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

The opadine OY-L-28900® - 14.6 mg (hypromellose - 4.09 mg, macrogol-4000 - 1.46 mg, titanium dioxide (E 171) - 3.80 mg, lactose monohydrate - 5.25 mg).

Description:Round biconvex tablets covered with a white film sheath, engraved with "HCQ" on one side and "200" on the other side.

Pharmacotherapeutic group:antimalarial

ATX: & nbsp

P.01.B.A.02 Hydroxychloroquine

Pharmacodynamics:

Plakvenil has antimalarial properties, and also has anti-inflammatory and immunosuppressive effects in chronic discoid or systemic lupus erythematosus (SLE) and acute and chronic rheumatoid arthritis (RA). The mechanism of its action for malaria, lupus erythematosus and rheumatoid arthritis is not fully 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 of the antigenic response and decreases the binding of peptides of the main histocompatibility complex (MHC) receptor peptides. 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;

- a decrease in the concentrations of IL-1 and IL-6 cytokines 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 of R. vivax and R. malariae, which disappear from the blood almost simultaneously with asexual forms.Plaquenyl does not affect the gametes of P. falciparum. Plakvenil is ineffective against chloroquine resistant P. falciparum strains, and is also inactive with respect to the extraerythrocyte forms of P. vivax, P. malariae and R. ovale and therefore can not prevent infection by these microorganisms when it is prescribed for prophylactic purposes, and also can not prevent recurrence 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 plasma varies depending on the time elapsed after taking the drug as follows: 5.9 hours (from reaching the maximum plasma concentration (Stach) 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, 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 extent with bile. The release 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:

- Rheumatoid arthritis; juvenile rheumatoid arthritis; lupus erythematosus (systemic and discoid).

- Malaria (with the exception of chloroquine-resistant strains R.falciparum);

- for the prevention and treatment of acute attacks of malaria caused by Plasmodium vivax, R. Novale and P. m.alariae, as well as sensitive strains R. falciparum;

- for the radical treatment of malaria caused by sensitive strains R.falciparum.

Contraindications:

- Hypersensitivity to hydroxychloroquine, a derivative of 4-aminoquinoline and any other component 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 35 kg).

- Pregnancy (see the section "Pregnancy and lactation").

- Hereditary lactose intolerance (lactase deficiency), galactosemia or glucose / galactose malabsorption syndrome (due to the presence of lactose in the formulation).

Carefully:

- For visual disorders (visual acuity, color vision, narrowing of visual fields), simultaneous administration of drugs capable of causing adverse ophthalmic reactions (danger of progression of retinopathy and visual disorders).

- When 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 renal failure and / or hepatic adverse effects on liver and / or kidney function (whensevere violations of the 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 "Side effects", "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.Therefore, the use of hydroxychloroquine in pregnancy should be avoided, unless the potential benefit to the mother exceeds the risk to the fetus.

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:

NOTE: All doses are given for hydroxychloroquine sulphate, and are not equivalent to the doses for the base!

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

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

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 Plaquenil for Combination Therapy of RA

Plakvenil can safely be used in combination with glucocorticosteroids, salicylates, nonsteroidal anti-inflammatory drugs, methotrexate and other second-line therapeutic agents. After several weeks of using Plaquenil, the doses of glucocorticosteroids and salicylates may be reduced or may be stopped.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. It 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 malaria

Prevention of acute attacks of malaria caused by R. malariae, and sensitive strains R. 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 an initial double (loading) dose can be prescribed: 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 at 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).

Alternative treatment: the efficacy of a single

intake of 800 mg.

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 higher than 2 g) is given for three days as follows:

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

The 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 R. vivax

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

Side effects:

The frequency of adverse reactions is presented in accordance with the following classification:

Often (> 1/10),

Often (≥ 1/100 < 1/10),

Infrequently (≥ 1/1000 < 1/100),

Rarely (≥ 1/10000 < 1/1000),

Rarely (< 1/10000),

Frequency unknown (it is not possible to determine the frequency of occurrence of an undesirable reaction according to the available data).

Violations of 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.

Disturbances from the nervous system

Often: headache.

Infrequently: dizziness.

Frequency unknown: convulsions.

Disturbances on the part of the organ of sight

Often: blurred vision associated with accommodation disorders, which are dose-dependent and reversible.

Infrequently: Retinopathy with changes in pigmentation and defects in the fields of vision. In the early form, these phenomena are usually reversible after stopping the intake of hydroxychloroquine.If the condition remains undiagnosed and the retinal lesions continue to develop further, there may be a risk of their progression even after the drug is discontinued. Changes in the retina at first can 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 transient or reversible after discontinuation of treatment.

Frequency unknown: maculopathy and macular degeneration, which can be irreversible.

Hearing disorders and labyrinthine disorders

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 (in some cases with a fatal outcome). Chronic cardiac toxicity should be taken into account when there is a conduction disturbance (bundle bundle blockade / atrioventricular conduction disturbance) or hypertrophy of both ventricles.

With the withdrawal of the drug, the reverse development of these changes is possible.

Disorders from the gastrointestinal tract

Often: pain in the abdomen, nausea.

Often: diarrhea, vomiting.

These symptoms usually occur immediately after a dose reduction or drug withdrawal.

Disturbances from the liver and bile ducts

Infrequently: deviation from the norm of functional "hepatic" samples.

Frequency unknown: fulminant liver failure.

Disturbances from the skin and 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, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, 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 musculoskeletal and connective tissue

Infrequently: sensorimotor disorders.

Frequency unknown: myopathy of skeletal muscles or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (myopathy can be reversible after drug cancellation, but it may take several months for complete recovery), suppression of tendon reflexes, and decreased nerve conduction.

Overdose:

Symptoms

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 impairment, collapse, convulsions, hypokalemia, rhythm and conduction disorders, including QT interval elongation, "pirouette" tachycardia, ventricular tachycardia and ventricular fibrillation, followed by sudden potentially fatal cardiac arrest and respiration. In case of an overdose, the patient needs urgent medical supervision, since these complications can occur in a very short time after an overdose.

Treatment

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. Parenteral administration of diazepam is advisable (a decrease in the cardiotoxicity of chloroquine on its background is described).

If necessary, it is necessary to carry out artificial ventilation and anti-shock therapy.

After cupping symptoms of overdose require continued medical supervision for at least 6 hours.

Interaction:

With 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 plasma concentrations of digoxin.

With drugs used to treat diabetes mellitus

Because the hydroxychloroquine can enhance the effects of insulin and oral hypoglycemic agents, it may be necessary to reduce the doses of these hypoglycemic drugs at the onset of hydroxychloroquine intake.

With 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.

In hydroxychloroquine, the following interactions with other drugs that have been described for chloroquine can not be ruled out, but have not yet been observed with hydroxylchloroquine.

With aminoglycosides

Potentiation of their direct blocking effect 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 QT interval 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

With the combined use of hydroxychloroquine 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. It is not known whether the same effect is possible with the combined use of hydroxychloroquine and praziquantel.Due to similarity in 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 starting a long course of treatment with the drug, a thorough examination of both eyes should be carried out. The survey 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 calculatedose may lead to an overdose);

- with renal insufficiency;

- at a total dose of more than 200 g;

- in the elderly;

- with reduced visual acuity.

If any visual disturbances occur (visual acuity, color vision changes), the drug should be immediately discarded and a careful observation of the patient's vision should be made, as the changes in the retina (and visual disturbances) may progress even after the drug is discontinued (see "Side Effects" ).

Patients receiving Plakvenil® received cases of cardiomyopathy leading to heart failure (in some cases with fatal outcome). Clinical monitoring of signs and symptoms of cardiomyopathy is recommended, in the case of cardiomyopathy, Plakvenil® should be stopped. Violation of the conduction of the heart (block bundle of the bundle of the bundle / atrioventricular block) and hypertrophy of both ventricles can develop against a background of chronic toxicity.

It was shown that hydroxychloroquine can cause the development of severe hypoglycemia (including loss of consciousness), which can be life-threatening for patients as host,and not taking hypoglycemic drugs. Patients receiving hydroxychloroquine, should be warned about the risk of developing hypoglycemia and associated clinical signs and symptoms. In patients who have clinical symptoms during treatment with hydroxychloroquine, indicating the development of hypoglycemia, it is necessary to 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, which may require lower dosages of the drug, as well as in patients taking medications that can adversely affect these organs.

In patients taking a long-term drug, a complete blood test should be performed periodically (if hematological disorders occur 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.

With malaria

Plakvenil® is ineffective against chloroquine resistant P. falciparum strains, and is also inactive with respect to the extra-erythrocytic forms of P. vivax, P. malariae and R. ovale and therefore can not prevent infection by these microorganisms when it is used to prevent acute attacks of malaria, and also can not prevent the recurrence of the disease caused by these pathogens.

Form release / dosage:

Tablets, film-coated, 200 mg.

Packaging:For 15 tablets in a blister of PVC and aluminum foil. For 4 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

List B.

Shelf life:

3 years.

Do not take the drug after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015606 / 01

Date of registration:03.03.2009 / 08.12.2015

The owner of the registration certificate:Sanofi-Synthelabo Co., Ltd.Sanofi-Synthelabo Co., Ltd. United Kingdom

Manufacturer: & nbsp

SANOFI-AVENTIS S.A. Spain

Information update date: & nbsp03.01.2016

Illustrated instructions

Instructions

Plaquenil (Plaquenil)