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.

MIRAPEX (NDA-020667)

(PRAMIPEXOLE DIHYDROCHLORIDE)

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

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07/12/2021 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 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 MIRAPEX. These symptoms generally do not respond to levodopa.

Prior to discontinuation of MIRAPEX, 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.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Withdrawal Symptoms [see Warnings and Precautions (5.11)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of MIRAPEX tablets, primarily in Parkinson’s disease patients. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets.

Cardiac Disorders: cardiac failure

Gastrointestinal Disorders: vomiting

General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.11)]

Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase

Musculoskeletal and Connective Tissue Disorders: postural deformity [see Warnings and Precautions (5.6)] Nervous System Disorders: syncope

Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

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(5.10)].

Withdrawal Symptoms

Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of MIRAPEX. 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 (5.11)].

…

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

How should I take MIRAPEX?

Take MIRAPEX exactly as your doctor tells you to take it.
Your doctor will tell you how much MIRAPEX to take and when to take it. Do not take more or less MIRAPEX than your doctor tells you to.
Your doctor may change your dose if needed.
MIRAPEX can be taken with or without food. Taking MIRAPEX tablets with food may lower your chances of getting nausea.
If you take more MIRAPEX than your doctor recommends, call your doctor or go to the nearest hospital emergency room right away.
If you miss a dose, do not double your next dose. Skip the dose you missed and take your next regular dose.

Do not stop taking MIRAPEX without talking to your doctor first. If your doctor tells you to stop taking MIRAPEX, you should ask your doctor for specific instructions on how to safely discontinue taking MIRAPEX. If you stop MIRAPEX you may have withdrawal symptoms (see “withdrawal symptoms” under “What are the possible side effects of MIRAPEX?”).

…

withdrawal symptoms. MIRAPEX is a dopamine agonist medicine. Dopamine agonist medicines, including MIRAPEX, can cause withdrawal symptoms as your dose is slowly lowered (tapered) or when treatment with MIRAPEX 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 about things you usually care about (apathy)
anxiety
depression
fatigue
insomnia
sweating

pain

After you have stopped taking MIRAPEX, your doctor may need to restart you at a low dose of MIRAPEX if you get severe withdrawal symptoms.

...

04/03/2020 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Impulse Control/Compulsive Behaviors

(Additions and/or revisions underlined)

Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including MIRAPEX, 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 MIRAPEX for Parkinson’s disease or RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking MIRAPEX.

5.4 Hallucinations and Psychotic-like Behavior

(Additions and/or revisions underlined)

In the three double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving MIRAPEX tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received MIRAPEX tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving MIRAPEX tablets compared with 3.8% (10 of 264) of patients receiving placebo.

Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.

Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

Postmarketing reports with medications used to treat Parkinson’s disease or RLS, including MIRAPEX, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with MIRAPEX or after starting or increasing the dose of MIRAPEX. 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 can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Hallucinations and Psychotic-like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur. In patients with Parkinson’s disease, the elderly are at a higher risk than younger patients.

05/10/2018 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

Addition of the following:

5.6 Postural Deformity

Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of MIRAPEX. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing MIRAPEX has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.8 Rhabdomyolysis

… Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

6 Adverse Reactions

Addition of the following:

Postural Deformity

6.2 Post Marketing Experience

Reformatted and revised information:

Cardiac Disorders: cardiac failure

Gastrointestinal Disorders: vomiting

Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase

Musculoskeletal and Connective Tissue Disorders: postural deformity

Nervous System Disorders: syncope

Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticarial)

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

PATIENT INFORMATION

What are the possible side effects of MIRAPEX? MIRAPEX may cause serious side effects, including:

Addition of the following:

posture changes. Talk with your doctor if you have posture changes you cannot control. These may include your neck bending forward, bending forward at the waist, or tilting sideways when you sit, stand, or walk.

Additions and/or revisions underlined:

How should I store MIRAPEX?

Store MIRAPEX at room temperature from 68ºF to 77ºF (20ºC to 25ºC).

07/28/2016 (SUPPL-34)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation (PLLR Conversion)

Risk Summary

There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MIRAPEX and any potential adverse effects on the breastfed infant from MIRAPEX or from the underlying maternal condition.

Data

In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma

Pregnancy (PLLR Conversion)

Risk Summary

There are no adequate data on the developmental risk associated with the use of MIRAPEX in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures.
In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, and 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD.

01/14/2016 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

…skin reactions (including erythema, rash, pruritus, urticaria)…