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About PAXLOVIDAbout
PAXLOVID

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High-Risk Factors & When to TreatDosingMechanism of ActionEfficacyEfficacy

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PAXLOVID has been assessed in the EPIC-HR clinical trial and real-world evidence (RWE) studies

In contrast to EPIC-HR, the Lewnard JA, et al real-world study of PAXLOVID included vaccinated patients and data from the Omicron era.1

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Randomized Controlled Trials (RCTs)2-4
  • Gold standard for medical scientific evidence
  • Measure efficacy and safety/tolerability
  • Answer questions in a controlled setting with well-defined inclusion/exclusion criteria

RWE2
  • Can address a wider range of questions
  • Measures effectiveness and safety/tolerability
  • Answers questions in variable real-world practice settings

Limitations of RWE Studies5-8

  • RWE analyses can only evaluate association, not causation, and therefore answer different questions than RCTs
  • Patients are not randomized, and therefore are not suitable for direct comparison with clinical trial results
  • The source and type of data used may limit the ability to generalize results and endpoints
  • There are varying levels of data availability and quality, including missing or incorrectly coded data, and fewer standards around study designs, which may lead to a range of robustness in RWE studies
Despite their limitations, RWE can complement data from RCTs by providing a more comprehensive clinical picture that may be useful to inform healthcare decision-making.2,3Lewnard study limitations1
Capture of several variables was incomplete within the data, and potential misclassification of immunity due to undiagnosed previous SARS-CoV-2 infections or those never reported to Kaiser Permanente Southern California (KPSC) remains a concern
Unmeasured confounding could have hindered causal inference. For example, other antivirals and monoclonal antibody therapies were rarely prescribed in the study sample but probably would have reduced the effectiveness of nirmatrelvir-ritonavir compared with not receiving nirmatrelvir-ritonavir, as these treatments were prioritized for patients who could not receive nirmatrelvir-ritonavir because of potential drug interactions
The investigators could not verify whether people who received nirmatrelvir-­ritonavir adhered to treatment as recommended
Approach to variable selection via a directed acyclic graph, and use of matching to accommodate potential interactions among confounding variables, prioritized validity over precision of estimates, resulting in wide confidence intervals
Because of the low risk of severe disease within the highly vaccinated study population, the primary and secondary endpoints occurred rarely among both treatment recipients and nonrecipients, further limiting the precision of the estimates and the ability to explore effect modification
The endpoint of hospital admission or death due to any cause after a positive outpatient SARS-CoV-2 test might have captured admissions unrelated to COVID-19
The adjusted hazard ratios used to calculate effectiveness could have been affected by underlying depletion-of-susceptibles bias
References:1. Lewnard JA, McLaughlin JM, Malden D, et al. Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system. Lancet Infect Dis. 2023;23(7):806-815. 2. Camm AJ, Fox KAA. Strengths and weaknesses of 'real-world' studies involving non-vitamin K antagonist oral anticoagulants. Open Heart. 2018;5(1):e000788 3. Chen D. Real-world studies: bridging the gap between trial-assessed efficacy and routine care. J Biomed Res. 2022;36(3):147-154. 4. Kabisch M, Ruckes C, Seibert-Grafe M, Blettner M. Randomized controlled trials: part 17 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2011;108(39):663-668. 5. Khosla S, White R, Medina J, et al. Real world evidence (RWE) - a disruptive innovation or the quiet evolution of medical evidence generation? F1000Res. 2018;7:111. 6. Berger ML, Sox H, Willke RJ, et al. Good practices for real-world data studies of treatment and/or comparative effectiveness: recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making. Pharmacoepidemiol Drug Saf. 2017;26(9):1033-1039. 7. Garrison LP Jr, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5):326-335. 8. Blonde L, Khunti K, Harris SB, Meizinger C, Skolnik NS. Interpretation and impact of real-world clinical data for the practicing clinician. Adv Ther. 2018;35(11):1763-1774.

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Important Safety Information
 WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID
  • PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, and/or fatal events
  • Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess for potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring
  • Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed
PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions (eg, toxic epidermal necrolysis or Stevens-Johnson syndrome) to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care. PAXLOVID is contraindicated with drugs that are primarily metabolized by CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions and drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. There are certain other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, interruption, or therapeutic monitoring is recommended. Drugs listed here are a guide and not considered a comprehensive list of all drugs that may be contraindicated with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor like PAXLOVID. Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions:
  • Alpha 1-adrenoreceptor antagonist: alfuzosin
  • Antianginal: ranolazine
  • Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
  • Anti-gout: colchicine (in patients with renal and/or hepatic impairment)
  • Antipsychotics: lurasidone, pimozide
  • Benign prostatic hyperplasia agents: silodosin
  • Cardiovascular agents: eplerenone, ivabradine
  • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
  • HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use)
  • Immunosuppressants: voclosporin
  • Microsomal triglyceride transfer protein inhibitor: lomitapide
  • Migraine medications: eletriptan, ubrogepant
  • Mineralocorticoid receptor antagonists: finerenone
  • Opioid antagonists: naloxegol
  • PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension
  • Sedative/hypnotics: triazolam, oral midazolam
  • Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
  • Vasopressin receptor antagonists: tolvaptan

Drugs that are strong CYP3A inducers: PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer:

  • Anticancer drugs: apalutamide, enzalutamide
  • Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
  • Antimycobacterials: rifampin, rifapentine
  • Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
  • Herbal Products: St. John’s Wort (hypericum perforatum)
 Risk of Serious Adverse Reactions Due to Drug Interactions: Initiation of PAXLOVID, which contains ritonavir, a strong CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:
  • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications
  • Loss of therapeutic effect of PAXLOVID and possible development of viral resistance
Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (eg, tacrolimus, cyclosporine), followed by calcium channel blockers. Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Because nirmatrelvir is coadministered 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. The most common adverse reactions in the PAXLOVID group (≥1%) that occurred at a greater frequency than in the placebo group were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively). The following adverse reactions have been identified during use of PAXLOVID under Emergency Use Authorization: Immune System Disorders: Anaphylaxis, hypersensitivity reactions Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome Nervous System Disorders: Headache Vascular Disorders: Hypertension Gastrointestinal Disorders: Abdominal pain, nausea, vomiting General Disorders and Administration Site Conditions: Malaise PAXLOVID is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp, and OATP1B1. Coadministration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse events. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring.Pregnancy: Available data on the use of nirmatrelvir during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage. There are maternal and fetal risks associated with untreated COVID-19 in pregnancy.Lactation: Nirmatrelvir and ritonavir are present in human breast milk in small amounts (less than 2%). There are no available data on the effects of nirmatrelvir or ritonavir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition.Contraception: Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception. Pediatrics: The optimal dose of PAXLOVID has not been established in pediatric patients. Renal impairment increases nirmatrelvir exposure. Reduce the PAXLOVID dosage in patients with moderate renal impairment (eGFR ≥30 to <60 mL/min). Reduce the dose and dose frequency in patients with severe renal impairment (eGFR <30 mL/min), including those requiring hemodialysis. On days when patients undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions. PAXLOVID is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). Please see Full Prescribing Information, including BOXED WARNING and Patient Information INDICATIONINDICATIONPAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.Limitations of UsePAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19.Please see Full Prescribing Information, including BOXED WARNING and Patient Information
INDICATION PAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

Limitations of Use

PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19.

Please see Full Prescribing Information, including BOXED WARNING and Patient Information