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.

ALTOPREV (NDA-021316)

(LOVASTATIN)

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

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09/25/2020 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

(New subsection added)

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMGCoA reductase antibody; muscle biopsy showing necrotizing myopathy and improvement with immunosuppressive agents.

Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

02/28/2018 (SUPPL-35)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

The use of Altoprev is contraindicated in the following conditions:

Pregnancy.
Lactation. Because another drug in this class passes into breast milk, and because statins have the potential to cause serious adverse reactions in breastfed infants, women who require Altoprev treatment should not breastfeed their infants.

7 Drug Interactions

(Additions and/or revisions are underlined)

Drug interaction studies have not been performed with Altoprev. The types, frequencies and magnitude of drug interactions that may be encountered when Altoprev is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate- release formulation…

8 Use in Specific Populations

8.1 Pregnancy

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

Risk Summary

Altoprev is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with Altoprev during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Altoprev may cause fetal harm when administered to pregnant women. Altoprev should be discontinued as soon as pregnancy is recognized . Limited published data on the use of lovastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of fetal malformations was seen in mice or rats at doses 5 and 25 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day lovastatin immediate-release, based on body surface area. No evidence of malformations was noted in rabbits with oral administration of lovastatin during organogenesis at doses up to 4 times the MRHD, based on body surface area. Skeletal malformations occurred at doses 50 times the MRHD in mice and rats, based on body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Limited published data on lovastatin have not shown an increased risk of major congenital malformations or miscarriage.

Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a greater than or equal to 3 to 4-fold increase in congenital anomalies over the background incidence…

Animal Data

In pregnant rats given oral gavage doses of 100, 200, 400, 800 mg/kg/day lovastatin from gestation days 6 through 20, reduced fetal body weights were observed at all doses and skeletal malformations were observed at greater than or equal to 400 mg/kg/day, corresponding to 50 times the 80 mg/day MRHD of lovastatin immediate-release, based on body surface area (mg/m2).

In pregnant mice given oral gavage doses of 8, 80, 800 mg/kg/day lovastatin from gestation days 6 through 15, reduced fetal body weights were observed at greater than or equal to 80 mg/kg/day and skeletal malformations were observed at 800 mg/kg/day, corresponding to 5 and 50 times the 80 mg/day MRHD, based on body surface area (mg/m2).

In pregnant rabbits given an oral gavage dose of 15 mg/kg/day lovastatin from gestation days 6 through 18, no teratogenic effects were observed. Doses were 4 times the 80 mg/day MRHD, based on body surface area (mg/m2).

In pregnant rats given oral gavage doses of 2, 20, 200 mg/kg/day lovastatin by oral gavage from gestation day 15 through lactation day 21 (weaning), increased mortality of offspring was observed at greater than or equal to 20 mg/kg/day and development delays were observed at 200 mg/kg/day, corresponding to 2.4 and 24 times, respectively, the 80 mg/day MRHD, based on body surface area (mg/m2).

8.2 Lactation

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

Risk Summary

Altoprev is contraindicated during breastfeeding. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, a small amount of another drug in this class is present in human breast milk. Because of the potential for serious adverse reactions in breastfed infants, advise patients that breastfeeding is not recommended during treatment with Altoprev.

8.3 Females and Males of Reproductive Potential

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

Contraception

Altoprev may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Altoprev.

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

17 PATIENT COUNSELING INFORMATION

17.3 Embryofetal Toxicity

(Additions and/or revisions are underlined)

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy.

17.4 Lactation

(Additions and/or revisions are underlined)

Advise women not to breastfeed during treatment with Altoprev.

08/04/2017 (SUPPL-34)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

Respiratory: interstitial lung disease

7 Drug Interactions

Additions and/or revisions underlined

… In addition, as the drug exposure with Altoprev® 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with Altoprev® 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs …