Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

PAXLOVID (COPACKAGED) (NDA-217188)

(NIRMATRELVIR; RITONAVIR)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/11/2026 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

…

Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.3)]:
…
- Non-opioid analgesic (selective blocker of Nav1.8 sodium channels): suzetrigine
  …

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Drug Class: Non-opioid analgesic (selective blocker of Nav1.8 sodium channels)

Drugs Within Class: suzetrigine

Effect on Concentration: Increase for suzetrigine and active metabolite M6-SUZ

Clinical Comments: Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions [see Contraindications (4)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is the most important information I should know about PAXLOVID?

PAXLOVID can interact with other medicines causing severe or life-threatening side effects or death. It is important to know the medicines that should not be taken with PAXLOVID.

…

suzetrigine

…

02/11/2026 (SUPPL-17)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Established and Other Potentially Significant Drug Interactions

Addition of the following to Table 2 underlined:

Drug Class: Cardiovascular agents

Drugs Within Class: mavacamten

Effect on Concentration: Increase for mavacamten

Clinical Comments: Co-administration with mavacamten may increase mavacamten plasma concentration and increase the risk of heart failure. Discontinue mavacamten for the duration of PAXLOVID treatment. Resumption of mavacamten within 5 days of completing PAXLOVID may result in higher exposure of mavacamten. Refer to the mavacamten

prescribing information for more information.

02/12/2025 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

. . .

Drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer [see Drug Interactions (7.3)]:

Anticancer drugs: apalutamide, enzalutamide

. . .

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

. . .

Table 2: Established and Other Potentially Significant Drug Interactions

Addition of enzalutamide to the anticancer drugs, drugs within class section of table; please refer to label for complete information

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

Do not take PAXLOVID if:

you are taking any of the following medicines:

. . .

enzalutamide

. . .

01/31/2025 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Trial C4671028 (EPIC-SRI) was a Phase 1, open-label trial that evaluated the effects of severe renal impairment on the pharmacokinetics, safety, and tolerability of PAXLOVID in non-hospitalized adult participants with COVID-19 and severe renal impairment. A total of 15 subjects with severe renal impairment were enrolled in this trial, with 12 subjects receiving intermittent hemodialysis and 3 subjects not on hemodialysis. Subjects received nirmatrelvir/ritonavir 300 mg/100 mg once on Day 1 followed by nirmatrelvir/ritonavir 150 mg/100 mg once daily from Days 2-5. The safety profile of PAXLOVID in subjects with severe renal impairment, including those requiring hemodialysis, was consistent with the safety profile observed in the Phase 2/3 randomized, placebo-controlled trials.

…

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

Renal impairment increases nirmatrelvir exposure, which may increase the risk of PAXLOVID adverse reactions. No dosage adjustment is recommended in patients with mild renal impairment (eGFR greater than or equal to 60 to <90 mL/min). Reduce the PAXLOVID dosage in patients with moderate renal impairment (eGFR greater than or eqaual to 30 to <60 mL/min). Reduce the PAXLOVID dose and dose frequency in patients with severe renal impairment (eGFR <30 mL/min), including those requiring hemodialysis. On days when patients undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Dosage Modification in Patients with Renal Impairment

…

Severe Renal Impairment (Including Those Requiring Hemodialysis)

To ensure appropriate dosing in patients with severe renal impairment, including those requiring hemodialysis, instruct patients that they will be taking two 150 mg nirmatrelvir tablets with one 100 mg ritonavir tablet together once on Day 1, followed by one 150 mg nirmatrelvir tablet with one 100 mg ritonavir together once daily on Days 2-5. Instruct patients to take their dose at approximately the same time each day. On days when patients undergo hemodialysis, instruct them to take the PAXLOVID dose after hemodialysis [see Dosage and Administration (2.3)].

Administration Instructions

Inform patients to take PAXLOVID with or without food at approximately the same time each day as instructed.

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking PAXLOVID, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems. You may need a different dose or dosing schedule of PAXLOVID.
…
How should I take PAXLOVID?

Take PAXLOVID exactly as your healthcare provider tells you to take it.
PAXLOVID consists of 2 medicines: nirmatrelvir tablets and ritonavir tablets. The 2 medicines are taken together for 5 days.
- Nirmatrelvir is an oval, pink tablet.
- Ritonavir is a white or off-white tablet.
PAXLOVID is available in 3 Dose Packs (see Figures A, B, and C below). Your healthcare provider will prescribe the PAXLOVID Dose Pack that is right for you. Follow the instruction for the Dose Pack you receive.
If you have kidney disease, your healthcare provider may prescribe a lower dose (see Figures B and C). Talk to your healthcare provider to make sure you receive the correct Dose Pack.
Please refer to label to view Figures A, B. and C.

Do not remove your PAXLOVID tablets from the blister card before you are ready to take your dose.
If you are taking PAXLOVID tablets twice daily (Figure A or Figure B), take your first dose of PAXLOVID in the morning or at bedtime, depending on when you pick up your prescription, or as your healthcare provider tells you to. Take your doses at around the same time each day.
If you have severe kidney disease and are taking PAXLOVID tablets once daily (Figure C), follow the daily dose instruction on the blister card. Take your dose at around the same time each day.
…
What are the possible side effects of PAXLOVID? PAXLOVID may cause serious side effects, including:
…
The most common side effects of PAXLOVID include: altered sense of taste (such as metallic, bitter taste) and diarrhea.
…

11/19/2024 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Nirmatrelvir and ritonavir are present in human breast milk in small amounts (less than 2%). In a clinical lactation study in 8 lactating women, nirmatrelvir and ritonavir were estimated to be present in human milk at a mean weight-normalized infant daily dose of 0.16 mg/kg/day (1.8% of maternal weight-adjusted daily dose) and 0.006 mg/kg/day (0.2% of maternal weight-adjusted daily dose), respectively (see Data).

There are no available data on the effects of nirmatrelvir or ritonavir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from

PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

Data

In a clinical pharmacokinetics study, 8 healthy lactating women who were at least 12 weeks postpartum were administered 3 oral doses every 12 hours (steady state dosing) of 300 mg/100 mg nirmatrelvir/ritonavir. The mean daily amount of nirmatrelvir and ritonavir recovered in breast milk was 0.752 mg and 0.027 mg, respectively, representing 0.13% and 0.014% of the corresponding administered daily maternal doses (unadjusted for weight). The estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 0.16 mg/kg/day and 0.006 mg/kg/day, 1.8% and 0.2% of the maternal dose, respectively, for nirmatrelvir and ritonavir.