What are the common side effects of Paxlovid (nirmatrelvir and ritonavir) in adults with impaired renal function?

Side Effects of Paxlovid

Most Common Side Effects

The most frequently reported side effects of Paxlovid are dysgeusia (altered taste) and diarrhea, which occur more commonly than with placebo but do not typically lead to treatment discontinuation. 1

• Dysgeusia (altered taste) is one of the most characteristic adverse effects, occurring frequently enough to be mentioned across multiple guidelines 1, 2
• Diarrhea is the other primary gastrointestinal side effect reported in clinical trials 1, 2
• These adverse effects did not result in increased rates of drug discontinuation in clinical trials, indicating they are generally tolerable 1, 2
• Patients with renal impairment may experience more pronounced dysgeusia and diarrhea due to higher drug levels and should be monitored for signs of drug accumulation 2

Critical Safety Concerns: Drug-Drug Interactions

The primary safety concern with Paxlovid is the extensive potential for drug-drug interactions caused by ritonavir, which is a potent CYP3A4 inhibitor. 1, 2

Mechanism and Timing

• Ritonavir causes drug interactions during active treatment and possibly for several days after treatment completion through inhibition of gastrointestinal and hepatic CYP450 enzymes 1
• The ritonavir component can increase plasma concentrations of co-administered drugs metabolized by CYP3A4 by up to 20-fold in some cases 1

Contraindicated Medications

• Cardiovascular drugs: alfuzosin, amiodarone, quinidine 1
• Antihistamines: astemizole, terfenadine 1
• Gastrointestinal: cisapride 1
• Ergot derivatives 1
• Statins: lovastatin, simvastatin, atorvastatin 1, 2
• Sedatives: oral midazolam, triazolam 1
• Antipsychotics: quetiapine 1
• Pulmonary: salmeterol, sildenafil for pulmonary arterial hypertension 1
• Enzyme inducers: carbamazepine, phenytoin, phenobarbital, rifampicin, St John's wort, enzalutamide 1

Practical Management

• Use the Liverpool COVID-19 Drug Interaction Tool systematically before prescribing to check for specific interactions 1, 2
• Medications like statins may require temporary discontinuation during the 5-day treatment course 2
• A comprehensive drug-drug interaction program has been undertaken, and interactions should be checked as a combination effect 1

Hormonal Contraceptive Interactions

• Ritonavir may reduce the efficacy of combined hormonal contraceptives 3
• Patients should use an effective alternative contraceptive method or an additional barrier method during treatment and for a period after completion 3

Renal Function Considerations

Patients with renal impairment experience increased nirmatrelvir exposure, which elevates the risk of adverse reactions. 3, 4

Exposure Increases by Renal Function

• Mild renal impairment (eGFR 60-89 mL/min): 124% increase in nirmatrelvir exposure - no dose adjustment needed 4
• Moderate renal impairment (eGFR 30-59 mL/min): 187% increase in exposure - dose reduction to 150/100 mg twice daily required 1, 3, 4
• Severe renal impairment (eGFR <30 mL/min): 304% increase in exposure - dose and frequency reduction required 3, 4
• Prescribing Paxlovid is contraindicated in patients with severe renal impairment without appropriate dose adjustment 5

Monitoring Requirements

• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury 2
• Advanced age (>65 years) combined with renal impairment significantly increases risk of excessive plasma concentrations (odds ratio 11.2) 6
• Patients with renally excreted comedications are at higher risk for elevated plasma levels 6

Hepatic Impairment

• No dose adjustment is needed for mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment 3
• Paxlovid is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment due to lack of safety data 1, 3
• Trials excluded patients with severe liver impairment, so use should be cautious in this population 1, 2

Special Populations

Pregnancy and Breastfeeding

• Paxlovid may be an option for pregnant people to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions 1, 2
• No reports of serious adverse reactions in parent or child have been documented in WHO Vigibase to date 1, 2
• Nirmatrelvir and ritonavir are present in breast milk in small amounts (less than 2% of maternal weight-adjusted dose) 3
• The estimated daily infant dose is 1.8% for nirmatrelvir and 0.2% for ritonavir of the maternal dose 3

Elderly Patients

• No overall differences in safety were observed between elderly (≥65 years) and younger patients in clinical studies 3
• However, elderly patients had significantly higher plasma trough concentrations and greater risk of excessive drug levels 6
• Greater sensitivity in some older individuals cannot be ruled out 3

General Tolerability

• Treatment-related adverse events in clinical trials were predominantly mild in severity 4
• There were no significant findings regarding laboratory measurements, vital signs, or electrocardiogram assessments in renal impairment studies 4
• Paxlovid exhibited an acceptable safety profile across studied populations 4

Clinical Practice Implications

• Pharmacist involvement is essential when prescribing Paxlovid - 87.1% of patients required interventions to prevent drug-related problems in one study 5
• Pharmacist intervention at dispensing was needed in 63.6% of cases 5
• A total of 313 drug-drug interactions were recorded in 81.4% of patients, with severe interactions in 17% 5