Adverse drug effect in the context of drug shortage: the CIRUPT prospective study from the French pharmacovigilance network.

OBJECTIVES: Drug shortages are of increasing concern to worldwide public health. The consequences of drug shortages for patient safety have been little studied, especially from a pharmacovigilance point of view. In this context, the network of French pharmacovigilance centres conducted the CIRUPT study (Conséquences Iatrogènes des RUPTures de stock/iatrogenic consequences of drug shortages) based on a prospective campaign of adverse effects occurring in the context of drug shortage notifications. METHODS: All notifications involving a shortage drug submitted to the French pharmacovigilance centres between 1 January 2020 and 30 June 2021 were collected and registered in the French national pharmacovigilance database with the standardised high level term 'product supply and availability issues' and with predefined keywords in the narrative section. RESULTS: 224 cases were included, involving mainly adverse drug reactions (ADRs) (n=131/224, 59%) and medication errors (n=51/224, 23%); 29% of the cases were serious. The most represented classes of shortage drugs were: vaccines (n=78/224, 35%); drugs for acid-related disorders (H2-receptor antagonists) (n=27/224, 12%); antineoplastic agents (n=17/224, 8%); and antiepileptics (n=15/224, 7%). In 82% of cases, the involved shortage drug was the subject of information delivered to health professionals by the National Agency for the Safety of Medicines and Health Products. Drug shortages were associated with an ADR related to replacement drugs in 59% (n=131/224) of the cases, drug inefficacy in 18% (n=41/224), and/or an aggravation of the underlying disease in 11% (n=25/224). CONCLUSIONS: From a pharmacovigilance point of view, a large diversity of anatomical therapeutic classes is involved and the risk related to drug shortages is not limited to drugs registered on 'major therapeutic interest or essential drug' lists. Information from health agencies is not sufficient to avoid the risks, and further strategies should be developed.

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.

Successful control of hidradenitis suppurativa with verapamil: a case report.

An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF-α inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39-year-old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF-α and IL-1ß in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF-α/IL-1 pathway involved in the HS physiopathology. Compared to biologic agents as anti-TNF-α (adalimumab) and anti-IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF-α/IL-1, verapamil may represent an alternative therapeutic option in mild and moderate HS.

Parachuting psychoactive substances: Pharmacokinetic clues for harm reduction.

BACKGROUND: Parachuting, also called bombing, is a way to ingest psychoactive substances wrapped into cigarette paper, toilet paper, etc. There is little data describing parachuting in terms of substances use, context of use and, most importantly, the motivations for using such wrappers, although some authors hypothesized that parachute could be used for pharmacokinetic reason. However, inconsistently, some authors report that parachutes are used for sustained-release whereas others report that users are looking for an immediate effect. RESEARCH DESIGN AND METHODS: Considering parachute as a "home-made" dosage form, we have applied the dissolution testing to characterize the dissolution performance of a substance wrapped into a parachute and to characterize whether a parachute represents an immediate-release form or not. RESULTS: This in-vitro study provides the first pharmacokinetic data for drugs wrapped in parachutes. It shows that parachute acts as sustained-release form when made with a cigarette paper wrapper, but as immediate release form in the presence of alcohol or if wrapped with toilet paper. CONCLUSIONS: An important message to harm reduction is that users must be aware that a parachute can have unexpected pharmacokinetics and have to avoid taking another parachute in the absence of an immediate-effect to avoid overdose.

Safety profile of etifoxine: A French pharmacovigilance survey.

Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine-related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs. Etifoxine-related ICSRs were extracted from the French Pharmacovigilance database from 1 January 2000 to 30 April 2012 and data from the marketing authorization holder up to 31 December 2011 were also obtained. Of the 350 cases retained for analysis, 123 (35%) were considered serious. Dermatological or acute hypersensitivity reactions were the most frequent ADRs (59%) mainly isolated cutaneous eruptions. However, there were 24 cases of severe toxidermia (DRESS in 5, erythema multiforme in 10 and Stevens-Johnson syndrome in 5) with etifoxine as the most suspected drug in 11 patients, and seven cases of vasculitis or serum sickness-like reaction. Liver disorders were reported in 34 patients of whom 25 developed acute hepatitis with a cytolytic biological pattern in 16. Other unexpected ADRs included 16 reversible cases of metrorrhagia with positive rechallenge in 5, and three cases of biopsy-proven microscopic colitis of which one recurred after etifoxine re-administration. Although etifoxine has been marketed for more than 30 years, this survey identified a number of unexpected and sometimes serious ADRs, in particularly severe toxidermia and acute cytolytic hepatitis. A recent update of the French etifoxine summary of the product characteristics (SPC) was based on these findings.

Illicit drugs or medicines taken by parachuting.

Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty-five cases of parachute use were identified and most (n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4-methylenedioxymethamphetamine (MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs.