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.

REMODULIN (NDA-021272)

(TREPROSTINIL)

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

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07/30/2018 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risk of Catheter-Related Bloodstream Infection

Additions and/or revisions underlined:

Chronic intravenous infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated …

In an open-label study of IV treprostinil (n=47) using an external infusion pump, there were seven …

… In an open-label study of an implantable pump (n=60), there were two blood stream infections (BSIs) related to the implant procedure during approximately 265 patient years.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. However, there are risks to the mother and

the fetus associated with pulmonary arterial hypertension. In animal studies, no adverse reproductive and developmental effects were seen in rats at about 123 and 48 times the human exposure based on Cmax and AUC, respectively. In rabbits, external fetal and soft tissue malformations and skeletal malformations were observed at about 7 and 5 times the human exposure based on Cmax and AUC, respectively.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality.

Data

Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous administration and with treprostinil diolamine administered orally. In pregnant rats, continuous

subcutaneous infusions of treprostinil during organogenesis and late gestational development, at

doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a ng/m2 basis and about 16 times … (reduction in body weight and food consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, on a ng/m2 basis, … treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. In studies with orally administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which represents about 123 and 48 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 7 and 5 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. No treprostinil treatment-related effects …

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Interruption of Therapy

Advise patients and caregivers to seek medical attention if they experience signs or symptoms of abrupt withdrawal of therapy or suspect a pump malfunction.

Overdose

Inform patients and their caregivers to seek medical attention if they experience signs or symptoms of Remodulin overdose.

06/08/2018 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

Addition of the following two subsections:

5.4 Risk of Symptomatic Hypotension

Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.

5.5 Risk of Bleeding

Remodulin inhibits platelet aggregation and increases the risk of bleeding.

6 Adverse Reactions

6.2 Post-Marketing Experience

Additions and/or revisions underlined:

… These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia, bone pain, pruritus, dizziness, arthralgia, myalgia/muscle spasm, and pain in extremity …

7 Drug Interactions

7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil

Dose adjustment of treprostinil may be necessary when co-administered with CYP2C8 inducers or inhibitors. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration … It has not been determined if the changes in exposure of treprostinil with inhibitors or inducers of CYP2C8 observed for the oral administration of treprostinil would be similar for treprostinil administered via the parenteral route.

8 Use in Specific Populations

8.7 Patients with Renal Impairment

Additions and/or revisions underlined:

No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by dialysis.