Hydroxychloroquine (available by the brand names of Plaquenil, HCQ, and Advaquenil) is a drug that is primarily used to treat malarial infections. It has also been recently incorporated in the treatment algorithm of COVID-19 (Coronavirus) infection. Compared to chloroquine, hydroxychloroquine is considered to be superior in the treatment of coronavirus infection [Ref].

Hydroxychloroquine uses:

• Systemic Lupus erythematosus:

  • It is used in the treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus (SLE) in adults.
  • It is also considered an essential medicine in the treatment of lupus nephritis.

• Malaria:

  • HCQ is used to treat uncomplicated malaria caused by susceptible strains of Plasmodium vivax, P. malariae, P. ovale, and P. falciparum.
  • It is also used for the prophylaxis of malaria in chloroquine-sensitive areas.
  • It is not recommended for the treatment or prophylaxis in patients with complicated malaria or chloroquine-resistant malaria.
  • Furthermore, it does not prevent relapses of P. vivax and P. ovale infections as it is not effective against the hypnozoite forms of these parasites.

• Rheumatoid arthritis:

  • With or without additional disease-modifying anti-rheumatic medications, it is approved for the treatment of rheumatoid arthritis (RA) in adults.

• Off Label Use of Hydroxychloroquine in Adults:

  • Porphyria cutanea tarda
  • Extraglandular manifestations of Primary Sjögren Syndrome
  • Chronic Q fever
  • COVID-19 infection with azithromycin.

It is important to note that hydroxychloroquine and azithromycin both prolong the QTc interval and should be used with caution in patients with cardiac disease.

Hydroxychloroquine Dose in Adults

Note:

200 mg of Hydroxychloroquine sulfate is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. All the doses mentioned below are expressed as hydroxychloroquine sulfate.

Hydroxychloroquine Dose in the treatment of Systemic Lupus erythematosus:

• 200 to 400 mg orally as once or in two divided doses.
• The maximum dose should not exceed 5 mg/kg/day of the actual body weight (or 400 mg daily) because of the potential retinal toxicity.

Hydroxychloroquine Dose as chemoprophylaxis for Malaria: 

• According to the Manufacturer’s labeling:

  • 400 mg once a week on the same day every week.
  • Chemoprophylaxis should begin two weeks before the expected exposure.
  • If the chemoprophylaxis is not begun two weeks prior to the exposure, a loading dose of 800 mg in two divided doses should be administered six hours apart and then once a week for 8 weeks after leaving the endemic area.

• Alternate dosing:

  • 400 mg once a week on the same day every week;
  • Treatment should begin 1 to 2 weeks before the travel to a malaria-endemic area.
  • Treatment must be continued for four weeks after leaving the area.

Hydroxychloroquine Dose in the treatment of an acute attack of Malaria:

• 800 mg orally initially, followed by 400 mg at 6, 24, and 48 hours.

Hydroxychloroquine Dose in the treatment of Rheumatoid arthritis:

• 400 mg orally once a day initially, as a single daily dose or in two divided doses.
• It may be given with or without concomitant non-biologic disease-modifying antirheumatic drugs.
• The usual maintenance dose is 300 mg daily after 3 months of the initial 400 mg dose.
• The maximum dose should not exceed 5 mg/kg/day of the actual body weight (or 400 mg daily) because of the potential retinal toxicity.

Hydroxychloroquine dose in the treatment of Porphyria Cutanea Tarda:

• 100 mg orally twice weekly.
• The treatment must be continued until plasma porphyrin levels are normal for at least one month.
• Data regarding its use in the treatment of Porphyria Cutanea Tarda is limited.

Hydroxychloroquine Dose in the treatment of extra-glandular manifestations of patients with Primary Sjögren syndrome:

• The usual is 200 mg daily.
• The maximum dose should not exceed 5 mg/kg/day of the actual body weight (or 400 mg daily) because of the potential retinal toxicity.

Hydroxychloroquine Dose in the treatment of chronic Q fever:

• Endocarditis or vascular infection:

  • 200 mg taken with doxycycline every 8 hours for at least 18 months.

• Noncardiac organ disease:

  • 200 mg taken with doxycycline every eight hours.
  • The duration is based on the serologic response.

• Postpartum with serologic evidence present for more than 12 months after delivery:

  • For 12 months, take 200 mg every 8 hours together with doxycycline.

Hydroxychloroquine dose in the treatment of coronavirus infection:

• Azithromycin is paired with a dose of 400 mg twice daily on day one, 200 mg twice daily for four days, and a dose of 500 mg twice daily for five days.

Hydroxychloroquine Dose in Childrens

Note:

200 mg of Hydroxychloroquine sulfate is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. All the doses mentioned below are expressed as hydroxychloroquine sulfate.

Hydroxychloroquine Dose in the treatment of Malaria:

• Dose in Chemoprophylaxis:

  • 6.5 mg/kg hydroxychloroquine sulfate once a week on the same day every week.
  • The maximum dose is 400 mg/dose of hydroxychloroquine sulfate.
  • The chemoprophylaxis should begin 1 to 2 weeks prior to the expected exposure.
  • Treatment should be continued for at least four weeks after leaving the endemic area [Ref].
  • If the chemoprophylaxis is not initiated two weeks prior to the expected exposure, the manufacturer recommends initiating treatment with a double dose i.e. 13 mg/kg of hydroxychloroquine sulfate and administering it 6 hours apart in two divided doses.
  • The maximum single dose of 400 mg/dose hydroxychloroquine sulfate should not be exceeded.
  • The treatment should be continued for 8 weeks after leaving the endemic area.

• Treatment of uncomplicated acute attack of malaria:

  • 13 mg/kg/dose of hydroxychloroquine sulfate orally initially.
  • The maximum initial dose is 800 mg/dose of hydroxychloroquine sulfate.
  • This is followed by 6.5 mg/kg hydroxychloroquine sulfate at 6, 24, and 48 hours after the initial dose.
  • The maximum dose is 400 mg/dose of hydroxychloroquine sulfate.

Hydroxychloroquine dose in Juvenile Rheumatoid arthritis or SLE (Systemic lupus erythematosus):

• 3 to 5 mg/kg/day orally in 1 to 2 divided doses to a maximum of 400 mg/day.
• The dose should not exceed 7 mg/kg/day.

Pregnancy Risk Factor: B

• The placental barrier is crossed by hydroxychloroquine. However, a heightened risk of fetal eye toxicity has not yet been identified.
• It is one of the few medications that has been approved for treatment of SLE in pregnant women.
• Use of hydroxychloroquine by mothers reduces the risk of developing cardiac malformations in neonatal lupus.
• Hydroxychloroquine is recommended as an alternative drug for the treatment of chloroquine-sensitive malaria in pregnant women.

Use of hydroxychloroquine while breastfeeding

• It is eliminated from breastmilk.
• The manufacturer suggests caution when giving hydroxychloroquine lactating women
• It is acceptable as a medication, and can be used in conjunction with breastfeeding to treat autoimmune conditions such as Rheumatoid and SLE.
• It is important to note that it does not provide sufficient prophylaxis for malaria in lactating mothers.

Dose in renal disease:

Dose reduction may be needed, however, the manufacturer does not recommend any dose adjustment in patient with renal disease. It should be used with caution in patients with renal disease.

Dose in liver disease:

The manufacturer does not recommend any dose adjustment in patient with liver disease. However, it should be used with caution in patients with liver disease.

Hydroxychloroquine side effects:

• Central Nervous System:

  • Ataxia
  • Dizziness
  • Emotional Disturbance
  • Emotional Lability
  • Headache
  • Irritability
  • Lassitude
  • Nervousness
  • Nightmares
  • Psychosis
  • Seizure
  • Sensorineural Hearing Loss
  • Suicidal Tendencies
  • Vertigo

• Dermatologic:

  • Acute Generalized Exanthematous Pustulosis
  • Alopecia
  • Bleaching Of Hair
  • Bullous Rash
  • Dyschromia (Black-Blue Color of the Skin And Mucosa)
  • Erythema (Annulare Centrifugum)
  • Erythema Multiforme
  • Exacerbation Of Psoriasis (Nonlight Sensitive)
  • Exfoliative Dermatitis
  • Lichenoid Eruption
  • Maculopapular Rash
  • Morbilliform Rash
  • Pruritus
  • Skin Photosensitivity
  • Stevens-Johnson Syndrome
  • Toxic Epidermal Necrolysis
  • Urticaria

• Endocrine & Metabolic:

  • Exacerbation Of Porphyria
  • Weight Loss

• Gastrointestinal:

  • Anorexia
  • Diarrhea
  • Nausea
  • Stomach Cramps
  • Vomiting

• Hematologic & Oncologic:

  • Agranulocytosis
  • Anemia
  • Aplastic Anemia
  • Hemolysis (In Patients With Glucose-6-Phosphate Deficiency)
  • Leukopenia
  • Purpuric Rash
  • Thrombocytopenia

• Hepatic:

  • Acute Hepatic Failure (Rare)
  • Hepatic Insufficiency (Rare)

• Hypersensitivity:

  • Angioedema

• Neuromuscular & Skeletal:

  • Myopathy (Including Palsy Or Neuromyopathy resulting in Progressive Weakness And Atrophy Of the Proximal Muscles that may Be Associated With Mild Sensory Changes
  • Loss Of Deep Tendon Reflexes
  • And Abnormal Nerve Conduction

• Ophthalmic:

  • Accommodation Disturbance
  • Corneal Changes:
    • Transient Edema,
    • Punctate To Lineal Opacities,
    • Decreased Sensitivity,
    • Deposits,
    • Visual Disturbances,
    • Blurred Vision,
    • Photophobia that is reversible On Discontinuation
  • Decreased Visual Acuity
  • Macular Edema
  • Nystagmus
  • Optic Disk Disorder including Pallor and Atrophy
  • Retinal Pigment Changes
  • Retinal Vascular Disease
  • Retinitis Pigmentosa
  • Retinopathy (Early Changes may be Reversible)
  • Scotoma
  • Vision Color Changes
  • Visual Field Defect

• Otic:

  • Tinnitus

• Respiratory:

  • Bronchospasm

Contraindication to Hydroxychloroquine:

• Allergy reactions to the drug, the 4-aminoquinoline derivatives or any component of its formulation.
• Preexisting retinopathy
• Children under 6 years old or less than 35kg should not use this product

Warnings and precautions

• Cardiovascular effects

  • Cardiomyopathy can lead to cardiac failure, which can sometimes prove fatal.
  • Patients with cardiac toxicities may have atrioventricular block or pulmonary hypertension.
  • Both short-term and longer-term drug use can lead to cardiac complications.
  • Stop taking the drug immediately if you experience shortness of breath, or any other symptoms that could indicate a cardiac condition.
  • According to the American Heart Association (AHA), Plaquenil can either cause myocardial toxicities or worsen existing myocardial dysfunction.
  • Chronic toxic effects of the drug can manifest as conduction disorders like bundle branch block, atrioventricular block, and biventricular hypertrophy.
  • It has been linked to an increased risk for QT-prolongation and ventricular arrhythmias.
  • Patients taking concomitant drugs that can increase the risk for QTc prolongation should be advised to stop using them.

• Dermatologic effects

  • Patients with skin diseases should not use it. Skin reactions can occur, especially if they are taking medication that could cause dermatitis.

• Hematologic effects

  • It has been reported that it can cause bone marrow suppression, such as anemia or aplastic anemia, leukopenia and thrombocytopenia.
  • It is important to monitor blood counts regularly.
  • If HCQ is detected in the marrow, it must be stopped immediately

• Hypoglycemia:

  • Hypoglycemia can lead to seizures and life-threatening brain damage.
  • Hypoglycemia is more common among diabetics, but it can also occur in non-diabetics.
  • Patients must be educated about hypoglycemia risks and clinical features.
  • Hypoglycemic symptoms should be reported immediately and the treatment must be stopped.

• Neuromuscular effects:

  • Long-term drug use can lead to neuromuscular and muscular disease.
    • Progressive weakness due to proximal myopathy, neuromyopathy, or proximal myopathy.
    • Atrophy of the proximal muscles
    • Depressed tendon reflexes,
    • An abnormal nerve conduction could occur
  • On nerve and muscle biopsies, curvilinear body and muscle fiber atrophy were noted with vacuolar changes.
  • Patients undergoing long-term therapy need to have their muscle strength, especially the proximal ones, and their reflexes checked periodically.

• Psychiatric effects

  • Suicidal behavior is more likely to be associated with HCQ.

• Toxicity to the retina:

  • Retinal toxicity, irreversible retinopathy, has been associated with long term (more than 5 years) and high doses of chloroquine or hydroxychloroquine in the treatment of rheumatic diseases.
  • Retinal toxicity may especially occur in patients with renal impairment, those on concurrent tamoxifen, patients with lower body weight, and those with the presence of macular disease.
  • Plaquenil can cause retinal toxicity if taken in higher doses than 5 mg/kg. This is approximately 10% to 40% for 10 and 20 years, respectively.
  • The AAO (American Academy of Ophthalmology), recommends a daily intake of 5 mg/kg.
  • AAO recommends that you screen for retinal toxicities at baseline and every 5 years after it has been used (or earlier if there are risk factors).
  • Retinal toxicity is a serious condition that should be treated immediately. Patients should continue to be monitored for any complications. Even if the drug is stopped, retinal toxicity can continue to progress.

• G6PD deficiency:

  • It is controversial to use it in patients with G6PD deficiencies.
  • Because of the possible risks of hemolytic Anemia, the manufacturer suggests that you use it with caution.
  • Most experts believe it is safe to be used in the normal therapeutic doses for WHO class II and III G6PD-deficient patients.
  • The safety of G6PD severe deficiency (WHO Class I) is unknown.
  • According to the ACR Rheumatology guidelines, it is not recommended that G6PD levels be tested before starting hydroxychloroquine treatment.

• Gastrointestinal disorders:

  • It should not be used in patients suffering from gastrointestinal problems.

• Hepatic impairment

  • Patients with liver disease, alcoholics, or those taking concomitant Hepatotoxic drugs should not use it.

• Porphyria

  • Patients with porphyria need to be cautious when using it as it can worsen the condition.

• Psoriasis:

  • Patients suffering from psoriasis need to be cautious as it can worsen the condition.

• Renal impairment

  • Patients with impaired renal function should be cautious and adjust the dosage.

Hydroxychloroquine: Drug Interaction

Monitor:

• CBC at baseline and periodically;
• liver function tests
• renal function especially in patients who are at risk for ocular toxicity
• blood glucose if symptoms of hypoglycemia are observed.
• muscle strength especially of the proximal muscles, as a symptom of neuromyopathy during long-term treatment with Plaquenil.
• Screen for retinal toxicity via fundus examination within the first year of the treatment plus visual fields and spectral-domain optical coherence tomography [SD OCT] if maculopathy is present, followed by yearly screening beginning after 5 years of use or sooner if major risk factors are present.
• The manufacturer also recommends evaluating best corrected distance visual acuity and an automated threshold visual field of the central 10 degrees (24 degrees in patients of Asian ancestry as retinal toxicity may appear outside of the macula).

How to administer Hydroxychloroquine?

It should be administered with food or milk. The film-coated tablets should not be crushed or divided.

Mechanism of action of Hydroxychloroquine (HCQ, Plaquenil):

• It raises intracellular pH and impairs the lysosomal degrading of hemoglobin. 
• This causes impaired function of the digestive vacuoles in sensitive malarial parasites.
• It also hinders neutrophil movement and chemotaxis by eosinophils, and impairs complement dependent antigen-antibody reactions.
• It may take several weeks for autoimmune rheumatic disease treatment to kick in. It can be variable.

Absorption40 percent of the drug's total weight is protein-bound, primarily to albumin. It is Metabolized in the liver to bidesethyl chloroquine, desethylhydroxy chloroquine, and desethyl chloroquine. The half-life elimination The average shelf life of the drug is approximately 40 days. It is excreted in urine as an unchanged drug (15-25%) and as metabolites (60%). Urinary acidification may increase the excretion of this drug.

Brand names of Hydroxychloroquine (International):

• Plaquenil
• APO-Hydroxyquine
• MINT-Hydroxychloroquine
• MYLAN-Hydroxychloroquine
• PRO-Hydroxychloroquine-200
• Advaquenil
• Arthroquin
• Axokine
• Chloguin
• Diclor
• Dimard
• Dolquine
• Duloc
• Duroc
• Ercoquin
• Evoquin
• Fen Le
• Futarhomal
• Geniquin
• Haloxin
• HCQS
• Hydroquin
• Hydroquine
• Hyquin
• Ilinol
• Immard
• Metirel
• Oxcq
• Oxiklorin
• Planil
• Plaquenil
• Plaquenil Sulfate
• Plaquinol
• Quensyl
• Quinnel
• Quinoric
• Reconil
• Reuquinol
• Roquin
• Supretic
• Uniquin
• Winflam
• Yuma
• Zyq

Hydroxychloroquine Brand Names in Pakistan: