Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

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 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 1 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 reactions associated with the concomitant medicinal products.

Hypersensitivity reactions

Anaphylaxis, hypersensitivity reactions and serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with Paxlovid (see section 4.8). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Paxlovid and initiate appropriate medications and/or supportive care.

Severe renal impairment

No clinical data are available in patients with severe renal impairment (including patients with ESRD).
Based on pharmacokinetic data (see section 5.2), the use of 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, Paxlovid should not be used in patients with severe renal impairment (eGFR < 30 mL/min, including patients with ESRD under haemodialysis).

Severe hepatic impairment

No pharmacokinetic and clinical data are available in patients with severe hepatic impairment.
Therefore, Paxlovid should not be used in patients with severe hepatic impairment.
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.




Elevation in blood pressure

Cases of hypertension, generally non serious and transient, have been reported during treatment with Paxlovid. Specific attention including regular monitoring of blood pressure should be paid notably to elderly patients since they are at higher risk of experiencing serious complications of hypertension.

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 Driving

4.7   Effects on ability to drive and use machines

Paxlovid is expected to have no influence on the ability to drive and use machines.