Drug-induced Sweet's syndrome: A case/non-case study in the French pharmacovigilance database.

AIMS: Sweet's syndrome is an acute febrile neutrophilic dermatosis first described in 1964 by Robert Douglas Sweet. The pathophysiological mechanism is not fully established; however, several cases of Sweet's syndrome have been reported following drug administration. METHODS: To investigate the existence of pharmacovigilance signals between drugs and the occurrence of Sweet's syndrome, we performed a case/non-case study on reports of 'acute febrile neutrophilic dermatosis' registered in the French pharmacovigilance database. Reporting odds ratio (ROR) with its 95% confidence interval were calculated. RESULTS: Amongthe 994 789 reports recorded in the database, 136 were Sweet's syndrome, of which 50.7% were men and the median age was 59 years (range 15-91). A total of 224 drugs were mentioned as suspects: 21.0% were antibacterials, 19.2% were antineoplastics and 12.1% were immunosuppressants. Median time to onset from drug initiation to the development of Sweet's syndrome was 15 days (range 1-1095). The highest RORs were observed with bortezomib (74.04 [40.8-134.2]), azacitidine (72.14 [29.4-176.9]), perfilgrastim (67.05 [21.2-211.6]), azathioprine (55.46 [34.8-88.4]) and bendamustine (35.84 [11.4-112.8]). CONCLUSIONS: Pharmacovigilance signals have been observed between the occurrence of Sweet's syndrome and colony-stimulating factors, immunosuppressants, antineoplastics and antibiotics. Clinicians should be aware of the potential associations with these drugs and should be encouraged to report any case of drug-induced Sweet's syndrome.

Intravenous and subcutaneous immunoglobulins-associated eczematous reactions occur with a broad range of immunoglobulin types: A French national multicenter study.

BACKGROUND: Human immunoglobulins are used for treating diverse inflammatory and autoimmune disorders. Eczema is an adverse event reported but poorly described. OBJECTIVES: To describe the clinical presentation, severity, outcome, and therapeutic management of immunoglobulin-associated eczema. METHODS: This retrospective and descriptive study included a query of the French national pharmacovigilance database, together with a national call for cases among dermatologists. RESULTS: We included 322 patients. Eczema occurred preferentially in men (78.9%) and in patients treated for neurological pathologies (76%). The clinical presentation consisted mainly of dyshidrosis (32.7%) and dry palmoplantar eczema (32.6%); 5% of cases exhibited erythroderma. Sixty-two percent of the eczema flares occurred after the first immunoglobulin course. Eczema was observed with 13 intravenous or subcutaneous immunoglobulin types and recurred in 84% of patients who maintained the same treatment and in 68% who switched the immunoglobulin type. After immunoglobulin discontinuation, 30% of patients still had persistent eczema. LIMITATIONS: Retrospective study, with possible missing data or memory bias. CONCLUSION: Immunoglobulin-associated eczema occurred with all immunoglobulin types, preferentially in patients with neurologic diseases who required prolonged immunoglobulin treatment. Recurrence was frequent, even after switching the immunoglobulin type, which can lead to a challenging therapeutic situation when immunoglobulin maintenance is required.

Psoriasis risk after beta-blocker exposure: Description of a pharmacovigilance signal.

AIM: We aimed to investigate French pharmacovigilance data. The objective was to characterize psoriatic conditions that occurred after beta-blocker (BB) exposure and bring to light a possible pharmacovigilance signal. METHODS: Spontaneous reports of psoriatic conditions recorded in the French National Pharmacovigilance Database (FPVD) between 1985 and 2019 were extracted. We performed a retrospective, descriptive analysis of reports linked to BB exposure. Association between psoriasis risk and BB exposure was assessed using a case/noncase study. RESULTS: Two hundred and twenty-five reports of psoriatic conditions after BB exposure were recorded in the FPVD during the study period. Both cardioselective and noncardioselective, topical and systemic BBs are involved. Therapeutic indication of BB was mainly hypertension. Mean time to onset was 5 months and outcome was favourable in 68% after BB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 8.95 (95% confidence interval 7.75-10.33). CONCLUSION: We highlighted a statistically significant disproportionality which constitutes a pharmacovigilance signal. Psoriasis risk with BBs is a class effect. Increasing surveillance during the first year of BB exposure is needed.

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity.

PURPOSE: Pembrolizumab is a humanized monoclonal antibody that binds to the programmed cell-death protein-1 (PD-1) on immune T-cells, thus blocking PD-1 activity. Pembrolizumab is indicated for the treatment of advanced melanoma, metastatic non-small-cell lung cancer, and head and neck squamous cell carcinoma. However, it is associated with immune-related adverse events. METHODS: We investigated the association between pembrolizumab and immune-mediated necrotizing myopathy (IMNM). We analyzed reports in the World Health Organization's global individual case safety report database, Vigibase, up to January 2020 with the MedDRA lower level term "IMNM." The association between exposure to pembrolizumab and occurrence of the adverse event was estimated by disproportionality analysis. The reporting odds ratio (ROR) was calculated with 95% confidence intervals (CIs). We analyzed the criteria of diagnosis of the adverse reaction. RESULTS: Five-hundred sixty-seven notifications were identified as IMNM of which 14 with pembrolizumab. The ROR was 17.59 (95% CI: 9.4-32.9). CONCLUSION: The diagnosis of IMNM does not always take into account recent criteria for the diagnosis of this pathology. This study highlights the existence of a signal, as well as the need for collaboration between oncologists and neurologists for these neurological pathologies.

Nightmares and hallucinations with aprepitant and opium powder: a suspected drug-drug interaction.

Polypharmacy of elderly oncology patients and fragmented medication management are well-known risk factors for drug-drug interactions (DDIs). These interactions can occur among antineoplastic, ongoing chronic treatment(s) and chemotherapy-associated treatments, like antiemetics. Clinically relevant interactions based on enzyme- or transporter-inhibition phenomena of active drugs can increase the frequency of their DDIs. We describe a strongly suspected elderly cancer patient's DDI between aprepitant and opium powder in the context of an irinotecan-based regimen manifested by nightmares and visual hallucinations. We discuss this DDI's hypothetical pharmacological mechanisms and management.

Eosinophilic pneumonia induced by non-steroidal anti-inflammatory drugs: An underestimated risk.

INTRODUCTION: Eosinophilic pneumonia (EP) is a rare but serious adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: We describe the second published case of EP induced by oral diclofenac. We also reviewed the literature as well as French pharmacovigilance database. Case presentation A 63 year-old woman with polyarthralgia had taken diclofenac for three days for analgesic purposes. Progressively, the patient presented weakness, dyspnea and fever. Computed tomography (CT) scan revealed bilateral interstitial infiltration. Broncho-alveolar lavage (BAL) showed an elevated level of eosinophils. After ruling out all other possible etiologies, drug-induced EP was diagnosed and treatment by corticosteroid was initiated. The patient recovered in three months. RESULTS: In the French pharmacovigilance database, six cases of EP were recorded (3 with naproxen, 2 with ibuprofen, 1 with piroxicam). In the literature, twenty-six cases of EP with NSAIDs were published. The most commonly involved drug was naproxen (n=8), followed by fenbufen (n=4), ibuprofen (n=3) and diclofenac (n=2). A high level of eosinophils was systematically observed in the blood cell count or BAL. Corticosteroid therapy was started in eleven cases. All patients recovered. CONCLUSION: Complete history taking and examination should be done to rule out other etiological diagnoses. BAL is sufficient to diagnose EP. Corticosteroid therapy should be indicated for more severe or refractory cases. This adverse drug reaction is underestimated, healthcare professionals should be informed.

[Adverse drug reactions in pediatrics: Experience of a regional pharmacovigilance center]. / Les effets indésirables médicamenteux en pédiatrie : expérience d'un centre régional de pharmacovigilance.

AIM: To describe the adverse drug reactions (ADR) and the drugs involved in pediatrics. METHODS: An observational study on all ADR notifications recorded in the French pharmacovigilance database by the Regional Pharmacovigilance Center of Champagne-Ardenne between 1 January 1985 and 31 December 2014 involving children from 0 to 17 years inclusive was performed. For all notifications, we studied the patient and the ADR characteristics. RESULTS: During the study period, 632 notifications were collected. The most frequently reported ATC (anatomical, therapeutic and chemical) classes were vaccines (15.9%), antineoplastics (12%) and antibiotics (11.1%). Forty-six percent of the notifications were serious. For serious ADRs, the most involved drugs were paracetamol, asparaginase and ibuprofen. Skin reactions were the most often reported ADRs. The most common lowest level terms (LLT) were urticaria (4.9%), hypersensitivity (4.1%), fever (2.9%) and vomiting (2.8%). CONCLUSION: ADR reporting to the pharmacovigilance system, in particular pediatric ADRs, should be encouraged. Information on the use of medicinal products, especially on self-medication use, need to be improve.

Methylphenidate and stuttering.

Methylphenidate (MPH) is a piperidine similar to amphetamines, and is indicated for attention deficit hyperactivity disorder. Studies concerning stuttering occurring with MPH are contradictory. We investigated the association between MPH and stuttering. We analysed reports in the World Health Organization global individual case safety reports database, Vigibase, up to 31 December 2018, with the MedDRA preferred term "dysphemia" and the lower level terms "stutter" and "stuttering". The association between exposure to MPH and occurrence of the adverse drug reaction was estimated by disproportionality analysis. Reporting odds ratios (RORs) were calculated with 95% confidence intervals (CIs). In total, 2975 cases of dysphemia were reported, of which 46 reports were associated with MPH. For the Preferred Term "dysphemia", the ROR was 7.3 (95% CI: 5.4-9.8). With the Lower Level Term "stuttering", 584 cases were registered in the database of which 17 involved MPH. The ROR was 13.9 (95% CI: 8.6-22.5). This study found a signal for stuttering with MPH.

Statins and immune-mediated necrotizing myopathy: Variability in the risk.

INTRODUCTION: Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti HMGCR). OBJECTIVES: The aim of this study was to investigate the relationship between the different statins and the risk of IMNM. METHODS: A two-time approach was used. First, we performed a descriptive analysis of the French national pharmacovigilance database (FNPV) for the period from 1985 to december2020. To identify relevant cases, we used Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) related to IMNM. We performed a quantitative and qualitative review of individual case safety reports (ICSRs) recorded in the french vigilance spontaneous reporting system. In a second time, we performed a comparative analysis with the World Health Organization global individual case safety reports database (Vigibase). The association between IMNM and statins exposure was assessed by calculating the reporting odds ratio (ROR) and its 95% confidence interval. RESULTS: After analysis, a total of 25 ICSRs were related to IMNM in the FNPV. The suspected statins were atorvastatin (n=21), simvastatin (n=2), pravastatin (n=1) and rosuvastatin (n=1). In Vigibase, 567 notifications were identified. A significant ROR value was found for atorvastatin, pitavastatin, simvastatin, pravastatin and rosuvastatin. CONCLUSION: Atorvastatin presents the highest risk of IMNM. Our data suggest that the occurrence of IMNM is a class effect.

Anti-NMDA receptor encephalitis and vaccination: A disproportionality analysis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto-immune neurological disorder characterized by the presence in the cerebrospinal fluid (CSF) of antibodies against the GluN1 subunit of NMDA receptors in the brain. The etiology of the disease remains largely unknown. In this study, we aimed to investigate the possible existence of pharmacovigilance signals relating to a link between vaccination and the occurrence of anti-NMDAR encephalitis. We performed a case/non-case study using data from the World Health Organization pharmacovigilance database (VigiBase) up to 31 December 2021. All individual case study reports (ICSRs) linked to a vaccine and coded with the MedDRA Lower Level Term (LLT) "anti-NMDA receptor encephalitis" were analysed. We calculated the Reporting Odds Ratio (ROR) and 95% Confidence Interval (CI) for each type of vaccine. A total of 29,758,737 ICSRs were registered in VigiBase, of which 70 were coded under the selected LLT, and 29/70 (41.4%) involved a vaccine. Of these cases, 53.8% involved children aged younger than 15 years. The median time to onset of anti-NMDAR encephalitis after vaccination was 4 days (range 0-730). The highest RORs were observed for the diphtheria/polio/tetanus/pertussis vaccine [54.72 (95% CI 26.2-114.3)], yellow fever vaccine [50.02 (95% CI 15.7-159)] and human papillomavirus vaccine [32.89 (15.8-68.7)]. All cases were coded as serious; 13 patients did not recover, or were left with permanent sequelae. Nine patients recovered without sequelae or are on the path to recovery, and one patient died. In summary, pharmacovigilance signals were observed for anti-NMDAR encephalitis and vaccination. Clinicians need to be aware of this potential risk, and encourage to report any case of anti-NMDAR encephalitis occurring after vaccination.

Penetration rate of anti-TNF biosimilars and savings at 5 years after their introduction in French hospitals.

OBJECTIVE: Since the expiry of the patents on originator anti-TNF agents in Europe, France has authorized the sale of biosimilars. The penetration rate of anti-TNF agents and their biosimilars, and the cost savings driven by the introduction of biosimilars appears to vary widely. This study aimed to describe the market share of anti-TNFs and their biosimilars, and the cost savings generated by the introduction of biosimilars in French hospitals 5 years ago. METHODS: The pharmaceutical component of the French national uniform hospital discharge data set database (PMSI) was used to study sales of infliximab, etanercept and adalimumab originators and biosimilars, and to estimate cost savings generated by the introduction of biosimilars onto the market, using the historical tariffs of the originators. RESULTS: The penetration rate of anti-TNF biosimilars in France in 76% for infliximab, 74% for etanercept and 77% for adalimumab. In 2020, Inflectra® (41%) was the Remicade® biosimilar with the highest sales volume, while Erelzi® (57%) and Amgevita® (64%) were the most widely sold biosimilars of Enbrel® and Humira® respectively. In terms of cost savings since the launch of biosimilars, overall, for all biosimilars taken together, over the 5-year period, a total of 824 million Euro was saved, in relation to the historical tariffs of the originators. CONCLUSIONS: This study shows firstly that the penetration rate of anti-TNF biosimilars in France 5 years after their launch is close to 80%. Secondly, we show that the cost savings generated by the use of biosimilars to anti-TNF agents exceed 820 million Euro over 5 years.

Drug induced stuttering: pharmacovigilance data.

Background: Stuttering is a speech disorder characterized by poor fluency of speech despite the speech production organs being normal. Numerous factors contribute to stuttering, and it may also be an iatrogenic effect of certain drugs. The aim of this study was to investigate the association between stuttering and drug exposure.Research design and methods: We investigated the association between drugs and stuttering. We analyzed reports in the World Health Organization global individual case safety reports database (Vigibase) up to 31 May 2020 with the MedDRA lower level terms 'stutter' and 'stuttering.' The association between a drug and the occurrence of the adverse drug reaction was estimated by disproportionality analysis. Reporting odds ratios (ROR) were calculated with 95% confidence intervals.Results: In total, 724 notifications were identified using the MedDRA terms selected. The main drugs implicated were methylphenidate (ROR = 19.58; 95% CI: 13.3-28.8), topiramate (ROR = 12.5; 95% CI: 7.1-22.1), olanzapine (ROR = 12; 95% CI: 8-17.9) and golimumab (ROR = 10.2; 95% CI: 5.5-19.1).Conclusions: When stuttering occurs in a patient treated by drugs affecting neurotransmission, a drug-induced origin of the stutter should be considered.

Calcium channel blocker exposure and psoriasis risk: Pharmacovigilance investigation and literature data.

INTRODUCTION: Evidence regarding a possible association between psoriatic manifestations and use of calcium channel blockers (CCBs) is sparse. Currently, psoriatic manifestations are not listed in the summary of product characteristics (SmPC) of CCBs. In this context, we aimed to investigate the association between psoriasis and CCB exposure. METHODS: We reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) between 1985 and 2019. The association between CCB exposure and risk of psoriasis was assessed using the case/non-case method. We also analyzed literature data. RESULTS: Ninety-four reports of psoriatic manifestations after CCB exposure were recorded in the FPVD. Both induction and exacerbation cases were observed. Time to onset was less than 2 years in 64% of reports and outcome was favorable in 71% of reports after CCB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 2.45 (95% CI 1.99-3.02). Concomitant use of betablockers or angiotensin II receptor blockers did not interact with the association between CCB exposure and psoriasis risk. The ROR for the stratum "use of angiotensin converting enzyme inhibitors" (ACEI) was 2.14 (95% CI 1.29-3.55), while the ROR for the stratum ACEI non-use was 0.12 (95% CI 0.10-0.15). Large-scale epidemiologic studies were focused only on first diagnoses and did not include exacerbations; psoriasis risk was therefore probably underestimated. CONCLUSION: We found a statistically significant association between CCB exposure and psoriasis risk, which constitutes a safety signal. This risk is a class effect, time to onset is mostly less than 2 years and outcome is favorable after CCB discontinuation. Psoriasis should be mentioned in the SmPCs of all CCBs, and healthcare workers should be aware of this risk. Attention should be paid to patients taking CCB and ACEI concomitantly.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

BACKGROUND: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal. METHODS: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups. RESULTS: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53). CONCLUSIONS: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

Psoriasis After Exposure to Angiotensin-Converting Enzyme Inhibitors: French Pharmacovigilance Data and Review of the Literature.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) can induce or aggravate psoriasis. This risk is not specified in the Summary of Product Characteristics (SmPC) of some drugs of this class, such as captopril or enalapril. We aimed to investigate the association between psoriasis and ACEI exposure. METHODS: We analyzed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD) from 1985 to 31 December 2018. The association between psoriasis and ACEI exposure was assessed using the case/non-case method. We also reviewed literature reports. RESULTS: One hundred reports of psoriasis after ACEI exposure were registered in the FPVD. The reporting odds ratio (ROR) was 2.40 (95% CI 1.96-2.95). Time to onset was < 1 year in 67% of reports. Outcome was favorable in 73% of reports after ACEI discontinuation. Almost all ACEIs were concerned. In the literature, we found 21 published reports of psoriasis with ACEIs. Time to onset ranged from 1 week to 4 months. Outcome was also favorable after ACEI discontinuation in over half of the literature reports. CONCLUSIONS: We found a statistically significant association between psoriasis and ACEI, which constitutes a potential safety signal. The risk of psoriasis is a class effect, time to onset is less than 1 year, and outcome is favorable after ACEI discontinuation. Psoriasis should be mentioned in the SmPCs of all ACEIs, and healthcare professionals should be informed about this risk.

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction.

BACKGROUND: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure. METHODS: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports. RESULTS: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92-6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature. CONCLUSIONS: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.