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 Saudi initiative for asthma - 2024 update: Guidelines for the diagnosis and management of asthma in adults and children.

The Saudi Initiative for Asthma 2024 (SINA-2024) is the sixth version of asthma guidelines for the diagnosis and management of asthma for adults and children that was developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up-to-date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA Panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5-12 years, and children aged <5 years. SINA guidelines have focused more on personalized approaches reflecting a better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

When single-inhaler triple therapy is a preferred option in asthma management?

Asthma control is the main goal of management. Unfortunately, most asthma patients with moderate-severe asthma remain uncontrolled despite receiving standard treatment of inhaled corticosteroids (ICS) with long-acting ß2 agonists (LABA). The addition of long-acting antimuscarinic agents (LAMA) has been shown to improve different aspects of asthma control, including symptoms, lung functions, and probably exacerbations. Such an option could be considered for low-T2 asthma phenotype. Umeclidinium and glycopyrronium bromide are other LAMA agents that have been recently made available in combination with ICS and LABA in single-inhaler triple therapy (SITT) devices. Here, we discuss the position of SITT as a new novel therapeutic option in asthma management and its clinical benefits, potential cost saving, and improved compliance.

Clinical and physiological characteristics of, medically treated, chronic thromboembolic pulmonary hypertension patients in Saudi Arabia: A single center experience.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is uncommon but well-known sequel of venous thromboembolism (VTE). At present, it is the only potential curable subtype of pulmonary hypertension. The aim of this study is to describe the medically treated-CTEPH patients' characteristics in a single specialized PH center in Saudi Arabia. METHODS: This study presents demographic, clinical, physiological, and hemodynamic characteristics of medically treated-CTEPH patients in a single PH center, namely Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Both incident and prevalent cases are included. RESULTS: A total of 20 patients with a confirmed diagnosis of CTEPH were included. Mean age at diagnosis was 43 years with a female preponderance of 75%. Most common presenting symptom was dyspnea (100%) followed by syncope (58%). At diagnosis, a mean of 15 ± 10 months had passed since symptoms onset. About 45% of patients were in WHO functional class IV. At baseline, mean 6-min walk distance was 354.3 meters. Overall, VTE was the most frequent risk factor identified (65% of all patients). Nearly 30% of patients had sickle cell disease. 13 out of 20 patients had radiographic (i.e., computed tomography [CT] pulmonary angiogram) features of chronic thromboembolism. About 75% of patients were found to have distal disease on radiographic imaging. At the time of diagnosis, 7 out of 20 (35%) patients demonstrated right ventricular failure on echocardiography. Mean tricuspid annular plane systolic excursion was 17.7 ± 1.20. Median NT-proBNP levels were found to be 688 pg/ml. Mean diffusing capacity for carbon monoxide was 74.8%. CONCLUSIONS: Diagnosis of CTEPH was established at a relatively younger age. Majority of patients had advanced but distal disease on radiographic imaging, not amenable to surgery.

Unmet need in the management of chronic obstructive pulmonary disease in the Middle East and Africa region: An expert panel consensus.

Chronic obstructive pulmonary disease (COPD) has a significant impact on healthcare systems and health-related quality of life. Increased prevalence of smoking is an important factor contributing to high burden of COPD in the Middle East and Africa (MEA). Several other factors including sedentary lifestyle, urbanization, second-hand smoke, air pollution, and occupational exposure are also responsible for the upsurge of COPD in the MEA. Frequent COPD exacerbations accelerate disease progression, progressively deteriorate the lung function, and negatively affect quality of life. This consensus is based on review of the published evidence, international and regional guidelines, and insights provided by the expert committee members from the MEA region. Spirometry, though the gold standard for diagnosis, is often unavailable and/or underutilized leading to underdiagnosis of COPD in primary care settings. Low adherence to the treatment guidelines and delayed use of appropriate combination therapy including triple therapy are additional barriers in management of COPD in MEA. It is necessary to recognize COPD as a screenable condition and develop easy and simple screening tools to facilitate early diagnosis. Knowledge of the disease symptomatology at patient and physician level and adherence to the international or regional guidelines are important to create awareness about harmful effects of smoking and develop national guidelines to focus on prevention on COPD. Implementation of vaccination program and pulmonary rehabilitation are equally valuable to manage patients with COPD at local and regional level. We present recommendations made by the expert panel for improved screening, diagnosis, and management of COPD in MEA.

The Saudi Initiative for Asthma - 2021 Update: Guidelines for the diagnosis and management of asthma in adults and children.

The Saudi Initiative for Asthma 2021 (SINA-2021) is the fifth version of asthma guidelines for the diagnosis and management of asthma for adults and children, which is developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5-12 years, and children aged less than 5 years. SINA guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. Medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Characteristics and outcome of viral pneumonia caused by influenza and Middle East respiratory syndrome-coronavirus infections: A 4-year experience from a tertiary care center.

BACKGROUND: After the emergence of new influenza viruses, the morbidity and mortality of viral pneumonia have received a great attention. OBJECTIVES: The objective of this study is to describe the epidemiologic, clinical and laboratory changes, and outcomes of viral pneumonia caused by influenza and the Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. METHODS: In a retrospective cohort study, the medical records of all patients diagnosed with viral pneumonia at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, during the period from January 2012 to December 2015 were screened. Cases who were > 18 years old and were confirmed by a respiratory viral panel to have viral pneumonia either MERS-CoV or influenza viruses were included in the analysis. Sociodemographic, clinical, laboratory, and outcome data were extracted from patients' medical files. The data were analyzed descriptively and inferentially to identify the predictors of poor outcome. RESULTS: A total of 448 patients with confirmed viral pneumonia were included, of those, 216 (48.2%) were caused by influenza A (non H1N1)/influenza B, 150 (33.5%) by H1N1, and 82 (18.3%) by MERS-CoV. The majority of patients presented with fever (82%), shortness of breath (64%), and flu-like symptoms (54.9%), particularly in MERS-CoV infected cases (92%). The peak incidence of viral pneumonia was in early spring and autumn. The mortality rate was 13.8%, and it was significantly higher among MERS-CoV cases. The predictors of death were age > 65 years, male gender, and associated comorbidities particularly diabetes mellitus, hypertension, and chronic kidney diseases. The number of comorbid illnesses was directly related to the increase in mortality in this group of patients. CONCLUSION: Viral pneumonia caused by influenza and MERS-CoV carries a high mortality rate, particularly among MERS-CoV infected cases. Old age, male gender, and comorbid illnesses are predictors of poor outcome. Routine testing for newly emergent viruses is warranted for adults who have been hospitalized with pneumonia.

The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children.

This is the fourth version of the updated guidelines for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is now more aligned for different age groups. The guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Pulmonary arterial hypertension in Saudi patients with systemic sclerosis: Clinical and hemodynamic characteristics and mortality.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). The objective of this study is to describe the clinical characteristics, mortality, and predictors of SSc-PAH in Saudi patients. METHODS: Retrospective chart review study of SSc patients who were followed for at least 1 year in three tertiary care centers in Saudi Arabia was conducted. Clinical information, echocardiographic findings, and right heart catheterization (RHC) results were collected. Descriptive statistics were used for demographic and disease characteristics. RESULTS: Fifty-seven patients with SSc were reviewed. PAH was confirmed by RHC in 40 patients (87.5%, females). Their mean age was 45.43 ± 13.48 years. The mean pulmonary artery pressure was 42.9 ± 12.7 mmHg, the pulmonary vascular resistance index was 19.4 ± 7.7 woods unit, and cardiac index was 2.43 ± 0.68 min/m2. The median time from symptoms to first assessment was 42.8 ± 115.62 months. Most patients (77.5%) presented with functional Class III or IV and more than half (22.55%) were on dual combination therapy. Ten patients (25%) SSc PAH died over a follow up period of 37 ± 7 months. Compared to SSc patients without PAH, SSc-PAH patients had shorter 6-min walk distance (6MWD) (296.1 ± 116.5 vs. 399.59 ± 40.60 m, P < 0.0001), higher pro-brain natriuretic peptide (1755.8 ± 2123.4 vs. 69.8 ± 44.3 pg/ml P = 0.004), and more frequent Raynaud's phenomenon (RP) (90% vs. 35%, P < 0.0001). Logistic regression showed RP (odds ratio [OR] =48.58, 95% confidence interval [CI]; 3.73-633.10) and 6MWD (OR 1.02: 95% CI; 1.01-1.03) were associated with the development of PAH. CONCLUSION: Our cohort of Saudi SSc-PAH patients has a younger disease onset and a lower mortality than what is described worldwide despite late presentation and requirement of combination therapy. The presence of RP and lower were associated with the development of SSc-PAH.

Knowledge, attitudes, and practice behavior of dental hygienists regarding the impact of systemic diseases on oral health.

OBJECTIVES: To assess the knowledge levels of dental hygienists in Saudi Arabia regarding the association between systemic and oral disease in addition to evaluating their attitude about integrating this knowledge into clinical practice. Methods: This was a cross-sectional survey using a questionnaire of 102 items among 192 randomly selected dental hygienists practicing in Riyadh, Saudi Arabia by individual interview. The research tool was pilot tested among 12 dental hygienists (8 females and 4 males) to obtain feedback about clarity and objectivity. Results: The response rate was 83%, and the majority of respondents were female (77.5%). The respondents' knowledge about the risk factors of cardiovascular diseases was better than other conditions. The level of education was considered to be a significant predictor in many items related to risk factors. More than the half, rated the evidence linking periodontal disease and diabetes mellitus as strong; however, the knowledge level of oral-systemic evidence was less than expected. A high percentage of the respondents were confident and comfortable managing patients with systemic conditions. Most agreed that dental hygienists must be prepared efficiently to manage medically compromised patients. Conclusion: Dental hygienists in Riyadh, Saudi Arabia have low level of knowledge about the oral-systemic disease relationship. This study suggests that greater emphasis should be placed on this association in current and continuing education programs.

The Saudi Initiative for Asthma - 2016 update: Guidelines for the diagnosis and management of asthma in adults and children.

This is an updated guideline for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of SINA is to have guidelines that are up to date, simple to understand and easy to use by nonasthma specialists, including primary care and general practice physicians. SINA approach is mainly based on symptom control and assessment of risk as it is the ultimate goal of treatment. The new SINA guidelines include updates of acute and chronic asthma management, with more emphasis on the use of asthma control in the management of asthma in adults and children, inclusion of a new medication appendix, and keeping consistency on the management at different age groups. The section on asthma in children is rewritten and expanded where the approach is stratified based on the age. The guidelines are constructed based on the available evidence, local literature, and the current situation in Saudi Arabia. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

The Saudi Thoracic Society guidelines for influenza vaccinations.

Influenza viruses are responsible for the influenza outbreaks that lead to significant burden and cause significant morbidity and mortality worldwide. Based on the core proteins, influenza viruses are classified into three types, A, B, and C, of which only A and B cause significant human disease and so the vaccine is directed against these two subtypes only. The effectiveness of the vaccine depends on boosting the immune system against the serotypes included within it. As influenza viruses undergo periodic changes in their antigen, the vaccine is modified annually to ensure susceptibility. In contrast to other countries, Saudi Arabia faces a unique and challenging situation due to Hajj and Umrah seasons, when millions of people gather at the holy places in Mecca and Madinah, during which influenza outbreaks are commonly found. Such challenges making the adoption of strict vaccination strategy in Saudi Arabia is of great importance. All efforts were made to develop this guideline in an easy-to-read form, making it very handy and easy to use by health care workers. The guideline was designed to provide recommendations for problems frequently encountered in real life, with special consideration for special situations such as Hajj and Umrah seasons and pregnancy.

Prevalence and severity of plaque-induced gingivitis in a Saudi adult population.

OBJECTIVES: To evaluate the prevalence and severity of plaque-induced gingivitis among a Saudi adult population in Riyadh region. METHODS: Three hundred and eighty-five eligible participants in this cross-sectional study were recruited from routine dental patients attending the oral diagnosis clinic at Al-Farabi College in Riyadh, Saudi Arabia from June 2013 to December 2013. A clinical examination was performed by 2 dentists to measure the gingival and plaque indices of Löe and Silness for each participant. RESULTS: The prevalence of gingivitis was 100% among adult subjects aged between 18-40 years old. Moreover, the mean gingival index was 1.68±0.31, which indicates a moderate gingival inflammation. In fact, males showed more severe signs of gingival inflammation compared with females (p=0.001). In addition, the mean plaque index was 0.875±0.49, which indicates a good plaque status of the participants. Interestingly, the age was not related either to the gingival inflammation (p=0.13), or to the amount of plaque accumulation (p=0.17). However, males were more affected than females (p=0.005). CONCLUSION: The results of this study show that plaque accumulation is strongly associated with high prevalence of moderate to severe gingivitis among Saudi subjects. 

Complete resolution of chronic pericardial effusion with an intensive course of inhaled iloprost in an adult patient with unrepaired ventricular septal defect, and life-threatening severe pulmonary arterial hypertension.

A 38-year-old male was diagnosed with unrepaired ventricular septal defect associated with severe pulmonary arterial hypertension, cyanosis, and significant exercise intolerance. His echocardiogram showed right ventricular dysfunction and moderate pericardial effusion with no signs of cardiac tamponade. He was treated with an intensive course of inhaled iloprost and sildenafil. He showed a dramatic clinical response; his saturation went up from 60% on admission to 90% on minimal oxygen with significant improvement in his symptoms and signs of heart failure and total resolution of pericardial effusion. On follow up 3 and 6 weeks later, he was stable and could walk 360 meters in a 6 minutes walk test with disappearance of pericardial effusion. With unavailability of intravenous prostacyclin, we have shown in this case that intensive administration of inhaled iloprost could be used intensively as a rescue therapy in severe cases of pulmonary arterial hypertension with excellent results. 

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pregnancy in pulmonary hypertension.

Pregnancy in pulmonary hypertension (PH) is known to be associated with high morbidity and mortality. The physiological changes occur during normal pregnancy, such as increase blood volume and cardiac output (CO) may be detrimental in PH patients. Several practice guidelines advise against pregnancy and even recommend termination of pregnancy. Occasionally PH may be diagnosed for the first time during pregnancy, as stress of pregnancy can unmask previously undiagnosed PH in an asymptomatic individual. This narrative review provides a detailed discussion about the physiologic parameters associated in pregnancy and their negative effect on the right ventricle. It also gives practical evidence-based recommendations about different management issues in PH pregnant patients.

Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates.

The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008.[1] That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face. All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Challenges in managing pulmonary hypertension in the developing countries.

There is scant published data about pulmonary hypertension (PH) from the developing countries. True prevalence of the disease, its biology, etiology and response to treatment are not well known, and they are likely to be somewhat different from that of the developed countries. In this review, we will discuss the main challenges for managing PH in developing countries and propose real-life recommendations to deal with such difficulties.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Portopulmonary hypertension.

Portopulmonary hypertension (POPH) is defined as pulmonary arterial hypertension (PAH) complicated by portal hypertension, with or without advanced hepatic disease. Significant percentage of patients with cirrhotic liver disease has high cardiac output and subsequently elevated pulmonary arterial pressures (PAP). However, patients with POPH develop a progressive increase in pulmonary vascular resistance (PVR), which is generally lower than that observed in other forms of PAH. The prognosis of untreated patients with POPH is very poor and the outcome of liver transplant (LT) in those patients is determined by the degree of severity of the associated pulmonary hemodynamics. In this narrative review, we describe the clinical presentation of POPH, the pathobiology, and the clinical implication of pulmonary hemodynamics. We also provide evidence-based recommendations for the diagnosic and management approaches of POPH.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension due to left heart disease.

Pulmonary hypertension (PH) due to left heart disease is the most common cause of pulmonary hypertension in the western world. It is classified as WHO PH group II. Different pathophysiologic abnormalities may take place in this condition, including pulmonary venous congestion and vascular remodeling. Despite the high prevalence of WHO group 2 PH, the major focus of research on PH over the past decade has been on WHO group 1 pulmonary arterial hypertension (PAH). Few investigators have focused on WHO group 2 PH; consequently, the pathophysiology of this condition remains poorly understood, and no specific therapy is available. Clinical and translational studies in this area are much needed and have the potential to positively affect large numbers of patients. In this review, we provide a detailed discussion upon the pathophysiology of the disease, the recent updates in classification, and the diagnostic and therapeutic algorithms.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension due to lung diseases and/or hypoxia.

Chronic lung diseases are common causes of pulmonary hypertension. It ranks second after the left heart disease. Both obstructive and restrictive lung diseases are know to cause pulmonary hypertension. The pathophysiology of the disease is complex, and includes factors affecting the blood vessels, airways, and lung parenchyma. Hypoxia and the inhalation of toxic materials are another contributing factors. Recent guidelines have further clarified the association between pulmonary hypertension and chronic lung disease and made general guidelines concerning the diagnosis and management. In this article, we will provide a detailed revision about the new classification and give general recommendations about the management of pulmonary hypertension in chronic lung diseases.