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.

LOPID (NDA-018422)

(GEMFIBROZIL)

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

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12/10/2020 (SUPPL-59)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECUATIONS

Additions and/or revisions underlined:

3. Drug Interactions

A. HMG – CoA Reductase Inhibitors: The concomitant administration of LOPID with simvastatin is contraindicated (see CONTRAINDICATIONS and WARNINGS). Avoid concomitant use of LOPID with rosuvastatin. If concomitant use cannot be avoided, initiate rosuvastatin at 5 mg once daily. The dose of rosuvastatin should not exceed 10 mg once daily. The risk of myopathy and rhabdomyolysis …

04/25/2018 (SUPPL-58)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

4. Combination therapy of gemfibrozil with simvastatin.

5. Combination therapy of gemfibrozil with repaglinide.

6. Combination therapy of gemfibrozil with dasabuvir.

7. Combination therapy of gemfibrozil with selexipag.

5 Warnings and Precautions

WARNINGS

(Additions and/or revisions are underlined)

7. CYP2C8 substrates - Gemfibrozil, a strong inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly.

8. OATP1B1 substrates – Gemfibrozil is an inhibitor of organic anion-transporter polyprotein (OATP) 1B1 and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly. Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated.

PRECAUTIONS

3. Drug Interactions –

(C) CYP2C8 Substrates: Gemfibrozil is a strong inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone). Therefore, dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly.

Dasabuvir: Co-administration of gemfibrozil with dasabuvir increased dasabuvir AUC and Cmax (ratios: 11.3 and 2.01, respectively) due to CYP2C8 inhibition. Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, co-administration of gemfibrozil with dasabuvir is contraindicated.

Selexipag: Co-administration of gemfibrozil with selexipag doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated

Enzalutamide: In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2 fold and corresponding Cmax was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. If co-administration is considered necessary, the dose of enzalutamide should be reduced.

(D) OATP1B1 substrates: Gemfibrozil is an inhibitor of OATP1B1 transporter and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly (see WARNINGS). Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated.

(E) In vitro studies of CYP enzymes, UGTA enzymes and OATP1B1 transporter: In vitro studies have shown that gemfibrozil is an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, OATP1B1, and UDP-glucuronosyltransferase (UGT) 1A1 and 1A3.

04/18/2017 (SUPPL-56)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(Additions and/or revisions are underlined)

3. Drug Interactions –

(C) CYP2C8 Substrates: Gemfibrozil is a strong inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone).

…

Enzalutamide: In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2 fold and corresponding Cmax was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. If co-administration is considered necessary, the dose of enzalutamide should be reduced.

WARNINGS

(Additions and/or revisions are underlined)

7. CYP2C8 substrates - Gemfibrozil, a strong inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly.

04/06/2016 (SUPPL-55)

Approved Drug Label (PDF)

4 Contraindications

Combination therapy of gemfibrozil with dasabuvir

5 Warnings and Precautions

…gemfibrozil is a CYP2C8 inhibitor, which may increase exposure of CYP2C8 substrates when administered concomitantly… gemfibrozil inhibits OATP1B1 and may increase exposure of drugs that are substrates of OATP1B1…

7 Drug Interactions

a precautionary statement for dose reduction of drugs that are mainly metabolized by the CYP2C8 enzyme when gemfibrozil is used concomitantly;
a subsection to detail the impact of gemfibrozil on dasabavir’s AUC and Cmax in support of the contraindication for concomitant use of gemfibrozil with dasabuvir;
information from in vitro studies showing the effect of gemfibrozil on CYP enzymes, UGTA enzymes and OATP1B1 transporter.