Package Insert: Information for the User

Duplaxil 400 mg Film-Coated Tablets

Hydroxychloroquine Sulfate

Read this package insert carefully before starting to take this medication, as it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribed only for you, and you should not give it to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

Each coated tablet of Duplaxil contains 400mg of hydroxychloroquine sulfate.

Hydroxychloroquine is an antimalarial drug of the 4-hydroxyquinoline family that combines rapid schizonticidal activity in the blood with gametocytocidal activity, and is also classified as a delayed-acting antirheumatic drug.

Duplaxil is indicated in adults for:

- The prevention and treatment of uncomplicated malaria caused by sensitive species ofplasmodium, as an alternative to chloroquine (if first-line treatments are not suitable or not available).

- Symptomatic treatment of rheumatoid arthritis.

- Treatment of discoid lupus erythematosus and systemic lupus erythematosus.

- Treatment of skin problems; that are sensitive to sunlight (photodermatosis).

Duplaxil is indicated in adolescents (from 12 years of age) and children aged 6 to 11 years (ideal body weight ≥31kg) for:

- Treatment of discoid lupus erythematosus.

- Treatment of systemic lupus erythematosus.

- Prevention and treatment of uncomplicated malaria caused by sensitive species ofplasmodium, as an alternative to chloroquine (when first-line treatments are not suitable or not available).

- Treatment of juvenile rheumatism in combination with other treatments (juvenile idiopathic arthritis).

Hydroxychloroquine is not effective against chloroquine-resistant P. falciparum strains, and is not active against pre-erythrocytic forms of P. vivax and P. ovale. Therefore, it does not prevent infection caused by these organisms when administered prophylactically, nor does it prevent recurrenceof the infection due to these organisms.

Do not take Duplaxil:

• if you are allergic to hydroxychloroquine or any of the other components of this medication (listed in section 6);
• if you have retinopathy, maculopathy;
• if you are allergic to other 4-aminoquinoline compounds (malaria agents);

Do not administer hydroxychloroquine to a child under 6 years of age (ideal body weight <31

Warnings and precautions

Consult your doctor or pharmacist before starting to take hydroxychloroquine, in case of:

- Liver or kidney disorders, or if you are taking medications that may affect the liver and/or kidneys (may require dose adjustment);

- Gastrointestinal disorders;

- Nervous system disorders;

- Blood disorders;

- Metabolic disorders;

- Heart conduction disorders;

- Hypersensitivity to quinine;

- Deficiency of an enzyme called glucose-6-phosphate dehydrogenase (the enzyme found in red blood cells);

- Porphyria (a hereditary metabolic disorder);

- Chronic inactive hepatitis B infection;

- Epilepsy;

- Concurrent use of potentially nephrotoxic or hepatotoxic drugs;

- Pre-existing psoriasis;

- Pregnancy and lactation.

Hydroxychloroquine may cause a decrease in blood glucose levels. Ask your doctor to inform you about the signs and symptoms of hypoglycemia. Blood glucose levels may need to be checked.

When taking hydroxychloroquine, you must protect yourself from direct sunlight.

Do not take medications containing gold or phenylbutazone (agents for rheumatoid arthritis and gout) at the same time.

Before starting a prolonged treatment with hydroxychloroquine, it is recommended to perform an eye examination (to evaluate visual acuity, central visual field, color vision, and fundus examination) and regular vision checks at least every 3 months during the entire treatment. These checks should be individualized in the following cases:

• for patients where the daily dose exceeds 6.5 mg/kg of ideal body weight (lean body mass, see section 3 "How to take Duplaxil");
• in patients with renal insufficiency;
• in patients with cumulative doses of over 200 g;
• in elderly patients;
• in patients with visual disturbances.

If visual problems (e.g., reduced visual acuity or loss of red color vision) occur, discontinue hydroxychloroquine treatment and consult your doctor for a new eye examination. The risk of retinal disease depends mainly on the dose. At daily doses of up to 6.5 mg/kg body weight, the risk is low. If this dose is exceeded, the risk of retinal disease increases significantly.

During long-term treatment, you must also have regular blood tests, as well as muscle and tendon function tests. If abnormalities occur (e.g., changes in blood or muscle weakness), your doctor will decide whether to discontinue or continue hydroxychloroquine treatment.

Cases of cardiomyopathy, some of which have been fatal, have been reported in patients treated with hydroxychloroquine. Your doctor will monitor you for signs and symptoms of cardiomyopathy. Hydroxychloroquine treatment should be discontinued if cardiomyopathy develops.

In the event of a diagnosis of conduction disorders (branch block, AV block) and biventricular hypertrophy, chronic toxicity should be suspected.

Hydroxychloroquine may cause cardiac arrhythmias in some patients: caution should be exercised when using hydroxychloroquine, if you were born with or have a family history of prolonged QT interval, if you have developed a prolonged QT interval (according to ECG, an electrocardiogram of the heart), if you have heart disorders or a history of heart attack (myocardial infarction), if you have an imbalance of salts in the blood (especially low levels of potassium and magnesium, see section "Other medications and Duplaxil"). If you experience palpitations or irregular heartbeats during treatment, inform your doctor immediately. The risk of cardiac problems may increase with increasing dose. Therefore, follow the recommended dose.

The treatment period should not exceed 3 years.

Patients with seizures should be regularly monitored by their doctor.

Hydroxychloroquine has an accumulative effect and may take several weeks to produce a therapeutic effect in the treatment of rheumatoid arthritis or systemic lupus erythematosus. Therefore, side effects may occur quickly. The efficacy of treatment should be evaluated after at least 4 to 12 weeks.

If there is no improvement after 6 months, treatment should be discontinued.

In the treatment of malaria, it should be noted that hydroxychloroquine should be used in combination with other medications in countries with known resistance to chloroquine.

During hydroxychloroquine treatment, extrapyramidal disorders may occur.

Some people treated with hydroxychloroquine may experience mental health problems such as irrational thoughts, anxiety, hallucinations, confusion, or depression, including thoughts of self-harm or suicide, even those who have never had similar problems before. If you or others around you notice any of these adverse effects (see section 4), consult a doctor immediately.

Severe skin eruptions have been reported with the use of hydroxychloroquine (see section 4 possible adverse effects). Often, the eruption consists of ulcers in the mouth, throat, nose, genitals, and conjunctivitis (red and inflamed eyes). These severe skin eruptions are often preceded by symptoms such as fever, headache, and body aches. The skin eruption may progress to generalized blisters and skin peeling. If you experience these skin symptoms, stop taking hydroxychloroquine and contact your doctor immediately.

Renal and hepatic insufficiency

Patients with liver or kidney insufficiency, as well as those taking medications that affect these organs, may require a reduction in the dose of the drug.

Pediatric population

Children are very sensitive to the group of medications to which hydroxychloroquine belongs. Therefore, you must be very careful and keep the product out of the reach of children to avoid poisoning.

Geriatric population

No specific information is available on the comparison of the use of hydroxychloroquine between elderly patients and other age groups.

Other medications and Duplaxil

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

Some medications may interact with hydroxychloroquine. It is essential to inform your doctor if you are taking the following medications:

• Basic therapeutic agents(medications for the treatment of rheumatoid arthritis). When used at the same time as hydroxychloroquine, these medications may increase side effects, so they should be avoided with hydroxychloroquine.

• Digoxin(a medication for heart failure). If used at the same time as hydroxychloroquine, it may increase the effect of digoxin. Your doctor should closely monitor your treatment.

• Antacids(a medication used in the treatment of excessive stomach acid) may reduce the absorption of hydroxychloroquine. Always allow at least 4 hours to pass between taking hydroxychloroquineand antacids.

• Cimetidine(an acid inhibitor) may delay the excretion of hydroxychloroquine.

• Neostigmine or pyridostigmine(medications used for the treatment of unwanted muscle relaxation). If used at the same time as hydroxychloroquine, the effect of neostigmine or pyridostigmine may be reduced.

• Aminoglycosides(a medication for infections). If used at the same time as hydroxychloroquine, it may increase neuromuscular inhibition.

• Pirimethamine/sulfadoxine (antimalarial medications):The combination of hydroxychloroquine with pirimethamine/sulfadoxine significantly increases the risk of skin reactions.

• Insulin:If you have diabetes, hydroxychloroquinemay increase the effect of medications used for diabetes (e.g., insulin), and you may need to reduce the dose of insulin or other antidiabetic medications.

• Inform your doctor if you are taking any medication that may affect heart rhythm. This includes medications used for abnormal heart rhythm (antiarrhythmics), for depression (tricyclic antidepressants), for psychiatric disorders (antipsychotics), for bacterial infections or malaria (e.g., halofantrine).

• Ciclosporin(a medication used after organ transplantation). If used at the same time as hydroxychloroquine, the blood level of ciclosporin may increase.

• Mefloquine, bupropion(medications that may reduce the seizure threshold): hydroxychloroquine may decrease the seizure threshold. If used at the same time as hydroxychloroquine, it may increase the risk of seizures.

• Anticonvulsants:The efficacy of certain anticonvulsants may be reduced by concurrent administration with hydroxychloroquine.

• Agalsidase(treatment of α-galactosidase). If used at the same time as hydroxychloroquine, the effect of agalsidase may be reduced.

• Praziquantel(an antihelmintic medication). If used at the same time as hydroxychloroquine, the blood level of praziquantel may be reduced.

• Fenilbutazona(an analgesic). If used at the same time as hydroxychloroquine, it may increase the risk of dermatitis exfoliativa (inflammatory skin disease with scales on the skin).

• Hepatotoxic substances(avoid drinking large amounts of alcohol) andMAO inhibitors(medications used for depression) should not be used with hydroxychloroquine.

• Tamoxifen(a medication used to treat breast cancer): if used at the same time as hydroxychloroquine, it is known to induce retinal toxicity.

• Probenecid(a medication that prevents an increase in uric acid levels) andindometacin(an anti-inflammatory medication). If used at the same time as hydroxychloroquine, the risk of sensitization and retinopathy may increase.

• Corticosteroid derivatives(medications for allergies and inflammation). If used at the same time as hydroxychloroquine, it may increase the risk of myopathy (muscle disease) or cardiomyopathy (heart muscle disease).

• Antifolic acid antagonists, such as methotrexate (used to treat cancer). If used at the same time as hydroxychloroquine, the effect of antifolic acid antagonists may be increased.

• Ampicillin(an antibiotic medication). If used at the same time as hydroxychloroquine, the absorption of ampicillin may be reduced.

• Chloroquine phosphate(an antimalarial medication). When used at the same time as hydroxychloroquine, interactions were observed, as this substance has a similar structure to hydroxychloroquine. Therefore, these side effects cannot be ruled out.

• Metronidazole(an antibiotic medication). After taking metronidazole, an acute reaction of dystonia (change in muscle tension and alteration in movement) was observed.

• Penicillamine(an antirheumatic medication) may increase the risk of hematological and/or renal side effects, as well as skin reactions.

• Vaccination. The production of antibodies may be reduced by vaccination against rabies with HDC vaccines (intramuscular vaccination for rabies prophylaxis is recommended). Routine vaccination (tetanus, diphtheria, measles, poliomyelitis, typhus, and tuberculosis) was not monitored for an effect.

Hydroxychloroquine inhibits the enzyme CYP2D6. Therefore, medications that inhibit CYP2D6 should not be administered concomitantly with hydroxychloroquine.

Duplaxil with alcohol

Avoid consuming large amounts of alcohol.

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication. Your doctor will inform you whether this medication is suitable for you.

Pregnancy

Do not use hydroxychloroquine during pregnancy at high daily doses unless your doctor tells you it is necessary because the risk of interrupting treatment is greater than the potential risk to the fetus.Hydroxychloroquine may be associated with a small increase in the risk of major malformations.

Lactation

Hydroxychloroquine passes into breast milk.No sufficient information is available on the effects of hydroxychloroquine on newborns/breastfeeding infants. Based on the disease and treatment duration, your doctor will decide whether you can use this medication during breastfeeding. If you take this medication once a week, as in the use to prevent malaria, you do not need to stop breastfeeding.

However, this amount is insufficient to prevent malaria in the infant.

Arthritis rheumatoid, lupus erythematosus:

Due to the long half-life and high daily dose of hydroxychloroquine, accumulation is expected.

Fertility

No data are available on hydroxychloroquine on human fertility. In studies with rats, chloroquine, a related substance to hydroxychloroquine, reduced testosterone secretion, testicular weight, and epididymis, and caused abnormal sperm.

Driving and operating machinery

Do not drive or use tools or machines until you know how this medication affects you. Adverse effects such as dizziness and visual disturbances may occur.

In some people, hydroxychloroquine may cause adverse effects that affect your ability to drive or use machines. Caution is recommended as hydroxychloroquine may reduce vision and cause blurred vision. These adverse effects may occur especially at the beginning of treatment.

Your ability to drive or use machines may be affected if you take hydroxychloroquine in combination with alcohol or sedatives.

Follow exactly the administration instructions of this medication as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

This medication is only for oral administration. The tablets should be taken with food or a glass of milk. The tablet can be divided into equal doses.

The dose should be applied according to body weight. In people with obesity, the dose should not be based on actual weight, but on ideal weight. If the dose is based on the patient's actual weight, it could cause an overdose in people with obesity.

Rheumatoid Arthritis

Adults:

Initially 400-600 mg per day. Maintenance dose 200-400 mg per day.

Pediatric Population:

The minimum effective dose should be used and should not exceed 6.5 mg/kg/day, based on ideal body weight or 400 mg per day (whichever is less).

SLE and Discoid Lupus

Adults and Adolescents:

Initially 400-600 mg per day. Maintenance dose: 200-400 mg per day.

Maintenance Dose:

WeightHidroxicloroquina mg/day

31-49 kg200 mg

50-64 kg200 mg one day – the next day 400 mg, then again 200 mg the next day, etc.

≥ 65 kg400 mg

Pediatric Population:

The minimum effective dose should be used and should not exceed 6.5 mg/kg/day, based on ideal body weight.

Photodermatosis

Adults:

400 mg per day in a single dose.

Treatment should only be administered during periods of maximum exposure to light.

Malaria Prophylaxis

The medication should be administered on the same day of the week each week.

In endemic areas ofPlasmodium ovaleand/orPlasmodium vivax, concomitant prophylaxis with phosphate primaquine during the last two weeks or immediately after completing hydroxychloroquine prophylaxis is recommended.

Adults:

400 mg (1 tablet) per week.

Prophylaxis should be initiated one week before arrival and continued for at least four weeks after leaving the malaria area.

Pediatric Population:

Prophylaxis should be initiated two weeks before arrival and continued for at least four weeks after leaving the malaria area. Prolonged use as malaria prophylaxis in children should be avoided.

The weekly prophylactic dose is 6.5 mg per kg of body weight, but should not exceed the adult maximum dose regardless of body weight.

Uncomplicated Malaria Treatment

In the case of malaria caused byPlasmodium ovaleand/orPlasmodium vivax, phosphate primaquine can be added for complete radical treatment.

Adults:

Initially 800 mg (2 tablets), 6 hours later 400 mg (1 tablet) and then 400 mg (1 tablet) per day for 2 or 3 days for people weighing more than 60 kg.

Pediatric Population

Adolescents (12 years and older) and children ≥ 6 years (≥ 31 kg):

A maximum treatment dose of 30 mg/kg based on ideal body weight should be administered over 2 days, following the following guidelines:

Initial dose: 13 mg/kg (not exceeding 800 mg)

Second dose: 6.5 mg/kg (not exceeding 400 mg), 6 hours later.

Third dose: 6.5 mg/kg (not exceeding 400 mg), 24 hours after the first dose.

Fourth dose: 6.5 mg/kg (not exceeding 400 mg), 48 hours after the first dose.

Special Population

Patients with Reduced Renal and Hepatic Function

Dose adjustment may be necessary during treatment with patients with renal or hepatic insufficiency.

Pediatric Population

The minimum effective dose should be used and should not exceed the adult maximum dose regardless of body weight. Hydroxychloroquine is contraindicated in children <6 years old.

If you take more Duplaxil than you should:

If you take morehydroxychloroquinethan you should, inform your doctor or go to the emergency department of the hospital immediately.

Overdose with 4-aminoquinolines is particularly hazardous in infants, as only 1-2g have been fatal.

Symptoms of overdose may include headache, visual disturbances, cardiovascular collapse, seizures, and arrhythmias and conduction disturbances, followed by sudden and early cardiac arrest. Since these effects can occur after a massive dose, immediate treatment is required.

If you forget to take Duplaxil

Do not take a double dose to make up for the missed dose.

If you interrupt treatment with Duplaxil

Continue taking hydroxychloroquineuntil your doctor tells you to stop. Do not stop taking hydroxychloroquine even if you feel better. If you do, your condition may worsen.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The most common side effects are gastrointestinal disorders, observed in 10-20% of patients. Side effects can disappear spontaneously or by reducing the dose, and are generally preventable with recommended controls.

Side effects are generally reversible, but irreversible side effects have been observed (e.g., deafness, visual field defects).

Patients with psoriasis appear to have a higher risk of severe skin reactions.

Stop taking Duplaxil and see a doctor immediately if you notice any of the following severe side effects; you may need urgent medical treatment:

• Severe skin reactions (see section 2, Warnings and precautions) such as:

• fever rash and flu-like symptoms, and swollen lymph nodes. It could be a disease called drug reaction with eosinophilia and systemic symptoms (DRESS).

• blistering, generalized scaly skin, pus-filled spots with fever. It could be a disease called generalized acute pustular exanthema (PEGA).

• blistering or peeling of the skin around the lips, eyes, mouth, nose, and genitals, flu-like symptoms, and fever. It could be a disease called Stevens-Johnson syndrome (SSJ).

• multiple skin lesions, itching, joint pain, fever, and general feeling of discomfort. It could be a disease called toxic epidermal necrolysis (NET).

• skin reaction, including purple-colored, raised, and painful ulcers, especially on the arms, hands, fingers, face, and neck, which can also be accompanied by fever. It could be a disease called Sweet syndrome.

• liver problems. Symptoms can include general feeling of discomfort, with or without jaundice (yellowing of the skin and eyes), dark urine, nausea, vomiting, and/or abdominal pain. Rare cases of liver failure (including fatal cases) have been observed.

Very common side effects(may affect more than 1 in 10 people):

- Nausea

- Abdominal pain

Common side effects(may affect up to 1 in 10 people):

- Loss of appetite

- Emotional instability, for example, irritability, nervousness, and agitation.

- Headache

- Visual disturbances such as halos, blurred vision, light sensitivity, visual acuity problems, and double vision

- Diarrhea with weight loss

- Flatulence

- Vomiting

- Skin rash

- Pruritus (seen in approximately 40% of patients with systemic lupus erythematosus)

- Sensory-motor function disorders

Uncommon side effects(may affect up to 1 in 100 people):

- Nervousness, insomnia, or somnolence, confusion, or paresthesia

- Dizziness

- Changes in the retina causing vision loss, visual field changes, irregular pigmentation, and retinal detachment

- Tinnitus

- Abnormal liver function tests

- Activation or increase of liver function

- Alopecia

- Changes in skin and mucous membrane pigmentation

- Hair discoloration and hair loss

Rare side effects(may affect up to 1 in 1,000 people)

- Inhibition of blood vessel formation (bone marrow)

- Changes in blood, such as a reduced number of white blood cells (leucopenia and agranulocytosis), decreased platelet count (thrombocytopenia), and anemia (anemia and aplastic anemia)

- Heart diseases (cardiomyopathy)

- Inflammation of the skin and/or mucosa

- Vesicular eruption

- Urticaria

Very rare side effects(may affect up to 1 in 10,000 people)

- Reversible phospholipidosis (increased intracellular phospholipid accumulation)

- Liver failure

Side effects of unknown frequency(cannot be estimated from available data)

- Respiratory bronchospasm leading to shortness of breath

- Metabolic disease (porphyria)

- Reduction of blood sugar levels

- Depression or thoughts of self-harm or suicide, hallucinations, nervousness or anxiety, confusion, agitation, difficulty sleeping, euphoria or overexcitement.

- Convulsions, epilepsy attacks, extrapyramidal disorders such as muscle tension alteration, spontaneous gestures, inability to sit quietly due to tremors

- Corneal opacity, corneal edema, poor visual fields, blurred vision, light sensitivity

- Maculopathy and macular degeneration

- Hearing loss

- Liver problems and liver failure

- Psoriasis eruption

- Reduction of nerves or muscle function (myopathy or neuromyopathy), which may disappear when treatment is stopped

- Reflex dampening

- Alteration of nerve conduction

- Changes in heart rhythm (your doctor may observe the electrical activity of your heart using an electrocardiogram).

- Light sensitivity reaction

- Peeling of the skin (dermatitis exfoliativa)

- Erythema multiforme (fever, rash on the face, arms, and legs)

Reporting of side effects

If you experience any type of side effect, consult your doctor,pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for the Vigilance of Medicinal Products for Human Use:https://www.notificaram.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

This medication does not require special storage conditions.

Medications should not be disposed of through drains or in the trash. Dispose of the packaging and the

medications you no longer need at the SIGRE disposal pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and the medications you no longer need. By doing so, you will help protect the environment.

Composition of Duplaxil

The active ingredient is hydroxychloroquine sulfate. Each film-coated tablet contains 400 mg of hydroxychloroquine sulfate (equivalent to 310 mg of hydroxychloroquine base).

The other excipients are:

Excipients, core:

Calcium hydrogen phosphate (E 341)

Maize starch

Povidone (E 1201)

Magnesium stearate (E 572)

Excipients, coating (Opadry 85F18422 White):

Polyvinyl alcohol (E 1203)

Titanium dioxide (E 171)

Macrogol (E 1521)

Talc (E 553b)

Appearance of the product and content of the container

Duplaxil 400 mg film-coated tablets are white, oblong, and have a notch.

Length: approximately 14 mm

Width: approximately 7 mm

Height: approximately 6 mm

Duplaxil 400 mg film-coated tablets are presented in PVC-aluminum blisters inside a printed cardboard box.

Pack sizes: 10, 30, 60, 100 tablets. Some pack sizes may not be marketed.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Laboratorios Gebro Pharma, S.A.

Avenida Tibidabo, 29

08022 Barcelona, Spain

Responsible for manufacturing

Recipharm Parets, S.L.U.

C/ Ramón y Cajal, 2

08150 Parets del Vallès (Barcelona)

Last review date of this leaflet: May 2023

Other sources of information

The detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) ( http://www.aemps.gob.es/ )