Paxlovid 5-Day Has More Drug Interactions Than Almost Any Other Antiviral

If there's one thing that makes Paxlovid 5-Day complicated, it's the drug interactions. The Ritonavir component — which is included to boost the antiviral Nirmatrelvir — also blocks liver enzymes that process dozens of other medications. This can cause dangerous buildups of those drugs in your body or, in some cases, make Paxlovid itself less effective.

This guide covers the major and moderate interactions you need to know about, including specific drug names, supplements to watch, and exactly what to tell your doctor.

How Paxlovid Drug Interactions Work

To understand why Paxlovid interacts with so many medications, you need to know about CYP3A enzymes.

Your liver uses a family of enzymes called CYP450 to break down medications and other substances. One of the most important is CYP3A, which processes roughly 50% of all prescription drugs.

Ritonavir, the second drug in Paxlovid, is a powerful CYP3A inhibitor. It blocks these enzymes so that Nirmatrelvir (the antiviral) stays in your system longer and works better. But the same blocking effect applies to every other medication processed by CYP3A — meaning their levels can shoot up to dangerous concentrations.

The interactions go both ways:

• Ritonavir blocks CYP3A → Other drugs build up in your body → Potential toxicity
• CYP3A inducers speed up CYP3A → Nirmatrelvir gets broken down too fast → Paxlovid becomes less effective

Medications That Interact With Paxlovid 5-Day

Contraindicated (Do Not Take Together)

These medications cannot be taken with Paxlovid. The combination could cause life-threatening side effects:

• Cholesterol medications: Lovastatin (Mevacor), Simvastatin (Zocor) — risk of severe muscle breakdown (rhabdomyolysis)
• Heart rhythm medications: Amiodarone (Cordarone), Flecainide (Tambocor), Propafenone (Rythmol) — risk of fatal heart rhythm changes
• Sedatives: Oral Midazolam (Versed), Triazolam (Halcion) — risk of extreme sedation and respiratory depression
• Migraine medications: Ergotamine (Ergomar), Dihydroergotamine (D.H.E. 45, Migranal) — risk of ergot toxicity
• Psychiatric medications: Pimozide (Orap), Lurasidone (Latuda) — risk of serious cardiac effects
• Sildenafil for pulmonary hypertension: Sildenafil (Revatio) when used for PAH — dangerously low blood pressure
• Colchicine (in patients with kidney or liver impairment) — risk of fatal Colchicine toxicity
• Alfuzosin (Uroxatral) — risk of severe low blood pressure
• Fentanyl — risk of respiratory depression

Major Interactions (Require Dose Adjustments or Close Monitoring)

• Other statins: Atorvastatin (Lipitor) and Rosuvastatin (Crestor) — need dose reduction. Temporarily hold or reduce dose during the 5-day course.
• Blood thinners: Rivaroxaban (Xarelto) and Apixaban (Eliquis) — increased bleeding risk; may need to hold or reduce dose. Warfarin (Coumadin) — monitor INR closely.
• Immunosuppressants: Tacrolimus (Prograf), Cyclosporine (Neoral, Sandimmune), Sirolimus (Rapamune), Everolimus (Zortress) — levels can increase dramatically. Requires specialist management, often with drug level monitoring.
• Calcium channel blockers: Amlodipine (Norvasc), Nifedipine (Procardia), Felodipine — increased levels, monitor blood pressure closely.
• Sedatives: Alprazolam (Xanax) — dose reduction needed.
• Colchicine (in patients without kidney/liver impairment) — significantly reduce dose.
• Erectile dysfunction drugs: Sildenafil (Viagra) for ED, Tadalafil (Cialis) — reduce dose and increase time between doses.
• Quetiapine (Seroquel) — reduce dose significantly.

Moderate Interactions (Monitor and Discuss With Your Doctor)

• Hormonal contraceptives: Ethinyl Estradiol levels may decrease — use backup contraception during treatment and for one full cycle after.
• Certain antidepressants: SSRIs metabolized by CYP3A may have increased effects — monitor for side effects.
• Methadone: Monitor for decreased efficacy.

Medications That Reduce Paxlovid's Effectiveness

These are strong CYP3A inducers that speed up the breakdown of Nirmatrelvir, potentially making Paxlovid ineffective:

• Anticonvulsants: Carbamazepine (Tegretol), Phenobarbital, Phenytoin (Dilantin)
• Antibiotics: Rifampin (Rifadin)
• Herbal: St. John's Wort (see below)

If you take any of these medications, Paxlovid may not be the right treatment for you. Talk to your doctor about alternatives to Paxlovid.

Supplements and OTC Medications to Watch

• St. John's Wort — This is contraindicated with Paxlovid. It's a potent CYP3A inducer that can make Paxlovid ineffective. Stop taking it before starting treatment.
• Grapefruit and grapefruit juice — Can increase Nirmatrelvir levels. Avoid large quantities during the 5-day course.
• Acetaminophen (Tylenol) — Generally safe to take with Paxlovid for fever and pain.
• Ibuprofen (Advil) and Naproxen (Aleve) — Generally okay for short-term use, but check with your doctor if you have kidney issues.
• Antihistamines — Over-the-counter allergy medications are generally safe.

Food and Drink Interactions

• Grapefruit and grapefruit juice: Avoid large quantities — grapefruit inhibits CYP3A enzymes similarly to Ritonavir, which could increase drug levels further.
• Alcohol: No specific contraindication, but alcohol can stress your liver and immune system. It's best to avoid it while fighting COVID-19.
• Food: Paxlovid can be taken with or without food. No specific food restrictions beyond grapefruit.

What to Tell Your Doctor Before Starting Paxlovid

Before your provider prescribes Paxlovid, give them a complete list of:

1. All prescription medications — including the dose and how often you take each one
2. Over-the-counter medications — pain relievers, allergy meds, sleep aids, acid reducers
3. Supplements and vitamins — especially St. John's Wort, but list everything
4. Herbal products — some interact with CYP3A enzymes
5. Recreational substances — some may interact
6. Kidney and liver status — let your doctor know if you've been told you have kidney or liver problems
7. HIV status — Ritonavir is also used in HIV treatment; undiagnosed HIV could lead to drug resistance

Your doctor or pharmacist can then review the full list and determine whether Paxlovid is safe for you. In some cases, they may temporarily hold or adjust doses of your other medications during the 5-day course.

Final Thoughts

Paxlovid 5-Day's drug interactions are serious — but they're also manageable when your healthcare team knows about every medication and supplement you take. Don't skip Paxlovid just because you're worried about interactions. Instead, have an honest conversation with your doctor and pharmacist. They may be able to temporarily adjust your other medications to make Paxlovid safe for you.

If Paxlovid isn't an option due to interactions, there are effective alternatives available. And if you're ready to fill your prescription, use Medfinder to find a pharmacy with Paxlovid 5-Day in stock near you.