Special Edition of Prescrire International

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Prescrire International • 2019 • SPECIAL EDITION

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Who are we?

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President of Association Mieux Prescrire: Pierre Chirac, pharmacist ASSOCIATION MIEUX PRESCRIRE  “To work, in all independence, in favour of quality healthcare, first and foremost in the interest of patients (...)” (Article 1 of the Association Mieux Prescrire bylaws). Prescrire International is a monthly journal of selected texts translated from the French journal Prescrire . Prescrire International is published 11 times a year by Association Mieux Prescrire, a non-profit continuing education organisation (N° 11 711 075) under the French law of 1901. EDITORIAL STAFF Members of the Prescrire Editorial Staff sign a yearly declaration of absence of conflicts of interest, in accordance with Prescrire’s “Non merci...” Charter. Members are free from any interest contrary to Association Mieux Prescrire’s objectives (the Charter and the Declaration are available online at english.prescrire.org). Publishing reliable reviews that are easy to use and adapted to readers’ needs depends upon complex editorial procedures, all initiated and overseen by the members of Prescrire’s Editorial Staff. Members of the Editorial Staff define editorial goals.They oversee the literature search, the writing and rewriting of texts, and the review by a panel of outside experts (medical specialists, methodologists, representatives of Prescrire’s subscriber base…).They organise internal and external quality control procedures, and edit the final copy. Every draft is submitted, before publication, to a large number of external reviewers.

Prescrire is a French non-profit continuing education organisation, committed to better patient care Prescrire International , the English-language edition of La Revue Prescrire provides independent information, by and for healthcare professionals. Independent information

Association Mieux Prescrire publishes a monthly journal in French, and an inter- national edition in English 11 times a year. A non-profit organisation, Prescrire is wholly financed by its subscribers, and accepts no advertising or other outside support. Reliable and relevant content Prescrire has the editorial and research capabilities necessary to ensure the accuracy of its reviews. Prescrire ’s editors are healthcare professionals, specially trained in Prescrire ’s editorial methods and free fromconflicts of interest. Exacting quality control procedures are applied to all editorial content.

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How we work Prescrire’s complex, collective editing process has been fine-tuned over the years Prescrire’s reviews, written by specially trained healthcare professionals, are based on an exhaustive search of the literature, and undergo scrutiny by a large panel of outside reviewers plus rigorous quality control procedures.

Editorial  Antibiotics: no market, no interest

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NEW PRODUCTS

Dupilumab ( dupixent °) in adults with atopic dermatitis An option for very troublesome eczema after failure of ciclosporin Midostaurin ( rydapt °) for some types of acute myeloid leukaemia Improved survival, but adverse effects underestimated Pembrolizumab (KEYTRUDA°) in urothelial carcinoma SC tocilizumab ( roactemra °) in giant cell arteritis An alternative to methotrexate Cladribine: insufficient clinical benefit in multiple sclerosis Methylphenidate during preg- nancy: teratogenic and fetotoxic, with concerns about long-term effects Gabapentin and pregabalin: deaths reported Silver sulfadiazine cream: dispro- portionate adverse effects Stable angina and antithrombotic drugs Addition of rivaroxaban to aspirin: uncertain benefits, proven harms Minor ischaemic stroke and anti- platelet drugs Very little advantage from adding clopidogrel to aspirin

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Editors free from conflicts of interest The absence of any direct or indirect financial links to the pharmaceutical industry is an absolute requirement to be a member of the Prescrire team. Any such link is cause for dismissal from the

All the reviews published in Prescrire (aside from a few clearly labelled exceptions, such as readers’ letters) are written by Prescrire’s Editorial Staff. Prescrire does not publish unsolicited manuscripts from outside contributors. The production of reviews draws upon a wide range of skills, all exer- cised under the supervision of Prescrire’s Editor.This team approach is reflected in the collective byline “©Prescrire”. Written and edited by healthcare professionals Prescrire’s editors are physicians (both general practitioners and specialists, in individual practice or on hospital staff), pharmacists (working in pharmacies or hospitals), nurses and dentists. A few are economists or journalists with specific expertise in the area of health- care. All Prescrire editors have received extensive in-house training in Prescrire’s editorial production process.

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Prescrire Editorial Staff. A vast network of reviewers

ADVERSE EFFECTS

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Once they are in an advanced stage of editing and quality control, all draft reviews are sent to outside reviewers (10 to 40 reviewers read each draft at this stage). These reviewers critique each article in terms of content, style, relevance, newsworthiness, presentation of argu- ments and usefulness in daily practice. The reviewers are specialists in the sub- ject being discussed, methodologists, or healthcare professionals representa- tive of Prescrire’s readers (and chosen from their midst).

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REVIEWS

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Reliable, rigorously independent information on treatments and healthcare strategies, to enable fully informed decision-making. No grants, no advertising. No shareholders, no sponsors. Prescrire is financed by its subscribers.

OUTLOOK

Drugs in 2018: a brief review

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Publicly-funded research: too opaque! Towards better patient care: drugs to avoid in 2019

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P rescrire I nternational S pecial E dition 2019 • P age 1

Antibiotics: no market, no interest

The growing resistance of bacteria to antibiotics is becoming a major global threat to public health, with hundreds of thousands of lives already lost each year, and millions more predicted (1). Major pharmaceutical companies, however, are abandoning their activity in this field. Historically, there is no doubt that it is through antibiotics (along with vaccines) that pharmaceutical companies have contributed most to extending life expectancy around the world, in particular through their ability to fight fatal childhood infections effectively. Antibiotics have also played a crucial role in many other fields of medicine, such as the management of patients with diabetes, and patients undergoing cancer chemotherapy or surgery (2). However, since the early 2000s, pharmaceutical companies have been progressively abandoning antibiotic research and development. Yet, faced with the phenomenon of increasing resistance, new effective and safe antibiotics are needed. Numerous plans and incentives have been promised or implemented worldwide to stimulate research by companies in this field, but with little effect (2,3). Among the most recent major drug companies to back out is Sanofi, historically a major player in the field of antibiotics, which has transferred this activity to a small German company. Another is Novartis, a major player whose management now prefers to devote its research budget to the more lucrative treatment of cancer and rare diseases (4,5). In the run-up to 2020, antibiotics no longer represent a sufficiently profitable market for the big pharmaceutical companies, who prefer the multiple niche markets offered by cancers and rare diseases, as a result of prolonged treatments and exorbitant prices. This trend emphasises the fact that meeting unmet public health needs is not pharmaceutical companies’ primary objective, and that the rules of the market do not operate in such a way as to meet these needs.These rules allow drug companies to generate the huge profits much appreciated by financial markets, while neglecting whole swathes of health needs. Public authorities bear the greatest responsibility for this trend, because it is their economic decisions that have allowed the development of a speculative business model, along with its harmful consequences, which were predictable. Governments today have a responsibility to devise and implement rules that will be effective in incentivising drug research and development that addresses public health needs. The development of new, effective and affordable antibiotics is a priority. Prescrire ▶▶ Translated from Rev Prescrire January 2019 Volume 39 N° 423 • Page 56

EDITORIAL

 Sources  1- “AMR: a major European and Global challenge” European Commission 2017: 2 pages. 2- Ventola CL “The antibiotic resistance crisis. Part 1: Causes and threats” Pharmacy and Therapeutics 2015; 40 (4): 277-283. 3- Darrow JJ et al. “When markets fail: patents and infectious disease products” FDA Law J 2018; 73 (3): 361-382. 4- “Despite Industry AMR Declaration commitments Sanofi quits R&D on anti-infectives” ReAct 27 June 2018: 3 pages. 5- “Alarm as Novartis exits the antibiotics space” Scrip 2018; (3914): 1-5.

Prescrire Int • May 2019

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dupilumab ( dupixent °) in adults with atopic dermatitis An option for very troublesome eczema after failure of ciclosporin

 POSSIBLY HELPFUL  In patients with troublesome atopic dermatitis in whom topical treatments have failed, it has not been shown that dupilumab is at least as effective as ciclosporin or any other immuno- suppressant. After failure of ciclosporin , an additional 30% of patients saw a significant improvement in their symptoms with dupi­ lumab , as compared with placebo. Dupilu­ mab ’s adverse effect profile appears to differ from that of ciclosporin , but in the absence of long-term data, much remains unknown about its harms. Based on the evaluation data available in late 2018, it is more prudent to only consider dupilumab therapy for patients in whom ciclosporin has failed and whose atopic dermatitis is very troublesome and greatly impacts their daily life. DUPIXENT° - dupilumab solution for subcutaneous injection • 300 mg of dupilumab per pre-filled syringe ■■ anti-interleukin-4 and 13 receptor monoclonal anti- body ■■ Indication: “moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy ”. [EU centralised procedure]

Abstract

● ● Atopic dermatitis (also called atopic eczema) is a chronic relapsing-remitting inflammatory skin condition.The severity of cutaneous symp- toms and their impact on daily life vary greatly from one patient to another. ● ● The first-choice treatments for alleviating the symptoms of atopic dermatitis are non-drug measures, emollients, and topical corticosteroids during flares. For adults whose daily life is severely affected despite these measures, treat- ment with an oral immunosuppressant, espe- cially ciclosporin , should be considered.The use of immunosuppressants is limited by their numerous and severe adverse effects. ● ● Dupilumab (Dupixent°, Sanofi Aventis) is a monoclonal antibody directed against the recep- tors for interleukins IL-4 and IL-13, which appear to be involved in the inflammatory response that occurs in atopic dermatitis. It has been authorised in the European Union for subcuta- neous use in adults with moderate-to-severe atopic dermatitis, after failure of topical treat- ments. ● ● Dupilumab has not been compared with ciclo­ sporin or other immunosuppressants. ● ● Clinical evaluation ismainly based on 4 double- blind randomised trials that compared dupilu- mab with placebo for 16 to 52 weeks in a total of 2444 adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. One of the trials included patients who could not receive ciclosporin or in whom ciclosporin had failed. ● ● The proportion of “responders” (free from eczema symptoms or whose eczema was rated as minor by the investigators) was 40% to 50% in the dupilumab groups, versus 10% to 20% in the placebo groups. Re-emergence of symp- toms was observed after dupilumab discontinu- ation. ● ● The main adverse effects of dupilumab observed in clinical trials included injection site reactions, eye disorders, oral herpes, and hyper- sensitivity reactions.

©Prescrire ▶▶ Excerpted from Rev Prescrire February 2019 Volume 39 N° 424 • Pages 93-94

Prescrire Int • May 2019

P rescrire I nternational S pecial E dition 2019 • P age 3

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midostaurin ( rydapt °) for some types of acute myeloid leukaemia Improved survival, but adverse effects underestimated

Abstract

actions. Additive adverse effects with drugs causing gastrointestinal or hepatic disorders and lymphopoenia can also be expected. ● ● Midostaurin is toxic to the embryo and fetus.  OFFERS AN ADVANTAGE  In a trial in 717 patients with acute myeloid leukaemia and a FLT3 mutation, midostaurin (a multi-tyrosine kinase inhibitor) added to induction and consolidation therapy, and then continued as maintenance monotherapy, increased the proportion of patients alive at 5 years by 8%. It was not evaluated in patients aged over 60 years, who generally have a worse prognosis.According to an incomplete assessment of its adverse effects, midostau­ rin mainly carries a risk of gastrointestinal disorders, elevated transaminase levels and lymphopoenia. In practice, midostaurin can be offered to patients aged less than 60 years with careful monitoring of adverse effects. It is important to report these adverse effects. RYDAPT° - midostaurin soft capsules • 25 mg of midostaurin per soft capsule ■■ antineoplastic; inhibitor of tyrosine kinases includ- ing FLT3 and KIT ■■ Indication: “ in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consoli­ dation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leu­ kaemia (AML) who are FLT3 mutation-positive”. [EU cen- tralised procedure – orphan drug].

● ● The standard treatment for patients with acute myeloid leukaemia is a combination of daunorubicin + cytarabine as induction therapy, followed by consolidation therapy with chemo- therapy or bone marrow transplantation. Main- tenance therapy has not been shown to be of benefit in prolonging survival. About one-third of patients have tumour cells carrying a muta- tion in the FLT3 gene, which is an adverse prog- nostic factor. ● ● Midostaurin (Rydapt°, Novartis) is an inhib- itor of multiple tyrosine kinases, including the FLT3 kinase. It has been authorised in the Euro- pean Union for patients with newly diagnosed acute myeloid leukaemia who carry a FLT3 muta- tion. ● ● In a randomised, double-blind, placebo-controlled trial in 717 patients aged less than 60 years, addition of midostaurin to the dauno­ rubicin + cytarabine combination in the induc- tion phase, then to high-dose cytarabine in the consolidation phase, with continuation of mido­ staurin in a maintenance phase, increased the proportion of patients alive at 5 years to 51% compared to 43%. However, midostaurin was not evaluated in patients aged over 60 years, who generally have a poor prognosis. ● ● Assessment of the adverse effects of mido­ staurin in the main trial was incomplete. Accord- ing to available data, midostaurin carries at least a risk of gastrointestinal disorders, catheter infections, lymphopoenia and elevated liver transaminase levels. ● ● Midostaurin is metabolised by cytochrome P450 isoenzyme CYP 3A4 and may be an in­ ducer of various cytochrome P450 isoenzymes and an inhibitor of P-glycoprotein, creating the potential for numerous pharmacokinetic inter-

©Prescrire ▶▶ Excerpted from Rev Prescrire November 2018 Volume 38 N° 421 • Pages 814-815

Prescrire Int • February 2019

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NEW PRODUCTS

pembrolizumab ( keytruda °) in urothelial carcinoma

 POSSIBLY HELPFUL  In a non-blinded comparative randomised trial after failure of platinum-containing chemotherapy, pembrolizumab prolonged survival by about 3 months compared with taxane- or vinflunine -containing chemother- apy. Its adverse effects were different and less frequent.

which the curves crossed, and mortality was sub- sequently higher in the chemotherapy group (2). The authorisation of pembrolizumab as first-line therapy when cisplatin -containing chemotherapy cannot be used is based on a single non- comparative trial, thus it cannot be demonstrated whether it constitutes an advance over existing options (2). A trial underway as of June 2018 includes a comparison of pembrolizumab monotherapy versus platinum-containing chemotherapy as first-line treatment. Preliminary analysis of the data showed that mortality was higher in the pembrolizumab monotherapy group among patients whose tumour cells and immune cells weakly expressed the ligand of the PD-1 receptor (PD-L1). In response to this finding, the European Medicines Agency (EMA) recommended restricting the indication for first-line pembrolizumab to patients in whom PD-L1 is ex- pressed by at least 10% of tumour cells and immune cells (4,5).This restriction was added to the European summary of product characteristics in June 2018 (6). In the comparative trial after failure of platinum-containing chemotherapy, adverse effects were less frequent in the pembrolizumab group (61% versus 90% in the chemotherapy group).This was also the case for serious adverse effects: about 10% in the pembrolizumab group versus 22% (2). As foresee- able, given its mechanism, immunological adverse effects were more frequent in the pembrolizumab group. Gastrointestinal, haematological and neuro- logical disorders and alopecia were more frequent in the chemotherapy group (2). ©Prescrire ▶▶ Excerpted from Rev Prescrire September 2018 Volume 38 N° 419 • Pages 654-655 Literature search up to 3 July 2018 In response to our request for information, MSD provided us with no documentation on its product. 1- Prescrire Rédaction “atézolizumab (Tecentriq°) et carcinome urothélial” Rev Prescrire 2018; 38 (418): 575-576. 2- EMA - CHMP “Public assessment report for Keytruda. EMEA/ H/C/003820/II/0023/G” 20 July 2017: 146 pages. 3- HAS - Commission de la Transparence “Projet d’avis-Opdivo” 25 October 2017 + “Avis-Keytruda” 21 February 2018: 49 pages. 4- EMA “EMA restricts use of Keytruda andTecentriq in bladder can- cer” 1 June 2018: 3 pages. 5- “Study of pembrolizumab with or without platinum-based combi- nation chemotherapy versus chemotherapy alone in urothelial carci- noma (MK-3475-361/Keynote-361). NCT02853305”. clinicaltrials.gov accessed 19 June 2018: 7 pages. 6- European Commission “SPC-Keytruda” 6 July 2018: 75 pages.

KEYTRUDA° - pembrolizumab powder for concentrate for solution, or concentrate for solution for intravenous infusion ■■ immunostimulant; anti-PD-1 ■■ New indication: “ as monotherapy (...) for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy [or] who are not eligible for cisplatin- containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10 ” . [EU centralised procedure] For patients with locally advanced or metastatic urothelial carcinoma, platinum-based chemother- apy is often proposed as first-line treatment.When it fails, there is no consensus on treatment.Taxanes such as docetaxel and paclitaxel are second-line options.The vinca alkaloid vinflunine has an unfa- vourable harm-benefit balance (1,2). Nivolumab and atezolizumab are immunostimulatory mono- clonal antibodies targeting the PD-1 receptor path- way. They have been authorised in the European Union for this situation, although they have not been shown to prolong survival (1,3). Pembrolizumab (Keytruda°, Merck Sharp & Dohme) is another immunostimulatory anti-PD-1 monoclo- nal antibody that is already authorised for various cancers in the European Union. It has now also been authorised for use in patients with locally advanced or metastatic urothelial carcinoma, after failure of platinum-based chemotherapy or when cisplatin -containing chemotherapy cannot be used. Clinical evaluation after failure of platinum-based chemotherapy is based on a single non-blinded randomised trial in 542 patients. Patients were randomised to receive either pembrolizumab or the investigator’s choice of chemotherapy regimen: docetaxel , paclitaxel or vinflunine (2). After a median follow-up of about 14 months, median survival was longer in the pembrolizumab group: 10.3 months versus 7.4 months in the chemotherapy group (p = 0.002) (2,3). Analysis of survival curves shows that mortality was higher in the pembrolizumab group during the first 2 months of treatment, after

Prescrire Int • January 2019

P rescrire I nternational S pecial E dition 2019 • P age 5

NEW PRODUCTS

SC tocilizumab ( roactemra °) in giant cell arteritis An alternative to methotrexate

 POSSIBLY HELPFUL  For patients with giant cell arteritis, the value of adding tocilizumab to prolonged cortico- steroid therapy with gradual dose reduction over a period of 18 months to 2 years has not been evaluated. Corticosteroid therapy alone therefore remains the standard treatment. In the rare patients who cannot tolerate cortico­ steroids, tocilizumab has not been compared with methotrexate . But in one trial, adding tocilizumab to corticosteroid therapy reduced the cumulative corticosteroid dose. The adverse effect profile of tocilizumab differs from that of methotrexate , making it a use- ful option for some patients.

in France recommend tapering over 18 months to 2 years. After an average treatment duration of two years, about half of patients manage to discontinue corticosteroid therapy without relapsing (1-4). Prolonged corticosteroid treatment has many, sometimes serious adverse effects: fluid and electro- lyte disturbances, cardiovascular disorders, metabol- ic disorders (including weight gain, hyperglycaemia, and adrenal insufficiency), musculoskeletal disorders (includingmuscle atrophy and osteoporosis), skin and eye disorders; mood and behavioural disorders; immunosuppression; and infections (1,3-5). In rare patients, corticosteroid doses must be kept to a minimum, in particular those with a condition liable to be worsened by corticosteroid therapy, such as complicated diabetes, depression or severe hypertension, or those who can no longer tolerate the adverse effects of corticosteroids. Another immunosuppressant is often added in such cases, with the aim of reducing the corticosteroid dose. Methotrexate is the best-evaluated option in this situation. According to a meta-analysis of three randomised placebo-controlled trials in a total of 161 patients with newly diagnosed giant cell arter­ itis, adding methotrexate to corticosteroid therapy for 48 weeks resulted in a modest but statistically significant reduction in the frequency of relapses, and reduced the cumulative corticosteroid dose over the 48-week period by 842 mg of prednisone or equivalent compared with the placebo group, i.e. a reduction of 2.5 mg of corticosteroid per day on average (3,4,6). The main adverse effects of methotrexate are: gastrointestinal disorders (including stomatitis, ab- dominal pain and intestinal perforation); haemato- logical disorders (including agranulocytosis, anae- mia, and thrombocytopenia); liver damage; and infections (7). Tocilizumab (RoActemra°, Roche) is a monoclonal antibody that binds to interleukin 6 receptors, thus inhibiting the action of interleukin 6, a cytokine in- volved in inflammatory phenomena. Tocilizumab was already authorised in the EU for use in rheuma- toid arthritis and a few other inflammatory conditions. It has now been authorised for use by subcutaneous injection in giant cell arteritis, in combination with a tapering course of corticosteroid therapy (2,5,8). In this situation, does the addition of tocilizumab to corticosteroid therapy constitute a therapeutic advance over corticosteroid therapy alone, espe- cially for the prevention of relapses? Is tocilizumab more effective than methotrexate in the rare patients What’s new?

ROACTEMRA° - tocilizumab solution for subcutaneous injection • 162 mg of tocilizumab per pre-filled syringe or pen. ■■ immunosuppressant; anti-interleukin-6 monoclo- nal antibody ■■ New indication : “giant cell arteritis”. [EU centralised pro- cedure]

Compare before deciding

Giant cell arteritis (also known as temporal or cra- nial arteritis, or Horton disease) is an inflammatory disease affecting the arteries, of undetermined cause. It mainly occurs in patients over the age of 70 years, predominantly women. The main symptoms are headache of varying severity, scalp tenderness (causing pain when combing or brushing hair), jaw pain on chewing, constitutional symptoms (including fever, fatigue, appetite or weight loss), inflammatory pain and joint stiffness, predominantly in the shoul- ders and hips. Signs of inflammation, including C-reactive protein (CRP) elevation, are very often present.The main complication of giant cell arteritis is sudden, irreversible blindness in one or sometimes both eyes, usually with no warning symptoms (1-3). Tapered corticosteroid therapy, sometimes adding methotrexate. Treatment of giant cell arteritis is based on high-dose oral corticosteroid therapy. Once in- flammatory markers have normalised, typically after 2 to 4 weeks of treatment, the corticosteroid dose is reduced very gradually to avoid relapses.There is no consensus over the duration of this taper. Specialists

P age 6 • P rescrire I nternational S pecial E dition 2019

NEW PRODUCTS

in whom it is particularly important to limit the corticosteroid dose? And what are its adverse effects?

infections); hypersensitivity reactions, including anaphylaxis; neutropenia and thrombocyto- penia; gastrointestinal bleeding and perforation; transaminase elevation; hypercholesterolaemia; cancers; and demyelinating disorders. Subcutane- ous injection of tocilizumab can provoke injection site reactions. As tocilizumab is an immunosup- pressant, concomitant use with a corticosteroid increases the risk of immunosuppression and infections (7,8,10,11). The data from the double-blind trial in patients with giant cell arteritis provided no new information about the adverse effect profile of tocilizumab . The most frequent adverse events were infections: 200 per 100 person-years in the tocilizumab group, ver- sus 156 per 100 person-years in the “placebo group with 26-week taper”, versus 210 per 100 person-years in the “placebo group with 52-week taper” (5,9). In patients with giant cell arteritis, the value of adding tocilizumab to prolonged corticosteroid therapy tapered gradually over a period of 18 months to 2 years (in accordance with French guidelines) has not been evaluated. Corticosteroid therapy alone, with gradual dose reduction, remains the standard treatment. For the rare patients who cannot tolerate cortico- steroids, tocilizumab has not been compared with methotrexate . But in one trial, adding tocilizumab to corticosteroid therapy reduced the cumulative corticosteroid dose. The adverse effect profile of tocilizumab differs from that of methotrexate , making it a useful option for some patients. ©Prescrire ▶▶ Excerpted from Rev Prescrire March 2019 Volume 39 N° 425 • Pages 177-179 Literature search up to 8 January 2019 In response to our request for information, Roche provided us with published articles and packaging items. 1- Prescrire Rédaction “Artérite à cellules géantes” Premiers Choix Prescrire, updated December 2017: 4 pages. 2- HAS - Commission de la Transparence “Avis-RoActemra” 19 Sep- tember 2018: 26 pages. 3- Mahr A et al. “Protocole national de diagnostic et de soins PNDS. Artérite à cellules géantes (Horton)” 2017: 35 pages. 4- DockenWP et al.“Treatment of giant cell arteritis”UpToDate. www. uptodate.com accessed 28 November 2018: 19 pages. 5- EMA - CHMP “Public assessment report for RoActemra. EMEA/ H/C/000955/II/0066” 20 July 2017: 117 pages. 6- Mahr AD et al. “Adjunctive methotrexate for treatment of giant cell arteritis” Arthritis Rheum 2007; 56 (8): 2789-2797. 7- Prescrire Rédaction “méthotrexate” + “tocilizumab” Interactions Médicamenteuses Prescrire 2019. 8- European Commission “SPC-RoActemra” 18 September 2017: 64 pages. 9- Stone JH et al. “Trial of tocilizumab in giant-cell arteritis” N Engl J Med 2017; 377 (4): 317-328 + appendices: 13 pages. 10- Prescrire Rédaction “Tocilizumab SC et polyarthrite rhumatoïde: pas de comparaison directe au rituximab” Rev Prescrire 2015; 35 (383): 660. 11- Prescrire Editorial Staff “Tocilizumab. Rheumatoid arthritis: another“mab”, no therapeutic advantage” Prescrire Int 2009; 18 (103): 198-201. In practice

Placebo-controlled trial: corticosteroid tapered too rapidly? Clinical evaluation of tocilizumab in this situation is mainly based on a double-blind ran- domised placebo-controlled trial in 251 adults (three-quarters of whomwere women) aged 50 years or older (median age 70 years) with giant cell arter- itis, either newly diagnosed (about half of cases) or relapsed despite corticosteroid treatment (2,5,9). The patients all received the corticosteroid pred­ nisone .The dose was tapered to zero over 26 weeks or 52 weeks, in accordance with a strict schedule as determined by the protocol. Patients were ran- domised to one of the four following groups: tocili­ zumab 162 mg weekly for 52 weeks, plus cortico- steroid therapy tapered over 26 weeks ( tocilizumab group); placebo with the same corticosteroid taper (“placebo group with 26-week taper”); placebo plus corticosteroid tapered over 52 weeks (“placebo group with 52-week taper”); or tocilizumab 162 mg every other week, a group not addressed in this article. A short course of corticosteroid therapy was permitted in patients whose disease worsened (2,5). After 52 weeks of treatment, the proportion of patients in sustained remission (mainly defined by the absence of symptoms and normalisation of CRP levels for 10 months, from week 12 to week 52) was 56% in the tocilizumab group, versus 14% in the “placebo group with 26-week taper”, versus 18% in the “placebo group with 52-week taper” (statistical- ly significant differences between the tocilizumab group versus both placebo groups) (5,9). The me- dian cumulative dose of prednisone was 1862 mg in the tocilizumab group, versus 3296 mg in the “pla- cebo group with 26-week taper” and 3818 mg in the “placebo group with 52-week taper” (p<0.0001) (5). Only a small proportion of patients in the placebo groups entered remission in this trial.This result may be related to the fact that prednisone was tapered and withdrawn over a shorter period of time than the 18 to 24 months generally recommended in France (1-3). After the initial analysis, 45 patients in sustained remission were followed for an additional two years after cessation of tocilizumab or placebo. At the start of this period, three patients were still on cor- ticosteroid therapy, one patient was receiving a corticosteroid plus methotrexate , and two patients were taking methotrexate . According to a preliminary analysis, relapses appeared more frequent in pa- tients who had received tocilizumab than in those who had received placebo (33% versus 20%) (no statistical analysis performed) (5). It is not possible to reach conclusions as to whether the risk of relapse is increased after tocilizumab cessation, due to the small number of patients included in this follow-up and its limited duration.

Mainly infections. The adverse effect profile of tocilizumab mainly comprises: sometimes serious and occasionally fatal infections (including lung and skin

Prescrire Int • June 2019

P rescrire I nternational S pecial E dition 2019 • P age 7

NEW PRODUCTS

Cladribine: insufficient clinical benefit in multiple sclerosis C ladribine is a purine analogue with immunosup- pressive effects linked to a prolonged cytotoxic action on B and T lymphocytes. Since 2017, it has been authorised in the European Union (as Mavenclad°) for oral administration in some patients with multiple sclerosis (1,2). In late 2018, the French pharmacoeconomic com- mittee, which provides recommendations on drug reimbursement, issued an unfavourable opinion regarding the inclusion of cladribine for multiple sclerosis in the list of drugs that are eligible for reimbursement by the French health insurance system. The medical benefit was rated as “insuffi- cient” due in particular to inappropriate evaluation and uncertainties regarding the serious long-term adverse effects of cladribine (2). This conclusion is consistent with what is known about the evaluation of cladribine in this situation. It carries a risk of infections, including opportunistic infections, and cancers (1). This opinion makes it unlikely that Mavenclad° will be marketed in France, which is welcome news, thus protecting patients from the drug’s adverse effects. ©Prescrire ▶▶ Translated from Rev Prescrire February 2019 Volume 39 N° 424 • Page 105 Selected references from Prescrire’s literature search 1- Prescrire Editorial Staff “Oral cladribine and multiple sclerosis” Prescrire Int 2018; 27 (196): 207. 2- HAS - Commission de la transparence“Compte rendu de la réunion du 19 septembre 2018” + “Avis-Mavenclad” 19 September 2018: 58 pages.

COMMON STEM

NN

-afil According to the nomenclature established by theWorld Health Organization (WHO) to devise international non- proprietary names (INNs), the INNs of phosphodies- terase type-5 inhibitors with vasodilator action end in the common stem -afil (1). Four drugs with this stem ( avanafil , sildenafil , tadal­ afil and vardenafil ) were marketed in France as of 2 Janu- ary 2019, for erectile dysfunction or benign prostatic hyperplasia. Sildenafil and tadalafil are also authorised for the treatment of pulmonary arterial hypertension. ©Prescrire ▶▶ Translated from Rev Prescrire February 2019 Volume 39 N° 424 • Page 103  Sources  1- World Health Organization“The use of stems in the selec- tion of International Nonproprietary Names (INN) for pharmaceutical substances -WHO/EMP/RHT/TSN/2013.1”: 63. A drug’s real name

Prescrire Int • June 2019

PRESCRIRE’S RATINGS Our judgement is based on the therapeutic advance of the new product. It considers not only the inherent value of each product in terms of its harm-benefit balance, but also its advantages and disadvantages relative to existing products available in France. Note that the relative value of new products can vary from one country to another.

Quality of information from pharmaceutical companies In response to our systematic requests

 BRAVO  The product is a major therapeutic advance in an area where previously no treatment was available.  A REAL ADVANCE  The product is an important therapeutic advance but has certain limitations.  OFFERS AN ADVANTAGE  The product has some value but does not fundamentally change the present therapeutic practice.  POSSIBLY HELPFUL  The product has minimal additional value, and should not change prescribing habits except in rare circumstances.

 NOTHING NEW  The product is a new substance but with no evidence that it has more clinical value than other substances of the same group. It can be a me-too or a near me-too.

Company provided detailed information including unpublished

data and packaging items.

Company provided information limited to published administrative data or packaging items.

 NOT ACCEPTABLE  Product without evident benefit but with potential or real disadvantages.

Company provided minimal information, mainly administrative

 JUDGEMENT RESERVED  The editors postpone their rating until better data and a more thorough evaluation of the drug are available.

and packaging items.

Company provided no information.

P age 8 • P rescrire I nternational S pecial E dition 2019

ADVERSE EFFECTS

Methylphenidate during pregnancy: teratogenic and fetotoxic, with concerns about long-term effects

First trimester: cardiac malformations

ABSTRACT

● ● Methylphenidate is an amphetamine-like psy- chostimulant. In animals, at high doses, various amphetamines carry a risk of cardiac malformations. Methylphenidate is teratogenic at toxic doses for the pregnant female, and can lead to skeletal abnor- malities and neural tube closure defects, depend- ing on the species. Behavioural disorders have also been reported. ● ● Two studies, including a total of about 3500 preg- nant women exposed to methylphenidate during the first trimester of pregnancy, have shown that the risk of cardiac malformations is probably great- er in children of exposed mothers compared to those of non-exposed mothers: around 3 addition- al cases per 1000 pregnancies. ● ● When exposure to methylphenidate occurred during the second and third trimesters of preg­ nancy, the risk of preeclampsia and premature birth seemed to be greater than in the absence of expo- sure. At birth, cardiorespiratory and neurological disorders associated with this exposure were observed. ● ● The long-term neuropsychiatric consequences of in utero exposure to methylphenidate are large- ly unknown. ● ● In practice, use of methylphenidate during preg- nancy should be avoided as far as possible. Rev Prescrire 2019; 39 (425): 188-190 M ethylphenidate is an amphetamine-like psychostimulant, used in attention deficit hyperactivity disorder (ADHD) in children and adolescents and, in some cases, in adults. It is also authorised for some types of narcolepsy (1-6). In 2017, several teams around the world published new studies carried out on thousands of pregnant women exposed to methylphenidate .These studies have brought important data to a hitherto poorly documented field (7-9). As of 2019, what are the chief known consequences of in utero exposure to methylphenidate for the unborn child, in the short and long term?

Studies in animals have shown that various am- phetamines have a teratogenic action, with mainly cardiac malformations at high doses (7). In animals: toxic and teratogenic at high doses. According to the French summaries of product char- acteristics (SPCs) from2017 or 2018, “methylphenidate is not considered to be teratogenic in rats or rabbits” (1,2). This is also stated by the French Teratogenic Agent Information Centre (CRAT) on its website as of 4 February 2019 (10). However, in the 2017 US Full Prescribing Information, methylphenidate is described as teratogenic in rabbits at doses higher than the maximum recommended human dose (1,2,11). Indeed, studies of methylphenidate in animals have yielded conflicting results.The oldest studies, in 2 species, did not show any teratogenic effect. More recent studies, in 2008 and 2016, showed that spina bifida (neural tube closure defects) occurred in rabbits, skeletal abnormalities at the highest doses in rats, and polydactyly, skeletal and cerebral abnormalities in mice at doses 4 times the doses recommended in humans. Behavioural abnormalities were observed in mice and rats after in utero exposure to methylpheni­ date (11-15). Thousands of women exposed: a few cardiac malformations. For pregnant women, the available data mainly come from studies using databases in the US and Scandinavia, covering a total of about 3500 women exposed to methylphenidate during the first trimester of pregnancy (7). There did not appear to be an increased risk of malformations (all types combined). However, these studies demonstrated a greater risk of cardiac malformations in exposed children, compared to unexposed children, at the limit of statistical significance. Pooling data from the 2 studies, the estimated relative risk was 1.3, with a 95% confidence interval (95CI) of 1.0 to 1.6. In other words, given that cardiac malformations affect around 10 children per 1000 births, there is a strong probability that around 3 additional children are born with a cardiac malformation for every 1000 women taking methylphenidate during the first trimester of pregnancy (7). The results only covered live births and therefore probably excluded a number of malformations (7). Methylphenidate also may carry a risk of miscar- riage (7,12).

P rescrire I nternational S pecial E dition 2019 • P age 9

ADVERSE EFFECTS

Three other studies, each dealing with only about 200 women exposed to methylphenidate, lack suf- ficient statistical power to detect a small increase in a rare malformation. There appeared to be a greater risk of cardiac malformations, major mal- formations or miscarriage, but this did not reach statistical significance (7,12-15).

including seizures (6 cases), hypotonia (2 cases), hypoxic ischaemic encephalopathy (1 case), and unspecified conditions (7 cases), i.e. about a 2-fold greater risk than in the control groups (8).

In the long term: perhaps more attention disorders, and many unknowns

Pre-eclampsia, prematurity, and neuropsychiatric disorders

Methylphenidate is an amphetamine-like psycho- stimulant. It crosses into the central nervous system (CNS) and can lead to so-called CNS stimulatory effects: anxiety, fear, agitation, insomnia, and hal- lucinations (17,18). Animals exposed to methylphenidate in utero had behavioural problems more often than unexposed animals (14). According to a conference abstract, a study in Quebec identified 25 000 children with ADHD out of about 166 000 children born at term. After adjustment for various confounding factors, including a maternal history of hyperactivity, the diagnosis of ADHD during childhood was twice as frequent in those exposed to ADHD drugs in utero (estimated relative risk = 2.0; 95CI: 1.3-3.3). The authors of the study attributed this finding to methyl­ phenidate (though with no numerical data) (21).  In practice  Avoid in utero exposure. When a pregnant woman takes methylphenidate, the unborn child is exposed to a risk of serious adverse effects, irrespective of the stage of pregnancy. As of early 2019, there have still been very few studies of the long-term effects on the neuropsychological devel- opment of the child. In addition, methylphenidate seems to expose women to a greater risk of pre- eclampsia. In those rare situations where methylphenidate is justified in a woman who could become pregnant, effective contraception is important. Where exposure during pregnancy has occurred, an effect on the child’s heart must be anticipated, and morphology ultrasound scanning should be carried out to monitor the fetus. When used towards the end of pregnancy and up to delivery, management of the pregnancy must be adjusted to take account of the effects of methyl­ phenidate and to monitor the newborn accordingly. Review produced collectively by the Editorial Staff: no conflicts of interest ©Prescrire ▶▶ Translated from Rev Prescrire March 2019 Volume 39 N° 425 • Pages 188-190 Literature search up to 11 December 2018 1- ANSM“RCP-Concerta LP 18 mg” 13 November 2018: 11 pages. 2- ANSM“RCP-Ritaline LP 10 mg” 15 November 2017: 12 pages. 3- Prescrire Editorial Staff “Methylphenidate and narcolepsy: when modafinil fails” Prescrire Int 2001; 10 (51): 7-9. 4- PrescrireRédaction“Méthylphénidate: banalisémalgré les dangers” Rev Prescrire 2017; 37 (406): 616. 5- Anderson NK et al. “Attention-deficit/hyperactivity disorder medi- cation prescription claims among privately insured women aged 15-44 years - United States, 2003-2015” MorbMortalWkly Rep 2018; 67 (2): 66-70.

The fetus is exposed to the sympathomimetic effects of methylphenidate, common to all amphetamines, which are difficult to demonstrate in utero. These are mainly neuropsychiatric disorders, cardiac disorders with hypertension and arrhythmia, and vasoconstriction (16-18). Cases of neonatal cardiorespiratory disorders, in particular tachycardia and respiratory distress, have been reported (19). Given the adverse effect profile of methylphenidate , intrauterine growth retardation, premature birth and withdrawal symptoms can be predicted (16-18). Epidemiological data concerning methylphenidate exposure during the third trimester of pregnancy are very limited. Preeclampsia. Using the US Medicaid database, a cohort study compared the occurrence of various obstetric complications (preeclampsia, placental abruption, fetal growth restriction, and preterm birth) in 3331 women exposed to an amphetamine- dextroamphetamine combination, 1515 exposed to methylphenidate and 453 to atomoxetine, prescribed for ADHD, during the first two trimesters of preg- nancy (9). Compared to about 1 500 000 unexposed pregnant women, the relative risk of preeclampsia was about 1.3 (95CI: 1.1-1.5) with all of the amphet- amines studied, after adjustment for various con- founding factors. The relative risk associated with at least 2 prescriptions of methylphenidate was of the same order of magnitude. Results following exposure during the third trimester of pregnancy are not available, whereas preeclampsia is more frequent after 34 weeks of pregnancy (20). Premature birth and admission to a neonatal intensive care unit (ICU). A study carried out using Swedish registries compared 1591 children exposed in utero to drugs used for ADHD with 2 control groups: 9475 children of mothers exposed to such drugs before or after pregnancy; and one million children born to mothers who had never been ex- posed (8).The 1591 children were mainly exposed to methylphenidate (92%), about 16% during the third trimester. After taking account of various confounding fac- tors, there was a greater risk of preterm birth and admission to a neonatal ICU as compared to the control groups: estimated relative risk of 1.3 (95CI:1.1- 1.6) and 1.5 (95CI: 1.3-1.7), respectively (8). Sixteen children exposed in utero had neurological disorders

P age 10 • P rescrire I nternational S pecial E dition 2019

ADVERSE EFFECTS

6- Prescrire Rédaction “Méthylphénidate: beaucoup d’adultes parmi les nouveaux utilisateurs en France” Rev Prescrire 2018; 38 (422): 912. 7- Huybrechts F et al. “Association between Methylphenidate and AmphetamineUse inPregnancy andRisk of CongenitalMalformations. A Cohort Study from the International Pregnancy Safety Study Con- sortium” JAMA Psychiatry 2018; 75 (2): 167-175. 8- Nörby U et al. “Perinatal outcomes after treatment with ADHD medication during pregnancy” Pediatrics 2017: 140 (6): 11 pages. 9- Cohen JM et al. “Placental complications associated with psycho- stimulant use in pregnancy” Obstet Gynecol 2017; 130 (6): 1192-1201. 10- Centre de référence sur les agents tératogènes“Méthylphénidate” 20December 2017. www.lecrat.fr accessed 4 February 2019: 2 pages. 11- US FDA “Full prescribing information-Concerta” 1 April 2017: 28 pages. 12- “Teris Teratogen Information System”. depts.washington.edu/ terisdb accesed April 2018. 13- “Shepard’s Catalog of Teratogenic Agents” 28 November 2016. depts.washington.edu/terisdb accessed October 2018.

14- “Reprotox” 9 March 2018. reprotox.org accessed October 2018. 15- “Briggs Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk” 11 th ed. Lippincott Williams and Wilkins, Philadelphia 2011. 16- Prescrire Rédaction “Mécanisme d’action des amphétaminiques en bref” Rev Prescrire 2015; 35 (376): 107. 17- PrescrireRédaction“FicheM2. Les sympathomimétiques en bref” Interactions Médicamenteuses Prescrire 2019. 18- “Methylphenidate”. In:“MartindaleTheCompleteDrugReference” The Pharmaceutical Press, London. www.medicinescomplete.com accessed 29 December 2018: 15 pages. 19- ANSM “Méthylphénidate: données d’utilisation et de sécurité d’emploi en France” April 2017: 34 pages. 20- August P et al. “Preeclampsia: Clinical features and diagnosis” UpToDate. www.uptodate.com accessed 7 October 2018: 25 pages. 21- Lemelin M et al. “Maternal ADHD medication use during preg- nancy and the risk of ADHD in children” Birth Defects Res 2018; 110 : 759. Prescrire Int • June 2018  In practice  The increased use of pregabalin and gabapentin is correlated with an increase in mor- tality linked to these substances.That represents a strong argument for not using them routinely, all the more so since it is sometimes difficult to stop these drugs, as a result of withdrawal symptoms. With patients already on treatment, there should be a regular reassessment of its value, the doses actually being taken and the adverse effects, whose link with the drug is sometimes unrecognised. ©Prescrire ▶▶ Translated from Rev Prescrire November 2018 Volume 38 N° 421 • Page 830 2- Lacobucci G“UK government to reclassify pregabalin and gabapen- tin after rise in deaths” BMJ 2017; 358 : j4441 doi: 10.1136/bmj.j4441. 3- Office for national statistics “Death related to drug poisoning in England andWales: 2016 registrations” 2 August 2017: 34 pages. 4- ANSM“RCP-Neurontin 400 mg” 22 January 2018: 11 pages.
 5- European Commission “SPC-Lyrica” 1 st August 2018: 111 pages. 6- Prescrire Editorial Staff “Gabapentin and pregabalin: abuse and addiction” Prescrire Int 2012; 21 (128): 152-154. 1- “Gabapentin and risk of severe respiratory depression” DrugTher Bull 2018; 56 (1): 3-4.


Gabapentin and pregabalin: deaths reported

At the end of 2017, the British Medicines and Healthcare products Regulatory Agency (MHRA) announced an increase in reports of deaths linked to pregabalin ,

an analogue of gamma-aminobutyric acid (GABA): 4 deaths had been reported in 2012 and 111 deaths in 2016.The number of deaths linked to gabapentin , another substance closely related to pregabalin , was 8 in 2012 and 59 in 2016 (1-3). Pregabalin and gabapentin are authorised for use in epilepsy, anx- iety and chronic neuropathic pain (4,5). Pregabalin and gabapentin carry a risk of respira­ tory depression, which is increased in patients having a respiratory or neurological disorder, in renal failure, when in combination with a central nervous system depressant, particularly an opioid, a benzodiazepine or alcohol, and in the elderly (1-5). Pregabalin and gabapentin carry a risk of addiction associated with withdrawal symptoms and abuse with increasing doses (6). In 5 years, the number of prescriptions in the United Kingdom increased by 350% for pregabalin and by 150% for gabapentin (2). One cause put forward is that these drugs are being used too readily and their use is becoming “routine”.

Prescrire Int • April 2019

P rescrire I nternational S pecial E dition 2019 • P age 11