PAXLOVID

Paxlovid is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir must be coadministered with ritonavir. Failure to correctly coadminister nirmatrelvir with ritonavir will result in plasma concentrations of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.

Posology The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) all taken together orally twice daily every 12 hours for 5 days. Paxlovid should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 5 days of onset of symptoms even if baseline COVID-19 symptoms are mild.

A missed dose should be taken as soon as possible and within 8 hours of the scheduled time, and the normal dosing schedule should be resumed. If more than 8 hours has elapsed, the missed dose should not be taken and the treatment should resume according to the normal dosing schedule.

If a patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course at the discretion of his/her healthcare provider. Special populations Paediatric population The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established.

Elderly No dosage adjustment is currently recommended for elderly patients. Renal impairment No dosage adjustment is needed in patients with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥ 60 to < 90 mL/min]. In patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min) or with severe renal impairment (eGFR < 30 mL/min) including those requiring haemodialysis, the dosage of Paxlovid should be reduced as shown in Table 1.

Paxlovid should be administered at approximately the same time each day for 5 days. 2).

Table 1:

Recommended dose and regimen for patients with renal impairment Renal function Days of treatment Dose and dose frequencya Moderate renal impairment (eGFR ≥ 30 to < 60 mL/min) Days 1-5 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily Day 1 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once Severe renal impairment (eGFR < 30 mL/min) including those requiring haemodialysisb Days 2-5 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily Abbreviation: eGFR=estimated glomerular filtration rate.

a. Paxlovid should be administered at approximately the same time each day for 5 days. b. On days of hemodialysis, the Paxlovid dose should be administered after hemodialysis. Special attention for patients with severe renal impairment Healthcare providers should pay special attention to dosing instructions for patients with severe renal impairment and alert the patient that the daily dose pack provided may contain more nirmatrelvir and ritonavir tablets than needed for accurate dosing in these patients.

Therefore, patients with severe renal impairment should be alerted that two tablets of nirmatrelvir with one tablet of ritonavir should be taken once on day 1 followed by one tablet of nirmatrelvir with one tablet of ritonavir once daily on days 2 to 5.

Special attention for patients with moderate renal impairment Healthcare providers should pay special attention to dosing instructions for patients with moderate renal impairment and alert the patient that the daily dose pack provided may contain more nirmatrelvir and ritonavir tablets than needed for accurate dosing in these patients.

Therefore, patients with moderate renal impairment should be alerted that only one tablet of nirmatrelvir with one tablet of ritonavir should be taken every 12 hours for 5 days. 6). Hepatic impairment No dosage adjustment of Paxlovid is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

2). Concomitant therapy with ritonavir- or cobicistat-containing regimen No dosage adjustment is needed; the dose of Paxlovid is 300 mg/100 mg twice daily for 5 days. Patients diagnosed with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection who are receiving ritonavir- or cobicistat-containing regimen should continue their treatment as indicated.

Method of administration For oral use. 2). The tablets should be swallowed whole and not chewed, broken or crushed.

1). • Study C4671005 (EPIC-HR) and Study C4671002 (EPIC-SR) investigated Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) every 12 hours for 5 days in symptomatic participants with a laboratory confirmed diagnosis of SARS- CoV-2 infection.

Participants were to present with mild-to-moderate COVID- 19 at baseline. • Study C4671006 (EPIC-PEP) investigated Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) every 12 hours for 5 or 10 days in asymptomatic household contact of individuals with a recent diagnosis of SARS-CoV-2 infection.

Participants were to have a negative SARS-CoV-2 result at baseline. Across the three studies, 3,515 participants received a dose of Paxlovid and 2,585 participants received a dose of placebo. 9%, respectively). The safety profile of Paxlovid in participants with severe renal impairment, including those requiring haemodialysis, was consistent with the safety profile observed in the placebo-controlled trials.

Tabulated summary of adverse reactions The adverse reactions in Table 4 are listed below by system organ class and frequency.

Frequencies are defined as follows:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (frequency cannot be estimated from the available data).

Table 4:

Adverse reactions with Paxlovid System organ class Frequency category Adverse reactions Uncommon Hypersensitivity*Immune system disorders Rare Anaphylaxis* Nervous system disorders Common Dysgeusia, headache Vascular disorders Uncommon Hypertension* Common Diarrhoea, nausea*Gastrointestinal disorders Uncommon Vomiting, abdominal pain* Skin and subcutaneous tissue disorders Rare Toxic epidermal necrolysis*, Stevens-Johnson syndrome* General disorders and administration site conditions Rare Malaise* * Adverse drug reaction (ADR) identified post-marketing.

Paediatric population The safety and efficacy of Paxlovid in paediatric patients have not been established. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

Risk of serious adverse reactions due to interactions with other medicinal products Initiation of Paxlovid, a CYP3A inhibitor, in patients receiving medicinal products metabolised by CYP3A or initiation of medicinal products metabolised by CYP3A in patients already receiving Paxlovid, may increase plasma concentrations of medicinal products metabolised by CYP3A.

Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Paxlovid, respectively. These interactions may lead to: • Clinically significant adverse reactions, potentially leading to severe, life-threatening or fatal events from greater exposures of concomitant medicinal products.

• Clinically significant adverse reactions from greater exposures of Paxlovid. • Loss of therapeutic effect of Paxlovid and possible development of viral resistance. Severe, life-threatening, and fatal adverse reactions due to drug interactions have been reported in patients treated with Paxlovid.

5). Potential for interactions should be considered with other medicinal products prior to and during Paxlovid therapy; concomitant medicinal products should be reviewed during Paxlovid therapy and the patient should be monitored for the adverse reactions associated with the concomitant medicinal products.

The risk of interactions with concomitant medications during the 5-day treatment period for Paxlovid should be weighed against the risk of not receiving Paxlovid. 5). 8). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Paxlovid and initiate appropriate medications and/or supportive care.

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.

HIV resistance As 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. Excipients Lactose Nirmatrelvir tablets contain lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

1. - with severe hepatic impairment. Paxlovid is also contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions.

Paxlovid is also contraindicated with medicinal products that are potent CYP3A inducers where significantly reduced plasma nirmatrelvir/ritonavir concentrations may be associated with the potential for loss of virologic response and possible resistance.

5) are a guide and not considered a comprehensive list of all possible medicinal products that may be contraindicated with Paxlovid.

Table 2:

Medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir Medicinal product class Medicinal products within class Clinical comments Interactions that result in increased concentrations of concomitant medicinal product as Paxlovid inhibits their CYP3A4 metabolic pathway Alpha1-adrenoreceptor antagonist alfuzosin Increased plasma concentrations of alfuzosin may lead to severe hypotension.

Antianginal ranolazine Potentially increased plasma concentrations of ranolazine may result in serious and/or life-threatening reactions. Anticancer agents neratinib venetoclax Increased plasma concentrations of neratinib which may increase the potential for serious and/or life-threatening reactions including hepatotoxicity.

Increased plasma concentrations of venetoclax which may increase the risk of tumour lysis syndrome at Table 2: Medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir Medicinal product class Medicinal products within class Clinical comments the dose initiation and during the dose-titration phase.

Antiarrhythmics amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine Potentially increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone and quinidine may result in arrhythmias or other serious adverse effects.

Antibiotic fusidic acid Increased plasma concentrations of fusidic acid and ritonavir. Anti-gout colchicine Increased plasma concentrations of colchicine may result in serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.

Antihistamines astemizole, terfenadine Increased plasma concentrations of astemizole and terfenadine may result in serious arrhythmias from these agents. Antipsychotics/neuroleptics lurasidone, pimozide quetiapine Increased plasma concentrations of lurasidone and pimozide result in serious and/or life-threatening reactions.

Increased plasma concentrations of quetiapine may lead to coma. Benign prostatic hyperplasia agents silodosin Increased plasma concentrations of benign prostatic hyperplasia agent. Cardiovascular agents eplerenone, ivabradine Increased plasma concentrations of cardiovascular agents.

Ergot derivatives dihydroergotamine, ergonovine, ergotamine, methylergonovine Increased plasma concentrations of ergot derivatives leading to acute ergot toxicity, including vasospasm and ischaemia. GI motility agent cisapride Increased plasma concentrations of cisapride, thereby increasing the risk of Table 2: Medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir Medicinal product class Medicinal products within class Clinical comments serious arrhythmias from this agent.

Immunosuppressants voclosporin Increased plasma concentrations of immunosuppressant. Lipid-modifying agents HMG-CoA reductase inhibitors Microsomal triglyceride transfer protein (MTTP) inhibitor lovastatin, simvastatin lomitapide Increased plasma concentrations of lovastatin and simvastatin resulting in increased risk of myopathy, including rhabdomyolysis.

Increased plasma concentrations of lomitapide. Migraine medications eletriptan, ubrogepant Increased plasma concentrations of migraine medications. Mineralocorticoid receptor antagonists finerenone Increased plasma concentrations of mineralocorticoid receptor antagonist.

Opioid antagonists naloxegol Increased plasma concentrations of opioid antagonist. PDE5 inhibitors avanafil, vardenafil sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH) Increased plasma concentrations of avanafil and vardenafil.

Increased plasma concentrations of sildenafil can potentially result in visual abnormalities, hypotension, prolonged erection and syncope. Sedative/hypnotics triazolam, oral midazolama Increased plasma concentrations of triazolam and oral midazolam can increase risk of extreme sedation and respiratory depression.

Serotonin receptor 1A agonists/serotonin receptor 2A antagonists flibanserin Increased plasma concentrations of serotonin receptor 1A agonist/serotonin receptor 2A antagonist.

Vasopressin receptor tolvaptan Increased plasma Table 2:

Medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir Medicinal product class Medicinal products within class Clinical comments antagonists concentrations of vasopressin receptor antagonist. Interactions that result in decreased concentrations of nirmatrelvir/ritonavir as the concomitant medicinal products induce Paxlovid’s CYP3A4 metabolic pathway Anticonvulsants carbamazepinea, phenobarbital, phenytoin, primidone Decreased plasma concentrations of nirmatrelvir/ritonavir may lead to loss of virologic response and possible resistance.

Anticancer agents enzalutamide Decreased plasma concentrations of nirmatrelvir/ritonavir may lead to loss of virologic response and possible resistance. Antimycobacterials rifampicin, rifapentine Potentially decreased plasma concentrations of nirmatrelvir/ritonavir may lead to loss of virologic response and possible […]