as a treatment option. The publications submitted by the MAH in context of this Art 45 procedure do not provide evidence of a significant improvement as a result of treatment with hydroxychloroquine in this indication. Therefore this indication remains unacceptable.

MAH response: Only 2 prospective clinical trials with hydroxychloroquine used alone in juvenile idiopathic arthritis (JIA) were published more than 20 years ago and were presented in the critical expert overview: the first one (1) showed a similar efficacy of hydroxychloroquine 5 mg/kg/day, Dpenicillamine and gold sodium thiomalate but a better tolerance, and the other (2) could not conclude to a superiority of hydroxychloroquine 6 mg/kg/day versus placebo, the only difference found being on pain on movement. As stated by McCann et al in 2006 (3) hydroxychloroquine has modest benefit but is rarely used alone for JIA. Adding hydroxychloroquine, ciclosporin or sulfasalazine to methotrexate can confer benefit. In combination, toxicity is comparable to single therapy. This approach of combination therapy was described in a pilot study presented in the critical expert overview (4). An additional randomised open-label clinical trial published in 2011 describes the use of hydroxychloroquine in combination with other drugs in patients with recent-onset polyarticular JIA (5;see below at question 5) for further details. The authors concluded that in early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone. In addition, the recently published results of a cohort study having included children with JIA in Denmark, Finland, Sweden and Norway show that despite an increased use of biologic agents, hydroxychloroquine is still used in this indication (6). In summary, hydroxychloroquine is still considered in combination therapy for the treatment of JIA. Assessor’s comments: As detailed above, there is evidence that hydroxychloroquine is considered to be useful, especially when used in combination with other drugs for JIA. ISSUE RESOLVED.


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2. The juvenile systemic lupus erythematodes and discoïd lupus erythematodes indications are acceptable, although it should be specified in the SmPC that HCQ is not suitable for treatment of acute SLE flares in children, but in the maintenance phase once remission is achieved.

MAH response No clinical study on hydroxychloroquine in the treatment of lupus erythematosus in children is available, thus its place in therapy is based on experts’ advice, on the basis of data obtained in adults as well as their personal experience. The efficacy of hydroxychloroquine in systemic lupus erythematosus (SLE) and in cutaneous lupus erythematosus (CLE) is well recognized (7,8). Hydroxychloroquine is a slow-acting agent and its therapeutic effects appear several weeks after starting treatment (8), which may explain that this drug has been included by some authors among the maintenance therapies in paediatric LE (9). Appropriate prospective randomized studies are lacking to determine the appropriate time for starting hydroxychloroquine. However, hydroxychloroquine is currently presented by several authors as the cornerstone of SLE therapy, which should be used more extensively in patients (10,11,12,13) including children and adolescents (14). In addition, benefits of an early use of hydroxychloroquine were suggested in a retrospective study in adults (15). Indeed, the treatment of systemic lupus should be tailored on a case by case basis, depending of the manifestations of the disease, and a review on lupus arthritis suggests the first line use of antimalarials (16). Furthermore, in a review on antimalarials in SLE, authors recommend a treatment with hydroxychloroquine of most patients with SLE, starting as soon as the diagnosis has been made (12). As an example, in a recent study performed in adults with active SLE, hydroxychloroquine therapy combined with prednisone and mycophenolate mofetil was started after 2 infusions of rituximab (17). As well, in CLE, hydroxychloroquine is considered as a first line systemic treatment in adults and children (18,19,20). In summary, in children like in adults, the treatment of lupus should be tailored on a case by case basis, depending on the manifestations of the disease. Hydroxychloroquine is a slow-acting agent, and evidence from clinical trials in children is lacking to demonstrate its efficacy for the treatment of acute flares and to determine the appropriate time for starting the treatment. However, based on consistent published reviews considering this drug as a first line systemic treatment and proposing an early use, it does not seems appropriate to restrict its use in situations when remission is achieved. Assessor’s comments: As stated above, hydroxychloroquine is a slow-acting agent and its therapeutic effects appear several weeks after starting treatment. Although clinical trials are lacking in the paediatric population, the evidence based on clinical practice suggests that it is useful early on in the disease. In addition, because of the drug’s anti-platelet effects, it is considered to be an adjunct to prevent thrombo-embolic episodes, particularly patients who have anti-phospholipid antibodies. ISSUE RESOLVED. 3. A dose range of 4-6 mg/kg/day is proposed for lupus. This may be sufficient in most mild-moderate cases and if only the skin is involved. It has however been suggested in the literature that higher doses are indicated in case of lung involvement up to 10 mg/kg/day (Acta Paed 2010;99:967-74) . This needs to be further discussed by the MAH. MAH response:


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In the above-mentioned publication (9), no reference is provided by authors to support this dosage of 10 mg/kg/day in SLE with lung involvement. No other publication has been identified which could support an higher dosage of hydroxychloroquine in adults or children for treating SLE with lung involvement. Moreover, according to the American Academy of Ophtalmology, in its update of recommendations published in 2011, among factors increasing the risk of hydroxychloroquine retinopathy is the daily dose above 6.5 mg/kg ideal body weight for short individuals, or 400 mg/day (21). In summary, available data do not support the use of higher doses of hydroxychloroquine.

Assessor’s comments:

As summarized above by the MAH, the available data do not support the use of higher doses of hydroxychloroquine. ISSUE RESOLVED.

4. A justification is needed to what extent the photodermatoses indications could be extrapolated from adults to children, as paediatric studies are lacking. The MAH is invited to provide more data and a justification why extrapolation form adult studies would be acceptable.

MAH response: Hydroxychloroquine has been shown to reduce the severity of skin manifestations in adults with polymorphic light eruption (22,23) and is considered as a second line option in this indication.

No clinical study or published review describing the use of hydroxychloroquine for treating photodermatosis in children was identified. It is not possible to extrapolate from studies performed in adults.

Assessor’s comments:

As summarized above by the MAH, the available data do not support the use of hydroxychloroquine for the photodermatoses indications in the paediatric population or extrapolation from data in adults. The assessor therefore proposes that this indication should be deleted in children. . ISSUE RESOLVED.

5. Further to the circulation of this report, the UK has sought expert advice from its paediatric committee, the Paediatric Medicines Expert Advisory Group. The committee commented that hydroxychloroquine is often used for the treatment of juvenile idiopathic arthritis in combination with other drugs and that there had recently been studies conducted with regard to this.

The MAH is therefore requested to review the available data and submit these for assessment.

This approach of combination therapy was described in a pilot study presented in the critical expert overview (4). An additional randomised open-label clinical trial published in 2011 describes the use of hydroxychloroquine in combination with other drugs in patients with recent-onset polyarticular JIA (5).


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This study is summarised below: Tynjala P, Vahasalo P, Tarkiainen M, Kröger L, Aalto K, Malin M et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTEJIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis 2011; 70: 1605-1612. In this 54-week multicentre trial, 60 Disease Modifying Antirheumatic Drug (DMARD)-naive patients aged 4–15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate was compared to methotrexate alone, and to a combination of methotrexate, sulphasalazine and hydroxychloroquine. The initial oral methotrexate dose was 15 mg/m² weekly, up to 25 mg; for sulphasalazine, it was 40 mg/kg daily, up to 2000 mg; and for hydroxychloroquine, 5 mg/kg daily, up to 300 mg. Infliximab was given at 100 or 200 mg (3–5 mg/kg), based on the recommendations then in use, as were infusion intervals at 0, 2 and 6 weeks, and thereafter every 6 weeks. The primary efficacy endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. In 59 patients, the mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and the number of active joints was 18±1. Results: Efficacy: The ACR Pedi 75 was achieved in 100% (19/19) of patients receiving infliximab + methotrexate, 65% (13/20) of patients receiving methotrexate + sulphasalazine + hydroxychloroquine (95% CI 44% to 86%) and 50% (10/20) of patients receiving methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving infliximab + methotrexate (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on methotrexate + sulphasalazine + hydroxychloroquine and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on infliximab + methotrexate spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving methotrexate + sulphasalazine + hydroxychloroquine (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Safety: The rates of adverse events/patient-year were respectively 4.8 %, 5.4 %, and 6.5 %. Serious adverse events were rare (3 unspecified serious adverse events involving the 3 groups of treatment and leading to hospitalization). Conclusions The authors concluded that in early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone. They also noted that the study was powered to detect differences between biological and synthetic DMARD, but not to compare the two synthetic treatment arms. For them, although early biological treatment was highly successful, these results do not necessarily imply that every new patient with polyarticular JIA should be treated with a biological agent. In addition, the recently published results of a cohort study having included children with JIA in Denmark, Finland, Sweden and Norway show that despite an increased use of biologic agents, hydroxychloroquine is still used in this indication (6). In summary, hydroxychloroquine is still considered in combination therapy for the treatment of JIA.


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Assessor’s comments: The study cited by Tynjala et all is small and open label; however, the ACR Pedi 75 is an appropriate primary efficacy endpoint. Although the results suggest that infliximab plus methotrexate is superior to synthetic DMARD in combination and to methotrexate alone; these findings are not surprising. However, the study also provides some supportive evidence for the use of hydroxychloroquine in early polyarticular JIA, especially when used in combination with other drugs for JIA. The assessor considers that it would be helpful for the prescriber to include these findings in section 5.1 of the SmPC. ISSUE RESOLVED.

VIII. RAPPORTEUR’S FINAL RECOMMENDATIONS The Rapporteur recommends that the product information should be up-dated in keeping with current guidance and also to include the results of the JIA clinical trial in section 5.1. IX: DAY 115 MS COMMENTS: Comments were received from Member States (NL and DE); it is noted that no comments were received from the latter at D85. IX.1 The Netherlands noted that the article 45 procedure is not intended for the harmonisation of product information. In addition the following comments were made: ‘The earlier Dutch position (day 85) that HCQ is not effective in JIA is maintained. The newly adapted add-on indication is not supported by the data. The additional text in 5.1 is neither considered relevant, as it does not provide information of the additional value of HCQ in the combination with other DMARDs. If the data of the ACUTEJIA are included in the SPC, results of other randomized placebo-controlled studies on JIA which turned out negative, and the higher incidence of side effects of the DMARD-HCQ arm in the ACUTEJIA trial, should be mentioned as well. Arguments The ACUTEJIA trial was not designed to show an additional benefit of HCQ, as HCQ was used in combination with two other DMARDs (MTX + SLZ), and not compared to a combination of MTX+SLZ alone. From SLZ it is know it is effective in JIA, so it is not surprising that the DMARD combination arm is numerically more effective than MTX monotherapy. Not only efficacy was lower of the DMARD-HCQ combination compared to the biological treatment, but also tolerance was less, as indicated by significant lower continuation rates . Gastrointestinal symptoms, nausea, loss of appetite and weight loss occurred more commonly in the DMARD-HCQ group than in other treatment groups. According to the recent ACR JIA guideline (2011) and Dutch National RA guideline, there is no evidence for the efficacy of HCQ monotherapy or in combination of DMARDs in the treatment of JIA. Considering earlier negative placebo-controlled


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studies on HCQ and the guidelines, the B/R balance of the JIA indication remains negative. Assessor’s comments: The assessor acknowledges the view of NL. However, the position of the UK remains unchanged. Issue not resolved. Other issues: The other juvenile indication is discoid and systemic lupus. These indications however can be supported, based on well-established use. With regard to the other questions raised at D 85, these issues were all considered to be resolved. IX.2 Germany – the following comments were received that were stated to relate to the Preliminary assessment report. ‘The Federal Institute for Drugs and Medical Devices agrees with the overall conclusions of the Rapporteur but proposes to address the following additional questions for clarification to the MAH: Hydroxychloroquine is approved in DE for use in children > 6 years of age in the following indications:

• Rheumatoid arthritis (chronic polyathritis) • Systemic lupus erythematosus • Treatment and prophylaxis of malaria against all four different species of Plasmodium (P.

falciparum, P. vivax, P. malariae and P. ovale) with the exception of chloroquin- resistant strains.

General comments: Recommendations for the SmPC

1. A general advice is given in the German SmPC that dosing is based on hydroxychloroquine sulphate and not on the amount of hydroxychloroquine base (200 mg hydroxychloroquine sulphate = 155 mg hydroxychloroquine base). This should be clarified by the MAH and also considered in the SmPC.

Assessor’s comments: At this late stage in the procedure, the assessor considers that it is inappropriate to seek further clarification from the MAH. ISSUE RESOLVED.

2. The use of hydroxychloroquine in different indications (please see above) is restricted to

children older than 6 years. Thus, the section 4.3 Contraindication should be updated as follows: ‘Hydroxychloroquine is contraindicated in children less than 6 years of age.’

Additionally, with respect to the known cardiac toxic effect of hydroxychloroquine, the MAH is asked to comment and discuss if there are any new findings regarding cardiac disorders particular in the paediatric population.


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Assessor’s comments: the use is limited to children aged 6 yrs and above. However, the assessor considers that the available data do not warrant a contraindication in this age group, as no specific and significant safety concern has been identified. ISSUE RESOLVED. Specific comments: Cutaneous lupus erythematosus This indication is not approved in DE. As prescribed in the AR, hydroxychloroquine is also used in children with cutaneous lupus erythematosus, despite the lack of clinical studies. Only two cases could be identified from literature. The Rapporteur concludes that the case reports provide very limited supportive efficacy and safety data regarding the use of hydroxychloroquine in children with cutaneous lupus erythematosus. An appropriate wording regarding the limited data on efficacy and safety in this indication should be considered. The approval of this indication for the paediatric population should be discussed in general. Assessor’s comments: As previously stated, the assessor endorses the view that the available data are limited. However, as stated also by NL, the indication is based on clinical usage. ISSUE RESOLVED. Malaria Based on the two case series (Loughlin EH et al. 1952; Clark HC 1954), we do not agree that these data provide supportive efficacy and safety data regarding the use of hydroxychloroquine in children with malaria. Also, data regarding the malaria prophylaxis are missing. In conclusion, the provided data do not substantiate the use of hydroxychloroquine for the treatment and prophylaxis of malaria in the paediatric population. More information and/or data should be submitted e. g. on:

o specific dosing with respect to the different age groups o duration of dosing o maximal daily dose regarding the age groups.

Assessor’s comments: At this late stage in the procedure, the assessor considers that it is inappropriate to seek further clarification from the MAH. As previously stated, the indication is based on long standing usage and guidelines. ISSUE RESLOVED. X RAPPORTEUR’S RECOMMENDATIONS FOLLOWING DAY 115 COMMENTS. Most of the outstanding issues have been resolved; however, the NL does not agree with the JIA indication or proposed wording in section 5.1. In addition, DE has provided comments requesting further information at a late stage in the procedure; the assessor considers that this is inappropriate. Also, DE does not support the malaria indications. As previously stated, the purpose of the Article 45 procedure is not to harmonise the SmPC. It is acknowledged that there are differences in MS with regard to clinical usage and with regard to the existing indications. However, the Rapporteur still considers that as in the UK hydroxychloroquine is used for the treatment of JIA and the treatment and prohylaxis of malaria, The UK position with regard to these indications and the SmPC wording still stands. Nevertheless, the assessor acknowledges the fact that the NL and DE may not wish to follow the proposed wording.


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XI MAH RESPONSE TO AGENCY REQUEST With regard to the indication in juvenile chronic arthritis, the MAH considers that the recent study describing the use of hydroxychloroquine in combination with methotrexate and sulphasalazine in children with early polyarticular JIA supports the fact that the product is used in combination, and provides efficacy data for a specific combination However, the mention of this study in the Section 5.1 does not appear to be useful for the prescriber taking into account the small size of the study and the resulting large confidence intervals (the ACR Pedi 75 interval is presented in the proposed text for methotrexate but not for the hydroxychloroquine combination). Moreover, this could suggest that only this specific combination should be used. Therefore, the MAH does not agree with this addition. In addition, the MAH would like to clarify a comment on the paediatric labelling: the proposed changes that are mentioned in the final assessment report are based on the UK SPC. It is to note that these changes might not be applicable to all the CMS if their currently approved labeling is not fully in line with the UK texts. In this case, each National Competent Health Authority will decide which changes are to be implemented into their National labelling. XII. RAPPORTEUR’S FINAL RECOMMENDATIONS Further to the MAH and the Day 115 Member States responses, the Rapporteur has re-considered the proposed changes of the SmPC; the additional wording in section 5.1 will not be recommended. As previously stated, the purpose of the Article 45 procedure is not to harmonise the SmPC; therefore each National Competent Health Authority will decide which changes are to be implemented into their National labelling. The following SmPC changes are recommended (in bold italics, underlined and strike through): Section 4.1 Therapeutic indications Adults Treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. Paediatric Population Treatment of juvenile chronic idiopathic arthritis (in combination with other therapies), discoid and systemic lupus erythematosus. Section 4.2. Posology and method of administration

Children Paediatric Population The minimum effective dose should be employed and should not exceed 6.5mg/kg/day based on ideal body weight. The 200mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg.


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Section 4.4 Special warnings and special precautions for use Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Plaquenil out of the reach of children. Section 4.9 Overdosage Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2g having proved fatal.

The following PIL changes are recommended (in bold italics, underlined and strike through): Section 1 Plaquenil contains a medicine called hydroxychloroquine sulphate. Plaquenil works by reducing inflammation in people with autoimmune diseases (this is where the body’s immune system attacks itself by mistake). It can be used for: • Rheumatoid arthritis (inflammation of the joints) • Juvenile chronic idiopathic arthritis (in children) • Discoid and systemic lupus erythematosus (a disease of the skin or the internal organs) • Skin problems which are sensitive to sunlight

REFERENCES 1. Kvien TK, Hoyeraal HM, Sandstad B. Slow acting antirheumatic drugs in patients with juvenile rheumatoid arthritis - Evaluated in a randomized, parallel 50-week clinical trial. J Rheumatol 1985; 12: 533-539 2. Brewer EJ, Giannini EH, Kuzmina N, Alekseev L. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. N Engl J Med 1986; 314: 1269-1276 3. McCann LJ, Wedderburn LR, Hasson N. Juvenile idiopathic arthritis. Arch Dis Child Ed Pract 2006; 91: 29-36 4. Lomater C, Gattinara M, Gerloni, Zeni S, Fantini F. Combination therapy of juvenile rheumatoid arthritis with hydroxychloroquine-gold-methotrexate: a pilot study. Acta Univ Carol (Med) 1994; 40 (1-4): 109-112 5. Tynjala P, Vahasalo P, Tarkiainen M, Kröger L, Aalto K, Malin M et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTEJIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis 2011; 70: 1605-1612 6. Nordal E, Zak M, Aalto K. Ongoing disease activity and changing categories in a long-term nordic cohort study of juvenile idiopathic arthritis. Arthr Rheum 2011; 63 (9): 2809-2818 7. Bertsias GK, Salmon JE, Boumpas DT. Therapeutic opportunities in systemic lupus


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erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis 2010; 69: 1603-1611 8. Wozniacka A, McCauliffe DP. Optimal use of antimalarials in treating cutaneous lupus erythematosus. Am J Clin Dermatol 2005; 6 (1): 1-11 9. Marks SD, Tullus K. Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paed 2010; 99: 967-974 10. Ruiz-Irastorza G, Egubirde MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006; 15: 577-583 11. Ruiz-Irastorza G, Khamashta MA. Hydroxychloroquine: the cornerstone of lupus therapy. Lupus 2008; 17: 271-273 12. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010; 69: 20-28 Response to Agency Request 02-Nov-2011 Hydroxychloroquine Property of the sanofi-aventis group - strictly confidential Page 9 13. Costedoat-Chalumeau N, Leroux G, Piette JC, Amoura Z. Why all systemic lupus erythematosus patients should be given hydroxychloroquine treatment ? Joint Bone Spine 2010; 77: 4-5 14. Tucker LB. Controversies and advances in the management of systemic lupus erythematosus in children and adolescents. Best Pract Res Clin Rheumatol 2002; 16 (3): 471-480 15. James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McCain MT, Arbuckle MR et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 2007; 16: 401-409 16. Grossman JM. Lupus arthritis. Best Pract Res Clin Rheumatol 2009; 23: 495-506 17. Galarza-Maldonado C, Kourilovitch MR, Molineros JE, Cardiel MH, Zurita L, Soroka NF et al. The administration of low doses of rituximab followed by hydroxychloroquine, prednisone and low doses of mycophenolate mofetil is an effective therapy in Latin American patients with active systemic lupus erythematosus. Autoimmunity Rev 2010; 10: 108-111 18. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options. Part I. J Am Acad Dermatol 2010 In Press 19. Wahie S, Daly AK, Cordell HJ et al. Clinical of pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study. J Invest Dermatol 2011; 131: 1981-1986 20. Hong J. Cordoro KM. Discoid lupus erythematosus in a teenager. J Paediatr 2011; 159: 350 21. Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy.Ophtalmology 2011; 118(475): 415-22. 22. Murphy GM, Hawk JLM, Magnus IA. Hydroxychloroquine in polymorphic light eruption: a controlled trial with drug and visual sensitivity monitoring. Br J Dermatol 1987; 116: 379-386 23. Pareek A, Khopkar U, Sacchidanand S et al. Comparative study of efficacy and safety of hydroxychloroquine and chloroquine in polymorphic light eruption: a randomized, doubleblind, multicentric study. Indian J Dermatol Venereol Leprol 2008; 74 (1): 18-22

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