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.

METHYLIN (NDA-021419)

(METHYLPHENIDATE HYDROCHLORIDE)

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

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10/13/2023 (SUPPL-23)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: ABUSE, MISUSE, AND ADDICTION

Methylin has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including Methylin, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing Methylin, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout Methylin treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].

5 Warnings and Precautions

5.1 Abuse, Misuse, and Addiction

Additions and or revisions underlined:

Methylin has a high potential for abuse and misuse. The use of Methylin exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylin can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2 )]. Misuse and abuse of CNS stimulants, including Methylin, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing Methylin, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store Methylin in a safe place, preferably locked, and instruct patients to not give Methylin to anyone else. Throughout Methylin treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

New subsection added:

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating Methylin, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor Methylin-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

5.8 Acute Angle Closure Glaucoma

New subsection added:

There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, Methylin-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.9 Increased Intraocular Pressure and Glaucoma

New subsection added:

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

Prescribe Methylin to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor Methylin-treated patients with a history of abnormally increased IOP or open-angle glaucoma.

6 Adverse Reactions

Additions and/or revisions underlined:

The following adverse reactions are discussed in more detail in other sections of the labeling:

Abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
…
Acute angle closure glaucoma [see Warnings and Precautions (5.8)]
Increased intraocular pressure and glaucoma [see Warnings and Precautions (5.9)]
Motor and verbal tics, and worsening of Tourette’s syndrome [see Warnings and Precautions (5.10)]
The following adverse reactions associated with the use of methylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine, motor and verbal tics
Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis, increased intraocular pressure
…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of Methylin, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store Methylin in a safe place, preferably locked, and instruct patients to not give Methylin to anyone else.

…

Increased Intraocular Pressure (IOP) and Glaucoma

Advise patients that IOP and glaucoma may occur during treatment with Methylin [see Warnings and Precautions (5.9)].

Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with Methylin. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10)].

…

MEDICATION GUIDE

Medication Guide has undergone extensive changes; please refer to label.

07/19/2021 (SUPPL-10)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion; as below:

WARNING: ABUSE AND DEPENDENCE

See full prescribing information for complete boxed warning.

CNS stimulants, including Methylin, other methylphenidate- containing products, and amphetamines, have a high potential for abuse and dependence. (5.1, 9.2, 9.3) Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy. (5.1, 9.2)

4 Contraindications

PLR conversion; additions and/or revisions underlined:

Methylin is contraindicated in patients:

with known hypersensitivity to methylphenidate or other components of Methylin. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6)].
receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7)].

5 Warnings and Precautions

PLR Conversion: subsection titles as below. Please refer to label for complete information:

5.1 Potential for Abuse and Dependence

5.2 Serious Cardiovascular Reactions

5.3 Blood Pressure and Heart Rate Increases

5.4 Psychiatric Adverse Reactions

5.5 Priapism

5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon

5.7 Long-Term Suppression of Growth

6 Adverse Reactions

PLR conversion; as below:

The following adverse reactions are discussed in more detail in other sections of the labeling:

Abuse and Dependence [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]

Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4), Drug Interactions (7)]
Serious cardiovascular reactions [see Warnings and Precautions (5.2)]
Blood pressure and heart rate increases [see Warnings and Precautions (5.3)]
Psychiatric adverse reactions [see Warnings and Precautions (5.4)]
Priapism [see Warnings and Precautions (5.5)]
Peripheral vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions (5.6)]
Long-term suppression of growth [see Warnings and Precautions (5.7)]

The following adverse reactions associated with the use of methylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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.

Infections and infestations: nasopharyngitis

Blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia, pancytopenia

Immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas

Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients

Psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, affect lability, mania, disorientation, libido changes

Nervous system disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine

Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis

Cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain, dyspnea Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia, diarrhea General disorders: fatigue, hyperpyrexia

Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura angioneurotic edema, erythema, fixed drug eruption

Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis, myalgia, muscle twitching

Renal and urinary disorders: hematuria

Reproductive system and breast disorders: gynecomastia

Urogenital disorders: priapism

Vascular disorders: peripheral coldness, Raynaud’s phenomenon

Investigations: weight loss

7 Drug Interactions

PLR conversion; as below:

7.1 Clinically Important Drug Interactions with Methylin

Table 1 presents clinically important drug interactions with Methylin.

Table 1: Clinically Important Drug Interactions with Methylin (Information restructured into table format; please refer to label for complete information.

8 Use in Specific Populations

PLR conversion; sections titled as below. Please refer to label for complete information:

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

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

MEDICATION GUIDE

PLR conversion; extensive revisions. Please refer to label for complete information.

PATIENT COUNSELING INFORMATION

PLR conversion; please refer to label for complete information.

Other

PLR conversion

06/25/2021 (SUPPL-20)

Approved Drug Label (PDF)

7 Drug Interactions

Additions underlined

Monoamine Oxidase Inhibitors (MAOI)

Concomitant use of MAOIs and CNS stimulants, including Methylin can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure (see CONTRAINDICATIONS). Concomitant use of Methylin with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.

Antihypertensive Drugs

Methylin may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.

Risperidone

Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

…

01/04/2017 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

… Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to severe hepatic injury; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss; serotonin syndrome in combination with serotonergic drugs. Very rare reports …