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.

KUVAN (NDA-022181)

(SAPROPTERIN DIHYDROCHLORIDE)

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

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03/16/2020 (SUPPL-20)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry has been established that monitors pregnancy outcomes in women who are exposed to Kuvan during pregnancy. For more information regarding the registry program call 1-800-983-4587.

Risk Summary

Available pregnancy registry data have not reported an association with Kuvan and major birth defects, miscarriage, or adverse maternal or fetal outcomes when Kuvan was used during pregnancy.

An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD.

All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy 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. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception.

Data

Human Data

Uncontrolled Maternal PKU

Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU-affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects.

Pregnancy Registry Data

Data from 62 live births reported 3 abnormalities at birth (one case each of microcephaly, cleft palate, and tongue tie). These outcomes were associated with Phe levels greater than 360 micromol/L during pregnancy.

Animal Data

No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis. However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).

8.2 Lactation

(PLLR conversion)

Risk Summary

There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production. In postmarketing pregnancy registries, a total of 16 women from both registries were identified as breastfeeding for a mean of 3.5 months. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with Kuvan.

Sapropterin is present in the milk of lactating rats following intravenous administration, but not following oral administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kuvan and any potential adverse effects on the breastfed child from Kuvan or from the underlying maternal condition.

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

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

What should I tell my doctor before taking Kuvan?

Before you take Kuvan, tell your doctor about all your medical conditions, including if you:

are allergic to sapropterin dihydrochloride or any of the ingredients in Kuvan. See the list of ingredients in Kuvan at the end of this leaflet.
have poor nutrition or have loss of appetite.
are pregnant or plan to become pregnant.
Pregnancy Exposure Registry: There is a pregnancy exposure registry for women who take Kuvan during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry or contact the registry program at 1-800-983-4587.

are breastfeeding or plan to breastfeed. It is not known if Kuvan passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take Kuvan.

…

12/13/2019 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Upper Gastrointestinal Mucosal Inflammation

(new subsection added)

Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with Kuvan. Serious adverse reactions included esophagitis and gastritis .If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving Kuvan. Monitor patients for signs and symptoms of upper GI mucosal inflammation.

5.3 Hypophenylalaninemia

(additions underlined)

In clinical trials of Kuvan, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with Kuvan. In a clinical study of pediatric patients younger than 7 years old treated with Kuvan 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients.

5.4 Monitoring Blood Phe Levels During Treatment

(additions underlined)

Prolonged elevations of blood Phe levels in patients with PKU can result in severe neurologic damage, including severe intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. Active management of dietary Phe intake while taking Kuvan is required to ensure adequate Phe control and nutritional balance. Monitor blood Phe levels during treatment to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population.

5.5 Lack of Biochemical Response to Kuvan

(additions underlined)

Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with Kuvan. In two clinical trials at a Kuvan dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to Kuvan, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients showed a biochemical response to Kuvan.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting.

Hyperactivity: Two cases have been reported. In one case, the patient received an accidental overdosage of Kuvan.

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

PATIENT COUNSELING INFORMATION

(extensive additions and revisions, please refer to label for complete information)

PATIENT INFORMATION

(additions underlined)

…

What are the possible side effects of KUVAN?

Kuvan can cause serious side effects, including:

…

Inflammation of the lining of the stomach (gastritis) or esophagus (esophagitis). Gastritis or esophagitis can happen with Kuvan and may be severe. Call your doctor right away if you have any of these signs or symptoms:
- severe upper stomach-area (abdominal) discomfort or pain, nausea and vomiting
- blood in your vomit or stool
- black, tarry stools
- difficulty swallowing
- loss of appetite
- pain in the throat
  
  …

02/01/2019 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Interaction with Levodopa

Additions and/or revisions underlined:

Monitor patients who are receiving levodopa for change in neurologic status during treatment with Kuvan.

7 Drug Interactions

Newly added information:

Table 4 includes drugs with clinically important drug interactions when administered with sapropterin dihydrochloride and instructions for preventing or managing them.

Table 4: Clinically Relevant Drug Interactions Please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

For more information regarding the registry program call 1-800-983-4587.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Advise patients who are taking Kuvan in combination with drugs that inhibit folate metabolism or drugs that inhibit nitric oxide-mediated vasorelaxation may require additional clinical monitoring while taking Kuvan.

06/13/2016 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

Clincial Trials Experiences

PKU Clinical Studies

In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received Kuvan 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%).

7 Drug Interactions

Based on in vitro study, there is potential for Kuvan to inhibit p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses. Co-administration of Kuvan may increase systemic exposure to drugs that are substrates for P-gp or BCRP.

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

PCI - How should I take Kuvan?

Kuvan comes as a tablet and powder for oral solution.

Be sure that you know what dose of Kuvan powder your doctor prescribed and whether you should use Kuvan 100 mg packets, Kuvan 500 mg packets, or both types of packets to prepare your dose. (addition)
Open Kuvan powder packets only when you are ready to use them. (addition)

PCI - Patients should be advised of the following information before beginning treatment with Kuvan:

(addition) Advise patients that Kuvan may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication.