Table 2. Management for Potentially Inappropriate Medications With Nirmatrelvir-Ritonavir Drug-Drug Interactions.
| PIMa | Interacting medication or class flagged as PIM, No./total No. (%)b | Triggering condition or medication for PIM alertc | General rationale for deprescribing | Preemptive deprescribing required? | Suggested medication management for nirmatrelvir-ritonavir interaction if unable to deprescribe in advance |
|---|---|---|---|---|---|
| Amiodarone | 61/126 (48.4) | Atrial fibrillation | Amiodarone is associated with multiple toxic effects, including thyroid disease, pulmonary disorders, and QT interval prolongation. Consider a safer alternative. | Yes | Do not coadminister. If unable to deprescribe well in advance (wks), likely precludes use of nirmatrelvir-ritonavir given increased risk of life-threatening cardiac arrhythmias. |
| Dronedarone | 12/29 (41.4) | Atrial fibrillation | Potential to increase mortality in older adults with heart failure. | Yes | Do not coadminister. If unable to deprescribe well in advance (d), likely precludes use of nirmatrelvir-ritonavir given increased risk of life-threatening cardiac arrhythmias. |
| Quinidine, flecainide, propafenone | NA | Atrial fibrillation | Data suggest that rate control yields better balance of benefits and harms than pharmacological rhythm control for most older adults. | No | Do not coadminister. If unable to deprescribe or hold, likely precludes use of nirmatrelvir-ritonavir given increased risk of life-threatening cardiac arrhythmias. |
| Digoxin | 31/225 (13.8) | Atrial fibrillation, CHF, CKD | A higher dose of digoxin (>125 µg daily) has an increased risk of toxic effect. | No | Adjust dose. Exercise caution. Individualize dose or dosing schedule based on plasma concentration, kidney function, and treatment indication. If digoxin levels are not available, evaluate the risks and benefits of coadministration. |
| Warfarin | 0/551 (0) | In combination with a second anticoagulant | Dual antithrombotic therapy increases the risk of major hemorrhage. | No | Adjust dose. Closely monitor anticoagulation parameters (INR) during coadministration. Warfarin dose may need to be increased. |
| Dabigatran | 6/111 (5.4) | eGFR <30 or in combination with a second anticoagulant | Dabigatran is not recommended at an eGFR<30; consider switching to apixaban or coumadin. Dual antithrombotic therapy increases the risk of major hemorrhage. | No | Adjust dose. Coadministration possible with dose reduction to 110 mg twice daily and clinical monitoring for signs of bleeding. |
| Rivaroxaban, apixaban | 0/977 (0) | In combination with a second anticoagulant | Dual antithrombotic therapy increases the risk of major hemorrhage. | No | Do not coadminister. Hold medication during coadministration with nirmatrelvir-ritonavir. Treatment should resume 3 d after last dose. Rivaroxaban carries a high risk for bleeding. Apixaban carries a moderate risk of bleeding. Some product monographs indicate a lower dose of apixaban (2.5 mg twice daily) may be coadministered. |
| Edoxaban | 0/3 (0) | In combination with a second anticoagulant | Dual antithrombotic therapy increases the risk of major hemorrhage. | No | Adjust dose. Coadministration is possible with dose reduction to 30 mg daily and clinical monitoring for signs of bleeding. |
| Ticagrelor, clopidogrel | 200/489 (41.0) | In combination with a second anticoagulant or reduced life expectancy/palliative | Dual antithrombotic therapy increases the risk of major hemorrhage. In general, dual antiplatelet therapy is time-limited after the insertion of a drug-eluting stent. Primary prevention with antiplatelet agents could be reconsidered in patients with limited life expectancy. | No | Do not coadminister; drug substitution. Prasugrel can be prescribed instead, unless the patient's clinical condition contraindicates its use. Coadministration with ticagrelor leads to increased risk of bleeding. Coadministration with clopidogrel leads to reduced efficacy and risk of thrombosis. |
| Phenobarbital | NA | Older adults without a seizure disorder or psychiatric condition | High rate of physical dependence, tolerance to sleep benefits, and risk of overdose at low doses. | Yes | Do not coadminister. If unable to deprescribe well in advance (wks), precludes use of nirmatrelvir-ritonavir because of decreased efficacy of nirmatrelvir-ritonavir and risk of developing virologic resistance. |
| Lovastatin, simvastatin, atorvastatin | 41/1901 (2.6) | Primary prevention in people with reduced life expectancy or receipt of palliative care | In patients with restricted life expectancy based on their age, demographics, and recent health care use, statins may offer little benefit and possible harm. | No | Hold medication during coadministration with nirmatrelvir-ritonavir. Treatment should only resume 3 d after last dose. Risk of severe myopathy and rhabdomyolysis. |
| Sildenafil, vardenafil | 2/28 (7.1) | In combination with isosorbide dinitrate | High risk of cardiovascular collapse. Avoid this combination of medications. | No | Do not coadminister. Hold medication during coadministration with nirmatrelvir-ritonavir. Treatment should resume 3 d after last dose. |
| Alfuzosin, tamsulosin | 174/779 (22.3) | Orthostatic hypotension or recurrent falls | High risk of orthostatic hypotension. Not recommended as routine treatment for hypertension. Alfuzosin is not recommended as routine treatment for hypertension. | No | Do not coadminister. Hold during therapy, and monitor for emergence of symptoms. Alfuzosin is absolutely contraindicated because of risk of severe orthostatic hypotension. Tamsulosin carries a moderate risk. |
| Clozapine, lurasidone, quetiapine, pimozide | 62/274 (22.6) | All older adults without a psychiatric disorder, such as schizophrenia or bipolar affective disorder | Do not routinely use antipsychotics for parkinsonism, dementia, and treatment of insomnia or sleep disorders. Increased risk of stroke, falls, confusion, extrapyramidal adverse effects, aspiration, and death. In parkinsonism, quetiapine and clozapine have a lower risk, but in general their use should be avoided. | Yes (for high doses) | Do not coadminister. If low dose for sleep or agitation (eg, <25 mg of quetiapine daily), consider holding during nirmatrelvir-ritonavir coadministration, and monitor closely for emergence of behavioral symptoms. For higher doses, do not coadminister. High risk of serious sedation and coma. Deprescribing usually requires tapering for higher doses. |
| Piroxicam | 1/1 (100) | Most older adults | Avoid NSAIDS with a history of ischemic heart disease, GI hemorrhages, hypertension, gastritis, CKD, GERD, or peptic ulcers because they may exacerbate the underlying condition. | No | Do not coadminister. Hold medication during coadministration because of potential for respiratory depression or hematologic abnormalities. |
| Fentanyl | 23/76 (30.3) | Older adults without cancer | Avoid opioids for chronic noncancer-related pain. | Yes | Do not coadminister. Fatal respiratory depression can occur. Temporarily holding maintenance, regular use opioids is not advised as this can precipitate withdrawal in the absence of tapering. Deprescribing requires tapering. |
| Methadone | 0/20 (0) | Older adults without cancer or treatment of substance use disorder | Avoid opioids for chronic noncancer-related pain. | Yes | Adjust dose. Increased methadone dose may be necessary when coadministered. |
| Diazepam, midazolam (oral), triazolam | 26/35 (74.3) | Older adults without a seizure disorder or severe anxiety | In general, all benzodiazepines increase risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. | Yes | Do not coadminister. If unable to deprescribe well in advance (wks), likely precludes use of nirmatrelvir-ritonavir. Deprescribing requires tapering. |
| Cisapride | NA | All older adults | Can cause extrapyramidal effects, including tardive dyskinesia. Risk may be greater in frail older adults and with prolonged exposure. | No | Do not coadminister. Hold medication during coadministration with nirmatrelvir-ritonavir because of known risk of life-threatening cardiac arrhythmias. |
| Colchicine | 41/117 (35.0) | Older adults with a reduced eGFR | There is a risk of colchicine toxic effects at reduced eGFR. Xanthine-oxidase inhibitors (eg, allopurinol and febuxostat) are first choice for prophylactic drugs in gout. | No | Do not coadminister. This interaction can be deadly, especially in patients with kidney and/or hepatic impairment. Life-threatening and fatal drug interactions have occurred with coadministration. |
Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GERD, gastroesophageal reflux disease; GI, gastrointestinal; INR, international normalized ratio; NA, not applicable; NSAID, nonsteroidal anti-inflammatory drug; PIM, potentially inappropriate medication.
a
Medication or medication class that interacts with nirmatrelvir-ritonavir.
b
Proportion of the interacting medication or medication class that was found to be potentially inappropriate by MedSafer. For example, 117 patients received colchicine prescription in the trial and 41 (35%) had the medication flagged as potentially inappropriate because of reduced kidney clearance.
c
Rationale for a medication being triggered as potentially inappropriate in the trial population. Examples included predisposing medical conditions (eg, orthostatic hypotension) or a second interacting medication (eg, 2 or more antithrombotic medications in the absence of a recent cardiac event or coronary artery stenting).