Plaquenil

General characteristics. Structure:

Active agent: hydroxychloroquine sulfate - 200 mg;
excipients: lactoses monohydrate, povidone (K25), starch corn, magnesium stearate, Opadray of OY-L-28900 (gipromelloza, macrogoal-4000, titanium dioxide (Е 171), lactoses monohydrate).
Description. Round biconvex tablets, film coated white color, with an engraving of "HCQ" on one party and "200" - on other party.

Pharmacological properties:

Pharmacodynamics. Plaquenil has antimalarial properties, and also has an antiinflammatory and immunodepressive effect at chronic diskoidny or the system lupus erythematosus (SLE) and the acute and chronic pseudorheumatism (P). The mechanism of its action at malaria, a lupus erythematosus and a pseudorheumatism is up to the end not known.
Gidroksikhlorokhin has properties of a moderate immunosuppressor, suppressing synthesis of a rhematoid factor and components of reaction of an acute phase. It also collects in leukocytes, stabilizing lizosomalny membranes, and suppresses activity of many enzymes, including a collagenase and proteases which cause disintegration of a cartilage.
Efficiency at hard currency and RA contacts the following antiinflammatory and immunomodulatory effects of hydroxychloroquine:
- increase intracellular рН leads to delay of the antigenic answer and reduces binding of peptides of receptors of the main complex of histocompatability (MCH). The smaller number of receptors antigen-GKG reaches a cell surface that leads to decrease in an antiself response.
- decrease of the activity of a phospholipase of A2 at high concentration, lizosomalny enzymes
- the decrease in concentration of IL-1 and IL-6 cytokines leading to reduction of clinical and laboratory indicators of an antiself response. As there is no interferon synthesis disturbance scale, these effects can be connected with the selection impact on cytokines.
- inhibition pre-and/or post-transcriptions of DNA and RNA.
Drug, actively suppresses sexless erythrocyte forms, and also gametes of P. vivax and P. malariae which disappear from blood almost along with sexless forms. Plaquenil does not affect gametes of P. falciparum. Plaquenil is not effective concerning strains of P. falciparum, resistant to chloroquine, and also is inactive concerning the ectoglobular P. vivax, P. malariae and P. ovale forms and therefore infection with these microorganisms at its appointment in the preventive purposes cannot warn, and also cannot prevent a recurrence of the disease caused by these activators.

Pharmacokinetics. After intake hydroxychloroquine quickly and almost is completely soaked up. At healthy volunteers after a single dose of 400 mg the maximum plasma concentration of hydroxychloroquine was reached in 1,83 hours and fluctuated from 53 to 208 ng/ml. Communication with proteins of plasma - 45%. Average value of plasma elimination half-life varies depending on time which passed after administration of drug as follows: 5,9 hours (from achievement of the maximum plasma concentration (Stakh) till 10 o'clock) 26,1 hours (from 10 to 48 hours) and 299 hours (from 48 to 504 hours). In a liver it partially turns into active ethylated metabolites. Not changed drug and its metabolites is well distributed in an organism. The volume of distribution makes 5-10 l/kg. Drug collects in fabrics with the high level of exchange (in a liver, kidneys, lungs, a spleen - in these bodies concentration exceeds plasma by 200-700 times; TsNS, erythrocytes, leukocytes), and also in the retina of an eye and fabrics rich with melanin. Gidroksikhlorokhin and his metabolites are removed generally with urine and to a lesser extent with bile. Release of drug slow, a terminal elimination half-life makes about 50 days (of whole blood) and 32 days (of plasma). In 24 hours with urine 3% of the entered drug dose are removed.
Gidroksikhlorokhin gets through a placental barrier and in insignificant quantities it is found in breast milk.

Indications to use:

- Pseudorheumatism; juvenile pseudorheumatism; lupus erythematosus (system and diskoidny).
- Malaria (behind an exception chloroquine - resistant strains of P. falciparum):
- for prevention and treatment of bad attacks of the malaria caused by Plasmodium vivax, P. ovale and P. malariae, and also sensitive strains of P. falciparum;
- for radical treatment of the malaria caused by sensitive strains of R. of falciparum.

Route of administration and doses:

Note. All doses are given for sulfate hydroxychloroquine, and are not equivalent to doses for the basis!
Drug is accepted only inside. Each dose needs to be accepted during food or to wash down with a glass of milk.
Treatment of RA
Gidroksikhlorokhin has cumulative activity. Manifestation of its therapeutic action requires several weeks of administration of drug while side effects can be shown relatively early. The necessary therapeutic effect develops after several months of administration of drug. In case of lack of objective improvement in a condition of the patient within 6 months of reception of hydroxychloroquine, use of drug should be stopped.
Adults (including elderly people)
It is necessary to accept minimal effective doses. They should not exceed 6,5 mg/kg of weight bodies/days (is calculated on "ideal" body weight, but not on actual body weight) and can make either 200, or 400 mg a day.
At the patients capable to accept 400 mg daily
Originally on 400 mg daily divided into several receptions. At achievement of obvious improvement of a state the dose can be lowered to 200 mg. At reduction of effect the maintenance dose can be increased to 400 mg.
Children
It is necessary to use a minimal effective dose. The dose should not exceed 6,5 mg/kg of body weight (proceeding from "ideal" body weight). Therefore tablets of 200 mg are not suitable for children with body weight less than 31 kg.
Use the drug Plaquenil for a combination therapy of RA
Plaquenil can safely be used in a combination with glucocorticosteroids, salicylates, non-steroidal anti-inflammatory drugs, a methotrexate and other therapeutic means of the second row. After several weeks of use of the drug Plaquenil of a Dose of Glucocorticosteroids and Salicylates can be reduced or reception of these drugs can be stopped. Doses of glucocorticosteroids have to decrease gradually each 4-5 days: a cortisone dose - no more than on 5-15 mg, a hydrocortisone dose - no more than on 5-10 mg, a dose of Prednisolonum and Prednisonum - no more than on 1-2,5 mg, a dose of Methylprednisolonum and Triamcinolonum - no more than on 1-2 mg and dexamethasone - no more than on 0,25-0,5 mg.
Treatment of hard currency
The initial average dose at adults makes 400 mg 1 or 2 times a day. It it has to be appointed within several weeks or months depending on reaction of the patient. For a long maintenance therapy, use of drug in a smaller dose is enough from 200 to 400 mg.
Treatment of malaria
Prevention of the bad attacks of malaria caused by P. malariae, and sensitive strains of P. falciparum
For adults - 400 mg weekly in the same day of the week.
For children the weekly dose makes 6,5 mg/kg of body weight (for calculation "ideal" body weight undertakes), however, regardless of body weight it should not exceed a dose for adults.
If conditions allow, then preventive therapy should be begun in 2 weeks prior to entrance to an endemic zone. If it is impossible, then it is possible to appoint an initial double (load) dose: adult - 800 mg, to children - 12,9 mg/kg of "ideal" body weight (but no more than 800 mg), divided into two receptions with a 6-hour interval. Preventive treatment should be continued within 8 weeks after departure from an endemic zone.
Treatment of bad attacks of malaria
For adults the initial dose of 800 mg is followed by a dose of 400 mg in six or eight hours, and then on 400 mg two next days (in total 2 g of hydroxychloroquine of sulfate).
Alternative way of treatment: also efficiency of a single dose of 800 mg was proved.
Doses for adults can be also calculated on "ideal" body weight, similar to calculation of doses at children (see below).
For children the total dose of 32 mg/kg of "ideal" body weight (but not higher than 2 g) is appointed within three days as follows:
First dose: 12,9 mg/kg of body weight (single dose no more than 800 mg). Second dose: 6,5 mg/kg of body weight (no more than 400 mg) in 6 hours after the first. Third dose: 6,5 mg/kg (no more than 400 mg) in 18 hours after the second dose. Fourth dose: 6,5 mg/kg (no more than 400 mg) in 24 hours after the third dose. Radical treatment of the malaria caused by P. malariae and P. vivax
The concomitant use of derivatives of a 8-aminokhinolon is necessary for radical treatment of the malaria caused by P. malariae and P. vivax.

Features of use:

The general
Toxic impact on a retina is substantially dozozavisimy. Frequency of developing of a retinopathy at use of doses to 6,5 mg/kg of "ideal" body weight is small. Exceeding of the recommended daily dose sharply increases risk of development of a retinopathy and accelerates its emergence.
Before a long course of treatment drug it is necessary to conduct careful examination of both eyes. Inspection has to include visual acuity definition, survey of an eyeground, assessment of color sight and fields of vision. During therapy such examination has to be conducted at least 1 time in 6 months.
Inspection has to be more frequent, in the following situations:
- at the daily dose exceeding 6,5 mg/kg of "ideal" body weight (at corpulent patients use of absolute body weight for calculation of a dose can lead to overdose);
- at a renal failure;
- at a total dose over 200 g;
- at elderly people;
- at reduced visual acuity.
At emergence of any visual frustration (decrease in visual acuity, change of color sight) drug it is necessary to cancel and conduct immediately careful observation of a condition of sight of the patient as changes of a retina (and visual frustration) can progress even after drug withdrawal.
It is recommended to be careful at purpose of hydroxychloroquine the patient with diseases of a liver and kidneys at which decrease in doses of drug can be required, and also in connection with a possibility of impact of drug on function of these bodies (at heavy renal failures or a liver the dose has to be selected under control of plasma concentration of hydroxychloroquine).
At the patients receiving prolonged treatment periodically it is necessary to carry out an integrated analysis of blood and at emergence of hematologic disturbances hydroxychloroquine has to be cancelled.
Children are especially sensitive to toxic effects of 4 aminoquinolines therefore it is necessary to watch that hydroxychloroquine was stored in the places unavailable to children carefully.
All patients, it is long receiving drug, have to be inspected periodically at the neuropathologist concerning functions of skeletal muscles and expressiveness of tendon jerks. At emergence of weakness in muscles, drug should be cancelled.
At malaria
Plaquenil is not effective concerning strains of P. falciparum, resistant to chloroquine, and also is inactive concerning the ectoglobular P. vivax, P. malariae and P. ovale forms and therefore infection with these microorganisms at its appointment for the purpose of prevention of bad attacks of malaria cannot warn, and also cannot prevent a recurrence of the disease caused by these activators.
Influence on ability to drive the car and to perform the works connected with the increased danger
Patients have to be careful at the driving of transport or performance of work requiring special attention as hydroxychloroquine can break accommodation and break vision clearness. If this state does not pass in itself, the dose can be temporarily lowered.

Side effects:

- From an organ of sight
Can develop, though it is rare, a retinopathy with changes of pigmentation and defects in fields of vision. In an early form these phenomena are usually reversible after the hydroxychloroquine reception termination. If the state remains not diagnosed and damages of a retina continue to develop further, then there can be a risk of their progressing even after drug withdrawal.
Changes of a retina can be asymptomatic in the beginning, or be shown by scotomas of paracentral or pericentral types, passing scotomas and disturbances of color sight.
Changes of a cornea, including hypostasis and opacification are possible. They can be asymptomatic or cause such vision disorders as emergence of auras, an illegibility of sight or photophobia. At the treatment termination these changes can undergo involution.
Also there can be vision disorders connected with accommodation disturbances, which are dozozavisimy and reversible.
- From integuments
Sometimes skin rashes meet; also the itch, changes of a xanthopathy and mucous membranes, decolouration of hair and an alopecia are described. These changes usually quickly take place after the treatment termination. It was reported about development of violent rash, including very exceptional cases of a multiformny erythema and Stephens-Johnson's syndrome, photosensitivity and separate cases of exfoliative dermatitis.
Very exceptional cases of the acute generalized exanthematous pustulez (AGEP) need to be distinguished from psoriasis though hydroxychloroquine and can provoke an exacerbation of psoriasis. OGEP can be followed by temperature increase and a hyperleukocytosis. After drug withdrawal an outcome usually favorable.
- From digestive tract
Nausea, diarrhea, anorexia, abdominal pains and seldom vomiting. These symptoms usually pass at once after a dose decline or drug withdrawal.
- From gepato-biliary system
At prolonged use in high doses development of a hepatotoxic action is possible. There are messages on isolated cases of abnormal liver functions and several cases of suddenly developed liver failure.
- From the central nervous system
Infrequently: dizziness, sonitus, hearing loss, headache, irritability, emotional instability, psychoses, spasms, muscular weakness, ataxy.
- From a peripheral nervous system and muscles
The cases of a myopathy of skeletal muscles or neuromyopathies leading to the progressing weakness and an atrophy of proximal muscular groups are noted. The myopathy can be reversible after drug withdrawal, but for a complete recovery several months can be required. At the same time weak touch changes, suppression of tendon jerks and decrease in nerve conduction can be observed.
- From cardiovascular system
There are rare messages on development of a cardiomyopathy.
Chronic cardial toxicity can be suspected at detection of disturbances of conductivity (blockade of legs of a bunch of Gisa / disturbances of atrioventricular conductivity) or hypertrophies of both ventricles. At drug withdrawal involution of these changes is possible.
- From bodies of a hemopoiesis
Cases of oppression of a marrowy hemopoiesis were seldom noted. It was reported about exceptional cases of anemia, aplastic anemia, an agranulocytosis, leukopenia and thrombocytopenia.
Gidroksikhlorokhin can provoke or cause a porphyria aggravation.
From immune system
Small tortoiseshell, Quincke's disease, bronchospasm.

Interaction with other medicines:

It was reported that hydroxychloroquine is capable to increase plasma concentration of digoxin therefore, in order to avoid development of glikozidny intoxication at a concomitant use of these drugs, it is necessary to reduce a digoxin dose under control of plasma concentration of digoxin.
With the drugs used for treatment of a diabetes mellitus
As hydroxychloroquine can strengthen effects of insulin and peroral hypoglycemic means, reduction of doses of these hypoglycemic drugs at the beginning of reception of hydroxychloroquine can be required.
With antacids
Antacids can reduce hydroxychloroquine absorption. Therefore at simultaneous use of antacids and hydroxychloroquine the interval between their reception has to make not less than 4 hours.
At hydroxychloroquine it is also impossible to exclude the listed below interactions with other medicines which were described for chloroquine, but were not observed at hydroxychloroquine reception yet.
From aminoglycoses ides
Potentiation of their direct blocking action on neuromuscular transmission. With Cimetidinum
Cimetidinum suppresses metabolism of anti-malarial drugs that can lead to increase in their plasma concentration and increase risk of development of their side effects, especially toxic.
With neostigminy and pyridostigmine
Antagonism of action.
With any intradermal human diploid and cellular vaccine against rage
Reduction of antibody formation in response to primary immunization by an intradermal human diploid and cellular vaccine against rage.

Contraindications:

- Hypersensitivity to derivatives 4 aminoquinolines.
- Retinopathy.
- Children's age in need of long therapy (children have an increased risk of development of toxic effects).
- Children's age up to 6 years (tablets on 200 mg are not intended for children with "ideal" body weight less than 31 kg).
- Pregnancy (see. "Pregnancy and lactation").
- A hereditary lactose intolerance, insufficiency of lactase, a galactosemia or a sprue of a glucose/galactose (because of presence at composition of drug of lactose)
With care
- At visual frustration (decrease in visual acuity, disturbance of color sight, narrowing of fields of vision), a concomitant use of the drugs capable to cause adverse ophthalmologic reactions (danger of progressing of a retinopathy and visual frustration);
- At hematologic diseases (including in the anamnesis);
- At a serious neurologic illness, psychoses (including in the anamnesis);
- At a late skin porphyria (risk of an aggravation), psoriasis (risk of strengthening of skin displays of a disease), a concomitant use of the drugs capable to cause skin reactions;
- At a renal failure and/or a liver failure, hepatitis, a concomitant use of the drugs capable it is adverse to influence function of a liver and/or kidneys (at heavy renal failures or a liver the dose has to be selected under control of plasma concentration of hydroxychloroquine);
- At deficit glyukozo-6-fosfatdegidrogenazy;
- At a serious gastrointestinal illness;
- At hypersensitivity to quinine (a possibility of cross allergic reactions).
PREGNANCY AND LACTATION
Gidroksikhlorokhin gets through a placenta. Concerning its use during pregnancy data are limited. It should be noted that 4 aminoquinolines in therapeutic doses can cause pre-natal injuries of the central nervous system, including an acoustical nerve (disturbance from hearing and a vestibular mechanism, inborn deafness), retinal apoplexies of an eye and abnormal pigmentation of a retina. Therefore it is necessary to avoid use of hydroxychloroquine at pregnancy, except for cases when the potential advantage for mother exceeds risk for a fruit.
It is necessary to weigh carefully need of use of drug during feeding by a breast as it is shown that it in small amounts is emitted in maternal milk, and small children are especially sensitive to toxic effects of 4 aminoquinolines.

Overdose:

The overdose of 4 aminoquinolines is especially dangerous at children, even 1-2 g of drug can lead to death.
Symptoms of overdose include a headache, vision disorders, a collapse, spasms, a hypopotassemia, disturbances of a rhythm and conductivity which the cardiac standstill and breath follows. As these effects can develop very quickly after acceptance of a high dose of drug, in these cases it is necessary to begin carrying out the appropriate measures immediately. Artificial calling of vomiting or a gastric lavage via the probe has to be carried immediately out. Absorbent carbon in a dose, at least by 5 times exceeding the accepted drug dose can slow down absorption. Reasonablly parenteral administration of diazepam (reduction of cardiotoxicity of chloroquine on its background is described).
If necessary it is necessary to carry out artificial ventilation of the lungs and antishock therapy.
After stopping of symptoms of overdose continuation of constant medical observation within not less than 6 hours is required.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. List B. Period of validity 3 years. Not to accept drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 200 mg.
On 10 tablets in the blister from PVC and aluminum foil. On 6 blisters together with the application instruction in a cardboard pack.