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.

DELSTRIGO (NDA-210807)

(DORAVIRINE; LAMIVUDINE; TENOFOVIR DISOPROXIL FUMARATE)

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

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10/29/2025 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Doravirine:

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Hepatobiliary Disorders: hepatitis

Investigations: hepatic enzyme increased

…

06/12/2025 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Bone Loss and Mineralization Defects

Additions and/or revisions underlined:

. . .

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric participants 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children are unknown.

. . .

11/07/2024 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe Skin Reactions

Newly added subsection:

Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens [see Adverse Reactions (6.2)]. Discontinue DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Doravirine:

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)

…

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Based on limited published data, both lamivudine and tenofovir are present in human milk. It is unknown whether doravirine is present in human milk, but doravirine is present in the milk of lactating rats (see Data). It is not known whether DELSTRIGO or the components of DELSTRIGO affects human milk production, or has effects on the breastfed infant. Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV- 1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults.

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Severe Skin Reactions

Inform patients that severe skin reactions including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with DELSTRIGO. Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking DELSTRIGO and seek medical attention if a painful rash with mucosal involvement develops [see Warnings and Precautions (5.1)].

…

Lactation

Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What should I tell my healthcare provider before treatment with DELSTRIGO?

Before treatment with DELSTRIGO, tell your healthcare provider about all of your medical conditions, including if you:

…

are breastfeeding or plan to breastfeed. Two of the medicines in DELSTRIGO (lamivudine and tenofovir) can pass into your breast milk. Doravirine may pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with DELSTRIGO:

the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.
the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.
your baby may get side effects from DELSTRIGO.\
…
DELSTRIGO may cause serious side effects, including:
…

Severe skin reactions have happened in people treated with DELSTRIGO. Call your healthcare provider right away if you develop a rash during treatment with DELSTRIGO. Stop taking DELSTRIGO and get medical help right away if you develop a painful rash with any of the following symptoms: fever, blisters or sores in the mouth, blisters or peeling of the skin, or redness or swelling of the eyes (conjunctivitis).
…

01/27/2022 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Bone Loss and Mineralization Defects

Bone Mineral Density

Additions and/or revisions underlined:

Clinical trials evaluating TDF in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adverse Reactions in Pediatric Patients

The safety of DELSTRIGO was evaluated in 45 HIV-1-infected virologically-suppressed or treatment-naïve pediatric patients 12 to less than 18 years of age through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3)]. The safety profile in pediatric subjects was similar to that in adults. There were no serious or Grade 3 or 4 adverse reactions. No subjects discontinued due to an adverse event.

8 Use in Specific Populations

8.1 Pregnancy

Data

Human Data

Lamivudine:

Additions and/or revisions underlined:

The APR has received a total of over 13,000 prospective reports with follow-up data of possible exposure to lamivudine-containing regimens; over 5,900 reports in the first trimester; over 5,600 reports in the second trimester; and over 1,800 reports in the third trimester. Birth defects occurred in 170 of 5,472 (3.1%, 95% CI: 2.7% to 3.6%) live births for lamivudine-containing regimens (first trimester exposure); and 218 of 7,513 (2.9%, 95% CI: 2.5% to 3.3%) live births for lamivudine-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lamivudine and overall birth defects observed in the APR.

TDF: The APR has received a total of over 7,000 prospective reports with follow-up data of possible exposure to tenofovir disoproxil-containing regimens; over 5,100 reports in the first trimester; over 1,300 reports in the second trimester; and over 600 reports in the third trimester. Birth defects occurred in 113 of 4,576 (2.5%, 95% CI: 2.0% to 3.0%) live births for TDF-containing regimens (first trimester exposure); and 51 of 1,965 (2.6%, 95% CI: 1.9% to 3.4%) live births for TDF-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between tenofovir and overall birth defects observed in the APR.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and efficacy of DELSTRIGO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.2)].

Use of DELSTRIGO in this group is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, safety, and efficacy data from an open-label trial in virologically- suppressed or treatment-naïve pediatric subjects 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric subjects were similar to that in adults, and there was no clinically significant difference in exposure for the components of DELSTRIGO. [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3).]

Safety and efficacy of DELSTRIGO in pediatric patients weighing less than 35 kg have not been established.

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

Patient Information

Additions and/or revisions underlined:

For more information about side effects, see “What are the possible side effects of DELSTRIGO?” What is DELSTRIGO?

DELSTRIGO is a prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults and children who weigh at least 77 pounds (35 kg):

who have not received HIV-1 medicines in the past, or

to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

DELSTRIGO contains the prescription medicines doravirine, lamivudine and tenofovir disoproxil fumarate. It is not known if DELSTRIGO is safe and effective in children who weigh less than 77 pounds (35 kg).

10/10/2019 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Adverse Reactions in Adults with No Antiretroviral Treatment History

For each notation of Week 48, it has been revised to Week 96.

The majority (66%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild).

Neuropsychiatric Adverse Events

Additions and/or revisions underlined:

At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. At Week 96, the prevalence of neuropsychiatric adverse events was 13% (47/364) in the DELSTRIGO group and 23% (82/364) in the EFV/FTC/TDF group.

Change in Lipids from Baseline

For DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. Changes from baseline at Week 96 were similar to findings at Week 48.

09/19/2019 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Immune Reconstitution Syndrome

(addition underlined)

…

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Adverse Reactions in Virologically-Suppressed Adults

The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 subjects in the DRIVE-SHIFT trial (Protocol 024), a randomized, international, multicenter, open-label trial in which virologically-suppressed subjects were switched from a baseline regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no antiretroviral treatment history.

Laboratory Abnormalities

Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of subjects in the immediate switch group experienced ALT and AST elevations of greater than 1.25 X ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent time patterns with regard to time to onset relative to switch were observed. One percent of subjects had ALT or AST elevations greater than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic, and not associated with bilirubin elevations. In comparison, 4% and 4% of subjects in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen.

Change in Lipids from Baseline

Changes from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in subjects on a PI plus ritonavir-based regimen at baseline are shown in Table 5. The LDL and non-LDL comparisons were pre-specified, and the differences were statistically significant, showing superiority for an immediate switch to DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated.

Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Subjects on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)

(please refer to label to view Table 5)

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

PATIENT INFORMATION

(additions underlined)

…

What is DELSTRIGO?

DELSTRIGO is a prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults:

who have not received HIV-1 medicines in the past, or
to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.

…