1 tablet contains:
active substance: hydroxychloroquine sulfate 200 mg;
excipients: calcium hydrophosphate dihydrate-99.86 mg, prosolv [microcrystalline cellulose-98%, silicon dioxide colloidal-2%] – 126.79 mg, GI-promellose (hydroxypropylmethylcellulose) – 24.25 mg, croscarmellose sodium-19.40 mg, silicon dioxide colloidal (Aerosil) – 4.85 mg, magnesium stearate – 4.85 mg;
shell composition: hypromellose (hydroxypropylmethylcellulose)-2,972 mg, titanium di – oxide (E171) – 1,363 mg, macrogol (polyethylene glycol) (E1521) – 0,665 mg.
The toxic effect on the retina is largely dose-dependent. The incidence of retinopathy with doses up to 6.5 mg / kg of “ideal” body weight is small. Exceeding the recommended daily dose dramatically increases the risk of developing retinopathy.
Before starting a long course of treatment with the drug, a thorough examination of both eyes should be performed. The examination should include determination of visual acuity, examination of the fundus, assessment of color vision and visual fields. During therapy, such an examination should be performed at least once every 6 months.
The survey should be more frequent in the following situations:
– with a daily dose exceeding 6.5 mg / kg of “ideal” body weight (in patients with a higher body weight, using absolute body weight to calculate the dose may lead to overdose);
– for kidney failure;
– at a total dose of more than 200 g;
– in the elderly;
– if the patient has a decrease in visual acuity of any severity before the start of treatment.
If any visual disorders occur (decreased visual acuity, color vision changes), the drug should be immediately discontinued and the patient’s visual condition should be carefully monitored, since retinal changes (and visual disorders) may progress even after the drug is discontinued (see the section “Side effects”).
In patients receiving the drug Hydroxychloroquine, cases of cardio-myopathy leading to heart failure have been noted (see the section “Side effects).
It has been shown that hydroxychloroquine can cause severe hypoglycemia (including loss of consciousness), which can endanger the lives of patients, both taking and not taking hypoglycemic drugs. Patients taking hydroxychloroquine should be warned about the risk of hypoglycemia and associated clinical signs and symptoms. In patients who have clinical symptoms indicating the development of hypoglycemia during treatment with hydroxychloroquine, it is necessary to determine the concentration of glucose in the blood and, if necessary, review the therapy.
Caution is recommended when using hydroxychloroquine in patients with liver and kidney diseases, who may need to reduce the doses of the drug, as well as in patients taking medications that can cause adverse effects on these organs.
In patients who take hydroxychloroquine for a long time, a complete blood test should be performed periodically (in case of hematological disorders, 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 the drug for a long time should be periodically examined by a neurologist regarding the function of skeletal muscles and the severity of tendon reflexes. If you experience weakness in the muscles of the drug should be discontinued.
In very rare cases, suicidal behavior has been reported in patients taking hydroxychloroquine. When using the drug Hydroxychloroquine, extrapyramidal disorders may develop (see the section “Side effects”).
Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum, nor is it active against non-erythrocyte forms of P. vivax, P. malariae, and P. ovale, and therefore cannot prevent infection with these microorganisms when used for prophylactic purposes, nor can it prevent relapse of disease caused by these pathogens.
Influence on the ability to drive vehicles, mechanisms.
During treatment with the drug, care should be taken when performing potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
It has been reported that hydroxychloroquine is able to increase the plasma concentrations of digoxin, so in order to avoid the development of glycosidic intoxication with the simultaneous administration of these drugs, it is necessary to reduce the dose of digoxin under the control of its plasma concentrations.
With medications used to treat diabetes
Hydroxychloroquine may increase the effects of insulin and oral hypoglycemic agents, and it may be necessary to reduce the doses of these drugs when starting to take hydroxychloroquine.
Antacids can reduce the absorption of hydroxychloroquine. Therefore, when antacids and hydroxychloroquine are used simultaneously, the interval between their intake should be at least 4 hours.
In hydroxychloroquine, it is also impossible to exclude the following interactions with other drugs that have been described for chloroquine, but have not yet been observed when taking hydroxychloroquine.
Potentiation of the direct blocking effect of aminoglycosides on neuromuscular transmission.
Cimetidine suppresses the metabolism of antimalarial drugs, which can lead to an increase in their plasma concentrations and increase the risk of their side effects, especially toxic ones.
With neostigmine and pyridostigmine-action antagonism.
With any intradermal human diploid cell rabies vaccine
Reducing the formation of antibodies in response to primary immunization with an intradermal human diploid-cell rabies vaccine.
With halofantrin and other arrhythmogenic drugs
Halofantrin extends the QT interval and in combination with hydroxychloroquine can cause arrhythmias (this combination is not recommended). In addition, there is an increased risk of ventricular arrhythmia when using hydroxychloroquine simultaneously with other arrhythmogenic drugs (such as amiodarone and moxifloxacin).
With other antimalarial drugs that lower the threshold of convulsive activity
The use of hydroxychloroquine can lead to a decrease in the convulsive threshold. Sov-local use of hydroxychloroquine with other known antimalarial drugs that lower the threshold of convulsive activity (for example, mefloquine) may increase the risk of convulsions.
An increase in the concentration of cyclosporine in blood plasma has been reported with the combined use of cyclosporine and hydroxychloroquine.
With antiepileptic drugs
When combined with antiepileptic drugs, the effectiveness of the latter may be insufficient.
A study of the interaction of chloroquine and praziquantel reported a decrease in the bioavailability of praziquantel. Due to the similarity of structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect can be expected when using hydroxychloroquine and praziquantel together.
There is a theoretical risk of inhibition of intracellular α-galactosidase when combined with hydroxychloroquine agalsidase.
Hydroxychloroquine has antimalarial properties, and also has a Pro-inflammatory and immunosuppressive effect in chronic discoid or systemic lupus erythematosus( SLE), acute and chronic rheumatoid arthritis (RA). the Mechanism of its action in malaria, lupus erythematosus and rheumatoid arthritis is not fully known.
Hydroxychloroquine has the properties of a moderate immunosuppressor, suppressing the synthesis of rheumatoid factor and components of the acute phase reaction. It also accumulates in white blood cells, stabilizing lysosomal membranes, and inhibits the activity of many enzymes, including collagenases and proteases, which cause cartilage to break down.
Effectiveness in SLE and RA is associated with the following anti inflammatory and immunomodulatory effects of hydroxychloroquine:
– an increase in the intracellular pH leads to a slowdown in the antigenic response and reduces the binding of peptides of the main histocompatibility complex (gkg) receptors. Fewer antigen-gkg receptors reach the cell surface, which leads to a decrease in the autoimmune response;
– reduced activity of phospholipase A2 at high concentrations of lysosomal enzymes;
– reduced concentrations of cytokines IL-1 and IL-6, leading to a decrease in clinical and laboratory indicators of autoimmune response. Since there is no violation of interferon gamma synthesis, these effects may be associated with selective effects on cytokines;
– inhibition of pre – and / or post-transcription of DNA and RNA.
The drug actively suppresses asexual erythrocyte forms, as well as gametes of P. vivax and P. malariae, which disappear from the blood almost simultaneously with asexual forms. Hydro-roxychloroquine does not act on the gametes of P. falciparum. Hydroxychloroquine is ineffective against chloroquine-resistant strains of P. falciparum, as well as inactive against non-erythrocyte forms of P. vivax, P. malariae and P. ovale, and therefore cannot prevent infection with these microorganisms when it is prescribed for prophylactic purposes, and cannot prevent the recurrence of the disease caused by these pathogens.
After oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In healthy volunteers, after a single dose of 400 mg, the maximum plasma concentration of hydroxychloroquine was reached after 1.83 hours and ranged from 53 to 208 ng / ml. Plasma protein binding is 45%. The average value of the plasma half-life varies depending on the time elapsed after taking the drug as follows: 5.9 hours (from reaching the maximum plasma concentration (Cmax) to 10 hours) 26.1 hours (from 10 to 48 hours) and 299 hours (from 48 to 504 hours). In the liver, it is partially converted to active ethylated metabolites. The unchanged drug and its metabolites are well distributed in the body. The volume of distribution is 5-10 l/kg. The drug accumulates in tissues with a high level of metabolism (in the liver, kidneys, lungs, spleen – in these organs, the concentration exceeds the plasma by 200-700 times; CNS, red blood cells, white blood cells), as well as in the retina and tissues rich in melanin. Guided oxyglobin and its metabolites are excreted mainly with urine and to a lesser extent in the bile. The drug is released slowly, with a terminal half-life of about 50 days (from whole blood) and 32 days (from plasma). For 24 hours, 3% of the administered dose of the drug is excreted in the urine.
Hydroxychloroquine penetrates the placental barrier and is found in small amounts in breast milk.
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. mA-lariae, as well as sensitive strains of P. falciparum; radical treatment of malaria caused by sensitive strains of P. Falciparum; rheumatoid arthritis; juvenile rheumatoid arthritis; lupus erythematosus (systemic and discoid); photodermatitis.
– Hypersensitivity to hydroxychloroquine and to derivatives of 4-aminoquinoline or to other components of the drug.
– 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 an “ideal” body weight of less than 31 kg).
– Pregnancy (see “Pregnancy and lactation”).
– In case of visual disorders (reduced visual acuity, impaired color vision, narrowing of the visual field), while taking medications that can cause adverse ophthalmological reactions (risk of progression of retinopathy and visual disorders).
– For hematological diseases (including a history).
– For neurological diseases, psychoses (including a history).
– With late skin porphyria (risk of exacerbation), psoriasis (risk of increased skin manifestations of the disease), while taking drugs that can cause skin reactions.
– In case of renal failure and/or liver failure, hepatitis, one-time administration of drugs that can adversely affect the function of the liver and / or kidneys (in severe violations of kidney or liver function, the dose should be selected under the control of plasma concentrations of hydroxychloroquine).
– With a deficiency of glucose-6-phosphate dehydrogenase.
– For gastrointestinal diseases.
– Hypersensitivity to quinine (possibility of cross-allergic reactions).
– In case of cardiac conduction disorders (GI-sa bundle legs block/atrioventricular block) and in case of hypertrophy of both ventricles.
– For cardiomyopathy.
– Due to the risk of hypoglycemia, the drug should be prescribed with caution to patients both taking and not taking hypoglycemic drugs (see the sections “Side effects”, “Interaction with other drugs”, “Special instructions”).
Use during pregnancy and breastfeeding
Hydroxychloroquine penetrates the placenta. There is limited data on its use during pregnancy. It should be noted that 4-aminoquinolines in therapeutic doses can cause intrauterine damage to the Central nervous system, including the auditory nerve (hearing and vestibular disorders, congenital deafness), retinal hemorrhages and abnormal set-chat pigmentation.
You should carefully weigh the need to use the drug during breast-feeding, as it is shown that it is released in small amounts into the mother’s milk, and young children are especially sensitive to toxic effects 4-aminoquinolines.
Overdose of 4-aminoquinolines is especially dangerous in children, even 1-2 g of the drug can lead to death.
Symptoms of overdose include headache, visual disturbances, collapse, convulsions, hypokalemia, rhythm and conduction disorders, followed by cardiac and respiratory arrest.
Since overdose symptoms can develop very quickly after taking a large dose of the drug, in these cases, you should immediately begin taking appropriate measures. Artificial vomiting or gastric lavage through a probe should be performed immediately. Slow down the absorption of activated carbon at a dose of at least 5 times higher than the accepted dose of the drug. Parenteral administration of diazepam is advisable, which will reduce the cardiotoxicity of chloroquine. If necessary, artificial ventilation and anti-shock therapy should be performed.
After relief of overdose symptoms, continuous medical monitoring is required for at least 6 hours.
The frequency of adverse reactions is presented in accordance with the world health organization (who) classification: very common (> 1/10), common (≥ 1/100 and < 1/10), infrequent (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency unknown (it is not possible to determine the frequency of an adverse reaction).
Disorders of the blood and lymphatic system: frequency unknown – inhibition of bone marrow hematopoiesis, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Immune system disorders: frequency unknown-urticaria, angioedema, bronchospasm.
Metabolic and nutritional disorders: often-anorexia; frequency unknown-hypoglycemia, possible exacerbation of porphyria.
Mental disorders: often-affective lability; infrequently-nervousness; frequency unknown-psychosis, suicidal behavior.
Disorders of the nervous system: often-headache; infrequently-dizziness; frequency unknown-convulsions, extrapyramidal disorders such as muscle dystonia, dyskinesia and tremor.
Disorders of the visual organ: often – blurred vision associated with accommodation disorders, which are dose-dependent and reversible; infrequently-retinopathy with changes in pigmentation and defects in the visual fields. In the case of timely withdrawal of the drug, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, there may be a risk of their progression even after discontinuation of the drug. Retinal changes may initially be asymptomatic or manifest as paracentral or pericentral scotomas, transient scotomas, and color vision disorders. Corneal changes may occur, including edema and clouding. They may be asymptomatic or cause visual disturbances such as halos, blurred vision, or photophobia. These changes may be transient or reversible. The frequency is unknown-maculopathy and macular degeneration, which may be irreversible.
Violations of the organ of hearing and labyrinth disorders: infrequent – vertigo, tinnitus; frequency is unknown – loss of hearing.
Cardiovascular disorders: frequency unknown-cardiomyopathy, which can lead to heart failure and, in some cases, death. Detection of cardiac conduction disorders (such as blockages of the GIS bundle legs/atrioventricular conduction disorders) and hypertrophy of both ventricles may indicate chronic cardiac toxicity. If the drug is canceled, the reverse development of these changes is possible.
Violations by the gastrointestinal tract: very often – pain in the abdomen, nausea; often – diarrhea, vomiting. These symptoms usually disappear immediately after reducing the dose or discontinuing the drug.
Disorders of the liver and biliary tract: infrequently-deviations from the norm of functional “liver” tests; frequency unknown-fulminant liver failure.
Disorders from the skin of subcutaneous tissues: often – skin rash, itching; infrequently: changes in pigmentation of the skin and mucous membranes, hair discoloration and alopecia (these changes usually pass quickly after discontinuation of treatment); frequency unknown – bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitization; exfoliative dermatitis; drug skin reaction accompanied by eosinophilia and systemic manifestations (dress syndrome); acute generalized exanthematous pustules (ogep). OGEP must be distinguished from psoriasis, although hydroxychloroquine can provoke an exacerbation of psoriasis. OGEP may be accompanied by an increase in temperature and hyperleukocytosis. After discontinuation of the drug, the outcome is usually favorable.
Disorders of the musculoskeletal and connective tissue: infrequently-sensory-motor disorders; frequency unknown-skeletal muscle myopathy or neuromyopathy, leading to progressive weakness and atrophy of the proximal muscle groups (myopathy may be reversible after discontinuation of the drug, but it may take several months for complete recovery), suppression of tendon reflexes and decreased nerve conduction.