Generic orphan drug substitution: a critical analysis of global practices and Saudi Arabia's perspective.

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

Real-world Experience in Managing Atrial Fibrillation in Patients with Renal Impairment; Rivaroxaban versus Warfarin.

Background: The use of rivaroxaban in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) poses the risk of over- or underdosing. We aimed to compare rivaroxaban and warfarin in AF patients with moderate and severe renal impairment. Methods: This retrospective study was conducted between 2015 and 2016 to compare the use of warfarin (n = 164) and rivaroxaban (n = 149) in patients with AF and moderate or severe CKD. The study outcomes were survival, stroke, and major bleeding events. The median follow-up was 50 months (interquartile range: 23-60). Results: Thirty-six patients had major bleeding: 24 with rivaroxaban and 12 with warfarin (P = 0.01). The rivaroxaban group had major bleeding in 3 patients with moderate CKD, 4 with severe CKD, and 17 on dialysis. Multivariable analysis of factors affecting major bleeding revealed that warfarin use lowered the risk of bleeding (hazard ratio: 0.34; P = 0.004). Stroke occurred in 14 patients: 6 in the rivaroxaban group and 8 in the warfarin group (P = 0.44). Survival at 1, 3, and 5 years was 89%, 77%, and 71% with warfarin and 99%, 94%, and 88% with rivaroxaban, respectively (P < 0.001). Multivariable analysis showed higher mortality in patients with lower creatinine clearance and those on warfarin. Conclusions: The safety of warfarin could be better than rivaroxaban in patients with CKD with fewer bleeding complications but similar stroke rates. Further studies on rivaroxaban dosing in patients on dialysis are required.

Better Survival in Morbidly Obese Patients with Atrial Fibrillation Treated with Non-vitamin K-dependent Oral Anticoagulants.

Background: The efficacy and safety of non-vitamin K-dependent anticoagulants (NOAC) are not well investigated in the obese population, and fixed dosing could lead to under-anticoagulation. Our objective was to evaluate the effect of obesity on anticoagulation outcomes and survival in non-valvular atrial fibrillation (AF) patients. Methods: We enrolled 755 patients who required anticoagulation for AF from 2015 to 2016. We grouped the patients into four groups. Group 1 (n = 297) included patients with BMI< 40 kg/m2 treated with NOACs, Group 2 (n = 358) included patients on warfarin with BMI< 40 kg/m2, Group 3 (n = 57) had patients on NOACs with BMI≥ 40 kg/m2 and Group 4 (n = 43) included patients on warfarin and BMI≥ 40 kg/m2. Study outcomes were the composite endpoint of stroke, bleeding, and survival. Results: Competing risk regression showed that stroke and bleeding were not affected by obesity or treatment (SHR: 1.09 (95% CI: 0.79-1.51); P = 0.62). Older age was the predictor of stroke/bleeding (HR:1.03 (95% CI:1.01-1.06); P = 0.02). Predictors of mortality were heart failure (HR:2.23 (95% CI:1.25-3.97); P = 0.007), lower creatinine clearance (HR: 0.98 (95% CI:0.97-0.98): P < 0.001), non-obese patients on warfarin (HR:3.51 (95%CI:1.6-7.7): P = 0.002) and obese patients on warfarin (HR: 6.7 (95% CI:2.51-17.92); P < 0.001). Conclusion: NOACs could have a similar risk profile to warfarin in obese and non-obese patients with non-valvular AF but could have better survival. Larger randomized trials are recommended.

Impact of Smoking Status and Nicotine Dependence on Academic Performance of Health Sciences Students.

Background: Smoking behavior has been associated with poor academic performance among adult students worldwide. However, the detrimental effect of nicotine dependence on several students' academic achievement indicators is still unclear. This study aims to assess the impact of smoking status and nicotine dependence on grade point average (GPA), absenteeism rate and academic warnings among undergraduate health sciences students in Saudi Arabia. Methods: A validated cross-sectional survey was conducted, in which, participants responded to questions evaluated cigarette consumption, urge to consume and dependency, learning performance, days of absentees, and academic warnings. Results: A total of 501 students from different health specialties have completed the survey. Of whom, 66% were male, 95% ranging between the age of 18-30 years old, and 81% reported no health issues or chronic diseases. Current smokers estimated to be 30% of the respondents, of which 36% revealed smoking history of 2-3 years. The prevalence of nicotine dependency (high to extremely high) was 50%. Overall, smokers had significantly lower GPA, higher absenteeism rate, and higher number of academic warnings when compared to nonsmokers (p<0.001). Heavy smokers demonstrated significantly less GPA (p=0.036), higher days of absences (p=0.017), and more academic warnings (p=0.021) compared to light smokers. The linear regression model indicated a significant association between smoking history (increased pack-per-year) and poor GPA (p=0.01) and increased number of academic warning last semester (p=0.01), while increased cigarette consumption was substantially linked with higher academic warnings (p=0.002), lower GPA (p=0.01), and higher absenteeism rate for last semester (p=0.01). Conclusion: Smoking status and nicotine dependence were predictive of worsening academic performance, including lower GPA, higher absenteeism rate and academic warnings. In addition, there is a substantial and unfavorable dose-response association between smoking history and cigarette consumption with impaired academic performance indicators.

Time in therapeutic range for virtual anticoagulation clinic versus in-person clinic during the COVID-19 pandemic: a crossover study.

BACKGROUND: COVID-19 infection affects the quality of the medical services globally. The pandemic required changes to medical services in several institutions. We established a virtual clinic for anticoagulation management during the pandemic using the Whatsapp application. OBJECTIVES: Compare anticoagulation management quality in virtual versus in-person clinics. DESIGN: A retrospective crossover study SETTINGS: Specialized cardiac care center PATIENTS AND METHODS: The study included patients who presented to Prince Sultan Cardiac Center in Riyadh for anticoagulation management during the pandemic from March 2020 to January 2021. We compared time in therapeutic range (TTR) in the same patients during virtual and in-person clinics. All international normalized ratio (INR) measures during the virtual clinic visits and prior ten INR measures from the in-person clinic were recorded. Patients who had no prior follow-up in the in-person clinic were excluded. MAIN OUTCOME MEASURE: TTR calculated using the Rosendaal method. SAMPLE SIZE: 192 patients RESULTS: The mean age was 58.6 (16.6) years and 116 (60.4%) were males. Patients were diagnosed with atrial fibrillation (n=101, 52.6%), mechanical mitral valve (n=88, 45.8%), mechanical aortic valve (n=79, 41%), left ventricular thrombus (n=5, 2.6%) and venous thromboembolism (n=8, 4.2%). Riyadh residents represented 56.7% of the study population (n=93). The median (IQR) percent TTR was 54.6 (27.3) in the in-person clinic versus 50.0 (33.3) (P=.07). CONCLUSION: Virtual clinic results were comparable to in-person clinics for anticoagulation management during the COVID-19 pandemic. LIMITATIONS: Number of INR measures during the virtual clinic visits, retrospective nature and single-center experience. CONFLICT OF INTEREST: None.

Antithrombotic Therapy for Transcatheter Valvular Interventions: A Revisit.

BACKGROUND: The optimal antithrombotic therapies for transcatheter aortic valve implantation (TAVI) and MitraClip implantation have not been well established. We conducted a narrative review from currently available studies between January 2002 and May 2016 to highlight the advantages and disadvantages of antithrombotic therapy use in cardiac catheter-based therapeutic techniques. Recently, these techniques have dramatically altered the approach towards valvular heart diseases management. The introduction into clinical practice, of TAVI for severe aortic stenosis and MitraClip for mitral regurgitation, has revolutionized interventional cardiology. However, TAVI is associated with a risk of cerebral embolization and ischaemic vascular events leading to neurological impairment and even death. These ischaemic complications might occur perioperatively or much later, although the estimated rate of occurrence is variable. CONCLUSION: We will discuss prior experience with MitraClip for antithrombotic use. It is imperative for patients undergoing transcatheter valvular interventions to have optimal antithrombotic therapy that balances between ischaemic and haemorrhagic complications. The appropriate timing, combination, and duration of antithrombotic medications need consensus to weigh between the efficacy, efficiency and adverse effects in patients with transcatheter valvular interventions.

Recurrent syndrome of inappropriate antidiuretic hormone secretion due to tolterodine in an elderly male patient.

Hyponatremia is defined as serum sodium of <135 mmol/L and equates with a low serum osmolality once translocational hyponatremia and pseudohyponatremia are ruled out. True hyponatremia develops when normal urine-diluting mechanisms are disturbed. In elderly patients, this complication is not uncommon, especially in nursing homes and assisted living facilities. Medications are often the most common cause of hyponatremia in these patients. Herewith, we reported a 65-year-old Saudi male, a known case of benign prostatic hypertrophy and hypertension, who developed recurrent hyponatremia secondary to tolterodine. To our knowledge, this is the fifth case reported in literature of such association.