Hydroxychloroquine sulfate is a colorless crystalline solid, soluble in water to at least 20 percent; chemically the drug is 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino] ethanol sulfate (1:1).

Hydroxychloroquine

Molecular Formula C18H26ClN3O.H2SO4

Molecular Weight 433.95

CAS Registry Number 747-36-4

Melting point 240 ºC

Water solubility FREELY SOLUBLE

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Hydroxychloroquine

Antimalarial

Synonym. Oxichlorochin

2-[[4-[(7-Chloro–4–quinolinyl)amino]pentyl]ethylamino]ethanol

C18H26ClN3O=335.9

CAS—118–42–3

Chemical structure

Crystals. M.p. 89° to 91°.

Hydroxychloroquine Sulfate

Proprietary names. Ercoquin; Plaquenil; Quensyl.

C18H26ClN3O,H2SO4=434.0

CAS—747–36–4

A white crystalline powder. There are 2 forms, one melting at about 198° and the other at about 240°.

Soluble 1 in 5 of water; practically insoluble in ethanol, chloroform, and ether.

Partition Coefficient.

Log P(octanol/water), 3.0.

Thin–layer Chromatography.

System TA—Rf 45; system TB—Rf 02; system TC—Rf 02; system TE—Rf 37; system TL—Rf 03; system TAE—Rf 07; system TAJ—Rf 00; system TAK—Rf 00; system TAL—Rf 04. (Acidified iodoplatinate solution, positive.)

Gas Chromatography.

System GA—RI 2872.

High Performance Liquid Chromatography.

System HX—RI 280; system HZ—retention time 1.9 min; system HAX—retention time 9.6 min; system HAY—retention time 3.2 min.

Ultraviolet Spectrum.

Aqueous acid—235 nm (A11=560a), 256, 329, 343 nm; aqueous alkali—253, 330 nm.

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Infra–red Spectrum.

Principal peaks at wavenumbers 1579, 1608, 1530, 1050, 1150, 810 cm−1 (KBr disk).

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Mass Spectrum.

Principal ions at m/z 102, 245, 247, 304, 305, 306, 58, 126.

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Quantification

High performance liquid chromatography.

In blood or plasma: hydroxychloroquine and its major metabolites, limit of detection 1 μg/L, fluorescence detection—S. E. Tett et al.,J. Chromatogr.,1985, 344, 241–248. In blood or urine: hydroxychloroquine and its major metabolites, limit of detection for hydroxychloroquine 10 ppb, fluorescence detection—S. B. Williams et al.,J. Chromatogr.,1988, 433, 197–206. In plasma, serum, whole blood or urine: hydroxychloroquine enantiomers, UV detection—D. R. Brocks et al.,J. Chromatogr.,1992, 581, 83–92. In urine: hydroxychloroquine enantiomers and metabolites—H. Fieger et al.,Chirality,1993, 5, 65–70. In serum, whole blood or dried blood: hydroxychloroquine, chloroquine, quinine, and desethylchloroquine, limit of detection <5 μg/L, fluorescence detection—K. Croes et al.,J. Anal. Toxicol.,1994, 18, 255–260. In serum: hydroxychloroquine, chloroquine, and corticosteroids, diode–array detection—P. Volin,J. Chromatogr.,1995, 666 B Biomed. Appl., 347–353.

Ultraviolet spectrophotometry.

In blood or urine—R. A. Dalley and D. Hainsworth,J. Forensic Sci. Soc.,1965, 5, 99–101.

Spectrofluorimetry.

In plasma—E. W. McChesney et al.,Antibiot. Chemother.,1962, 12, 583–594.

Disposition in the Body.

Rapidly and almost completely absorbed after oral administration. It is metabolised by de–ethylation. About 6% of a single dose is excreted in the urine over a period of 10 days and about 25% of a dose is eliminated in the faeces in 3 days as unchanged drug plus the de–ethylated metabolites. During daily therapy, less than 13% of a dose is excreted in the 24-h urine with 8% of the dose as unchanged drug, 2% as desethylchloroquine, 2% as desethylhydroxychloroquine, and 0.5% as didesethylchloroquine.

Therapeutic concentration

After an oral dose of hydroxychloroquine sulfate equivalent to 310 mg of the base to 6 subjects, peak plasma concentrations of 0.003 to 0.20 mg/L (mean 0.08) were attained in 3 h. Following oral administration of hydroxychloroquine diphosphate equivalent to 1264 mg of the base to 3 subjects, peak plasma concentrations of 0.29 to 1.0 mg/L (mean 0.64) were attained in 3 h and therapeutic concentrations greater than 0.01 mg/L were maintained for 240 h. [E. W. McChesney et al.,Antibiot. Chemother.,1962, 12, 583–594.]

In 23 subjects receiving 200 or 400 mg hydroxychloroquine sulfate orally daily, mean steady–state hydroxychloroquine concentrations at 6 months were 450.6 and 870.3 μg/L, respectively. [S. E. Tett et al,J. Rheumatol.,2000, 27, 1656–1660.]

Toxicity

In a fatality due to the ingestion of at least 12 g, the following postmortem tissue concentrations of hydroxychloroquine were reported: blood 48 mg/L, heart blood 61 mg/L, liver 71 μg/g, urine 970 mg/L. [R. A. Dalley and D. Hainsworth,J. Forensic Sci. Soc.,1965, 5, 99–101.]

Postmortem tissue concentrations in a 2½-year–old boy who died after ingesting an estimated 1800 mg of hydroxychloroquine were: blood 104 mg/L, stomach 1.2 mg in total, small intestine 75 mg in total, liver 500 μg/g. [A. V. Kemmenoe,J. Anal. Toxicol.,1990, 14, 186–188.]

An 18–year–old girl who survived after ingesting 20 g of hydroxychloroquine had a plasma level of 9.87 mg/L 2 h after ingestion [P. Jordan et al.,J. Toxicol. Clin. Toxicol.,1999, 37, 861–864.]

Half–life.

Plasma half–life, about 3 days.

Dose.

For an acute attack of malaria, 2 g of hydroxychloroquine sulfate given over 3 days (1.2 g on the first day). In rheumatoid arthritis, initially 400 to 800 mg daily.

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Accessibility | Terms and Conditions

Systematic (IUPAC) name

(RS)-2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol

Clinical data

Trade names Plaquenil

AHFS/Drugs.com monograph

MedlinePlus a601240

Pregnancy cat. D (Au), C (U.S.)

Legal status POM (UK), ℞-only (U.S.)

Routes Oral

Pharmacokinetic data

Half-life 1–2 months

Excretion Renal

Identifiers

CAS number 118-42-3 YesY

ATC code P01BA02

PubChem CID 3652

DrugBank DB01611

ChemSpider 3526 YesY

UNII 4QWG6N8QKH YesY

KEGG D08050 YesY

ChEMBL CHEMBL1535 YesY

Chemical data

Formula C18H26ClN3O

Mol. mass 335.872 g/mol

SMILES eMolecules & PubChem

InChI[show]

* InChI=1S/C18H26ClN3O/c1-3-22(11-12-23)10-4-5-14(2)21-17-8-9-20-18-13-15(19)6-7-16(17)18/h6-9,13-14,23H,3-5,10-12H2,1-2H3,(H,20,21) YesY

Key:XXSMGPRMXLTPCZ-UHFFFAOYSA-N YesY

YesY(what is this?) (verify)

Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal(In India), Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis (see disease-modifying antirheumatic drugs) and lupus. Hydroxychloroquine differs from chloroquine by the presence of a hydroxyl group at the end of the side chain: The N-ethyl substituent is beta-hydroxylated. It is available for oral administration as hydroxychloroquine sulfate (plaquenil) of which 200 mg contains 155 mg base in chiral form. Hydroxychloroquine has similar pharmacokinetics to chloroquine, with quick gastrointestinal absorption and is eliminated by the kidney. Cytochrome P450 enzymes (CYP 2D6, 2C8, 3A4 and 3A5) N-desethylated Hydroxychloroquine to Ndesethylhydroxychloroquine. [1], [2]

Contents

[hide]

* 1 Mechanism of Action

* 2 Classification and use

* 3 Dosage

o 3.1 Malaria

o 3.2 Lupus erythematosus

o 3.3 Rheumatoid arthritis

* 4 Side effects

o 4.1 Eyes

o 4.2 Interactions

o 4.3 Overdose symptoms

* 5 References

* 6 External links

[edit] Mechanism of Action

Antimalarials are lipophilic weak bases and easily go through plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and then protonated, in an ionized state.[3], Resulting in concentrations within lysosomes up to 1000 times higher than in culture media, increasing the pH of the lysosome from 4 to 6 [4]. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect [5]. Higher pH within lysosomes causes decreased intracellular processing, glycosylation, and secretion of proteins with many immunologic and nonimmunologic consequences [6]. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils [7]. Recently a novel mechanism has been describe whereas hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system [8]

[edit] Classification and use

Hydroxychloroquine is classified as an anti-malarial medication and is one of a number of drugs that have been used for many years in the treatment of malaria. It is also useful in treating systemic lupus erythematosus as well as rheumatoid arthritis and Sjögren's Syndrome (all rheumatic disorders). While hydroxychloroquine has been known for some time to increase[9] lysosomal pH in antigen presenting cells, its mechanism of action in inflammatory conditions has been recently elucidated and involves blocking the activation of toll-like receptors on plasmacytoid dendritic cells (PDCs). Toll-like receptor 9 (TLR 9), which recognizes DNA-

containing immune complexes, leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells. Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells thus mitigating the inflammatory process.

Hydroxychloroquine is also widely used in the treatment of post-Lyme arthritis that can be induced by Lyme disease. The action of the drug may involve both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.[10]

[edit] Dosage

[edit] Malaria

For prevention of malaria the usual adult dose is 400 milligrams per seven days, on the same day, begun two weeks prior to exposure, or two 400 milligrams doses taken six hours apart. Suppressive therapy continues for eight weeks after leaving the transmission area. For acute malaria the recommendation is either a single 800 milligram dose or 800 milligrams followed by 400 milligrams six to eight hours later, and 400 milligrams once per day for two consecutive days. The children's dose will depend on the weight of the child but should be supervised by a doctor.

[edit] Lupus erythematosus

The adult starting dose is 6.5 mg/kg daily, for several weeks or months, depending on the reaction. This may be reduced to for maintenance. With systemic lupus, it is especially useful in relieving skin inflammation, hair loss, oral sores, fatigue and joint pain as well as preventing relapse.

[edit] Rheumatoid arthritis

The adult starting dose is 400 to 600 milligrams per day with food or milk; with improvement (between four to twelve weeks) the maintenance dose is 200 to 400 milligrams daily. Hydroxychloroquine has not been proven safe for the treatment of juvenile arthritis.

[edit] Side effects

Side effects are difficult to anticipate, and should be reported to a doctor immediately if new symptoms develop or old symptoms change in intensity. Generally side effects are not common, but can include (for short-term treatment of acute malaria) abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting. The symptoms for prolonged treatment of lupus or arthritis include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, significant vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, and weight loss. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.

The most common side effects are a mild nausea and occasional stomach cramps with mild diarrhea.

[edit] Eyes

One of the most serious side effects is a toxicity in the eye.[11] (generally with chronic use) The daily safe maximum dose for eye toxicity can be computed from one's height and weight using this calculator. It should be noted that macular toxicity is related to the total cumulative dose rather than the daily dose. People taking 400mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.[12]

Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye, the cornea, and the macula. The cornea may become affected (relatively commonly) by an innocuous vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.

The macular changes are potentially serious and are related to dosage and length of time taking hydroxychloroquine. Established maculopathy is characterized by moderate reduction of visual acuity and an obvious "bulls eye" macular lesion. End stage maculopathy is characterized by severe reduction in visual acuity and severe atrophy of the retinal pigment epithelium.

[edit] Interactions

A type of enzyme deficiency (enzyme G6PD) found most frequently in those of African descent can develop into severe anemia and should also be monitored.[13] Children are more sensitive to hydroxychloroquine than adults are, and small doses can be potentially fatal.

Hydroxychloroquine generally does not have significant interactions with other medications but care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). It will transfer into breast milk and should be used with care by pregnant or nursing mothers.

[edit] Overdose symptoms

Symptoms of overdose can occur within a half-hour of taking the medication. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.

[edit] References

1. ^ New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):160-74. PMID:17970883

2. ^ Pharmacogenetics of disease-modifying anti-rheumatic drugs. Best Pract Res Clin Rheumatol 2004:18: 233–247.

3. ^ .Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci 2007:96: 729–746.

4. ^ Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 1978:75:3327–3331.

5. ^ The effects of basic substances and acidic ionophores on the digestion of exogenous and endogenous proteins in mouse peritoneal macrophages. J Cell Biol 1986:102: 959–966.

6. ^ Effects of weakly basic amines on proteolytic processing and terminal glycosylation of secretory proteins in cultured rat hepatocytes. Biochem J 1986:240: 739–745.

7. ^ Chloroquine and hydroxychloroquine inhibit multiple sites in metabolic pathways leading to neutrophil superoxide release. J Rheumatol 1988:15: 23–27

8. ^ Toll-like receptors. Annu Rev Immunol 2003:21: 335–376.

9. ^ Waller et al. 2nd ed.'medical pharmacology and therapeutics'pg 370

10. ^ Steere AC, Angelis SM (October 2006). "Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis". Arthritis Rheum. 54 (10): 3079–86. doi:10.1002/art.22131. PMID 17009226.

11. ^ Flach AJ (2007). "IMPROVING THE RISK-BENEFIT RELATIONSHIP AND INFORMED CONSENT FOR PATIENTS TREATED WITH HYDROXYCHLOROQUINE". Transactions of the American Ophthalmological Society 105: 191–4; discussion 195–7. PMC 2258132. PMID 18427609. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2258132.

12. ^ Marmor, MF; Kellner, U, Lai, TY, Lyons, JS, Mieler, WF, American Academy of, Ophthalmology (2011 Feb). "Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy". Ophthalmology 118 (2): 415–22. doi:10.1016/j.ophtha.2010.11.017. PMID 21292109.

13. ^ "Hydroxychloroquine (Oral Route) - MayoClinic.com". http://www.mayoclinic.com/health/drug-information/DR600761. Retrieved 2008-10-30.

Hydroxychloroquine SulfateHydroxychloroquine Sulfate pronunciation

Class: AntimalarialsVA Class: AP101CAS Number: 747-36-4Brands: PlaquenilIntroduction

Antimalarial; 4-aminoquinoline derivative.aUses for Hydroxychloroquine SulfateMalaria

Prevention (prophylaxis) of malaria caused by Plasmodium malariae, P. ovale, P. vivax, or susceptible strains of P. falciparum.105 109 CDC and others recommend chloroquine for prevention of malaria caused by Plasmodium susceptible to 4-aminoquinoline derivatives;105 110 hydroxychloroquine is as effective and may be better tolerated105 and may be used when chloroquine is unavailable.105 110

Treatment of uncomplicated malaria caused by P. malariae, P. ovale, P. vivax, or susceptible strains of P. falciparum.109 110

Active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages) and cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria or provide a radical cure; primaquine usually also indicated to eradicate hypnozoites and prevent relapse in patients exposed to or being treated for P. ovale or P. vivax malaria.105 109

Detailed recommendations regarding prevention of malaria available from CDC 24 hours a day from the voice information service (877-394-8747), fax information service (888-232-3299), or Internet at .105

Assistance with diagnosis or treatment of malaria available from CDC Malaria Epidemiology Branch by contacting CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.118Rheumatoid Arthritis

Treatment of rheumatoid arthritis in patients whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs).103 104 109

One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.103 104 If used for prolonged periods in treatment of rheumatoid arthritis, the risk of severe and sometimes irreversible toxicity should be considered.109 (See Cautions.)Lupus Erythematosus

Treatment of discoid lupus erythematosus and systemic lupus erythematosus.109 Used as an adjunct to corticosteroids and/or other appropriate therapy.a

If used for prolonged periods in treatment of lupus erythematosus, the risk of serious and sometimes irreversible toxicity should be considered. (See Cautions.)Q Fever

Treatment of Q fever endocarditis† caused by Coxiella burnetii; used in conjunction with doxycycline.111 112 113

CDC recommends a 2- to 3-week regimen of doxycycline for treatment of acute Q fever, a 1-year regimen of doxycycline and hydroxychloroquine for treatment of acute Q fever in patients with preexisting valvular heart disease (to prevent progression of acute disease to endocarditis), and a 1.5- to 3-year regimen of doxycycline and hydroxychloroquine for treatment of chronic Q fever.113Porphyria Cutanea Tarda and Polymorphous Light Eruptions

Has been used in treatment of porphyria cutanea tarda†.115 116 117 (See Patients with Psoriasis or Porphyria under Cautions.)

Has been effective in some cases when used in the treatment of polymorphous light eruptions†.Hydroxychloroquine Sulfate Dosage and AdministrationAdministrationOral Administration

Administer orally.109

When used in treatment of rheumatoid arthritis, administer with a meal or a glass of milk.109Dosage

Available as hydroxychloroquine sulfate; dosage usually expressed as hydroxychloroquine.109

Each 200 mg of hydroxychloroquine sulfate is equivalent to 155 mg of hydroxychloroquine.109Pediatric PatientsMalariaPrevention of Malaria in Areas Without Chloroquine-resistant PlasmodiumOral

5 mg/kg (6.5 mg/kg of hydroxychloroquine sulfate) once weekly on the same day each week.105 109

Initiate prophylaxis 1–2 weeks prior to entering a malarious area and continue for 4 weeks after leaving the area.105 114 CDC states it may be advisable to initiate prophylaxis 3–4 weeks prior to travel to ensure that the drug or combination of drugs (in individuals receiving other drugs) is well tolerated and to allow ample time if a switch to another antimalarial agent is required.105

If not initiated prior to entering a malarious area, manufacturer recommends a loading dose of 10 mg/kg (13 mg/kg of hydroxychloroquine sulfate) given in 2 equally divided doses 6 hours apart followed by the usual dosage.109Treatment of Uncomplicated Chloroquine-susceptible MalariaOral

An initial dose of 10 mg/kg (13 mg/kg of hydroxychloroquine sulfate) followed by 5-mg/kg doses (6.5 mg/kg of hydroxychloroquine sulfate) given at 6, 24, and 48 hours after the initial dose.109AdultsMalariaPrevention of Malaria in Areas Without Chloroquine-resistant PlasmodiumOral

310 mg (400 mg of hydroxychloroquine sulfate) once weekly on the same day each week.105 109

Initiate prophylaxis 1–2 weeks prior to entering a malarious area and continue for 4 weeks after leaving the area.105 114 CDC states it may be advisable to initiate prophylaxis 3–4 weeks prior

to travel to ensure that the drug or combination of drugs (in individuals receiving other drugs) is well tolerated and to allow ample time if a switch to another antimalarial agent is required.105

If not initiated prior to entering a malarious area, the manufacturer recommends a loading dose of 620 mg (800 mg of hydroxychloroquine sulfate) followed by the usual dosage regimen.109Treatment of Uncomplicated Chloroquine-susceptible MalariaOral

An initial dose of 620 mg (800 mg of hydroxychloroquine sulfate) followed by 310-mg doses (400 mg of hydroxychloroquine sulfate) given 6–8 hours, 24, and 48 hours after the initial dose.109 This represents a total hydroxychloroquine dose of 1.55 g (2 g of hydroxychloroquine sulfate) in 3 days.109 Alternatively, adults may receive a single 620-mg dose (800 mg of hydroxychloroquine sulfate).109Rheumatoid ArthritisOral

Initiate treatment with 310–465 mg (400–600 mg of hydroxychloroquine sulfate) daily.109 If adverse effects occur, dosage may be temporarily reduced; after 5–10 days, increase dosage gradually until an optimum response occurs without recurrence of adverse effects.109

A response may not occur until after 4–12 weeks and several months of therapy may be required to attain optimum response.109 When a good response is obtained, decrease dosage by 50% and continue treatment with a maintenance dosage of 155–310 mg (200–400 mg of hydroxychloroquine sulfate) daily.109

If relapse occurs after hydroxychloroquine is discontinued, the drug can be reinitiated or continued on an intermittent schedule if there is no evidence of adverse ocular effects.109

If objective improvement of rheumatoid arthritis (e.g., reduced joint swelling, increased mobility) does not occur within 6 months, hydroxychloroquine should be discontinued.109Lupus ErythematosusOral

310 mg (400 mg of hydroxychloroquine sulfate) once or twice daily for several weeks or months depending on response of the patient.109 For prolonged maintenance therapy, 155–310 mg (200–400 mg of hydroxychloroquine sulfate) daily may be adequate.109Q Fever†Acute Q Fever in Patients with Preexisting Valvular Heart Disease†Oral

CDC recommends 465 mg (600 mg of hydroxychloroquine sulfate) daily in conjunction with oral doxycycline (200 mg daily) for 1 year.113 Adjust hydroxychloroquine dosage to maintain plasma hydroxychloroquine concentrations at 1 ± 0.2 mcg/mL.113Chronic Q Fever†Oral

CDC recommends 465 mg (600 mg of hydroxychloroquine sulfate) daily in conjunction with oral doxycycline (200 mg daily) for 1.5–3 years.113Prescribing LimitsPediatric PatientsMalariaPrevention of Malaria in Areas Without Chloroquine-resistant PlasmodiumOral

Maximum of 310 mg (400 mg of hydroxychloroquine sulfate) daily, regardless of weight.105Cautions for Hydroxychloroquine SulfateContraindications

*

Hypersensitivity to 4-aminoquinoline derivatives.109 *

Retinal or visual field changes attributable to 4-aminoquinoline derivatives or to any other etiology.109 *

Long-term use in children.109

Warnings/PrecautionsWarningsChloroquine-resistant Plasmodium

Hydroxychloroquine is not effective against chloroquine-resistant P. falciparum.105 109 For prevention of malaria, use only in individuals traveling to malarious areas where chloroquine-resistant P. falciparum malaria has not been reported.105

For prevention or treatment of malaria, consider that chloroquine-resistant P. falciparum have been reported in all areas where malaria occurs, except the Dominican Republic, Haiti, Mexico and Central America west of the former Panama Canal zone, Paraguay, northern Argentina, Egypt, most of the Middle East (chloroquine resistance has been reported in Iran, Oman, Saudi Arabia, and Yemen), and most of China (chloroquine resistance has been reported in Hainin and Yunnan provinces).105 110 114Ocular Effects

Dose-related retinopathy reported, which may progress even after the drug is discontinued.109 Irreversible retinal damage has occurred in some patients who received long-term or high-dosage 4-aminoquinoline therapy for treatment of discoid and systemic lupus erythematosus or rheumatoid arthritis.109

Whenever long-term therapy is contemplated, perform initial (base line) and periodic (every 3 months) ophthalmologic examinations, including visual acuity, slit-lamp, funduscopic, and visual field tests.109

Discontinue drug immediately and closely observe patient for possible progression if there is any indication of abnormalities in visual acuity or visual field, abnormalities in the retinal macular area (such as pigmentary changes or loss of foveal reflex), or if any other visual symptoms (e.g., light flashes and streaks) occur which are not fully explainable by difficulties of accommodation or corneal opacities.109Neuromuscular Effects

Skeletal muscle palsies or skeletal muscle myopathy or neuromyopathy reported.109 May lead to progressive weakness and atrophy of proximal muscle groups and may be associated with mild sensory changes, depression of tendon reflexes, and abnormal nerve conduction.109

Patients receiving prolonged therapy should be questioned and examined periodically for evidence of muscular weakness; knee and ankle reflexes should be tested.109

Discontinue hydroxychloroquine if muscular weakness occurs.109Patients with Psoriasis or Porphyria

May exacerbate psoriasis and precipitate a severe attack in patients with the disease.109 Use in psoriasis patients only if potential benefits outweigh risks.109

May exacerbate porphyria.109 Use in patients with porphyria only if potential benefits outweigh risks.109General PrecautionsDermatologic Effects

Dermatologic reactions may occur; use with caution in patients with tendency for dermatitis.109Hematologic Effects

Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia (hemolysis in patients with G-6-PD deficiency) reported rarely.109

Periodically monitor CBCs in patients receiving prolonged treatment.109 Consider discontinuing hydroxychloroquine if any severe blood disorder occurs which is not attributable to the disease being treated.109

Use with caution in patients with G-6-PD deficiency.109Specific PopulationsPregnancy

Category C.b

Avoid use during pregnancy unless the clinician determines that the benefits of prevention or treatment of malaria outweigh the risks.109 Chloroquine has been used for prophylaxis and treatment of malaria in pregnant women without evidence of adverse effects on the fetus,105 110 and CDC states that the benefits of chloroquine or hydroxychloroquine prophylaxis in pregnant women exposed to malaria outweigh potential risks to the fetus.105 110Lactation

Distributed into milk.102 Amount of drug present in human milk does not appear to be harmful to nursing infants, but is insufficient to provide adequate protection against malaria in these infants.105 When chemoprophylaxis is necessary in such infants, they should receive recommended dosages of the appropriate antimalarial agent(s).105Pediatric Use

Pediatric patients are especially sensitive to 4-aminoquinoline derivatives.109 Fatalities have been reported following accidental ingestion of relatively small doses.109

Prolonged therapy with hydroxychloroquine is contraindicated in children; safe use of the drug for treatment of juvenile arthritis has not been established.109Hepatic Impairment

Hydroxychloroquine may concentrate in the liver;a use with caution in patients with hepatic disease or alcoholism and in patients receiving other hepatotoxic drugs.109Common Adverse Effects

Ocular effects; skeletal muscle myopathy or neuromyopathy; GI effects (anorexia, diarrhea, nausea, abdominal cramps, vomiting); CNS effects (headache, dizziness); dermatologic effects.109Hydroxychloroquine Sulfate PharmacokineticsDistributionExtent

Distributed into milk.102EliminationMetabolism

Partially metabolized; the major metabolites are desethylhydroxychloroquine and desethylchloroquine.100 Bisdesethylchloroquine, a carboxylic acid derivative, also is formed in small amounts.100Elimination Route

Hydroxychloroquine and its metabolites are slowly excreted by the kidneys.100StabilityStorageOralTablets

Room temperature ≤30°C in tight, light-resistant container.109Actions and SpectrumActions

*

A blood schizonticidal agent active against asexual erythrocytic forms of most strains of Plasmodium malariae, P. ovale, P. vivax, and many strains of P. falciparum.a Not active against preerythrocytic or exoerythrocytic forms of plasmodia.a Gametocidal for P. malariae and P. vivax, but has no direct activity against the gametocytes of P. falciparum.a *

Chloroquine-resistant P. falciparum also are resistant to hydroxychloroquine109 and may be cross-resistant to pyrimethamine or quinine.a *

Has anti-inflammatory activity; mechanism(s) of action in the treatment of rheumatoid arthritis and lupus erythematosus has not been determined.a

Advice to Patients

*

Importance of keeping hydroxychloroquine out of reach of children since they are especially sensitive to 4-aminoquinoline derivatives.109 *

Necessity of taking protective measures to reduce contact with mosquitoes (protective clothing, insect repellents, mosquito nets, remaining in air-conditioned or well-screened areas).105 110 *

Possibility of contracting malaria during travel, regardless of prophylactic regimen used.105 110 *

Importance of seeking medical attention as soon as possible if febrile illness develops during or after return from a malaria-endemic area and of informing clinician of possible malaria exposure.105 110 *

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. *

Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.109

*

Importance of advising patients of other important precautionary information. (See Cautions.)