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.

ADEMPAS (NDA-204819)

(RIOCIGUAT)

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

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09/10/2021 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

4.4 Soluble Guanylate Cyclase Stimulators

(Newly Added Subsection)

Adempas is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Drug Interactions (7.1)].

7 Drug Interactions

7.1 Pharmacodynamic Interactions with Adempas

(Additions and/or revisions are underlined)

Other Soluble Guanylate Cyclase Stimulators: Co-administration of Adempas is contraindicated in patients with use of other soluble guanylate cyclase (sGC) stimulators [see Contraindications (4.4)].

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

MEDICATION GUIDE

(Extensive changes; please refer to labeling)

01/11/2018 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

4.1 Pregnancy

(additions underlined)

Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

5 Warnings and Precautions

5.1 Embryo-Fetal Toxicity

(additions underlined)

Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with ADEMPAS and for at least one month after the last dose.

For females, Adempas is only available through a restricted program under the Adempas REMS Program.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity and miscarriage when administered to a pregnant woman and is contraindicated during pregnancy. There are limited available data with ADEMPAS use in pregnant women. In animal reproduction studies, oral administration of riociguat to pregnant rats during organogenesis was teratogenic and embryotoxic at exposures approximately 8 times and 2 times, respectively, the human exposure. In reproduction studies with pregnant rabbits, oral administration of riociguat during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human (MRHD). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population 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 2–4% and 15– 20%, respectively.

Data

Animal Data

In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time- concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.

8.2 Lactation

(PLLR conversion, additions unserlined)

Risk Summary

There are no data on the presence of riociguat in human milk, the effects on the breastfed infant, or the effect on milk production. Riociguat is present in rat milk. Because of the potential for serious adverse reactions from ADEMPAS, such as hypotension, in breastfed infants.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Lactation

Advise women not to breastfeed during treatment with ADEMPAS

…

01/17/2017 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

4.3 Phosphodiesterase Inhibitors

(Additions and/or revisions are underlined)

… Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.

4.4 Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP)

(New Subsection added)

Adempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

7 Drug Interactions

7.1 Pharmacodynamic Interactions with Adempas

(Additions and/or revisions are underlined)

PDE Inhibitors: …Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Other Risks Associated with Adempas

Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Instruct patients to report all current medications and new medications to their physician.
Advise patients that antacids should not be taken within 1 hour of taking Adempas.
Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines. Advise patients to be aware of how they react to Adempas before driving or operating machinery, and if needed, consult their physician. Patients should consult their physicians if dizziness gets worse with Adempas.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Who should not take Adempas? Do not take Adempas if:

you have pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

How should I take Adempas?

Do not take Adempas within 24 hours of sildenafil. Do not take Adempas 24 hours before or 48 hours after tadalafil.

General Information about Adempas

…For more information go to www.Adempas-us.com or call 1-888-842-2937.