Paxlovid · 4.8 Undesirable effects · 1

HOS-288875 · has-adverse-reaction-information · PDF-Seite 24

Summary of the safety profile The most common adverse reactions reported during treatment with Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) were dysgeusia (4.6%), diarrhoea (3.0%), headache (1.2%) and vomiting (1.2%). Tabulated list 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 below 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). 24  Table 4: Adverse reactions with Paxlovid Frequency System organ class category Adverse reactions Immune system disorders Uncommon Hypersensitivity Rare Anaphylaxis Nervous system disorders Common Dysgeusia, headache Vascular disorders Uncommon Hypertension Gastrointestinal disorders Common Diarrhoea, vomiting, nausea Uncommon Abdominal pain Skin and subcutaneous tissue disorders Uncommon Rash* Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus* Musculoskeletal and connective tissue Uncommon Myalgia disorders General disorders and administration site Rare Malaise conditions * These adverse reactions are also manifestations of hypersensitivity reaction. Description of selected adverse reactions Patients with severe renal impairment Based on limited data from a Phase 1, open-label study, the safety profile of Paxlovid in participants with severe renal impairment, including those requiring haemodialysis, was consistent with the safety profile observed in clinical trials. Paediatric population The safety of Paxlovid in paediatric patients was evaluated

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HOS-288871 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 4 Medicinal products listed below are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated with Paxlovid. 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. • Alpha1-adrenoreceptor antagonist: alfuzosin • Antianginal: ranolazine • Antiarrhythmic: dronedarone, propafenone, quinidine • Anticancer drugs: neratinib, venetoclax • Anti-gout: colchicine • Antihistamines: terfenadine • Antipsychotics/neuroleptics: 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: o HMG Co-A reductase inhibitors: lovastatin, simvastatin o Microsomal triglyceride transfer protein (MTTP) inhibitor: lomitapide • Migraine medicinal products: eletriptan • Mineralocorticoid receptor antagonists: finerenone • Neuropsychiatric agents: cariprazine • Opioid antagonists: naloxegol • 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, rifapentine • Anticancer drugs: apalutamide, enzalutamide • Anticonvulsants: carbamazepine, phenobarbital, phenytoin, primidone • Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor • Herbal products: St. John’s wort (Hypericum perforatum) Paxlovid cannot be started immediately after discontinuation of CYP3A4 inducers due to the delayed offs

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HOS-288870 · has-indication-information · PDF-Seite 2

Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and paediatric patients 6 years of age and older weighing at least 20 kg who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19 (see section 5.1).

HOS-288873 · has-interaction-information · PDF-Seite 7

Effect of other medicinal products on Paxlovid Nirmatrelvir and ritonavir are CYP3A substrates. Coadministration of Paxlovid with medicinal products that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce Paxlovid therapeutic effect. Coadministration of Paxlovid with medicinal product that inhibits CYP3A4 may increase nirmatrelvir and ritonavir plasma concentrations. Effects of Paxlovid on other medicinal products Medicinal products CYP3A4 substrates Paxlovid (nirmatrelvir/ritonavir) is a strong inhibitor of CYP3A and increases plasma concentrations of medicinal products that are primarily metabolised 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 Table 3). Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction (see Table 3) 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 Paxlovid with drug substrates of CYP2D6 may increase the CYP2D6 substrate concentration. Medicinal products P-glycoprotein substrates 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. Paxlovid may induce glucuronidation and oxidation by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these 7 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 and OATP1B1 at clinically relevant concentrations. Dedicated drug-drug interactions studies conducted with Paxlovid indicate that the drug interactions are primarily due to ritonavir. Hence, drug interactions pertaining to ritonavir are applicable for Paxlovid. Medicinal products li

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HOS-288874 · has-pregnancy-information · PDF-Seite 23

Women of childbearing potential There are limited data on the use of 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 this medicinal product and as a precautionary measure for 7 days after completing the treatment. 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 this medicinal product, and until one menstrual cycle after stopping the treatment (see section 4.5). Pregnancy There are limited data from the use of Paxlovid in pregnant women. 23 Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower foetal body weights) but not in the rat (see section 5.3). 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 section 5.3). Paxlovid is not recommended during pregnancy and in women of childbearing potential not using contraception unless the clinical condition requires treatment with this medicinal product. Breast-feeding Nirmatrelvir and ritonavir are excreted in breast milk (see section 5.2). There are no available data on the effects of nirmatrelvir and 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 48 hours after completing the treatment. Fertility There are no human data on the effect of Paxlovid (nirmatrelvir and ritonavir) or ritonavir alone on fertility. Both nirmatrelvir and ritonavir, tested separately, produced no effects on fertility in rats (see section 5.3).

HOS-288872 · has-warning-information · PDF-Seite 5

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 5 approach (e.g., involving physicians and specialists in clinical pharmacology) should be considered for management of DDIs especially if concomitant medications are withheld, their dose is reduced, or if monitoring of side effects is necessary. Effects of Paxlovid on 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 (see section 4.5). 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 blood concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see section 4.5). Effects of other medicinal products on Paxlovid 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 with 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. See Table 3 for medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir and for potentially significant interactions with other medicinal products (see section 4.5). 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

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