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Guide
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.
NEUPRO (NDA-021829)
(ROTIGOTINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/12/2021 (SUPPL-21)
5 Warnings and Precautions
5.15 Withdrawal Symptoms(Newly added subsection)
Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating and pain have been reported during taper or after discontinuation of dopamine agonists, including NEUPRO. These symptoms generally do not respond to levodopa.
Prior to discontinuation of NEUPRO, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.
(Additions and/or revisions underlined)
Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including NEUPRO, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with NEUPRO for Parkinson’s disease or RLS. Dopamine dysregulation syndrome, the repeated use of more NEUPRO than as prescribed to manage their symptoms of Parkinson’s disease or RLS, was observed in some patients during treatment with NEUPRO. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking NEUPRO.
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Withdrawal Symptoms [see Warnings and Precautions (5.15)]
(Additions and/or revisions underlined)
The following adverse reaction has been identified during post-approval use of NEUPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.15)]
Nervous System Disorders: Dropped head syndrome
Musculoskeletal and connective tissue disorders: Rhabdomyolysis
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
…
Impulse Control/Compulsive Behaviors
Advise patients that they may experience impulse control and/or compulsive behaviors and dopamine dysregulation syndrome while taking NEUPRO. Ask patients and advise them to inform their physicians about the development of new or increased gambling urges, sexual urges, other urges, or repeated use of more NEUPRO than as prescribed to manage their symptoms [see Warnings and Precautions (5.6)].
…
Withdrawal-Emergent Hyperpyrexia and Confusion
Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have symptoms such as fever, muscular rigidity, or altered consciousness [see Warnings and Precautions (5.14)].
Withdrawal Symptoms
Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of NEUPRO. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as apathy, anxiety, depression, fatigue, insomnia, sweating, or pain. Notify patients that in case of severe withdrawal symptoms, a trial re- administration of a dopamine agonist at the lowest effective dose may be considered [see Warnings and Precautions (5.15)].
…
(Additions and/or revisions underlined)
…
How should I use NEUPRO for Parkinson’s disease?
Read the Instructions for Use at the end of this leaflet for specific information about the right way to apply the NEUPRO patch.
Use NEUPRO exactly as your doctor tells you to use it.
NEUPRO comes in 4 different size (dose) patches for Parkinson’s disease. Your doctor should start you on a low dose of NEUPRO. Your doctor will change the dose weekly until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach the dose that controls your symptoms best.
Apply NEUPRO 1 time each day at the same time each day.
You may bathe, shower, or swim while wearing a NEUPRO patch. Water may loosen your NEUPRO patch.
If the edges of the patch lift, you may tape them down with bandaging tape.
If your NEUPRO patch falls off, apply a new NEUPRO patch for the rest of the day. The next day, apply a new patch at your regular time.
If you miss a dose or forget to change your NEUPRO patch, apply a new NEUPRO patch as soon as you remember. Replace the NEUPRO patch at your normal time the next day.
Do not stop using NEUPRO without talking to your doctor first. If your doctor tells you to stop using NEUPRO, you should ask your doctor for specific instructions on how to slowly and safely discontinue using NEUPRO. If you stop using NEUPRO, you may have withdrawal symptoms (see “What are the possible side effects of NEUPRO?”).
…
unusual urges. Some patients using NEUPRO get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, strong urges to spend money, binge eating, or increased sexual urges and behaviors. Some patients may want to use more NEUPRO than prescribed for their symptoms (dopamine dysregulation syndrome). If you notice or your family notices that you are developing any unusual behaviors, talk to your doctor.
changes in heart rate. NEUPRO can increase your heart rate.
increased weight and fluid retention can occur in patients using NEUPRO. NEUPRO can cause your body to keep extra fluid which leads to swelling and weight gain. Tell your doctor if you have swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.
uncontrolled, sudden movements. NEUPRO may cause uncontrolled, sudden movements or make such movements you already have worse or more frequent. Tell your doctor if this happens. The doses of your anti-Parkinson’s medicine may need to be changed.
skin site reactions. Skin reactions may occur at the site where you apply NEUPRO. Tell your doctor if you get a rash, redness, swelling, or itching that will not go away at the skin site where you have applied NEUPRO.
withdrawal symptoms. NEUPRO is a dopamine agonist medicine. Dopamine agonist medicines, including NEUPRO, can cause withdrawal symptoms as your dose is slowly lowered (tapered) or when treatment with NEUPRO is stopped. Tell your doctor right away if you get any of the following withdrawal symptoms:
fever
confusion
severe muscle stiffness
feeling like you do not care things you usually care about (apathy)
anxiety
depression
fatigue
insomnia
sweating
- pain
…
07/12/2021 (SUPPL-22)
5 Warnings and Precautions
5.15 Withdrawal Symptoms(Newly added subsection)
Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating and pain have been reported during taper or after discontinuation of dopamine agonists, including NEUPRO. These symptoms generally do not respond to levodopa.
Prior to discontinuation of NEUPRO, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.
(Additions and/or revisions underlined)
Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including NEUPRO, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with NEUPRO for Parkinson’s disease or RLS. Dopamine dysregulation syndrome, the repeated use of more NEUPRO than as prescribed to manage their symptoms of Parkinson’s disease or RLS, was observed in some patients during treatment with NEUPRO. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking NEUPRO.
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Withdrawal Symptoms [see Warnings and Precautions (5.15)]
(Additions and/or revisions underlined)
The following adverse reaction has been identified during post-approval use of NEUPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.15)]
Nervous System Disorders: Dropped head syndrome
Musculoskeletal and connective tissue disorders: Rhabdomyolysis
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
…
Impulse Control/Compulsive Behaviors
Advise patients that they may experience impulse control and/or compulsive behaviors and dopamine dysregulation syndrome while taking NEUPRO. Ask patients and advise them to inform their physicians about the development of new or increased gambling urges, sexual urges, other urges, or repeated use of more NEUPRO than as prescribed to manage their symptoms [see Warnings and Precautions (5.6)].
…
Withdrawal-Emergent Hyperpyrexia and Confusion
Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have symptoms such as fever, muscular rigidity, or altered consciousness [see Warnings and Precautions (5.14)].
Withdrawal Symptoms
Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of NEUPRO. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as apathy, anxiety, depression, fatigue, insomnia, sweating, or pain. Notify patients that in case of severe withdrawal symptoms, a trial re- administration of a dopamine agonist at the lowest effective dose may be considered [see Warnings and Precautions (5.15)].
…
(Additions and/or revisions underlined)
…
How should I use NEUPRO for Parkinson’s disease?
Read the Instructions for Use at the end of this leaflet for specific information about the right way to apply the NEUPRO patch.
Use NEUPRO exactly as your doctor tells you to use it.
NEUPRO comes in 4 different size (dose) patches for Parkinson’s disease. Your doctor should start you on a low dose of NEUPRO. Your doctor will change the dose weekly until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach the dose that controls your symptoms best.
Apply NEUPRO 1 time each day at the same time each day.
You may bathe, shower, or swim while wearing a NEUPRO patch. Water may loosen your NEUPRO patch.
If the edges of the patch lift, you may tape them down with bandaging tape.
If your NEUPRO patch falls off, apply a new NEUPRO patch for the rest of the day. The next day, apply a new patch at your regular time.
If you miss a dose or forget to change your NEUPRO patch, apply a new NEUPRO patch as soon as you remember. Replace the NEUPRO patch at your normal time the next day.
Do not stop using NEUPRO without talking to your doctor first. If your doctor tells you to stop using NEUPRO, you should ask your doctor for specific instructions on how to slowly and safely discontinue using NEUPRO. If you stop using NEUPRO, you may have withdrawal symptoms (see “What are the possible side effects of NEUPRO?”).
…
unusual urges. Some patients using NEUPRO get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, strong urges to spend money, binge eating, or increased sexual urges and behaviors. Some patients may want to use more NEUPRO than prescribed for their symptoms (dopamine dysregulation syndrome). If you notice or your family notices that you are developing any unusual behaviors, talk to your doctor.
changes in heart rate. NEUPRO can increase your heart rate.
increased weight and fluid retention can occur in patients using NEUPRO. NEUPRO can cause your body to keep extra fluid which leads to swelling and weight gain. Tell your doctor if you have swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.
uncontrolled, sudden movements. NEUPRO may cause uncontrolled, sudden movements or make such movements you already have worse or more frequent. Tell your doctor if this happens. The doses of your anti-Parkinson’s medicine may need to be changed.
skin site reactions. Skin reactions may occur at the site where you apply NEUPRO. Tell your doctor if you get a rash, redness, swelling, or itching that will not go away at the skin site where you have applied NEUPRO.
withdrawal symptoms. NEUPRO is a dopamine agonist medicine. Dopamine agonist medicines, including NEUPRO, can cause withdrawal symptoms as your dose is slowly lowered (tapered) or when treatment with NEUPRO is stopped. Tell your doctor right away if you get any of the following withdrawal symptoms:
fever
confusion
severe muscle stiffness
feeling like you do not care things you usually care about (apathy)
anxiety
depression
fatigue
insomnia
sweating
- pain
…
04/24/2020 (SUPPL-17)
5 Warnings and Precautions
Additions and/or revisions underlined:
5.3 Hallucinations/Psychosis
… Post-marketing reports indicate that patients with Parkinson’s disease or RLS may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic behavior during NEUPRO treatment or after starting or increasing the dose of NEUPRO. Other drugs prescribed to improve the symptoms of Parkinson’s disease or RLS can have similar effects on thinking and behavior. This abnormal thinking and behavior may consist of one or more of the following: paranoid ideation, delusions, hallucinations, confusion, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium …
5.6 Impulse Control/Compulsive Behaviors
… Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with NEUPRO for Parkinson’s disease or RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking NEUPRO.
6 Adverse Reactions
6.2 Laboratory Changes
Additions and/or revisions underlined:
… Studies of NEUPRO conducted outside of Japan did not include assessments of serum CPK in patients treated for Parkinson’s disease. Increased CPK was also reported in postmarketing data.
6.3 Postmarketing Experience
Newly added information:
Musculoskeletal and connective tissue disorders: Rhabdomyolysis
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION Leaflet for Restless Legs SyndromeWhat are the possible side effects of NEUPRO?
NEUPRO can cause serious side effects, including:
Newly added information
hallucinations and other psychosis. NEUPRO can cause or worsen psychotic symptoms including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson’s disease who are elderly, taking NEUPRO, or taking higher doses of NEUPRO. If you have hallucinations or any of these other psychotic-like changes, talk with your doctor.
Other
There are separate Patient Information Leaflets for each approved indication – Parkinson’s and Restless Legs Syndrome. The Parkinson’s Patient Information Leaflet already had the hallucinations information.
01/18/2019 (SUPPL-16)
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
There are no adequate data on the developmental risk associated with the use of NEUPRO in pregnant women. In animal studies, rotigotine was shown to have adverse effects on embryofetal development when administered during pregnancy at doses similar to or lower than those used clinically.
In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
There are no data on the presence of rotigotine in human milk, the effects of rotigotine on the breastfed infant, or the effects of rotigotine on milk production. However, inhibition of lactation may occur because rotigotine decreases secretion of prolactin in humans Studies have shown that rotigotine and/or its metabolite(s) are excreted in rat milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEUPRO and any potential adverse effects on the breastfed infant from NEUPRO or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Pregnancy
Because the teratogenic potential of rotigotine has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy.
Lactation
Because of the possibility that rotigotine may be excreted in breast milk, advise women to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
(Additions and/or revisions are underlined)
What should I tell my doctor before using NEUPRO? Before you start using NEUPRO, tell your doctor if you:
are breastfeeding or plan to breastfeed. It is not known if NEUPRO passes into your breastmilk. The amount of breast milk you make may be decreased while taking NEUPRO. Talk to your doctor about the best way to feed your baby if you take NEUPRO.
11/29/2018 (SUPPL-15)
6 Adverse Reactions
Addition of the following subsection:
6.3 Postmarketing Experience
The following adverse reaction has been identified during post-approval use of NEUPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous System Disorders: Dropped head syndrome