Table 1.
PIM according to the EU(7)-PIM lista
| PIM | Main reason | Dose adjustment/special considerations of use | Alternative drugs and/or therapies |
|---|---|---|---|
| Drugs for peptic ulcer and gastro-oesophageal reflux | |||
| Ranitidine | CNS adverse effects including confusion | CrCl <50 mL/min 150 mg q 24h (oral); 50 mg q 18–24 h (iv). E | When indication is appropriate, PPI (<8 weeks, low dose). E |
| PPI (>8 weeks) e.g. omeprazole, pantoprazole | Long-term high dose PPI therapy is associated with an increased risk of C. difficile infection and hip fracture. Inappropriate if used >8 weeks in maximal dose without clear indication | ||
| Propulsives | |||
| Metoclopramide | Antidopaminergic and anticholinergic effects, may worsen peripheral arterial blood flow and precipitate intermittent claudication | Short-term use and dose reduction; CrCl <40 mL/min 50 % of normal dose; maximum dose 20 mg/d; may be used in palliative care. E | Domperidone (<30 mg/d) if no contraindications. E |
| Laxatives | |||
| Senna glycosides | Stimulant laxative. Adverse events include abdominal pain, fluid and electrolyte imbalance and hypoalbuminemia. May exacerbate bowel dysfunction | Recommend proper dietary fibre and fluid intake; osmotically active laxatives: macrogol, lactulose. E, P | |
| Sodium picosulfate | |||
| Antipropulsives | |||
| Loperamide (>2 days) | Risk of somnolence, constipation, nausea, abdominal pain and bloating. Rare adverse events include dizziness. May precipitate toxic megacolon in inflammatory bowel disease, may delay recovery in unrecognised gastroenteritis | Start with a dose of 4 mg followed by 2 mg in each deposition until normalisation of bowel; do not exceed 16 mg/d; use no longer than 2 days; may be useful in palliative care for persisting non-infectious diarrhoea. E | Non-pharmacological measures, e.g. diet; phloroglucinol. E |
| Insulins and analogues | |||
| Insulin, sliding scale | No benefits demonstrated in using sliding-scale insulin. Might facilitate fluctuations in glycemic levels | Lower doses to avoid hypoglycemia. E | Basal insulin. E |
| Blood glucose lowering drugs, excluding insulins | |||
| Glibenclamide | Risk of protracted hypoglycemia | Use conservative initial dose (1.25 mg/d for non-micronized glibenclamide; 0.75 mg/d for micronized glibenclamide) and maintenance dose; not recommended if CrCl <50 mL/min. M | Diet; metformin (<2 × 850 mg/d); insulin; gliclazide may be safer than the other short-acting sulphonilureas. E |
| Glimepiride | Risk of protracted hypoglycemia | Adjust according to renal function. E For patients with renal failure and for older people, use initial dose of 1 mg/d followed by a conservative titration scheme. Titrate dose in increments of 1 to 2 mg no more than every 1 to 2 weeks based on individual response. M | |
| Sitagliptine | Limited safety data available for adults aged ≥75 years old. Subjects aged 65 to 80 had higher plasma concentrations than younger subjects. Risk of hypoglycemia, dizziness, headache and peripheral oedema | Reduce dose to 50 mg/d in cases of renal failure (CrCl 30–50 mL/min); reduce dose to 25 mg/d in cases of severe renal insufficiency (CrCl <30 mL/min). E, M | |
| Antithrombotic agents | |||
| Acenocoumarol | Risk of bleeding, especially in people with difficult control of INR value | ||
| Dipyridamole | Less efficient than aspirin; risk of vasodilatation and orthostatic hypotension. Proven beneficial only for patients with artificial heart valves | Clopidogrel; aspirin (<325 mg)b. E, L | |
| Iron preparations | |||
| Iron supplements / Ferrous sulfate (>325 mg/d) | Doses >325 mg/d do not considerably increase the amount absorbed but greatly increase the incidence of constipation | Intravenous iron. E | |
| Cardiovascular system | |||
| Cardiac glycosides | |||
| Digitoxin | Elevated glycoside sensitivity in older people (women > men); risk of intoxication | Calculate digitalizing doses based on lean body mass and maintenance doses using actual CrCl. M | For tachycardia/atrial fibrillation: beta-blockers (except oxprenolol, pindolol, propranolol, sotalol, nadolol, labetalol). E, P For congestive heart failure: diuretics (except spironolactone >25 mg/d), ACE inhibitors. E |
| Digoxin | Calculate digitalizing doses based on lean body mass and maintenance doses using actual CrCl. M For older people, use dose 0.0625–0.125 mcg/d; in cases of renal failure (CrCl 10–50 mL/min), administer 25–75 % of dose or every 36 h; in cases of renal failure (CrCl <10 ml/min), administer 10–25 % of dose or every 48 h. E | ||
| Antiarrhythmics, classes I and III | |||
| Amiodarone | Associated with QT interval problems and risk of provoking torsades de pointes | Start dose at the low end of the dosing range. M Use lower maintenance dose, e.g. 200 mg/48 h. E | Data suggest that for most older people rate control yields better balance of benefits and harms than rhythm control for most of older people. B |
| Other cardiac preparations | |||
| Trimetazidine | Can cause or worsen parkinsonian symptoms (tremor, akinesia, hyperthonia); caution in cases of moderate renal failure and with older people (>75 years old); efficacy for the treatment of tinnitus or dizziness not proven | 20 mg twice per day for patients with moderate renal insufficiency. E | |
| Antiadrenergic agents, centrally acting | |||
| Rilmenidine | Risk of orthostatic hypotension, bradycardia, syncope, CNS side effects (sedation, depression, cognitive impairment) | Reduce dose in cases of renal failure (CrCl <15 mL/min). M, E | Other antihypertensive drugs, e.g. ACE inhibitors, or other medication groups depending on comorbidity (exclude PIM). E |
| Antiadrenergic agents, peripherally acting | |||
| Doxazosin | Higher risk of orthostatic hypotension, dry mouth, urinary incontinence/ impaired micturition, CNS side effects (e.g. vertigo, light-headedness, somnolence) and cerebrovascular and cardiovascular disease | Start with half of usual dose, taper in and out. P Start with 0.5 mg/d (immediate release) or 4–8 mg/d (extended release). E | Other antihypertensive drugs, e.g. ACE inhibitors, or other medication groups depending on comorbidity (exclude PIM). E |
| Potassium-sparing agent | |||
| Spironolactone (>25 mg/d) | Higher risk of hyperkalaemia and hyponatremia in older people, especially if doses >25 mg/d, requiring periodic controls | Reduce dose in cases of moderate renal insufficiency. E, M GFR ≥50 mL/min/1.73 m: initial dose 12.5–25 mg/d, increase up to 25 mg 1–2/d; GFR 30–49 mL/min/1.73 m: initial dose 12.5 mg/d, increase up to 12.5–25 mg/d; reduce dose if potassium levels increase or renal function worsens. GFR <10 mL/min: avoid. M | Consider alternatives depending on the indication; exclude PIMs |
| Peripheral vasodilators | |||
| Pentoxifylline | No proven efficacy; unfavourable risk/benefit profile; orthostatic hypotension and fall risks are increased with most vasodilators | Reduce dose to 400 mg twice daily in cases of moderate renal failure and to 400 mg once daily in cases of severe renal failure; close monitoring for toxicities. Avoid use if CrCl <30 mL/min. M | |
| Beta blocking agents | |||
| Propranolol | Non-selective beta-adrenergic blocker; may exacerbate or cause respiratory depression; possible CNS adverse events | 3 doses of 20 mg daily E start low—go slow for older people and patients with renal failure. M | Depending on the indication: cardioselective beta-blockers, ACE inhibitors, diuretics. E |
| Sotalol | Start at half or one third of the typical dose and increase slowly. P Reduce dose and dosing interval in cases of renal failure. M | Cardioselective beta-blockers (e.g. metoprolol, bisoprolol, carvedilol, atenolol). E | |
| Selective calcium channel blockers with mainly vascular effects | |||
| Nifedipine (non-sustained-release) | Increased risk of hypotension; myocardial infarction; increased mortality | Lower initial dose, half of usual dose, taper in and out. P | Other antihypertensive drugs (amlodipine, cardioselective beta-blockers, ACE inhibitors, diuretics). E, L |
| Nifedipine (sustained-release) | Lower initial dose, half of usual dose, taper in and out. P Initial dose 30 mg/d; maintenance dose 30–60 mg/d. E | ||
| Selective calcium channel blockers with direct cardiac effects | |||
| Verapamil | May worsen constipation; risk of bradycardia | Immediate-release tablets: initial dose 40 mg three times daily; sustained release tablets initial dose 120 mg daily; oral controlled onset extended release initial dose 100 mg/d. M | Other antihypertensive drugs (amlodipine, cardioselective beta-blockers, ACE inhibitors, diuretics). E |
| Diltiazem | Reduce dose or increase dosing interval. M 60 mg three times daily. E | ||
| Oestrogens | |||
| Oestrogen | Evidence for carcinogenic potential (breast and endometrial cancer) and lack of cardioprotective effect in older women | Specific treatment for osteoporosis. E Local administration (i.e. vaginal application) considered safe and efficient. E, B | |
| Other urologicals, including antispasmodics | |||
| Oxybutynine (non-sustained-release) | Anticholinergic side effects (e.g. constipation, dry mouth, CNS side effects); ECG changes (prolonged QT) | Start immediate-release oxybutynin chloride in frail older people with 2.5 mg orally 2 or 3 times daily. M | Non-pharmacological treatment (pelvic floor exercises, physical and behavioural therapy). E |
| Oxybutynine (sustained-release) | |||
| Tolterodine (non-sustained-release) | 1 mg orally twice daily in cases of significantly impaired renal function. M | ||
| Tolterodine (sustained-release) | Use 2 mg orally once daily in cases of severe renal failure (CrCl 10–30 mL/min); avoid use if CrCl <10 mL/min. M | ||
| Solifenacin | Dose reduction may be needed. M | ||
| Anti-inflammatory and antirheumatic products, non-steroid (NSAID) | |||
| Diclofenac | Very high risk of GI bleeding, ulceration, or perforation, which may be fatal; cardiovascular contraindications | 50 mg/d; start using low dose; the risk of bleeding may be reduced if combined with proton-pump inhibitors (use <8 weeks, low dose). E | Paracetamol; ibuprofen (≤3 × 400 mg/d or for a period shorter than one week); naproxen (≤2 × 250 mg/d or for a period shorter than one week). E Opiods with lower risk of delirium (e.g. tilidine/naloxone, morphineb, oxycodone, buprenorphine, hydromorphone). E, P |
| Dexketoprofen | Start with lower dose, up to 50 mg/d in older people; in postoperative pain: 50 mg/d in case of renal or hepatic failure, maximum dose 50 mg/8 h; maximum length 48 h; the risk of bleeding may be reduced if combined with proton-pump inhibitors (use <8 weeks, low dose). E | ||
| Etoricoxib | Shortest possible duration of therapy. P Start with lower dose; the risk of bleeding may be reduced if combined with proton-pump inhibitors (use <8 weeks, low dose). E | ||
| Meloxicam | Very high risk of GI bleeding, ulceration, or perforation, which may be fatal | 11 mg/d; start with lower dose; the risk of bleeding may be reduced if combined with proton-pump inhibitors (use <8 weeks, low dose). E | |
| Ibuprofen (>3 × 400 mg/d or for a period longer than one week) | Risk of GI bleeding and increased risk of cardiovascular complications at higher doses (>1200 mg/d), especially in case of previous cardiovascular disease | The risk of bleeding may be reduced if combined with proton-pump inhibitors (use <8 weeks, low dose). E | |
| Drugs affecting bone structure and mineralization | |||
| Strontium ranelate | Higher risk of venous thromboembolism in persons who are temporarily or permanently immobilised. Evaluate the need for continued therapy for patients over 80 years old with increased risk of venous thromboembolism | Avoid in cases of severe renal failure (CrCl <30 mL/min). M | Bisphosphonates, vitamin D. E |
| Opioids | |||
| Tramadol (sustained-release) | More adverse effects in older people; CNS side effects such as confusion, vertigo and nausea | Start low—go slow. Not to be used in cases of severe renal failure. E, M | Paracetamol; ibuprofen (≤3 × 400 mg/d or for a period shorter than one week); naproxen (≤2 × 250 mg/d or for a period shorter than one week). E Opioids with lower risk of delirium (e.g. tilidine/naloxone, morphineb, oxycodone, buprenorphine, hydromorphone). E, P |
| Tramadol (non-sustained-release) | Start low—go slow; in persons older than 75 years, daily doses over 300 mg are not recommended. M Start with 12.5 mg/8 h and progressive increases of 12.5 mg/8 h; maximum 100 mg/8 h. E Reduce dose and extend the dosing interval for patients with severe renal failure. M | ||
| Antiepileptics | |||
| Clonazepam | Risk of falls, paradoxical reactions. | Start low—go slow; 0.5 mg/day. E | Levetiracetamb; gabapentinb; lamotrigineb; valproic acidb. E |
| Carbamazepine | Increased risk of SIADH-like syndrome; adverse events like carbamazepine-induced confusion and agitation, atrioventricular block and bradycardia | Adjust dose to the response and serum concentration. E | |
| Dopaminergic agents | |||
| Ropinirole | Risk of orthostatic hypotension, hallucinations, confusion, somnolence, nausea | Start with three intakes of 0.25 mg per day, increase gradually by 0.25 mg per intake each week for four weeks, up to 3 mg/d. Afterwards the dose may be increased weekly by 1.5 mg/d up to 24 mg/d. E | Levodopa; carbidopa-levodopa; benserazide levodopa; irreversible inhibitor of monoamine oxidase as rasagiline. E |
| Pramipexole | Side effects include orthostatic hypotension, GI tract symptoms, hallucinations, confusion, insomnia, peripheral oedema | Reduce dose in cases of moderate to severe renal failure. M Start with three intakes of 0.125 per day, increase gradually by 0.125 mg per intake every five to seven days, up to 1.5 to 4.5 mg. E | |
| Antipsychotics | |||
| Chlorpromazine | Muscarinic-blocking drug; risk of orthostatic hypotension and falls; may lower seizure thresholds in patients with seizures or epilepsy | Start low—go slow; use one third to one half the normal adult dose for debilitated older people; use maintenance doses of 300 mg or less; doses greater than 1 g do not usually offer any benefit, but may be responsible for an increased incidence of adverse effects. M | Non-pharmacological treatment; risperidone (<6 weeks), olanzapine (<10 mg/d), haloperidol (<2 mg single dose; < 5 mg/d); quetiapineb. E |
| Levomepromazine | Anticholinergic and extrapyramidal side effects (tardive dyskinesia); parkinsonism; hypotonia; sedation; risk of falling; increased mortality in persons with dementia | Administer cautiously in cases of renal failure; start with doses of 5 to 10 mg in geriatric patients. M | |
| Haloperidol (>2 mg single dose; >5 mg/d) | Use oral doses of 0.75-1.5 mg; use for the shortest period possible. E | ||
| Zuclopenthixol | Risk of hypotension, falls, extrapyramidal effects, QTc-prolongation | Use low oral doses of 2.5–5 mg/d. M | |
| Clozapine | Anticholinergic and extrapyramidal side effects (tardive dyskinesia); parkinsonism; hypotonia; sedation; risk of falling; increased mortality in persons with dementia; increased risk of agranulocytosis and myocarditis | Start with 12.5 mg/d. E Start low—go slow; reduce dose in cases of significant renal failure. M | |
| Risperidone (>6 weeks) | Problematic risk-benefit profile for the treatment of behavioural symptoms of dementia; increased mortality, with higher dose, in patients with dementia | Use the lowest dose required (0.5–1.5 mg/d) for the shortest time period necessary. E For geriatric patients or in cases of severe renal failure (CrCl <30 mL/min), start with 0.5 mg twice daily; increase doses by 0.5 mg twice daily; increases above 1.5 mg twice daily should be done at intervals of at least 1 week; slower titration may be necessary. For geriatric patients, if once-daily dosing desired, initiate and titrate on a twice-daily regimen for 2 to 3 days to achieve target dose and switch to once-daily dosing thereafter. M | |
| Anxiolytics | |||
| Diazepam | Risk of falling with hip fracture; prolonged reaction times; psychiatric reactions (can also be paradoxical, e.g. agitation, irritability, hallucinations, psychosis); cognitive impairment; depression | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P, M Use initial oral dose of 2–2.5 mg once a day to twice a day. M | Non-pharmacological treatment; low doses of short-acting benzodiazepines such as lormetazepam (≤0.5 mg/d), brotizolam (≤0.125 mg/d); antidepressants with anxiolytic profile (SSRIc). E, P If used as hypnotics or sedatives: see alternatives proposed for “hypnotics and sedatives” |
| Lorazepam (>1 mg/d) | Reduce dose; use doses of 0.25–1 mg/d. E | ||
| Bromazepam | Use the lowest possible dose, up to half of the usual dose, taper in and out according to individual response, shortest possible duration of treatment. P, M | ||
| Alprazolam | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P Starting dose 0.25 mg/12 h. E Immediate release tablets (including orally disintegrating tablets): start with 0.25 mg administered two to three times a day and titrate as tolerated; extended-release tablets: start with 0.5 mg once daily, gradually increase as needed and tolerated. M | ||
| Hypnotics and sedatives | |||
| Flunitrazepam | Risk of falls and hip fracture, prolonged reaction time, psychiatric reactions (which can be paradoxical, e.g. agitation, irritability, hallucinations, psychosis), cognitive impairment and depression | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P Reduce dose, e.g. 0.5 mg/d; start low—go slow. E, M For induction of anaesthesia in older, poor-risk people, titrate dose carefully; administer in small intravenous increments of 0.3 to 0.5 mg, at 30-s intervals. M | Non-pharmacological treatment; mirtazapineb; passiflora, low doses of short-acting benzodiazepines such as lormetazepam (≤0.5 mg/d), brotizolam (≤0.125 mg/d); zolpidem (≤5 mg/d), zopiclon (≤3.75 mg/d), zaleplon (≤5 mg/d); trazodone. E, P |
| Lormetazepam (>0.5 mg/d) | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P | ||
| Temazepam | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P Start with 7.5 mg/d and watch individual response. M | ||
| Zopiclone (>3.75 mg/d) | Use the lowest possible dose, up to half of the usual dose, taper in and out, shortest possible duration of treatment. P | ||
| Zolpidem (>5 mg/d) | |||
| Clomethiazole | Risk of respiratory depression | Reduce dose. E, M Use sedative dose 500–1000 mg at bedtime. M | |
| Antidepressants | |||
| Amitriptyline | Peripheral anticholinergic side effects (e.g. constipation, dry mouth, orthostatic hypotension, cardiac arrhythmia); central anticholinergic side effects (drowsiness, inner unrest, confusion, other types of delirium); cognitive deficit; increased risk of falling | Start at half the usual daily dose, increase slowly; reduce dose; start with 10 mg 3 times per day and 20 mg at bedtime. M, E, P Its use for treating neuropathic pain may be considered appropriate, with benefits overweighting the risks. E | Non-pharmacological treatment, SSRI (except PIM: fluoxetine, paroxetine, fluvoxamine)c, mirtazapineb, trazodone. E |
| Nortriptyline | Use 30–50 mg/d in divided doses. E, M Its use for treating neuropathic pain may be considered appropriate, with benefits overweighting the risks. E | ||
| Fluoxetine | CNS side effects (nausea, insomnia, dizziness, confusion); hyponatremia | Reduce dose; start with 20 mg/d; maximum dose also 20 mg/d; avoid administration at bedtime. E, M | |
| Paroxetine | Higher risk of all-cause mortality, higher risk of seizures, falls and fractures. Anticholinergic adverse effects | For older people or for patients with renal failure, start immediate-release tablets with 10 mg/d (12.5 mg/d if controlled-release tablets), increased by 10 mg/d (12.5 mg/d if controlled-release tablets), up to 40 mg/d (50 mg/d if controlled-release tablets). E, M | |
| Venlafaxine | Higher risk of all-cause mortality, attempted suicide, stroke, seizures, upper gastrointestinal bleeding, falls and fracture | Start with 25–50 mg, two times per day and increase by 25 mg/dose; for extended-release formulation start with 37.5 mg once daily and increase by 37.5 mg every 4–7 days as tolerated. E Reduce the total daily dose by 25–50 % in cases of mild to moderate renal failure. M | |
| Psychostimulants, agents used for ADHD and nootropics | |||
| Piracetam | No efficacy proven; unfavourable risk/benefit profile | Reduce dose for older people and for patients with renal failure. M | Non-pharmacological treatment; consider pharmacotherapy of Alzheimer-type dementia: acetylcholinesterase, memantine. E |
| Anti-dementia drugs | |||
| Ginkgo biloba | No efficacy proven; increased risk of orthostatic hypotension and fall | Non-pharmacological treatment; consider pharmacotherapy of Alzheimer-type dementia: acetylcholinesterase, memantine. E | |
| Other systemic drugs for airway diseases | |||
| Theophylline | Higher risk of CNS stimulant effects | Start with a 25 % reduction compared to the doses for younger people. E Start with a maximum dose of 400 mg/d; monitor serum levels and reduce doses if needed; for healthy older people (>60 years), theophylline clearance is decreased by an average of 30 %. M | |
| Cough suppressants, excluding combinations with expectorants | |||
| Codeine (>2 weeks) | Higher risk of adverse events (hypotension, sweating, constipation, vomiting, dizziness, sedation, respiratory depression). Avoid use for longer than 2 weeks for persons with chronic constipation without concurrent use of laxatives and for persons with renal impairment | Start treatment cautiously for older people (especially in cases of renal failure); start low—go slow; reduce dose to 75 % of the usual dose if GFR 10–50 mL/min and to 50 % if GFR <10 mL/min. M | If used for pain management consider alternative drugs proposed for “anti-inflammatory and antirheumatic products, non-steroid (NSAID)” |
| Antihistamines for systemic use | |||
| Promethazine | Anticholinergic side effects (e.g. confusion, sedation) | Reduce dose; start low—go slow. M Reduce starting dose to 6.25–12.5 mg for iv injection. M | Non-sedating, non-anticholinergic antihistaminesd like loratadine, cetirizine, but not terfenadine (which is PIM). E If used for insomnia see alternatives proposed for “hypnotics and sedatives” |
| Hydroxyzine | Anticholinergic side effects (e.g. constipation, dry mouth); impaired cognitive performance, confusion, sedation; electrocardiographic changes (prolonged QT) | Reduce dose to at least 50 % less than dose used for healthy younger people. E, M | Non-sedating, non-anticholinergic antihistaminesd like loratadine, cetirizine, but not terfenadine (which is PIM). E Alternative therapies depending on indication. E |
Note: if nothing is stated under “Dose adjustment/special considerations of use”, this means that no suggestion was made either by the experts or in Micromedex®
E experts, M Micromedex® [32], P PRISCUS list [22], L Laroche et al. (2007) [3], B Beers list (2012) [18], ACE angiotensin-converting enzyme, CNS central nervous system, ECG electrocardiographic, GI gastrointestinal, PIM potentially inappropriate medication, PPI proton-pump inhibitors, RTPC RightTimePlaceCare [23], SIADH syndrome of inappropriate antidiuretic hormone secretion, ADHD attention deficit hyperactivity disorder
Dosage abbreviations: CrCl creatinine clearance, d day, GFR glomerular filtration rate, iv intravenous, mcg micrograms, mg milligram, min minute, mL millilitre, q every
aOnly the details on the drugs most commonly used in the RTPC database are presented—see also EU(7)-PIM long version in Appendix 1
bCaution: this drug was judged to be questionable PIM
cThe following drugs belonging to this medication group were judged to be questionable PIM: citalopram, sertraline, and escitalopram
dIn the group of non-sedating antihistamines, only loratadine was evaluated and judged to be questionable PIM; other drugs such as cetirizine were not evaluated