COVID-19 drug Paxlovid could be risky for people taking these commonly used medications
Delhi: As the number of Omicron cases continues to increase in India and worldwide, recently approved antiviral pills could be a game-changer for the most vulnerable. However, the experts have cautioned that some of these new medications may not be safe for everyone and might require careful monitoring by doctors and pharmacists.
The U.S. Food and Drugs Administration (FDA) had recently given approval for Emergency Use Authorisation (EUA) Paxlovid, developed by Pfizer Inc for treating mild-to-moderate Covid-19 in adults and children 12 years and older, who are likely to be at greater risk for severe infection. This came after, in clinical trials Paxlovid was shown to reduce COVID-19-related hospitalization or death from any cause by 89% compared to placebo in patients treated within three days of symptom onset (as observed in the company's EPIC-HR trial). This degree of efficacy is probably the highest seen till now, however, use of the drug comes with a word of caution for patients with co-morbidities, due to the drug-to-drug interaction involved with the use of Paxlovid that can alter the systemic concentration of co-administered medications.
Paxlovid was authorized by US FDA for mild to moderate Covid in people as young as 12 having an underlying condition that increases the risk of hospitalization and death from the coronavirus, such as diabetes and heart disease.
Paxlovid's treatment is a combination of two pills taken over five days-- the Paxlovid cocktail consists of two tablets of the antiviral nirmatrelvir and one tablet of ritonavir. However, one of the two drugs in the antiviral cocktail could result in severe or life-threatening interactions with widely used medications, including blood thinners, statins, and some antidepressants. Further, Paxlovid is not recommended for people with severe kidney or liver disease.
As per the factsheet released by the USFDA, Co-administration of Paxlovid can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of Paxlovid. There is a need for doctors and pharmacists to consider the potential for drug interactions prior to and during the Paxlovid and review concomitant medications during Paxlovid therapy.
Paxlovid (nirmatrelvir co-packaged with ritonavir) is an inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Paxlovid's co-administration with drugs is highly dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring.
Ritonavir and nirmatrelvir are CYP3A substrates; therefore drugs that induce CYP3A may decrease the plasma concentrations of nirmatrelvir and ritonavir and in turn, reduce the therapeutic effect of Paxlovid.
Based on this, Paxlovid is contraindicated with the following drugs:
- Alpha1-adrenoreceptor antagonist: alfuzosin
- Analgesics: pethidine, piroxicam, propoxyphene
- Antianginal: ranolazine
- Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
- Anti-gout: colchicine
- Antipsychotics: lurasidone, pimozide, clozapine
- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: lovastatin, simvastatin
- PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension
- Sedative/hypnotics: triazolam, oral midazolam
Based on the FDA factsheet, Described below are the clinically significant drug interactions, including contraindicated drugs.
Calcium channel blockers
Caution is warranted and clinical monitoring of patients administered with amlodipine, diltiazem, felodipine, nicardipine, nifedipine, is recommended. A dose decrease may be needed for these drugs when co-administered with PAXLOVID.
If co-administered, refer to individual product label for calcium channel blocker for further information.
- Co-administration of apalutamide is contraindicated due to potential loss of virologic response and possible resistance.
- Avoid co-administration of encorafenib or ivosidenib due to the potential risk of serious adverse events such as QT interval prolongation. Avoid the use of neratinib, venetoclax or ibrutinib.
- Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects.
Alpha 1-adrenoreceptor antagonist
- Co-administration of alfuzosin is contraindicated due to potential hypotension.
- Co-administration of pethidine, piroxicam, propoxyphene is contraindicated due to the potential for serious respiratory depression or hematologic abnormalities.
- Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with Paxlovid.
- Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
- Co-administration of ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions.
- Co-administration of amiodarone, dronedarone, flecainide, propafenone, quinidine is contraindicated due to the potential for cardiac arrhythmias.
- Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics (bepridil, lidocaine (systemic) if available.
- Closely monitor INR if co-administration with warfarin is necessary.
- Increased bleeding risk with rivaroxaban. Avoid concomitant use.
- Co-administration of carbamazepinea, phenobarbital, phenytoin is contraindicated due to potential loss of virologic response and possible resistance.
- Monitor for an adequate clinical response to bupropion.
- Adverse reactions of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
- Avoid concomitant use of voriconazole.
- Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information.
- Co-administration of colchicine is contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.
- Ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor
- Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or protease inhibitor adverse events with concomitant use of these protease inhibitors.
- Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
- Co-administration of lurasidone, pimozide, clozapine contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias.
- If co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions.
- Co-administration of rifampin is contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered.
- Cardiac glycosides
- Caution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor Antagonists
- Discontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID.
- Co-administration of dihydroergotamine, ergotamine, methylergonovine is contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
Hepatitis C direct acting antivirals
- Increased grazoprevir concentrations can result in ALT elevations.
- It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir.
- Patients on ritonavir-containing HCV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or HCV drug adverse events with concomitant use.
- Co-administration of St. John's Wort (hypericum perforatum) is contraindicated due to potential loss of virologic response and possible resistance.
HMG-CoA reductase inhibitors
- Co-administration of lovastatin, simvastatin contraindicated due to potential for myopathy including rhabdomyolysis.
- Discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID.
- Consider temporary discontinuation of atorvastatin and rosuvastatin during treatment with PAXLOVID.
- An additional, non-hormonal method of contraception other than ethinyl estradiol should be considered.
- Therapeutic concentration monitoring is recommended for immunosuppressants (cyclosporine, tacrolimus, sirolimus).
- Avoid use of PAXLOVID when close monitoring of immunosuppressant serum concentrations is not feasible.
- Avoid concomitant use of sirolimus and PAXLOVID.
Long-acting beta-adrenoceptor agonist
- Co-administration of salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
- Co-administration of sildenafil is contraindicated due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope.
- Co-administration of triazolam, oral midazolam is contraindicated due to potential for extreme sedation and respiratory depression.
- Co-administration of midazolam (parenteral) should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
- Increased risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone should be considered.
"The drugs listed above are a guide and should not be considered a comprehensive list of all possible drugs that may interact with Paxlovid. There is a need for the healthcare provider to consult appropriate references for comprehensive information" the fact sheet stated.
To sum up, the medications include but are not limited to: blood thinners; anti-seizure medications; drugs for irregular heart rhythms, high blood pressure, and high cholesterol; antidepressants and anti-anxiety medications; immunosuppressants; steroids (including inhalers); HIV treatments; and erectile dysfunction medications.
The factsheet can be seen at the link below