Suitability of APINCH high-risk medications use in diabetes mellitus

European Journal of Pharmacology 867 (2020) 172845

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Suitability of APINCH high-risk medications use in diabetes mellitus Mohammad Ishraq Zafar a b

T

a,b

Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hang Kong Street, 430030, Wuhan, PR China Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, PR China

A R T I C LE I N FO

A B S T R A C T

Keywords: High-risk medication Drug safety Diabetes APINCH

High-risk medicines are those that carry a high risk of causing fatal or serious injury if used in error. The globally used Institute for Safe Medication Practices's list of high-risk medicines refers to the general population without taking into account special populations, such as diabetic. By means of the literature search, the current review identified several medicines that were previously not included, and have the potential to cause harm to diabetes patients when used inappropriately, including fluoroquinolones, targeted cancer therapies, and tramadol. Additionally, this review identified risks that the included medicines may carry for diabetes patients, such as interactions between warfarin and sulfonylureas that may cause severe hypoglycemia or potentiation of gastrointestinal side effects with co-administration of opioids and various hypoglycemics. The proposed inclusions and respective recommendations are to be taken into consideration in diabetes care and help with the creation of high-risk medicine lists adapted to diabetes patients on an individual hospital level.

1. Introduction

solutions (peritoneal and hemodialysis) epidural or intrathecal medications, antidiabetic agents (oral), inotropic medications (IV), neuromuscular blocking agents, parenteral nutrition preparations, radiocontrast agents (IV), and sterile water for injection, inhalation, and irrigation in containers of 100 mL or more (Institute for Safe Medication Practices , 2014). The APINCH list is most widely used in the United States, Canada, and Australia whereas other regions have their own high-risk medication lists such as one of the UK National Patient Safety Agency (NPSA) (UK National Patient Safety Agency, 2011). While the authors of all lists encourage the hospitals to modify the lists according to their everyday practice and the population treated, neither APINCH nor other high-risk medication lists take into account special patient populations such as diabetes mellitus (DM) population (UK National Patient Safety Agency, 2011). Overall, the use of pharmacological agents in DM patients may lead to harmful effects due to several reasons: 1) pharmacokinetic alterations resulting from DM and associated hepatic/renal impairment, 2) polypharmacy, 3) increased number of comorbidities, 4) electrolyte disturbances associated with DM, and 5) prolonged hospitalizations (Breuker et al., 2017). Furthermore, mainly due to polypharmacy and comorbidities, diabetes patients suffer medication errors (ME) more frequently than their non-diabetes counterparts, both in inpatient and outpatient settings (Breuker et al., 2017). Recently, Caughey et al. (2017) found that one-third of hospitalized diabetes patients had at least one treatment conflict defined as the use of a drug that may affect blood glucose levels.

The use of so-called high-risk medicines represents the key medication safety priority worldwide (World Health Organization, 2011). According to the definition of the Institute for Safe Medication Practices (ISMP) from 2012, high-risk medicines are those with a heightened risk of causing significant harm or death when used in error (Institute for Safe Medication Practices, 2014). Although errors with these medicines may not be more common than with other drugs, patient harms associated with them may be more severe. Factors that increase the highrisk medicines' potential for harm include: 1) a narrow therapeutic index, 2) complex dosing and monitoring, 3) clinically significant interactions with other medicines, herbals, and food, 4) availability in multiple forms and strengths, especially the concentrated ones, 5) lookalike and sound-alike naming, and packaging, 6) patient-controlled dosing (Institute for Healthcare Improvement, 2012). On the basis of error reports submitted to the ISMP National Medication Errors Reporting Program (NMERP), reports of errors identified in the literature, and input from practitioners, ISMP has created a list of potential highalert medicines in acute care settings which includes 22 classes/categories of medicines, highlighting 6 core categories that every hospital's list should include: antimicrobials, potassium and other electrolytes, insulin, narcotics and other sedatives, chemotherapy, heparin, and other anticoagulants/antithrombotics – APINCH list. Additionally, the exhaustive ISMP's list includes adrenergic agonists and antagonists (IV), antiarrhythmics (IV), cardioplegic solutions, dextrose (≥20%), dialysis

E-mail address: [email protected]. https://doi.org/10.1016/j.ejphar.2019.172845 Received 31 August 2019; Received in revised form 15 November 2019; Accepted 3 December 2019 Available online 05 December 2019 0014-2999/ © 2019 Elsevier B.V. All rights reserved.

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Table 1 APINCH list - drug categories and drugs included with the most frequently observed risks and potential harms to the patient. Drug category

Drug name/subcategory

Associated risk

Harm to the patient

A/Antimicrobials

Amphotericin

Confusion between the formulations of amphotericin

Vancomycin

Incorrect dosing with respect to age, weight and renal function Lack of monitoring of serum levels in all patients expected to receive therapy for more than 72 h Rapid administration (rate > 10 mg/min) Incorrect dosing with respect to age, weight and renal function Lack of monitoring of serum levels in all patients expected to receive therapy for more than 72 h Rapid administration/use of an excessively strong solution *K-chloride: > 10 mEq/h or 200 mEq for a 24-h *K-phosphate: > 15 mmol phosphate/h (i.e. K+ > 22.5 mEq/h) *Na-chloride, hypertonic: > 100 mL/h or 400 mL/24 h *Magnesium sulfate: > 1.5 ml/min of a 10% solution or its equivalent for Mg2+ deficiency or a loading dose > 5 g MgSO4 (20 mmol Mg2+) for prevention of seizures associated with eclampsia Selection of the wrong ampoule (e.g. potassium chloride ampoules mistaken for ampoules of sodium chloride 0.9% when reconstituting a drug for injection or potassium chloride ampoule mistaken for a local anesthetic) Incorrect preparation of an intravenous infusion (e.g. high concentration potassium solutions given as a direct push injection) Mix-ups because of sound-a-like names (e.g. Humalog and Humulin) Mix-ups because of look-a-like prescriptions (e.g. insulin and heparin ordered in units) Incorrect dosing

Overdosing: dose-dependent adverse effects (e.g. GIT side effects, renal toxicity) or underdosing: lack of therapeutic effect Overdosing: dose-dependent adverse effects (e.g. ototoxicity) or underdosing: lack of therapeutic effect Increased serum concentrations leading to toxicity or subtherapeutic serum concentrations and development of vancomycin resistance “Red-man's" syndrome and hemodynamic changes Dose-dependent adverse effects (e.g. ototoxicity) or lack of therapeutic effect Increased serum concentrations leading to toxicity or subtherapeutic serum concentrations and development of vancomycin resistance

Aminoglycosides

P/Potassium and other electrolytes

I/Insulin

Potassium chloride and phosphate (IV) Sodium chloride for injection, > 0.9% (IV) Magnesium sulfate (IV)

All insulins (SC and IV)

Incorrect IV infusion rate

N/Narcotics and other sedatives

C/Chemotherapeutic agents

Fentanyl Alfentanil Remifentanil Hydromorphone Morphine Oxycodone (PO, TD, IV) Diazepam, Midazolam Thiopentone Propofol and other short-term anesthetics (inhaled and IV)

Cytotoxic drugs (PO and IV)

Incorrect administration in regard to meals Incorrect dosing Incorrect IV infusion rate Interactions with other medicinal and herbal products and environmental factors Anti-emetics and laxatives not prescribed when appropriate Lack of monitoring in patients parallelly administered an opioid and a sedative agent Increased absorption from patches when exposed to heat sources or in patients with high fever Use of patches in opioid-naïve patients Incorrect dosing Incorrect IV infusion/pump rate Incorrect administration route (e.g. vincristine given by the intrathecal route)

Mix-ups between drugs (e.g. vincristine, vinblastine, vindesine, vinorelbine)

Hyperkalemia (e.g. muscle paralysis, ECG changes, cardiac arrest) Hyperphosphatemia and the fall in serum ionized calcium Hypernatremia, congestive states, central pontine myelinolysis Hypermagnesiemia, neuromuscular blockade

Adverse effects resulting from an unintended electrolyte administration (e.g. hyperkalemia and associated effects)

Adverse effects resulting from an increased electrolyte serum concentration (e.g. hyperkalemia and associated effects) Variations in blood glucose levels due to different onset, peak, and duration of the effect Adverse effects resulting from an unintended drug administration (e.g. bleeding and hyperglycemia in a patient administered heparin instead of insulin) Hypoglycemia/associated adverse effects or insufficient glucose-lowering effect Hypoglycemia/associated adverse effects or insufficient glucose-lowering effect Hypoglycemia Inadequate analgesia, excessive sedation, and potentially lethal respiratory depression

Nausea, vomiting, constipation Cumulative sedation

Excessive sedation and potentially lethal respiratory depression Greater risk of adverse effects Toxicity or lack of therapeutic effect Administration site reactions, increased serum concentrations, specific organ toxicity (e.g. fatal ascending radiculomyeloencephalopathy with vincristine) Lack of therapeutic effect

(continued on next page)

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Table 1 (continued) Drug category

Drug name/subcategory

Associated risk

Harm to the patient

H/Heparin and other anticoagulants or antithrombotic agents

Anticoagulants (e.g., warfarin, low molecular weight heparin, IV unfractionated heparin) Factor Xa inhibitors Direct thrombin inhibitors Thrombolytics (e.g.,alteplase, reteplase, tenecteplase) Glycoprotein IIb/IIIa inhibitors (e.g.,eptifibatide)

Incorrect dosing, especially regarding patients with renal impairment, low weight (< 50 kg) and patients > 75 years Interactions with food, other medicines, herbal products Confusion between tablet strengths Inappropriate monitoring Use in patients with high risk of bleeding

Overdosing: Increased risk of bleeding, Increased clotting times. Under dosing: increased risk for thrombus formation, lack of thrombolytic effect Increased or decreased antithrombotic/anticoagulant effect

Potentially fatal bleeding episodes

Legend: GIT – gastrointestinal, IV – intravenous, PO – per os, SC – subcutaneous, TD – transdermal.

hypoglycemia due to the use of sulfonylureas or systemic inflammation such as sepsis. It is not clear whether diabetes type influences changes in blood glucose homeostasis induced by fluoroquinolones. All previously mentioned reported cases of dysregulation of glucose homeostasis have been reported in either non-diabetic or type 2 DM patients. Today we know that, at the time of the diagnosis, a considerable number of type 1 DM patients secrete insulin in different amounts (Steele et al., 2004). If fluoroquinolones indeed have the potential to increase the release of insulin from the pancreas, patients with the existing pancreatic reserve may experience fluoroquinolone-induced hypoglycemia, as well. On the other hand, literally all fluoroquinoloneinduced dysglycemias reported so far in diabetes patients were observed in the elderly, usually > 60 years of age (Mohr et al., 2005; Lawrence et al., 2006; Park-Wyllie et al., 2006; Singh et al., 2008a; 2008b; Vallurupalli et al., 2008; Garber et al., 2009; Kelesidis et al., 2009; Yousefzadeh et al., 2014). As hypothesized by several researchers, this is probably due to decreased renal function in this patient group (Mehlhorn et al., 2007; LaPlante et al., 2008; Chou et al., 2013). Whether this means that this effect could also be expected in type 1 diabetes patients with impaired renal function, remains to be explored. Additionally, it is important to say that fluoroquinolones inhibit the cytochrome P450 system and the clearance of certain oral hypoglycemic agents, which is particularly important for patients with genetic polymorphisms in the cytochrome system (Yousefzadeh et al., 2014). The Summary of Product Characteristics (SPC) of levofloxacin recommends careful monitoring of blood glucose in diabetes patients, defining hypoglycemia as a rare side effect (≥1/10,000 to < 1/ 1,000), but provides no data regarding the concomitant use of levofloxacin and oral antidiabetic agents or insulin (American Food and Drugs Administration, 2008). The SPC of moxifloxacin also recommends „careful monitoring of blood glucose”, stating that administration of oral moxifloxacin with glibenclamide to diabetic volunteers resulted in a decrease of app. 21% in the peak plasma concentrations of glibenclamide (American Food and Drugs Administration, 1999). However, although this could theoretically result in hyperglycemia, the SPC further states that the observed pharmacokinetic changes for glibenclamide did not result in changes of the pharmacodynamic parameters measured (blood glucose, insulin) (American Food and Drugs Administration, 1999). Moxifloxacin's SPC classifies hyperglycemia as a rare side effect (≥1/10,000 to < 1/1,000), whereas hypoglycemia appears as a very rare side effect (< 1/10,000), with no available data regarding interactions with other oral hypoglycemics (American Food and Drugs Administration, 1999). Both hyper- and hypoglycemia are reported as rare side effects of ciprofloxacin (American Food and Drugs Administration, 2016).

Considering that the existing lists may not be exhaustive enough, the literature was searched and reviewed for additional risks that drug categories included in the APINCH list carry for diabetes patients. 2. APINCH list Many hospitals select medicines from ISMP's APINCH List of HighAlert Medicines, which is updated every few years (Institute for Safe Medication Practices , 2014). The current version of the list, published in 2014, with the respective drug categories and drugs included is presented in Table 1. Table 1 also contains the most frequently observed errors with the listed medicines and consequent harms to the patient, as reported in the literature (World Health Organization, 2011; Institute for Healthcare Improvement, 2012; Western Australian Department of Health, 2014). As shown, electrolytes, insulins, and antithrombotics/anticoagulants comprise all agents included in these medication groups, whereas the antimicrobial drug category, as well as the narcotics/sedatives and chemotherapeutics drug categories, are restricted to several potentially harmful agents. As already mentioned, the list applies to a general patient population with no reference to specific populations such as diabetic. 3. The A – Antimicrobials Specific anti-infectives that have a high risk of causing harm according to the APINCH list include amphotericin, aminoglycosides, and vancomycin (Institute for Safe Medication Practices , 2014). However, antimicrobials different from those may impose a significant risk for the diabetes population, whereas some of the agents included in the list such as vancomycin, may be harmful for the diabetes population in a way different from the one identified in the list (Lawrence et al., 2006). 3.1. Antimicrobials not included in APINCH list 3.1.1. Fluoroquinolones Several observational studies and case reports raised concerns regarding the safety of severe dysglycemia associated with fluoroquinolone use, especially with levofloxacin (Lawrence et al., 2006; Singh et al., 2008a; 2008b; Vallurupalli et al., 2008; Garber et al., 2009; Kelesidis et al., 2009). Dysregulation of glucose homeostasis seems to be a class effect, given the fact that further studies confirmed the appearance of dysglycemia induced by gatifloxacin, banned in 2006 due to its harmful side effects, moxifloxacin, and ciprofloxacin (Mohr et al., 2005; Park-Wyllie et al., 2006; LaPlante et al., 2008; Kapoor et al., 2012; Chou et al., 2013). The effect has mostly been observed in patients treated with oral antidiabetic agents or insulin, but cases of fatal hypoglycemia in non-diabetic patients have been reported, as well (Yousefzadeh et al., 2014). The exact mechanism of this effect is not clear. It is thought, however, that, similarly to sulfonylureas, fluoroquinolones bind to the ATP-sensitive potassium channel on β-cells causing increased release of insulin (Yousefzadeh et al., 2014). The effect appears to be more pronounced in patients already at risk for

3.1.2. Other antimicrobials not included in APINCH list A study from Schelleman et al. (2010) found that, in patients taking glipizide or glyburide, several anti-infective agents besides fluoroquinolones may cause severe hypoglycemia. In glipizide and glyburide users, statistically significant associations were found with co3

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require an even more strict approach given the fact that they frequently develop a constellation of electrolyte disorders resulting from an impaired renal function, malabsorption syndromes, acid-base disorders, multi-drug regimens or associated autoimmune glandular malfunctions (Liamis et al., 2014). Hypo- and hypernatremia, hypo- and hyperkalemia, hypo- and hypercalcemia, hypomagnesemia, and hypophosphatemia found in this patient group are associated with an increased morbidity and mortality (Liamis et al., 2002, 2009, 2013, 2014), and as such, predispose patient to potentially serious harms even in cases of minor mistakes in dosing or administration.

trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83–5.37 and OR = 2.68; 95% CI: 1.59–4.52, respectively), clarithromycin (OR = 2.90; 95% CI: 1.69–4.98 and OR = 5.02; 95% CI: 3.35–7.54, respectively) and fluconazole (OR = 2.53; 95% CI: 1.23–5.23 and OR = 2.20; 95% CI: 1.04–4.68, respectively), using cephalexin as the reference (Schelleman et al., 2010). In glyburide users, a statistically significant association was also found for ciprofloxacin (OR = 2.08; 95% CI: 1.23–3.52) (Schelleman et al., 2010). Hypoglycemias with concomitant administration of these drugs and hypoglycemic agents are expected due to a strong and very well-known CYP450 inhibiting the potential of clarithromycin, co-trimoxazole, and fluconazole. In addition, clarithromycin displaces glipizide and glyburide from protein binding sites, thereby increasing the unbound portion of the drug and inhibits P-glycoprotein in the intestinal wall (Bussing et al., 2002), whereas severe hypoglycemia reported in patients who were concomitantly treated with clarithromycin and other hypoglycemic agents, such as nateglinide and repaglinide, is most probably induced by inhibition of CYP3A enzyme (Electronic medicines compendium, 2008). Similarly, hypoglycemias induced by fluconazole and metronidazole are, expectedly, due to CYP2C9 inhibition that interferes with sulfonylurea metabolism (Tirkkonen et al., 2010; Parekh et al., 2014). On the other hand, cases of severe hypoglycemia with cotrimoxazole reported by several authors in both diabetes and non-diabetes patients are thought to be due to a sulfonylurea-similar mechanism of stimulation of insulin secretion by pancreatic beta-cells (Juurlink et al., 2003; Strevel et al., 2006; Nunnari et al., 2010). Due to their pharmacokinetic interactions with hypoglycemics and interference with insulin secretion, the above-mentioned antibiotics should be considered high-risk in type 2 diabetes patients treated with oral hypoglycemic agents and used with caution.

5. The I – Insulin As shown in Table 1, all insulins are considered high-risk medicines. This is mainly owing to possibly fatal harms resulting from incorrect dosing, incorrect administration or mix-ups because of sound-a-like names or look-a-like prescriptions (Western Australian Department of Health, 2014). To diabetes patients, in terms of safety, equally important may be newly introduced antidiabetic drugs containing insulin combined with a non-insulin active substance such as insulin degludec combined with liraglutide (Xultophy®). In 2015, the EMA released a note warning clinicians about the confusion that may arise over the way the doses are expressed for the individual components − the dose of the insulin is expressed in units while the dose of the non-insulin medicine is expressed in other units such as mg and provided a set of recommendations intended to minimize the possibility of such error (European Medicines Agency, 2015). 6. The N - Narcotics and sedatives 6.1. Over-sedation

3.2. Antimicrobials included in APINCH list Opioids and sedative agents that have a high risk of causing harm include fentanyl, alfentanil, remifentanil, hydromorphone, morphine, oxycodone, diazepam, and midazolam, as well as thiopentone, propofol and other short-term anesthetics (Institute for Safe Medication Practices , 2014). Incorrect dosing of opioids can lead to inadequate analgesia, excessive sedation and potentially lethal respiratory depression (Western Australian Department of Health, 2014). These effects may be due to incorrect dosing, but also due to other mechanisms such as concomitant administration of these drugs with inhibitors of CYP450 enzymes (Western Australian Department of Health, 2014). Although oral hypoglycemic agents do not show the CYP450 inhibiting potential, bromocriptine, a sympatholytic D2-dopamine agonist approved for the treatment of type 2 DM, is a potent CYP3A4 inhibitor and, as such, it may reduce clearance of fentanyl, alfentanil, oxycodone, diazepam, and midazolam, and significantly increase the unbound concentration of these drugs (Electronic medicines compendium, 1999, 2011). Similarly, bromocriptine may decrease methadone clearance when co-administered with it as both drugs are metabolized by CYP3A4 (Electronic medicines compendium, 1994). Therefore, doses of the above-mentioned drugs may need to be adjusted when used concomitantly with bromocriptine and methadone should be considered as a potentially harmful agent in patients on treatment with bromocriptine.

3.2.1. Vancomycin Vancomycin is included in the APINCH list due to the high risk of causing harm with incorrect dosing with respect to weight and high monitoring requirements (World health organization, 2011; Institute for Healthcare Improvement, 2012; Western Australian Department of Health, 2014). Nonetheless, it has recently been shown that, in diabetes patients with mild to moderate limb infections, vancomycin serum concentrations do not adequately predict tissue exposure, which may be the mechanism responsible for lower rates of treatment success in diabetes patients compared to their non-diabetes counterparts (Hamada et al., 2015). Equils et al. (2016) found that among 183 diabetes patients with methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia, treatment with linezolid, compared to treatment with vancomycin, was associated with higher clinical and microbiologic success rates (57.6% vs. 39.3% and 58.9% vs. 41.1%, respectively). The authors hypothesized that this was due to reduced vancomycin penetration into pulmonary infection sites resulting from the thickening of alveolar epithelial and capillary basal laminae seen in diabetes patients (Equils et al., 2016). These data suggest that the use of vancomycin in patients with diabetes requires additional caution, mostly due to the possibility of higher rates of toxicity associated with increased dosing required for achieving adequate tissue concentrations. All the currently available data have been obtained from patients with type 2 DM.

6.2. Influence on glucose homeostasis

4. The P - Potassium and other concentrated electrolytes

A recent review emphasized that patients suffering from DM on opioid treatment are more prone to hyperglycemia and worsening of diabetes (Sharma et al., 2016). A study that included 49 patients with non-insulin dependent diabetes found that opium smoking increases glycemia, adding to the complications of diabetes (Karam et al., 2004). In heroin addicts, the fasting concentration of insulin is higher and plasma insulin responses to intravenous glucose are significantly reduced (Passariello et al., 1983). The glycemic response in opioid-dependent patients given a glucose load shows a delayed peak time, the

The risks associated with intravenous administration of electrolytes comprise too rapid administration/administration of wrong doses or selection of the wrong ampoule (an ampoule mistaken for other of similar appearance) (Western Australian Department of Health, 2014). Erroneous administration of concentrated electrolytes is well-known for causing serious harm or even cardiac arrest and as such, it should be prevented by all means. Patients with both type 1 and type 2 DM 4

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et al., 2011; Schumacher et al., 2012). Despite the fact that these effects normally do not cause significant harm to patients, when potentiated, they may be a reason for discontinuation of therapy and a source of great unpleasantness for patients. In type 2 diabetes patients, potentiation of opioid GI effects may be due to their co-administration with a vast number of hypoglycemic drugs - biguanides, < alpha > glucosidase inhibitors, bromocriptine, glinides, and SGLT-2 inhibitors, insulin analogs, glucagon-like peptide-1 receptor agonists, and pramlintide (Chaudhury et al., 2017). The mechanisms by which the abovementioned hypoglycemics cause nausea and vomiting are not yet fully explained, but a potential of pharmacodynamic interaction with the opioids and potentiation of GI side effects should not be overlooked.

insulin curves show an increase in insulin peaks, delay in peak time, and prolongation of hyperinsulinemia (Brambilla et al., 1976; Ghodse et al., 1977). Regardless of the period and route of administration, the level of HbA1C is significantly higher in opium users than in non-users, as found by Asgary et al. (2008). In a review by Giugliano et al. (1984), the author hypothesizes that the fact that heroin addicts, like patients with non-insulin-dependent diabetes, do not respond appropriately to glucose signals is owing to the central effect of opiates and opioid peptides, which cause hyperglycemia and impaired insulin secretion via the sympathetic nervous system. Although there is evidence supporting the contrast hypothesis, such as a large case-control study of Li et al. (2013) that found no association between use of opioids and risk of type DM among adult patients, majority of currently available evidence point toward the role of opioids in glucose homeostasis, leading to higher chances of individuals having diabetes or worsening the existing disease. Tramadol, although not included in the APINCH list, is another opioid drug with a potentially important influence on glucose homeostasis and harmful effect on diabetes patients. Tramadol binds to < mu > opioid receptors and inhibits the neuronal reuptake of serotonin and norepinephrine (Minami et al., 2015). In pharmacological models, these actions have been shown to enhance insulin effects and promote glucose utilization which, unlike other opioids, results in decreased blood glucose concentrations (Choi et al., 2005; Cheng et al., 2013). Indeed, several case reports described severe hypoglycemia following standard and overdose of tramadol (Mugunthan et al., 2012; Odonkor et al., 2016), whereas recent studies reported increased risk for symptomatic hypoglycemia among both diabetics and non-diabetics taking therapeutic doses of tramadol (Abadie et al., 2013; Fournier et al., 2015; Golightly et al., 2017). The study of Golightly et al. (2017) included patients with both type 1 and type 2 DM, reporting hypoglycemia (blood glucose ≤70 mg/dL) in 22 (46.8%) of 47 patients with type 1 DM, 113 (16.8%) of 673 patients with type 2 DM, and 103 (4.7%) of 2207 patients who did not have a DM diagnosis. It must be added here that a special risk of hypoglycemia exists in diabetes patients treated with bromocriptine given the fact that tramadol uses CYP3A4 in Phase I of its metabolism (Electronic medicines compendium, 2012). In conclusion, when it comes to the diabetes population, tramadol may impose an important risk, especially in patients prone to hypoglycemia or treated with bromocriptine. It is postulated that the competition for renal tubular transporters between metformin and cationic drugs such as morphine, cimetidine, digoxin, and procainamide, may be responsible for an increased risk of lactic acidosis in diabetes patients concomitantly treated with metformin and cationic agents (Iacobellis, 2006). Although cases of lactic acidosis have not yet been observed in patients treated with metformin and morphine, both single- and multiple-dose metformin-cimetidine interaction studies showed a 60% increase in peak metformin plasma concentrations and 40% increase in metformin plasma AUC, whereas cimetidine pharmacokinetics remained unchanged (Somogyi et al., 1987). This suggests that clinicians should be careful when using morphine and metformin in a parallel way and patients advised to monitor their blood glucose levels and promptly notify their physician if they experience any signs consistent with lactic acidosis. The metformin dosage should be slowly and cautiously titrated in patients concomitantly treated with morphine until further information about this interaction is available.

7. The C – Chemotherapeutic agents 7.1. Cytotoxic drugs According to the APINCH list, all oral and parenteral chemotherapeutic agents are considered high-risk medicines (Institute for Safe Medication Practices, 2014). This is due to their complicated dosing and scheduling, occupational exposure during transport and administration of cytotoxic drugs and handling or disposal of patient waste, and numerous adverse effects (Western Australian Department of Health, 2014). Acute hyperglycemia has been reported during treatments with several cytotoxic drugs such as 5-fluorouracil and L-asparaginase (Mohn et al., 2004; Feng et al., 2013). Diabetes and elevated fasting glucose levels were found to occur in 11.6% and 11.3% of patients with colorectal cancer treated with 5-fluorouracil, respectively, whereas, in the study of 32 children with no family history of diabetes treated with L-asparaginase for acute lymphoblastic leukemia, 69% patients had an impaired first-phase insulin response (Mohn et al., 2004; Feng et al., 2013). In the study of Mohn et al., L-asparaginase-induced inhibition of insulin production and release persisted even after the termination of chemotherapy. Similarly, a large study conducted on 24,976 breast cancer survivors and 124,880 controls, showed that the patients who were treated with adjuvant chemotherapy (n = 4.404) had the highest risk of diabetes within two years after cancer diagnosis (HR 1.24 (95% CI 1.12, 1.38)) (Lipscombe et al., 2013). 7.2. Targeted therapies Targeted therapies, widely used in oncology for the treatment of a variety of malignancies in recent years, are not currently included in the APINCH list. However, according to a review published in 2014, some of these drugs may lead to important metabolic disturbances in treated patients, which may expose patients already suffering from metabolic disorders to an extreme danger (Vergès et al., 2014). Drugs used for targeted therapies with significant metabolic consequences are the mammalian target of rapamycin (mTOR) inhibitors, particularly sirolimus, everolimus and temsirolimus, and to a much lesser extent, the tyrosine kinase inhibitors (TKIs) - imatinib, sunitinib, pazopanib, and nilotinib (Vergès et al., 2014). mTOR is a serine/threonine kinase that plays a key role in the regulation of cell growth, and lipid and glucose metabolism. The activity of mTOR complex 1 (mTORC1), is increased in insulin-target tissues (adipose tissue, skeletal muscle, and liver) and, as shown in preclinical models, once activated, mTORC1 promotes insulin resistance in those tissues through inhibition of insulin signaling (Um et al., 2004; Khamzina et al., 2005; Tremblay et al., 2007). In humans, long-term treatment with sirolimus impaired insulin signaling in circulating mononuclear cells of kidney-transplanted patients, whereas insulin-stimulated glucose uptake was reduced in human adipocytes treated for a short-term (15 min) or long-term treatment (20 h) with everolimus at therapeutic concentrations (Kulke et al., 2009; Pereira et al., 2012). Accordingly, based on the effects observed during clinical studies and postmarketing reports, SPCs of both sirolimus and everolimus classify hyperglycemia as a very common adverse effect

6.3. Gastrointestinal effects Exerting their effect on < mu > and < kappa > receptors that are highly dense within the gastrointestinal (GI) tract, opioids are associated with side effects such as nausea, vomiting, and gastroesophageal reflux (Rausch et al., 2012). It is thought that this is due to the reduction in gastric motility, activation of the chemoreceptor trigger zone (CTZ) and enhanced vestibular sensitivity (Swegle et al., 2006; Yaksh 5

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food-drug interactions in case of oral Vit K antagonists are the main reasons for this (Western Australian Department of Health, 2014). In diabetes patients, no specific drug-disease interactions have been found for heparin and other anticoagulants (Dumbreck et al., 2015). Nonetheless, certain conditions that occur more frequently in diabetes patients, such as renal impairment, may have an important influence on anticoagulant therapy (Hughes et al., 2014). Although administration of heparins and oral Vit K to patients with renal impairment is generally considered safe, caution is recommended in patients with severely damaged renal function (CrCl < 30 mL/min) due to a higher risk of bleeding (Hughes et al., 2014). The same risk carries the administration of DOC (Hughes et al., 2014). Regarding hepatic impairment, DOC is contraindicated in patients with Child-Pugh C liver damage and requires caution when used in patients with Child-Pugh A and B, similarly to heparins and OKA, owing to an increased risk of bleeding, as well (Dhar et al., 2017). While the above-mentioned interactions are largely known, several potential interactions that highlight the risk of the use of anti-coagulants in the diabetes population have emerged in recent years (Romley et al., 2015; Nam et al., 2018). One such interaction may arise from the concomitant use of warfarin and sulfonylureas. Romley et al. (2015) reported that hospital admissions or emergency department treatment of hypoglycemia was more frequent in patients when warfarin was coadministered with glipizide/glimepiride (adjusted OR: 1.22, 95% CI 1.05–1.42) than in patients not treated with anticoagulants. Although this study did not establish a causal relationship between hypoglycemia and warfarin administration, warfarin and glipizide/glimepiride may compete both for CYP29 as they are both primarily metabolized by this enzyme, and for binding sites on plasma albumin, owing to the fact that each drug is more than 99% bound (Romley et al., 2015). A very recent study reported that warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glipizide (risk ratio (RR) 1.72; 95% CI 1.29, 2.29), glyburide (RR 1.57; 95% CI 1.15, 2.15), metformin (RR 2.26; 95% CI 1.67, 3.05), and glimepiride (RR 1.56; 95% CI 0.97, 2.50) (Nam et al., 2018). Therefore, pending more definitive data, patients taking sulfonylureas or even metformin should be monitored for altered plasma glucose levels if warfarin is added or removed from their drug regimen. Conversely, only a single case report describes an interaction between warfarin and glibenclamide resulting in an increased International Normalized Ratio (INR) and this outcome, although mentioned as a possibility in SPCs of sulphonylureas, remains to be investigated (Armstrong et al., 1991). Among antithrombotic agents, salicylates have the potential to increase the hypoglycemic effect of sulphonylureas, as well (Electronic medicines compendium, 1980). As suggested by Aquilante (2010), this is most probably due to a salicylate-associated increase in sulfonylurea concentration caused by the displacement of the drug from its proteinbinding sites, along with a decrease in the sulfonylureas renal excretion caused by salicylates. Table 2 shows inclusions to the APINCH list that have the potential to interfere with glucose metabolism or may lead to ME and potential harm to the patient, whereas Table 3 lists the additional risks that drugs already included in the list carry when used in patients with DM.

(Electronic medicines compendium, 2001, 2009). In normoglycemic patients, fasting plasma glucose should be checked every 2 weeks during the first month of treatment and then monthly. In addition, HbA1c should be measured every 3 months in all patients. In patients with prediabetes and/or metabolic syndrome, once-daily self-monitoring blood glucose assessment should be recommended, whereas, for the patients with known diabetes, self-monitoring of blood glucose should be intensified (Vergès et al., 2014). TKIs are valuable cytotoxic agents that influence glucose homeostasis by unknown mechanisms (Vergès et al., 2014). A disturbing observation that TKIs may induce both hyper- and hypoglycemia makes an important difference between this drug group and mTOR inhibitors, although glucose homeostasis disturbances occur less frequently with TKIs (Vergès et al., 2014). A number of studies with four different TKIs, imatinib, pazonipab, sunitinib, and nilotinib used in patients with different types of malignancies, reported hypoglycemia/regression of long-standing diabetes studies, with nilotinib causing hyperglycemia more frequently than other drugs (Breccia et al., 2004; Veneri et al., 2005; Hamberg et al., 2006; Billemont et al., 2008; Saglio et al., 2010; Sternberg et al., 2010; Oh et al., 2012; Iurlo et al., 2015). Thirty-eight percent of patients (G3–4 = 5%) with chronic myeloid leukemia treated by nilotinib had hyperglycemia in the phase III trial (Saglio et al., 2010). Sunitinib, on the other hand, was found to be associated with both hyper- and hypoglycemia, as reported by two contrasting studies in patients with metastatic renal carcinoma (Motzer et al., 2007; Billemont et al., 2008). The effects of different TKIs were investigated among type 2 DM patients, but data from studies with type 1 DM patients are lacking (Breccia et al., 2004; Ono et al., 2012). Until more data is available, tight monitoring of glucose homeostasis is required in both groups of diabetes patients under TKI administration. In recent years, several humanized antibodies acting to inhibit the association of the programmed cell death-ligand 1 with its receptor, programmed cell death protein 1, has been approved for the treatment of advanced melanoma, renal cell carcinoma and non-small cell lung carcinoma (Collin, 2017). Descriptions of endocrinological adverse events associated with the use of these drugs have been accumulating since their approval, with several studies reporting new-onset diabetes in patients treated with two particular anti-PD-1 antibodies, nivolumab, and pembrolizumab (Gaudy et al., 2015; Hughes et al., 2015; MartinLiberal et al., 2015; Mellati et al., 2015; Okamoto et al., 2016). Still limited to case reports or case series, the evidence suggests that diabetes can develop in previously normoglycemic patients or worsen in patients previously diagnosed with type 2 DM. At conventional doses, the time between the treatment initiation and the appearance of diabetes in the reported cases varied from less than 1 week to more than 12 months. Some patients had positive islet cell autoantibodies, whereas others were negative for this parameter, but all cases showed high-risk HLA genotypes for autoimmune diabetes (Gaudy et al., 2015; Hughes et al., 2015; Martin-Liberal et al., 2015; Mellati et al., 2015; Okamoto et al., 2016). Given the fact that some of the cases had fulminant onset with ketonuria and extremely high plasma glucose levels (908 mg/dL), the fact that all cases showed a rapid fall into insulin-dependence and that pathogenesis remains unclear, in all patients, especially diabetic ones, physicians should carry out routine blood testing during anti-PD-1 therapy and anti-PD-1 inhibitors should be considered for inclusion in APINCH list when it comes to patients with pre-existing glucose homeostasis disturbances.

9. Discussion While there are several high-alert drugs lists developed for pediatric and geriatric population (American Geriatrics Society, 2012; Cotrina Luque, 2013), clinicians lack such a list for use in diabetes patients despite many factors that might affect the safety of drugs' use in this population, such as altered pharmacokinetics, polypharmacy, comorbidities, etc. The existing studies that identify common diabetesrelated ME show that risky drug prescribing occurs in 9.9% of the study population (n = 5,729) (O'Connor et al., 2005; Breuker et al., 2017). However, the definition of high-risk medicines or risky drug prescribing in diabetes, for that matter, has not been established to date and little

8. The H - Heparin and other anticoagulants/antithrombotic agents Heparins, oral Vit K antagonists (OKA), direct thrombin inhibitors and other direct oral anticoagulants (DOC) are all considered high-risk medicines and, as such, are included in the APINCH list (Institute for Safe Medication Practices , 2014). High risk of bleeding/thrombotic events, along with complicated dosing and monitoring and drug- and 6

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Table 2 Inclusions to APINCH list – drugs that interfere with glucose metabolism or may lead to medication error and potential harms to the patient. Drug category

Drug name/subcategory

Reason for inclusion

Harm to the patient

A/Antimicrobials

Fluoroquinolones

Required monitoring of blood glucose levels, especially in diabetic patients already at risk of hypoglycemia (e.g. treatment with sulphonylureas) Potential PK interaction with oral hypoglycemics at the protein-binding level (glipizide and glyburide) and at the CYP450 level (glipizide, glyburide, nateglinide, repaglinide) Potential PK interaction with oral hypoglycemics at the CYP450 level. Potential PD interaction - sulfonylurea-similar mechanism of stimulation of insulin secretion by pancreatic beta cells (glipizide, glyburide) Minor mistakes may cause serious harm owing to pre-existing

Hypoglycemia/dysglycemia

Clarithromycin

Co-trimoxazole Fluconazole

P/Potassium and other electrolytes

I/Insulin N/Narcotics and other sedatives

Potassium chloride and phosphate Sodium chloride Magnesium sulfate (IV) Combinations of insulin and non-insulin active substances Methadone

Tramadol

C/Chemotherapeutic agents

mTOR inhibitors (everolimus, temsirolimus) TK inhibitors (imatinib, pazonipab, sunitinib, nilotinib) Anti-PD-1 antibodies (nivolumab, pembrolizumab)

Incorrect dosing due to doses expressed in different units Potential PK interaction with bromocriptine at the CYP450 level Required monitoring for hypoglycemia, especially in diabetic patients prone to hypoglycemia or treated with bromocriptine Required monitoring of blood glucose levels

Hypoglycemia

Hypoglycemia

electrolyte disorders

Hypoglycemia/insufficient glucoselowering effect Inadequate analgesia, excessive sedation and potentially lethal respiratory depression Hypoglycemia

Hyperglycemia

Required monitoring of blood glucose levels

Hypo/hyperglycemia

Required monitoring of blood glucose levels

Hypo/hyperglycemia

Legend: CYP450 – cytochrome P450, IV – intravenous, mTOR - mammalian target of rapamycin, PD-1 - programmed cell death protein 1, PK – pharmacokinetic, PD – pharmacodynamic, TK - tyrosine kinase.

October 1987 through April 2017, the FDA identified 56 reports in their internal adverse reports system (FAERS) and 11 additional cases in the medical literature (U.S. Food and Drug Administration, 2018). Thirteen cases out of sixty-seven were fatal, and nine resulted in permanent and disabling injuries. Most patients had risk factors for hypoglycemia, most important being a concomitant use of hypoglycemic drugs, especially sulfonylureas. Besides fluoroquinolones, high-risk drugs for use in diabetes that we identified in this work are also related to potentially inadequate glycemic-control caused by PK interactions with oral hypoglycemics at the CYP450 level (clarithromycin, co-trimoxazole, fluconazole, tramadol), incorrect dosing due to doses expressed in

evidence regarding which drugs should be considered high-risk in diabetes is available. Given that fact, we decided to use the basic version of the ISMP's high-risk medications list (APINCH) as a starting point, at all times bearing in mind that the list may need to be supplemented by drug categories other than those already included, on which we will focus in our further research. In this review, we identified fluoroquinolones as medicines whose interactions with blood glucose homeostasis is best documented in the literature. The importance of this interaction is best illustrated by the FDA's drug safety communication of July 10, 2018, which states that, searching for fluoroquinolone-induced hypoglycemic coma, from

Table 3 Drugs included in APINCH list that carry additional risks when used in diabetes patients. Drug category

Additional risk

Harm to the patient

A/Antimicrobials

Increased dosing of vancomycin required for achieving adequate tissue concentrations Potential PK interaction with bromocriptine at the CYP450 level (fentanyl, alfentanil, oxycodone, diazepam, and midazolam) Impaired insulin secretion due to central effects of opiates and opioid peptides Possible interaction between morphine and metformin at the tubular transporters level Potentiation of GIT side effects with co-administration of opioids and oral hypoglycemic agents (biguanides, alpha-glucosidase inhibitors, bromocriptine, glinides, and SGLT-2 inhibitors, insulin analogs, GLP-1 receptor agonists, pramlintide) Possible influence on insulin response (5-fluorouracil, L- asparaginase)

Possible toxicity

Potential interaction between warfarin and sulphonylureas at the albumin binding and CYP2C9 level Potential interaction between salycilates and sulphonylureas at the albumin binding level; potential salicylate-induced decrease in renal excretion of sulphonylureas

Hypoglycemia

N/Narcotics and other sedatives other sedatives

C/Chemotherapeutic agentsChemotherapeutic agents H/Heparin and other anticoagulants or antithrombotic agents

Inadequate analgesia, excessive sedation and potentially lethal respiratory depression Hyperglycemia, new-onset diabetes Increased risk of lactic acidosis Nausea, vomiting

Hyperglycemia, possibly new-onset diabetes

Legend: CYP450 – cytochrome P450; CYP2C9 - cytochrome P450 2C9; GIT – gastrointestinal; SGLT-2 - sodium-glucose co-transporter-2; GLP-1 - glucagon-like peptide 1. 7

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Acknowledgment

different units (combinations of insulin and non-insulin agents) and unknown mechanisms (mTOR inhibitors, TK inhibitors, anti-PD-1 antibodies). In accordance with these results, we suggest current risk reduction strategies to be supplemented by recommendations on blood glucose monitoring in diabetes patients treated with the above-mentioned drugs and by EMA's recommendations on prevention of potentially fatal errors with agents containing insulin and a non-insulin active substance (European Medicines Agency, 2015). We also suggest careful blood glucose monitoring to be carried out in patients concomitantly treated with warfarin or salicylates and sulphonylureas due to the risk of severe hypoglycemia. Finally, our review indicates that patients treated with narcotics or sedatives and bromocriptine require close monitoring of the level of sedation owing to metabolic inhibition induced by bromocriptine. Although less harmful in their nature, opioid-induced gastrointestinal side effects potentiated by a vast number of oral hypoglycemic agents may be the source of great discomfort or even treatment discontinuation. Our work also opens important questions. While the influence on fluoroquinolones on glucose homeostasis seems to be evident in patients with type 2 DM, probably due to fluoroquinolone-induced increased insulin secretion associated with dose-related fluoroquinolone effect resulting from decreased renal function, are dysglycemias also to be expected in type 1 DM patients who still produce insulin and suffer from age- or disease-related impaired renal function? Is it possible that the preserved renal function in young type 1 DM patients compensates for fluoroquinolone-induced increased insulin secretion, preventing, therefore, hypoglycemic events? What are the real effects of targeted therapies and other drugs, such as tramadol, on insulin secretion and signaling, and are there any differences in safety concerns when it comes to type 1 and type 2 DM? What key patient-related factors predispose patients treated with drugs that influence glucose homeostasis to blood glucose disturbances? The significant lack of knowledge about drugs whose use could be risky for the diabetes population puts emphasis on the importance of the careful selection of pharmacological therapy for this patient group. I believe that the inclusions to APINCH list proposed in this review and identification of additional risks that the included drugs carry for diabetes patients could improve clinical care in several ways: firstly, the clinicians could alert their patients of the symptoms of hypoglycemia, advise them to monitor blood glucose levels more frequently, discuss with them how to treat themselves if they have symptoms of hypoglycemia, or prescribe an alternative drug; secondly, they could bring to clinicians’ attention glycemic effects of some novel therapeutic agents such as anti-PD1-antibodies or traditional agents whose glycemic effects are insufficiently recognized among clinicians; thirdly, they could motivate the researchers to identify the subtle mechanisms responsible for drug-induced disturbances of glucose homeostasis and their interaction with the disease itself; lastly, they could help with the creation of high-risk medicine lists on an individual hospital level and serve as a basis for setting-up risk-reduction strategies.

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Author statement Mohammad Ishraq Zafar conceived and conceptualized the topic, outlined the review, literature search, wrote the manuscript, reviewed, revised, and finalized the manuscript. Funding information None.

Declaration of competing interest None. 8

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