Hydroxychloroquine (Tablets) Instructions for Use

ATC Code

P01BA02 (Hydroxychloroquine)

Active Substance

Hydroxychloroquine

Clinical-Pharmacological Group

A 4-aminoquinoline derivative. An antimalarial and amoebicidal drug. An immunosuppressant

Pharmacotherapeutic Group

Antimalarial agent

Pharmacological Action

Hydroxychloroquine has antimalarial properties and also exerts anti-inflammatory and immunosuppressive effects in chronic discoid or systemic lupus erythematosus (SLE), and acute and chronic rheumatoid arthritis (RA). Its mechanism of action in malaria, lupus erythematosus, and rheumatoid arthritis is not fully understood.

Hydroxychloroquine has the properties of a moderate immunosuppressant, suppressing the synthesis of rheumatoid factor and acute-phase reaction components. It also accumulates in leukocytes, stabilizing lysosomal membranes, and inhibits the activity of many enzymes, including collagenase and proteases, which cause cartilage breakdown.

Efficacy in SLE and RA is associated with the following anti-inflammatory and immunomodulatory effects of hydroxychloroquine: an increase in intracellular pH leads to a slowing of the antigenic response and reduces the binding of peptides to major histocompatibility complex (MHC) receptors. A smaller number of antigen-MHC receptors reaches the cell surface, leading to a reduction in the autoimmune response; decreased activity of phospholipase A2 at high concentrations, lysosomal enzymes; decreased concentrations of cytokines IL-1 and IL-6, leading to a reduction in clinical and laboratory parameters of the autoimmune response. Since there is no impairment of interferon gamma synthesis, these effects may be related to a selective effect on cytokines; inhibition of pre- and/or post-transcription of DNA and RNA.

Hydroxychloroquine actively suppresses asexual erythrocytic forms, as well as gametocytes of P. vivax and P. malariae, which disappear from the blood almost simultaneously with the asexual forms. Hydroxychloroquine does not act on gametocytes of P. falciparum. Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum, and is also inactive against the exoerythrocytic forms of P. vivax, P. malariae, and P. ovale, and therefore cannot prevent infection with these microorganisms when prescribed for prophylactic purposes, nor can it prevent relapse of the disease caused by these pathogens.

Pharmacokinetics

After oral administration, Hydroxychloroquine is rapidly and almost completely absorbed. Plasma protein binding is 45%. The mean plasma T_1/2 varies depending on the time elapsed after hydroxychloroquine administration as follows: 5.9 h (from reaching C_max to 10 h), 26.1 h (from 10 to 48 h), and 299 h (from 48 to 504 h). In the liver, Hydroxychloroquine is partially converted into active ethylated metabolites. Unchanged Hydroxychloroquine and its metabolites are well distributed in the body. The volume of distribution is 5-10 L/kg. Hydroxychloroquine accumulates in tissues with high turnover rates (in the liver, kidneys, lungs, spleen – concentrations in these organs exceed plasma concentrations by 200-700 times; CNS, erythrocytes, leukocytes), as well as in the retina and tissues rich in melanin. Hydroxychloroquine and its metabolites are excreted mainly in the urine and to a lesser extent in the bile. The elimination of hydroxychloroquine is slow, the terminal T_1/2 is about 50 days (from whole blood) and 32 days (from plasma). Within 24 hours, 3% of the administered dose of hydroxychloroquine is excreted in the urine. Hydroxychloroquine crosses the placental barrier and is found in small amounts in breast milk.

Indications

Malaria (except for chloroquine-resistant strains of P. falciparum): prophylaxis and suppression of acute attacks of malaria caused by Plasmodium vivax, P. ovale, and P. malariae, as well as sensitive strains of P. falciparum; radical cure of malaria caused by sensitive strains of P. falciparum; rheumatoid arthritis; juvenile rheumatoid arthritis; lupus erythematosus (systemic and discoid); photodermatitis.

ICD codes

Dosage Regimen

Administer orally with food or milk to minimize gastrointestinal upset.

Calculate the dosage based on the patient’s ideal body weight, not actual body weight.

The total daily dose must not exceed 6.5 mg/kg to minimize the risk of irreversible retinopathy.

For rheumatoid arthritis, initiate therapy at 400 mg to 600 mg (as a single daily dose or in divided doses).

Once a satisfactory response is observed, reduce the dose by 50% to a maintenance level of 200 mg to 400 mg daily.

For systemic lupus erythematosus, the usual initial dose is 400 mg once or twice daily.

Continue this dose for several weeks or months, depending on the patient’s response, then reduce to a long-term maintenance dose.

For chronic discoid lupus erythematosus, administer 400 mg once or twice daily.

Continue treatment for several weeks, then reduce to a maintenance dose.

For malaria suppression in adults, administer 400 mg on exactly the same day once per week.

Begin prophylaxis 1 to 2 weeks prior to exposure and continue for 4 weeks after leaving the endemic area.

For acute malaria attack in adults, administer an initial dose of 800 mg, followed by 400 mg in 6 to 8 hours.

Then, administer 400 mg on each of the next 2 consecutive days (total dose: 2 grams).

For pediatric patients, calculate the dose meticulously based on ideal body weight.

For malaria suppression in children, administer 6.5 mg/kg (not to exceed 400 mg) once weekly.

Follow the same schedule as for adults: start 1 to 2 weeks before exposure and continue for 4 weeks after.

For acute malaria attack in children, administer an initial dose of 13 mg/kg (not to exceed 800 mg).

Follow with 6.5 mg/kg (not to exceed 400 mg) at 6, 24, and 48 hours after the initial dose.

Perform baseline and regular ophthalmological examinations at least every 6 months during long-term therapy.

Increase the frequency of eye exams for patients with renal impairment, those taking high doses, or with cumulative doses exceeding 200 g.

Monitor for signs of hypoglycemia, especially in patients with or without diabetes.

Perform periodic complete blood counts during prolonged therapy to monitor for hematological toxicity.

Discontinue therapy immediately if any visual disturbances, muscle weakness, or severe skin reactions occur.

Adverse Reactions

Blood and lymphatic system disorders frequency unknown – bone marrow suppression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Immune system disorders frequency unknown – urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders common – anorexia; frequency unknown – hypoglycemia, possibility of porphyria exacerbation.

Psychiatric disorders common – affective lability; uncommon – nervousness; frequency unknown – psychoses, suicidal behavior.

Nervous system disorders common – headache; uncommon – dizziness; frequency unknown – seizures, extrapyramidal disorders such as muscle dystonia, dyskinesia, and tremor.

Eye disorders common – blurred vision associated with accommodation disturbance, which is dose-dependent and reversible; uncommon – retinopathy with pigmentary changes and visual field defects. If hydroxychloroquine is discontinued in a timely manner, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, there is a risk of their progression even after discontinuation of hydroxychloroquine. Retinal changes may initially be asymptomatic or manifest as paracentral or pericentral scotomas, transient scotomas, and color vision disturbances. Corneal changes are possible, including edema and opacities. They may be asymptomatic or cause visual disturbances such as halos, blurred vision, or photophobia. These changes may be transient or reversible. Frequency unknown – maculopathy and macular degeneration, which may be irreversible.

Ear and labyrinth disorders uncommon – vertigo, tinnitus; frequency unknown – hearing loss.

Cardiac disorders frequency unknown – QT interval prolongation in patients with risk factors, which may lead to the development of cardiac arrhythmias (torsades de pointes, ventricular tachycardia), cardiomyopathy, which may lead to heart failure and, in some cases, death. Detection of cardiac conduction disorders (such as bundle branch block/AV conduction disorders) and biventricular hypertrophy may indicate chronic cardiac toxicity. Discontinuation of hydroxychloroquine may lead to reversal of these changes.

Gastrointestinal disorders very common – abdominal pain, nausea; common – diarrhea, vomiting. These symptoms usually resolve immediately after dose reduction or discontinuation of hydroxychloroquine.

Hepatobiliary disorders uncommon – abnormal liver function tests; frequency unknown – fulminant hepatic failure.

Skin and subcutaneous tissue disorders common – skin rash, pruritus; uncommon – pigmentation changes of the skin and mucous membranes, hair depigmentation and alopecia (these changes usually resolve quickly after treatment cessation); frequency unknown – bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitivity; exfoliative dermatitis; drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP). AGEP must be distinguished from psoriasis, although Hydroxychloroquine may exacerbate psoriasis. AGEP may be accompanied by fever and hyperleukocytosis. After discontinuation of hydroxychloroquine, the outcome is usually favorable.

Musculoskeletal and connective tissue disorders uncommon – sensorimotor disorders; frequency unknown – skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (myopathy may be reversible after discontinuation of hydroxychloroquine, but complete recovery may take several months), suppression of tendon reflexes and decreased nerve conduction.

Contraindications

Hypersensitivity to hydroxychloroquine and to 4-aminoquinoline derivatives; retinopathy (including history of maculopathy); children requiring long-term therapy (children have an increased risk of toxic effects); children under 6 years of age (200 mg tablets are not intended for children with an “ideal” body weight less than 31 kg); pregnancy.

With caution in visual disorders (decreased visual acuity, impaired color vision, visual field narrowing), with concurrent use of drugs that can cause adverse ophthalmological reactions (risk of progression of retinopathy and visual disorders). In hematological diseases (including history). In neurological diseases, psychoses (including history). In porphyria cutanea tarda (risk of exacerbation), psoriasis (risk of exacerbation of skin manifestations of the disease), with concurrent use of drugs that can cause skin reactions. In renal and/or hepatic impairment, hepatitis, with concurrent use of drugs that can adversely affect liver and/or kidney function (in severe impairment of renal or hepatic function, the dose should be adjusted under the control of plasma concentrations of hydroxychloroquine). In glucose-6-phosphate dehydrogenase deficiency. In gastrointestinal diseases. In hypersensitivity to quinine (possibility of cross-allergic reactions). In cardiac conduction disorders (bundle branch block/AV block) and in biventricular hypertrophy. In cardiomyopathy. In congenital or acquired QT interval prolongation and/or the following risk factors for QT interval prolongation in history: heart disease (e.g., heart failure, myocardial infarction); proarrhythmic conditions (e.g., bradycardia with heart rate less than 50 beats/min); ventricular arrhythmias; uncorrected hypokalemia and/or hypomagnesemia; concurrent use of drugs that prolong the QT interval (increased risk of ventricular arrhythmias). Due to the risk of hypoglycemia, Hydroxychloroquine should be prescribed with caution to patients both taking and not taking hypoglycemic drugs.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy.

If use during breastfeeding is necessary, the expected benefit of therapy for the mother and the potential risk for the breastfed infant should be carefully assessed, taking into account the indications for use and the duration of therapy.

Use in Hepatic Impairment

Use with caution in hepatic impairment, hepatitis, with concurrent use of drugs that can adversely affect liver function (in severe hepatic impairment, the dose should be adjusted under the control of plasma concentrations of hydroxychloroquine).

Use in Renal Impairment

Use with caution in renal impairment, with concurrent use of drugs that can adversely affect kidney function (in severe renal impairment, the dose should be adjusted under the control of plasma concentrations of hydroxychloroquine).

Pediatric Use

Contraindicated for use in children requiring long-term therapy (children have an increased risk of toxic effects).

Contraindicated for use in children under 6 years of age (200 mg tablets are not intended for children with an “ideal” body weight less than 31 kg).

Geriatric Use

Used in elderly patients according to indications.

Special Precautions

The toxic effect of hydroxychloroquine on the retina is largely dose-dependent. The incidence of retinopathy with doses up to 6.5 mg/kg of “ideal” body weight is low. Exceeding the recommended daily dose sharply increases the risk of developing retinopathy.

Before starting a long-term course of treatment with hydroxychloroquine, a thorough examination of both eyes should be performed. The examination should include determination of visual acuity, fundus examination, assessment of color vision and visual fields. During therapy, such an examination should be performed at least once every 6 months.

Examination should be performed more frequently in the following situations: with a daily dose exceeding 6.5 mg/kg of “ideal” body weight (in overweight patients, using absolute body weight for dose calculation may lead to overdose); in renal impairment; with a cumulative dose over 200 g; in elderly individuals; if the patient had any degree of decreased visual acuity before starting treatment.

If any visual disturbances occur (decreased visual acuity, changes in color vision), Hydroxychloroquine should be discontinued immediately and the patient’s visual status should be carefully monitored, as retinal changes (and visual disturbances) may progress even after discontinuation of hydroxychloroquine.

Cases of cardiomyopathy leading to heart failure have been observed in patients taking hydroxychloroquine. Hydroxychloroquine has been shown to cause severe hypoglycemia (including loss of consciousness), which can be life-threatening in patients both taking and not taking hypoglycemic drugs. Patients taking Hydroxychloroquine should be warned about the risk of hypoglycemia and its associated clinical signs and symptoms. In patients who develop clinical symptoms suggestive of hypoglycemia during treatment with hydroxychloroquine, blood glucose concentration should be determined and, if necessary, therapy should be reconsidered.

Caution is recommended when using hydroxychloroquine in patients with liver and kidney diseases, in whom dose reduction may be required, as well as in patients taking medications that can cause adverse effects on these organs.

In patients taking Hydroxychloroquine long-term, a complete blood count should be performed periodically (if hematological disorders occur, Hydroxychloroquine should be discontinued).

Children are particularly sensitive to the toxic effects of 4-aminoquinolines, so care should be taken to ensure that Hydroxychloroquine is stored in places inaccessible to children.

All patients taking Hydroxychloroquine long-term should be periodically examined by a neurologist regarding skeletal muscle function and tendon reflex severity. If muscle weakness occurs, Hydroxychloroquine should be discontinued.

In very rare cases, suicidal behavior has been reported in patients taking Hydroxychloroquine. Extrapyramidal disorders may develop with the use of hydroxychloroquine.

Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum, and is also inactive against the exoerythrocytic forms of P. vivax, P. malariae, and P. ovale, and therefore it cannot prevent infection with these microorganisms when used for prophylactic purposes, nor can it prevent relapse of the disease caused by these pathogens.

Effect on ability to drive vehicles and operate machinery

During treatment with hydroxychloroquine, caution should be exercised when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Caution should be exercised when prescribing hydroxychloroquine to patients receiving drugs that prolong the QT interval (e.g., class IA and III antiarrhythmic agents, tricyclic antidepressants, antipsychotic drugs, some antimicrobial agents [e.g., moxifloxacin]), due to an increased risk of ventricular arrhythmias.

There are reports that Hydroxychloroquine can increase plasma concentrations of digoxin, therefore, to avoid the development of digitalis intoxication with their concurrent use, the dose of digoxin should be reduced – under the control of its plasma concentration.

Hydroxychloroquine may enhance the effects of insulin and oral hypoglycemic agents; a reduction in the doses of these drugs may be required at the start of hydroxychloroquine administration.

Antacids may reduce the absorption of hydroxychloroquine. Therefore, with the concurrent use of antacids and hydroxychloroquine, the interval between their administration should be at least 4 hours.

The following interactions with other drugs described for chloroquine, but not yet observed with hydroxychloroquine use, cannot be excluded for hydroxychloroquine.

With aminoglycosides – potentiation of the direct blocking effect of aminoglycosides on neuromuscular transmission.

With cimetidine – cimetidine inhibits the metabolism of antimalarial drugs, which may lead to an increase in their plasma concentrations and increase the risk of their adverse effects, especially toxic ones.

With neostigmine and pyridostigmine – antagonism of action.

With any intradermal human diploid cell rabies vaccine – reduction in antibody formation in response to primary immunization with this vaccine.

With arrhythmogenic drugs – increased risk of developing ventricular arrhythmia when using chloroquine simultaneously with other arrhythmogenic drugs (such as amiodarone and moxifloxacin).

Halofantrine prolongs the QT interval and, in combination with chloroquine, can cause arrhythmias (this combination is not recommended).

With other antimalarial drugs that lower the convulsive threshold – the use of chloroquine can lead to a decrease in the convulsive threshold. The combined use of chloroquine with other known antimalarial drugs that lower the convulsive threshold (for example, mefloquine) may increase the risk of seizures.

With cyclosporine – there are reports of an increase in the plasma concentration of cyclosporine when cyclosporine and chloroquine are used together.

With antiepileptic drugs – when used concomitantly with chloroquine, the effectiveness of antiepileptic drugs may be insufficient.

With praziquantel – in a drug interaction study of chloroquine and praziquantel, a decrease in the bioavailability of praziquantel was reported. Due to the similarity in structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect can be expected when hydroxychloroquine and praziquantel are used together.

With agalsidase – there is a theoretical risk of inhibition of intracellular alpha-galactosidase when hydroxychloroquine is used concomitantly with agalsidase.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.