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.

PLAQUENIL (NDA-009768)

(HYDROXYCHLOROQUINE SULFATE)

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

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12/12/2023 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiomyopathy and Ventricular Arrhythmias

(Additions and/or revisions underlined)

…

PLAQUENIL has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in PLAQUENIL-treated patients. The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded [see Adverse Reactions (6), Overdosage (10)]. Avoid PLAQUENIL administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:

Cardiac disease, e.g., heart failure, myocardial infarction.
Proarrhythmic conditions, e.g., bradycardia (< 50 bpm).
History of ventricular dysrhythmias.
Uncorrected hypokalemia and/or hypomagnesemia.
Concomitant administration with QT interval prolonging agents as this may lead to an increased risk for ventricular arrhythmias [see Drug Interactions (7.1)].

5.8 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, 5.11)].

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

5.11 Renal Toxicity

(Newly added subsection)

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

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 PLAQUENIL. Drug- induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.8)]. Discontinue PLAQUENIL if renal toxicity is suspected or demonstrated by tissue biopsy.

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)]

Renal Toxicity [see Warnings and Precautions (5.11)]

7 Drug Interactions

7.2 Insulin or Other Antidiabetic Drugs

(Additions and/or revisions underlined)

PLAQUENIL may enhance the effects of insulin and antidiabetic drugs, and consequently increase the hypoglycemic risk. Therefore, a decrease in dosage of insulin and other antidiabetic drugs may be necessary [see Warnings and Precautions (5.10)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Hepatotoxicity Associated with Porphyria Cutanea Tarda

Inform the patient that liver toxicity has been reported in when PLAQUENIL was used in patients with porphyria cutanea tarda. In some cases, PCT was diagnosed only after the occurrence of liver injury, when PLAQUENIL was prescribed for an approved indication. Advise the patient to seek medical attention if experiencing fatigue, rash, nausea, dark urine, or jaundice [see Warnings and Precautions (5.5)].

07/24/2023 (SUPPL-60)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Risks Associated with Use in Porphyria

(Newly added subsection)

Administration of PLAQUENIL to patients with porphyria may exacerbate porphyria. Avoid PLAQUENIL 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 PLAQUENIL, and investigate further to establish the probable cause.

The safety and effectiveness of PLAQUENIL for the treatment of PCT have not been established and PLAQUENIL 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 PLAQUENIL [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 PLAQUENIL 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)]

…

- 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 PLAQUENIL 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 PLAQUENIL 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)].

05/04/2022 (SUPPL-56)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiomyopathy and Ventricular Arrhythmias

Additions underlined

… 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)].

…

Therefore, PLAQUENIL 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 PLAQUENIL therapy. Discontinue PLAQUENIL if cardiotoxicity is suspected or demonstrated by tissue biopsy.

5.10 Renal Toxicity

New subsection added

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

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 PLAQUENIL. Drug- induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.7)]. Discontinue PLAQUENIL if renal toxicity is suspected or demonstrated by tissue biopsy.

5.7 Skeletal Muscle Myopathy or Neuropathy

Additions underlined

05/03/2021 (SUPPL-53)

Approved Drug Label (PDF)

5 Warnings and Precautions

(The following subsections created to comply with PLR; please refer to labeling for complete information)

5.1 Cardiomyopathy and Ventricular Arrhythmias

5.2 Retinal Toxicity

5.3 Serious Skin Reactions

5.4 Worsening of Psoriasis and Porphyria

5.5 Hematologic Toxicity

5.6 Hemolytic Anemia Associated with G6PD Deficiency

5.7 Skeletal Muscle Myopathy or Neuropathy

5.8 Neuropsychiatric Reactions Including Suicidality

5.9 Hypoglycemia

6 Adverse Reactions

(PLR conversion)

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 and Porphyria [see Warnings and Precautions (5.4)]
Hematologic Toxicity [see Warnings and Precautions (5.5)]
Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)]
Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)]
Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)]
Hypoglycemia [see Warnings and Precautions (5.9)]

The following adverse reactions have been identified during post-approval use of 4- aminoquinoline drugs, including PLAQUENIL. 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)
Psychiatric disorders: Affect/emotional lability, irritability, nervousness, nightmares, psychosis, suicidal ideation, suicidal behavior
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)

7 Drug Interactions

(The following subsections created to comply with PLR; please refer to labeling for complete information)

7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs

7.2 Insulin or Other Antidiabetic Drugs

7.3 Drugs that Lower the Seizure Threshold

7.4 Antiepileptics

7.5 Methotrexate

7.6 Cyclosporine

7.7 Digoxin

7.8 Cimetidine

7.9 Rifampicin

7.10 Praziquantel

7.11 Antacids and kaolin

7.12 Ampicillin

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PLAQUENIL during pregnancy. Encourage patients to register by contacting 1-877-311-8972.

Risk Summary

Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with PLAQUENIL use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal, or fetal outcomes (see Data). There are risks to the mother and fetus associated with untreated or increased disease activity from malaria, rheumatoid arthritis, and systemic lupus erythematosus in pregnancy (see Clinical Considerations). Animal reproduction studies were not conducted with hydroxychloroquine.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Malaria: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.

Rheumatoid Arthritis: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Systemic Lupus Erythematosus: Pregnant women with systemic lupus erythematosus, especially those with increased disease activity, are at increased risk of adverse pregnancy outcomes, including spontaneous abortion, fetal death, preeclampsia, preterm birth, and intrauterine growth restriction. Passage of maternal auto-antibodies across the placenta may result in neonatal illness, including neonatal lupus and congenital heart block.

Data

Human Data

Data from published epidemiologic and clinical studies have not established an association with PLAQUENIL use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Hydroxychloroquine readily crosses the placenta with cord blood levels corresponding to maternal plasma levels. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine in utero. Available epidemiologic and clinical studies have methodological limitations including small sample size and study design.

8.2 Lactation

(PLLR conversion)

Risk Summary

Published lactation data report that hydroxychloroquine is present in human milk at low levels. No adverse reactions have been reported in breastfed infants. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine through breastmilk. There is no information on the effect of hydroxychloroquine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PLAQUENIL and any potential adverse effects on the breastfed child from PLAQUENIL or from the underlying maternal condition.

8.4 Pediatric Use

(PLR conversion)

The safety and effectiveness of PLAQUENIL have been established in pediatric patients for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. vivax, and P. ovale, as well as for the prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. However, this product cannot be directly administered to pediatric patients weighing less than 31 kg because the film-coated tablets cannot be crushed or divided [see Dosage and Administration (2.1, 2.2)].

The safety and effectiveness of PLAQUENIL have not been established in pediatric patients for the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, or systemic lupus erythematosus.

8.5 Geriatric Use

(PLR conversion)

Clinical trials of PLAQUENIL did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. Nevertheless, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. In general, dose selection in geriatric patients should start with the lowest recommended dose, taking into consideration the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8.6 Patients with Renal or Hepatic Disease

(PLR conversion)

A reduction in the dosage of PLAQUENIL may be necessary in patients with hepatic or renal disease.

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

PATIENT COUNSELING INFORMATION

(PLR conversion)

Important Administration Instructions

Advise the patient to take PLAQUENIL with food or milk and not to crush or divide the tablet.

Cardiomyopathy and Ventricular Arrhythmias

Inform the patient that serious cardiac effects, life-threatening and fatal cases have been reported with use of PLAQUENIL Advise patients to seek medical attention immediately if they experience any symptoms of heart rhythm changes including fast or irregular heartbeat, lightheadedness, dizziness, or syncope [see Warnings and Precautions (5.1)].

Retinal Toxicity

Inform the patient that irreversible retinal damage has been observed in some patients with the use of PLAQUENIL. Advise patients of the importance of the ophthalmology visits for monitoring their eyes. Instruct patients to seek medical attention promptly if they experience decreased vision or decreased dark adaptation [see Warnings and Precautions (5.2)].

Serious Skin Reactions

Inform the patient that severe, life-threatening skin reactions have been reported with the use of PLAQUENIL. Advise the patient to seek medical attention immediately if experiencing any of the following signs and symptoms: blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever [see Warnings and Precautions (5.3)].

Skeletal Muscle Myopathy or Neuropathy

Inform the patient that muscle weakness and atrophy has been reported with PLAQUENIL use Advise patients to report to the physician symptoms of muscle weakness [see Warnings and Precautions (5.7)].

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 (5.8)].

Hypoglycemia

Pregnancy

Inform the patient that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to PLAQUENIL during pregnancy. Encourage patients to register by contacting 1-877- 311-8972 [see Use in Specific Populations (8.1)].

Other

(PLR conversion)

01/27/2017 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

(Additions and/or revisions are underlined)

WARNINGS

Resistant strains of malaria: PLAQUENIL is not effective against chloroquine-resistant strains of P. falciparum.

Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease.

A baseline ocular examination is recommended within the first year of starting PLAQUENIL. The baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT).

For individuals with significant risk factors (daily dose of hydroxychloroquine sulfate greater than 5.0 mg/kg base of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until five years of treatment.

In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees.

It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy.

Cardiac Effects, including Cardiomyopathy and QT prolongation: Postmarketing cases of life-threatening and fatal cardiomyopathy have been reported with use of PLAQUENIL as well as with use of chloroquine. Patients may present with atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appeared during acute and chronic treatment. Clinical monitoring for signs and symptoms of cardiomyopathy is advised, including use of appropriate diagnostic tools such as ECG to monitor patients for cardiomyopathy during PLAQUENIL therapy. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of PLAQUENIL may prevent life-threatening complications.

PLAQUENIL prolongs the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking PLAQUENIL. Therefore, PLAQUENIL should not be administered with other drugs that have the potential to prolong the QT interval.

Worsening of psoriasis and porphyria: Use of PLAQUENIL in patients with psoriasis may precipitate a severe attack of psoriasis…

Proximal Myopathy and Neuropathy: 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 been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with PLAQUENIL.

Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely reported in patients treated with PLAQUENIL.

Hypoglycemia: PLAQUENIL has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications. Patients treated with PLAQUENIL should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with PLAQUENIL should have their blood glucose checked and treatment reviewed as necessary.

PRECAUTIONS

General: Use with caution in patients with gastrointestinal, neurological, or blood disorders, and in those with a sensitivity to quinine.

Hepatic/Renal Disease: … A reduction in dosage may be necessary in patients with hepatic or renal disease, as well as in those taking medicines known to affect these organs.

Hematologic Effects/Laboratory Tests: Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. Periodic blood cell counts should be performed if patients are given prolonged therapy. If any severe blood disorder such as aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia, appears which is not attributable to the disease under treatment, consider discontinuation of PLAQUENIL.

Dermatologic Effects: Dermatologic reactions to PLAQUENIL may occur…

Carcinogenesis, mutagenesis, impairment of fertility:

Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of PLAQUENIL.

The mutagenic potential of hydroxychloroquine was not evaluated. However, chloroquine has been shown to be a catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval use of PLAQUENIL or other 4-aminoqunoline compounds. 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 failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome. PLAQUENIL prolongs the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking PLAQUENIL.

Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve deafness, deafness.

Eye disorders: Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance), visual field defects (paracentral scotomas) and visual disturbances (visual acuity), maculopathies (macular degeneration), decreased dark adaptation, color vision abnormalities, corneal changes (edema and opacities) including corneal deposition of drug with or without accompanying symptoms (halo around lights, photophobia, blurred vision).

Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain.

General disorders and administration site conditions: Fatigue.

Hepatobiliary disorders: Liver function tests abnormal, hepatic failure acute.

Immune system disorders: Urticaria, angioedema, bronchospasm

Metabolism and nutrition disorders: Decreased appetite, hypoglycemia, porphyria, weight decreased.

Musculoskeletal and connective tissue disorders: Sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction.

Nervous system disorders: Headache, dizziness, seizure, ataxia and extrapyramidal disorders such as dystonia, dyskinesia, and tremor have been reported with this class of drugs.

Psychiatric disorders: Affect/emotional lability, nervousness, irritability, nightmares, psychosis, suicidal behavior.

Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation disorders in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity, dermatitis exfoliative, acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although PLAQUENIL may precipitate attacks of psoriasis. It may be associated with pyrexia and hyperleukocytosis.

To report SUSPECTED ADVERSE REACTIONS, contact Concordia Pharmaceuticals Inc. at 1-877-370-1142 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 Drug Interactions

(Additions and/or revisions are underlined)

Digoxin: Concomitant PLAQUENIL and digoxin therapy may result in increased serum digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy.

Insulin or antidiabetic drugs: As PLAQUENIL may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

Drugs that prolong QT interval and other arrhythmogenic drugs: PLAQUENIL prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias. Also, there may be an increased risk of inducing ventricular arrhythmias if PLAQUENIL is used concomitantly with other arrhythmogenic drugs.

Mefloquine and other drugs known to lower the convulsive threshold: PLAQUENIL can lower the convulsive threshold. Co-administration of PLAQUENIL with other antimalarials known to lower the convulsion threshold (e.g., mefloquine) may increase the risk of convulsions.

Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered with PLAQUENIL.

Methotrexate: Combined use of methotrexate with PLAQUENIL has not been studied and may increase the incidence of adverse effects.

Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and PLAQUENIL were co-administered.

The following interactions have been observed on treatment with the structurally related substance chloroquine phosphate, and therefore cannot be ruled out for hydroxychloroquine.

Praziquantel: Chloroquine has been reported to reduce the bioavailability of praziquantel.

Antacids and kaolin: Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed.

Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided.

Ampicillin: In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin.

8 Use in Specific Populations

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Pregnancy

Teratogenic Effects: Human pregnancies resulting in live births have been reported in the literature and no increase in the rate of birth defects has been demonstrated. Embryonic deaths and malformations of anophthalmia and microphthalmia in the offspring have been reported when pregnant rats received large doses of chloroquine.

Nursing Mothers: Caution should be exercised when administering PLAQUENIL to nursing women. It has been demonstrated that hydroxychloroquine administered to nursing women is excreted in human milk and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines

Pediatric Use: Safety and efficacy have not been established in the chronic use of PLAQUENIL for systemic lupus erythematosus and juvenile idiopathic arthritis in children. Children are especially sensitive to the 4-aminoquinoline compounds. Most reported fatalities followed the accidental ingestion of chloroquine, sometimes in small doses (0.75 g or 1 g in one 3-year-old child). Patients should be strongly warned to keep these drugs out of the reach of children.

Geriatric Use: Clinical studies of PLAQUENIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

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

PATIENT INFORMATION

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Information for Patients: Patients should be informed of the early signs and symptoms of toxicity such as rash or visual changes. Patients must see their physicians promptly in case of the appearance of these or of any unusual effects. Periodic laboratory tests may be recommended in some patients. Patients should be fully informed of the potential risks of the use of PLAQUENIL, especially in pregnancy and in children.

01/27/2017 (SUPPL-45)