Prescrire International - Free Special Edition - 2022

SPECIALEDITION

A critical eye on new drugs authorised in Europe

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Prescrire International Special Edition 2022

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Prescrire is a French non-profit continuing education organisation, committed to better patient care Prescrire International is a monthly journal on new drugs authorised in Europe with selected texts from La Revue Prescrire Who are we?

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President of Association Mieux Prescrire: Antoinne Grandvuillemin, pharmacist ASSOCIATIONMIEUXPRESCRIRE “Towork, inall independence, infavourof quality healthcare, first and foremost intheinterest ofpatients(...)” (Article 1 of the Association Mieux Prescrire bylaws). Prescrire International is published 11 times a year byAssociation Mieux Prescrire, a non-profit continuing education organisation (N° 11 711 075) under the French lawof 1901. EDITORIALSTAFF 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 Staffdefine 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. Around 250 people participate in the production and distribution of every issue of La Revue Prescrire , including: -  around 150members of the Prescrire team ; -  around 100 external reviewers, experts in the subjects discussed and practising healthcare professionals. For each issue, readers are provided with a list of the contributors to that issue.

drugs and therapeutic and diagnostic strategies. Association Mieux Prescrire publishes a monthly journal inFrench, andanedition in English 11 times a year. A non-profit organisation, Prescrire is wholly financed by 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. Most of Prescrire’s editors are healthcare professionals, specially trained in Prescrire’s editorial methodsandfreefromconflictsof interest. Exacting quality-control procedures are applied to all editorial content.

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SPECIALEDITION

TOPTEXTS OF 2022

EDITORIAL  The EMA is withholding too much information �������������������������������������������������������������������������� 2

MARKETING AUTHORISATIONS

Ivacaftor + tezacaftor + elexacaftor ( KAFTRIO ° ) in cystic fibrosis with at least one F508del mutation Respiratory symptoms alleviated in the short term ��������������������������������������� 3

The new, redesigned Prescrire International casts a critical eye on newdrugs authorised in Europe.

Nasal naloxone 1.8 mg ( NYXOID° ) in opioid overdose ���������������������� 4

Fenfluramine ( FINTEPLA ° ) in Dravet syndrome Higher incidence of convulsive status epilepticus, and serious cardiovascular risks in the long term ������������������������������������������������������������������ 5 Dupilumab ( DUPIXENT °) in severe atopic eczema from 6 years of age ������������������������������������������������������������������������������������������������������ 6 EDITORS’ OPINION Negligence ������������������������������������������������������������������������ 7 Prescrire's ratings of new drugs in 2021: a brief review ����������� 8 Inset  Therapeutic advances in 2021 compared with the previous 9 years ����������������������������������������������������������������������������������������� 9

Everymonth, you’ll find varied and useful content:

Adverse Effects to keep abreast of key pharmacovigilance data Outlook for insights into European medicines and health policy MarketingAuthorisations critical analysis and unbiased ratings of newmedicines and newauthorisations

ADVERSE EFFECTS

Clopidogrel + a proton pump inhibitor: increased mortality �������� 10

Update on myocarditis linked to the covid-19 messenger RNA vaccines tozinameran ( COMIRNATY ° )

and elasomeran ( SPIKEVAX ° ) ��������������������������������������������������������������������������� 11 COMMON STEM -azam, -azepam, -azolam ������������������������������������������������� 12 Perioperative benzodiazepines: a risk factor for persistent use ��� 12

OUTLOOK

Towards better patient care: drugs to avoid in 2022 ������������������������� 13 Inset  Main changes in the 2022 update ���������������������������������������������� 14 European Medicines Agency: transparency policy marred by too many failings �������������������������������������������������������������������������� 15 The Innovative Medicines Initiative: a European public-private partnership that mostly benefits Big Pharma ������������������������������������������������������������������������������������ 16

P rescrire I nternational S pecial E dition 2022 • Page 1

EDITORIAL

The EMA is withholding too much information The creation of the European Medicines Agency (EMA) in 1995 consti tuted a step forward, compared with the practices of France’s drug regulatory agency at the time. For example, the EMA’s online publication of information on drug evaluations, such as European Public Assessment Reports, was a major ad vance in transparency as to the data in its possession. The level of transparency at the EMA has since fluctuated over the years (see “European Medicines Agency: transparency policy marred by too many failings” pp. 130-139 ). Yet the basic texts on which the European Union is founded guarantee transparency over the activities and decisions of European bodies. The EMA has made progress overall since its inception, thanks to action by the European Ombudsman, the European Parliament, researchers and civil society, including Prescrire. However, in 2022, the Agency is still putting up barriers to transparency. For example, when requesting access to documents held by the EMA, Prescrire has come up against new procedures in recent years that have the effect of withholding informa tion, with response times of several months. And important information, in particular on clinical data, is redacted on the grounds that pharmaceutical companies feel that its disclosure could jeopardise their commercial interests. It is one thing for pharmaceutical companies to consider that data showing the limitations of their drugs are commercially sensitive. But it is quite another – and utterly unacceptable – for the EMA to actually orchestrate the concealment of these data by pharmaceutical companies. Transparency is not a fador an end in itself. In the pharmaceutical field, it is a requirement for better and safer patient care. There is no valid reason to hide information about clinical trials, their methodology or their results, or evalu ation data obtained on drugs after their market introduction, particularly data on adverse effects. Perhaps there are certain individuals within the EMAwho are dissatis fied with this situation? Or who are simply resigned to the power relations at play? Or who feel that the way the EMA operates is a necessary compromise, given the varying legislation? If so, these individuals are not speaking up and their opinions are not reflected in the EMA’s practices. Whatever the case may be, Prescrire’s negative assessment of the level of transparency at the EMA is intended as a wake-up call for policy makers and for legal bodies (such as the Ombudsman) who are in a position to improve the EMA’s operational practices. So that the EMA might at last embrace full transparency, and disclose all the information that is necessary for patient care and safety. Prescrire

Prescrire Int • May 2021

Page 2 • Prescrire International Special Edition 2022

MARKETING AUTHORISATIONS

NEW SUBSTANCE Ivacaftor + tezacaftor + elexacaftor ( kaftrio °) in cystic fibrosis with at least one F508del mutation Respiratory symptoms alleviated in the short term

Compare before deciding Cystic fibrosis is a serious genetic disorder, with an autosomal recessive pattern of inheritance. It is caused by mutations in the gene that encodes the CFTR (cystic fibrosis transmembrane conductance regulator) protein. This protein plays a role in the transport of ions across cell membranes, particularly through chloride channels. The most common mutation is the F508del (or deltaF508) mutation. There is no known cure for cystic fi brosis as of late 2021 (1-4). A number of drugs referred to as CFTR “modulators” were authorised in the European Union in the 2010s: the CFTR “po tentiator” ivacaftor , which is claimed to promote the opening of chloride channels; and the CFTR “correctors” lumacaftor and tezacaftor , which are thought to facilitate maturation of the CFTR protein and its transport to the cell surface (1-3). Patients homozygous for F508del: fewer exacer bations with ivacaftor + a CFTR corrector. In patients homozygous for the F508del mutation, a combination of ivacaftor and a CFTR corrector reduces the incidence of pulmonary exacerbations that require intravenous antibiotic therapy or hospitalisation. For example, in a 24-week randomised trial, 1 exacerbation was prevented for every 4 patients treated with ivacaftor + tezacaftor for one year, comparedwith patients who received placebo (1). The potential long-term effects of this treatment, especially on cystic fibrosis progression, have not been adequately evaluated and therefore remain unknown (1). Patients heterozygous for F508del: uncertain harm-benefit balance of ivacaftor alone or iva caftor + tezacaftor. The level of CFTR protein activity in patients who are heterozygous for the F508del mutation de pends on which mutation they have on their other CFTR allele. The CFTR protein is said to have “minimal” function when this other mutation results in no CFTR protein production or in a CFTR protein with greatly reduced activity. None of the CFTR modulators has proven efficacy in these situations (3).

OFFERS ANADVANTAGE In patients with cystic fibrosis and at least one F508del mutation in the CFTR gene, triple therapy comprising ivacaftor + tezacaftor + elexacaftor

alleviated respiratory symptoms in comparative trials, none of which had a duration of more than 24weeks. Triple therapy with these drugs was more effective by this measure than the comparator, which was tailored to patients’ CFTR mutations. A reduced incidence of pulmonary exacerbations was demonstrated, mainly in a trial in patients hetero zygous for the F508del mutation and a mutation resulting in minimal CFTR protein function. The adverse effects of this combinationmainly include upper respiratory tract infections, hepatic disorders, rash, muscle disorders. It is also involved in many drug interactions. Any longer-termadverse effects, or the possible effect on disease progression, are not yet known. KAFTRIO° - ivacaftor + tezacaftor + elexacaftor tablets • 75 mg of ivacaftor + 50 mg of tezacaftor + 100 mg of elexacaftor per tablet Vertex Pharmaceuticals ■ CFTR potentiator + CFTR correctors ■ Indication : cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene. [EU centralised procedure - orphan drug] ■ Dosage : in general, two tablets of Kaftrio° ( ivacaftor + tezacaftor + elexacaftor ) in themorning and one tablet of Kalydeco° (containing 150mg of ivacaftor ) in the evening, taken with fat-containing food.

Full review(4 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire December 2021 Volume 41 N° 458 • Pages 885-889

Prescrire Int • March 2022

Prescrire International Special Edition 2022 • Page 3

MARKETING AUTHORISATIONS

NEW PRODUCT/ NEW PHARMACEUTICAL FORM

Nasal naloxone 1.8 mg (NYXOID°) in opioid overdose

Nyxoid° was granted marketing authorisation mainly on the basis of a pharmacokinetic study comparing various doses of nasal naloxone versus 0.4 mg of intramuscular or intravenous naloxone , as well as previously published data. No studies have specifically evaluated this product (3,4). Each box of Nyxoid° contains two ready-to-use, single-dose spray devices, each delivering 1.8 mg of naloxone . The patient is positioned on their back with their head tilted back, and the entire contents of one spray device is administered into one nostril, in a single actuation of the device. If after 2 to 3 minutes the effect is deemed insufficient, the procedure is repeated in the other nostril (1,5). Whenever naloxone is used outside a hospital setting, re gardless of the form administered, the emergency services must be contacted (for example by calling the European emer gency number 112), since they may need to administer additional doses of naloxone , which has a shorter duration of action than some opioids (1). It is useful to help the family and friends of opioid users to learn how to use the device. In general, opioid users and their close contacts stand to gain from knowing the signs of an opioid overdose and the factors that increase the risk of overdose (1). Nyxoid°’s European marketing authorisation specifies that it can only be obtained with a prescription. This requirement has the drawback of hindering access to this drug, for example in healthcare facilities that treat opioid-dependent patients but have no prescribing doctors on staff. Since 2017, access to ready to-use naloxone for intramuscular or intranasal administration has remained too limited in France, yet these medicines help prevent overdose-related deaths (5-7). ©Prescrire

OFFERS ANADVANTAGE Nasal naloxone is effective at pre venting death in the event of an opi oid overdose resulting frommedical or illicit opioid use. It has a favourable harm-benefit balance in both medical and non-­ medical settings. NYXOID° - naloxone nasal spray solution • 1.8mg of naloxone in 0.1 ml of solution per single-dose spray device Mundipharma ■ Antidote; opioid receptor antagonist ■ Indication : emergency therapy for known or suspectedopioidover dose, presenting as respiratory and/or central nervous systemdepres sion, in both non-medical and healthcare settings, in adults and ado lescents aged 14 years and over. [EU centralised procedure] ■ Dosage : 1.8 mg (i.e. the contents of one spray device) into a single nostril. If the patient’s state does not improve within 2 to 3 minutes after receiving this dose, a second dose, administered into the other nostril, is recommended. Opioid overdoses occur in persons using opioid medications or illicit opioids. They reduce the respiratory rate and can cause loss of consciousness, sometimes leading to respiratory arrest, then cardiac arrest. Several hundred fatal opioid overdoses are estimated to occur every year in France (1-3). Naloxone is an opioid receptor antagonist. It is an effective antidote for preventing death following an opioid overdose, whether administered by injection or intranasally. In this situ ation, naloxone ’s main adverse effect is an acute opioid with drawal syndrome, consisting primarily of agitation, anxiety, nausea, myalgia and sweating. This is a minor risk, however, in a life-threatening emergency (1-3). Naloxone has been available for several decades as an in jectable solution supplied in ampoules, for use in the commu nity, restricted to healthcare professionals, and in the hospital. Two additional formats were then authorised in France, in 2017 and 2018, for emergency use in medical or non-medical settings, for example by friends or relatives of opioid users: a nasal spray authorised for use in adults and children from the age of one month (no longer marketed since late 2020); and a solution for intramuscular injection supplied in a prefilled syringe, for use in adults only (1-3). A new naloxone -containing nasal spray (Nyxoid°) has been authorised in the European Union for emergency use in medi cal and non-medical settings in adults and adolescents aged 14 years and over (3,4).

▶ Translated from Rev Prescrire November 2021 Volume 41 N° 457 • Pages 805-806

Literature search up to 13 September 2021

In response to our request for information, SanofiAventis provided us with no documentation on its product.

1- Prescrire Editorial Staff “Nasal naloxone in opioid overdose. Opioid antidote nasal spray, useful and convenient in an emergency” Prescrire Int 2018; 27 (199): 285-287. 2- Prescrire Rédaction “Naloxone (Prenoxad°) en kit pour injection IM dans les surdoses d’opioïdes” Rev Prescrire 2018; 38 (417): 488-489. 3- HAS - Commission de la Transparence “Avis-Nyxoid” 5 February 2020: 19 pages. 4- EMA - CHMP “Public assessment report for Nyxoid. EMEA/H/C/004325/0000” 14 September 2017: 59 pages. 5- EMA “SPC + PIL-Nyxoid” 5 February 2021: 29 pages. 6- Jehanne C et al. “Chroniques de la mise à disposition des kits naloxone (Nalscue, Prenoxad et bientôt Nyxoid), échec ou succès en demi-teinte?” Le Flyer 2021; 79 : 6 pages. 7- France Patients Experts Addictions et al. “Overdose day 2021. Journée inter nationale de sensibilisation aux surdoses. Où en sommes-nous?” Press release 31 August 2021: 2 pages. Prescrire Int • February 2022

Page 4 • Prescrire International Special Edition 2022

MARKETING AUTHORISATIONS

NEW PRODUCT Fenfluramine ( fintepla °) in Dravet syndrome

Higher incidence of convulsive status epilepticus, and serious cardiovascular risks in the long term

NOT ACCEPTABLE Intwo randomisedplacebo-controlled trials, conducted for only a few months even though Dravet syn drome is a chronic disease, adding

other neurological disorders, such as uncoordinatedmovements and hypotonia, as well as disorders of psychomotor develop ment and behavioural disturbances. About 15% of children with Dravet syndrome die before the age of 10 years (1-3). Some antiepileptics have partial efficacy. In Dravet syndrome, antiepileptic drugs generally reduce the number of seizures without preventing them entirely, and are therefore used in combination. The first-choice drug is valproic acid , possibly combined with clobazam . Other antiepileptic drugs, such as stiripentol , topiramate , and cannabidiol, are sometimes useful ( a ). On the other hand, some antiepileptics, such as carbamazepine and lamotrigine , can worsen the disease and are therefore best avoided (1). What’s new? Fenfluramine is an amphetamine. It was authorised around the world in the 1960s for its appetite suppressing properties, to help obese patients lose weight. It was used at doses of 60 mg to 120 mg per day. Fenfluramine was withdrawn from the mar ket worldwide several decades later, because it provoked sometimes-fatal pulmonary arterial hypertension and irrevers ible heart valve disease when used for at least 3 months. However, data obtained from follow-up of 21 patients with Dravet syndrome who received fenfluramine after its market withdrawal suggested that it might have some efficacy in this disease. In these patients, it was generally used at a dose of 10mg or 20mg per day, corresponding to daily doses of 0.8 to 1 mg/kg in young children and 0.1 to 0.3 mg/kg in older patients (4-7). Fenfluramine (Fintepla°) has been authorised in the European Union for use in patients aged 2 years or older with Dravet syndrome, in combination with antiepileptic drugs. It is thought to exert antiepileptic effects by increasing serotonin release. But its precise mechanism of action in Dravet syndrome is unknown (6,8). Does adding fenfluramine to antiepileptic therapy in Dravet syndrome reduce mortality and improve children’s psycho motor development more effectively than adding another antiepileptic, in particular cannabidiol ?

fenfluramine to prior antiepileptic therapy increased the incidence of convulsive status epilepticus, despite a decrease in the overall frequency of con vulsive seizures. The long-term impact on children’s psychomotor development and mortality are unknown. Fenfluramine can provoke heart valve disease and pulmonary arterial hypertension, which is why its use as an appetite suppressant was dis continued. It can also cause neuropsychiatric dis orders and other cardiovascular disorders. In prac tice, fenfluramine is not an acceptable option for children with frequent convulsive seizures despite optimised antiepileptic therapy.

FINTEPLA° - fenfluramine oral solution • 2.2mg of fenfluramine per ml of solution Zogenix ■ Amphetamine

■ Indication: “ seizures associated with Dravet syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older ” [EU centralised procedure - orphan drug] ■ Dosage : startingdoseof0.1mg/kg twicedaily, increased ifnecessary: – without stiripentol : to0.2mg/kg or0.35mg/kg twicedaily, not exceed ing 26mg per day. – in combinationwith stiripentol : to0.2mg/kg twice daily, not exceed ing 17 mg per day. Compare before deciding Dravet syndrome is a rare, serious form of infantile epilepsy, usually genetic in origin. The disease presents before the age of 2 years with convulsive seizures, especially tonic-clonic seizures, often triggered by fever. Between the ages of 1 year and 4 years, tonic-clonic seizures become increasingly frequent and other types of seizure occur, especially myoclonic seizures. The severity of the seizures is linked in particular to convulsive status epilepticus, which are prolonged convulsive seizures that last more than 30 minutes and can leave neurological sequelae or be fatal. The seizures are generally associated with

Full review(3 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire October 2021 Volume 41 N° 456 • Pages 736-740

Prescrire Int • January 2022

Prescrire International Special Edition 2022 • Page 5

MARKETING AUTHORISATIONS

NEW INDICATION

Dupilumab (DUPIXENT°) in severe atopic eczema from 6 years of age

mainly when ciclosporin therapy has failed due to insufficient effectiveness or adverse effects. Dupilumab has now been authorised for use in children with severe eczema, aged 6 years and older (1-4). In this situation, dupilumab has not been compared to an other immunosuppressant. Its clinical evaluation is mainly based on one double-blind, randomised, placebo-controlled trial, as an addition to a topical corticosteroid. This trial includ ed 367 children with an average age of 8.5 years who had been affected by severe atopic eczema for at least one year, and in whom at least one treatment with a topical corticosteroid had been judged to be inadequate. One-third of these children had already received systemic treatment with an immunosuppres sant. About 17% had received an immunosuppressant other than a corticosteroid, mainly ciclosporin , which was often discontinued due to insufficient effectiveness (2,3). After 16 weeks of treatment, complete or near-complete clearance of lesions, without the need for another drug, was observed in 32% of children who had received dupilumab, versus 11% in the placebo group (p<0.001). 68% of the patients who had received dupilumab had a reduction of at least 75% in the extent and severity of their eczema, versus 27% in the placebo group (p<0.001). For the small group of children in whom previous ciclosporin therapy had failed, it is not known whether some of them obtained relief with dupilumab (2,3). The known adverse effect profile of dupilumab mainly consists of: injection site reactions; eye disorders including conjunctiv itis, blepharitis (inflammation of the edges of the eyelids) and keratitis; and hypersensitivity reactions. The immunosuppres sive action exposes patients to a risk of infections, in particular herpetic infections, and possibly a risk of cancer. In the trial described above, the adverse effects of dupilumab in children were similar to those reported in adults and adolescents (1,3,4). Since experience with use of dupilumab is shorter than with ciclosporin , its long-term adverse effects in children are more uncertain, particularly the possible effects on growth and the risk of cancer. ©Prescrire

JUDGEMENT RESERVED When an immunosuppressant is being considered for children with atopic eczema, dupilumab shows some effi cacy, as in adults and adolescents,

based on its evaluation data. However, given the usually spontaneous improvement in this condition before adolescence, and themany unknowns regard ing the long-term adverse effects of dupilumab in children, its harm-benefit balance remains uncer tain. As of late 2021, in view of the potential risks to children treatedwith this drug, it should be reserved for use in the supervised setting of clinical trials. DUPIXENT° - dupilumab solution for subcutaneous injection • 200mg or 300mg of dupilumab per pre-filled syringe SanofiAventis ■ Monoclonal antibody inhibiting interleukin 4 and 13 receptors ■ New indication : “ severe atopic dermatitis in children 6 to 11 years old who are candidates for systemic therapy ”. [EU centralised pro cedure] ■ Newdosage : – in childrenweighing 15 kg to less than 60 kg: two injections of 300mg 2 weeks apart, followed by one injection of 300 mg every 4 weeks or 200mg every 2 weeks; – in children weighing 60 kg or more: initial dose of 600 mg, followed by 300mg every 2 weeks. Atopic eczema (atopic dermatitis) is a chronic inflammatory skin disorder characterised by dry skin, skin lesions and intense pruritus. It usually begins in early childhood and follows a re lapsing course. It most often regresses or disappears before adolescence (1). In children suffering from atopic eczema, application of an emollient, combined if necessary with a topical corticosteroid during flare-ups, is aimed at reducing symptoms. If topical treatments are not sufficiently effective, ciclosporin (an immuno suppressant) is sometimes prescribed, despite the low level of evidence provided by its evaluation data . Methotrexate and azathioprine are other immunosuppressants used off-label in this setting. Given their immunosuppressive action, they carry a risk of sometimes serious adverse effects, such as infections and cancer. Ciclosporin also exposes patients to a risk of renal failure, hypertension and neurological disorders (1-3). Dupilumab is an immunosuppressant monoclonal antibody directed against the interleukin 4 and 13 receptors, which was already authorised in the European Union for use in adults and adolescents with troublesome atopic eczema. For these pa tients, dupilumab represents another line of treatment, used

▶ Translated from Rev Prescrire January 2022 Volume 42 N° 459 • Pages 6-7

Literature search up to 4 November 2021

In response to our request for information, SanofiAventis provided us with no documentation on its product. 1- Prescrire Rédaction “Dupilumab (Dupixent°) et eczéma atopique à partir de l’âge de 12 ans” Rev Prescrire 2020 ; 40 (442) : 574-575. 2- HAS - Commission de la transparence “Avis-Dupixent” 21 April 2021: 37 pages. 3- EMA - CHMP “Public assessment report for Dupixent. EMA/H/C/004390/II/0027” 15 October 2020: 117 pages. 4- EMA “SPC-Dupixent” 24 June 2021: 67 pages.

Prescrire Int • April 2022

Page 6 • Prescrire International Special Edition 2022

MARKETING AUTHORISATIONS

EDITORS’ OPINION

Negligence

The evaluation data for a new drug, or for an existing drug in a new clinical situation, are cru cial in determining its harm-benefit balance. The results available, however, usually leave a great er or lesser degree of ongoing uncertainty. This is particularly true when a drug, which is already being used in adults, is proposed for use in children. Evaluation in children is often less extensive and leaves numerous questions unanswered. Evaluation of the benefit provided by the drug in children requires certain factors to be taken into account, in particular: the natural history of the disease during child development; the adverse effects and potentially unrecognised long-term consequences at each age; and the expected duration of exposure to the drug, which will be greater the earlier long-term treatment is initiated. For example, dupilumab (Dupixent°) has a favourable harm-benefit balance in some adults affected by atopic eczema, despite unknowns with long-term use, in particular the risk of can

cer (see “Dupilumab in adults with atopic derma- titis: an option for very troublesome eczema after failure of ciclosporin” Prescrire Int n° 204). In adolescents, specific evaluation data along with extrapolation from data in adults, also show that dupiluma b can sometimes be useful (see Rev Prescrire n° 442). However, in children, such extrapolation is much less reliable, and the harm-benefit balance of dupiluma b is uncertain for them (see “Dupilumab in severe atopic ecze ma from 6 years of age” opposite). First, because atopic eczema most often regresses or disappears before adolescence and also because no data are available on the potential consequences of such treatment on their development. In the field of drugs and therapeutics, as in other fields, it would be negligent to consider children as just small adults. Prescrire

▶ Translated from Rev Prescrire January 2022 Volume 42 N° 459 • Page 4

Prescrire Int • April 2022

Our website: english.prescrire.org

Instant online access to the current issue, plus the complete archive of rigorously evidence-based reviews that Prescrire has published in English over the past 30 years.

Prescrire International Special Edition 2022 • Page 7

MARKETING AUTHORISATIONS

Prescrire’s ratings of new drugs in 2021: a brief review

● Seventeen of the 108 newmarketing authorisations analysed and rated in our French edition in 2021 represented a major or notable therapeutic advance for patients. E very month, Prescrire publishes inde pendent, comparative, systematic

advances in the treatment of children: sofosbuvir alone, the combination of so fosbuvir + ledipasvir , and the combination of sofosbuvir + velpatasvir . The reintroduction of fenflur amine, and a new amphetamine: drugs to avoid. The verdict in France’s criminal trial involving the Mediator° disaster was delivered in 2021, with sen tences for Servier, the company that mar keted Mediator° ( benfluorex, an amphet amine related to fenfluramine ), and the French Health Products Agency. Yet the very same year, fenfluramine made a comeback, this time authorised for Dravet syndrome, a rare and serious form of in fantile epilepsy. And a new amphetamine, solriamfetol , was authorised in the Euro pean Union for certain patients with ex cessive daytime sleepiness. Neither drug has a positive harm-benefit balance in the clinical situations for which they have been authorised, exhibiting limited effi cacy and carrying the risks common to all amphetamines, in particular cardiovascular risks. In summary. Three newdrugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year’s new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options. ©Prescrire

As in 2020, about half of the authorisa tions we analysed in 2021 did not advance patient care (with 51 out of 108 rated “Nothing New”). Twelve had been too poorly evaluated to determine their harm-­ benefit balance (rated “Judgement Re served”). Finally, the data available on 9 authorisations showed that they are more dangerous than useful (rated “Not Acceptable”). Two covid-19 vaccines and a drug used in acute hepatic por phyria are major advances. In 2021, two vaccines developed urgently in the midst of the covid-19 pandemic were major therapeutic advances: themessen ger RNAvaccines tozinameran and elaso meran . In a completely different field, givosiran, a “small interfering” RNA, rep resented a major therapeutic advance for patients with acute hepatic porphyria, because it is highly effective at reducing the incidence of attacks, at least in the short term. Most of the notable advances involved existing active sub stances. Two of the 14 notable advances were viral vector covid-19 vaccines au thorised in the European Union: covid‑19 vaccine Ad26.CoV2-S and covid-19 vaccine ChAdOx1-S . Most of the other advances involved existing, sometimes rather old drugs, pre viously authorised for a different indication (e.g. rituximab , now authorised for pem phigus vulgaris), in a different pharma ceutical form (e.g. budesonide , now au thorised in the form of orodispersible tablets for eosinophilic œsophagitis), or for a new route of administration (e.g. glu cagon nasal spray). Three antiviral med icines used in hepatitis C, and already authorised for use in adults, were notable

reviews of the latest developments in the European pharmaceutical market, includ ing recent marketing authorisations for newactive substances, newcombinations, new dose strengths, new pharmaceutical forms and new indications ( a ). We also closely monitor news on adverse effects, market withdrawals (instigated by pharma ceutical companies or regulatory au thorities), re-introductions of previously withdrawn products, new clinical evalu ation data on drugs already on themarket, shortages, and the regulatory environment for health products, particularly at EU level. Our aim is to help subscribers dis tinguish between genuine pharmaceutical advances and new products or new uses that are no better than existing treatments or should never have been authorised, due to uncertainty over their harms or benefits, or because they are clearly dangerous. 17 major or notable advances among 108 new authorisations. Prescrire analysed and rated 108 new marketing authorisations in 2021 (see the table opposite). We noted a slight improvement in 2021 compared with the previous 5 years, with 36 of these new authorisations (about one-third of the reviews we published) offering some degree of benefit, at least for some patients. Three of them repre sented a major advance (earning the rat ing “A Real Advance”) and 14 a notable advance (rated “Offers an Advantage”); five of the authorisations in these top two categories were for covid-19 vaccines. The remaining 19 of these 36 authorisations wereminimal advances (rated as “Possibly Helpful”).

a- Prescrire International focuses on reviews related to marketing authorisations granted under the EUcentralised procedure, and there fore does not publish all the reviews from the French edition.

▶ Translated from Rev Prescrire February 2022 Volume 42 N° 460 • Page 148

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MARKETING AUTHORISATIONS

Therapeutic advances in 2021 compared with the previous 9 years Therapeutic advances in 2021 compared with the previous 9 years

2012-2020

2021

Prescrire’s ratings Our judgement is based on the therapeutic advance of theproduct in the relevant clinical situation. It considers not only the inherent value of each product in terms of its harm-­ benefit balance, but also its advantages and disadvantages relativetoexistingtreatments. Note that the relative value of new products can vary fromone country to another. BRAVO The product is a major therapeutic advance in an area where previously no treatment was available. A REALADVANCE The product is an important therapeutic advance but has certain limitations. OFFERS ANADVANTAGE The product has some value but does not fun damentally change the present therapeutic practice. POSSIBLYHELPFUL The product has minimal additional value, andshouldnotchangeprescribinghabitsexcept in rare circumstances. NOTHING NEW The product is a new substance but with no evi dence that it has more clinical value than other substances of the same group. It can be ame-too or a nearme-too.  NOTACCEPTABLE Productwithout evidentbenefitbutwithpotential or real disadvantages.  JUDGEMENT RESERVED The editors postpone their rating until better data and a more thorough evaluation of the drug are available. Quality of information from pharmaceutical companies In response to our systematic requests

Notable advance Minimal advance

No proven advantages More dangerous than useful

▶ Translated from Rev Prescrire February 2022 Volume 42 N° 460 • Page 149

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Companyprovideddetailed informa tion including unpublished data and packaging items. Company provided information limited to published administrative data or packaging items. Companyprovidedminimal informa tion,mainlyadministrativeandpack aging items. Company provided no information.

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ADVERSE EFFECTS

Clopidogrel + a proton pump inhibitor: increased mortality

● Since 2009, several meta-analyses of epidemio logical studies and post-hoc analyses of clinical trials have studied the interaction between clopi dogrel and proton pump inhibitors (PPIs) such as omeprazole . They show a higher risk of cardio vascular events with all PPIs and, overall, increased mortality. ● Apharmacokinetic interactionwith clopidogrel has been documented for omeprazole , esome prazole and pantoprazole . PPIs inhibit formation of the activemetabolite of clopidogrel , thus redu cing its antiplatelet effect. ● It seems prudent to avoid combining PPIs with clopidogrel whenever possible. There is no justi fication for the routine use of a PPI during clopi dogrel treatment. C lopidogrel is an antiplatelet drug used after angioplasty with stent placement, for example, in combination with aspirin (1,2). Proton pump inhibitors (PPIs) such as omeprazole are sometimes given to patients who are on anti platelet medication, mainly to prevent upper gastrointestinal bleeding (3,4). A pharmacokinetic interaction that may reduce clopidogrel ’s antithrombotic effect has been described between clopidogrel and omeprazole . On the basis of the data available in 2009, it was not possible to establish whether an interaction between clopidogrel and omeprazole increases the incidence of cardio vascular events. However, a prudent approach to the arguments in favour of this risk was to avoid this combination (5). Other epidemiological studies have since shown higher all cause and cardiovascular mortality in patients using PPIs for any reason, than in non-users (6). What more is known as of mid-2021? Do the data available from clinical trials and epidemiological studies indicate that clopidogrel is less effective when combined with a PPI? Do all PPIs have this effect?

Higher mortality A systematic review and meta-analysis identified 47 epidemio logical studies and 3 randomised trials that compared patients taking clopidogrel and a PPI versus patients taking clopidogrel alone, published between 2009 and 2018 (7). Differences of about 15% to 30% in general. According to this systematic review, 19 case-control and cohort studies have evaluated all-cause mortality. Ameta-analysis of these studies found that all-causemortality was about 1.26 times higher in patients taking clopidogrel + PPI than in patients taking clopidogrel (95% confidence interval (95CI) 1.11-1.42). However, when themeta-analysis only took into account the 7most robust studies, i.e. the results of randomised trials and the results of epidemiological studies adjusted for factors that influence the choice between these treatments (propensity score), the difference appeared slightly smaller (risk ratio (RR) 1.17) and did not reach statistical significance. There was considerable heterogeneity in both cases (7). Similarly, cardiovascular mortality appeared higher with clopidogrel + PPI than with clopidogrel (RR 1.21; 95CI 1.09-1.34). When the analysis only took into account the 5 most robust studies, the difference appeared slightly smaller (RR 1.16) and did not reach statistical significance (7). Meta-analysis of 15 case-control and cohort studies that evalu ated the risk of myocardial infarction found a higher risk with clopidogrel + PPI than with clopidogrel (RR 1.23; 95CI 1.04-1.47). A similar difference was found when the analysis only took into account the 7most robust studies (RR 1.15; 95CI 1.00-1.32) (7). Meta-analysis of 5 epidemiological studies that evaluated the risk of stroke did not show a higher risk with clopidogrel + PPI (RR 1.05; 95CI 0.85-1.29). However, when the analysis was restricted to the two most robust studies (epidemiological studies with propensity score adjustment), the risk was higher in patients receiving clopidogrel + PPI than in patients receiving clopidogrel (RR 1.75; 95CI 1.45-2.11) (7). Other meta-analyses with similar results. Several other meta-analyses have produced similar results, showing either a slightly higher risk of cardiovascular events with clopi dogrel in various settings, or no difference (8-10).

Full review(3 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire October 2021 Volume 41 N° 456 • Pages 751-753

intervention showed a higher risk of major adverse cardio vascular events (odds ratio (OR) 1.37; 95CI 1.23-1.53) with clopidogrel + PPI than with clopidogrel . Analysis of short-term Prescrire Int • January 2022

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ADVERSE EFFECTS

Update onmyocarditis linked to the covid-19messenger RNAvaccines tozinameran ( comirnaty °) and elasomeran ( spikevax °)

● As of autumn 2021, a number of peer-reviewed articles and drug regulatory agency reports have been published around the world about cases of myocarditis attributed to the covid-19 messen ger RNAvaccines tozinameran (Comirnaty°) and elasomeran (Spikevax°). What is currently known about the incidence, severity and risk factors for this adverse effect? I nmid-2021, after analysing reports in Europe and elsewhere, the European Pharmacovigilance Risk Assessment Com mittee (PRAC) concluded that the covid-19 messenger RNA vaccines tozinameran (Comirnaty°) and elasomeran (Spikevax°) provoke very rare cases of myocarditis (1). These generally occurred within 14 days of the second injection in adolescents or men under the age of 30 years, and regressed within a few days. Similar data were obtained in the United States. A few months on, what more is known about this adverse effect, in particular its incidence, severity and risk factors? Do both vaccines carry the same risk? This article summarises a few key findings from Prescrire’s literature search. Increased incidence of myocarditis detected at the population level in studies involving several million individuals. A study analysing data from 40 hos pitals belonging to a private healthcare network in the United States showed that the mean monthly incidence of myocarditis in these hospitals was about 60% higher after the start of the covid-19 vaccination campaign using tozinameran or elaso meran than during the previous 24 months (p<0.001) (2). An analysis of the medical records of about 2 million (mostly adult) patients in this network who had received at least one dose of either of these vaccines identified about 10 cases ofmyocarditis for every million doses of vaccine administered. The risk of myocarditis appeared more marked in men, in younger vac cinees, after the second dose, and with elasomeran . Similar results were obtained in a study in Israel, based on a national healthcare database that included about 5 million tozinameran recipients (3). The incidence of myocarditis was clearly (and statistically significantly) higher after the vaccin ation campaign than during the previous 3 years, especially after the second dose, when it was about five times higher. The risk of myocarditis was more marked in men, after the second dose, and in younger vaccinees (aged 16 to 24 years). A few dozen reports of myocarditis per million doses of messenger RNA vaccine. On 30 September 2021, the French Health Products Agency (ANSM) had received

377 reports of myocarditis attributed to tozinameran , corres ponding to a total incidence of about 5 cases per million doses. The incidencewasmoremarked inmen than inwomen, after the second dose than after the first dose, and in young vaccinees than in older vaccinees. For example, about 40 cases were re ported per million second doses in men aged 18 to 24 years, versus about 2 cases per million first doses in women aged 30 years or older (4). With elasomeran , about 11 cases of myocarditis were report ed per million doses, with similar variations between subgroups, ranging from about 140 reported cases per million second doses of elasomeran in men aged 18 to 24 years, down to only about 1 reported case per million first doses of elasomeran in women aged 30 years or older (4). On 20 October 2021, the British Medicines and Healthcare Products Regulatory Agency (MHRA) had received about 8 re ports ofmyocarditis permillion doses of tozinameran and about 31 permillion doses of elasomeran. By way of comparison, there were about 3 reports of myocarditis per million doses of the viral vector vaccine covid-19 vaccine ChAdOx1-S (Vaxzevria°) (5). On 24 October 2021, the Australian Therapeutic Goods Ad ministration (TGA) had received about 17 reports ofmyocarditis per million doses of tozinameran in men and 7 per million doses in women. Only 500 000 doses of elasomeran had been administered (6). Especially in young men after the second dose. The US Centers for Disease Control and Prevention (CDC) pub lished the data available as of 6 October 2021, based on about 2500 reports, focusing on reports ofmyocarditis that occurred within a week of vaccination (7). The highest incidence seenwith tozinameran was about 69 re ports of myocarditis per million second doses in boys aged 16 or 17 years (and about 37 formen aged 18 to 24 years), versus fewer than 1 permillion first doses inwomen, even youngwomen (7). With elasomeran , which was only authorised for use from the age of 18 years in the United States, the CDC received about 38 reports per million second doses given to men aged 18 to 24 years, versus fewer than 1 per million first doses for women, even young women (7). Mainly within days of vaccination. In the study based on the medical records of about 2 million patients seen in a private US healthcare network, half of the cases of myocarditis occurred within 3.5 days following vaccination (2).

Full review(2 pages) available to subscribers at english.prescrire.org

▶ Translated from “Dans l’actualité”, 5 November 2021 - www.prescrire.org

Prescrire Int • February 2022

Prescrire International Special Edition 2022 • Page 11 private US healthcare network, half of the cases of myocarditis occurred within 3.5 days follow ing vaccination (2). In the Israeli study in about 5 million tozinameran recipients, P ri n

ADVERSE EFFECTS

Perioperative benzodiazepines:

COMMON STEM -azam, -azepam, -azolam

NN A drug’s real name

a risk factor for persistent use

A cohort study published in 2021 identified 2.5 million adults in a US health insurance databasewho had undergone surgery between 2009 and 2017 and had not been prescribed a benzodiazepine during the year before their operation (excluding the month before the operation). The most common surgical pro cedures were cataract surgery, cholecystec tomy and hysterectomy. The patients’ mean age was 54 years, and 63% of them were women (1). 64 000 (2.6%) of these patients received a benzodiazepine during the perioperative period, and half of them received more than a 10-day supply of the drug. The most com monly used benzodiazepines were diazepam (32%) and alprazolam (29%). 19.5% of the patients who had been pre scribed a benzodiazepine around the time of surgery continued taking it afterwards. 56% of these persistent users received another pre scription for a benzodiazepine between 90days and 180 days after the surgery, and 44% re ceived two or more prescriptions. The factors shown to be associated with persistent benzodiazepine use in this study were: being 70 years of age or older, female gender, more medical comorbidities, or a history of anxiety, depression, insomnia or substance use disorder. INPRACTICE  Repeated or persistent benzo diazepine use is common after occasional use, and the risk of addiction is real. When a benzo diazepine is justified, it is important to plan its withdrawal with the patient, as soon as treat ment is initiated (2). ©Prescrire

According to the nomenclature established by theWorld Health Organization (WHO) to devise international nonproprietary names (INNs), the INNs of psychotropic drugs derived from diazepam , i.e. benzodiazep ines, end in -azepam (or -azepate in the case of salts, and -azepoxide in the case of oxides) (1,2). We have identified 13 drugs whose INNs contain this common stem: bromazepam ; chlordiazepoxide (sometimes combined with clidinium , an antimuscarinic); clonazepam ; clorazepate dipotassium ; clotiazepam ; di azepam ; ethyl loflazepate ; lorazepam ; lormet azepam ; nitrazepam ; nordazepam ; oxazepam ; and prazepam . Some benzodiazepines have an INN which contains another common stem: -azam in the case of clobazam ; and -azolam in the case of alprazolam , estazolam , loprazolam and midazolam (1,2). The benzodiazepines constitute a homo geneous group.They all have anticonvulsant, muscle relaxant, sedative, anxiolytic and amnesic effects. Their adverse effect profile mainly includes: drowsiness and difficulty concentrating; memory disturbances; cog nitive disorders persisting after withdrawal; confusion, ataxia and falls, especially in elder ly patients; reduced efficacy (i.e. tolerance); dependence and withdrawal syndrome; and respiratory depression (3,4). ©Prescrire

▶ Translated from Rev Prescrire December 2021 Volume 41 N° 458 • Page 907

▶ Translated from Rev Prescrire November 2021 Volume 41 N° 457 • Page 825

References 1- World Health Organization “The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceut ical substances 2018 (Stem Book 2018)”: 64-65. 2- “Common stems: -azepam, -azam, -azolam” Prescrire Int 2012; 21 (127): 125. 3- “Quelques éléments pour le choix d’une benzodiazépine dans les plaintes de mauvais sommeil” Rev Prescrire 2018; 38 (415): 356-357. 4- “Benzo diazépines ou apparentés” Interactions Médicamenteuses Prescrire 2022.

References 1- Wright JD et al. “Association of new perioperative benzodiazepine use with persistent benzo diazepine use” JAMA Netw Open 2021; 4 (6): e2112478 + suppl.: 24 pages. 2- Prescrire Rédaction “Réussir l’arrêt d’une benzodiazépine (suite)” Rev Prescrire 2010; 30 (319): 372.

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