INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSYNOKSIS® (KSYNOKSIS)

Composition:

Active substance: hydroxychloroquine;

1 tablet contains hydroxychloroquine sulfate 200 mg;

Excipients: lactose monohydrate, corn starch, povidone, magnesium stearate;
Coating: Opadry 03F180011 White (hypromellose, titanium dioxide, macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round-shaped, biconvex tablets, film-coated.

Pharmacotherapeutic group. Antiparasitic medicinal products. Antimalarial agents. Aminoquinolines. Hydroxychloroquine.

ATC code P01BA02.

Pharmacological Properties

Pharmacodynamics

Antimalarial drugs 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 effect on monocyte production of interleukin-1, and inhibition of superoxide release by neutrophils.

Pharmacokinetics

Absorption

After oral administration, peak blood concentrations are reached in approximately 4 hours. The absolute bioavailability following oral administration is 79%.

Distribution

Hydroxychloroquine has a large volume of distribution due to extensive tissue accumulation (5500 L – in blood, 44000 L – in plasma) 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 bisdesethylchloroquine. Based on data from chloroquine, it can be extrapolated that hydroxychloroquine may be metabolized in vitro by the same CYP enzymes as chloroquine, namely CYP2C8 and CYP3A, and to a lesser extent CYP2D6.

Elimination

Hydroxychloroquine exhibits a multi-phase elimination profile with a prolonged terminal half-life ranging from 30 to 60 days. Approximately 20–25% of the hydroxychloroquine dose is excreted in urine as unchanged drug.

Clinical characteristics.

Indications.

Adults

Treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, as well as dermatological conditions whose onset 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 Xynoxys®.
Age under 6 years (200 mg tablets are not suitable for patients with body weight <35 kg) or ideal body weight <31 kg (see section "Method of administration and dosage").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Medicinal products with known QT-prolonging effect/potential to cause cardiac arrhythmia

Hydroxychloroquine should be used with caution in patients receiving medicinal products with known QT-prolonging effects, such as class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, and certain anti-infective agents, due to increased risk of ventricular arrhythmia (see sections "Special precautions for use" and "Overdose"). Halofantrine must not be co-administered with hydroxychloroquine.

Since hydroxychloroquine may potentiate the effect of hypoglycemic therapy, dosage reduction of insulin or antidiabetic agents may be required.

Concomitant use of hydroxychloroquine and antimalarial agents known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures. A decreased efficacy of antiepileptic medicinal products may be observed when used concomitantly with hydroxychloroquine.

Where possible, concomitant use of the drug with medicinal products having ocular or hematotoxic potential should be avoided.

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.

Effect of other medicinal products on hydroxychloroquine

Antacids

Concomitant use with magnesium-containing antacids or kaolin may reduce the absorption of chloroquine. Therefore, by extrapolation, hydroxychloroquine should be administered separately, at least two hours before or after antacids or kaolin.

Inhibitors or inducers of CYP

Concomitant use of cimetidine, a moderate inhibitor of CYP2C8 and CYP3A4, resulted in a doubling of chloroquine exposure. By extrapolating these data, considering the structural and pharmacokinetic similarities between hydroxychloroquine and chloroquine, a similar effect can be expected with hydroxychloroquine. Caution is recommended (e.g., monitoring for adverse effects) when co-administering strong or moderate inhibitors of CYP2C8 and CYP3A4 (such as gemfibrozil, clopidogrel, ritonavir, itraconazole, clarithromycin, grapefruit juice).

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

Effect of hydroxychloroquine on other medicinal products

P-glycoprotein substrates

The potential of hydroxychloroquine to inhibit P-glycoprotein substrates has not been evaluated. In vitro observations show that all other tested aminoquinolines inhibit P-glycoprotein. Therefore, there is a possibility of increased plasma concentrations of P-glycoprotein substrates when co-administered with hydroxychloroquine. Increased plasma levels of cyclosporine have been reported when cyclosporine and hydroxychloroquine were used concomitantly. Elevated serum levels of digoxin have been reported when digoxin and hydroxychloroquine were co-administered. Caution is recommended (e.g., monitoring for adverse effects or plasma concentrations, if appropriate) when co-administering with P-glycoprotein substrates with a narrow therapeutic index (such as digoxin, cyclosporine, dabigatran).

In a drug interaction study, single-dose administration of chloroquine reduced the bioavailability of praziquantel. It is currently unknown whether a similar effect will occur with concomitant administration 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 initiating treatment with Xynoxys®. Subsequently, such examinations should be performed at least every 12 months. Toxic reactions affecting the retina are predominantly dose-dependent. The risk of retinal damage is low when daily doses do not exceed 6.5 mg/kg body weight. Exceeding the recommended daily dose increases the risk of retinal toxic reactions.

During ophthalmological examination, visual acuity should be assessed, thorough ophthalmoscopy and fundoscopy performed, and central visual field testing with red target and color vision evaluated.

Examinations should be performed more frequently, adapted to individual patient characteristics, in the following cases:

daily dose exceeds 6.5 mg per 1 kg of ideal (non-increased) body weight; using actual body weight for dose calculation in obese patients may lead to overdosing;
renal impairment;
visual acuity below 6/8;
age over 65 years;
cumulative dose exceeding 200 g.

Treatment with Xynoxys® should be discontinued immediately if pigmentary disturbances, visual field defects, or other abnormalities not attributable to accommodation disorders are observed (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 bpm));
history of ventricular arrhythmias;
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").

Chronic cardiac toxicity

Cases of cardiomyopathy leading to heart failure, sometimes fatal, have been reported in patients receiving hydroxychloroquine treatment (see sections "Side effects" and "Overdose"). Clinical monitoring for signs and symptoms of cardiomyopathy is therefore recommended. If cardiomyopathy develops, treatment with Xynoxys® should be discontinued. In cases of diagnosed conduction disorders (bundle branch block/atrioventricular block) or biventricular hypertrophy, chronic drug toxicity should be considered (see section "Side effects").

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

The drug should also be used with caution:

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

Other monitoring during long-term treatment

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

In all patients receiving long-term treatment with the drug, periodic assessment of skeletal muscle function and tendon reflexes should be performed. 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, those with glucose-6-phosphate dehydrogenase deficiency, patients suffering from chronic hematoporphyria, as the course of these conditions may worsen under the influence of hydroxychloroquine, and in psoriatic patients, as the risk of skin reactions increases.

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 initiation of 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 occur 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 Xynoxys® 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 presenting clinical symptoms suggestive of hypoglycemia during hydroxychloroquine treatment, blood glucose levels should be monitored; if necessary, treatment should be reviewed.

Extrapyramidal disorders may occur during treatment with Xynoxys® (see section "Side effects").

Potential carcinogenic risk

Experimental data indicate a potential risk of inducing gene mutations. Carcinogenicity study data in animals are available only for one animal species treated with the parent compound chloroquine, and the results obtained were negative. In humans, there are currently insufficient data to exclude an increased risk of cancer in patients receiving long-term treatment.

Severe skin adverse reactions

Cases of severe skin adverse reactions have been reported, including drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, and toxic epidermal necrolysis. 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.

Use during pregnancy or breastfeeding

Pregnancy

There are only limited preclinical data available for hydroxychloroquine. In animal studies, chloroquine (a compound related to hydroxychloroquine) showed reproductive toxicity after administration at high doses in the maternal organism. Preclinical data for chloroquine indicate a potential genotoxicity risk in certain test systems.

For hydroxychloroquine used in long-term therapy of autoimmune diseases at high doses: observational studies and a meta-analysis including data from prospective studies with long-term, high-dose use did not reveal a statistically significant increase in the risk of congenital malformations or adverse pregnancy outcomes.

Hydroxychloroquine crosses the placenta. 4-aminoquinolines at therapeutic doses may cause central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal hemorrhages, and abnormal retinal pigmentation. These effects have not been confirmed in larger series/observational studies. Observational studies and a meta-analysis including data from prospective studies with long-term, high-dose use did not reveal a statistically significant increase in the risk of congenital malformations or adverse clinical outcomes of pregnancy.

Therefore, the use of hydroxychloroquine sulfate during pregnancy should be avoided, except when, in the physician's opinion, the individual potential benefit outweighs the potential risks.

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. It is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

Currently, very limited data are available on the safety of long-term hydroxychloroquine use in breastfed infants; 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. In animal studies, chloroquine (a compound related to hydroxychloroquine) showed adverse effects on male fertility.

Ability to influence reaction speed when driving vehicles or operating machinery

Since visual disturbances due to accommodation disorders, which may cause blurred vision, may occur shortly after initiation of treatment, patients should exercise caution when driving 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.

Xinoksis® is intended for oral administration. Each dose should be taken with food or with 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 the patient's condition does not improve within 6 months of treatment for a rheumatic disease, the drug should be discontinued.

In diseases associated with increased sensitivity to light, treatment should be conducted only during periods of maximum insolation.

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 children with an ideal body weight less than 31 kg.

Children.

The minimum effective dose should be used, not exceeding 6.5 mg per 1 kg of ideal body weight per day. Therefore, 200 mg tablets are not suitable for children with an ideal body weight less than 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 disturbances, including QT interval prolongation, ventricular tachycardia torsade de pointes, ventricular tachycardia, and ventricular fibrillation, widening of QRS complexes, bradyarrhythmia, junctional rhythm, atrioventricular block, followed suddenly by 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 by gastric lavage. Activated charcoal, 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, parenteral administration of diazepam should be considered. This agent has been shown to reduce cardiotoxic effects caused by chloroquine.

If necessary, measures should be taken to maintain respiration and to provide anti-shock therapy.

Side effects.

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

Blood and lymphatic system disorders

Frequency not known: bone marrow depression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Immune system disorders

Frequency not known: urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders

Common: loss of appetite.

Frequency not known: hypoglycemia.

Hydroxychloroquine may exacerbate the course of porphyria.

Psychiatric disorders

Common: affective lability.

Uncommon: nervousness.

Frequency not known: psychosis, suicidal behavior, depression, hallucinations, anxiety, agitation, confusion, delirium, 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 precautions").

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.

In the early stages, retinopathy may be reversible after discontinuation of Xinoxis®. However, if treatment is not promptly discontinued, there is a risk of progression of retinopathy even after stopping the drug.

In patients with retinopathy, symptoms may initially be asymptomatic or may include paracentral or pericentral ring scotomas, temporal scotomas, or disturbances in color vision.

Corneal changes, including edema 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 precautions" and "Overdose").

If conduction disorders (bundle branch block/atrioventricular block) or biventricular hypertrophy are diagnosed, chronic drug toxicity should be considered. Discontinuation of the drug may lead to resolution of these abnormalities.

Gastrointestinal disorders

Very common: abdominal pain, nausea.

Common: diarrhea, vomiting.

These symptoms usually resolve immediately 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 reactions usually resolve quickly after discontinuation of treatment.

Frequency not known: bullous eruptions, including 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 syndrome), acute generalized exanthematous pustulosis (see section "Special precautions"), which should be differentiated from psoriasis.

Hydroxychloroquine may trigger psoriasis flare-ups, which may be accompanied by fever and hyperleukocytosis. The outcome is usually favorable after discontinuation of hydroxychloroquine.

Musculoskeletal and connective tissue disorders

Uncommon: sensory-motor disorders.

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.

Decreased tendon reflexes and abnormal nerve conduction.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister. 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.