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SPECIALEDITION

A critical eye on new drugs authorised in Europe

INTERNATIONAL

TOP TEXTS of 2023

Prescrire International Special Edition 2023

Specially selected to introduce you to our wholly independent journal on drugs and health policy in Europe

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Prescrire is a French non-profit continuing education organisation, committed to better patient care Prescrire International is a monthly journal consisting of selected articles translated from La Revue Prescrire

President of Association Mieux Prescrire: Antoine 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) registered 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 including 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 2023

EDITORIAL  Building the evidence base ������������������ 2

MARKETING AUTHORISATIONS Difelikefalin ( KAPRUVIA ° ) in pruritus associated with chronic kidney disease An option for patients experiencing major discomfort, despite the uncertainties ��������������������������� 3 Sotorasib ( LUMYKRAS° ) in non-small cell lung cancer with KRAS G12C mutation ���������������������������������������������������������������������������� 4 Relugolix + estradiol + norethisterone ( ryeqo ° ) in uterine fibroids A risky hormone cocktail ���������������������������������������������������������������������� 5 EDITORS’ OPINION  Cascade ������������������������������������������������������������������������������ 5 Daridorexant ( QUVIVIQ °) in insomnia Evaluation not designed to demonstrate a therapeutic advance ������������������������������������������ 6 EDITORS’ OPINION  New is not necessarily better ������������������������������ 7 Luspatercept ( REBLOZYL °) in anaemia associated with myelodysplastic syndrome ��������������������������������������������������������������� 7 Prescrire’s ratings of new drugs in 2022: a brief review ������ 8-9

Prescrire International casts a critical eye on newdrugs authorised in Europe.

Everymonth, you’ll find varied and useful content:

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

ADVERSE EFFECTS

Paracetamol, pregnancy and urogenital endocrine disruption: inconclusive studies ����������������������������������������������������������������� 10 Janus kinase inhibitors: higher incidence of serious adverse effects and death than with TNF-alpha inhibitors ������������� 11 COMMON STEM -grel ��������������������������������������������������������������������������������������������������� 12 Known allergy to chlorhexidine: a preventable death ������������������������ 12

OUTLOOK

Towards better patient care: drugs to avoid in 2023 ������������������ 13-14 Inset  Main changes in the 2023 update ���������������������������������������� 14 Conflicts of interest in medical faculties and hospitals (continued) ������ 15 Commercial deals to delay introduction of generics: European companies fined ���������������������������������������������������������������������� 16 The evaluation of drugs to treat type 2 diabetes ������������������������������� 16

P rescrire I nternational S pecial E dition 2023 • Page 1

EDITORIAL Building the evidence base

Shared healthcare decisions result from the relationship between a patient and one or more healthcare professionals, and are based on the available evaluation data, also referred to as “evidence”. This evidence base is constantly evolving, through a process of continuous construction and reconstruction, add ing to and strengthening scientific knowledge. This process is a mark of vitality, not weakness: it ensures that all knowledge, even when considered a matter of fact, is open to debate, which in some cases proves productive and improves patient care. Data published in peer-reviewed journals are not set in stone. The authors may correct or add to them, either on their own initiative or in response to readers’ comments. A subsequent analysis of the data, perhaps more critical, systematic or rigorous than the first, may also alter results that have already been reported and, in turn, the conclusions that can be drawn from them. Published articles are sometimes later retracted, due to a glaring error for example, or if fraud is proven or strongly suspected. This renders the reported data worthless, and unusable as a basis for healthcare decisions. Data are also sometimes released prematurely in preprint form, without peer review, but are never formally published in revised form. Whatever the reasons, this raises serious doubts about their quality or even their authenticity. Scientific fraud and the publication of poor-quality data are failings fuelled by the pressure to publish more in order to achieve more, especially pro motion or funding. Other approaches are possible, however, as evidenced by choices certain universities havemade in line with the international San Francisco Declaration (see “Universities challenge the impact factor” Prescrire Int n° 245). Prescrire plays its part in this process, for the benefit of thosewhowork to improve the quality of health care and put patients’ interests first, by valuing debateandby taking a stand itself. Every comment receivedfroma reviewer repre sents an opportunity for reflection; some readers’ feedback gives rise to a clarifi cation or a correction and sometimes to an article in the “Queries andComments” section; we re-analyse the harm-benefit balance of drugs “with more follow-up” when newdata emerge; and so on. We can all play our part, in our own way, in building this ever-evolving evidence base. Prescrire

Prescrire Int • February 2023

Page 2 • Prescrire International Special Edition 2023

MARKETING AUTHORISATIONS

NEW SUBSTANCE Difelikefalin ( kapruvia °) in pruritus associated with chronic kidney disease An option for patients experiencing major discomfort, despite the uncertainties

POSSIBLY HELPFUL In two double-blind randomised trials including about 850 patients with chronic kidney disease and on haemo dialysis, difelikefalin , a kappa opioid

● There is a risk of pharmacodynamic drug inter actions with difelikefalin , particularly when com binedwith drugs known to lead to somnolence and dizziness. KAPRUVIA° - difelikefalin solution for intravenous injection • 50microgram of difelikefalin per ml of solution (vials of 1 ml) Vifor ■ Kappa opioid receptor agonist ■ Indication: “ moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis ”. [EU centralised procedure] ■ Dosage: 0.5 microgram/kg of dry body weight (the target postdial ysis weight) three times per week, by intravenous bolus injection into the venous line of the dialysis circuit, at the end of the haemodialysis session, during or after rinse-back. If there are additional haemodialy sis sessions, a fourth dose perweek can be considered, but nomore. COMPARE BEFORE DECIDING Pruritus associated with chronic kidney disease, in brief 20% to 40% of chronic kidney disease patients on haemo dialysis report having pruritus graded as moderate to severe in intensity. It can be diffuse, or localisedmainly to the back, arms, head or abdomen. As for all types of pruritus, skin irritation due to scratching can lead to infection and thickening of the skin (lichenification). Pruritus sometimes has a marked impact on quality of life, particularly as a result of sleep disturbance and its consequences (1-5).

receptor agonist, was effective in reducing pruritus in the short-term in 15% to 20%more patients than in the placebo groups. Difelikefalin mainly carries a risk of gastrointestinal, neuropsychiatric, and per haps sometimes serious cardiac disorders. In prac tice, despite the uncertainties, difelikefalin is an option to consider, with care, in patientswho experi encemajordiscomfort despitenon-pharmacological measures. ● Patientswithchronickidneydiseasewhoareunder going haemodialysis sometimes experience major discomfort due to pruritus. One hypothesis put for wardtoexplainthemechanismforthispruritus is an imbalance of the endogenous opioid system, with overexpression of mu opioid receptors and a con comitant underexpressionof kappa receptors. ● Difelikefalin is a “selective” kappa opioid recep tor agonist. ● In this situation, two double-blind randomised trials including a total of 851 patients have evalu ated difelikefalin , administered for 12weeks via the venous access line at the end of each session of haemodialysis. It was effective in relieving pruritus in 15% to 20% more patients than in the placebo groups. These results are, however, weakened by missing data for a significant number of patients, especially in the difelikefalin groups. ● The main adverse effects of difelikefalin are gastrointestinal disorders, hyperkalaemia, andpos sibly cardiac disorders. Despite a supposedly limit ed ability to cross the blood-brain barrier, it also carries a risk of neuropsychiatric disorders.

Excerpt from Prescrire Int June 2023 Full article (4 pages) available to subscribers at english.prescrire.org

Prescrire International Special Edition 2023 • Page 3

MARKETING AUTHORISATIONS

NEW SUBSTANCE

Sotorasib (LUMYKRAS°) in non-small cell lung cancer with KRAS G12C mutation

NOTHING NEW Conditional marketing authorisation granted on the basis of one non-­ comparative trial, but full authorisa tion will depend on the results of a

size (partial response) was seen in about 35%. Median overall survival was estimated at about 1 year (1,3). In the absence of a comparator, it is not possible to determine whether sotorasib represents a therapeutic advance for patients. In its public assessment report, the European Medicines Agency (EMA) pointed out that the basis for the recommended daily dose of 960 mg had not been well established, and as of early 2023, an evaluation of a 240 mg daily dose is underway (3). A trial versus docetaxel: results expected in 2026. Given this scanty evaluation, the European MA is conditional, and the company will have to provide the EMAwith the results of a randomised non-blinded comparative trial versus docetaxel (a cytotoxic drug) into which 345 patients have been enrolled (1,3,4). As of early 2023, this trial is underway with the final results expected in 2026 (5). Hepatic, pulmonary, gastrointestinal and other harms. In the EMApublic report, evaluation of adverse effects was carried out using data obtained from 200 patients with lung cancer who had received sotorasib at the recommended dose. About 70% of these patients had at least one adverse event attributed to sotorasib : mainly diarrhoea, nausea and elevated transaminase levels. 7% of the patients had at least one serious adverse effect, and 6% stopped treatment as a result of an adverse effect. Serious interstitial lung disease was reported, including one fatal case possibly linked to sotorasib . The risk seemed to be greater in pa tientswho had previously received immunotherapy or radiother apy (3,6,7). In the trial versus docetaxel , based on the limited data available, more patients in the sotorasib group had diarrhoea and transaminase elevation linked to the drug, whereasmore patients in the docetaxel group had anaemia, neutropenia and alopecia. These results areweakened by the absence of blinding (4).

trial versus docetaxel underway as of early 2023. Sotorasib mainly carries a risk of gastrointestinal, hepatic and pulmonary disorders which are some times serious, plus multiple drug interactions.

LUMYKRAS° - sotorasib tablets • 120mg of sotorasib per tablet (240 tablets in a blister pack) Amgen ■ Antineoplastic; KRAS G12C protein inhibitor ■ Indication : as monotherapy for adults with “advanced non-small cell lung cancer with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy”. [EU centralised pro cedure – conditional authorisation] ■ Dosage : 960mg (i.e. 8 tablets) once daily, until disease progression orunacceptabletoxicity. Dose reductions shouldbeconsidereddepend ing on hepatic, pulmonary, gastrointestinal, or other adverse effects. In approximately 14% of patients with non-small cell lung cancer, the tumour cells carry a G12C mutation in one of the KRAS genes (1). In general, a KRAS gene mutation is an adverse prognostic factor, but as of early 2023, it is not known if this is true for the G12Cmutation (1,2). The KRAS proteins are involved in particular in the regulation of cell division, and mutations affecting these proteins can stimulate cell proliferation (3). The treatment of non-small cell lung cancer with a KRAS gene mutation is usually identical to that ofcancers lacking thismutation. When the cancer progresses after a first line of drug treatment, various antineoplastics are used, and the choicemainly depends on which drugs the patient has already received, the histological features of the tumour cells and the patient’s general health (1,2). Sotorasib is the first inhibitor of mutated protein KRAS G12C. It has been authorised in the European Union for patients with advanced non-small cell lung cancerwith a KRAS G12Cmutation, which has progressed after at least one line of drug treatment (3). A non-comparative trial: tumour response in a minority of patients. This marketing authorisation (MA) is based on one non-comparative trial in 126 patients, in which all patients received 960mg of sotorasib daily. The cancer was at a metastatic stage in nearly all the patients. They had already received one to three lines of drug treatment (1,3). Over a median follow-up of 15 months, complete disappear ance of the tumour as assessed by radiology (so-called complete response) was seen in 2.4% of patients, and a reduction in tumour

Multiple drug interactions. Sotorasib is primarily metabolised by the cytochrome P450 isoenzymes CYP3A4, CYP3A5 and CYP2C8. It is a substrate of P-glycoprotein, and it is an inhibitor or

an inducer of several P450 isoenzymes. It is also an inhibitor of various transporter proteins. In addition, the use of acid- reducing agents decreases gastrointestinal absorption of sotorasib (3). In summary, numerous pharmacokinetic interactions can be expected.

Excerpt from Prescrire Int May 2023 Full articles available to subscribers at english.prescrire.org

Page 4 • Prescrire International Special Edition 2023

MARKETING AUTHORISATIONS

NEW SUBSTANCE, NEW COMBINATION Relugolix + estradiol + norethisterone ( ryeqo °) in uterine fibroids A risky hormone cocktail

EDITORS’ OPINION

Cascade An imaginary scenario: when the fictional pharmaceutical company

MultiCombin suggested preventing the adverse effects of gizmoline by adding noxiozine , they still needed to prevent noxiozine ’s adverse effects. They soon found a solution: adding a third drug! It may sound far-fetched, yet that was the thinking behind the development and author isation of the combination of relugolix + estra diol + norethisterone (Ryeqo°) as a treatment for uterine fibroids (see opposite). To prevent the adverse effects of the hypoestrogenism caused by the GnRH antagonist relugolix , the company added the oestrogen estradiol . And to prevent the adverse effects of oestrogen on the endometrium, in particular the risk of cancer, it added the progestogen norethis terone . As a result, pre-menopausal women taking this combination are at risk of both the adverse effects of hypoestrogenism, which are similar to the effects of menopause, and those of postmenopausal hormone replace ment therapy with an oestrogen + progesto gen combination. Piling up drugs in this way, and the ensuing cascade of adverse effects, might be accept able if efficacy had been demonstrated and outweighed the risks. But that is far from the case for this three-drug combination. It is sometimes in patients’ interests to take a drug to relieve the adverse effects of another, very useful, drug. But before layering drug upon drug, the first step is to carefully consider how useful the first drug in the pile is to patients. Surely forgoing a drug of little value, rather than attempting to mitigate its adverse effects, is less dangerous and more beneficial for patients. ©Prescrire

NOT ACCEPTABLE The three-drug combination of relugolix + estradiol + norethisterone was mainly evaluated in two placebo-­ controlled trials. It markedly reduced

menstrual bleeding inmost women, but not fibroids, and no conclusive evidence of effects on other symptoms was obtained. Its adverse effects were mostly symptoms of menopause, including loss of bone mineral density, as well as hypertension and alopecia. Nothing is known of the long-termeffects of this treatment: in clinical trials, only 32 patients were treated for 2 years. In practice, it is more prudent to continue using treatments with better-established harms and benefits (despite their limitations), and to avoid exposing patients to this risky hormone cocktail. RYEQO° - relugolix + estradiol + norethisterone tablets • 40mg of relugolix + 1mg of estradiol + 0.5mg of norethisterone per tablet Gedeon Richter ■ Gonadorelin (GnRH) receptor antagonist + oestrogen progestogen hormone replacement ■ Indication : “ moderate to severe symptoms of uterine fibroids in adult women of reproductive age ”. [EUmarketing authorisation, cen tralised procedure] ■ Dosage : 1 tablet perday. “ The first tabletmust be takenwithin 5days of the onset of menstrual bleeding ”, given the risk of irregular heavy bleeding at the start of treatment when initiated on other days of the menstrual cycle.

Excerpt from Prescrire Int January 2023 Full article (4 pages) available to subscribers at english.prescrire.org

Prescrire Int • January 2023

Prescrire International Special Edition 2023 • Page 5

MARKETING AUTHORISATIONS

NEW SUBSTANCE Daridorexant ( quviviq °) in insomnia Evaluation not designed to demonstrate a therapeutic advance

NOTHING NEW The clinical evaluation of darid orexant in patients with chronic insomniawas not designed to demon strate a potential advance compared

cive to sleep. Physical exercise during the day helps with sleep, but vigorous activity in the hours preceding bedtime should be avoided (1). Cognitive behavioural therapy is a first-line option in chron ic insomnia, but it is sometimes difficult to access (1). Some drugs for temporary use. When cognitive be havioural therapy is not accessible or is not sufficiently effective, drugs such as benzodiazepines are an option, but their use should be limited to as short a period as possible because of their adverse effects (1,3). The efficacy of benzodiazepines or related drugs diminishes after less than two weeks of daily use (1). These drugs mainly carry a risk of somnolence, som nambulism and sleep automatisms, impairment of memory and concentration, cognitive disorders, confusion, falls, de pendence and withdrawal symptoms (1,2). Daridorexant is an antagonist of the receptors for orexins A and B (hypocretins 1 and 2), neuropeptides involved in main tenance of the waking state (3). Blocking the action of orexins is aimed at reducing wakefulness (4). A complete lack of orexins is associated with narcolepsy, a rare condition characterised by excessive daytime sleepiness, sleep attacks, hallucinations, sleep paralysis when falling asleep or awakening, cataplexy, nightmares and often disturbed sleep (5). Daridorexant has been granted marketing authorisation in Europe for adults with chronic insomnia that has an impact on daily activities (6). It is the first representative of this pharmaco logical class to be authorised in the European Union (3). Two other orexin receptor antagonists are already authorised for insomnia in various countries including Canada, the United States and Japan: suvorexant since 2014 and lemborexant since 2019 (3). Does daridorexant improve patients’ perception of sleep quality in chronic insomnia, particularly compared with other sleep-inducing drugs? Does it reduce the impact of sleep dis turbances on daily activities? And what are its adverse effects? WHAT’S NEW? An orexin receptor antagonist

with already available sleep-inducing drugs. While its mechanism of action is indeed different, there is no evidence that it represents a tangible clinical advance for patients. Follow-up is still too short to fully determine its adverse effects. In practice, as of early 2023, daridorexant has not been evaluated thoroughly enough to risk exposing patients to this drug, outside the setting of a clinical trial. When considering a pharmacological approach, it would be more prudent to continue to use the hypnotic drugs already available, despite their limitations, because of their longer history of use.

QUVIVIQ° - daridorexant tablets • 25mg or 50mg of daridorexant per tablet Idorsia Pharmaceuticals ■ Hypnotic; antagonist of orexinAand B receptors

■ Indication : adultswith “insomniacharacterised by symptoms pres ent for at least 3 months and considerable impact on daytime func tioning” . [EU centralised procedure] ■ Dosage : 25 or 50 mg once per day, to be taken 30 minutes before bedtime. “The treatment duration should be as short as possible”.

COMPARE BEFORE DECIDING

Insomnia in adults, in brief Patients who complain of insomnia describe an impact on daily activities due to fatigue or lack of energy, impairment of concentration and memory, or mood disturbances such as irritability (1,2). When the sleep disturbance has been occurring at least three times per week for three months or more, insom nia is said to be “chronic” (3,4). A non-pharmacological approach first. One of the first steps in helping a patient with troublesome insomnia is to look for contributing factors or a medical cause (psychiatric or other conditions) (1,2). A range of measures aimed at restoring good quality sleep include: not catching up sleep during the day, even after a poor night’s sleep; avoiding the use of stimu lants; limiting alcohol consumption; opting for light meals before bedtime; and creating a bedroom environment that is condu

Excerpt from Prescrire Int July/August 2023 Full article (5 pages) available to subscribers at english.prescrire.org

Page 6 • Prescrire International Special Edition 2023

MARKETING AUTHORISATIONS

NEW SUBSTANCE

EDITORS’ OPINION

Luspatercept (REBLOZYL°) in anaemia associated with myelodysplastic syndrome

New is not necessarily better

Poor-quality sleep is a common complaint, and can be very troublesome or distressing for patients and those around them. Patients in this situation are sometimes offered pharmacological treatment. Benzo- diazepines and benzodiazepine-like drugs have been used to treat insomnia for decades and, over the years, it has become clear that their efficacy is modest at best and often short lived. And they have adverse effects that are sometimes serious. This knowledge, accrued over time, contributes to the decision of whether or not to use a benzodiazepine, which, in the absence of a better alternative, is sometimes a reasonable option. It has been years since a hypnotic belonging to a new pharmacological class has been grant ed marketing authorisation in the European Union for the treatment of insomnia. Hopes were therefore high among certain patients and health professionals when daridorexant (Quviviq°) was authorised in Europe. Unfortunately, after a rigorous analysis of the available evaluation data, Prescrire can only conclude that daridorexant is yet another new drug that offers “Nothing new” for patients (see page 6 ). In trials conducted in highly selected patients, daridorexant had modest efficacy, enabling patients to get a few more minutes of sleep per night on aver age compared to placebo. This is unlikely to transform the lives of patients or the people around them, even in patients who experience severe insomnia every night. And what about the risks of depression, suicide, narcolepsy, cataplexy, dependence and other rare but potentially serious adverse effects? They remain unclear as of 2023, but could well eventually be confirmed, after years on the market. When a drug appears to have limited efficacy, uncertainties due to the lack of long-term data weigh heavily on its harm-benefit balance. A drug that is “new” is not necessarily a thera peutic advance: recognising this distinction is important to the provision of high-quality care.

NOT ACCEPTABLE For patients with anaemia associated withmyelodysplastic syndrome,when an epoetin is no longer an option, lus patercept has beenevaluated ina sin

gle placebo-controlled trial. A 5q deletion was not present intheneoplasticcells inanyofthesepatients. In this trial, a minority of patients from the luspater cept groupwere able todispensewithtransfusions in the short term compared to those in the placebo group. However, there was no reduction in the main symptoms ofanaemia, andthe level ofevidencepro videdbythesedata is lowduetomethodological flaws in the trial. Luspatercept has numerous adverse effects, including: fatigue, dyspnoea, infections, gastro intestinal disorders, hypersensitivity reactions, kidney damage (sometimes fatal), liverdamage (sometimes severe), tachyarrhythmias, andpossibly cancer inthe longterm. Redbloodcell transfusions, or lenalidomide inpatientswith5qdeletion, arebetteroptions, despite their limitations.

REBLOZYL° - luspatercept powder for solution for subcutaneous injection • 25mg or 75mg of luspatercept per vial Bristol-Myers Squibb ■ Erythroidmaturation agent

■ Indication : “ transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes with ring sidero blasts [in adults] who had an unsatisfactory response to or are ineli gible for erythropoietin-based therapy. ” [EU centralised procedure – orphan drug] ■ Dosage : initial dose of 1 mg/kg every 3 weeks, adjusted there after according to haemoglobin level, transfusion requirements and adverse effects, with in general an ongoing dose between 0.8 and 1.75mg/kg every 3weeks.

©Prescrire

▶ Translated from Rev Prescrire November 2022 Volume 42 N° 469 • Full French version: 4 pages Prescrire Int • February 2023

©Prescrire

Prescrire Int • July/August 2023

Prescrire International Special Edition 2023 • Page 7

MARKETING AUTHORISATIONS

Prescrire’s ratings of new drugs in 2022: a brief review

● Only 11 of the 124 newmarketing authorisations analysed and rated in our French edition in 2022 represent ed a notable therapeutic advance for patients.

E very month, Prescrire publishes independent, comparative, systematic reviews of the latest developments in the Euro- pean pharmaceutical market, including recent marketing authorisations for new active substances, new combinations, new pharmaceutical forms, and new indications. We also close ly monitor news concerning adverse effects, market withdraw als (instigated by pharmaceutical companies or regulatory authorities), re-introductions of previously withdrawn products, re-evaluations of drugs already on the market, and the regula tory environment for health products. Our aim is to help sub scribers distinguish between genuine advances and new products or newuses that are no better than existing treatments or that should never have been authorised, due to uncertainty over their harms or benefits or because they are clearly dan gerous. No major therapeutic advances in 2022. Prescrire examined 124 newmarketing authorisations in 2022 in order to determine whether or not they advanced patient care. Thirty-four of these offered some degree of added benefit compared with existing treatments, at least for some patients, with 11 (9%) representing a notable advance (rated “Offers an Advantage”), and the remaining 23 (19%) a minimal advance (rated as “Possibly Helpful”). Half of the new authorisations we analysed in 2022 offered no proven advantages over existing treatment options (rated “Nothing New”). In 13 cases (10%), the harm-benefit balance could not be determined, because the clinical evaluation data provided insufficient evidence of their efficacy or potential serious adverse effects (rated “Judgement Reserved”). Finally, the evaluation data available on 14 authorisations (11%) showed them to be more dangerous than useful (rated “Not Accept able”). A few new authorisations worth using. After the advances seen in 2021 with the first covid-19 vaccines, those observed in 2022 are far more modest, marking a return to the pattern generally seen before the pandemic. A few new active substances are worth using, for example: sacituzumab govitecan , tucatinib and the combination of pertuzumab + trastuzumab for certain patients with breast cancer; as well as nirmatrelvir (combined with ritonavir ) and tocilizumab for patients at risk of developing severe covid-19. The antibody sotrovimab was temporarily an advance for pa tients with covid-19, but not a durable advance due to the virus’s variability. Sodium oxybate constitutes a notable therapeutic advance for children aged 7 years or older with narcolepsy, as was the case for adults.

Dose strengths ill-suited to the recommended doses. Some drugs Prescrire examined in 2022 are marketed at dose strengths that necessitate 2 to 4 injections in succession to achieve the recommended dose, for example: bimekizumab , supplied in pre-filled pens or syringes that contain 160 mg of the drug, yet the recommended dose for plaque psoriasis is 320 mg every 4 or 8 weeks ( Prescrire Int n° 245); natalizumab , supplied in pre-filled syringes each containing 150 mg for sub cutaneous administration, yet the recommended dose for multiple sclerosis is 300 mg per month ( Rev Prescrire n° 464); and tralokinumab, marketed in pre-filled syringes containing only 150mg of the drug, when the recommended dose is 600mg, then 300 mg every 2 weeks, for certain patients with atopic dermatitis ( Prescrire Int n° 239). A few welcome restrictive measures at European level. A few welcome restrictive measures were taken in the European Union in 2022, in particular: the European Medicines Agency (EMA) issued a negative opinion on granting marketing authorisation for aducanumab , a drug with no demonstrated efficacy in Alzheimer’s disease, leading the pharmaceutical company to withdraw its application (1); and authorisation for the use of dapagliflozin in type 1 diabetes was withdrawn. Au thorisation for the use of rucaparib in relapsed ovarian cancer, recklessly granted in 2020 on the basis of a very tenuous eval uation, was finally revoked. And in late 2022, the EMA confirmed its earlier opinion recommending the withdrawal of products containing amfepramone . The dangers of this amphetamine have been known since the 1990s, and it had already been withdrawn in many countries, including France (2). In contrast, etifoxine was not withdrawn from the European market, despite the fact that it has been known for many years to have an unfavourable harm-benefit balance. In summary: a disappointing year. 2022 was a return to the bad old days for medicines in Europe. Therapeutic ad vances were few and far between. Most newly authorised products or indications offered no proven advantages over existing treatment options, or were excessively dangerous. And yet again, certain pharmaceutical companies gave too little consideration to the ease of use of their products, choosing to market them in pack sizes ill-suited to the doses to be admin istered. ©Prescrire

▶ Translated from Rev Prescrire February 2023 Volume 43 N° 472 • Pages 146-147

References 1- EMA “Withdrawal of application for the marketing authorisation of Aduhelm (aducanumab)” 22 April 2022: 2 pages. 2- EMA “EMA confirms recom mendation to withdrawmarketing authorisations for amfepramone medicines” 11 November 2022: 3 pages.

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MARKETING AUTHORISATIONS

Progrès de l’année 2022 Comparaison aux 9 années précédentes Therapeutic advances in 2022 compared with the previous 9 years

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 fundamentally change curent therapeutic practice. POSSIBLYHELPFUL 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 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

2013-2021

2022

Notable advance Minimal advance

No proven advantages More dangerous than useful

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

Paracetamol, pregnancy and urogenital endocrine disruption: inconclusive studies

● Prompted by observations in animal studies, about a dozen epidemiological studies have inves tigated the possibility that in-utero exposure to paracetamol has an endocrine-disrupting effect on the urogenital system. ● The quality of the evidence provided by these studies is weakened by theirmanymethodological limitations, related in particular to the method used to collect drug exposure data, or failure to analyse the cases of cryptorchidism that required surgical correction. The results on hypospadias in boys exposed to paracetamol in utero are no more robust. ● Among the other drugs available to alleviate fever or pain, nonsteroidal anti-inflammatory drugs (NSAIDs) pose a known risk of serious adverse effects in the unborn child. Opioids can provoke hypogonadism in adults, but this effect has not been demonstrated in children exposed to opioids in utero. ● In practice, during pregnancy, paracetamol remains the analgesic with the best harm-benefit balance, despite its limitations. Given the uncer tainty concerning the possible long-term effects of in-utero exposure to paracetamol , it makes sense to use it selectively, without trivialising its use in pregnancy. P aracetamol is the drug of choice for occasional use to treat fever or mild to moderate pain, including during pregnancy (1). Its main adverse effect is serious liver injury in the event of an overdose (1). It was long thought to present no particular dangers in pregnancy (2). However, in late pregnancy, paracetamol is a risk factor for premature closure of the ductus arteriosus (3). And effects on the neuropsycho logical development of children exposed to paracetamol in utero, especially with high doses, have not been ruled out (4). In the early 2010s, a few animal studies produced conflicting results concerning a risk of testicular disorders. Two cohort studies, including a total of almost 49 000 boys, found no particular risk of persistent cryptorchidism following in-utero exposure to paracetamol ; cryptorchidism (undescended

testes) is described as persistent when surgery would be re quired to correct it. A case-control study demonstrated a link with cryptorchidism in a subgroup of boys exposed to para cetamol in utero for more than 15 days, but did not specify whether the affected boys had persistent cryptorchidism (2). Is more known about the urogenital development of children exposed to paracetamol in utero as of 2022, and the risk of hypospadias or cryptorchidism in particular? This article reviews the main data identified through our lit erature search. In male and female animals: effects on the re productive system. Our 2012 reviewmentioned 5 studies in which high (but unspecified) doses of paracetamol , admin istered orally to animals, reduced testosterone production and spermatogenesis, and caused testicular atrophy (2). Since that review, about a dozen studies in rats and mice have been pub lished on the effects of paracetamol on the progeny of exposed gravid females. Reduced ovarian reserve and fertility were observed in female progeny, even at doses that were not toxic to the gravid females (5,6). Observations in animals cannot always be extrapolated to humans. However, these studies served as a warning of para cetamol ’s potential endocrine-disrupting effects on the uro genital system, prompting epidemiological studies to be conducted (7-9). About a dozen epidemiological studies: mostly negative results. Since 2012, 3 cohort studies and 3 case-control studies have investigated the potential link between in-utero exposure to paracetamol and cryptorchidism or hypospadias (10-15). Cryptorchidismwas primarily evaluated in 3 cohort studies, in a total of almost 80 000 boys (10-12). As in our previous review, the definitions and diagnostic criteria used for cryptorchidism varied. The published results did not distinguish between the risk of cryptorchidismobserved at birth and cryptorchidism present after the first months of life (2). In one cohort study, including a total of 3000 boys, the risk of cryptorchidismwas about twice as high in boys exposed to paracetamol in utero (about 10% to 20%, depending on the period of pregnancy) than in unexposed boys (10). No link was demonstrated in the other two cohort studies and one case-­ control study (11-13).

Excerpt from Prescrire Int April 2023 Full article (2 pages) available to subscribers at english.prescrire.org

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ADVERSE EFFECTS

Janus kinase inhibitors: higher incidence of serious adverse effects and death thanwith TNF-alpha inhibitors

● The EMA recommends using the Janus kinase (JAK) inhibitors abrocitinib , baricitinib , filgotinib , tofacitinib and upadacitinib , authorised mainly for chronic inflammatory diseases, only as a last resort, in certain patients. J anus kinase (JAK) inhibitors are immunosuppressants. Some have been authorised in the European Union for oral use in various chronic inflammatory rheumatological, intestinal or cutaneous disorders, without evidence that they represent a therapeutic advance over the immunosuppressants already available, in particular TNF-alpha inhibitors. These JAK inhibitors are: abrocitinib (Cibinqo°), baricitinib (Olumiant°), filgotinib (Jyseleca°), tofacitinib (Xeljanz°) and upadacitinib (Rinvoq°) (1). Two other JAK inhibitors, fedratinib (Inrebic°) and ruxolitinib (Jakavi°), are authorised for use in cancer, in particu lar myelofibrosis (1,2). JAK inhibitors have the adverse effects common to all im munosuppressants, including serious infections and cancer, but they can also provoke venous or arterial thromboembolism, hypertension, hypercholesterolaemia, weight gain, haem atological disorders, etc. (1). In 2019, the “interim” results of a clinical trial in 4362 patients aged 50 years or over (including about one-third aged 65 years or older) with rheumatoid arthritis, showed that tofacitinib exposes patients to a greater risk of cancer and thromboembolic events, in particular myocardial infarction, than TNF-alpha inhibitors. These risks were increased with both authorised doses of tofacitinib : 5 mg or 10 mg, twice daily (1-3). Higher incidence of serious infections, hepatic disorders and all-cause death than with TNF-­ alpha inhibitors. Other data from this trial, made public in 2022, also showed that, compared with TNF-alpha inhibitors, tofacitinib was associated with a higher incidence of: – serious infections (9.7% of patients in the tofacitinib 5 mg twice daily group, 11.6% in the tofacitinib 10mg twice daily group, versus 8.2% in the TNF-alpha inhibitor group); – hepatic disorders (3.2%, 4.9%, versus 2.4%, respectively); – death from any cause (1.8%, 2.7%, versus 1.2%, respectively). For each of these adverse effects, the difference between the tofacitinib 10 mg twice daily group and the TNF-alpha in hibitor group was statistically significant (2,3). In 2022, data from a clinical trial of baricitinib in patients with rheumatoid arthritis also suggested a higher incidence of car diovascular and venous thromboembolic adverse events than with TNF-alpha inhibitors (2).

In light of these data, the European Commission requested a review of the harm-benefit balance of the five JAK inhibitors authorised for use in chronic inflammatory disorders. The Commission considered that the characteristics of the patients concerned justified examining JAK inhibitors authorised for cancer separately, even though a class effect is suspected (2). As of 1 February 2023, the European Medicines Agency (EMA) website makes no mention of fedratinib and ruxolitinib being under review. Effects common to all of these substances. In late 2022, the EMA considered that there was a “ class effect ”, meaning that the increased incidence of certain adverse effects identified with tofacitinib and baricitinib compared with TNF-­ alpha inhibitors in the two above-mentioned clinical trials is shared by the three other JAK inhibitors authorised for use in chronic inflammatory diseases (4). The EMA therefore recom mended that abrocitinib , baricitinib , filgotinib , tofacitinib and upadacitinib only be prescribed as a last resort in patients: aged 65 years or over; at increased risk of serious cardiovascular events, such as stroke or myocardial infarction; who smoke or are ex-smokers; or are at increased risk of cancer. The EMA also recommended using these drugs “ with caution ” in patients with risk factors for venous thromboembolism (in cluding pulmonary embolism). It recommended reducing the doses of JAK inhibitors for all of these patients, without speci fying by howmuch (4). IN PRACTICE  The increased incidence of serious adverse effects associated with tofacitinib and baricitinib , and probably also the three other JAK inhibitors used in chronic inflammatory diseases, raises questions about the harm-benefit balance of drugs of this class, especially since they have not been demon strated to have tangibly greater efficacy thanTNF-alpha inhibitors. In addition, their most serious adverse effects (infections and thromboembolism) are difficult to predict, even when patients are carefully monitored. ©Prescrire References 1- “Inhibiteurs de Janus kinases: ruxolitinib, etc.” Interactions Médica menteuses Prescrire 2023. 2- EMA “Notification to the PRAC/EMA secretariat of a referral under article 20 (…)” 28 January 2022 + “Addendum to notification to the PRAC/EMA secretariat of a referral under article 20 (…)” 13 June 2022: 6 pages. 3- Ytterberg SR et al. “Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis” N Engl J Med 2022; 386 (4): 316-326. 4- EMA “EMA confirms measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders” 11 November 2022 + 27 January 2023 + “Alignment of dose recommendations for Janus kinase inhibitors in patients with certain risk factors” 13 January 2023: 7 pages. ▶ Translated from Rev Prescrire March 2023 Volume 43 N° 473 • Pages 180-181

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ADVERSE EFFECTS

Known allergy to chlorhexidine:

COMMON STEM -grel

NN A drug’s real name

a preventable death The Netherlands Pharmacovigilance Centre (Lareb) has received a case report of anaphylactic shock in an elderly patient, which occurred 10 minutes after the product Instillagel° was used for inserting a urinary catheter. This brand name does not indicate that this urethral gel contains chlorhexidine , an antiseptic, plus lidocaine , a local anaesthetic. The patient was known to have an allergy to chlorhexidine . He was resuscitated, but he died 2months later from the consequences of anaphylactic shock (1). Analysis of this event by the healthcare team and the Dutch Institute for prevention of medication incidents identified, among the contributory factors, lack of awareness that this patient might have chlorhexidine allergy and a lack of knowledge of the substances contained in drugs and medical devices that can cause allergic reactions (1). Hypersensitivity reactions, including sometimes fatal ana phylaxis, had already been reported with chlorhexidine (2,3). Patients and healthcare workers have frequent contact with this substance (sometimes leading to sensitisation), due to its presence in many products in everyday use, e.g. topical medi cines, mouthwash, dressings and tubes. After a first allergic episode, further exposure is therefore difficult to avoid. In many situations, it is not known that this antiseptic is present, and the value of using it has not been demonstrated (1-5). IN PRACTICE  Chlorhexidine is an allergen. Allergy to chlor hexidine should be considered whenever an allergic-type re action occurs that is associated with a healthcare procedure in which it has been used. It is important that patients (and their family and friends) familiarise themselves with this information, and that it is recorded in their medical records. When prescribing, dispensing or administering a product containing chlorhexidine, it is essential to check with the patient that they are not allergic to it, if necessary by looking in their medical records. If there is a known allergy, it is important to read the composition of the product. ©Prescrire References 1- Instituut Verantwoord Medicijngebruik - Voorkomen Medicatie-­ Incidenten “Praktijkprikkel Anafylaxie bij bekende chloorhexidineallergie” Praktijk prikkel 2022; (8): 2 pages. 2- Prescrire Editorial Staff “Chlorhexidine: anaphylaxis following skin application” Prescrire Int 2017; 26 (188): 296. 3- Opstrup MS et al. “Chlorhexidine allergy: On the rise and often overlooked” Curr Allergy Asthma Rep 2019; 19 (5): 23. 4- Prescrire Rédaction “Exposition professionnelle des soignants aux médicaments: bilan des notifications en France de 2009 à 2019” Rev Prescrire 2022; 42 (460): 111-112. 5- Prescrire Rédaction “Lidocaïne + chlorhexidine en gel urétral (Instillagel°). Des risques mais pas d’avantage en termes d’efficacité” Rev Prescrire 2003; 23 (239): 337-338. ▶ Translated from Rev Prescrire January 2023 Volume 43 N° 471 • Page 25

According to the nomenclature for international non-proprietary

names (INNs) established by theWorld Health Organization (WHO), the INNs of antiplatelet drugs contain, or end in, the common stem -grel (1). As of 26 October 2022, we have identified 5 drugs whose INN contains this stem: ana grelide (Xagrid° or other brands), which also has a platelet-lowering action, used in some patients with essential thrombocythemia (see “Anagrelide: thrombosis following discon tinuation” Prescrire Int n° 246); clopidogrel used for prevention of ischaemic events and, in combination with aspirin , after certain acute coronary events; and cangrelor (Ken grexal°), prasugrel (Efient° or other brands) and ticagrelor (Brilique°) also used, in com bination with aspirin , after some acute cor onary events (1). The INNs of some older antiplatelet drugs do not contain this common stem, resulting in exceptions to the rule: for example aspirin , ticlopidine and dipyridamole (1). All the antiplatelet drugs carry a risk of haemorrhage. This risk is increased when they are combined with another drug that can lead to bleeding, such as a nonsteroidal anti-inflammatory drug or an anticoagu lant (2). ©Prescrire

▶ Translated from Rev Prescrire December 2022 Volume 42 N° 470 • Page 899

References 1- World Health Organization “The use of stems in the selection of International Nonproprietary Names (INN) for pharma ceutical substances 2018 (Stem Book 2018)”: 105. 2- “Clopidogrel, prasugrel et ticlopidine” + “Dipyridamole” + “Ticagrélor et cangrélor” Interactions Médicamenteuses Prescrire 2023.

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Prescrire Int • April 202 3

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