Side Effects of Paxlovid (Nirmatrelvir and Ritonavir)
Paxlovid commonly causes dysgeusia (altered taste sensation) and diarrhea, with no significant increase in adverse effects leading to drug discontinuation compared to placebo. 1
Common Side Effects
The most frequently reported side effects of Paxlovid include:
- Altered sense of taste (dysgeusia) - often described as metallic or bitter taste 2
- Diarrhea 1, 2
- Headache 2, 3
- Vomiting 2
- Abdominal pain 2
- Nausea 2
- High blood pressure 2
- Feeling generally unwell 2
Serious Side Effects
While less common, Paxlovid may cause serious side effects that require immediate medical attention:
1. Allergic Reactions
- Stop taking Paxlovid and seek medical help immediately if you experience: 2
- Skin rash, hives, blisters, or peeling skin
- Painful sores or ulcers in mouth, nose, throat, or genital area
- Swelling of mouth, lips, tongue, or face
- Trouble swallowing or breathing
- Throat tightness
- Hoarseness
2. Liver Problems
- Contact your healthcare provider right away if you develop: 2
- Loss of appetite
- Yellowing of skin and eyes
- Dark-colored urine
- Pale colored stools
- Itchy skin
- Abdominal pain
Neurological Side Effects
Recent analysis of FDA adverse event data shows that Paxlovid is associated with a higher number of neurological adverse events compared to other COVID-19 medications, with a strong signal value (ROR = 2.27) 3. The most common neurological side effects include:
- Dysgeusia (altered taste)
- Ageusia (loss of taste)
- Headache
- Anosmia (loss of smell)
These neurological side effects appear to be more common in female patients and typically occur within the first 30 days of treatment 3.
Drug Interactions - A Major Concern
The ritonavir component of Paxlovid is a potent inhibitor of CYP3A enzymes, which can lead to significant drug-drug interactions 1, 2, 4. This is one of the most important considerations when prescribing Paxlovid:
- Ritonavir affects metabolism and clearance of many medications during treatment and possibly for several days after treatment completion 1
- Approximately 60% of available medications have oxidative metabolism involving CYP3A4, making interactions common 5
- Of the top 100 most prescribed medications in the US for high-risk COVID-19 patients, 30 have potential interactions with Paxlovid 6
Medications contraindicated with Paxlovid include: 2
- Cardiovascular drugs (amiodarone, flecainide, propafenone, quinidine, etc.)
- Psychiatric medications (lurasidone, triazolam, etc.)
- Pain medications
- Certain statins (lovastatin, simvastatin)
- Ergot derivatives
- Various other medications
Special Considerations
Renal Impairment
- For moderate renal impairment (eGFR 30-59 mL/min): Reduce dose to 150 mg nirmatrelvir with 100 mg ritonavir twice daily 1, 2
- For severe renal impairment (including hemodialysis): Special dosing schedule required 2
Immunosuppressive Drugs
When coadministered with Paxlovid, immunosuppressive drugs require significant dosage adjustments: 4
- Tacrolimus: Should be discontinued or given as microdose on day 1
- Cyclosporine: Reduce to 20% of initial dosage during antiviral treatment
- mTOR inhibitors: Require dosage adjustments
- Mycophenolic acid and corticosteroids: Less affected
Effectiveness vs. Side Effects
Despite these side effects, Paxlovid has demonstrated significant benefits in reducing:
- Hospitalization risk by 39% (absolute risk reduction of 0.9 percentage points) 7
- Death risk by 61% (absolute risk reduction of 0.2 percentage points) 7
These benefits are particularly pronounced in patients aged 65+ years 7, making the side effect profile generally acceptable given the mortality and morbidity benefits.
Key Practical Points
- Always check for drug interactions before prescribing (use resources like the Liverpool COVID-19 drug interaction tool) 1
- Take Paxlovid with or without food at approximately the same time each day 2
- Complete the full 5-day treatment course 2
- If a dose is missed within 8 hours, take it as soon as possible; if more than 8 hours have passed, skip the missed dose 2
- Do not double the dose to make up for a missed dose 2