ACH-HYDROXYCHLOROQUINE SULFATE TABLET

Canada - English - Health Canada

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Active ingredient:
HYDROXYCHLOROQUINE SULFATE
Available from:
ACCORD HEALTHCARE INC
ATC code:
P01BA02
INN (International Name):
HYDROXYCHLOROQUINE
Dosage:
200MG
Pharmaceutical form:
TABLET
Composition:
HYDROXYCHLOROQUINE SULFATE 200MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
ANTIMALARIALS
Product summary:
Active ingredient group (AIG) number: 0107403001; AHFS: 08:30.08
Authorization status:
APPROVED
Authorization number:
02506696
Authorization date:
2020-10-19

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PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

ACH-HYDROXYCHLOROQUINE SULFATE

(Hydroxychloroquine Sulfate Tablets, USP)

200 mg tablets, oral

ATC Code: P01BA02

Anti-Inflammatory – Antimalarial – Aminoquinolines

Accord Healthcare Inc.

Date of Approval:

3535 boul. St. Charles, Suite 704

October 15, 2020

Kirkland, QC, H9H 5B9

Canada

Submission Control No.: 238316

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ...........................................3

1

INDICATIONS ....................................................................................................3

Pediatrics .....................................................................................................3

Geriatrics .....................................................................................................3

2

CONTRAINDICATIONS ...................................................................................3

3

DOSAGE AND ADMINISTRATION ...............................................................4

Dosing Considerations .................................................................................4

Recommended Dose and Dosage Adjustment .............................................4

Missed Dose ................................................................................................6

4

OVERDOSAGE ...................................................................................................6

5

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ..7

6

WARNINGS AND PRECAUTIONS .................................................................7

Special Populations....................................................................................12

6.1.1

Pregnant Women ....................................................................................12

6.1.2

Breast-feeding ........................................................................................12

6.1.3

Pediatrics ................................................................................................12

7

ADVERSE REACTIONS .................................................................................12

Clinical Trial Adverse Reactions ...............................................................12

8

DRUG INTERACTIONS..................................................................................15

Overview ...................................................................................................15

Drug-Drug Interactions ..............................................................................15

Drug-Food Interactions..............................................................................21

9

ACTION AND CLINICAL PHARMACOLOGY ..........................................21

Mechanism of Action ................................................................................21

Pharmacokinetics .......................................................................................21

10

STORAGE, STABILITY AND DISPOSAL ...................................................22

PART II: SCIENTIFIC INFORMATION ..................................................................23

11

PHARMACEUTICAL INFORMATION ........................................................23

12

NON-CLINICAL TOXICOLOGY ..................................................................24

13

SUPPORTING MONOGRAPHS ....................................................................25

PATIENT MEDICATION INFORMATION .............................................................25

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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PART I: HEALTH PROFESSIONAL INFORMATION

1.

INDICATIONS

ACH-HYDROXYCHLOROQUINE SULFATE (hydroxychloroquine sulfate tablets) is

indicated for the treatment of rheumatoid arthritis, and discoid and systemic lupus

erythematosus, in patients who have not responded satisfactorily to drugs with less

potential for serious side effects.

ACH-HYDROXYCHLOROQUINE SULFATE is also indicated for the suppressive

treatment and treatment of acute attacks of malaria due to P. vivax, P. malariae, P. ovale,

and susceptible strains of P. falciparum. ACH-HYDROXYCHLOROQUINE SULFATE

is not active against the exo-erythrocytic forms of P. vivax, P. malariae and P. ovale and

therefore will neither prevent infection due to these organisms when given

prophylactically, nor prevent relapse of infection due to these organisms. It is highly

effective as a suppressive agent in patients with vivax or malariae malaria in terminating

acute attacks and significantly lengthening the interval between treatment and relapse. In

patients with falciparum malaria, ACH-HYDROXYCHLOROQUINE SULFATE

abolishes the acute attack and effects complete cure of the infection, unless due to a

resistant strain of P. falciparum. see WARNINGS AND PRECAUTIONS (6), General,

Malaria).

1.1

Pediatrics

Pediatrics (< 18 years of age): ACH-HYDROXYCHLOROQUINE SULFATE is

contraindicated in children below 6 years of age (see CONTRAINDICATIONS (2)).

The safety of hydroxychloroquine sulfate for the treatment of juvenile

rheumatoid

arthritis has not been established (see DOSAGE AND ADMINISTRATION (3.2),

Rheumatoid Arthritis). The safety and efficacy of hydroxychloroquine sulfate in

children have not been established in rheumatoid arthritis or systemic lupus

erythematosus (see WARNINGS AND PRECAUTIONS, Pediatrics (6.1.3)).

1.2

Geriatrics

Geriatrics (≥ 65 years of age): Hydroxychloroquine sulfate can prolong the QTc

interval, especially in patients with underlying risk factors, which may lead to an

increased risk of ventricular arrhythmias including torsade de pointes. Risk factors for

torsade de pointes in the general population include the age of ≥ 65 years (see

WARNINGS AND PRECAUTIONS (6), Cardiovascular, Electrocardiogram

Changes and Potential for Cardiac Arrhythmias).

Extreme caution should be taken

when using ACH-HYDROXYCHLOROQUINE SULFATE in geriatric patients aged ≥

65 years

due to the drug toxicity.

2.

CONTRAINDICATIONS

ACH-HYDROXYCHLOROQUINE SULFATE is contraindicated in:

Patients with pre-existing retinopathy of the eye

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Patients with known hypersensitivity to 4-aminoquinoline compounds

Patients who are hypersensitive to hydroxychloroquine sulfate or to any

ingredient in the

formulation, including any non-medicinal ingredient, or

component of the container. For

a complete listing, see DOSAGE FORMS,

STRENGTHS, COMPOSITION AND PACKAGING (5).

Children below 6 years of age (200 mg tablets not adapted for weight <35 kg)

(see WARNINGS AND PRECAUTIONS, Special Populations – Pediatrics

(6.1.3)).

3.

DOSAGE AND ADMINISTRATION

3.1

Dosing Considerations:

Absolute body weight used as a guide to dosage could result in an overdosage; daily

doses should not exceed 6.5 mg (salt form)/kg ideal (lean) body weight. Exceeding the

recommended daily dose sharply increase the risk of retinal toxicity as well as cardiac

arrhythmias (see WARNINGS AND PRECAUTIONS (6), Ophthalmic and,

Cardiovascular).

ACH-HYDROXYCHLOROQUINE SULFATE should be discontinued if signs and

symptoms of cardiomyopathy develop, in patients who develop torsade de pointes,

polymorphic ventricular tachycardia, signs/symptoms of serious arrhythmia, severe

hypoglycemia, severe blood disorder, muscular weakness, or extrapyramidal reactions.

ACH-HYDROXYCHLOROQUINE SULFATE dosage may need to be temporarily

reduced in patients who develop impaired accommodation and blurring of vision that is

not self-limiting (see WARNINGS AND PRECAUTIONS (6), Cardiovascular,

Endocrine and Metabolism, Hematologic, Musculoskeletal, Neurologic, and Driving

and Operating Machinery).

The dosages cited below are stated in terms of hydroxychloroquine sulfate. Each dose

should be taken with a meal or a glass of milk.

3.2

Recommended Dose and Dosage Adjustment

Rheumatoid Arthritis

The compound is cumulative in action and will require several weeks to exert its

beneficial therapeutic effects, whereas minor side effects may occur somewhat early.

Several months of therapy may be required before maximum effects can be obtained. If

objective improvement (such as reduced joint swelling, increased mobility) does not

occur within six months, the drug should be stopped. Safe use of the drug in the treatment

of juvenile rheumatoid arthritis has not been established.

Initial dosage In adults, from 400 to 600 mg daily. In a few patients, the side effects

may require temporary reduction of the initial dosage. Generally, after five to ten days the

dose may be gradually increased to the optimum response level, frequently, without

return of side effects.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Maintenance dosage – When a good response is obtained (usually in four to twelve

weeks), the dosage is reduced by 50 percent and continued at an acceptable maintenance

level of 200 to 400 mg daily. The incidence of retinopathy has been reported to be higher

when the maintenance dose is exceeded.

If a relapse occurs after medication is withdrawn, therapy may be resumed or continued

on an intermittent schedule if there are no ocular contraindications.

Use in Combination Therapy: ACH-HYDROXYCHLOROQUINE SULFATE may be

used safely and effectively in combination with corticosteroids, salicylates, NSAIDS, and

methotrexate and other second line therapeutic agents. Corticosteroids and salicylates can

generally be decreased gradually in dosage or eliminated after the drug has been used for

several weeks. When gradual reduction of steroid dosage is suggested, it may be done by

reducing every four to five days, the dose of cortisone by no more than 5 to 15 mg; of

hydrocortisone from 5 to 10 mg; of prednisolone and prednisone from 1 to 2.5 mg; of

methylprednisolone and triamcinolone from 1 to 2 mg and dexamethasone from 0.25 to

0.5 mg. Regimens of treatment using other agents than steroids and NSAIDS are under

development. No definitive dose combinations have been established.

Lupus Erythematosus

Initially, the average adult dose is 400 mg once or twice daily. This may be continued for

several weeks or months, depending upon the response of the patient. For prolonged

maintenance therapy, a smaller dose, from 200 to 400 mg daily will suffice. The

incidence of retinopathy has been reported to be higher when this maintenance dose is

exceeded.

Malaria

Suppression – In adults, 400 mg on exactly the same day of each week. In children (6

years of age and older), the weekly suppressive dose is 5 mg base/kg, but should not

exceed the adult dose regardless of body weight.

Suppressive therapy should begin two weeks before exposure. When not administered

before exposure, give an initial loading dose of 800 mg to adults, or 10 mg base/kg to

children in two divided doses, six hours apart. The suppressive therapy should be

continued for eight weeks after leaving the endemic area.

Treatment of the acute attack – In adults, an initial loading dose of 800 mg followed by

400 mg in six to eight hours. This is followed by 400 mg on each of the next two days for

a total of 2 g of hydroxychloroquine sulfate or 1.55 g base. Alternatively, the

administration of a single dose of 800 mg has also proved effective. The dosage for

adults may also be calculated by body weight.

For children (6 years of age and older) – dosage calculated by body weight is preferred.

A total dose representing 25 mg of base/kg is administered over three days as follows:

First dose: 10 mg base/kg (not to exceed 620 mg base)

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Second dose: 5 mg base/kg 6 hours after the first dose (not to exceed 310 mg base)

Third dose: 5 mg base/kg 18 hours after the second dose

Fourth dose: 5 mg base/kg 24 hours after the third dose

For radical cure of vivax and malariae malaria - concomitant therapy with an 8-

aminoquinoline compound is necessary.

Dosing in Special Populations

Patients with Hepatic Impairment: ACH-HYDROXYCHLOROQUINE SULFATE

should be used with caution in patients with hepatic impairment; a reduction in dosage

may be necessary (see WARNINGS AND PRECAUTIONS (6),

Hepatic/Biliary/Pancreatic).

Patients with Renal Impairment: ACH-HYDROXYCHLOROQUINE SULFATE

should be used with caution in patients with renal impairment; a reduction in dosage may

be necessary (see WARNINGS AND PRECAUTIONS (6), Renal).

3.3

Missed Dose

If a dose is missed, it should be taken as soon as possible. If the missed dose is within

twelve hours of the next dose, the missed dose should be skipped, and the regular

dosing schedule should be resumed. The patient should be advised never to take a

double dose (see OVERDOSAGE (4)).

4

OVERDOSAGE

Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-

2 grams having proved fatal.

Symptoms

The 4-aminoquinoline compounds are very rapidly and completely absorbed following

ingestion and in accidental overdosage toxic symptoms may occur within 30 minutes.

These consist of headache, drowsiness, visual disturbances, cardiovascular collapse,

hypokalemia and convulsions, rhythm and conduction disorders, including QT interval

prolongation, torsade de pointes, ventricular tachycardia, ventricular fibrillation, width-

increased QRS complex, PR interval prolongation, bradyarrhythmias, nodal rhythm,

atrioventricular block, followed by sudden potentially fatal respiratory and cardiac arrest.

Immediate medical attention is required, as these effects may appear shortly after

overdose.

In the event of acute overdose, the patient should be carefully observed (e.g., ECG

monitoring) and given symptomatic and supportive treatment. The ECG may reveal atrial

standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive

bradycardia leading to ventricular fibrillation and/or arrest.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Treatment

Treatment is symptomatic and must be prompt with immediate evacuation of the stomach

by emesis (at home, before transportation to the hospital), or gastric lavage until the

stomach is completely emptied. If finely powdered activated charcoal is introduced by

the stomach tube, after lavage and within 30 minutes after ingestion of the tablets, it may

inhibit further intestinal absorption of the drug. To be effective, the dose of activated

charcoal should be at least five times the estimated dose of ingested hydroxychloroquine.

Convulsions, if present, should be controlled before attempting gastric lavage. If due to

cerebral stimulation, cautious administration of an ultrashort-acting barbiturate may be

tried but, if due to anoxia, convulsions should be corrected by oxygen administration,

artificial respiration or, in shock with hypotension, by vasopressor therapy. Because of

the importance of supporting respiration, tracheal intubation or tracheostomy, followed

by gastric lavage, has also been advised. Exchange transfusions have been used to reduce

the level of 4-aminoquiolines in the blood.

Consideration should be given to administering diazepam parenterally since studies have

reported it beneficial in reversing chloroquine cardiotoxicity.

A patient who survives the acute phase and is asymptomatic should be closely observed

for at least 6 hours. Fluids may be forced, and sufficient ammonium chloride may be

administered for a few days to acidify the urine to help promote urinary excretion.

If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that

ammonium chloride (8 g daily in divided doses for adults) three or four days a week be

administered for several months after therapy has been stopped, as acidification of the

urine increases renal excretion of the 4-aminoquinoline compounds by 20 to 90 percent.

However, caution must be exercised in patients with impaired renal function and/or

metabolic acidosis.

For management of a suspected drug overdose, contact your regional Poison Control

Centre.

5

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Route of

Administration

Dosage Form /

Strength/Composition

Non-medicinal Ingredients

Oral

Tablets, 200 mg

Lactose monohydrate, polyethylene

glycol, magnesium stearate, maize

starch, povidone K30, talc and

titanium dioxide

ACH-HYDROXYCHLOROQUINE SULFATE (hydroxychloroquine sulfate tablets) is

available as: White to off-white, peanut shaped, biconvex, film-coated tablets debossed

with “H11” on one side and plain on the other side.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Available in bottles of 100’s, 500’s and 10’s PVC-Alu Blister Pack.

6

WARNINGS AND PRECAUTIONS

General

Observe caution in patients with gastrointestinal or neurological disorders, in those with

sensitivity to quinine, and in porphyria.

Malaria

Hydroxychloroquine sulfate is not effective against chloroquine-resistant strains of P.

falciparum and is not active against the exo-erythrocytic forms of P. vivax, P. ovale and

P. malarias and therefore will neither prevent infection due to these organisms when

given prophylactically, nor prevent relapse of infection due to these organisms (see

INDICATIONS (1)).

Carcinogenesis and Mutagenesis

Non-clinical studies showed a potential risk of chloroquine inducing gene mutations.

Long term studies in animals have not been conducted to evaluate the carcinogenic

potential (see NON- CLINICAL TOXICOLOGY (12)). In humans, there are

insufficient data to rule out an increased risk of cancer in patients receiving-long term

treatment.

Cardiovascular

Cardiomyopathy

Cases of cardiomyopathy resulting in cardiac failure, in some cases with a fatal outcome,

have been reported in patients treated with hydroxychloroquine sulfate. ACH-

HYDROXYCHLOROQUINE SULFATE should be discontinued if signs and

symptoms of cardiomyopathy develop. Chronic toxicity should be considered when

conduction disorders (bundle branch block/atrio-ventricular heart block) as well as

biventricular hypertrophy is diagnosed (see OVERDOSAGE (4) and ADVERSE

REACTIONS (7.1), Cardiac disorders).

Electrocardiogram (ECG) Changes and Potential for Cardiac Arrhythmias:

Hydroxychloroquine sulfate can prolong the PR, QRS and QTc intervals, especially in

patients with underlying risk factors. Serious adverse events, including fatal outcomes,

have been reported in patients taking hydroxychloroquine sulfate including ventricular

arrhythmias, heart blocks, ventricular fibrillation and torsade de pointes (see

OVERDOSAGE (4), WARNINGS AND PRECAUTIONS (6), Monitoring and

Laboratory Tests, ADVERSE REACTIONS (7.1), Cardiac disorders and DRUG

INTERACTIONS (8.1 and 8.2)).

QTc prolongation may lead to an increased risk of ventricular arrhythmias including

torsade de pointes. Torsade de pointes may be asymptomatic or experienced by the

patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes

can progress to ventricular fibrillation and sudden cardiac death. Permanently

discontinue ACH-HYDROXYCHLOROQUINE SULFATE in patients who

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 9 of 36

develop torsade de pointes or polymorphic ventricular tachycardia or

signs/symptoms of serious arrhythmia. If cardiac complications due to ACH-

HYDROXYCHLOROQUINE SULFATE are suspected, treatment should be

discontinued.

ACH-HYDROXYCHLOROQUINE SULFATE is not recommended for use in patients

with baseline QTc prolongation (e.g., congenital or acquired Long QT Syndrome),

second-or third-degree atrioventricular block. Electrolyte imbalances (e.g.

hypokalemia/hypomagnesemia/hypocalcemia) must be corrected prior to use. Use of

ACH-HYDROXYCHLOROQUINE SULFATE should be undertaken with extreme

caution in patients with other risk factors for torsade de pointes.

Risk factors for torsade de pointes in the general population include, but are not limited

to, the following: female gender; age ≥ 65 years; baseline prolongation of the QT/QTc

interval; presence of genetic variants affecting cardiac ion channels or regulatory

proteins, especially congenital long QT syndromes; family history of sudden cardiac

death at <50 years of age; cardiac disease (e.g., myocardial ischemia or infarction,

congestive heart failure, cardiomyopathy, conduction system disease); history of

arrhythmias; electrolyte disturbances or conditions leading to electrolyte disturbances

(e.g., persistent vomiting, eating disorders); bradycardia; acute neurological events (e.g.,

intracranial or subarachnoid haemorrhage, stroke, intracranial trauma); diabetes mellitus;

and autonomic neuropathy.

Concomitant use with other QTc, PR or QRS interval prolonging drugs should be

avoided or undertaken with particular caution (see DRUG INTERACTIONS (8.1 and

8.2)).

The magnitude of QT, PR or QRS prolongation with ACH-

HYDROXYCHLOROQUINE SULFATE may increase with increasing

concentrations of the drug. Therefore, the recommended dose should not be

exceeded (see DOSAGE AND ADMINISTRATION (3)).

Driving and Operating Machinery

Patients should be warned about driving and operating machinery since

hydroxychloroquine sulfate can impair accommodation and cause blurring of vision. If

the condition is not self-limiting, dosage may need to be temporarily reduced (see

DOSAGE AND ADMINISTRATION (3.1)).

Endocrine and Metabolism

Hydroxychloroquine sulfate has been shown to cause severe hypoglycemia including

loss of consciousness that could be life threatening in patients treated with and without

antidiabetic medications. Patients treated with ACH-HYDROXYCHLOROQUINE

SULFATE 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 ACH-HYDROXYCHLOROQUINE SULFATE

should have their blood glucose level checked and the need for ACH-

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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HYDROXYCHLOROQUINE SULFATE treatment reviewed as necessary. In cases of

severe hypoglycemia, ACH-HYDROXYCHLOROQUINE SULFATE should be

discontinued and alternative therapy should be considered. If patients use ACH-

HYDROXYCHLOROQUINE SULFATE concomitantly with antidiabetic drugs, a

decrease in doses of insulin or antidiabetic drugs may be required as

Hydroxychloroquine sulfate may enhance the effects of hypoglycemic treatment (see

ADVERSE REACTIONS (7.1) and DRUG INTERACTIONS (8.2)).

Hematologic

Periodic blood counts should be obtained in patients requiring prolonged therapy due to

the risk of bone marrow depression (see WARNINGS AND PRECAUTONS (6),

Monitoring and Laboratory Tests, and ADVERSE REACTIONS (7.1)). If any

severe blood disorder appears that is not attributable to the disease under treatment, the

drug should be discontinued.

Observe caution in patients with blood disorders or glucose-6-phosphate dehydrogenase

deficiency.

Hepatic/Biliary/Pancreatic

ACH-HYDROXYCHLOROQUINE SULFATE should be used with caution in patients

with hepatic disease or alcoholism, in whom a reduction in dosage may be necessary, or

in conjunction with known hepatotoxic drugs. Isolated cases of abnormal liver function

tests as well as fulminant hepatic failure have been reported (see DOSAGE AND

ADMINISTRATION (3.2), Dosing in Special Populations, ADVERSE

REACTIONS (7.1), Hepatobiliary disorders, and DRUG INTERACTIONS

(8.2)).

Use of hydroxychloroquine sulfate in patients with hepatic impairment as well as with

concomitant CYP2C8 or CYP3A4 inhibitors can result in elevation of

hydroxychloroquine plasma concentrations, with the magnitude of the effect depending

on the degree of hepatic impairment, as well as the enzyme inhibited and the potency of

the inhibitor (see DOSAGE AND ADMINISTRATION (3.2), Dosing in Special

Populations, WARNINGS AND PRECAUTIONS (6), Cardiovascular, and DRUG

INTERACTIONS (8.2)).

Monitoring and Laboratory Tests

ECG assessments are recommended at baseline and periodically during treatment with

ACH-HYDROXYCHLOROQUINE SULFATE. More frequent monitoring is

recommended if ACH-HYDROXYCHLOROQUINE SULFATE is administered to

patients with baseline ECG abnormalities or who are being treated concomitantly with

other QTc-, QRS-, or PR-interval prolonging drugs. Monitor electrolytes regularly (see

WARNINGS AND PRECAUTIONS (6), Cardiovascular, and DRUG

INTERACTIONS (8.2)).

Periodic assessment of full blood counts should be performed in patients requiring

prolonged treatment with ACH-HYDROXYCHLOROQUINE SULFATE (see

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 11 of 36

WARNINGS AND PRECAUTIONS (6), Hematologic, and ADVERSE

REACTIONS (7.1)).

Musculoskeletal

All patients on long term therapy with this preparation should be questioned and

examined periodically, including the examination of skeletal muscle function and tendon

reflexes, testing of knee and ankle reflexes, to detect any evidence of muscular

weakness. If weakness occurs, discontinue the drug (see ADVERSE REACTIONS

(7.1), Musculoskeletal disorders).

Neurologic

Extrapyramidal reactions have been reported in patients taking hydroxychloroquine

sulfate (see ADVERSE REACTIONS (7.1), Nervous system disorders). Symptoms

may persist in some patients after discontinuation of therapy.

Ophthalmologic

Irreversible retinal damage has been observed in some patients who had received long-

term or high-dosage 4-aminoquinoline therapy for discoid and systemic lupus

erythematosus, or rheumatoid arthritis. Before starting a long term treatment, both eyes

should be examined by careful ophthalmoscopy for visual acuity, central visual field and

colour vision, and fundoscopy. Then, the examination should be repeated at least

annually.

Retinal toxicity is largely dose-related. The risk of retinal damages is small with daily

doses of up to 6.5 mg/kg ideal (lean) body weight. Exceeding the recommended daily

dose sharply increases the risk of retinal toxicity. Significant risk factors for toxic

retinopathy reported during long-term (≥5 years) treatment with hydroxychloroquine

include daily doses greater than 6.5 mg/kg (5 mg/kg base) of actual body weight,

subnormal glomerular filtration rate, durations of use longer than five years, and

concurrent treatment with tamoxifen citrate. Concomitant use of ACH-

HYDROXYCHLOROQUINE SULFATE with drugs known to induce retinal toxicity,

such as tamoxifen, is not recommended.

Careful ophthalmologic examination should be more frequent and adapted to the patient,

in the following situations:

daily doses exceeding 6.5 mg (salt form)/kg ideal (lean) body weight. Absolute

body weight used as a guide to dosage, could result in an overdosage in the

obese;

renal insufficiency;

cumulative dose more than 200 g (salt form);

elderly;

impaired visual acuity.

If there is any indication of abnormality in the visual acuity, visual field, or retinal

macular areas (such as pigmentary changes, loss of foveal reflex), or any visual

symptoms (such as light flashes and streaks, abnormal colour vision) that are not fully

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 12 of 36

explainable by difficulties of accommodation or corneal opacities, the drug should be

stopped immediately. The patient should be closely observed for possible progression of

the abnormality. Retinal changes (and visual disturbances) may progress even after

cessation of the therapy (see ADVERSE REACTIONS).

Methods recommended for early diagnosis of retinopathy consist of (1) funduscopic

examination of the macula for fine pigmentary disturbances or loss of the foveal reflex

and (2) examination of the central visual field with a small red test object for pericentral

or paracentral scotoma or determination of retinal thresholds to red. Any unexplained

visual symptoms, such as light flashes or streaks also should be regarded with suspicion

as possible manifestations of retinopathy.

Psychiatric

Suicidal behaviour has been reported in patients treated with hydroxychloroquine sulfate

(see ADVERSE REACTIONS).

Renal

ACH-HYDROXYCHLOROQUINE SULFATE should be used with caution in patients

with renal disease, in whom a reduction in dosage may be necessary, as well as in those

taking medicines known to affect this organ. During treatment and after discontinuation,

monitoring for adverse reactions may be warranted in patients with severe renal

impairment or end-stage renal disease (ESRD), given the long half-life of

hydroxychloroquine (see DOSAGE AND ADMINISTRATION (3.2), Dosing in

Special Populations, WARNINGS AND PRECAUTIONS (6), Cardiovascular, and

DRUG INTERACTIONS (8.2)).

Sexual Health

Fertility

Animal studies showed an impairment of male fertility with chloroquine treatment (see

NON- CLINICAL TOXICOLOGY (12), Reproductive and developmental

toxicity). There are no data in humans.

Skin

Dermatological reactions to hydroxychloroquine sulfate may occur. ACH-

HYDROXYCHLOROQUINE SULFATE is not recommended for the treatment of

psoriasis or porphyria as these conditions may be exacerbated by its use. Observe

caution in patients with psoriasis.

Hydroxychloroquine sulfate may cause acute generalized exanthematous pustulosis

(AGEP). AGEP has to be distinguished from psoriasis, although hydroxychloroquine

sulfate may precipitate attacks of psoriasis. It may be associated with fever and

hyperleukocytosis. Outcome is usually favorable after discontinuation of drug.

6.1

Special Populations

6.1.1

Pregnant Women

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Hydroxychloroquine crosses the placenta. Data are limited regarding the use of

hydroxychloroquine sulfate during pregnancy. ACH-HYDROXYCHLOROQUINE

SULFATE should be avoided in pregnancy. It should be noted that the 4-

aminoquinolines in therapeutic doses have been associated with central nervous system

damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness),

retinal hemorrhages and abnormal retinal pigmentation to the foetus.

Embryonic deaths and ocular malformations in the offspring have been reported when

pregnant rats received large doses of chloroquine (see NON-CLINICAL

TOXICOLOGY (12), Reproductive and developmental toxicity).

6.1.2

Breast-feeding

Careful consideration should be given to using hydroxychloroquine sulfate during

breastfeeding, since it is excreted in small amounts (approximately 2% of the maternal

dose after bodyweight correction) in human breast milk and it is known that infants are

extremely sensitive to the toxic effects of 4-aminoquinolines. There are very limited data

on the safety in the breastfed infant during hydroxychloroquine long-term treatment. The

prescriber should assess the potential risks and benefits of use during breastfeeding,

according to the indication and duration of treatment.

Although hydroxychloroquine is excreted in breast milk, the amount is insufficient to

confer any protection against malaria to the infant. Separate chemoprophylaxis for the

infant is required.

6.1.3

Pediatrics

Safety and efficacy have not been established in rheumatoid arthritis or systemic lupus

erythematosus in children. Children are especially sensitive to the 4-aminoquinoline

compounds. The most reported fatalities follow the accidental ingestion of chloroquine,

sometimes in small doses. Patients should be strongly warned to keep these drugs out of

the reach of children (see CONTRAINDICATIONS (2)).

7

ADVERSE REACTIONS

7.1

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and should

not be compared to the rates in the clinical trials of another drug. Adverse reaction

information from clinical trials is useful for identifying drug-related adverse events and for

approximating rates.

The following Council for International Organizations of Medical Sciences (CIOMS)

frequency rating is used, when applicable: Very common ≥ 10 %; Common ≥ 1 and <10

%; Uncommon ≥ 0.1 and < 1 %; Rare ≥ 0.01 and <0.1 %; Very rare < 0.01 %; Not

known (frequency cannot be estimated from available data).

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Blood and lymphatic system disorders

Not known: Bone marrow depression, anemia, aplastic anemia, agranulocytosis,

leucopenia, thrombocytopenia (see WARNINGS AND PRECAUTIONS (6),

Hematologic).

Cardiac disorders

Not known: Cardiomyopathy, which may result in cardiac failure and in some cases a

fatal outcome.

Chronic toxicity should be considered when conduction disorders (bundle branch block/

atrioventricular heart block) as well as biventricular hypertrophy are found.

Drug discontinuation may lead to recovery (see OVERDOSAGE (4), WARNINGS

AND PRECAUTIONS (6), Cardiovascular, and DRUG INTERACTIONS (8)).

Hydroxychloroquine sulfate prolongs the QT, PR and/or QRS intervals which may lead

to an arrhythmia. Ventricular arrhythmias and torsade de pointes have been reported in

patients taking hydroxychloroquine sulfate (see OVERDOSAGE (4), WARNINGS

AND PRECAUTIONS (6), Cardiovascular and DRUG INTERACTIONS (8)).

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus.

Not known: Hearing loss, including cases of irreversible hearing loss.

Eye disorders

Common: Blurring of vision due to a disturbance of accommodation which is dose

dependent and reversible (see WARNINGS AND PRECAUTIONS (6),

Ophthalmologic).

Uncommon: Maculopathies, which may be irreversible.

Retinopathy with changes in pigmentation and visual field defects (see WARNINGS

AND PRECAUTIONS (6), Ophthalmologic). In its early form it appears reversible

upon discontinuation of the drug. If allowed to develop however, there may be a risk of

progression even after treatment withdrawal.

Patients with retinal changes may be asymptomatic initially, or may have scotomatous

vision with paracentral, pericentral ring types, temporal scotomas, abnormal colour

visions, reduction in visual acuity, night blindness, difficulty reading and skipping words.

Corneal changes including edema and opacities. They are either symptomless or may

cause disturbances such as halos around lights especially at night, blurring of vision,

vision disturbances, or photophobia. They may be transient or are reversible upon

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 15 of 36

discontinuation of therapy (see WARNINGS AND PRECAUTIONS (6),

Ophthalmologic).

Not known: Macular degeneration, which may be irreversible.

Gastrointestinal disorders

Very common: Abdominal pain, nausea.

Common: Diarrhea, vomiting.

These symptoms usually resolve immediately upon reducing the dose or upon stopping

the treatment.

Hepatobiliary disorders

Uncommon: Abnormal liver function tests.

Not known: Fulminant hepatic failure (see WARNINGS AND PRECAUTIONS (6),

Hepatic/Biliary/Pancreatic).

Immune system disorders

Not known: Urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders

Common: Anorexia (usually resolves immediately upon reducing the dose or upon

stopping the treatment).

Not known: hypoglycemia (see WARNINGS AND PRECAUTIONS (6), Endocrine

and Metabolism).

Hydroxychloroquine sulfate may exacerbate porphyria (see WARNINGS AND

PRECAUTIONS (6), General).

Musculoskeletal and connective tissue disorders

Uncommon: Sensorimotor disorders.

Not known: Skeletal muscle palsies or skeletal muscle myopathy or neuromyopathy

leading to progressive weakness and atrophy of proximal muscle groups. Depression of

tendon reflexes, abnormal results of nerve conduction tests. Myopathy may be reversible

after drug discontinuation, but recovery may take many months (see WARNINGS AND

PRECAUTIONS (6), Musculoskeletal).

Nervous system disorders

Common: Headache.

Uncommon: Dizziness.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Not known: Convulsions. Extrapyramidal reactions such as: akathisia, dystonia,

dyskinesia, gait disturbance, tremor.

Psychiatric disorders

Common: Affect lability.

Uncommon: Nervousness.

Not known: Psychosis, suicidal behavior.

Skin and subcutaneous tissue disorders

Common: Skin rash, pruritus.

Uncommon: Pigmentary changes in skin and mucous membranes, bleaching of hair,

alopecia. These usually resolve readily upon cessation of therapy.

Not known: Bullous eruptions (including urticarial, morbilliform, lichenoid,

maculopapular, purpuric, erythema annulare centrifugum), toxic epidermal necrolysis,

erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and

Systemic Symptoms (DRESS syndrome), photosensitivity, exfoliative dermatitis, acute

generalized exanthematous pustulosis (AGEP) (see WARNINGS AND

PRECAUTIONS (6), Skin).

8

DRUG INTERACTIONS

8.1

Overview

Drugs that Prolong the PR, QRS and/or QTc Intervals

ACH-HYDROXYCHLOROQUINE SULFATE has the potential to prolong the PR, QRS

and/or QTc intervals in a concentration-related manner (see WARNINGS AND

PRECAUTIONS (6), Cardiovascular). Caution is recommended if ACH-

HYDROXYCHLOROQUINE SULFATE is used concomitantly with other drugs that

prolong the PR, QRS and QTc intervals. Current information sources should be consulted

for drugs that prolong the QTc interval, the QRS duration, or the PR interval.

Halofantrine should not be administered with ACH-HYDROXYCHLOROQUINE

SULFATE.

Drugs that Affect Electrolytes

Caution is recommended if ACH-HYDROXYCHLOROQUINE SULFATE is used with

drugs that have the potential to decrease electrolytes levels. Current information sources

should be consulted for drugs that disrupt electrolytes.

A table with potential drug interaction with hydroxychloroquine sulfate is included

below. This list of possible drug interactions is not exhaustive. ACH-

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 17 of 36

HYDROXYCHLOROQUINE SULFATE should also be used with caution in patients

taking medicines which may cause adverse ocular or skin reactions (see WARNINGS

AND PRECAUTIONS (6), Ophthalmologic and Skin).

8.2

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or

potential interactions due to the expected magnitude and seriousness of the interaction (i.e.,

those

identified as contraindicated).

Table 1 - Established or Potential Drug-Drug Interactions

Proper/Common

Name

Source

of

Evidence

Effect

Clinical comment

Agalsidase

↓ activity

There is a theoretical risk of inhibition

of intra-cellular α-galactosidase

activity when hydroxychloroquine

sulfate is co-administered with

agalsidase.

Aminoglycoside

antibiotics

↑ blocking

action

Hydroxychloroquine sulfate may also

be subject to several of the known

interactions of chloroquine, even

though specific reports have not

appeared, including potentiation of its

direct blocking action at the

neuromuscular junction by

aminoglycoside antibiotics.

Antacids

(e.g.

magnesium-

containing

antacids, kaolin)

↓ absorption

As with chloroquine, co-

administration with antacids (such as

magnesium-containing antacids or

kaolin) may result in reduced

absorption of hydroxychloroquine

sulfate. Per extrapolation, ACH-

HYDROXYCHLOROQUINE

SULFATE should therefore be

administered at least two hours apart

from antacids or kaolin.

Antidiabetic

drugs

and insulin

↑ effect

As ACH-

HYDROXYCHLOROQUINE

SULFATE may enhance the effects of

a hypoglycemic treatment, a decrease

in doses of antidiabetic drugs or insulin

may be required (see WARNINGS

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

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Proper/Common

Name

Source

of

Evidence

Effect

Clinical comment

AND PRECAUTIONS (6),

Endocrine and Metabolism).

Antiepileptic

drugs

↓ activity

The activity of antiepileptic drugs

might be impaired if co-administered

with ACH-

HYDROXYCHLOROQUINE

SULFATE.

Antimalarials

known

to

lower

the

convulsion

threshold

(e.g.

mefloquine)

↑ risk of

convulsions

Hydroxychloroquine sulfate can lower

the convulsive threshold. Co-

administration of ACH-

HYDROXYCHLOROQUINE

SULFATE with other antimalarials

known to lower the convulsion

threshold (e.g. mefloquine) may

increase the risk of convulsions.

CYP2C8

and

CYP3A4 inducers

(e.g. rifampin, St.

John's Wort,

carbamazepine,

phenobarbital)

↓ efficacy

Lack of efficacy of

hydroxychloroquine sulfate was

reported when rifampin, a CYP2C8

and CYP3A4 strong inducer, was

concomitantly administered. Caution is

advised (e.g. monitoring for efficacy)

when CYP2C8 and CYP3A4 strong

inducers (such as rifampin, St. John's

Wort, carbamazepine, phenobarbital)

are concomitantly administered.

CYP2C8 and

CYP3A4

inhibitors

(e.g. cimetidine,

ketoconazole,

itraconazole,

erythromycin,

aprepitant,

fluconazole,

clopidogrel,

teriflunomide,

↑ exposure

Concomitant use of cimetidine, a

moderate CYP2C8 and CYP3A4

inhibitor, resulted in a 2-fold increase

of chloroquine exposure. Per

extrapolation, due to the similarities in

structure and metabolic elimination

pathways between hydroxychloroquine

and chloroquine, a similar interaction

could be observed for ACH-

HYDROXYCHLOROQUINE

SULFATE.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 19 of 36

Proper/Common

Name

Source

of

Evidence

Effect

Clinical comment

letermovir,

gemfibrozil,

ritonavir,

clarithromycin)

Co-administration of

hydroxychloroquine sulfate with

moderate and strong CYP2C8 and

CYP3A4 inhibitors (such as, but not

limited to, ketoconazole, itraconazole,

erythromycin, aprepitant, fluconazole,

clopidogrel, teriflunomide, letermovir)

may result in increased plasma

concentrations of hydroxychloroquine.

Caution is advised (e.g. monitoring for

adverse reactions).

Drugs that induce

retinal toxicity

(e.g. tamoxifen)

↑ risk of

retinopathy

An increased risk of toxic retinopathy

was reported when

hydroxychloroquine sulfate was used

concurrently with tamoxifen citrate.

Concomitant use of ACH-

HYDROXYCHLOROQUINE

SULFATE with drugs known to

induce retinal toxicity, such as

tamoxifen, is not recommended (see

WARNINGS AND PRECAUTIONS

(6), Ophthalmologic).

Drugs that

prolong the QRS

and/or QT

interval and

other

arrhythmogenic

drugs

(e.g. Class IA, IC

and III

antiarrhythmics,

certain

antidepressants,

antipsychotics,

certain anti-

infectives,

domperidone, 5-

hydroxytryptamine

(5-HT)3 receptor

↑ risk of

arrhythmia

Hydroxychloroquine sulfate prolongs

the QT interval and should not be

administered with other drugs that

have the potential to induce cardiac

arrhythmias. There may be an

increased risk of inducing ventricular

arrhythmias if hydroxychloroquine

sulfate is used concomitantly with

other drugs that prolong the QT

interval, including, but not limited to,

Class IA, IC and III antiarrhythmics;

certain antidepressants, antipsychotics,

and anti-infectives; domperidone; 5-

hydroxytryptamine (5-HT)3 receptor

antagonists; kinase inhibitors; histone

deacetylase inhibitors beta-2

adrenoceptor agonists (see

OVERDOSAGE (4) and

WARNINGS AND PRECAUTIONS

(6), Cardiovascular).

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 20 of 36

Proper/Common

Name

Source

of

Evidence

Effect

Clinical comment

antagonists, kinase

inhibitors, histone

deacetylase

inhibitors beta-2

adrenoceptor

agonists)

Drugs that affect

electrolytes

(e.g. loop, thiazide,

related diuretics,

laxatives, enemas,

amphotericin B)

↑ risk

Caution is recommended if ACH-

HYDROXYCHLOROQUINE

SULFATE is used with drugs that have

the potential to decrease electrolytes

levels, including, but not limited to,

loop, thiazide, and related diuretics,

laxatives and enemas, amphotericin B,

high dose corticosteroids, and proton

pump inhibitors (see OVERDOSAGE

(4) and WARNINGS AND

PRECAUTIONS, Cardiovascular

and Monitoring and Laboratory

Tests).

Neostigmine

↓ effect

Hydroxychloroquine sulfate may also

be subject to several of the known

interactions of chloroquine even

though specific reports have not

appeared including antagonism of

effect of neostigmine.

P-glycoprotein

(Pgp) substrates

(e.g. cyclosporine,

digoxin,

dabigatran)

↑plasma/serum

levels

The inhibitory potential of

hydroxychloroquine sulfate on P-gp

substrates has not been evaluated. In

vitro observations show that all other

aminoquinolines tested inhibit Pgp.

Therefore, there is a potential for

increased concentrations of Pgp

substrates when hydroxychloroquine

sulfate is concomitantly administered.

Increased plasma cyclosporine levels

were reported when cyclosporine and

hydroxychloroquine sulfate were co-

administered.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 21 of 36

Proper/Common

Name

Source

of

Evidence

Effect

Clinical comment

Increased digoxin serum levels were

reported when digoxin and

hydroxychloroquine sulfate were

coadministered. Serum digoxin levels

should be closely monitored in

patients receiving concomitant

treatment.

Caution is advised (e.g. monitoring

for adverse reactions or for plasma

concentrations as appropriate) when

P-gp substrates with narrow

therapeutic index (such as digoxin,

cyclosporine, dabigatran) are

concomitantly administered.

Praziquantel

bioavailability

Chloroquine has been reported to

reduce the bioavailability of

praziquantel. Due to the similarities

in structure and pharmacokinetic

parameters between

hydroxychloroquine and chloroquine,

a similar effect may be expected for

ACH-HYDROXYCHLOROQUINE

SULFATE.

Pyridostigmine

↓ effect

Hydroxychloroquine sulfate may also

be subject to several of the known

interactions of chloroquine, even

though specific reports have not

appeared, including antagonism of

effect of pyridostigmine.

Vaccine:

Human

diploid cell rabies

vaccine

↓ antibody

response

Hydroxychloroquine sulfate may also

be subject to several of the known

interactions of chloroquine, even

though specific reports have not

appeared, including reduction of the

antibody response tfo primary

immunization with intradermal

human diploid cell rabies vaccine.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

8.3

Drug-Food Interactions

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 22 of 36

Grapefruit products contain one or more components that strongly inhibit CYP3A4 and

can increase plasma concentrations of hydroxychloroquine. Consumption of grapefruit or

its juice should be avoided while taking ACH-HYDROXYCHLOROQUINE SULFATE.

9

ACTION AND CLINICAL PHARMACOLOGY

9.1

Mechanism of Action

Hydroxychloroquine sulfate tablets belongs to the 4-aminoquinoline class.

Hydroxychloroquine sulfate has been beneficial for patients with rheumatoid arthritis and

lupus erythematosus, especially chronic discoid lupus. The exact mode of action in

controlling these diseases is unknown. The action of this compound against malarial

parasites is similar to that of chloroquine phosphate.

9.2

Pharmacokinetics

Absorption:

Following oral administration, peak blood concentrations is achieved in approximately 4

hours.

Oral absolute bioavailability is 79%.

Distribution:

Hydroxychloroquine has a large volume of distribution due to extensive tissue

accumulation (5500 L in blood, 44 000 L in plasma), and has been shown to accumulate

in blood cells, with a blood to plasma ratio of 7.2. Approximately 50% of

hydroxychloroquine is bound to plasma proteins.

Metabolism:

Hydroxychloroquine is mainly metabolized to N-desethylhydroxychloroquine, and two

other metabolites in common with chloroquine, desethylchloroquine and

bidesethylchloroquine. It can be extrapolated from chloroquine, that hydroxychloroquine

could be metabolized in vitro by the

same CYPs as for chloroquine, i.e. CYP2C8 and

CYP3A, and to a lesser extent by CYP2D6.

Elimination:

Hydroxychloroquine presents a multi-phasic elimination profile with a long terminal half-

life

ranging from 30 to 60 days. Approximately 20-25% of the hydroxychloroquine dose

is eliminated as unchanged drug in the urine.

10

STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15°C -30°C).

Keep in a safe place out of reach of children.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 23 of 36

PART II: SCIENTIFIC INFORMATION

11

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Hydroxychloroquine sulfate

Chemical name:

(RS)-2-N-[4-(7-chloro-4-quinolylamino)pentyl]-N-

ethylaminoethanol sulfate

Ethanol, 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]-

ethylamino]-, (±), sulfate (1:1)

(±)-2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]-

ethylamino]ethanol sulfate (1:1)

Molecular formula:

O·H

Molecular mass:

433.95 g/mol

Structural formula:

Physicochemical properties: White or practically white crystalline powder, odorless or

almost

odorless. Solubility: Freely soluble in water and practically insoluble in

alcohol, in chloroform and in ether. Melting point: about 240°C.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 24 of 36

CLINICAL TRIALS

Comparative Bioavailability Studies

A double blind, balanced, randomized, two-treatment, single-period, single oral dose,

parallel, bioequivalence study comparing 1 x ACH-HYDROXYCHLOROQUINE

SULFATE tablets, 200 mg (Accord Healthcare Inc.) with 1 x

PLAQUENIL

tablets,

200 mg (sanofi-aventis Canada Inc.) was conducted on 144 healthy adult human male

subjects under fasting conditions. A summary of the results is presented in the following

table.

Hydroxychloroquine

(1 × 200 mg)

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric Means

90% Confidence

Interval

0-72

(ng.h/mL)

5725.22

6004.08 (31.8)

5211.85

5471.92 (30.9)

109.9

101.0 - 119.5

(ng/mL)

278.03

291.89 (32.8)

256.76

272.43 (33.6)

108.3

98.8 - 118.6

4.33

(1.00 - 7.00)

4.00

(1.33 - 6.00)

Due to the design of the study, AUC

and T

could not be accurately estimated and were not reported.

ACH-HYDROXYCHLOROQUINE SULFATE tablets, 200 mg (Accord Healthcare Inc.).

PLAQUENIL

tablets, 200 mg

(sanofi-aventis Canada Inc.) were purchased from Canada.

Expressed as the median (min - max).

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 25 of 36

12

NON-CLINICAL TOXICOLOGY

Only limited preclinical data are available for hydroxychloroquine, therefore chloroquine

data are considered due to the similarity of structure and pharmacological properties

between the 2 products.

Genotoxicity

There are limited data on hydroxychloroquine genotoxicity.

Chloroquine is reported in the literature to be a weak genotoxic agent which may elicit

both gene mutations and chromosomal/DNA breaks. Mechanisms may involve DNA

intercalation or induction of oxidative stress. Positive and negative results were observed

in in vitro reverse gene mutation assays using bacteria (Ames test) and in in vivo studies

using rodents (mouse bone marrow cell sister chromatid exchange, mouse bone marrow

cell chromosome abnormality, and rat DNA strand-breaks in multiple organs when

animals were dosed by intraperitoneal route).

Carcinogenicity

There are no data on hydroxychloroquine carcinogenicity from animal studies and

insufficient data on carcinogenicity is available for chloroquine. Both drugs are not

classifiable as to their carcinogenicity to humans.

Reproductive and developmental toxicity

There are limited data on hydroxychloroquine teratogenicity.

Supratherapeutic doses of chloroquine resulted in a fetal mortality rate of 25% and ocular

malformations in 45% of fetuses. Autoradiographic studies have shown that when

administered at the start or the end of gestation, chloroquine accumulates in the eyes and

ears.

There are no data on hydroxychloroquine action on fertility.

A study in male rats after 30 days of oral treatment at 5 mg/day of chloroquine showed a

decrease in testosterone levels, weight of testes, epididymis, seminal vesicles and

prostate, and caused production of abnormal sperm. The fertility rate was also decreased

in another rat study after 14 days of intraperitoneal treatment at 10 mg/kg/day.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 26 of 36

13

SUPPORTING PRODUCT MONOGRAPHS

Product Monograph of

PLAQUENIL

; sanofi-aventis Canada Inc.; Submission Control

No.: 238801; Date of Revision: September 10, 2020

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 27 of 36

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

ACH-HYDROXYCHLOROQUINE SULFATE

Hydroxychloroquine Sulfate Tablets, USP

Read this carefully before you start taking ACH-HYDROXYCHLOROQUINE

SULFATE and each time you get a refill. This leaflet is a summary and will not tell you

everything about this drug. Talk to your healthcare professional about your medical

condition and treatment and ask if there is any new information about ACH-

HYDROXYCHLOROQUINE SULFATE.

What is ACH-HYDROXYCHLOROQUINE SULFATE used for?

ACH-HYDROXYCHLOROQUINE SULFATE is used in adults to:

Treat Rheumatoid Arthritis (RA): a disease marked by stiffness, swelling and

pain in your joints.

Treat Systemic Lupus Erythematosus (SLE): a disease where your immune

system attacks healthy parts of your body by mistake. It can affect your skin, joints,

kidneys, brain, and other organs.

Treat Discoid Lupus Erythematosus (DLE): a disease similar to SLE. DLE only

affects your skin with red rash or scaly patches.

ACH-HYDROXYCHLOROQUINE SULFATE is used in patients 6 years of age and

older to:

Prevent and treat certain forms of Malaria: an infection caused by parasites in your

red blood cells. Symptoms can include high fever, shaking, chills, and extreme

sweating.

You can only get ACH-HYDROXYCHLOROQUINE SULFATE with a doctor’s

prescription.

How does ACH-HYDROXYCHLOROQUINE SULFATE work?

It is not known how hydroxychloroquine sulfate works in the body to treat RA, SLE, and

DLE. ACH-HYDROXYCHLOROQUINE SULFATE may take up to six months to take

effect. For malaria, ACH-HYDROXYCHLOROQUINE SULFATE works by killing the

parasite that causes the infection.

What are the ingredients in ACH-HYDROXYCHLOROQUINE SULFATE?

Medicinal ingredient: hydroxychloroquine sulfate.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 28 of 36

Non-medicinal ingredients: lactose monohydrate, polyethylene glycol, magnesium

stearate, maize starch, povidone K30, talc and titanium dioxide.

ACH-HYDROXYCHLOROQUINE SULFATE comes in the following dosage form:

Tablets, 200 mg.

Do not use ACH-HYDROXYCHLOROQUINE SULFATE if:

you are allergic to

hydroxychloroquine sulfate

any of the other ingredients of ACH-HYDROXYCHLOROQUINE SULFATE

any similar drugs such as chloroquine

you have retinopathy. This is an eye problem affecting the retina at the back of your

eye. ACH-HYDROXYCHLOROQUINE SULFATE may cause irreversible

damage to your retina. You should tell your doctor right away if you have any

Visual Problems.

you are a child below 6 years of age or weigh less than 35 kg.

To help avoid side effects and ensure proper use, talk to your healthcare

professional before you take ACH-HYDROXYCHLOROQUINE SULFATE. Talk

about any health conditions or problems you may have, including if you:

were born with, now have, or have a family history of long QT interval.

Hydroxychloroquine sulfate may cause Heart Rhythm Disorders in some patients.

These Heart Rhythm Disorders can be seen on an ECG, or an electrical recording

of the heart. Caution should be taken when taking ACH-

HYDROXYCHLOROQUINE SULFATE if you:

have heart disease, which can include heart failure, slow heartbeat, heart

palpitations or irregular heartbeat. The risk of heart problems may increase with

higher doses of ACH-HYDROXYCHLOROQUINE SULFATE.

have had a heart attack (myocardial infarction)

have a family history of sudden death from heart attack before the age of 50

take other drugs that can cause prolonged QT interval

have a low level of potassium, calcium or magnesium in your blood, or have a

condition that may affect the levels of those salts in the blood. Examples are an

eating disorder or prolonged vomiting.

are allergic or sensitive to a drug called to quinine.

are pregnant, or you are planning to get pregnant. Hydroxychloroquine sulfate may

be passed to your unborn baby. ACH-HYDROXYCHLOROQUINE SULFATE

may harm your unborn baby. Your doctor will evaluate the benefit and risk of using

ACH-HYDROXYCHLOROQUINE SULFATE during pregnancy.

are breastfeeding. Hydroxychloroquine sulfate passes into breast milk in small

amounts. Infants can be very sensitive to the toxic effects of drugs like ACH-

HYDROXYCHLOROQUINE SULFATE. There is not enough

hydroxychloroquine sulfate in breast milk to protect an infant against malaria. The

infant should receive their own malaria treatment if necessary. Talk to your doctor

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 29 of 36

about the risks ACH-HYDROXYCHLOROQUINE SULFATE can have on your

baby. These risks depend on:

why you are taking ACH-HYDROXYCHLOROQUINE SULFATE;

how long you will be taking ACH-HYDROXYCHLOROQUINE SULFATE

for.

have diabetes or symptoms of low blood sugar. Hydroxychloroquine sulfate can

cause low blood sugar, and sometimes, low blood sugar can be very dangerous.

You may pass out or need to go to the hospital.

have liver or kidney disease.

have alcoholism.

have a blood disease, including a rare blood disease called porphyria. ACH-

HYDROXYCHLOROQUINE SULFATE can make this worse.

have nervous system disease.

have a skin disease called psoriasis.

have a genetic red blood cell disease known as “glucose-6-phosphate

dehydrogenase deficiency”.

have gastrointestinal disorders. These are problems in the intestines, stomach, or

gut.

have decreased vision.

have weakness in your muscles.

have thoughts of suicide or depression.

are over 65 years old.

Other warnings you should know about:

Hydroxychloroquine sulfate can cause long QT interval or torsade de pointes. This is a

dangerously fast heart rate. It can lead to cardiac arrest, sudden collapse and death.

Heart problems or failure, cardiomyopathy, an enlarged or weak heart can occur if

you take ACH-HYDROXYCHLOROQUINE SULFATE for long periods of time. These

are serious and can result in death. Your doctor will check your heart regularly.

When you go outside, protect your skin from the sun by:

wearing appropriate clothing, and

using sunscreen cream with a minimum SPF 30 rating.

It is unclear whether hydroxychloroquine sulfate may affect male fertility. Talk to your

doctor if you would like to father a child in the future.

Driving and Using Machines: You may have blurry vision when taking ACH-

HYDROXYCHLOROQUINE SULFATE. Do not drive or do things that require you to

be alert. Wait until you know how you respond to ACH-HYDROXYCHLOROQUINE

SULFATE and can see well. If you continue to have difficulty, your doctor may reduce

your dose.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 30 of 36

Tell your healthcare professional about all the medicines you take, including any

drugs, vitamins, minerals, natural supplements or alternative medicines.

The following may interact with ACH-HYDROXYCHLOROQUINE SULFATE:

Drugs for depression (tricyclic antidepressants) and psychiatric disorders

(antipsychotics).

Digoxin. If you are taking both ACH-HYDROXYCHLOROQUINE SULFATE and

digoxin, your doctor may decide to check the level of digoxin in your blood, as the

dose may need to be reduced.

Anti-diabetic drugs, including insulin. If you take ACH-

HYDROXYCHLOROQUINE SULFATE and a drug for diabetes or high blood

sugar, there is a risk of having very low blood sugar. This can be life-threatening.

Your doctor may decide to reduce the doses of the drug or insulin to control diabetes.

Antiepileptic drugs.

Some antibiotics used for infections (e.g. aminoglycoside antibiotics, erythromycin).

Neostigmine and pyridostigmine (medicines used to treat muscle disorders).

Cimetidine (medicine used to treat heartburn).

Cyclosporine (an immunosuppressant medication).

Drugs known as CYP2C8 and CYP3A4 inhibitors (e.g. ketoconazole, itraconazole,

erythromycin, aprepitant, fluconazole, clopidogrel, teriflunomide, letermovir,

gemfibrozil, ritonavir, clarithromycin).

Drugs known as CYP2C8 and CYP3A4 inducers (e.g. rifampin, St. John’s Wort,

carbamazepine, phenobarbital).

Medicines that are known to cause cardiac arrhythmias (irregular heartbeats).

Halofantrine (a medicine used to treat malaria). If you are taking halofantrine, you

should not be taking ACH-HYDROXYCHLOROQUINE SULFATE at the same

time.

Antacids. You should take antacids at least 2 hours before or 2 hours after taking

ACH-HYDROXYCHLOROQUINE SULFATE.

Rabies vaccine.

Medicines that may affect the liver, the kidney, the skin or the eye.

Medicines that may increase the risk of convulsions (e.g. antimalarials (mefloquine)).

Medicines that decrease blood salt levels (e.g. water pills, laxatives, amphotericin B,

high dose corticosteroids, and proton pump inhibitors).

Agalsidase (a medicine used to treat a rare genetic disease called Fabry disease).

Medicines that may increase risk of retinal toxicity. An example is tamoxifen, which

is used to treat breast cancer. When taken alone, both ACH-

HYDROXYCHLOROQUINE SULFATE and tamoxifen can cause damage to your

retina at in the eye. Taking both drugs at the same time can increase your risk of

retinal damage.

Praziquantel (a medicine used to treat some infestations).

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 31 of 36

Do NOT eat grapefruit or drink grapefruit juice while taking ACH-

HYDROXYCHLOROQUINE SULFATE.

Hydroxychloroquine sulfate has been used safely with salicylates (aspirin), non-steroidal

anti-inflammatory medications, methotrexate and corticosteroids.

How to take ACH-HYDROXYCHLOROQUINE SULFATE:

Take ACH-HYDROXYCHLOROQUINE SULFATE exactly as your doctor told you to.

Never take more ACH-HYDROXYCHLOROQUINE SULFATE than your doctor has

prescribed.

To help avoid an upset stomach, take ACH-HYDROXYCHLOROQUINE SULFATE

with a meal or a glass of milk.

Usual dose:

Your doctor will decide on the best dose for you. It may be based on your weight,

physical health and other factors such as what other medications you are taking. The dose

may need to be stopped or temporarily reduced due to side effects. The dose may then be

re-started or increased to an optimum level by your doctor. Your dose will likely be

lowered during treatment, after your Initial Dose. You may take the lower dose for a

lengthy amount of time. This is called a Maintenance Dose.

Condition

Recommended dose

Number of

tablets a day

Rheumatoid

Arthritis

Initial:

400 – 600 mg a day

Maintenance: 200 – 400 mg a day

2 - 3

1 - 2

Lupus

Erythematosus

Initial:

Maintenance:

400 mg, once or twice a day

200 – 400 mg a day

2 - 4

1 - 2

Malaria (adults)

Prevention:

400 mg a week, on the

same day of each week,

starting 2 weeks before

exposure.

Treatment:

800 mg initially,

followed by 400 mg 6-8

hours later, and then 400 mg

daily for the next two days.

Malaria

(children)

Your dose will be calculated by your doctor

based on each child’s body weight.

Should you have a serious change of health at any point while taking ACH-

HYDROXYCHLOROQUINE SULFATE, see your doctor.

For patients with RA, SLE or DLE, if ACH-HYDROXYCHLOROQUINE SULFATE

makes your symptoms completely better, talk to your doctor. They may want to bring

down your daily dose. Never change your dose without talking with your doctor first.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 32 of 36

Overdose:

If you think you have taken too much ACH-HYDROXYCHLOROQUINE

SULFATE, contact your healthcare professional, hospital emergency department or

regional poison control centre immediately, even if there are no symptoms.

Taking too much ACH-HYDROXYCHLOROQUINE SULFATE is dangerous and can

lead to death. You could have symptoms of overdose within 30 minutes after taking it.

Taking too much ACH-HYDROXYCHLOROQUINE SULFATE is also dangerous for

children. Children have died by taking too much hydroxychloroquine sulfate. If you think

an infant or small child has swallowed even one pill, immediately take them to the

nearest hospital emergency room or dial “911" on your telephone.

Symptoms of overdose include:

headache

feeling drowsy

vision problems, like seeing blurry or in double

heart problems like uneven heartbeats or rapid heartbeats

fainting

muscle weakness

convulsions

serious trouble breathing

Missed Dose:

If you forget to take a dose, take it as soon as you remember. But if it’s within twelve

hours of your next dose, skip the one you missed and take only the regularly scheduled

dose. Never take a double dose.

What are possible side effects from using ACH-HYDROXYCHLOROQUINE

SULFATE?

These are not all the possible side effects you may feel when taking ACH-

HYDROXYCHLOROQUINE SULFATE. If you experience any side effects not listed

here, contact your healthcare professional.

Before and during your treatment with ACH-HYDROXYCHLOROQUINE SULFATE

your doctor may do some tests. These may include:

blood tests

an electrocardiogram (ECG)

a periodic exam of your muscles and tendon reflexes

complete eye exams

Hydroxychloroquine sulfate can cause permanent eye damage. To help prevent this, you

should have an eye exam before you start taking ACH-HYDROXYCHLOROQUINE

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 33 of 36

SULFATE. You will need more eye exams while you are taking ACH-

HYDROXYCHLOROQUINE SULFATE.

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare

professional

Stop taking

drug and get

immediate

medical help

Only if

severe

In all

cases

VERY COMMON

Nausea, stomach pain, stomach cramps

COMMON

Diarrhea

Vomiting

Anorexia: loss or lack of appetite

Visual problems and damage to the retina of

the eye: blurred vision, seeing halos around

lights, especially at night. Seeing light flashes

and streaks. Night blindness with difficulty

seeing at night or in poor light. Visual field loss

including blind spots or blind areas in your

vision. Change in eye colour. Difficulty

focusing your eyes, or skipping words when

reading.

Headache

Rash, itchy rash with raised red bumps

Nervousness, quick changes in mood (emotional

lability)

RARE

Dizziness or vertigo: feel as if you or the

objects around you are moving when they are

not.

Change in colour of skin, mucous

membranes and hair: bleaching of hair. Loss

or increase in skin pigment (bluish-black

colour).

Alopecia: hair loss from your head or any part

of your body.

Hearing problems: ringing in the ears. Hearing

loss.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 34 of 36

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare

professional

Stop taking

drug and get

immediate

medical help

Only if

severe

In all

cases

Nerve and muscle problems: tingling,

numbness, burning pain, weakness, cramps,

spasms, restlessness, rigidity, tremors, twitches,

difficulty walking

UNKNOWN FREQUENCY

Allergic reaction or angioedema: rash, hives,

swelling of the face, lops, tongue or throat,

difficulty swallowing or breathing

Heart rhythm disorders including long QT

interval, torsade de pointes and heart block:

abnormal heartbeat, life-threatening irregular

heartbeat, palpitations

Severe, life-threatening skin problems

including Toxic Epidermal Necrolysis,

Erythema Multiforme, Stevens-Johnson

syndrome, Drug Rash with Eosinophilia and

Systemic Symptoms (DRESS syndrome):

rash, red skin, red or purple skin patches

possibly with blister or crust in the center. Pus

filled rash. Peeling skin, blisters on lips, eyes,

skin or in the mouth.

Itching or burning. Flu-like fever.

Severe breathing problems including

bronchospasm, angioedema: sudden shortness

of breath

Increased sensitivity to sunlight. Skin rash due

to sunlight can be reduced by appropriate use of

sunscreen creams.

Muscle weakness

Permanent damage to vision

Fainting spells or loss of consciousness

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 35 of 36

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare

professional

Stop taking

drug and get

immediate

medical help

Only if

severe

In all

cases

Heart problems or heart failure,

cardiomyopathy, an enlarged or weak heart:

shortness of breath with exercise or even at rest.

Swelling of the legs, ankles and feet. Irregular

heartbeats that feel rapid or pounding. Chest

pain. Sudden fainting or feeling tired, light-

headed and dizzy, You can have a seizure or fit.

Liver problems: unusual tiredness, nausea,

vomiting, abdominal pain, jaundice (yellow

discoloration of the eyes or skin), dark urine

Bone Marrow Depression or a decrease in

production of cells:

Low White Blood cells (leukocytes): Fever and

chills. Infections.

Anemia or low red blood cells (erythrocytes):

Fatigue, extreme tiredness that doesn't get better

with rest. Paleness of skin, lips, and nail beds.

Low platelets used for blood clotting

(thrombocytes): Bleeding: nose bleeds, gums,

or mouth. Tiny red spots on the skin

Convulsions, seizures or fits

Psychosis: hallucinations, loss of contact with

reality

Suicidal thoughts or actions

Hypoglycemia or low blood sugar: hunger

pains, sweating, shakiness, weakness, dizziness,

fast heartbeat, nausea, irritability, blurred vision,

confusion, loss of consciousness

Muscle, nerve and tendon problems: long-

lasting involuntary muscle contraction,

impairment of voluntary movements, tremor.

Weakness. Decreased reflexes or feeling by

nerves.

ACH-HYDROXYCHLOROQUINE SULFATE Product Monograph

Page 36 of 36

If you have a troublesome symptom or side effect that is not listed here or becomes bad

enough to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products

to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/healthcanada/services/drugs-health-

products/medeffect-canada/adverse-reaction-reporting.html) for information

on how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to

manage your side effects. The Canada Vigilance Program does not provide medical

advice.

Storage:

Keep out of reach and sight of infants and small children.

Store at room temperature (15

C - 30

Do not use ACH-HYDROXYCHLOROQUINE SULFATE after the expiry date.

If you want more information about ACH-HYDROXYCHLOROQUINE

SULFATE:

Talk to your healthcare professional

Find the full product monograph that is prepared for healthcare professionals and

includes this Patient Medication Information by visiting the Health Canada website

(https://health-products.canada.ca/dpd-bdpp/index-eng.jsp); or by calling the sponsor

Accord Healthcare Inc. at 1-866-296-0354.

This leaflet was prepared by

Accord Healthcare Inc.

3535 boul. St. Charles suite 704

Kirkland, QC, H9H 5B9

Canada

Last Approved: October 15, 2020

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