Paxlovid

Nirmatrelvir, ritonavir.

Nirmatrelvir: Film-coated tablet (tablet).
Pink, oval, with a dimension of approximately 17.6 mm in length and 8.6 mm in width debossed with 'PFE' on one side and '3CL' on the other side.
Each pink film-coated tablet contains 150 mg of Nirmatrelvir.
Ritonavir: Film-coated tablet (tablet).
White to off white, capsule shaped tablets, with a dimension of approximately 17.1 mm in length and 9.1 mm in width, debossed with 'H' on one side and 'R9' on other side.
Each white film-coated tablet contains 100 mg of Ritonavir.
Excipients with known effect: Each pink 150 mg film-coated tablet of Nirmatrelvir contains 176 mg of lactose.
Excipients/Inactive Ingredients: Nirmatrelvir film-coated tablets: Tablet core: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Colloidal silicon dioxide, Sodium stearyl fumarate.
Film coat: Hydroxypropyl methylcellulose (E464), Titanium dioxide (E171), Polyethylene glycol (E1521), Iron oxide red (E172).
Ritonavir film-coated tablets: Tablet core: Copovidone, Sorbitan laurate, Colloidal anhydrous silica (E551), Anhydrous calcium hydrogen phosphate, Sodium stearyl fumarate.
Film coat: Hypromellose (E464), Titanium dioxide (E171), Macrogol (E1521), Hydroxypropyl cellulose (E463), Talc (E553b), Colloidal anhydrous silica (E551), Polysorbate 80 (E433).

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors. ATC code: J05AE30.
Pharmacology: Pharmacodynamics: Mechanism of action: Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (M^pro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of the SARS-CoV-2 M^pro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.
Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.
Antiviral activity: Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line (EC₅₀ value of 61.8 nM and EC₉₀ value of 181 nM) after 3 days of drug exposure. Nirmatrelvir had cell culture antiviral activity (with EC₅₀ values in the low nanomolar range ≤3-fold relative to USA WA1/2020) against SARS CoV 2 isolates belonging to the 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. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
Antiviral resistance in cell cultures and biochemical assays: SARS-CoV-2 M^pro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with M^pro substitutions, and biochemical assays with recombinant SARS-CoV-2 M^pro containing amino acid substitutions. Table 1 indicates M^pro substitutions and combinations of M^pro substitutions that have been observed in nirmatrelvir selected SARS-CoV-2 in cell culture. Individual M^pro substitutions are listed regardless of whether they occurred alone or in combination with other M^pro substitutions. Note that the M^pro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of M^pro. Substitutions at other M^pro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown. (See Table 1.)

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Most single M^pro mutations and some double mutations identified which reduced the susceptibility of SARS CoV 2 to nirmatrelvir resulted in an EC₅₀ shift of <5-fold compared to wild type SARS CoV 2. In general, triple mutations and some double mutations led to EC₅₀ changes of >5-fold to that of wild type. The clinical significance of these mutations needs to be further understood.
Viral load rebound and treatment-emergent mutations: Post-treatment viral nasal RNA rebounds were observed on Day 10 and/or Day 14 in a subset of Nirmatrelvir+Ritonavir (Paxlovid) and placebo recipients in EPIC-HR, irrespective of COVID-19 symptoms. The incidence of viral rebound in EPIC-HR occurred in both the Nirmatrelvir+Ritonavir (Paxlovid) treated participants and the untreated (placebo) participants, but at higher incidence in the Nirmatrelvir+Ritonavir (Paxlovid) arm (6.96% vs. 4.08%). So far, viral rebounds and symptoms recurrences of COVID-19 are not associated with more severe disease or emergence of resistance.
Clinical efficacy: The efficacy of Nirmatrelvir+Ritonavir (Paxlovid) is based on the interim analysis and the supporting final analysis of EPIC HR, a phase 2/3, randomized, double-blind, placebo-controlled study in non hospitalized, symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible participants were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically related technological dependence, or were 60 years of age and older regardless of comorbidities. Participants with COVID-19 symptom onset of ≤5 days were included in the study. The study excluded individuals with a history of prior COVID-19 infection or vaccination.
Participants were randomized (1:1) to receive Nirmatrelvir+Ritonavir 300 mg + 100 mg (Paxlovid) or placebo orally every 12 hours for 5 days. The primary efficacy endpoint was the proportion of participants with COVID 19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set (all treated participants with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), the mITT1 analysis set (all treated participants with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated participants with onset of symptoms ≤5 days).
A total of 2246 participants were randomized to receive either Nirmatrelvir+Ritonavir (Paxlovid) or placebo. At baseline, mean age was 46 years with 13% of participants 65 years of age and older (3% were 75 years of age and older); 51% were male; 72% were White, 5% were Black or African American, and 14% were Asian; 45% were Hispanic or Latino; 66% of participants had onset of symptoms ≤3 days before initiation of study treatment; 81% had a BMI >25 kg/m² (37% a BMI >30 kg/m²); 12% had diabetes mellitus; less than 1% of the study population had immune deficiency, 47% of participants were serological negative at baseline and 51% were serological positive. The mean (SD) baseline viral load was 4.63 log₁₀ copies/mL (2.87); 26% of participants had a baseline viral load of >10^7 (copies/mL); 6.2% of participants either received or were expected to receive COVID-19 therapeutic mAb treatment at the time of randomization and were excluded from the mITT and mITT1 analyses. The primary SARS-CoV-2 variant across both treatment arms was Delta (98%), mostly clade 21J (based on interim analysis).
The baseline demographic and disease characteristics were balanced between the Nirmatrelvir+Ritonavir (Paxlovid) and placebo groups.
The determination of primary efficacy was based on a planned interim analysis of 774 participants in mITT population. The estimated risk reduction was -6.3% with unadjusted 95% CI of (-9.0%, -3.6%) and a 95% CI of (-10.61%, -2.02%) when adjusting for multiplicity. The 2-sided p-value was <0.0001 with 2-sided significance level of 0.002.
Table 2 provides results of the primary endpoint in the mITT1 analysis population for the full data set at final study completion. (See Table 2.)

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The estimated risk reduction was -5.8% with 95% CI of (-7.8%, -3.8%) in participants dosed within 3 days of symptom onset, and -4.9% with 95% CI of (-7.7%, -2.2%) in the mITT1 subset of participants dosed >3 days from symptom onset.
Consistent results were observed in the final mITT and mITT2 analysis populations. A total of 1379 participants were included in the mITT analysis population. The event rates were 5/697 (0.72%) in the Nirmatrelvir+Ritonavir (Paxlovid) group, and 44/682 (6.45%) in the placebo group. (See Table 3.)

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Efficacy results for mITT1 were consistent across subgroups of participants including age (≥65 years) and BMI (BMI >25 and BMI >30) and diabetes.
Pediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with Nirmatrelvir+Ritonavir (Paxlovid) in one or more subsets of the pediatric population in treatment of COVID-19 (see Pediatric population under Dosage & Administration).
Pharmacokinetics: The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants and in participants with mild-to-moderate COVID-19.
Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir.
Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.
Absorption: Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir C_max and AUC_inf at steady-state was 2.21 µg/mL and 23.01 µg*hr/mL, respectively. The median time to C_max (T_max) was 3.00 hrs. The arithmetic mean terminal elimination half-life was 6.1 hours.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir C_max and AUC_inf was 0.36 µg/mL and 3.60 µg*hr/mL, respectively. The median time to C_max (T_max) was 3.98 hrs. The arithmetic mean terminal elimination half-life was 6.1 hours.
Effect of food on oral absorption: Dosing with a high fat meal increased the exposure of nirmatrelvir (approximately 61% increase in mean C_max and 20% increase in mean AUC_last) relative to fasting conditions following administration of 300 mg nirmatrelvir (2 × 150 mg)/100 mg ritonavir tablets.
Distribution: The protein binding of nirmatrelvir in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.
Biotransformation: In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolized by cytochrome P450 (CYP) 3A4. However, administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only medicinal product-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the feces and urine.
In vitro studies utilizing human liver microsomes have demonstrated that CYP3A is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M-2.
Elimination: The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact medicinal product. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and feces, respectively. Nirmatrelvir was the predominant drug related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
Specific populations: Age and gender: The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.
Racial or ethnic groups: Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants.
Patients with renal impairment: Compared to healthy controls with no renal impairment, the C_max and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively.
Patients with hepatic impairment: Compared to healthy controls with no hepatic impairment, the pharmacokinetics of nirmatrelvir in participants with moderate hepatic impairment was not significantly different. Adjusted geometric mean ratio (90% CI) of AUC_inf and C_max of nirmatrelvir comparing moderate hepatic impairment (test) to normal hepatic function (reference) was 98.78% (70.65%, 138.12%) and 101.96% (74.20%, 140.11%), respectively.
Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.
Interaction studies conducted with nirmatrelvir/ritonavir: CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of nirmatrelvir and other drugs that are primarily metabolized by CYP3A. Despite being coadministered with ritonavir as a pharmacokinetic enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.
Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.
The effect on the pharmacokinetics of nirmatrelvir/ritonavir was assessed with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer). The test/reference ratios of the adjusted geometric means for nirmatrelvir AUC_inf and C_max were 44.50% and 56.82%, respectively, following nirmatrelvir/ritonavir 300 mg/100 mg coadministration with multiple oral doses of carbamazepine. The test/reference ratios of the adjusted geometric means for nirmatrelvir AUC_tau and C_max were 138.82% and 118.57%, respectively, when nirmatrelvir/ritonavir was coadministered with multiple doses of itraconazole as compared to nirmatrelvir/ritonavir administered alone.
The effect of nirmatrelvir/ritonavir on other drugs was assessed with midazolam (CYP3A substrate) and dabigatran (P-gp substrate). The test/reference ratios of the adjusted geometric means for midazolam AUC_inf and C_max were 1430.02% and 368.33%, respectively, when midazolam was coadministered with multiple doses of nirmatrelvir/ritonavir compared to midazolam administered alone. The test/reference ratios of the adjusted geometric means for dabigatran AUC_inf and C_max were 194.47% and 233.06%, respectively, following dabigatran administration with multiple doses of nirmatrelvir/ritonavir as compared to administration of dabigatran alone.
Toxicology: Preclinical Safety Data: No nonclinical safety studies have been conducted with nirmatrelvir in combination with ritonavir.
Nirmatrelvir: Studies of repeated dose toxicity and genotoxicity revealed no risk due to nirmatrelvir. No adverse effects were observed in fertility, embryo-fetal development, or pre- and postnatal development studies in rats. A study in pregnant rabbits showed an adverse decrease in fetal body weight, in the absence of significant maternal toxicity. Systemic exposure (AUC₂₄) in rabbits at the maximum dose without adverse effect in fetal body weight was estimated to be approximately 3 times higher than exposure in humans at recommended therapeutic dose of Nirmatrelvir+Ritonavir (Paxlovid).
No carcinogenicity studies have been conducted with nirmatrelvir.
Ritonavir: Repeat-dose toxicity studies of ritonavir in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests.
Renal changes including tubular degeneration, chronic inflammation and proteinuria were noted in rats and are considered to be attributable to species specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Genotoxicity studies revealed no risk due to ritonavir. Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no relevance for humans. Ritonavir produced no effects on fertility in rats. Developmental toxicity observed in rats (embryo-lethality, decreased fetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryo-lethality, decreased litter size and decreased fetal weights) occurred at a maternally toxic dosage.

Nirmatrelvir+Ritonavir (Paxlovid) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID 19 (see Pharmacology: Pharmacodynamics under Actions).

Posology: The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) all taken together orally every 12 hours for 5 days. Nirmatrelvir+Ritonavir (Paxlovid) should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset. Completion of the full 5-day treatment course is recommended even if the patient requires hospitalization due to severe or critical COVID-19 after starting treatment with Nirmatrelvir+Ritonavir (Paxlovid).
If the patient misses a dose of Nirmatrelvir+Ritonavir (Paxlovid) within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.
Special populations: Renal impairment: No dose adjustment is needed in patients with mild renal impairment (eGFR ≥60 to <90 mL/min). In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dose of Nirmatrelvir+Ritonavir (Paxlovid) should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg every 12 hours for 5 days to avoid over-exposure (this dose adjustment has not been clinically tested). Nirmatrelvir+Ritonavir (Paxlovid) should not be used in patients with severe renal impairment [eGFR <30 mL/min, including patients with End Stage Renal Disease (ESRD) under hemodialysis] (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment of Nirmatrelvir+Ritonavir (Paxlovid) is needed for patients with either mild (Child Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Nirmatrelvir+Ritonavir (Paxlovid) should not be used in patients with severe (Child-Pugh Class C) hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Concomitant therapy with ritonavir- or cobicistat-containing regimen: No dose adjustment of Nirmatrelvir+Ritonavir (Paxlovid) is needed. 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.
Pediatric population: The safety and efficacy of Nirmatrelvir+Ritonavir (Paxlovid) in patients below 18 years of age have not been established. No data are available.
Method of administration: For oral use.
Nirmatrelvir must be coadministered with ritonavir. Failure to correctly coadminister nirmatrelvir with ritonavir will result in plasma levels of this active substance that will be insufficient to achieve the desired therapeutic effect.
Nirmatrelvir+Ritonavir (Paxlovid) can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions). The tablets should be swallowed whole and not chewed, broken or crushed, as no data is currently available.

Treatment of overdose with Nirmatrelvir+Ritonavir (Paxlovid) should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Nirmatrelvir+Ritonavir (Paxlovid).

Hypersensitivity to the active substances or to any of the excipients listed in Description.
Medicinal products listed as follows are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated with Nirmatrelvir+Ritonavir (Paxlovid).
Medicinal products that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions: Alpha₁-adrenoreceptor antagonist: alfuzosin.
Antianginal: ranolazine.
Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine.
Antibiotics: fusidic acid.
Anticancer drugs: neratinib, venetoclax.
Anti-gout: colchicine.
Antihistamines: terfenadine.
Antipsychotics/neuroleptics: clozapine, lurasidone, pimozide, quetiapine.
Benign prostatic hyperplasia medicinal products: silodosin.
Cardiovascular medicinal products: eplerenone, ivabradine.
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine.
GI motility agents: cisapride.
Immunosuppressants: voclosporin.
Lipid-modifying agents: HMG Co-A reductase inhibitors: lovastatin, simvastatin; Microsomal triglyceride transfer protein (MTTP) inhibitor: lomitapide.
Migraine medicinal products: eletriptan.
PDE5 inhibitor: avanafil, sildenafil, tadalafil, vardenafil.
Sedative/hypnotics: clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam.
Vasopressin receptor antagonists: tolvaptan.
Medicinal products that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance: Antibiotics: rifampicin.
Anticancer drugs: apalutamide.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Herbal products: St. John's wort (Hypericum perforatum).
Nirmatrelvir+Ritonavir (Paxlovid) cannot be started immediately after discontinuation of CYP3A4 inducers due to the delayed offset of the recently discontinued CYP3A4 inducer (see Interactions).
A multi-disciplinary approach (e.g., involving physicians and specialists in clinical pharmacology) should be considered to determine the adequate timing for Nirmatrelvir+Ritonavir (Paxlovid) initiation taking into account the delayed offset of the recently discontinued CYP3A inducer and the need to initiate Nirmatrelvir+Ritonavir (Paxlovid) within 5 days of symptom onset.

Special attention for patients with moderate renal impairment: The daily blister contains two separated parts each containing two tablets of nirmatrelvir and one tablet of ritonavir corresponding to the daily administration at the standard dose.
Therefore, patients with moderate renal impairment should be alerted on the fact that only one tablet of nirmatrelvir with the tablet of ritonavir should be taken every 12 hours.

Risk of serious adverse reactions due to interactions with other medicinal products: Management of drug-drug interactions (DDIs) in high-risk COVID-19 patients receiving multiple concomitant medications can be complex and require a thorough understanding of the nature and magnitude of interaction with all concomitant medications. In certain patients, a multi-disciplinary approach (e.g., involving physicians and specialists in clinical pharmacology) should be considered for management of DDIs especially if concomitant medications are withheld, their dosage is reduced, or if monitoring of side effects is necessary.
Effects of Nirmatrelvir+Ritonavir (Paxlovid) on other medicinal products: Initiation of Nirmatrelvir+Ritonavir (Paxlovid), a CYP3A inhibitor, in patients receiving medicinal products metabolized by CYP3A or initiation of medicinal products metabolized by CYP3A in patients already receiving Nirmatrelvir+Ritonavir (Paxlovid), may increase plasma concentrations of medicinal products metabolized by CYP3A (see Interactions).
Coadministration of Paxlovid with calcineurin inhibitors and mTOR inhibitors: Consultation of a multidisciplinary group (e.g., involving physicians, specialists in immunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle the complexity of this coadministration by closely and regularly monitoring immunosuppressant serum concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see Interactions).
Effects of other medicinal products on Nirmatrelvir+Ritonavir (Paxlovid): Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Nirmatrelvir+Ritonavir (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 Nirmatrelvir+Ritonavir (Paxlovid).
Loss of therapeutic effect of Nirmatrelvir+Ritonavir (Paxlovid) and possible development of viral resistance.
See Tables 5a, 5b, 5c and 5d for medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir and for potentially significant interactions with other medicinal products (see Interactions). Potential for interactions should be considered with other medicinal products prior to and during Nirmatrelvir+Ritonavir (Paxlovid) therapy; concomitant medicinal products should be reviewed during Nirmatrelvir+Ritonavir (Paxlovid) therapy and the patient should be monitored for the adverse reactions associated with the concomitant medicinal products.
Hypersensitivity reactions: Anaphylaxis and other hypersensitivity reactions have been reported with Nirmatrelvir+Ritonavir (Paxlovid) (see Adverse Reactions). Cases of Toxic Epidermal Necrolysis and Stevens-Johnson syndrome have been reported with ritonavir, a component of Nirmatrelvir+Ritonavir (Paxlovid) (refer to ritonavir Product information). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Nirmatrelvir+Ritonavir (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 Nirmatrelvir+Ritonavir (Paxlovid) to patients with pre existing liver diseases, liver enzyme abnormalities or hepatitis.
Risk of HIV-1 resistance development: 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.
Excipients: Nirmatrelvir tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
Effects on Ability to Drive and Use Machines: Nirmatrelvir+Ritonavir (Paxlovid) is expected to have no influence on the ability to drive and use machines.
Severe renal impairment: No clinical data are available in patients with severe renal impairment (including patients with ESRD). Based on pharmacokinetic data (see Pharmacology: Pharmacokinetics under Actions), the use of Nirmatrelvir+Ritonavir (Paxlovid) in patients with severe renal impairment could lead to over-exposure with potential toxicity. No recommendation in terms of dose adjustment could be elaborated at this stage pending dedicated investigation. Therefore, Nirmatrelvir+Ritonavir (Paxlovid) should not be used in patients with severe renal impairment (eGFR <30 mL/min, including patients with ESRD under hemodialysis).
Severe hepatic impairment: No pharmacokinetic and clinical data are available in patients with severe hepatic impairment. Therefore, Nirmatrelvir+Ritonavir (Paxlovid) should not be used in patients with severe hepatic impairment.

Women of childbearing potential: There are no data on the use of Nirmatrelvir+Ritonavir (Paxlovid) in pregnant women to inform the drug-associated risk of adverse developmental outcomes; women of childbearing potential should avoid becoming pregnant during treatment with Nirmatrelvir+Ritonavir (Paxlovid) and as a precautionary measure for 7 days after completing Nirmatrelvir+Ritonavir (Paxlovid).
Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with Nirmatrelvir+Ritonavir (Paxlovid), and until one menstrual cycle after stopping Nirmatrelvir+Ritonavir (Paxlovid) (see Interactions).
Pregnancy: There are limited data from the use of Nirmatrelvir+Ritonavir (Paxlovid) in pregnant women.
Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower fetal body weights) but not in the rat (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
A large number of women exposed to ritonavir during pregnancy indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems.
Animal data with ritonavir have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Nirmatrelvir+Ritonavir (Paxlovid) is not recommended during pregnancy and in women of childbearing potential not using contraception unless the clinical condition requires treatment with Nirmatrelvir+Ritonavir (Paxlovid).
Breast-feeding: There are no data on the use of Nirmatrelvir+Ritonavir (Paxlovid) in breast-feeding women.
It is unknown whether nirmatrelvir is present in human or animal milk, and the effects of it on the breast fed newborn/infant, or the effects on milk production. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breast-fed newborn/infant or on milk production. A risk to the newborn/infant cannot be excluded.
Breast-feeding should be discontinued during treatment and as a precautionary measure for 7 days after completing Nirmatrelvir+Ritonavir (Paxlovid).
Fertility: There are no human data on the effect of Nirmatrelvir+Ritonavir (Paxlovid) (nirmatrelvir and ritonavir) or ritonavir alone on fertility. Both nirmatrelvir and ritonavir, tested separately, produced no effects on fertility in rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).

Summary of the safety profile: The most common adverse reactions reported during treatment with Nirmatrelvir+Ritonavir 300 mg+100 mg (Paxlovid) were dysgeusia (5.6%), diarrhea (3.1%), headache (1.4%) and vomiting (1.1%).
Tabulated summary of adverse reactions: The safety profile of the product is based on adverse reactions reported in clinical trials and spontaneous reporting.
The adverse reactions in Table 4 are listed as follows by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); not known (frequency cannot be estimated from the available data). (See Table 4.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Effect of other medicinal products on Nirmatrelvir+Ritonavir (Paxlovid): Nirmatrelvir and ritonavir are CYP3A substrates.
Coadministration of Nirmatrelvir+Ritonavir (Paxlovid) with medicinal products that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce Nirmatrelvir+Ritonavir (Paxlovid) therapeutic effect.
Coadministration of Nirmatrelvir+Ritonavir (Paxlovid) with medicinal product that inhibits CYP3A4 may increase nirmatrelvir and ritonavir plasma concentrations.
Effects of Nirmatrelvir+Ritonavir (Paxlovid) on other medicinal products: Medicinal products CYP3A4 substrates: Nirmatrelvir+Ritonavir (Paxlovid) is a strong inhibitor of CYP3A and increases plasma concentrations of medicinal products that are primarily metabolized by CYP3A. Thus, coadministration of nirmatrelvir/ritonavir with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events is contraindicated (see Tables 5a, 5b, 5c and 5d). Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction (see Tables 5a, 5b, 5c and 5d) should be considered only if the benefits outweigh the risks.
Medicinal products CYP2D6 substrates: Based on in vitro studies, ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Coadministration of Nirmatrelvir+Ritonavir (Paxlovid) with drug substrates of CYP2D6 may increase the CYP2D6 substrate concentration.
Medicinal products P-glycoprotein substrates: Nirmatrelvir+Ritonavir (Paxlovid) also has a high affinity for P glycoprotein (P gp) and inhibits this transporter; caution should thus be exercised in case of concomitant treatment. Close drug monitoring for safety and efficacy should be performed, and dose reduction may be adjusted accordingly, or avoid concomitant use.
Nirmatrelvir+Ritonavir (Paxlovid) may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolized by these pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Based on in vitro studies there is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.
Dedicated drug-drug interactions studies conducted with Nirmatrelvir+Ritonavir (Paxlovid) indicate that the drug interactions are primarily due to ritonavir. Hence, drug interactions pertaining to ritonavir are applicable for Nirmatrelvir+Ritonavir (Paxlovid).
Medicinal products listed in Tables 5a, 5b, 5c and 5d are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated or may interact with nirmatrelvir/ritonavir. (See Tables 5a, 5b, 5c and 5d.)

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Incompatibilities: Not applicable.
Special Precautions for Disposal and Other Handling: No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

This medicinal product does not require any special storage conditions.
Store below 25°C.
Do not refrigerate or freeze.
Shelf-Life: 2 years.

Antivirals

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

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