Hydroxychloroquine - instructions for use, dose, side effects, contraindications

Active substanceHydroxychloroquineHydroxychloroquine

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Hydroxychloroquine

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New Farm Inc.

Hydroxychloroquine

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BIOKOM, CJSC Russia

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Ipka Laboratories Ltd. India

Plaquenil

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Sanofi-Synthelabo Co., Ltd. United Kingdom

Dosage form: & nbspfilm coated tablets

Composition:

1 tablet contains:

active substance: hydroxychloroquine sulphate - 200 mg;

Excipients: calcium hydrophosphate dihydrate - 99.86 mg, salted [microcrystalline cellulose - 98%, silicon dioxide colloid - 2%] - 126.79 mg, hypromellose (hydroxypropylmethylcellulose) - 24.25 mg, croscarmellose sodium - 19.40 mg, silicon dioxide colloid (aerosil) - 4.85 mg, magnesium stearate - 4.85 mg; composition of the shell: hypromellose (hydroxypropylmethylcellulose) - 2.972 mg, titanium dioxide (E171) - 1.363 mg, macrogol (polyethylene glycol) (E1521) - 0.665 mg.

Description:Round biconvex tablets coated with a film coat, white. Insignificant roughness of the surface is permissible. Color of tablets on a break - white or white with a yellowish shade.

Pharmacotherapeutic group:Anti-malarial drug

ATX: & nbsp

P.01.B.A.02 Hydroxychloroquine

Pharmacodynamics:

Hydroxychloroquine has anti-malarial properties,and also has anti-inflammatory and immunosuppressive effects in chronic discoid or systemic lupus erythematosus (SLE), acute and chronic rheumatoid arthritis (RA). The mechanism of its action for malaria, lupus erythematosus and rheumatoid arthritis is not completely known.

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

Efficacy in SLE and RA is associated with the following anti-inflammatory and immunomodulating effects of hydroxychloroquine:

- an increase in intracellular pH leads to a slowing down of the antigenic response and decreases the binding of the peptides of the main histocompatibility complex receptor (PSG) receptors. A smaller number of antigen-MHC receptors reaches the cell surface, which leads to a decrease in the autoimmune response;

- decrease in activity of phospholipase A2 at high concentrations, lysosomal enzymes;

- decrease in cytokine concentrations IL-1 and IL-6, leading to a decrease in the clinical and laboratory parameters of the autoimmune response. Since there is no violation of the synthesis of interferon gamma, these effects can 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 gametes R. vivax and P. malariae, which disappear from the blood almost simultaneously with asexual forms. Hydroxychloroquine does not affect gametes R. falciparum. Hydroxychloroquine is ineffective against chloroquine resistant strains of P. falciparum, and is also inactive in relation to out-erythrocyte forms of R. vivax, R. malariae and P. ovale and therefore can not prevent infection with these microorganisms when it is prescribed for preventive purposes, and also can not prevent the relapse of the disease caused by these pathogens.

Pharmacokinetics:

After oral administration hydroxychloroquine quickly 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 average value of the half-life from the plasma varies depending on the time elapsed after taking the drug as follows: 5.9 hours (from reaching the maximum plasma concentration (Cmah) up 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 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, CNS, erythrocytes, leukocytes), as well as in the retina and tissues rich in melanin. Hydroxychloroquine and its metabolites are excreted mainly with urine and to a lesser degree with bile. Youthe division of the drug is slow, the terminal half-life is about 50 days (from whole blood) and 32 days (from the plasma). Within 24 hours with urine, 3% of the administered dose of the drug is excreted.

Hydroxychloroquine penetrates the placental barrier and in small amounts is found in breast milk.

Indications:

Malaria (with the exception of chloroquine-resistant strains R. falciparum): prevention and management of acute attacks of malaria caused by Plasmodium vivax, R. ovale and R. malariae, as well as sensitive strains R. falciparum; radical treatment of malaria caused by susceptible strains R. Falciparum; rheumatoid arthritis; juvenile rheumatoid arthritis; lupus erythematosus (systemic and discoid); photodermatitis.

Contraindications:

Hypersensitivity to hydroxychloroquine and to derivatives of 4-aminoquinoline or to other components of the drug.

Retinopathy (including maculopathy in the anamnesis).

Children's age if necessary long-term therapy (children have an increased risk of toxic effects).

Children under 6 years of age (200 mg tablets are not suitable for children with an "ideal" body weight of less than 31 kg).

Pregnancy (see "Pregnancy and lactation").

Carefully:

With visual disorders (reduced visual acuity, impaired color vision, narrowing of visual fields), simultaneous administration of drugs that can cause adverse ophthalmic reactions (the danger of progression of retinopathy and visual disorders).

With hematological diseases (including in the anamnesis).

With neurological diseases, psychoses (including in the anamnesis).

With late cutaneous porphyria (risk of exacerbation), psoriasis (the risk of increasing skin manifestations of the disease), simultaneous administration of drugs that can cause skin reactions.

In case of renal insufficiency and / or hepatic insufficiency, hepatitis, simultaneous administration of drugs that can adversely affect liver and / or kidney function (for severe violations of kidney or liver function, the dose should be selected under the control of plasma concentrations of hydroxychloroquine).

With deficiency of glucose-6-phosphate dehydrogenase.

With gastrointestinal diseases.

When hypersensitivity to quinine (the possibility of cross-allergic reactions).

When the conduction of the heart is disturbed (blockade of the bundle of the fascicle bundle / atrioventricular block) and with hypertrophy of both ventricles.

With cardiomyopathy.

Because of the risk of developing hypoglycemia, the drug should be administered with caution to patients who are both taking and not taking hypoglycemic drugs (see the sections "Side effect", "Interaction with other drugs", "Special instructions").

Pregnancy and lactation:

Hydroxychloroquine penetrates the placenta. With regard to its use during pregnancy, data are limited. It should be noted that 4-aminoquinolines in therapeutic doses can cause intrauterine damages of the central nervous system, including the auditory nerve (hearing and vestibular disorders, congenital deafness), retinal hemorrhages and abnormal retinal pigmentation.

We must carefully weigh the need for the drug during breastfeeding, as it is shown that it is excreted in small amounts in breast milk, and small children are particularly sensitive to the toxic effects of 4-aminoquinolines.

Dosing and Administration:

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

Treatment of malaria

Prevention of acute attacks of malaria caused by R. 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 of body weight (the "ideal" body weight is taken for calculation), however, regardless of body weight, it should not exceed the dose for adults.

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

Treatment of acute attacks of malaria

For adults for an initial dose of 800 mg, a dose of 400 mg should be given after six or eight hours, and then 400 mg on two consecutive days (a total of 2 g of hydroxychloroquine sulphate).

An alternative method of treatment: the effectiveness of a single dose of 800 mg has been proven. Doses for adults can also be calculated according to the "ideal" body weight, similar to the calculation of doses in children (see below).

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

the first dose: 12.9 mg / kg body weight (single dose not more than 800 mg); second dose: 6.5 mg / kg body weight (not more than 400 mg) 6 hours after the first; the third dose: 6.5 mg / kg (not more than 400 mg) 18 hours after the second dose; the fourth dose: 6.5 mg / kg (not more than 400 mg) 24 hours after the third dose.

Radical treatment of malaria caused by R. malariae and P. vivax

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

Treatment of RA

Hydroxychloroquine has cumulative activity. For the manifestation of its therapeutic effect, several weeks of taking the drug are necessary, while side effects may appear relatively early. The necessary 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)

Minimum effective doses should be taken. They should not exceed 6.5 mg / kg body weight / day (calculated according to the "ideal" body weight, and not by the actual body weight) and can be either 200 or 400 mg per day.

In patients who are able to take 400 mg daily

Initially, 400 mg daily, divided into several receptions. When an obvious improvement in the condition is achieved, the dose can be reduced to 200 mg.With a reduction in the effect, the maintenance dose can be increased to 400 mg.

Children over 6 years of age and weighing more than 31 kg

The minimum effective dose should be used. The dose should not exceed 6.5 mg / kg of 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 RA

Hydroxychloroquine can be safely used in combination with glucocorticosteroids, salicylates, nonsteroidal anti-inflammatory drugs, methotrexate and other second-line therapeutic agents. After several weeks of drug administration Hydroxychloroquine doses of glucocorticosteroids and salicylates may be reduced or may be stopped taking these drugs. Doses of glucocorticosteroids should decrease 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.

Treatment of SLE

The initial average dose in adults is 400 mg 1 or 2 times a day. Hydroxychloroquine should be administered within a few weeks or months, depending on the patient's response. For prolonged maintenance therapy, it is sufficient to use the drug in a smaller dose of 200 to 400 mg.

Treatment of photodermatitis: up to 400 mg / day. Treatment should be limited to periods of maximum solar exposure.

Side effects:

The incidence of adverse reactions is presented in accordance with the classification of the World Health Organization (WHO): Often (> 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), rarely (< 1/10000), frequency unknown (it is not possible to determine the frequency of the occurrence of an undesirable reaction).

Violations from the blood and lymphatic system: frequency unknown - oppression of bone marrow hematopoiesis, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Immune system disorders: frequency unknown - urticaria, angioedema, bronchospasm.

Disorders from the metabolism and nutrition: often anorexia; frequency unknown - hypoglycemia, the possibility of exacerbation of porphyria.

Disorders of the psyche: often - affective lability; infrequently - nervousness; frequency unknown - psychosis, suicidal behavior.

Impaired nervous system: often - headache; infrequently - dizziness; frequency unknown - convulsions, extrapyramidal disorders, such as muscular dystonia, dyskinesia and tremor.

Disorders 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 the drug, these phenomena are reversible. If the condition remains undiagnosed and the retinal lesions continue to develop, then the risk of their progression is possible even after the drug is discontinued. Changes in the retina can initially be asymptomatic or manifest as scotomas of paracentral or pericentral types, transient scotomas and color vision disorders. There may be changes in the cornea, including swelling and turbidity.They may be asymptomatic or cause visual disturbances such as halos, blurred vision or photophobia. These changes can be transitory or reversible. Frequency unknown - maculopathy and macular degeneration, which can be irreversible.

Hearing disorders and labyrinthine disturbances: infrequently - Vertigo, noise in the ears; frequency unknown - loss of hearing.

Disorders from the cardiovascular system: frequency unknown - cardiomyopathy, which can lead to heart failure and, in some cases, to death. The detection of cardiac conduction abnormalities (such as bundle bundle blockade / atrioventricular conduction disturbances) and hypertrophy of both ventricles may indicate chronic cardiac toxicity. With the withdrawal of the drug, the reverse development of these changes is possible.

Disorders from the gastrointestinal tract: Often - abdominal pain, nausea; often - diarrhea, vomiting. These symptoms usually occur immediately after a dose reduction or drug withdrawal.

Disorders from the liver and bile ducts: infrequently - deviations from the norm of functional "hepatic" samples; frequency unknown fulminant liver failure.

Disturbances from the skin of the subcutaneous tissues: often - skin rash, itching; infrequently: changes in pigmentation of the skin and mucous membranes, hair discoloration and alopecia (these changes usually quickly pass after discontinuation of treatment); frequency unknown - Bullous rash including erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis; photosensitization; exfoliative dermatitis; a drug-induced skin reaction accompanied by eosinophilia and systemic manifestations (DRESS syndrome); acute generalized exanthematous pustulosis (OGEEP). OGEP should be distinguished from psoriasis, although hydroxychloroquine and can provoke an exacerbation of psoriasis. OGEP may be accompanied by an increase in temperature and hyperleukocytosis. After the withdrawal of the drug, the outcome is usually favorable.

Disturbances from the musculoskeletal and connective tissue: infrequently - sensory-motor disorders; frequency unknown - myopathy of skeletal muscles or neuromyopathy,leading to progressive weakness and atrophy of proximal muscle groups (myopathy may be reversible after drug withdrawal, but it may take several months for complete recovery), suppression of tendon reflexes, and decreased nerve conduction.

Overdose:

Overdose of 4-aminoquinolines is especially dangerous in children, even 1-2 g of the drug can lead to death.

Symptoms

Symptoms of overdose include headache, visual impairment, collapse, convulsions, hypokalemia, rhythm and conduction disorders, followed by cardiac and respiratory arrest.

Treatment

Since the symptoms of overdose can develop very quickly after taking a large dose of the drug, in these cases, immediate action should be taken. Immediate vomiting or gastric lavage through the probe should be performed immediately. Slow absorption may Activated carbon in a dose at least 5 times higher than the accepted dose of the drug. It is advisable to use parenteral diazepam, which will reduce the cardiotoxicity of chloroquine.If necessary, it is necessary to carry out artificial ventilation and anti-shock therapy.

After relief of overdose symptoms, continuous medical supervision is required for at least 6 hours.

Interaction:

FROM digoxin

It was reported that hydroxychloroquine is able to increase plasma concentrations of digoxin, therefore, 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 drugs used to treat diabetes mellitus

Hydroxychloroquine can enhance the effects of insulin and oral hypoglycemic agents; it may be necessary to reduce the doses of these drugs with the initiation of hydroxychloroquine administration.

FROM antacids

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.

Hydroxychloroquine can also not exclude the following interactions with other drugs that have been described for chloroquine, but have not yet been observed with the administration of hydroxychloroquine.

FROM aminoglycosides

Potentiation of direct blocking action of aminoglycosides on neuromuscular transmission.

With cimetidine

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 - antagonism of action.

With any intradermal human diploid-cell vaccine against rabies

Reduction of the formation of antibodies in response to primary immunization with intradermal human diploid-cell rabies vaccine.

With halofantrine and other arrhythmogenic drugs

Halofantrine prolongs the interval QT and in combination with hydroxychloroquine can cause arrhythmias (this combination is not recommended). In addition, there is an increased risk of developing ventricular arrhythmia when using hydroxychloroquine concomitantly 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.The combined use of hydroxychloroquine with other known antimalarial drugs that lower the threshold of seizure activity (for example, mefloquine), may increase the risk of seizures.

With cyclosporine

An increase in the concentration of cyclosporine in the blood plasma was 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.

With praziquantel

In a study of the interaction of chloroquine and praziquantel, a decrease in the bioavailability of praziquantel was reported. Because of 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 inhibiting intracellular α-galactosidase in the combined use of hydroxychloroquine with agalicidase.

Special instructions:

Are common

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 retinopathy.

Before the start of a long course of treatment with the drug, a thorough examination of both eyes should be carried out. The examination should include the definition of visual acuity, examination of the fundus, assessment of color vision and visual fields. During the therapy, this examination should be conducted 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 insufficiency;

- at a total dose of more than 200 g;

- in the elderly;

- if the patient has any degree of severity of visual acuity before starting treatment.

In the event of any visual disorders (visual acuity, change in color vision), the drug should be immediately canceled and carefully monitored for the patient's vision,because the changes in the retina (and visual disorders) can progress even after the drug is discontinued (see the "Side effect" section).

Patients receiving the drug Hydroxychloroquine cases of cardiomyopathy leading to heart failure were noted (see "Side effect.") It was shown that hydroxychloroquine can cause the development of severe hypoglycemia (including loss of consciousness), which can threaten the lives of patients, both taking and not taking hypoglycemic drugs. Patients receiving hydroxychloroquine, should be warned about the risk of developing hypoglycemia and associated clinical signs and symptoms. Patients who experience clinical signs of hydroxychloroquine during the treatment, indicating the development of hypoglycemia, should determine the concentration of glucose in the blood and, if necessary, revise the therapy.

It is advisable to use caution when using hydroxychloroquine in patients with liver and kidney disease who may need to reduce the dose of the drug, as well as in patients taking medications,They can cause adverse effects on these organs.

In patients taking long-term hydroxychloroquine, you should periodically perform a complete blood test (if there are hematological disorders of hydroxychloroquine must be canceled).

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

All patients taking a long-term drug should be periodically examined by a neurologist regarding the functions of skeletal muscles and the severity of tendon reflexes. If there is weakness in the muscles, the drug should be discarded.

In very rare cases, suicidal behavior was reported in patients taking hydroxychloroquine. When using the drug Hydroxychloroquine possibly the development of extrapyramidal disorders (see section "Side effect").

With malaria

Hydroxychloroquine is not effective against chloroquine resistant strains of P. falciparum, and is also not active against non-erythrocytic forms of P. vivax, R. malariae and P. ovale, and therefore can not prevent infection with these microorganisms when it is used for preventive purposes, and also can not prevent the recurrence of the disease caused by these pathogens.

Effect on the ability to drive transp. cf. and fur:

During drug treatment, care should be taken when performing potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 200 mg.

Packaging:

10 tablets per contour cell pack.

By 1, 2, 3, 5, 6 or 10 contour mesh packages together with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004300

Date of registration:18.05.2017

Expiration Date:18.05.2022

The owner of the registration certificate:BIOKOM, CJSC BIOKOM, CJSC Russia

Manufacturer: & nbsp

BIOKOM, CJSC Russia

Information update date: & nbsp21.06.2017

Illustrated instructions

Instructions

Hydroxychloroquine (Hydroxychloroquine)