Hydroxychloroquine has antimalarial properties, and also has anti-inflammatory and immunosuppressive effects in chronic discoid or systemic lupus erythematosus (SLE), 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 immunosuppressive agent, suppressing the synthesis of rheumatoid factor and components of the acute phase reaction. It also accumulates in leukocytes, stabilizing lysosomal membranes, and inhibits the activity of many enzymes, incl. collagenases and proteases, which cause cartilage breakdown.
The effectiveness in SLE and RA is associated with the following anti-inflammatory and immunomodulatory effects of hydroxychloroquine: an increase in intracellular pH leads to a slowdown in the antigenic response and decreases the binding of peptides to receptors of the major histocompatibility complex (MHC). Fewer antigen-MHC receptors reach the cell surface, which leads to a decrease in the autoimmune response; decreased activity of phospholipase A2 at high concentrations, lysosomal enzymes; decrease in the concentration of cytokines IL-1 and IL-6, leading to a decrease in clinical and laboratory parameters of the autoimmune response. Since there is no violation of the synthesis of interferon gamma, these effects may be associated with a selective effect on cytokines; inhibition of pre- and / or post-transcription of DNA and RNA.
Hydroxychloroquine actively suppresses asexual erythrocyte forms, as well as the gametes of P. vivax and P. malariae, which disappear from the blood almost simultaneously with asexual forms. Hydroxychloroquine has no effect on P. falciparum gametes. Hydroxychloroquine is ineffective against chloroquine-resistant strains of P. falciparum, and is also inactive against extra-erythrocytic forms of P. vivax, P. malariae and P. ovale, and therefore cannot prevent infection with these microorganisms when administered for prophylactic purposes, and also cannot prevent recurrence of the disease caused by these pathogens.
After oral administration, hydroxychloroquine is rapidly and almost completely absorbed. Connection with plasma proteins – 45%. The mean T 1/2 from plasma varies with the time elapsed after taking hydroxychloroquine as follows: 5.9 h (from reaching C max up to 10 hours), 26.1 hours (from 10 to 48 hours) and 299 hours (from 48 to 504 hours). In the liver, hydroxychloroquine is partially converted to 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 a high level of metabolism (in the liver, kidneys, lungs, spleen – in these organs, the concentration exceeds plasma by 200-700 times; central nervous system, 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. Release of hydroxychloroquine is slow, 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.
1 film-coated tablet contains:
hydroxychloroquine sulfate – 200 mg;
croscarmellose sodium – 3.0 mg,
magnesium stearate – 4.0 mg,
colloidal silicon dioxide – 0.5 mg,
microcrystalline cellulose (PH 102) – 92.5 mg;
film shell: hyprolose (hydroxypropyl cellulose), LF – 2.4 mg, hypromelose 2910 (hydroxypropyl methylcellulose) – 0.6 mg, macrogol (polyethylene glycol) 8000 – 1.8 mg, titanium dioxide (E 171) – 2.4 mg.
- malaria (with the exception of chloroquine-resistant strains of P. falciparum): prevention and relief of acute attacks of malaria caused by Plasmodium vivax, P. ovale and P. malariae, as well as sensitive strains of P. falciparum;
- radical treatment of malaria caused by susceptible strains of P. falciparum;
- rheumatoid arthritis;
- juvenile rheumatoid arthritis;
- lupus erythematosus (systemic and discoid);
Application during pregnancy and lactation
Contraindicated for use during pregnancy.
If it is necessary to use it during breastfeeding, the ratio of the expected benefits of therapy to the mother and the potential risk to the infant should be carefully evaluated, taking into account the indications for use and the duration of therapy.
Hypersensitivity to hydroxychloroquine and to 4-aminoquinoline derivatives; retinopathy (including a history of maculopathy); children’s age, if long-term therapy is necessary (children have an increased risk of developing toxic effects); children under 6 years of age (200 mg tablets are not intended for children with “ideal” body weight less than 31 kg); pregnancy.
With caution: with visual disorders (decreased visual acuity, impaired color vision, narrowing of the visual fields), while taking drugs that can cause adverse ophthalmic reactions (risk of progression of retinopathy and visual disorders). With hematological diseases (including history).
With neurological diseases, psychosis (including a history).
With late cutaneous porphyria (risk of exacerbation), psoriasis (risk of increased skin manifestations of the disease), while taking drugs that can cause skin reactions.
With renal and / or hepatic failure, hepatitis, while taking drugs that can adversely affect the function of the liver and / or kidneys (in severe renal or hepatic impairment, the dose should be selected under the control of plasma concentrations of hydroxychloroquine). With a deficiency of glucose-6-phosphate dehydrogenase.
With gastrointestinal diseases. With hypersensitivity to quinine (the possibility of cross-allergic reactions).
In case of violation of the conduction of the heart (blockade of the bundle of His / AV-blockade) and with hypertrophy of both ventricles. With cardiomyopathy.
With congenital or acquired prolongation of the QT interval and / or the following risk factors for prolongation of the QT interval in history: heart disease (eg, heart failure, myocardial infarction); proarrhythmic conditions (for example, bradycardia with a heart rate of less than 50 beats / min); ventricular rhythm disturbances; uncorrected hypokalemia and / or hypomagnesemia; the simultaneous use of drugs that lengthen the QT interval (increased risk of ventricular arrhythmias.
Because of the risk of hypoglycemia, hydroxychloroquine should be used with caution in patients who are taking and not taking hypoglycemic drugs.
From the side of the hematopoietic system: the frequency is unknown – inhibition of bone marrow hematopoiesis, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
From the immune system: the frequency is unknown – urticaria, angioedema, bronchospasm.
From the side of metabolism: often – anorexia; the frequency is unknown – hypoglycemia, the possibility of exacerbation of porphyria.
From the side of the psyche: often – affective lability; infrequently – nervousness; frequency unknown – psychosis, suicidal behavior.
From the nervous system: often – headache; infrequently – dizziness; frequency unknown – seizures, extrapyramidal disorders such as muscular dystonia, dyskinesia and tremors.
From the side of the organ of vision: often – blurred vision associated with a violation of accommodation, which is dose-dependent and reversible; infrequently – retinopathy with changes in pigmentation and visual field defects. In the case of timely withdrawal of hydrochloroquine, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, then there is a risk of their progression even after discontinuation of hydrochloroquine. Retinal changes may initially be asymptomatic or manifest as paracentral or pericentral scotomas, transient scotomas, and color vision disorders. Changes in the cornea including edema and opacity are possible. They may be asymptomatic or cause visual disturbances such as halos, blurred vision, or photophobia. These changes may be transient or reversible.
On the part of the organ of hearing and labyrinth disorders: infrequently – vertigo, tinnitus; frequency unknown – hearing loss.
From the side of the cardiovascular system: frequency unknown – prolongation of the QT interval in patients with risk factors, which can lead to the development of cardiac arrhythmias (ventricular arrhythmia of the “pirouette” type, ventricular tachycardia), cardiomyopathy, which can lead to heart failure and, in in some cases, death. Detection of cardiac conduction abnormalities (such as bundle-branch blocks / AV conduction abnormalities) and hypertrophy of both ventricles may indicate chronic cardiac toxicity. With the abolition of hydrochloroquine, the reverse development of these changes is possible.
From the digestive system: very often – abdominal pain, nausea; often diarrhea, vomiting. These symptoms usually resolve immediately after dose reduction or withdrawal of hydrochloroquine.
From the liver and biliary tract: infrequently – deviations from the norm of functional liver tests; frequency unknown – fulminant hepatic failure.
From the side of the skin of the subcutaneous tissues: often – skin rash, itching; infrequently – changes in the pigmentation of the skin and mucous membranes, hair discoloration and alopecia (these changes usually quickly disappear after stopping treatment); frequency unknown – bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitivity; exfoliative dermatitis; drug skin reaction, accompanied by eosinophilia and systemic manifestations (DRESS syndrome); acute generalized exanthematous pustulosis (OGEP). OGEP must be distinguished from psoriasis, although hydroxychloroquine can exacerbate psoriasis. OGEB can be accompanied by fever and hyperleukocytosis. After discontinuation of hydrochloroquine, the outcome is usually favorable.
On the part of the musculoskeletal system: infrequently – sensory-motor disorders; the frequency is unknown – skeletal muscle myopathy or neuromyopathy, leading to progressive weakness and atrophy of the proximal muscle groups (myopathy can be reversible after discontinuation of hydrochloroquine, but it may take several months for complete recovery), suppression of tendon reflexes and decreased nerve conduction.
Caution should be exercised when prescribing hydroxychloroquine to patients receiving drugs that prolong the QT interval (eg, class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some antimicrobial agents [eg, moxifloxacin]) due to an increased risk of ventricular arrhythmias …
There are reports that hydroxychloroquine is able to increase plasma concentrations of digoxin, therefore, in order to avoid the development of glycosidic intoxication with their simultaneous use, it is necessary to reduce the dose of digoxin – under the control of its concentration in plasma.
Hydroxychloroquine may potentiate the effects of insulin and oral hypoglycemic agents, and it may be necessary to reduce doses of these drugs at the start of hydroxychloroquine.
Antacids can reduce the absorption of hydroxychloroquine. Therefore, with the simultaneous use of antacids and hydroxychloroquine, the interval between their intake should be at least 4 hours.
For hydroxychloroquine, the following interactions with other drugs that have been described for chloroquine, but have not yet been observed with hydroxychloroquine, cannot be excluded.
With aminoglycosides – potentiation of the direct blocking action of aminoglycosides on neuromuscular transmission.
With cimetidine – cimetidine inhibits the metabolism of anti-malarial drugs, which can lead to an increase in their plasma concentrations and increase the risk of developing their side effects, especially toxic ones.
With neostigmine and pyridostigmine – action antagonism.
With any intradermal human diploid cell rabies vaccine, a reduction in antibody production in response to primary immunization with that vaccine.
With arrhythmogenic drugs – an increased risk of developing ventricular arrhythmias when chloroquine is used concurrently with other arrhythmogenic drugs (such as amiodarone and moxifloxacin).
Halofantrine prolongs the QT interval and, in combination with chloroquine, may cause arrhythmias (this combination is not recommended).
With other antimalarial drugs that lower the seizure threshold – the use of chloroquine may lower the seizure threshold. Concomitant use of chloroquine with other known antimalarial drugs that lower the seizure threshold (eg, mefloquine) may increase the risk of seizures.
With cyclosporine – there are reports of an increase in the concentration of cyclosporine in the blood plasma with the combined use of cyclosporine and chloroquine.
With antiepileptic drugs – with the combined use of chloroquine, the effectiveness of antiepileptic drugs may be insufficient.
With Praziquantel – A decrease in the bioavailability of praziquantel has been reported in a study on the interaction of chloroquine and praziquantel. Due to the similarity of structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect can be expected with the combined use of hydroxychloroquine and praziquantel.
With agalsidase – there is a theoretical risk of inhibition of intracellular a-galactosidase with the combined use of hydroxychloroquine with agalsidase.
How to take, course of administration and dosage
Only the minimum effective dose should be used.
The dose should not exceed 6.5 mg / kg / day (calculated on the basis of “ideal” body weight, not real body weight) and can be 200 mg or 400 mg per day.
The scheme of application, the duration of therapy is determined individually, depending on the indications, the clinical situation and the patient’s age.
The toxic effect of hydroxychloroquine on the retina is highly dose-dependent. The incidence of retinopathy at doses up to 6.5 mg / kg of “ideal” body weight is low. Exceeding the recommended daily dose dramatically increases the risk of developing retinopathy.
Before starting a long course of treatment with hydroxychloroquine, a thorough examination of both eyes should be performed. The examination should include the determination of visual acuity, examination of the fundus, assessment of color vision and visual fields. During therapy, such an examination should be carried out at least once every 6 months.
The examination should be carried out more frequently in the following situations: at a daily dose exceeding 6.5 mg / kg of “ideal” body weight (in patients with increased body weight, the use of absolute body weight to calculate the dose may lead to overdose); with renal failure; with a total dose of over 200 g; in the elderly; if the patient has a decrease in visual acuity of any severity before starting treatment.
In the event of any visual disturbances (decreased visual acuity, changes in color vision), hydroxychloroquine should be discontinued immediately and the patient’s visual condition should be closely monitored, since changes in the retina (and visual disturbances) can progress even after discontinuation of hydroxychloroquine.
Cases of cardiomyopathy leading to heart failure have been reported in patients taking hydroxychloroquine. It has been shown that hydroxychloroquine can cause the development of 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 the associated clinical signs and symptoms. In patients who, during treatment with hydroxychloroquine, have clinical symptoms indicating the development of hypoglycemia, the concentration of glucose in the blood should be determined and, if necessary, therapy should be reviewed.
It is recommended to be careful when using hydroxychloroquine in patients with liver and kidney disease, who may need to reduce its doses, as well as in patients taking drugs that can cause adverse effects on these organs.
In patients taking hydroxychloroquine for a long time, a complete blood count should be performed periodically (if hematological disorders occur, hydroxychloroquine should be canceled).
Children are particularly sensitive to the toxic effects of 4-aminoquinolines, so care should be taken to ensure that hydroxychloroquine is kept out of the reach of children.
All patients taking hydroxychloroquine for a long time should be periodically examined by a neurologist regarding skeletal muscle function and the severity of tendon reflexes. If muscle weakness occurs, hydroxychloroquine should be discontinued.
In very rare cases, suicidal behavior has been reported in patients taking hydroxychloroquine. With the use of hydroxychloroquine, the development of extrapyramidal disorders is possible.
Hydroxychloroquine is not effective against chloroquine-resistant P. falciparum strains, and is also inactive against extra-erythrocytic forms of P. vivax, P. malariae and P. ovale, and therefore it cannot prevent infection with these microorganisms when used for prophylactic purposes, and also cannot prevent recurrence of the disease caused by these pathogens.
Influence on the ability to drive vehicles and mechanisms
During the period of treatment with hydroxychloroquine, caution should be exercised when performing potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.