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.

HYDROXYCHLOROQUINE SULFATE (NDA-214581)

(HYDROXYCHLOROQUINE SULFATE)

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

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07/24/2023 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Worsening of Psoriasis

(Additions and/or revisions underlined)

Administration of hydroxychloroquine sulfate to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid hydroxychloroquine sulfate in patients with psoriasis, unless the benefit to the patient outweighs the possible risk.

5.5 Risks Associated with Use in Porphyria

(Additions and/or revisions underlined)

Administration of hydroxychloroquine sulfate in patients with porphyria may exacerbate porphyria. Avoid hydroxychloroquine sulfate in patients with porphyria.

Hepatotoxicity Associated with Porphyria Cutanea Tarda

Cases of hepatotoxicity have been reported when hydroxychloroquine was used in patients with porphyria cutanea tarda (PCT). Patients received dosages ranging from 200 mg twice weekly to 400 mg daily. Most of the PCT-related cases presented with marked elevations in transaminases (>20 times upper limit of the reference range) within days to a month of hydroxychloroquine

initiation. In some cases, PCT was diagnosed only after the occurrence of treatment-induced liver injury, when hydroxychloroquine was prescribed for an approved indication. Some of the cases were associated with other risk factors for hepatic injury (e.g., alcohol use, concomitant hepatotoxic medications).

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, rash, nausea, dark urine, or jaundice. In this clinical context, if the patient is found to have abnormal serum liver tests (e.g., ALT level greater than three times the upper limit of the reference range, total bilirubin greater than two times the upper limit of the reference range), interrupt treatment with hydroxychloroquine sulfate, and investigate further to establish the probable cause.

The safety and effectiveness of hydroxychloroquine sulfate for the treatment of PCT have not been established and hydroxychloroquine sulfate is not approved for this use.

5.9 Neuropsychiatric Reactions Including Suicidality

(Additions and/or revisions underlined)

Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with hydroxychloroquine sulfate [see Adverse Reactions (6)].

Neuropsychiatric adverse reactions typically occurred within the first month after the start of treatment with hydroxychloroquine and have been reported in patients with and without a prior history of psychiatric disorders.

The risks and benefits of continued treatment with hydroxychloroquine sulfate should be assessed for patients who develop these symptoms. Given the long half-life of the drug, some patients may require several weeks off drug for symptoms to partially or fully abate.

Advise patients to contact their healthcare provider promptly if they experience new or worsening neuropsychiatric symptoms such as depression, suicidal thoughts or behavior, or mood changes.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are described in greater detail in other sections:

· Cardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5.1)]

· Retinal Toxicity [see Warnings and Precautions (5.2)]

· Serious Skin Reactions [see Warnings and Precautions (5.3)]

· Worsening of Psoriasis [see Warnings and Precautions (5.4)]

· Risks Associated with Use in Porphyria [see Warnings and Precautions (5.5)]

· Hematologic Toxicity [see Warnings and Precautions (5.6)]

· Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.7)]

· Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.8)]

· Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.9)]

· Hypoglycemia [see Warnings and Precautions (5.10)]

The following adverse reactions have been identified during post-approval use of 4- aminoquinoline drugs, including hydroxychloroquine sulfate. 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:

· Blood and lymphatic system disorders: Bone marrow depression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia

· Cardiac disorders: Cardiomyopathy, cardiac failure, QT-interval prolongation, ventricular tachycardia, torsades de pointes, atrioventricular block, bundle branch block, sick sinus syndrome, pulmonary hypertension

· Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, sensorineural hearing loss

· Eye disorders: Retinopathy, retinal pigmentation changes (typically bull’s eye appearance), visual field defects (paracentral scotomas), macular degeneration, corneal edema, corneal opacities, decreased dark adaptation

· Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain

· General disorders: Fatigue

· Hepatobiliary disorders: Abnormal liver function tests, fulminant hepatic failure

· Immune system disorders: Urticaria, angioedema, bronchospasm

· Metabolism and nutrition disorders: Anorexia, hypoglycemia, weight loss

· Musculoskeletal and connective tissue disorders: Proximal myopathy, depressed tendon reflexes, abnormal nerve conduction

· Nervous system disorders: Ataxia, dizziness, headache, seizure, extrapyramidal disorders (dystonia, dyskinesia, tremor)

· Neuropsychiatric disorders: Affect/emotional lability, irritability, nervousness, psychosis, suicidal ideation, suicidal behavior, depression, hallucinations, anxiety, agitation, confusion, delusions, paranoia, mania and sleep disorders (insomnia, night terrors, nightmares)

· Skin and subcutaneous tissue disorders: Alopecia, hair color changes, rash, pruritus, photosensitivity, psoriasis exacerbation, hyperpigmentation, exfoliative dermatitis, erythema multiforme, acute generalized exanthematous pustulosis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Skeletal Muscle Myopathy or Neuropathy

Inform the patient that muscle weakness and atrophy has been reported with hydroxychloroquine sulfate use Advise patients to report to the physician symptoms of muscle weakness [see Warnings and Precautions (5.8)].

Neuropsychiatric Reactions Including Suicidality

Alert patients to seek medical attention immediately if they experience new or worsening depression, suicidal thoughts, or other mood changes [see Warnings and Precautions (5.9)].

Hypoglycemia

Inform the patient that hydroxychloroquine sulfate has been associated with severe hypoglycemia. Advise the patient to monitor blood sugar levels if possible and to seek medical attention if experiencing any of the signs and symptoms of hypoglycemia such as sweating, shakiness, weakness, dizziness, tachycardia, nausea, blurred vision, confusion, fainting, or loss of consciousness [see Warnings and Precautions (5.10)].

…

01/12/2023 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiomyopathy and Ventricular Arrhythmias

Additions and/or revisions underlined:

Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine sulfate. Signs and symptoms of cardiac compromise have occurred during acute and chronic hydroxychloroquine sulfate treatment. In multiple cases, endomyocardial biopsy showed association of the cardiomyopathy with phospholipidosis in the absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.7, 5.10)].

Patients may present with ventricular hypertrophy, pulmonary hypertension and conduction disorders including sick sinus syndrome …

… Therefore, hydroxychloroquine sulfate is not recommended in patients taking other drugs that have the potential to prolong the QT interval. Correct electrolyte imbalances prior to use.

Monitor cardiac function as clinically indicated during hydroxychloroquine sulfate therapy. Discontinue hydroxychloroquine sulfate if cardiotoxicity is suspected or demonstrated by tissue biopsy.

5.7 Skeletal Muscle Myopathy or Neuropathy

Additions and/or revisions underlined:

Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have shown associated phospholipidosis. Drug- induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.10)].

Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine sulfate. Discontinue hydroxychloroquine sulfate if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.

Newly added subsection:

5.10 Renal Toxicity

Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of hydroxychloroquine sulfate.

Renal biopsy showed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Physicians should consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders who are receiving hydroxychloroquine sulfate. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.7)]. Discontinue hydroxychloroquine sulfate if renal toxicity is suspected or demonstrated by tissue biopsy.