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.

The impact of child-specific characteristics on warfarin dosing requirements.

Background: The influence of child characteristics on warfarin dosing has been reported; however, there is no consensus on the nature and extent of this effect. Objectives: To investigate the impacts of the demographic and clinical characteristics of children on the warfarin dose required to achieve a therapeutic international normalization ratio (INR). Methods: This retrospective cohort study included children aged 3 months to 14 years old who were prescribed warfarin for 3 months or longer with a "stable INR." The primary outcome was the total daily dose (TDD) and total weekly dose of warfarin required to achieve a therapeutic INR target. Results: We included 127 patients with a mean age of 7.7 ± 3.7 years and a median weight of 22 (IQR, 16-33) kg. Of the sample, 55 patients (43.3%) required a TDD of ≤0.1 mg/kg. The TDD for children younger than 5 years, 5 to 10 years, and older than 10 years were 0.14 ± 0.06 mg/kg, 0.12 ± 0.05 mg/kg, and 0.096 ± 0.04 mg/kg, respectively (P = .002). Overweight and obese children required a smaller TDD than normal-weight children: 0.09 ± 0.05 vs 0.13 ± 0.05 mg/kg (P = .004), which was similar for underweight children. A lower body surface area (<0.5 m2) required a higher dose. All the other variables did not affect warfarin doses. The incidence of a subtherapeutic or supratherapeutic INR was independent of demographic or clinical variables. Conclusion: The study confirmed that the patient demographics affect the daily warfarin dose required to achieve the INR target. However, they do not have any predictive value for the incidence of out-of-range-INR.

Vancomycin dosing required to achieve a therapeutic level in children post-surgical correction of congenital heart disease.

The vancomycin dosing range for safe and effective treatment remains uncertain for children who had corrective surgery for a congenital heart disease (CHD). We aimed to determine the vancomycin dosing requirements for this subgroup of patients. This prospective cohort study included children younger than 14 years old with CHD who received intravenous vancomycin for at least 3 days at the Pediatric Cardiology section of King Abdulaziz Medical City, Riyadh. In total, 140 pediatric patients with CHD were included with a median age of 0.57 years (interquartile range 0.21-2.2). The mean vancomycin total daily dose (TDD), 37.71 ±â€…6.8 mg/kg/day, was required to achieve a therapeutic trough concentration of 7-20 mg/L. The patient's age group and the care setting were significant predictors of the vancomycin dosing needs. Neonates required significantly lower doses of 34 ±â€…6.03 mg/kg/day (P = .002), and young children higher doses of 43.97 ±â€…9.4 mg/kg/day (P = .003). The dosage requirements were independent of the type of cardiac lesion, cardiopulmonary surgery exposure, sex, and BMI percentile. However, the patients in the pediatric cardiac ward required higher doses of vancomycin 41.08 ±â€…7.06 mg/kg/day (P = .039). After the treatment, 11 (8.5%) patients had an elevated Scr, and 3 (2.3%) patients developed AKI; however, none of the patients' sociodemographic factors or clinical variables, or vancomycin therapy characteristics was significantly associated with the renal dysfunction. Overall, the vancomycin TDD requirements are lower in pediatric post-cardiac surgery compared to non-cardiac patients and are modulated by several factors.

Vasopressin associated hyponatremia in critically ill children: A cross-sectional study.

Background: The association of hyponatremia with vasopressin therapy in children is controversial. We aimed to evaluate the incidence and severity of hyponatremia associated with the administration of vasopressin in critically ill pediatric patients. Methods: This retrospective cross-sectional study included children younger than 14 years who were admitted to the pediatric or pediatric cardiac intensive care units and received vasopressin for at least 24 h. Results: In total, 176 critically ill pediatric patients were enrolled, with a median age of 22 days (7.3-146). The mean sodium level was notably decreased from 143.5 mEq/L ± 7.15 at the baseline to 134.3 mEq/L ± 7.7 at the 72-hour measurement after the initiation of vasopressin and varied significantly at all intervals from the baseline measurement (P < 0.001). Twenty-four hours after the discontinuation of vasopressin, more than half of the patients had hyponatremia. The highest proportion had mild hyponatremia (32.8%), followed by moderate hyponatremia (13.1%), and profound hyponatremia (7.5%). The incidence of hyponatremia was independent of gender (P = 0.94) or age group (P = 0.087). However, more than two-thirds of the moderate-profound cases and more than one-third of mild cases were observed in the neonate group (P = 0.043). The vasopressin dose did not affect the incidence (P = 0.25) or the severity of the hyponatremia (P = 0.56). Notably, all laboratory and hemodynamic parameters varied significantly at the end of therapy, compared to the baseline. Conclusions: Continuous monitoring for hyponatremia when children are placed on vasopressin is essential to protect against more severe complications.

An assessment of asthma exacerbations in pediatric patients using a long-acting B2-agonist plus inhaled corticosteroid versus an inhaled corticosteroid alone.

Background: An asthma exacerbation is an anticipated sudden worsening of the disease severity, which usually does not respond to conservative therapy. The management of asthma depends on the severity of the disease symptoms, which includes an inhaled corticosteroid (ICS) and a bronchodilator. This study aimed to assess the efficacy of combining a long-acting B2-agonist (LABA) with ICS, compared to ICS alone, to reduce the incidence of asthma exacerbations in pediatric patients, diagnosed with severe persistent asthma. Methods: A retrospective analysis of the medical records was conducted for 586 children, admitted to the Emergency Department (ED) at King Abdullah Specialized Children Hospital in Riyadh, Saudi Arabia, for the management of severe persistent asthma symptoms, from January 2016 to September 2019. Results: The majority (n = 480, 81.9%) of the patients received fluticasone (Flovent)® as the standard of care ICS treatment for controlling asthma, and a small proportion (n = 106, 18.1%) were treated with a combination of LABA and ICS. A significant increase in the frequency of recurrent asthma exacerbation episodes occurred in the group receiving ICS alone (98.5%), compared to 67.0% in the combination group (p < 0.0001). Moderate to severe exacerbations were significantly higher in the ICS group compared to the combination group (95.6% versus 84.5%, respectively, p = 0.0005). Conclusions: The current results confirm the substantial efficacy of the LABA/ICS combination therapy in reducing the incidence and severity of asthma exacerbations in pediatric patients, compared to ICS alone.

The effects of the antecedent use of inhaled steroid on the clinical course of COVID-19: A retrospective study of asthmatic patients.

BACKGROUND: There is conflicting evidence regarding the effect of asthma and its different therapeutic options on COVID-19 severity and the clinical outcomes. AIM: This study aimed to investigate the relationship between using inhaled corticosteroids (ICS) by asthmatic patients and the severity of COVID-19. MATERIALS AND METHODS: This retrospective observational study was conducted from March 15 to October 23, 2020 and included data of all COVID-19 asthmatic patients (n = 287) at King Abdulaziz Medical City. Twelve patients were excluded due to poor medication history documentation or using ICS for non-asthma indication. Ordinal logistic regression was used to determine the clinical variables that affect COVID-19 severity. The clinical outcomes of ICS and non-ICS users were compared. RESULTS: Of the sample (n = 275), 198 (72%) were using ICS therapy. No significant difference was found between ICS and non-ICS users in disease severity (P = 0.12), mortality (P = 0.45), ICU admission (P = 0.78), and the occurrence of complications. However, the number of days on ventilation were significantly increased in ICS users (P = 0.006). Being prescribed the ICS/LABA combination (adj OR: 0.72 [0.15,1.2]; P = 0.021), being hypertensive (adj OR: 0.98 [0.28,1.6]; P = 0.006), having cancer (adj OR: 1.49 [0.12, 2.8]; P = 0.033), or having diabetes (adj OR: 0.75 [0.09, 1.4]; P = 0.024) could not increase the risk for more severe disease. CONCLUSION: Overall, ICS therapy did not alter the COVID-19 severity or mortality in asthmatic patients. The continued use of ICS during the pandemic should be encouraged to prevent asthma exacerbations.

Parenteral versus enteral nutrition in children with post-surgical congenital heart disease.

OBJECTIVE: The association of malnutrition with congenital heart disease (CHD) is well documented. Studies comparing the effects of parenteral nutrition (PN) and enteral feeding (EF) on the post-surgical correction of CHD are not available. We compared the effects of PN with EF on the nutritional status of children post-cardiac surgery. METHODS: A retrospective cohort study was conducted with 72 children aged ≤6 years who had at least one heart surgery between 2010 and 2016. Malnutrition was defined as a weight for height Z-score (WHZ) below -2. The primary endpoint was the change in the mean WHZ Z-score from the baseline. All statistical analyses were performed using SPSS 21.0 [Release 21.0.0.0, IBM, USA]. RESULTS: The sample size realized as 72 (n = 72). The overall prevalence of malnutrition was 48%. The change in height of the PN group was significantly higher than the EF group (14.2 ± 7.6 cm vs. 7.4 ± 6.3, P = 0.010), but the weight change was not significantly different (P = 0.28). The post-surgery Z-scores were significantly lower in the PN group and the Z-score change was marginally smaller (P = 0.086), indicating lower growth levels post-surgery. The PN group had a significantly higher incidence of post-surgical malnutrition (P = 0.046). Patients who received PN had significantly less improvement (more negative change) in the Z-score levels compared to the EF group (PE = -1.42, 95% confidence interval [CI] = [-2.48, -0.35]; P = 0.011). CONCLUSION: Malnutrition occurs frequently with CHD. PN does not add any nutritional benefits compared with EF. EF should always be the preferred method of nutrition unless contraindicated.