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.

ADDERALL 10 (NDA-011522)

(AMPHETAMINE ASPARTATE; AMPHETAMINE SULFATE; DEXTROAMPHETAMINE SACCHARATE; DEXTROAMPHETAMINE SULFATE)

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

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10/13/2023 (SUPPL-45)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: ABUSE, MISUSE, AND ADDICTION

ADDERALL 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 ADDERALL, can result in overdose and death [see OVERDOSAGE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing ADDERALL, 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 ADDERALL 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 DRUG ABUSE AND DEPENDENCE].

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

Abuse, Misuse, and Addiction

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

Before prescribing ADDERALL, 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 amphetamine sulfate in a safe place, preferably locked, and instruct patients to not give ADDERALL to anyone else. Throughout ADDERALL treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulant treatment at the recommended ADHD dosages.

Avoid ADDERALL use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

Increased Blood Pressure and Heart Rate

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all ADDERALL-treated patients for potential tachycardia and hypertension.

…

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

CNS stimulants, including amphetamine sulfate, have been associated with the onset or

exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. Before initiating ADDERALL, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome with ADDERALL, and discontinue treatment if clinically appropriate.

PRECAUTIONS

Additions and/or revisions underlined:

Information for Patients

…

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of ADDERALL, which can lead to overdose and death, and proper disposal of any unused drug [see WARNINGS, DRUG ABUSE AND DEPENDENCE, OVERDOSAGE]. Advise patients

to store ADDERALL in a safe place, preferably locked, and instruct patients to not give ADDERALL to anyone else.

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with ADDERALL use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see WARNINGS].

Increased Blood Pressure and Heart Rate

Advise patients that ADDERALL can elevate blood pressure and heart rate [see WARNINGS].

Psychiatric Adverse Reactions

Advise patients that ADDERALL, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see WARNINGS].

Long-Term Suppression of Growth in Pediatric Patients

Advise patients that ADDERALL may cause slowing of growth including weight loss [see

WARNINGS].

…

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of ADDERALL and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see CONTRAINDICATIONS, WARNINGS, and DRUG INTERACTIONS]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

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 ADDERALL. Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs [see WARNINGS].

6 Adverse Reactions

Additions and/or revisions underlined:

…

Central Nervous System

Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, motor and verbal tics, aggression, anger, logorrhea, dermatillomania.

…

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

MEDICATION GUIDE

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

02/25/2022 (SUPPL-44)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions underlined

…

Gastrointestinal

Dryness of the mouth, unpleasant taste, diarrhea, constipation, intestinal ischemia, and other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.

…

01/04/2017 (SUPPL-43)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma.

Agitated states.

Known hypersensitivity or idiosyncrasy to amphetamine. Patients with a history of drug abuse.

In patients known to be hypersensitive to amphetamine, or other components of Adderall®.

Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products.

Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis.

5 Warnings and Precautions

Serotonin Syndrome

(additions underlined)

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism . The potential for a pharmacokinetic interaction exists with the coadministration of CYP2D6 inhibitors which may increase the risk with increased exposure to Adderall®. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,

delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of Adderall® with MAOI drugs is contraindicated. Discontinue treatment with Adderall® and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Adderall® with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Adderall® with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

7 Drug Interactions

(additions underlined)

Acidifying Agents

Lower blood levels and efficacy of amphetamines. Increase dose based on clinical response. Examples of acidifying agents include gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) and urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).

Adrenergic Blockers

Adrenergic blockers are inhibited by amphetamines.

Alkalinizing Agents

Increase blood levels and potentiate the action of amphetamine. Co-administration of Adderall® and gastrointestinal alkalinizing agents should be avoided. Examples of alkalinizing agents include gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) and urinary alkalinizing agents (e.g. acetazolamide, some thiazides).

Tricyclic Antidepressants

May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Monitor frequently and adjust or use alternative therapy based on clinical response. Examples of tricyclic antidepressants include desipramine, protriptyline.

CYP2D6 Inhibitors

The concomitant use of Adderall® and CYP2D6 inhibitors may increase the exposure of Adderall® compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during Adderall® initiation and after a dosage increase. If serotonin syndrome occurs, discontinue Adderall® and the CYP2D6 inhibitor. Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.

Serotonergic Drugs

The concomitant use of Adderall® and serotonergic drugs increases the risk of serotonin syndrome.

Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during Adderall® initiation or dosage increase. If serotonin syndrome occurs, discontinue Adderall® and the concomitant serotonergic drug(s) Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort.

MAO Inhibitors

Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer Adderall® concomitantly or within days after discontinuing MAOI. Examples of MAOIs include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

…

Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. Monitor patients for changes in clinical effect and adjust therapy based on clinical response. An example of a proton pump inhibitor is omeprazole.

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

MEDICATION GUIDE

(additions underlined)

• Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when medicines such as Adderall® are taken with certain other medicines. Symptoms of serotonin syndrome may include:

agitation, hallucinations, coma or other changes in mental status o problems controlling your movements or muscle twitching
fast heartbeat
high or low blood pressure
sweating or fever
nausea or vomiting
diarrhea
muscle stiffness or tightness