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Hydroxychloroquine (Systemic)


VA CLASSIFICATION
Primary: AP101
Secondary: MS109; TN900{19}

Commonly used brand name(s): Plaquenil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiprotozoal—

antirheumatic (disease-modifying)—

lupus erythematosus suppressant—

antihypercalcemic—

polymorphous light eruption suppressant—

porphyria cutanea tarda suppressant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Malaria (prophylaxis and treatment)—Hydroxychloroquine is indicated in the suppressive treatment and the treatment of acute attacks of malaria caused by Plasmodium vivax, P. malariae, P. ovale , and susceptible strains of P. falciparum . The radical cure of P. vivax and P. ovale malaria requires the concurrent or subsequent administration of primaquine {08} {11} {14} {15} {18} {41} {61}.

Arthritis, rheumatoid (treatment)—Hydroxychloroquine is indicated in the treatment of acute and chronic rheumatoid arthritis {11} {14} {15} {17} {18} {71} {72}. [ It may be used in addition to nonsteroidal anti-inflammatory agents.]

Lupus erythematosus, discoid (treatment) or
Lupus erythematosus, systemic (treatment)—Hydroxychloroquine is indicated as a suppressant for chronic discoid and systemic lupus erythematosus {11} {15} {18} {21}.

[Arthritis, juvenile (treatment)]1—Hydroxychloroquine is used in the treatment of juvenile arthritis {24}.

[Hypercalcemia, sarcoid-associated (treatment)]1—Hydroxychloroquine is used to reduce urinary calcium excretion and the levels of 1,25-dihydroxyvitamin D in the serum of sarcoid patients who are unable to take corticosteroids {62}.

[Polymorphous light eruption (treatment) ]1—Hydroxychloroquine is used as a suppressant for polymorphous light eruption {21}.

[Porphyria cutanea tarda (treatment) ]1—Hydroxychloroquine is used in the treatment of porphyria cutanea tarda {06} {21} {23}.

[Urticaria, solar (treatment)]1 or
[Vasculitis, chronic cutaneous (treatment) ]1—Hydroxychloroquine is used in the treatment of solar urticaria and chronic cutaneous vasculitis unresponsive to other therapy {25} {26}.

—Chloroquine-resistant strains of P. falciparum , originally seen only in Southeast Asia and South America, are now documented in all malarious areas except Central America west of the Canal Zone, the Middle East, and the Caribbean. Chloroquine is still the drug of choice for the treatment of susceptible strains of P. falciparum and the other 3 malarial species; however, chloroquine-resistant P. vivax has recently been reported {36} {56}.

Unaccepted
Hydroxychloroquine does not prevent relapses in patients with P. vivax or P. ovale malaria since it is not effective against exo-erythrocytic forms of the parasite. In these species, “hypnozoites”, which remain dormant in the liver, are responsible for relapses.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Because hydroxychloroquine concentrates in the cellular fraction of blood, hydroxychloroquine concentrations measured in the blood are higher than those measured in the plasma {60}.


Physicochemical characteristics:
Molecular weight—
    433.95 {27} {28} {33} {34} {39}

Mechanism of action/Effect:

Antiprotozoal—Malaria: Unknown, but may be based on ability of hydroxychloroquine to bind to and alter the properties of DNA. Also has been found to be taken up into the acidic food vacuoles of the parasite in the erythrocyte. This increases the pH of the acid vesicles, interfering with vesicle functions and possibly inhibiting phospholipid metabolism {57} {58}. In suppressive treatment, hydroxychloroquine inhibits the erythrocytic stage of development of plasmodia {08} {29} {18}. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitized erythrocytes may account for their selective toxicity against the erythrocytic stages of plasmodial infection.

Antirheumatic—Hydroxychloroquine is thought to act as a mild immunosuppressant, inhibiting the production of rheumatoid factor and acute phase reactants {57}. It also accumulates in white blood cells, stabilizing lysosomal membranes and inhibiting the activity of many enzymes, including collagenase and the proteases that cause cartilage breakdown {36} {57}.

Absorption:

Variable rate of absorption; absorption half-life of 3.6 hours (range, 1.9 to 5.5 hours). Bioavailability is approximately 74% {68}.

Distribution:

Widely distributed in body tissues such as the eyes, kidneys, liver, and lungs where retention is prolonged. Concentrations are 2 to 5 times higher in erythrocytes than in plasma {59} {60}. Very low concentrations in intestinal wall. Crosses the placenta, also {14} {21} {30}.

Apparent Vol D = 5,522 L (measured in blood); 44,257 L (measured in plasma) {60}.

Protein binding:

Moderate (approximately 45%) {60}.

Biotransformation:

Hepatic (partially), to active de-ethylated metabolites {32} {63}.

Half-life:


Terminal elimination half-life:

In blood: Approximately 50 days.

In plasma: Approximately 32 days {68}.


Time to peak concentration:

Approximately 3.2 hours (range, 2 to 4.5 hours) {68}.

Peak concentrations


Steady state concentration in whole blood (achieved at 6 months):

155 mg (base) daily: 948 nanograms per mL.

310 mg (base) daily: 1895 nanograms per mL.


Elimination:
    Renal; 23 to 25% of hydroxychloroquine excreted unchanged in the urine {68}. Hydroxychloroquine is excreted very slowly; may persist in urine for months or years after medication is discontinued {21} {31} {63}. Also excreted in bile {55}.
    Hemodialysis does not remove appreciable amounts of hydroxychloroquine from blood {68}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to chloroquine, a 4-aminoquinoline compound structurally similar to hydroxychloroquine, may also be hypersensitive to hydroxychloroquine {08} {11} {14} {15}.

Pregnancy/Reproduction

Pregnancy—
Hydroxychloroquine crosses the placenta. Use is not recommended during pregnancy except in the suppression or treatment of malaria or hepatic amebiasis since malaria poses greater potential danger to the mother and fetus (i.e., abortion and death) than prophylactic administration of hydroxychloroquine {08} {14} {16}. Hydroxychloroquine, given in weekly chemoprophylactic doses, has not been shown to cause adverse effects in the fetus. However, risk-benefit must be considered since 4-aminoquinolines, given in therapeutic doses, have been shown to cause central nervous system (CNS) damage, including ototoxicity (auditory and vestibular); congenital deafness; retinal hemorrhages; and abnormal retinal pigmentation {35} {37}. In addition, hydroxychloroquine has been shown to accumulate selectively in melanin structures of fetal eyes. It may be retained in ocular tissues for up to 5 months after elimination from the blood {08} {14} {16} {18}.

Breast-feeding

One case report found that a very small amount of hydroxychloroquine is distributed into breast milk {20}; chloroquine is also distributed into breast milk. Although problems in humans have not been documented, risk-benefit must be considered since infants and children are especially sensitive to the effects of 4-aminoquinolines.

Pediatrics

Infants and children are especially sensitive to the effects of hydroxychloroquine and chloroquine. Fatalities have been reported following the ingestion of as little as 750 mg to 1 gram of chloroquine {08} {18}; hydroxychloroquine is assumed to be equally toxic. Long-term therapy with hydroxychloroquine is not generally recommended in children {18}. However, it has been used in juvenile arthritis for as long as 6 months with little or no toxicity {05}.


Geriatrics


No information is available on the relationship of age to the effects of hydroxychloroquine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Penicillamine    (concurrent use of penicillamine with hydroxychloroquine may increase penicillamine plasma concentrations, increasing the potential for serious hematologic and/or renal adverse reactions, as well as the possibility of severe skin reactions {22})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Blood disorders, severe    (hydroxychloroquine may cause blood dyscrasias, including agranulocytosis, aplastic anemia, neutropenia, or thrombocytopenia {15} {53})


Gastrointestinal disorders, severe    (hydroxychloroquine may cause gastrointestinal irritation {11})


Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (hydroxychloroquine may cause hemolytic anemia in G6PD-deficient patients, although this is unlikely when hydroxychloroquine is given in therapeutic doses {11} {15} {18} {54})


» Hepatic function impairment    (because hydroxychloroquine is metabolized in the liver, hepatic function impairment may increase blood concentrations of hydroxychloroquine, increasing the risk of side effects {11} {15})


Hypersensitivity to hydroxychloroquine or chloroquine {11} {15} {18}
» Neurological disorders, severe    (hydroxychloroquine may cause neuromyopathy, ototoxicity, polyneuritis, or seizures {08} {14})


Porphyria    (hydroxychloroquine may cause exacerbation of porphyria {15} {18})


Psoriasis    (hydroxychloroquine may precipitate severe attacks of psoriasis {15} {18})


» Renal function impairment    (because hydroxychloroquine is excreted very slowly in urine, renal function impairment may cause increased blood concentrations of hydroxychloroquine, increasing the risk of side effects {21} {31} {63} {69} {70})


» Retinal or visual field changes, presence of    (hydroxychloroquine may cause corneal opacities, keratopathy, or retinopathy {11} {15} {18})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Ophthalmologic examinations, including visual acuity, expert slit lamp, funduscopic, visual field tests, central field screening with a red Amsler grid (Amsler's chart), and retinoscopy {08} {14} {15} {69} {70}    (recommended before and at least every 6 months during prolonged daily {03} {71} {72} therapy since irreversible retinal damage has been reported with long-term or high-dosage therapy; serious ocular injury has been thought to be correlated with a total cumulative dose of greater than 200 grams (base) of hydroxychloroquine; however, a daily dose of greater than 310 mg (base), or 5 mg (base) per kg daily, of hydroxychloroquine may be a more important determinant {57} {64} {67} {69} {70}; any retinal or visual abnormality that is not fully explainable by difficulties of accommodation or corneal opacities should be monitored following discontinuation of therapy, since retinal changes and visual disturbances may progress even after cessation of therapy {08} {14} {15} {16} {18} {71} {72})




Side/Adverse Effects

Note: Side/adverse effects of hydroxychloroquine are usually dose-related. When hydroxychloroquine is used for the short-term treatment of malaria or other parasitic diseases, side/adverse effects are usually mild and reversible. However, following prolonged use and/or high-dose therapy, such as in the treatment of rheumatoid arthritis, lupus erythematosus, or polymorphous light eruption, side/adverse effects may be serious and sometimes irreversible.
Irreversible retinal damage may be more likely to occur when the daily dosage equals or exceeds the equivalent of 310 mg (base), or 5 mg (base) per kg daily, of hydroxychloroquine {64} {67}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Ocular toxicity specifically corneal opacities (blurred vision or any other change in vision)
    
keratopathy (blurred vision or any other change in vision)
    
retinopathy (blurred vision or any other change in vision){16}{42}{44}{45}{46}

Note: The risk of retinopathy is reduced when the daily maintenance dose is less than 6.5 mg (5 mg base) per kg of body weight (mg/kg) and the cumulative dose is less than 200 grams, the duration of treatment is less than 10 years, and renal function is not impaired {69} {70}.


Incidence rare
    
Aplastic anemia (fatigue; weakness)
    
blood dyscrasias, specifically agranulocytosis (sore throat and fever){42}{49}
    
emotional changes or psychosis (mood or other mental changes){08}{38}
    
neuromyopathy (increased muscle weakness){08}{47}
    
neutropenia (sore throat and fever)
    
ototoxicity (any loss of hearing; ringing or buzzing in ears)—usually in patients with pre-existing auditory damage{08}{16}{48}
    
seizures{08}{16}
    
thrombocytopenia (unusual bleeding or bruising)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Ciliary muscle dysfunction (difficulty in reading)
    
gastrointestinal irritation (diarrhea; loss of appetite; nausea; stomach cramps or pain; vomiting){08}{11}{16}{18}
    
headache{08}{11}{16}
    
itching (especially in black patients)—not an indication for discontinuation of therapy in black patients

Incidence less frequent
    
Bleaching of hair or increased hair loss{08}{15}{50}
    
blue-black discoloration of skin, fingernails, or inside of mouth{08}{16}{51}
    
dizziness or lightheadedness{11}
    
nervousness or restlessness{08}{16}
    
skin rash or itching{08}{16}{52}



Those indicating possible retinal changes, visual disturbances and the need for medical attention if they occur or progress after medication is discontinued
    
Blurred vision or any other change in vision{11}{14}




Overdose
For specific information on the agents used in the management of hydroxychloroquine overdose, see:
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
After ingestion of an overdose of hydroxychloroquine, toxic symptoms may occur within 30 minutes. These include drowsiness, visual disturbances, cardiovascular collapse, and seizures, followed by sudden respiratory and cardiac arrest {18} {40} {42}.

Doses of chloroquine phosphate as small as 0.75 to 1 gram in children, and 2.25 to 3 grams in adults, may be fatal. It is assumed that hydroxychloroquine is equally toxic {65}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parenthesis where appropriate)—not necessarily inclusive:
Acute
    
Cardiovascular toxicities {42} {65} , specifically conduction disturbances or hypotension
    
neurotoxicity, specifically drowsiness
headache
hyperexcitability
seizures
or coma
    
respiratory and cardiac arrest
    
visual disturbances (blurred vision)


Treatment of overdose
Since there is no specific antidote, treatment of hydroxychloroquine overdose should be symptomatic and supportive with possible utilization of the following:


To decrease absorption:
Emptying stomach with gastric lavage.

Administering activated charcoal with a cathartic. The dose of activated charcoal should be 5 to 10 times the estimated dose of the drug ingested {18} {40} {42} {43}.



To enhance elimination:
Forcing diuresis and acidifying the urine, with ammonium chloride, for example, can help promote urinary excretion of 4-aminoquinolines {18} {40} {42}. Adjusting the dose of the acidifying agent to maintain a urinary pH of 5.5 to 6.5 {43}. Monitoring of plasma potassium is recommended. Using with caution in patients with renal function impairment and/or metabolic acidosis {40} {42} {43}.



Specific treatment:
For seizures: Treating repetitive seizures or status epilepticus with intravenous diazepam (in 2.5 to 5 mg increments) {43}.

For arrhythmias: Managing life-threatening ventricular arrhythmias or cardiac arrest appropriately, as per Advanced Cardiac Life Support guidelines {43}.

For hypotension and circulatory shock: Administering fluids at a sufficient rate to maintain urine output. Administering intravenous pressors and/or inotropic drugs, such as norepinephrine, dopamine, isoproterenol, or dobutamine, if required. One study found that administration of a high-dose diazepam infusion improved hemodynamic function, and epinephrine decreased the myocardial depressant and vasodilatory effects of chloroquine overdose. This may also apply to a hydroxychloroquine overdose {18} {43} {66}.



Monitoring:
Monitoring of plasma potassium is recommended {40} {42} {43}.



Supportive care:
Securing and maintaining a patent airway, administering oxygen, and instituting assisted or controlled respiration as required. In severe overdoses, early mechanical ventilation has been suggested to prevent hypoxemia {18} {43} {66}. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Hydroxychloroquine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to hydroxychloroquine or chloroquine

Pregnancy—May cause toxicity to the fetus when given to mother in therapeutic doses; however, hydroxychloroquine has not been shown to cause adverse effects in the fetus when used as a prophylactic agent against malaria





Use in children—Infants and children are especially sensitive to effects of hydroxychloroquine

Other medical problems, especially impaired hepatic function, impaired renal function, presence of retinal or visual field changes, severe blood disorders, or severe neurologic disorders

Proper use of this medication
» Taking with meals or milk to minimize possible gastrointestinal irritation

» Keeping medication out of reach of children; fatalities reported with as few as 3 or 4 tablets (250-mg strength) of chloroquine phosphate; hydroxychloroquine is assumed to be equally toxic

» Importance of not taking more medication than the amount prescribed

» Compliance with full course of therapy

» Importance of not missing doses and taking medication on regular schedule

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For prevention of malaria
Starting medication 1 to 2 weeks before entering malarious area to ascertain patient response and allow time to substitute another medication if reactions occur {07}

» Continuing medication while staying in area and for 4 to 6 weeks after leaving area; checking with physician immediately if fever develops while traveling or within 2 months after departure from endemic area {07}

For arthritis and lupus erythematosus
Importance of taking medication on regular schedule

May require up to 6 months for full benefit

For patients unable to swallow hydroxychloroquine tablets
Crushing tablets and putting each dose in capsules; contents of capsules may be mixed with jam, jelly, or jello

Precautions while using this medication
» Regular visits to physician for ophthalmologic examinations during or after long-term therapy

Checking with physician if no improvement within a few days (or a few weeks or months for arthritis)

» Caution if blurred vision, difficulty in reading, other change in vision, dizziness, or lightheadedness occurs

Mosquito-control measures to reduce the chance of getting malaria:

• Sleeping under mosquito netting


• Wearing long-sleeved shirts or blouses and long trousers to protect arms and legs between dusk and dawn


• Applying mosquito repellent to uncovered areas of skin between dusk and dawn



Side/adverse effects
Signs of potential side effects, especially ocular toxicity, blood dyscrasias, emotional or psychological changes, neuromyopathy, ototoxicity, and seizures


General Dosing Information
Long-term and/or high-dosage therapy may cause irreversible retinal damage and/or neurosensorial deafness {08}.

Hydroxychloroquine should be discontinued if any of the following problems occur: any abnormality in visual acuity, visual fields, retinal macular changes, or any other visual symptoms; muscle weakness; or severe blood disorders {08}.

Malaria-suppressive therapy should be started 1 to 2 weeks before the patient enters a malarious area and should be continued for 4 to 6 weeks after patient leaves the area. Starting the medication in advance will help to determine the patient's tolerance to the medication and allow time to substitute other antimalarials if the patient develops allergies to the medication or develops other adverse effects {07}.

Hydroxychloroquine should be taken with meals or milk to minimize the possibility of gastrointestinal irritation {14}.

Corticosteroids and/or nonsteroidal anti-inflammatory analgesics (including salicylates) {03} {05} may be given concurrently with hydroxychloroquine in the treatment of rheumatoid arthritis. These medications can usually be reduced gradually in dosage or discontinued after hydroxychloroquine has been given for several weeks.

When hydroxychloroquine is used in the treatment of rheumatoid arthritis, several months of therapy may be required for it to reach its maximum effectiveness. If improvement (such as reduced joint swelling and increased mobility) does not occur within 6 months, the medication should be discontinued {11}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HYDROXYCHLOROQUINE SULFATE TABLETS USP

Usual adult and adolescent dose
Malaria {15} {18}
Suppressive: Oral, 400 mg (310 mg base) once every seven days.

Therapeutic: Oral, 800 mg (620 mg base) as a single dose; or {02} 800 mg (620 mg base) initially, followed by 400 mg (310 mg base) in six to eight hours, and 400 mg (310 mg base) once a day on the second and third days.

Antirheumatic (disease-modifying)
Oral, up to 6.5 mg (5 mg base) per kg of lean body weight daily, with meals or a glass of milk {03} {04}.

Note: In a small number of patients who experience side effects with the usual initial dose in the treatment of rheumatoid arthritis, a temporary reduction in the initial dose of hydroxychloroquine may be required. After five to ten days the dose may be gradually increased until the desired response is obtained.
If relapse occurs after withdrawal of hydroxychloroquine, therapy may be resumed or continued on an intermittent schedule if there are no ocular contraindications.


Lupus erythematosus suppressant
Oral, up to 6.5 mg (5 mg base) per kg of lean body weight daily {03} {04}.

[Polymorphous light eruption suppressant]1
Oral, 200 mg (155 mg base) two or three times a day.


Usual pediatric dose
Malaria
Suppressive: Oral, 6.4 mg (5 mg base) per kg of body weight, not to exceed the adult dose, once every seven days.

Therapeutic: Oral, 32 mg (25 mg base) per kg of body weight administered over a period of three days as follows: 12.9 mg (10 mg base) per kg of body weight, not to exceed a single dose of 800 mg (620 mg base); then 6.4 mg (5 mg base) per kg of body weight, not to exceed a single dose of 400 mg (310 mg base), six, twenty-four, and forty-eight hours after the first dose.


Note: Children are especially sensitive to the effects of the 4-aminoquinolines.
Long-term therapy with hydroxychloroquine is not recommended in children {42}.


Strength(s) usually available
U.S.—


200 mg (equivalent to 155 mg base) (Rx) [Plaquenil{10}{11}{12}{13}{18}{42}]

Canada—


200 mg (equivalent to 155 mg base) (Rx) [Plaquenil (scored){15}{09}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Preparation of dosage form:
According to the manufacturer, the tablets may be crushed and each dose placed in a capsule. The contents of each compounded capsule may then be mixed with a teaspoonful of jam, jelly, or jello prior to administration. Preparation of hydroxychloroquine sulfate oral suspensions is not recommended.

Auxiliary labeling:
   • Continue medication for full time of treatment.
   • Keep out of reach of children.
   • Take with food or milk.
   • May cause dizziness.

Note: Explain potential danger of accidental overdose in children.
Consider dispensing in unit-dose packaging in child-resistant containers (``double-barrier'' packaging).




Revised: 05/24/1999



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  1. Panel comment, 2/90.
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  1. Titus EO. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit 1989; 11(4): 369-79.
  1. Krogstad DJ, Schlesinger PH. The basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH. Am J Trop Med Hyg 1987; 36(2): 213-20.
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  1. Tett SE, et al. A dose-ranging study of the pharmacokinetics of hydroxychloroquine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1988; 26: 303-13.
  1. White NJ, et al. Parenteral chloroquine for treating falciparum malaria. J Infect Dis 1987 Feb; 155(2): 192-201.
  1. Barre PE, et al. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am J Med 1987 Jun; 82: 1259-62.
  1. Estes ML, et al. Chloroquine neuromyotoxicity. Am J Med 1987 Mar; 82: 447-55.
  1. Johnson MW, Vine AK. Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol 1987 Aug 12; 104(2): 139-44.
  1. Loney PD, Walling AD. Chloroquine overdose in infancy: a case report. Am Fam Physician 1989 Jul; 40(1): 164-6.
  1. Riou B, et al. Treatment of severe chloroquine poisoning. N Eng J Med 1988 Jan 7; 318(1): 1-6.
  1. Rynes RI. Ophthalmologic safety of long-term hydroxychloroquine sulfate treatment. Am J Med 1983 Jul 18: 35-9.
  1. Tett SE, et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol 1989; 27: 771-9.
  1. Grierson DJ. Hydroxychloroquine and visual screening in a rheumatology outpatient clinic. Ann Rheum Dis 1996; 56: 188-90.
  1. Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol 1991; 23: 292-6.
  1. Panel comment, 5/99.
  1. Panel comment, 5/99.
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