Nirmatrelvir

Oral
Coronavirus disease 2019 (COVID-19)

Severe (eGFR <30 mL/min/1.73 m²): Not recommended until more data are available. Moderate (eGFR ≥30 to <60 mL/min/1.73 m²): Reduce dose to 150 mg (one tablet) nirmatrelvir to be taken together with 100 mg (one tablet) ritonavir bid for 5 days. Mild (eGFR ≥60 to <90 mL/min/1.73 m²): No dosage adjustment required.

Mild to moderate (Child-Pugh class A to class B): No dosage adjustment required. Severe (Child-Pugh class C): Currently, pharmacokinetic or safety data of giving nirmatrelvir with ritonavir in patients with severe hepatic impairment have not been established; until such data are available, use in these patients is not recommended.

May be taken with or without food. Swallow whole, do not chew/break/crush.

History of clinically significant hypersensitivity reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) to nirmatrelvir or ritonavir. Concomitant use with drugs that are highly dependent on CYP3A isoenzyme for clearance and for which increased concentrations are associated with serious adverse reactions (e.g. alfuzosin, pethidine, propoxyphene, piroxicam, ranolazine, amiodarone, bepridil, dronedarone, propafenone, quinidine, flecainide, encainide, neratinib, venetoclax, colchicine, clozapine, quetiapine, lurasidone, pimozide, dihydroergotamine, ergotamine, methylergonovine, ergonovine, lovastatin, simvastatin, lomitapide, astemizole, terfenadine, cisapride, fusidic acid, silodosin, eplerenone, ivabradine, eletriptan, ubrogepant, voclosporin, finerenone, naloxegol, flibanserin, tolvaptan, oral midazolam, triazolam, clorazepate, clonazepam, diazepam, estazolam, flurazepam, avanafil, tadalafil, vardenafil, sildenafil [when used for pulmonary arterial hypertension]). Concurrent use with potent CYP3A inducers (e.g. apalutamide, carbamazepine, phenobarbital, primidone, phenytoin, rifampicin, lumacaftor/ivacaftor, St. John's wort).

Patient with pre-existing liver enzyme abnormalities, hepatitis, or liver diseases. Co-administration of nirmatrelvir with ritonavir (HIV-1 protease inhibitor) may increase the risk of developing resistance to HIV-1 protease inhibitor in individuals with uncontrolled or undiagnosed HIV-1 infection. Patients taking other ritonavir- or cobicistat-containing HIV or hepatitis C virus (HCV) regimens must continue their therapy as indicated; no dosage adjustment is needed when nirmatrelvir with ritonavir is co-administered with other products containing ritonavir or cobicistat. Renal and hepatic impairment. Children. Pregnancy and lactation; use only if potential benefits justify potential risks as there is limited data regarding the use of nirmatrelvir with ritonavir in pregnant and lactating women.

It should be noted that:

- Use of nirmatrelvir with ritonavir for the treatment of COVID-19 have not been fully established, some data are available from several initial clinical trials in the US and other countries.
- According to microbiological studies, nirmatrelvir has shown antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line, following 3 days of drug exposure. Additionally, it exhibited similar cell culture antiviral activity against SARS-CoV-2 isolates belonging to Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621), and Omicron (B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.4, and BA.5) variants. Currently, the Beta (B.1.351) variant was the least susceptible tested variant (approx 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate). Data on the antiviral activity of nirmatrelvir evolve through time as clinical trials are being conducted continuously. For more information on the antiviral activity of nirmatrelvir, refer to the latest local guidelines.
- Nirmatrelvir co-packaged with ritonavir may be available for use in some countries under emergency use authorisation (EUA) or conditional approval. Registration status and/or availability may vary between countries.
- The safety and efficacy of nirmatrelvir with ritonavir for the treatment of mild to moderate cases of COVID-19 continue to be evaluated. Preliminary clinical trial data showed that the use of nirmatrelvir with ritonavir early in the disease process when viral loads are high provided maximum benefit and reduced the risk of hospitalisation and/or death when given within 5 days of onset of symptoms.
- Currently available COVID-19 treatment guidelines recommend limiting the use of nirmatrelvir with ritonavir to nonhospitalised patients with mild to moderate cases who are at high risk of progression to severe COVID-19, including hospitalisation. If the patient requires hospitalisation due to severe or critical COVID-19 after treatment initiation, the remainder of the full 5-day treatment course may be completed per the discretion of the healthcare provider.
- Nirmatrelvir with ritonavir is not indicated for use as pre-exposure or postexposure prophylaxis of COVID-19.
- Completion of the recommended full 5-day treatment course and continued isolation in accordance with the local public health guidelines are important to maximise viral clearance and minimise SARS-CoV-2 transmission.

For healthcare professionals:

- Refer to the local health authority for the most up-to-date information when prescribing nirmatrelvir with ritonavir.
- The US Centers for Disease Control and Prevention (CDC) issued a Health Alert Network (HAN) Health Advisory for the potential recurrence of COVID-19 or “COVID-19 rebound”. It has been reported to occur between 2 and 8 days following initial recovery and is characterised by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. A brief symptom return may be part of the natural history of SARS-CoV-2 infection in some persons, independent of treatment with nirmatrelvir and ritonavir and regardless of vaccination status. Nirmatrelvir with ritonavir is continued to be recommended in early-stage therapy of mild to moderate COVID-19 among individuals at high risk for progression to severe disease. Limited data currently available from case reports suggests that patients treated with nirmatrelvir and ritonavir who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. Currently, there is no evidence that additional therapy is needed with nirmatrelvir and ritonavir or other anti-SARS-CoV-2 treatments in cases where COVID-19 rebound is suspected. Based on the available data, patient monitoring continues to be the most appropriate management in individuals with symptom recurrence after completion of treatment with nirmatrelvir and ritonavir.
- Nirmatrelvir with ritonavir has significant and complex drug-drug interactions, mainly due to the ritonavir component. Consider the potential for drug interactions before initiation and during nirmatrelvir with ritonavir treatment. Carefully review the patient's concomitant medications (including over-the-counter and herbal medicines) prior to and during therapy and monitor for adverse effects associated with the use of concomitant agents. The risk of interactions with concurrent medications during the full 5-day treatment period for nirmatrelvir with ritonavir must be weighed against the benefits of receiving the therapy. Consider a multidisciplinary approach to determine the adequate timing when initiating nirmatrelvir with ritonavir treatment and take into account the delayed offset of recently stopped CYP3A inducer and the need to start nirmatrelvir with ritonavir within 5 days of symptom onset. For a more detailed list of all possible drugs that may interact with nirmatrelvir with ritonavir, may consider referring to local treatment guidelines and specific product information of ritonavir.
- To alleviate the risks of this unapproved drug during pandemic use, local regulatory agencies may require healthcare providers to comply with certain regulations on the use of nirmatrelvir with ritonavir. Please refer to respective local regulatory agencies for further information.

Significant: Hypersensitivity reactions including pruritus, mild skin eruptions, urticaria, dyspnoea, angioedema, and anaphylaxis; toxic epidermal necrolysis and Stevens-Johnson syndrome (particularly due to the ritonavir component); elevated hepatic transaminases, clinical hepatitis, and jaundice in patients taking ritonavir.
Gastrointestinal disorders: Diarrhoea, vomiting, dysgeusia, abdominal pain, nausea.
General disorders and administration site conditions: Malaise.
Musculoskeletal and connective tissue disorders: Myalgia.
Nervous system disorders: Headache.
Vascular disorders: Hypertension.

PO: Z (Ritonavir-boosted nirmatrelvir is not recommended during pregnancy unless the benefits outweigh the risks.)

Individuals using combined hormonal contraceptives must use an effective alternative birth control method or an additional barrier method of contraception during therapy and until after 1 complete menstrual cycle after discontinuing nirmatrelvir with ritonavir treatment.

Evaluate renal and hepatic function prior to treatment initiation. Monitor for signs and symptoms of hepatotoxicity, dermatologic effects, and hypertension. Consider the potential for drug interactions before and during treatment.

May increase the plasma concentrations of amphetamine derivatives (e.g. methylphenidate, dexamfetamine), buprenorphine, afatinib, abemaciclib, vincristine, ibrutinib, tofacitinib, systemic lidocaine, trazodone, ketoconazole, itraconazole, erythromycin, clarithromycin, rifabutin, bedaquiline, amprenavir, atazanavir, darunavir, efavirenz, maraviroc, amlodipine, diltiazem, digoxin, bosentan, riociguat, loratadine, fexofenadine, saxagliptin, darifenacin, rimegepant, suvorexant, aripiprazole, cariprazine, sofosbuvir/velpatasvir/voxilaprevir, imipramine, sertraline, paroxetine, haloperidol, risperidone, thioridazine, atorvastatin, rosuvastatin, ciclosporin, tacrolimus, salmeterol, dexamethasone, zolpidem, fentanyl, parenteral midazolam, vorapaxar. Increased risk of bleeding with rivaroxaban, apixaban, and dabigatran. May decrease the plasma concentrations of bupropion, warfarin, ethinylestradiol, methadone, morphine, theophylline, atovaquone, zidovudine, raltegravir, voriconazole. Increased risk of Cushing's syndrome and adrenal suppression with budesonide, fluticasone and triamcinolone. May reduce the efficacy of combined hormonal contraceptives.
Potentially Fatal: Nirmatrelvir with ritonavir increases the plasma concentrations of agents primarily metabolised by CYP3A (e.g. alfuzosin, pethidine, propoxyphene, piroxicam, ranolazine, amiodarone, bepridil, dronedarone, flecainide, encainide, propafenone, quinidine, neratinib, venetoclax, colchicine, clozapine, quetiapine, lurasidone, pimozide, ergotamine, methylergonovine, dihydroergotamine, ergonovine, lovastatin, simvastatin, lomitapide, astemizole, terfenadine, cisapride, fusidic acid, silodosin, eplerenone, ivabradine, eletriptan, ubrogepant, voclosporin, finerenone, naloxegol, flibanserin, tolvaptan, oral midazolam, triazolam, clorazepate, clonazepam, diazepam, estazolam, flurazepam, avanafil, tadalafil, vardenafil, sildenafil [when used for pulmonary arterial hypertension]) which may result in serious adverse effects. Potent CYP3A inducers (e.g. apalutamide, carbamazepine, phenobarbital, primidone, phenytoin, rifampicin, lumacaftor/ivacaftor) significantly decrease the plasma levels of nirmatrelvir and ritonavir which may lead to reduced therapeutic effect and possible viral resistance development; treatment initiation of nirmatrelvir with ritonavir must be delayed after the discontinuation of the potent CYP3A inducers due to the delayed offset of the CYP3A inducer.

St. John's wort significantly decreases the plasma levels of nirmatrelvir and ritonavir which may lead to reduced therapeutic effect and possible viral resistance development; treatment initiation of nirmatrelvir with ritonavir must be delayed after the discontinuation of St. John's wort due to the delayed offset of St John's wort.

Description:
Mechanism of Action: Nirmatrelvir, an investigational antiviral agent, is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro), also known as 3C-like protease (3CLpro) or nsp5 protease. The inhibition of SARS-CoV-2 M^pro prevents the processing of polyprotein precursors, thereby blocking viral replication. Ritonavir, an HIV-1 protease inhibitor, has no activity against SARS-CoV-2 M^pro. However, it acts as a pharmacokinetic enhancer by inhibiting the CYP3A-mediated metabolism of nirmatrelvir leading to increased nirmatrelvir plasma concentrations.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: Nirmatrelvir when given with ritonavir: 3 hours (range: 1.02-6 hours).
Distribution: Plasma protein binding: 69% (nirmatrelvir when given with ritonavir).
Metabolism: Minimal metabolism (nirmatrelvir when given with ritonavir).
Excretion: Nirmatrelvir when given with ritonavir: Via urine (49.6%); faeces (35.3%). Elimination half-life: 6.05 ± 1.79 hours (nirmatrelvir when given with ritonavir).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 155903259, Nirmatrelvir. https://pubchem.ncbi.nlm.nih.gov/compound/Nirmatrelvir. Accessed Mar. 30, 2023.

Store between 20-25°C. Do not refrigerate or freeze.

Antivirals

J05AE30 - nirmatrelvir and ritonavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.

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