Hydroxychloroquine, rheumatoid arthritis, photodermatitis 30 tablets

Composition Hydroxychloroquine:

1 tablet contains:

active substance: hydroxychloroquine sulfate - 200 mg;
excipients: calcium hydrogen phosphate dihydrate - 99.86 mg, salvage [microcrystalline cellulose - 98%, colloidal silicon dioxide - 2%] - 126.79 mg, hypromellose (hydroxypropyl methylcellulose) - 24.25 mg, croscarmellose sodium - 19.40 mg , colloidal silicon dioxide (aerosil) - 4.85 mg, magnesium stearate - 4.85 mg;
shell composition: hypromellose (hydroxypropyl methylcellulose) - 2.972 mg, titanium dioxide (E171) - 1.363 mg, macrogol (polyethylene glycol) (E1521) - 0.665 mg.

Special conditions Hydroxychloroquine:

General
The toxic effect on the retina is highly 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 dramatically increases the risk of developing retinopathy.
Before starting a long course of drug treatment, a thorough examination of both eyes should be carried out. 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 more frequent 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 an 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 the start of treatment.
If any visual disturbances occur (decreased visual acuity, change in color vision), the drug should be canceled immediately and the patient's visual condition should be carefully monitored, since changes in the retina (and visual disturbances) may progress even after the drug is discontinued (see the section "Side Effects" ).
In patients taking the drug Hydroxychloroquine, cases of cardiomyopathy, leading to heart failure, have been noted (see the section "Side effects"). 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 have clinical symptoms indicating the development of hypoglycemia during treatment with hydroxychloroquine, the blood glucose concentration should be determined and, if necessary, the 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 doses of the drug, as well as in patients taking medications 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 keep hydroxychloroquine out of the reach of children.
All patients taking the drug for a long time should be periodically examined by a neuropathologist regarding the functions of skeletal muscles and the severity of tendon reflexes. If muscle weakness occurs, the drug should be canceled.
In very rare cases, suicidal behavior has been reported in patients taking hydroxychloroquine. When using the drug Hydroxychloroquine may develop extrapyramidal disorders (see section "Side effects").
For malaria
Hydroxychloroquine is not effective 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 used for prophylactic purposes, as well as cannot prevent recurrence of the disease caused by these pathogens.
Influence on the ability to drive vehicles, mechanisms
During the period of drug treatment, care should be taken when performing potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Drug interaction Hydroxychloroquine:

With digoxin
It has been reported that hydroxychloroquine is capable of increasing plasma concentrations of digoxin, therefore, in order to avoid the development of glycosidic intoxication while taking these drugs, it is necessary to reduce the dose of digoxin under the control of its plasma concentrations.
With drugs Hydroxychloroquine used to treat diabetes
Hydroxychloroquine may potentiate the effects of insulin and oral hypoglycemic agents and may require dose reductions when starting hydroxychloroquine.
With antacids
Antacids may decrease 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 cimetidip
Cimetidine inhibits the metabolism of antimalarial 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
Reducing antibody production in response to primary immunization with intradermal human diploid cell rabies vaccine.
With halofantrine and other arrhythmogenic drugs
Halofantrine prolongs the QT interval and, in combination with hydroxychloroquine, may cause arrhythmias (this combination is not recommended). In addition, there is an increased risk of ventricular arrhythmias when hydroxychloroquine is used concomitantly with other arrhythmogenic drugs (such as amiodarone and moxifloxacin).
With other antimalarial drugs that lower the seizure threshold
The use of hydroxychloroquine can lead to a decrease in the seizure threshold. Concomitant use of hydroxychloroquine with other known antimalarial drugs that lower the seizure threshold (eg, mefloquine) may increase the risk of seizures.

With cyclosporine
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 used together with antiepileptic drugs, the effectiveness of the latter may be insufficient.
With praziquantel
Hydroxychloroquine

In a study of the interaction of chloroquine and praziquantel, a decrease in the bioavailability of praziquantel was reported. 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 the intracellular plex NANOLEK territory Tel. +7 (495) 648-26-87. β-galactosidase with the combined use of hydroxychloroquine with agalsidase.

Pharmacodynamics Hydroxychloroquine:

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, including collagenase and proteases, that 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 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;
- a decrease in the activity of phospholipase A2 at high concentrations of lysosomal enzymes;
- a decrease in the concentrations of the 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.
The drug actively suppresses asexual erythrocyte forms, as well as the gametes of R. vivax and R. 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 relapse of the disease caused by these pathogens.

Pharmokinetics Hydroxychloroquine:

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. Connection with plasma proteins - 45%. The mean plasma half-life varies with the time elapsed after taking the drug as follows: 5.9 hours (from reaching maximum plasma concentration (Cmax) to 10 hours) 26.1 hours (10 to 48 hours) and 299 hours (from 48 to 504 hours). In the liver, it is partially converted into 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 concentration 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. The drug is released slowly, with a terminal half-life of about 50 days (from whole blood) and 32 days (from plasma). Within 24 hours, 3% of the administered dose of the drug is excreted in the urine.
Hydroxychloroquine crosses the placental barrier and is found in small amounts in breast milk.

Indications Hydroxychloroquine:

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); photodermatitis.

Contraindications Hydroxychloroquine:

Hypersensitivity to hydroxychloroquine and to 4-aminoquinoline derivatives 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 "ideal" body weight less than 31 kg).
Pregnancy (see "Pregnancy and lactation").

Carefully
In case of visual disorders (decreased visual acuity, impaired color vision, narrowing of the visual fields), while taking medications 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 tardive cutaneous porphyria (risk of exacerbation), psoriasis (risk of increased skin manifestations of the disease), while taking medications that can cause skin reactions.
In case of renal failure and / or liver failure, hepatitis, concomitant use of drugs that can adversely affect liver and / or kidney function (in severe renal or liver dysfunction, the dose should be adjusted under the control of plasma concentrations of hydroxychloroquine).
With a deficiency of glucose-6-phosphate dehydrogenase.
With gastrointestinal diseases.
In case of hypersensitivity to quinine (the possibility of cross-allergic reactions).
In case of violation of the conduction of the heart (blockade of the legs of the bundle of His / atrioventricular block) and with hypertrophy of both ventricles.
With cardiomyopathy.
Due to the risk of hypoglycemia, the drug should be prescribed with caution to patients who are taking and not taking hypoglycemic drugs (see the sections "Side effects", 

"Interaction with other drugs", "Special instructions").
Application during pregnancy and during breastfeeding
Hydroxychloroquine crosses the placenta. Limited data are available for its use in 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 retinal pigmentation.
The need to use the drug during breastfeeding should be carefully weighed, since it has been shown that it is excreted in small quantities in breast milk, and young children are especially sensitive to the toxic effects of 4-aminoquinolines.

Side effects Hydroxychloroquine:

The frequency of adverse reactions is presented in accordance with the classification of the World Health Organization (WHO): very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10000 and <1/1000), very rarely (<1/10000), the frequency is unknown (it is not possible to determine the frequency of occurrence of an adverse reaction).
Disturbances from the blood and lymphatic system: the frequency is 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; the frequency is unknown - hypoglycemia, the possibility of exacerbation of porphyria.
Mental disorders: often - affective lability; infrequently - nervousness; frequency unknown - psychosis, suicidal behavior.
Nervous system disorders: often - headache; infrequently - dizziness; frequency unknown - seizures, extrapyramidal disorders such as muscular dystonia, dyskinesia and tremors.
Violations 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 case of timely withdrawal of the drug, these phenomena are reversible. If the condition remains undiagnosed and retinal lesions continue to develop, then 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. 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. Frequency unknown - maculopathy and macular degeneration, which may be irreversible.
Hearing disorders and labyrinth disorders: infrequently - vertigo, tinnitus; frequency unknown - hearing loss.

Cardiovascular disorders: frequency unknown - cardiomyopathy, which can lead to heart failure and, in some cases, death. Detection of cardiac conduction abnormalities (such as bundle branch blocks / AV conduction abnormalities) and hypertrophy of both ventricles may be indicative of chronic cardiac toxicity. When the drug is discontinued, the reverse development of these changes is possible.
Disturbances from the gastrointestinal tract: very often - abdominal pain, nausea; often - diarrhea, vomiting. These symptoms usually resolve immediately after dose reduction or drug withdrawal.
Disturbances from the liver and biliary tract: infrequently - deviations from the norm of functional "liver" tests; frequency unknown - fulminant hepatic failure.
Skin disorders of 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 the drug, the outcome is usually favorable.
Musculoskeletal and connective tissue disorders: 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 may be reversible after drug withdrawal, but it may take several months to fully recover), suppression of tendon reflexes and decreased nerve conduction.

Overdose Hydroxychloroquine:

An overdose of 4-aminoquinolines is especially dangerous in children, even 1-2 g of the drug Hydroxychloroquine can be fatal.

Symptoms
Overdose symptoms include headache, visual disturbances, collapse, seizures, hypokalemia, rhythm and conduction disturbances, followed by cardiac and respiratory arrest.
Treatment
Since overdose symptoms can develop very quickly after taking a large dose of the drug, in these cases, appropriate measures should be taken immediately. Artificial vomiting or gastric lavage through a tube should be performed immediately. Absorption can be slowed down by activated carbon in a dose of at least 5 times the dose of the drug taken. It is advisable to parenteral administration of dia

Application methods Hydroxychloroquine:

The drug is taken only internally. Each dose must be taken with meals or with a glass of milk.

Malaria treatment
Prevention of acute attacks of malaria caused by P. malariae and sensitive strains of P. falciparum

For adults - 400 mg weekly, on the same day of the week.

For children, the weekly dose is 6.5 mg / kg body weight (the "ideal" body weight is taken for the calculation), however, regardless of body weight, it should not exceed the adult dose.

If conditions permit, then preventive therapy should be started 2 weeks before entering the endemic area. If this is not possible, then an initial double (loading) dose can be prescribed: adults - 800 mg, children - 12.9 mg / kg of "ideal" body weight (but not more than 800 mg), divided into two doses with a 6-hour interval. Prophylactic treatment should be continued for 8 weeks after leaving the endemic area.

Treatment of acute attacks of malaria

For adults, an initial dose of 800 mg is followed by 400 mg every six or eight hours, followed by 400 mg on two consecutive days (for a total of 2 g of hydroxychloroquine sulfate).

Alternative treatment: the effectiveness of a single dose of 800 mg has been proven.

Doses for adults can also be calculated based on “ideal” body weight, similar to calculating doses for children (see below).

For children, a total dose of 32 mg / kg of "ideal" body weight (but not higher than 2 g) is prescribed for three days as follows:

first dose: 12.9 mg / kg body weight (single dose not more than 800 mg);

second dose: 6.5 mg / kg of body weight (not more than 400 mg) 6 hours after the first;

third dose: 6.5 mg / kg (not more than 400 mg) 18 hours after the second dose;

fourth dose: 6.5 mg / kg (not more than 400 mg) 24 hours after the third dose.

Radical treatment of P. malariae and P. vivax malaria

For the radical treatment of malaria caused by R. malariae and R. vivax, the simultaneous administration of 8-aminoquinolone derivatives is necessary.

RA treatment

Hydroxychloroquine has cumulative activity. For the manifestation of its therapeutic effect, several weeks of taking the drug are required, while side effects can appear relatively early. The required therapeutic effect develops after several months of taking the drug. If there is no objective improvement in the patient's condition within 6 months of taking hydroxychloroquine, the drug should be discontinued.

Adults (including the elderly)

The minimum effective dose should be taken. They should not exceed 6.5 mg / kg body weight / day (calculated on the basis of "ideal" body weight, not real body weight) and can be either 200 or 400 mg per day.

In patients capable of taking 400 mg daily

Initially, 400 mg daily in divided doses. When an obvious improvement is achieved, the dose can be reduced to 200 mg. With a decrease in the effect, the maintenance dose can be increased to 400 mg.

Children over 6 years old and weighing more than 31 kg

The minimum effective dose should be used. The dose should not exceed 6.5 mg / kg body weight (based on the "ideal" body weight). Therefore, 200 mg tablets are not suitable for children weighing less than 31 kg.
Use of the drug Hydroxychloroquine for combination therapy of RA Hydroxychloroquine can be safely used in combination with glucocorticosteroids, salicylates, non-steroidal anti-inflammatory drugs, methotrexate and other second-line therapies. After several weeks of using the drug Hydroxychloroquine, the doses of glucocorticosteroids and salicylates may be reduced or these drugs may be discontinued. Doses of glucocorticosteroids should be reduced gradually every 4-5 days: the dose of cortisone - no more than 5-15 mg, the dose of hydrocortisone - no more than 5-10 mg, the dose of prednisolone and prednisone - no more than 1-2.5 mg , the dose of methylprednisolone and triamcinolone - no more than 1-2 mg and dexamethasone - no more than 0.25-0.5 mg.

SLE treatment
The initial average dose in adults is 400 mg 1 or 2 times a day. Hydroxychloroquine should be given over several weeks or months, depending on the patient's response. For long-term maintenance therapy, it is sufficient to use the drug in a lower dose of 200 to 400 mg.

Photodermatitis treatment: up to 400 mg / day. Treatment should be limited to periods of maximum sun exposure.