Plaquenil^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Sanofi-Aventis S.A. (Spain)

Contact Information

SANOFI

ATC Code

P01BA02 (Hydroxychloroquine)

Active Substance

Hydroxychloroquine (Rec.INN registered by WHO)

Dosage Form

Plaquenil®

Film-coated tablets, 200 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, engraved with “HCQ” on one side and “200” on the other.

Excipients: lactose monohydrate, povidone K25, corn starch, magnesium stearate, Opadry OY-L-28900 (hypromellose, macrogol 4000, titanium dioxide (E171), lactose monohydrate).

10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

A 4-aminoquinoline derivative. An antimalarial and amoebicidal drug. An immunosuppressant

Pharmacotherapeutic Group

Antiprotozoal agents; antimalarial agents; aminoquinolines

Pharmacological Action

Plaquenil^® has antimalarial properties and also has anti-inflammatory and immunosuppressive effects in chronic discoid or systemic lupus erythematosus (SLE), acute and chronic rheumatoid arthritis. Its mechanism of action in malaria, SLE, and rheumatoid arthritis is not fully known.

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

Efficacy in SLE and rheumatoid arthritis is associated with the following anti-inflammatory and immunomodulatory effects of hydroxychloroquine:

• Increased intracellular pH leads to a slowed antigenic response and reduces the binding of peptides to major histocompatibility complex (MHC) receptors; fewer antigen-MHC receptors reach the cell surface, leading to a reduced autoimmune response;
• Decreased activity of phospholipase A2 at high concentrations, lysosomal enzymes;
• Decreased concentrations of cytokines IL-1 and IL-6, leading to a reduction in clinical and laboratory parameters of autoimmune response; since there is no impairment of interferon gamma synthesis, these effects may be associated with a selective effect on cytokines;
• Inhibition of pre- and/or post-transcription of DNA and RNA.

The drug actively suppresses asexual erythrocytic forms, as well as gametocytes of Plasmodium vivax and Plasmodium malariae, which disappear from the blood almost simultaneously with the asexual forms. Plaquenil^® does not act on gametocytes of Plasmodium falciparum. It is not effective against chloroquine-resistant strains of Plasmodium falciparum, and is not active against the exoerythrocytic forms of Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale and therefore cannot prevent infection with these microorganisms when prescribed for prophylactic purposes, nor can it prevent relapse of the disease caused by these pathogens.

Pharmacokinetics

Absorption

After oral administration, Hydroxychloroquine is rapidly and almost completely absorbed from the gastrointestinal tract. In healthy volunteers after a single dose of 400 mg, C_max of hydroxychloroquine in plasma was reached in 1.83 h and ranged from 53 to 208 ng/ml.

Distribution

Plasma protein binding – 45%.

The unchanged drug and its metabolites are well distributed in the body. V_d is 5-10 L/kg. Hydroxychloroquine accumulates in tissues with high metabolic rates – in the liver, kidneys, lungs, spleen (concentrations in these organs exceed plasma concentrations by 200-700 times), in the CNS, erythrocytes, leukocytes, as well as in the retina and tissues rich in melanin.

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

Metabolism

In the liver, Hydroxychloroquine is partially converted into active ethylated metabolites.

Excretion

The mean T_1/2 from plasma varies depending on the time elapsed after drug administration as follows: 5.9 h (from reaching C_max to 10 h), 26.1 h (from 10 to 48 h) and 299 h (from 48 to 504 h).

Hydroxychloroquine and its metabolites are excreted mainly in the urine and to a lesser extent in the bile. Drug elimination is slow, the terminal T_1/2 is about 50 days (from whole blood) and 32 days (from plasma). Within 24 hours, 3% of the administered dose of the drug is excreted in the urine.

Indications

• Rheumatoid arthritis;
• Juvenile rheumatoid arthritis;
• Systemic lupus erythematosus;
• Discoid lupus erythematosus.

Malaria (except for chloroquine-resistant strains of Plasmodium falciparum)

• For the prevention and treatment of acute attacks of malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, as well as susceptible strains of Plasmodium falciparum;
• For radical cure of malaria caused by susceptible strains of Plasmodium falciparum.

ICD codes

Dosage Regimen

Plaquenil^® is intended for oral use only. The drug should be taken with meals or with a glass of milk.

All drug doses are given based on Hydroxychloroquine sulfate and are not equivalent to base doses.

Treatment of rheumatoid arthritis

Hydroxychloroquine has cumulative activity. Several weeks of drug administration are required for its therapeutic effect to manifest, while side effects may appear relatively early. The required therapeutic effect develops after several months of drug administration. If there is no objective improvement in the patient’s condition within 6 months of taking hydroxychloroquine, the use of the drug should be discontinued.

Adults (including elderly persons) the drug is prescribed at the minimum effective dose. The dose should not exceed 6.5 mg/kg of body weight per day (calculated based on ideal, not actual body weight) and can be either 200 mg or 400 mg/day.

In patients able to take 400 mg daily, the initial dose is 400 mg daily in divided doses. When obvious improvement in condition is achieved, the dose may be reduced to 200 mg. If effectiveness decreases, the maintenance dose may be increased to 400 mg.

Children the drug is prescribed at the minimum effective dose. The dose should not exceed 6.5 mg/kg of body weight (based on ideal body weight), therefore 200 mg tablets are not intended for children weighing less than 31 kg.

The use of Plaquenil^® in combination with corticosteroids, salicylates, NSAIDs, methotrexate and other second-line therapeutic agents is safe. After several weeks of Plaquenil^® use, the doses of corticosteroids and salicylates may be reduced or the use of these drugs may be discontinued. Corticosteroid doses should be reduced gradually every 4-5 days: cortisone dose – by no more than 5-15 mg, hydrocortisone dose – by no more than 5-10 mg, prednisolone and prednisone dose – by no more than 1-2.5 mg, methylprednisolone and triamcinolone dose – by no more than 1-2 mg and dexamethasone dose – by no more than 0.25-0.5 mg.

Treatment of systemic lupus erythematosus

Adults are prescribed an initial average dose of 400 mg 1-2 times/day for several weeks or months depending on the patient’s response. For long-term maintenance therapy, the use of the drug in a lower dose from 200 to 400 mg is sufficient.

Treatment of malaria

For the prevention of acute attacks of malaria caused by Plasmodium malariae and susceptible strains of Plasmodium falciparum, adults are prescribed the drug at a dose of 400 mg weekly on the same day of the week. For children, the weekly dose is 6.5 mg/kg (ideal body weight is used for calculation), but regardless of body weight, the dose for children should not exceed the dose for adults.

If conditions allow, prophylactic therapy should be started 2 weeks before entering the endemic area. If this is not possible, an initial double (loading) dose can be prescribed: adults – 800 mg, children – 12.9 mg/kg of ideal body weight (but not more than 800 mg), divided into two doses with a 6-hour interval. Prophylactic treatment should be continued for 8 weeks after leaving the endemic area.

For treatment of acute attacks of malaria, adults are prescribed the drug at a dose of 800 mg, then after 6-8 hours – 400 mg, then on the next 2 days – 400 mg each (a total of 2 g of hydroxychloroquine sulfate).

Alternative treatment method the efficacy of a single dose of 800 mg has also been proven.

The dose for adults, as well as for children, can be calculated taking into account the ideal body weight.

Children are prescribed the drug in a total dose of 32 mg/kg (but not more than 2 g) over 3 days according to the following scheme:

First dose – 12.9 mg/kg (not exceeding a single dose of 800 mg);

Second dose – 6.5 mg/kg (not exceeding 400 mg) 6 hours after the first dose;

Third dose – 6.5 mg/kg (not exceeding 400 mg) 18 hours after the second dose;

Fourth dose – 6.5 mg/kg (not exceeding 400 mg) 24 hours after the third dose.

For radical cure of malaria caused by Plasmodium malariae and Plasmodium vivax, simultaneous administration of 8-aminoquinoline derivatives is necessary.

Adverse Reactions

From the organ of vision rarely – retinopathy with changes in pigmentation and visual field defects. In the early form, retinopathy is reversible upon discontinuation of hydroxychloroquine treatment. If retinopathy persists, there may be a risk of irreversible retinal damage even after treatment discontinuation. Retinal changes may initially be asymptomatic, or manifest as paracentral or pericentral scotomas, transient scotoma, impaired color vision.

Corneal changes are possible, including edema and opacities. They may be asymptomatic or cause disturbances such as halos, blurred vision, or photophobia. These changes may be reversible upon discontinuation of treatment.

Decreased vision due to accommodation disturbance is possible, which is dose-dependent and reversible.

Dermatological reactions skin rashes, itching, changes in skin and mucous membrane pigmentation, hair discoloration and alopecia are possible. These reactions usually resolve quickly upon discontinuation of treatment.

Development of bullous rash has been reported, including very rare cases of erythema multiforme and Stevens-Johnson syndrome, photosensitivity and isolated cases of exfoliative dermatitis.

Very rare cases of acute generalized exanthematous pustulosis (AGEP) must be distinguished from psoriasis, although Hydroxychloroquine can provoke exacerbation of psoriasis. AGEP may be accompanied by fever and hyperleukocytosis. After drug withdrawal, the outcome is usually favorable.

From the digestive system nausea, diarrhea, anorexia, abdominal pain; rarely – vomiting. These reactions usually resolve immediately after dose reduction or discontinuation of treatment. With long-term use and in high doses, hepatotoxicity is possible. In isolated cases – impaired liver function; in rare cases – sudden onset liver failure.

From the CNS and peripheral nervous system: sometimes – dizziness, tinnitus, hearing loss, headache, irritability, emotional lability, psychoses, convulsions, muscle weakness, ataxia; in isolated cases – skeletal muscle myopathy or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups. Myopathy may be reversible after drug withdrawal, but complete recovery may take several months. Mild sensory changes, suppression of tendon reflexes and decreased nerve conduction are possible.

From the cardiovascular system rarely – cardiomyopathy. If conduction disturbances (bundle branch block/AV block) or hypertrophy of both ventricular myocardium are detected, the possibility of chronic cardiotoxicity should be considered (in these situations, drug withdrawal is required). After drug withdrawal, reversal of these changes is possible.

From the hematopoietic system rarely – suppression of bone marrow hematopoiesis; in isolated cases – anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

From metabolism Hydroxychloroquine can provoke or cause exacerbation of porphyria.

Allergic reactions urticaria, angioedema, bronchospasm.

Contraindications

• Retinopathy;
• Childhood – when long-term therapy is necessary (children have an increased risk of developing toxic effects);
• Children under 6 years of age (200 mg tablets are not intended for children with an ideal body weight of less than 31 kg);
• Pregnancy;
• Hereditary lactose intolerance, lactase deficiency, galactosemia or glucose/galactose malabsorption syndrome (due to the presence of lactose in the drug composition);
• Hypersensitivity to 4-aminoquinoline derivatives.

With caution the drug should be used for visual disorders (decreased visual acuity, impaired color vision, narrowed visual fields), simultaneous use of drugs that can cause adverse ophthalmological reactions (risk of progression of retinopathy and visual disorders); for hematological diseases (including in history); for severe neurological diseases, psychoses (including in history); for porphyria cutanea tarda (risk of exacerbation), psoriasis (risk of increased skin manifestations of the disease), simultaneous use of drugs that can cause skin reactions; for renal failure and/or hepatic failure, hepatitis, simultaneous use of drugs that can adversely affect liver and/or kidney function (in case of severe impairment of renal or hepatic function, the dose should be selected under the control of plasma hydroxychloroquine concentrations); for glucose-6-phosphate dehydrogenase deficiency; for severe gastrointestinal diseases; for hypersensitivity to quinine (possibility of cross-allergic reactions).

Use in Pregnancy and Lactation

Data on the use of the drug during pregnancy are limited. Hydroxychloroquine crosses the placental barrier. It should be noted that 4-aminoquinolines in therapeutic doses can cause intrauterine damage to the CNS, including the auditory nerve (auditory and vestibular disorders, congenital deafness), retinal hemorrhages and abnormal retinal pigmentation. Therefore, the use of hydroxychloroquine during pregnancy should be avoided, except in cases where the potential benefit of therapy to the mother outweighs the risk to the fetus.

The need to use the drug during lactation (breastfeeding) should be carefully weighed, as Hydroxychloroquine is shown to be excreted in small amounts in breast milk, and it is also known that infants are particularly sensitive to the toxic effects of 4-aminoquinolines.

Use in Hepatic Impairment

The drug should be used with caution in hepatic failure.

Use in Renal Impairment

The drug should be used with caution in renal failure.

Pediatric Use

Contraindication: childhood – when long-term therapy is necessary (children have an increased risk of developing toxic effects); children under 6 years of age (200 mg tablets are not intended for children with an ideal body weight of less than 31 kg).

Geriatric Use

In elderly patients, the drug is used in the same dosages as in adults.

Special Precautions

The toxic effect on the retina is largely dose-dependent. The incidence of retinopathy when using the drug in doses up to 6.5 mg/kg of ideal body weight is low. Exceeding the recommended daily dose sharply increases the risk of developing retinopathy and accelerates its onset.

Before starting a long course of treatment with the drug, a thorough examination of both eyes should be performed. The examination should include determination of visual acuity, fundus examination, assessment of color vision and visual fields. During therapy, such an examination should be performed at least once every 6 months.

More frequent examination should be performed in the following cases:

• Daily dose exceeding 6.5 mg/kg of ideal body weight (when calculating the dose based on absolute body weight, overdose is possible in obese patients);
• Renal failure;
• Total dose more than 200 g;
• Elderly patients;
• Reduced visual acuity.

If any visual disturbances occur (decreased visual acuity, change in color vision), the drug should be immediately discontinued and careful monitoring of the patient’s visual status should be ensured, as retinal changes (and visual disturbances) may progress even after drug discontinuation.

It is recommended to use the drug with caution in patients with liver and kidney diseases. In case of severe impairment of renal or hepatic function, the dose should be selected under the control of plasma concentrations of hydroxychloroquine.

Since the drug affects liver and kidney functions, dose reduction may be required.

During long-term therapy, a complete blood count should be performed periodically; if hematological disorders appear, Hydroxychloroquine should be discontinued.

Children are particularly sensitive to the toxic effects of 4-aminoquinolines, so patients should be especially careful to keep Hydroxychloroquine out of places accessible to children.

All patients receiving the drug long-term should be periodically examined by a neurologist regarding skeletal muscle function and tendon reflex severity. If muscle weakness is observed, the drug should be discontinued.

Plaquenil^® is not effective against chloroquine-resistant strains of Plasmodium falciparum, and is not active against the exoerythrocytic forms of Plasmodium vivax, Plasmodium ovale and Plasmodium malariae and therefore cannot prevent infection with these microorganisms when prescribed for the purpose of preventing acute attacks of malaria, nor can it prevent relapse of the disease caused by these pathogens.

Effect on the Ability to Drive Vehicles and Machinery

Patients should exercise caution when driving or performing work requiring increased attention, as Hydroxychloroquine may impair accommodation and reduce visual clarity.

If this condition does not resolve on its own, the drug dosage can be temporarily reduced.

Overdose

Overdose with 4-aminoquinolines is particularly dangerous in children, as a fatal outcome is possible even with a dose of 1-2 g.

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

Since these effects may develop immediately after taking an excessive dose of the drug, emergency therapy is required.

Measures should be taken immediately to remove the drug from the stomach (induce vomiting artificially or perform gastric lavage) and administer activated charcoal in a dose at least 5 times the ingested dose of the drug.

Parenteral administration of diazepam is advisable (a reduction in chloroquine cardiotoxicity against its background has been described).

Treatment if necessary, artificial ventilation and anti-shock therapy should be performed.

Constant medical supervision is required for at least 6 hours after the overdose symptoms have been relieved.

Drug Interactions

Concomitant use of hydroxychloroquine and digoxin may increase the serum concentration of digoxin (with this combination, the digoxin dose should be reduced under the control of plasma digoxin concentrations).

Since Hydroxychloroquine may enhance the effects of hypoglycemic drugs, a reduction in the dose of insulin or hypoglycemic drugs may be required at the start of hydroxychloroquine administration.

When used concomitantly with antacids, the interval between administrations should be at least 4 hours, as a decrease in the absorption of hydroxychloroquine is possible.

The following drug interaction, described for chloroquine but not observed with hydroxychloroquine use, also cannot be ruled out when using hydroxychloroquine.

Concomitant use with aminoglycoside antibiotics potentiates the inhibitory effect on neuromuscular transmission.

Cimetidine inhibits the metabolism of antimalarial drugs, which may lead to an increase in their plasma concentrations, increasing the risk of side effects, especially toxic ones.

Chloroquine exhibits an antagonistic effect against neostigmine and pyridostigmine.

Against the background of chloroquine use, a decrease in antibody formation in response to primary immunization with intradermal human diploid cell rabies vaccine is observed.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.