Plaquenil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PLAKVENIL® (PLAQUENIL)

Composition:

Active substance: hydroxychloroquine;

1 tablet contains hydroxychloroquine sulfate 200 mg;

Excipients: lactose monohydrate, povidone, maize starch, magnesium stearate; coating: Opadry OY-L-28900 (hypromellose, titanium dioxide (E 171), polyethylene glycol, lactose monohydrate).

Pharmaceutical form. Film-coated tablets

Main physicochemical properties: white, biconvex, film-coated tablets with flat edges, marked «HСQ» on one side and «200» on the other.

Pharmacotherapeutic group. Antiparasitic medicinal products. Antimalarial agents. Aminoquinolines. Hydroxychloroquine. ATC code P01BA02.

Pharmacological properties.

Pharmacodynamics.

Antimalarial agents such as chloroquine and hydroxychloroquine exert several pharmacological effects that contribute to their therapeutic efficacy in the treatment of rheumatic diseases, although the role of each of these mechanisms remains unknown. These effects include interaction with sulfhydryl groups, alteration of enzyme activity (including phospholipase, NADH-cytochrome C reductase, cholinesterase, proteases and hydrolases), binding to DNA, stabilization of lysosomal membranes, inhibition of prostaglandin production, inhibition of chemotaxis and phagocytosis by polymorphonuclear cells, possible influence on monocyte production of interleukin-1, and inhibition of superoxide release by neutrophils.

Pharmacokinetics.

Absorption

Following oral administration, peak blood or plasma concentrations are reached approximately within 3–4 hours. The mean absolute bioavailability after oral administration on an empty stomach is 79% (CV 12%). Food intake does not affect the oral bioavailability of hydroxychloroquine.

Distribution

Hydroxychloroquine has a large volume of distribution (5,500 L in blood, 44,000 L in plasma) due to extensive tissue accumulation (such as in eyes, kidneys, liver, and lungs) and demonstrates accumulation in blood cells with a whole blood to plasma concentration ratio of 7.2. Approximately 50% of hydroxychloroquine is protein-bound in plasma.

Metabolism

Hydroxychloroquine is primarily metabolized to N-desethylhydroxychloroquine and two other metabolites shared with chloroquine, desethylchloroquine and bidesethylchloroquine. In vitro, hydroxychloroquine is metabolized mainly by CYP2C8, CYP3A4, and CYP2D6, as well as by FMO-1 and MAO-A, without significant involvement of any single CYP or enzyme.

Elimination

Hydroxychloroquine has a multi-phasic elimination profile with a prolonged terminal half-life ranging from 30 to 50 days. Approximately 20–25% of the dose is excreted unchanged in urine. After long-term repeated oral administration of hydroxychloroquine sulfate at doses of 200 mg and 400 mg once daily in adult patients with lupus or rheumatoid arthritis, the mean steady-state blood concentration was 450–490 ng/mL and 870–970 ng/mL, respectively.

The pharmacokinetics of hydroxychloroquine are linear within the therapeutic dose range of 200 to 500 mg per day.

Pharmacokinetic interactions

Effect of hydroxychloroquine on other medicinal products

In vitro, hydroxychloroquine has no potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Hydroxychloroquine inhibits CYP2D6 and CYP3A4 in vitro. Interaction studies have demonstrated that hydroxychloroquine is a weak inhibitor of CYP2D6 (see section "Interaction with other medicinal products and other types of interactions").

In vitro, hydroxychloroquine has no significant potential to induce CYP1A2, CYP2B6, or CYP3A4. In vitro, hydroxychloroquine did not substantially inhibit the major transporters BCRP, OATP1B1, OATP1B3, OAT1, or OAT3. At high concentrations, hydroxychloroquine inhibited P-glycoprotein (see section "Interaction with other medicinal products and other types of interactions"). In vitro, hydroxychloroquine has the potential to inhibit the transporters OCT1, OCT2, MATE1, and MATE2-K.

Renal impairment

Renal impairment is not expected to significantly alter the pharmacokinetics of hydroxychloroquine in patients with impaired renal function, as hydroxychloroquine is primarily metabolized and only 20–25% of the dose is excreted unchanged in urine. An increase in hydroxychloroquine exposure by up to 46% may occur in patients with moderate to severe renal impairment (see section "Special warnings and precautions for use").

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of hydroxychloroquine has not been evaluated in a dedicated pharmacokinetic study. Given that hydroxychloroquine is primarily metabolized, increased exposure to hydroxychloroquine is expected in patients with hepatic impairment (see section "Special warnings and precautions for use").

Elderly patients

Available limited data in elderly patients with rheumatoid arthritis suggest that hydroxychloroquine exposure remains within the same range as in younger patients.

Paediatric population

The pharmacokinetics of hydroxychloroquine in children (under 18 years of age) has not been studied.

Preclinical safety data

Genotoxicity/carcinogenicity

Based on available studies, hydroxychloroquine has not shown genotoxicity. Appropriate non-clinical carcinogenicity studies with hydroxychloroquine are lacking.

Reproductive toxicity and developmental toxicity

Hydroxychloroquine crosses the placenta. Studies in mice and monkeys, which were not conducted in compliance with Good Laboratory Practice requirements, have demonstrated that transplacental transfer of chloroquine, a derivative of hydroxychloroquine, occurs with accumulation in fetal eye and ear tissues. High doses of chloroquine administered to pregnant rats were fetotoxic and caused anophthalmia and microphthalmia. Studies in rats showed that chloroquine reduces testosterone secretion, testicular and epididymal weight, and leads to an increased number of abnormal spermatozoa.

Clinical characteristics.

Indications.

Adults

Treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, as well as dermatological diseases whose occurrence or worsening is caused by exposure to sunlight.

Pediatric population

Treatment of juvenile idiopathic arthritis (in combination with other medicinal products), discoid and systemic lupus erythematosus.

Contraindications.

• Known hypersensitivity to 4-aminoquinoline compounds.
• Maculopathy diagnosed prior to initiation of treatment with Plaquenil®.
• Age under 6 years (200 mg tablets are unsuitable for patients with body weight < 35 kg) or ideal body weight < 31 kg (see section "Dosage and administration").

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions

Medicinal products with known QT-prolonging effect / potential to induce cardiac arrhythmia. Hydroxychloroquine should be used with caution in patients receiving medicinal products with known QT-prolonging effect, such as Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, certain anti-infective agents (antibacterials such as fluoroquinolones, e.g. moxifloxacin, macrolides, e.g. azithromycin, antiretrovirals such as saquinavir, antifungals such as fluconazole, antiparasitic agents such as pentamidine), due to increased risk of ventricular arrhythmia (see sections "Special warnings and precautions for use", "Overdose" and "Adverse reactions"). Halofantrine should not be administered concomitantly with hydroxychloroquine.

Since hydroxychloroquine may enhance the effect of hypoglycemic therapy, a reduction in the dose of insulin or antidiabetic agents may be required (see also "Hypoglycemia" in section "Special warnings and precautions for use" and section "Adverse reactions").

Concomitant use of hydroxychloroquine and antimalarial agents known to reduce the seizure threshold (e.g. mefloquine) may increase the risk of seizures (see section "Adive reactions").

Reduced efficacy of antiepileptic drugs may occur when used concomitantly with hydroxychloroquine.

Concomitant use of the drug with medicinal products having ocular toxicity (see also "Retinopathy" in section "Special warnings and precautions for use") or hematotoxic potential should be avoided if possible due to potential additive effects (see section "Adverse reactions").

There is a theoretical risk of inhibition of intracellular α-galactosidase activity when hydroxychloroquine is used concomitantly with agalsidase.

Hydroxychloroquine sulfate may also interact with some agents known to interact with chloroquine, even if specific reports are lacking. These include: enhanced direct neuromuscular blocking effect of aminoglycoside antibiotics; antagonism of the effects of neostigmine and pyridostigmine; reduced antibody response following primary immunization with intradermal human diploid cell rabies vaccine.

Pharmacokinetic interactions

Effect of other medicinal products on hydroxychloroquine

Antacids and kaolin

Concomitant administration with magnesium-containing antacids or kaolin may reduce the absorption of chloroquine. Therefore, by extrapolation, hydroxychloroquine should be administered separately from antacids and kaolin, with an interval of at least two hours.

CYP inhibitors or inducers

In vitro, hydroxychloroquine is primarily metabolized by CYP2C8, CYP3A4, and CYP2D6, without significant involvement of individual CYP enzymes. Concomitant use of cimetidine, a non-selective CYP inhibitor, has been shown to double the exposure to chloroquine. In the absence of in vivo drug interaction studies, caution is recommended (e.g. monitoring for adverse effects) when cimetidine or potent inhibitors of CYP2C8 and/or CYP3A4 or CYP2D6 (such as gemfibrozil, clopidogrel, ritonavir, itraconazole, clarithromycin, grapefruit juice, fluoxetine, paroxetine, quinidine) are used concomitantly.

Reduced efficacy of hydroxychloroquine has been reported when used concomitantly with rifampicin, a potent inducer of CYP2C8 and CYP3A4. Caution is recommended (e.g. monitoring of efficacy) when hydroxychloroquine is used concomitantly with strong inducers of CYP2C8 and/or CYP3A4 (such as rifampicin, St. John’s wort, carbamazepine, phenobarbital, phenytoin).

Effect of hydroxychloroquine on other medicinal products

P-glycoprotein substrates

At high concentrations, hydroxychloroquine inhibits P-glycoprotein in vitro. Therefore, there is a potential for increased concentrations of P-glycoprotein substrates when used concomitantly with hydroxychloroquine. Increased serum digoxin levels have been reported with concomitant use of digoxin and hydroxychloroquine. Caution is recommended (e.g. monitoring for adverse effects or plasma concentrations, if appropriate) when used concomitantly with P-glycoprotein substrates with a narrow therapeutic index (such as digoxin, dabigatran).

CYP2D6 substrates

Hydroxychloroquine inhibits CYP2D6 in vitro. In patients receiving hydroxychloroquine and a single dose of metoprolol for CYP2D6 phenotyping, Cmax and AUC of metoprolol increased by 1.7-fold, indicating that hydroxychloroquine is a weak inhibitor of CYP2D6. Caution is recommended (e.g. monitoring for adverse reactions or plasma concentrations, if appropriate) when concomitantly using CYP2D6 substrates with a narrow therapeutic index (such as flecainide, propafenone).

CYP3A4 substrates

Hydroxychloroquine inhibits CYP3A4 in vitro. Increased plasma levels of cyclosporine (a substrate of both CYP3A4 and P-glycoprotein) have been reported with concomitant use of cyclosporine and hydroxychloroquine. In the absence of in vivo interaction studies with sensitive CYP3A4 substrates, caution is recommended (e.g. monitoring for adverse reactions) when CYP3A4 substrates (such as cyclosporine, statins) are used concomitantly with hydroxychloroquine.

Praziquantel

In a drug interaction study with single-dose administration, chloroquine was shown to reduce the bioavailability of praziquantel. It is currently unknown whether a similar effect occurs with concomitant use of hydroxychloroquine and praziquantel. By extrapolating these data, considering the structural and pharmacokinetic similarities between hydroxychloroquine and chloroquine, a similar effect can be expected with hydroxychloroquine.

Special precautions for use.

Retinopathy.

All patients should undergo an ophthalmological examination before starting treatment with Plaquenil®. Subsequently, such examinations should be performed at least every 12 months.

Retinal toxic reactions are predominantly dose-dependent. The risk of retinal damage is low when daily doses do not exceed 6.5 mg/kg of body weight. Exceeding the recommended daily dose increases the risk of retinal toxic reactions.

During ophthalmological examination, visual acuity, careful ophthalmoscopy and fundoscopy, as well as central visual field testing with red target and color vision testing, should be performed.

More frequent examinations, adapted to individual patient characteristics, are required in the following cases:

− daily dose exceeds 6.5 mg per 1 kg of ideal (not increased) body weight; using actual body weight to calculate the dose in obese patients may lead to overdosing;

− renal insufficiency;

− visual acuity below 6/8;

− age over 65 years;

− cumulative dose exceeding 200 g.

Treatment with Plaquenil® should be discontinued immediately if the patient develops pigmentary disturbances, visual field defects, or other abnormalities unexplained by accommodation disorders (see also section "Side effects"). Monitoring of such patients should continue, as retinal changes and visual disturbances may progress even after discontinuation of the drug (see also section "Side effects").

Concomitant use of hydroxychloroquine with medicinal products known to cause retinal toxicity, such as tamoxifen, is not recommended.

QT interval prolongation. Hydroxychloroquine has the potential to prolong the QTc interval in patients with specific risk factors. Hydroxychloroquine should be used with caution in patients with congenital or documented acquired QT interval prolongation and/or known risk factors for QT interval prolongation, such as:

• cardiac diseases (e.g., heart failure, myocardial infarction);
• proarrhythmic conditions, e.g., bradycardia (< 50 beats/min);
• history of ventricular rhythm disorders;
• uncorrected hypokalemia and/or hypomagnesemia;
• concomitant use with drugs that prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction"), as this may increase the risk of developing ventricular arrhythmias.

The degree of QT interval prolongation may increase with increasing drug concentration. Therefore, the recommended dose should not be exceeded (see also sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

If signs of cardiac arrhythmias occur during hydroxychloroquine treatment, treatment should be discontinued and an ECG performed.

Chronic cardiac toxicity. Cases of cardiomyopathy leading to heart failure, sometimes with fatal outcome, have been reported in patients receiving treatment with Plaquenil® (see sections "Side effects" and "Overdose"). Therefore, clinical monitoring for signs and symptoms of cardiomyopathy is recommended. If cardiomyopathy develops, Plaquenil® should be discontinued. In case of diagnosed conduction disorders (bundle branch block / atrioventricular block), as well as biventricular hypertrophy, chronic drug toxicity should be considered (see section "Side effects").

Other warnings

The drug should be used with caution in patients taking medications that may cause adverse reactions affecting the eyes or skin. The drug should also be used with caution:

• in patients with liver or kidney disease, and in patients taking drugs that may adversely affect the function of these organs. In patients with severe impairment of kidney or liver function, plasma levels of hydroxychloroquine should be determined and the dose adjusted accordingly;
• in patients with severe gastrointestinal, neurological, and hematological disorders.

Other monitoring during long-term treatment.

In patients receiving long-term treatment, a complete blood count should be performed periodically. If pathological changes are detected, Plaquenil® should be discontinued (see section "Side effects").

In all patients receiving long-term treatment, periodic assessment of skeletal muscle function and tendon reflexes is necessary. If muscle weakness occurs, the drug should be discontinued (see section "Side effects").

The drug should be used with caution in patients sensitive to quinine, with glucose-6-phosphate dehydrogenase deficiency, chronic hematoporphyria, as the course of these diseases may worsen under the influence of hydroxychloroquine, and in patients with psoriasis, as the risk of skin reactions increases.

Severe skin reactions. Cases of severe skin adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during hydroxychloroquine treatment. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. If signs and symptoms suggestive of severe skin reactions occur, hydroxychloroquine should be discontinued immediately and alternative therapy considered.

Suicidal behavior and psychiatric disorders. Reports of suicidal behavior and psychiatric disorders have been received in some patients receiving hydroxychloroquine therapy (see section "Side effects").

Psychiatric adverse reactions usually occur within the first month after starting hydroxychloroquine treatment; such cases have also been reported in patients without prior history of psychiatric disorders. Patients should be advised to seek immediate medical attention if psychiatric symptoms develop during treatment.

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Young children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore, patients should be warned that Plaquenil® must be stored out of reach of children.

Hypoglycemia. Hydroxychloroquine has been shown to cause severe hypoglycemia, including loss of consciousness, which may be life-threatening, in patients taking or not taking antidiabetic medicinal products. Patients receiving hydroxychloroquine treatment should be warned about the risk of hypoglycemia and its associated clinical signs and symptoms. In patients with clinical symptoms suggestive of hypoglycemia during hydroxychloroquine treatment, blood glucose levels should be monitored and treatment reviewed if necessary.

Extrapyramidal disorders.

Extrapyramidal disorders may occur during the use of Plaquenil® (see section "Side effects").

Potential carcinogenic risk. Carcinogenicity study data in animals are available only for one biological species treated with the parent compound chloroquine, and the results were negative. For humans, insufficient data are currently available to exclude an increased risk of cancer in patients receiving long-term treatment.

Use during pregnancy or breastfeeding.

Pregnancy.

Moderate observational data (from 300 to 1000 pregnant women) and a meta-analysis with long-term use of the drug at high doses (mainly for autoimmune diseases) do not demonstrate a statistically significant increase in the risk of congenital malformations or fetal/neonatal toxicity associated with hydroxychloroquine use. Animal studies with structurally related chloroquine have shown toxic effects on reproductive function after administration of high doses to the maternal organism (see section "Preclinical safety data"). In humans, hydroxychloroquine crosses the placenta, and fetal blood concentrations are similar to maternal concentrations.

Hydroxychloroquine should be avoided during pregnancy, except when, in the physician's opinion, the individual potential benefit outweighs the potential risks. If hydroxychloroquine treatment is necessary during pregnancy, the lowest effective dose should be used. In cases of long-term treatment during pregnancy, the safety profile of hydroxychloroquine, particularly ophthalmological side effects, should be considered for monitoring the child's condition.

Breastfeeding. Hydroxychloroquine is excreted in breast milk (in amounts less than 2% of the maternal dose, adjusted for body weight). The necessity of long-term hydroxychloroquine use during breastfeeding should be carefully considered, taking into account the slow elimination rate of the drug and its potential to accumulate in toxic amounts in the infant's body. Infants are known to be extremely sensitive to the toxic effects of 4-aminoquinolines.

Currently, very limited data are available on the safety of long-term hydroxychloroquine use in infants breastfed; when prescribing the drug, the physician must evaluate the potential risks and benefits of its use during breastfeeding, considering the indication and duration of treatment.

Fertility. Data on the effect of hydroxychloroquine sulfate on human fertility are lacking. Animal studies have shown that chloroquine impairs fertility in males (see section "Preclinical safety data").

Ability to affect reaction speed when driving vehicles or operating machinery.

Since visual disturbances due to accommodation disorders, which may cause blurred vision, may occur shortly after starting treatment, patients should exercise caution when driving vehicles or performing tasks requiring high attention. If this condition does not resolve spontaneously, it resolves with dose reduction or discontinuation of treatment.

Method of Administration and Dosage

Plaquenil® is intended for oral administration. Each dose should be taken with food or a glass of milk.

The effect of hydroxychloroquine is cumulative; therefore, several weeks are required to achieve a therapeutic effect, while minor adverse effects may occur relatively early. If there is no improvement in the patient's condition within 6 months of treatment for rheumatic disease, the drug should be discontinued.

For diseases associated with increased photosensitivity, treatment should only be carried out during periods of maximum sun exposure.

Adults and elderly patients.

The minimum effective dose should be used. This dose must not exceed 6.5 mg/kg/day (based on ideal body weight, not actual body weight) and should be either 200 mg or 400 mg per day.

Children.

The minimum effective dose should be used, not exceeding 6.5 mg/kg/day based on ideal body weight. Therefore, 200 mg tablets are not suitable for use in children with an ideal body weight below 31 kg.

Children. The minimum effective dose should be used, not exceeding 6.5 mg per kg of ideal body weight per day. Thus, 200 mg tablets are not suitable for use in children with an ideal body weight below 31 kg.

Overdose.

Overdose of 4-aminoquinolines is particularly dangerous in infants, as ingestion of even 1–2 grams may result in a fatal outcome.

Symptoms of overdose may include headache, visual disturbances, cardiovascular collapse, seizures, hypokalemia, rhythm and conduction disorders, including QT interval prolongation, ventricular tachycardia torsade de pointes, ventricular tachycardia and ventricular fibrillation, widened QRS complexes, bradyarrhythmias, junctional rhythm, atrioventricular block, followed by sudden, sometimes fatal, respiratory and cardiac arrest. These events may occur shortly after overdose; therefore, immediate medical intervention is required. Gastric contents must be promptly removed by inducing emesis or gastric lavage. Activated charcoal, administered in a dose at least five times greater than the ingested dose of the drug, may slow further absorption if administered via a gastric tube after lavage and no later than 30 minutes after drug ingestion.

In case of overdose, consider the possibility of parenteral administration of diazepam. This drug has been shown to reduce cardiotoxic effects caused by chloroquine.

If necessary, measures should be taken to support respiration and to carry out anti-shock therapy.

Adverse Reactions

The following frequency criteria, as recommended by the Council for International Organizations of Medical Sciences (CIOMS), have been used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Disorders of the blood and lymphatic system

Frequency not known: bone marrow suppression, anaemia, aplastic anaemia, agranulocytosis, leucopenia, thrombocytopenia.

Immune system disorders

Frequency not known: urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders

Common: loss of appetite.

Frequency not known: hypoglycaemia.

Hydroxychloroquine may exacerbate the course of porphyria.

Psychiatric disorders

Common: affective lability.

Uncommon: nervousness.

Frequency not known: psychosis, suicidal behaviour, depression, hallucinations, anxiety, agitation, confusion, delirium, delusions, mania, and sleep disorders.

Nervous system disorders

Common: headache.

Uncommon: dizziness.

Frequency not known: seizures have been reported with the use of this class of medicinal products.

Extrapyramidal disorders such as dystonia, dyskinesia, and tremor (see section "Special warnings and precautions for use").

Eye disorders

Common: blurred vision due to impaired accommodation, which is dose-dependent and reversible.

Uncommon: retinopathy may occur, with pigmentary changes and visual field defects.

At an early stage, retinopathy associated with Plaquenil® treatment is reversible after discontinuation of the drug. If treatment is not promptly discontinued, there is a risk of progression of retinopathy even after stopping the drug.

Patients with retinopathy may initially be asymptomatic or may experience paracentral or pericentral ring-shaped scotomas, temporal scotomas, or disturbances in colour vision.

Corneal changes, including oedema and clouding, have been reported. These may be asymptomatic or may cause disturbances such as halos, blurred vision, or photophobia. These changes may be transient and resolve after discontinuation of treatment.

Frequency not known: cases of maculopathy and macular degeneration have been reported, which may be irreversible.

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus.

Frequency not known: hearing loss.

Cardiac disorders

Frequency not known: QT interval prolongation in patients with specific risk factors, which may lead to arrhythmias (torsade de pointes, ventricular tachycardia); cardiomyopathy, which may lead to heart failure, in some cases with fatal outcome (see sections "Special warnings and precautions for use" and "Overdose").

In cases of diagnosed conduction disorders (bundle branch block / atrioventricular block) or biventricular hypertrophy, chronic drug toxicity should be considered. Discontinuation of the drug may result in resolution of these abnormalities.

Gastrointestinal disorders

Very common: abdominal pain, nausea.

Common: diarrhoea, vomiting.

These symptoms usually resolve promptly after dose reduction or discontinuation of treatment.

Hepatobiliary disorders

Uncommon: abnormal liver function test results.

Frequency not known: fulminant hepatic failure.

Skin and subcutaneous tissue disorders

Common: skin rash, pruritus.

Uncommon: skin and mucous membrane pigmentation changes, hair decolorization, alopecia.

These effects usually resolve rapidly after discontinuation of treatment.

Frequency not known: erythema multiforme, photosensitivity, exfoliative dermatitis, Sweet’s syndrome, and severe skin adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (see section "Special warnings and precautions for use"), which should be differentiated from psoriasis. Hydroxychloroquine may trigger psoriasis flares, which may be accompanied by fever and hyperleukocytosis. The outcome is usually favourable after discontinuation of hydroxychloroquine.

Musculoskeletal and connective tissue disorders

Uncommon: sensory-motor disturbances.

Frequency not known: myopathy of skeletal muscles or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups.

Myopathy may be reversible after discontinuation of the drug, but full recovery may take several months.

Diminished tendon reflexes and abnormal nerve conduction.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of reach of children. Store at a temperature not exceeding 25 °C.

Packaging.

No. 60 (15×4): 15 tablets in a blister, 4 blisters in a cardboard box.

No. 60 (10×6): 10 tablets in a blister, 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

SANOFI-AVENTIS S.A., Spain.

Manufacturer's address and location of operations.

Ctra. C-35 (La Batlloria-Hostalric, km 63,09) 17404 Riells i Viabrea (Girona), Spain.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine", Ukraine / Sanofi-Aventis Ukraine LLC, Ukraine.