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.

KALETRA (NDA-021226)

(LOPINAVIR; RITONAVIR)

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

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10/21/2020 (SUPPL-49)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions underlined)

…

Renal and Urinary Disorders

Nephrolithiasis

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

MEDICATION GUIDE

(Additions underlined)

…

What are the possible side effects of KALETRA?

KALETRA can cause serious side effects, including:

…

Kidney stones
…

08/21/2019 (SUPPL-47)

Approved Drug Label (PDF)

4 Contraindications

Section has been revised from a chart format to a bulleted line listing.

Addition of the lipid modifying agent lomitapide

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Addition of the following drug-drug interaction information to Table 5 Established and Other Potentially Significant Drug Interactions:

anticancer agents: neratinib and abemaciclib

lipid modifying agent: lomitapide

hepatitis C direct acting antivirals: glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir

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

MEDICATION GUIDE

Who should not take KALETRA? Do not take KALETRA if you:

if you take any of the following medicines:

Addition of ‘lomitapide’

11/15/2018 (SUPPL-46)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Added ibrutinib to the list of Anticancer Agents under Table 6, please refer to label to view Table 6)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(new subsection added)

Contraception

Use of KALETRA may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.

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

MEDICATION GUIDE

(reformatted and revised to be consistent with changes to the USPI, please refer to label)

PATIENT COUNSELING INFORMATION

(revised to be consistent with changes to the USPI, please refer to label)

06/15/2017 (SUPPL-45)

Approved Drug Label (PDF)

4 Contraindications

Table 1. Drugs That are Contraindicated with KALETRA (The antianginal drug, ranolazine, has been added to the table; please refer to label)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 6. Established and Other Potentially Significant Drug Interactions (Information about the anticancer drug, venetoclax, and corticosteroids has been added/revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Risk Summary

Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.

Data

Human Data

KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial. No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.

Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for HIV-1 transmission in breastfed infants, advise women not to breastfeed.

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

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Who should not take KALETRA?

Do not take KALETRA if you take any of the following medicines:

ranolazine (Ranexa)

What should I tell my doctor before taking KALETRA?

Especially tell your doctor if you take:

triamcinolone (Kenalog)
venetoclax (Venclexta)

11/22/2016 (SUPPL-43)

Approved Drug Label (PDF)

4 Contraindications

Section updated with the anti-arrhythmic drug, dronedarone, anti-gout drug, colchicine, and hepatitis C direct acting antiviral, elbasvir/grazoprevir.

Table 1. Drugs That are Contraindicated with KALETRA (table updated; please refer to label).

5 Warnings and Precautions

5.6 Diabetes Mellitus/Hyperglycemia (addition underlined)

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with KALETRA.

7 Drug Interactions

7.1 Potential for KALETRA to Affect Other Drugs (addition underlined)

Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.

Additionally, KALETRA induces glucuronidation.

Published data suggest that lopinavir is an inhibitor of OATP1B1.

7.3 Established and Other Potentially Significant Drug Interactions

Table 6. Established and Other Potentially Significant Drug Interaction (table update; please refer to label)

7.4 Drugs with No Observed or Predicted Interactions with KALETRA (addition underlined)

Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine , or rilpivirine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

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

MEDICATION GUIDE (addition underlined)

Who should not take KALETRA?

Do not take KALETRA if you take any of the following medicines:

· alfuzosin (Uroxatral®)

· cisapride (Propulsid®, Quicksolv®)

· colchicine (Colcrys®), if you have kidney and/or liver problems

· dronedarone (Multaq®)

· elbasvir/grazoprevir (Zepatier®)

· ergot containing medicines including

· ergotamine tartrate (Cafergot®, Migergot®, Ergomar®, Ergostat®, Medihaler®, Ergotamine, Wigraine®, Wigrettes®)

· dihydroergotamine mesylate (D.H.E. 45®, Migranal®)

· methylergonovine (Methergine®)

· lovastatin (Advicor®, Altoprev®, Mevacor®)

· midazolam oral syrup

· lurasidone (Latuda®), pimozide (Orap®)

· rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®)

· sildenafil (Revatio®), when used for the treatment of pulmonary arterial hypertension

· simvastatin (Zocor®, Vytorin®, Simcor®)

· St. John’s Wort (Hypericum perforatum)

· triazolam (Halcion®)

Serious problems can happen if you or your child take any of the medicines listed above with

KALETRA.

• Do not take KALETRA if you are allergic to lopinavir, ritonavir or any of the ingredients in KALETRA. See the end of this Medication Guide for a complete list of ingredients in KALETRA.

Tell your doctor about all the medicines you take

· isavuconazonium (Cresemba®)

· ombitasvir/parataprevir/ritonavir and dasabuvir (Viekira Pak®)

09/15/2016 (SUPPL-44)

Approved Drug Label (PDF)

4 Contraindications

Table 1. Drugs That are Contraindicated with KALETRA

· Drug Class-

Antipsychotics: (added)

Lurasidone- Potential for serious and/or life- threatening reaction.

Pimozide- Potential for cardiac arrhythmias.

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

MEDICATION GUIDE

Who should not take KALETRA?

Do not take KALETRA if you take any of the following medicines:

· Lurasidone( Latuda) (added)