1. NAME OF THE MEDICINAL PRODUCT
Hydroxychloroquine ratiopharm 200 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 200 mg of hydroxychloroquine sulfate.
To counsel the total rundown of excipients, see area 6.1.
3. PHARMACEUTICAL FORM
Hydroxychloroquine ratiopharm are white, round, approximately 9.5 mm, biconvex tablets, debossed with “200” on one side of the tablet and plain on the other.
4. CLINICAL DATA
4.1. Therapeutic indications
Adults
Rheumatoid arthritis
Systemic and discoid lupus erythematosus
Treatment of intense assaults of straightforward jungle fever and prophylaxis of intestinal sickness brought about by Plasmodium vivax, P. falciparum, P. ovale and P. malariae
Children (≥ 6 years and ≥ 35 kg)
Systemic and discoid lupus erythema cough
Treatment of intense assaults of straightforward intestinal sickness and prophylaxis of jungle fever brought about by Plasmodium vivax, P. falciparum, P. ovale and P. malariae .
Chloroquine-resistant P. falciparum and increasingly chloroquine-resistant P. vivax are found in many areas, limiting the usefulness of hydroxychloroquine in these areas. Official recommendations and local information on the development of resistance to antimalarial agents (eg WHO and public health directives) should be observed .
4.2. Dosage and method of administration
Posology
Rheumatoid arthritis
The action of hydroxychloroquine is cumulative and takes several weeks to have a therapeutic effect in rheumatic conditions, while minor side effects can occur relatively soon.
Adults: the starting dose is 400 mg per day.
Treatment should be continued for 6-8 weeks before evaluating the effect. During this period, hydroxychloroquine can be combined with prostaglandin synthase inhibitors (eg, acetylsalicylic acid or indomethacin). Combination therapy with gold or phenylbutazone is not recommended.
Treatment should be stopped if there is no improvement at 6 months.
In an adequate response, the daily dose can be reduced after three months, to a maintenance dose of 200 mg per day and later possibly 200 mg every other day.
Systemic and discoid lupus erythematosus
Adults: Starting dose of 400 mg to 600 mg per day (a few weeks if necessary).
Maintenance dose: 200 to 400 mg per day.
Children: 6.5 mg per kg of ideal body weight or 400 mg per day, whichever is less. The 200 mg tablet is not suitable for children under 6 years (<35 kg) (see section 4.3).
Malaria
Prophylaxis
Adults: 400 mg per week. The dose should be taken on the same day of the week.
Children: The weekly prophylactic dose is 6.5 mg per kg of body weight, not to exceed the maximum dose for adults regardless of body weight. The 200 mg tablet is not suitable for children under 6 years (<35 kg) (see section 4.3).
Prophylaxis should begin and continue one week prior to arrival and continue for at least four to eight weeks after departure from the malaria area.
Treatment of the acute attack of uncomplicated malaria
Adults: Initially 800 mg followed by 400 mg after 6-8 hours and then 400 mg daily for the next two days (total 2 grams of hydroxychloroquine sulfate).
For the treatment of an attack of Plasmodium falciparum infection and an acute attack of Plasmodium vivax infection , a dose of 800 mg is sufficient.
When prescribing a treatment, official guidelines and local information should be provided.
The development of resistance to antimalarial agents should be observed. (Examples of this include the WHO and public health directives).
Treatment of a Plasmodium malariae , vivax, and ovale infection should be concluded with 8-aminoquinoline therapy to control the extra-nitrocytic phase of the plasma cycle.
Children: 13 mg / kg of hydroxychloroquine sulfate in children is similar to 800 mg in adults and 6.5 mg / kg of hydroxychloroquine sulfate in children is comparable to 400 mg in adults. The 200 mg tablet is not suitable for children under 6 years (<35 kg) (see section 4.3).
A total dose of up to 2 grams will be administered over three days as follows:
First dose: 13 mg per kg (maximum single dose of 800 mg).
Second dose: 6.5 mg per kg (maximum 400 mg) 6 hours after the first dose.
Third dose: 6.5 mg per kg (maximum 400 mg) 18 hours after the second dose.
Fourth dose: 6.5 mg per kg (maximum 400 mg) 24 hours after the third dose.
Reduced kidney and liver function
Caution is advised in patients with renal or hepatic impairment. A dose reduction may be required (see section 4.4).
Form of administration
Hydroxychloroquine ratiopharm should be taken after meals.
Prolonged use as a prophylaxis of malaria in children should be avoided.
4.3. Contraindications
Hypersensitivity to the active substance, to the 4-aminoquinoline compounds or to any of the excipients included in section 6.1.
Myasthenia gravis
Pre-existing maculopathy of the eye
Retinitis pigmentosa
The 200 mg tablets are not suitable for a body weight less than 35 kg.
4.4. Special warnings and precautions for use
general
Retinopathy
Before starting treatment, the patient should be examined by careful ophthalmoscopy and fundoscopy to determine visual acuity, field of vision, color vision, and retinal changes (eg, scotomy, nyctalopia) or other retinal changes. The tests must be repeated every 3 months. If visual changes appear, hydroxochloroquine treatment should be discontinued and eye tests repeated every 3-6 months.
Retinal toxicity is predominantly dose related. The risk of retinal damage is small at daily doses up to 6.5 mg / kg of body weight. Exceeding the recommended daily dose significantly increases the risk of retinal toxicity.
The recurrence of follow-up ought to be expanded and adjusted to the person in the accompanying cases:
Doses greater than 6.5 mg / kg of body weight. Absolute body weight used as a guide for dosing could result in an overdose in obese patients
o Renal insufficiency
o Cumulative dose greater than 200mg
o Elderly people
o Decreased visual acuity
If only visual field distortion (visual acuity, color vision, etc.) occurs, immediately discontinue hydroxychloroquine treatment. The patient must be carefully monitored.
Changes in the retina and visual disturbances may even progress after completion of treatment (see section 4.8).
In the case of prolonged therapy, the daily dose should be kept as low as possible, with a total maintenance dose of 400 mg / day / year as the upper limit, corresponding to 6 mg / kg.
Hypoglycemia
Hydroxychloroquine has been shown to cause severe hypoglycemia including life-threatening loss of consciousness in patients treated with and without antidiabetic medications. Patients treated with hydroxychloroquine should be warned about the risk of hypoglycemia and associated clinical signs and symptoms. In patients with clinical symptoms suggestive of hypoglycaemia during treatment with hydroxychloroquine, their blood glucose should be monitored and the treatment reviewed as necessary.
Chronic cardiac toxicity
Cases of cardiomyopathy with heart failure, in some cases with fatal outcome, have been reported in patients treated with hydroxychloroquine (see sections 4.8 and 4.9). Clinical monitoring for signs and symptoms of cardiomyopathy is recommended and hydroxychloroquine should be discontinued if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrioventricular heart block) and biventricular hypertrophy are diagnosed (see section 4.8).
Other follow-up during long-term treatments
Patients receiving long-term treatment should have regular blood tests (complete blood count) and if abnormalities occur, hydroxychloroquine treatment should be discontinued (see section 4.8).
All patients in long-term therapy should be periodically examined for musculoskeletal function and tendon reflexes.In the event that shortcoming happens, quit taking the medication (see segment 4.8)
Extrapyramidal symptoms may occur in patients treated with hydroxychloroquine (see section 4.8).
Although the risk of bone marrow depression is low, it is recommended that the blood count be checked regularly.
Caution is advised in patients with impaired liver or kidney function. A dose reduction may be necessary (see section 4.2).
Alert is exhorted in patients with gastrointestinal, neurological, or blood issues.
Alert is likewise exhorted in patients with sensitivity to quinine. Patients with glucose-6-phosphate dehydrogenase deficiency, porphyria (which can be exacerbated by hydroxychloroquine), or psoriasis may be at increased risk for skin reactions.
Small kids are particularly delicate to the poisonous impacts of 4-aminoquinolines. Hydroxychloroquine ought to be kept out of the sight and reach of kids.
Malaria
Hydroxychloroquine isn't powerful against chloroquine safe strains of P. falciparum and P. vivax , and it is not active against exo-erythrocytic forms of P. vivax, P. ovale, and P. malariae .
QT interval prolongation
Hydroxychloroquine can possibly delay the QTc span in certain patients.
Hydroxychloroquine should be used with caution in patients with documented or congenital QT prolongation and / or known risk factors for QT prolongation, such as:
heart disease, eg. heart failure, myocardial infarction,
proarrhythmic conditions, for example bradycardia (<50 bpm)
history of ventricular dysrhythmias.
hypokalemia and / or uncorrected hypomagnesemia
and during concomitant administration with QT-prolonging agents
(see section 4.5), as this may increase the risk of ventricular arrhythmias, sometimes with fatal outcome.
The magnitude of QT interval prolongation may increase with increasing drug concentrations. Therefore, the recommended dose should not be exceeded
(see also sections 4.8 and 4.9).
If signs of cardiac arrhythmia appear during treatment with hydroxychloroquine, treatment should be discontinued and an ECG performed.
4.5. Interaction with other medicinal products and other forms of interaction
There are indications that 4-aminoquinolines, such as hydroxychloroquine, are pharmacologically incompatible with mono-amino oxidase inhibitors.
Hydroxychloroquine sulfate has been reported to increase plasma levels of digoxin: serum levels of digoxin should be closely monitored in patients receiving concomitant treatment.
As hydroxychloroquine may increase the effects of a hypoglycaemic treatment, a decrease in insulin doses or antidiabetic medications may be required.
Hydroxychloroquine inhibits CYP2D6. The concomitant use of medicinal products that inhibit CYP2D6 is discouraged.
Chloroquine can decrease the immunizer reaction to the rabies vaccine. Intracutaneous administration of the rabies vaccine has been discontinued. Response after intramuscular administration is generally considered sufficient.
The activity of antiepileptic drugs may be affected if they are co-administered with hydroxychloroquine.
Hydroxychloroquine can lower the seizure threshold. Co-administration of hydroxychloroquine with other antimalarials known to lower the seizure threshold (eg, mefloquine) may increase the risk of seizures.
Drugs known to prolong the QT interval / with potential to induce cardiac arrhythmia
Hydroxychloroquine should be used with caution in patients taking medications that prolong the QT interval, eg. class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some enemy of infectives because of expanded danger of ventricular arrhythmia (see areas 4.4 and 4.9). Halofantrine should not be administered with hydroxychloroquine.
4.6. Fertility, pregnancy and lactation
Pregnancy
A moderate amount of data on pregnant women (between 300-1000 prospective pregnancies) indicates that there is no malformative or fetal / neonatal toxicity of hydroxychloroquine.
Creature considers are deficient concerning conceptive poisonousness
(see area 5.3).
Chloroquine derived from quinine is considered safe for pregnant women at recommended doses for the prophylaxis (and treatment) of malaria. After prolonged and daily use of chloroquine in high doses during human pregnancy, sporadic adverse effects (abnormalities in the cochleovestibular and retinal parts) were observed that were not confirmed in larger series. Although these effects have not been described for hydroxychloroquine, daily use of hydroxychloroquine in high doses (such as for systemic lupus erythematosus, rheumatoid arthritis, and treatment of acute attack of malaria) should only be done under a strict indication and if the risk of stopping treatment is greater than the possible risk to the fetus.
Hydroxychloroquine can be used for prophylaxis of malaria during pregnancy, as no adverse effects on the fetus were demonstrated when prophylactic doses were used.
Lactation
Hydroxychloroquine is excreted in human milk.
Due to the slow rate of elimination and the risk of accumulation of a toxic amount in the infant with prolonged daily use of high doses of hydroxychloroquine, it is recommended to discontinue breastfeeding. In once-weekly doses, as for malaria prophylaxis, the amount of hydroxychloroquine available to the infant is significantly reduced and the possibility of accumulation and toxicity is much less. Although breastfeeding is not considered harmful during treatment for the prophylaxis of malaria, the amount excreted is insufficient to achieve any prophylactic effect on the child.
Fertility
No information is available on the effect of hydroxychloroquine sulfate on human fertility (see section 5.3).
4.7. Impacts on capacity to drive and utilize machines
Hydroxychloroquine can cause impaired visual accommodation and blurred vision. In addition, dizziness may occur (see section 4.8). Hydroxychloroquine, therefore, can affect the ability to drive and use machine
4.8. Adverse reactions
The frequencies of adverse reactions are classified according to the following MedDRA convention: Very common (≥1 / 10); Common (≥1 / 100 to <1/10); Uncommon (≥1 / 1,000 to <1/100); Rare (≥1 / 10,000 to <1 / 1,000); Very rare (<1 / 10,000); Unknown (cannot be estimated from the available data).
| Organ system | Very frequent | Frequent | Infrequent | Rare | Very rare | Unknown |
| Blood and lymphatic system disorders | | | | Myelosuppression | | Anemia, aplastic anemia, granulocytosis , leukopenia, thrombocytopenia, precipitated or exacerbated porphyria. |
| Metabolism and nutrition disorders | | Anorexy | | | | Hypoglycemia (see section 4.4) |
| Psychiatric disorders | | | | Psychosis | | Dizziness, nervousness, instability of character |
| Nervous system disorders | | | | Convulsions | | Vertigo, tinnitus, emotional disturbances, headache, extrapyramidal phenomena such as dystonia, dyskinesia, tremor (see section 4.4) |
| Eye disorders | | | | Retinopathy with changes in pigmentation and visual field defects 1 | | Patients with retinal changes may be initially asymptomatic, or they may have scotomatous vision with paracentral, pericentral ring types, temporal scotomas, and abnormal color vision. Changes in the cornea, including edema and opacities 2 Blurred vision due to impaired accommodation 3 |
| Ear and labyrinth disorders | | | | | Hearing loss (irreversible) | |
| Cardiac disorders | | | | Cardiomyopathy , which can lead to heart failure, in some cases fatal T-top deviations in ECG. | | Conduction disturbance and (bundle branch block / atrioventricular heart block) (see section 4.4) Biventricular hypertrophy (see section 4.4) QT prolongation in patients at risk, which may cause arrhythmia (torsades de pointes, ventricular tachycardia) (see sections 4.4 and 4.9) |
| Gastrointestinal disorders | | | Nausea, diarrhea, abdominal pain 4 | Vomiting 4 | | |
| Hepatobiliary disorders | | | | | | Abnormal liver function tests, fulminant liver failure. |
| Skin and subcutaneous tissue disorders | | | Eruption | | Bullous eruptions included; Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, usually associated with fever and hyperleukocytosis. | Itching, changes in pigmentation of the skin and mucous membranes, hair discoloration and alopecia 4 . Lichen planus-like skin reactions, photosensitivity, exfoliative dermatitis, psoriasis, drug reduction with eosinophilia and systemic symptoms. |
| Musculoskeletal and connective tissue disorders | | | | | | Myopathy, 5 Neuromyopathy leading to progressive weakness and atrophy of the proximal muscle groups. Mild sensory changes, depression of tendon reflexes, and abnormal nerve conduction may be observed |
| Renal and urinary disorders | | | | | During long-term therapy with the structurally related chloroquine phosphate , reversible phospholipidosis (increased accumulation of intracellular phospholipids) occurred, including renal phospholipidosis. Due to the structural similarity, this side effect can occur for hydroxychloroquine as well. In this case, altered kidney function can be intensified. | |
| General disorders and administration site conditions | | | | | | Urticaria, angioedema and bronchospasm. |
1 In its early form, it appears reversible on discontinuation of hydroxychloroquine. If allowed to develop, there may be a risk of progression even after withdrawal of treatment.
2 The changes are asymptomatic or may cause disorders such as halos, blurred vision, or photophobia. They can be temporary and are reversible when treatment is stopped.
3 This is dose dependent and reversible.
4. These symptoms generally disappear after dose reduction or after treatment is stopped.
5. This may be reversible if treatment is terminated, however recovery can take many months.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions to the medicinal product after authorization. This permits consistent observing of the advantage/hazard proportion of the restorative item. Healthcare professionals are invited to report suspected adverse reactions through the Spanish Pharmacovigilance System for Medicines for Human Use: https://www.notificaram.es .
o 4.9. Overdose
o Overdose with 4-aminoquinolines is particularly dangerous in infants, as only 1-2 g have been fatal.
Symptoms
Symptoms of an overdose can include headache, visual disturbances, cardiovascular collapse, seizures, and hypokalemia. Mood and conduction problems, including QT prolongation, Torsade de Pointes, ventricular tachycardia and ventricular fibrillation, trailed by abrupt and early respiratory and heart failure. Immediate medical attention is required as these effects can appear shortly after overdose.
With severe poisoning, a widening QRS complex, bradyarrhythmias, nodal rhythm, QT prolongation, atrioventricular block, ventricular tachycardia, torsades de pointes, and ventricular fibrillation may occur.
Driving
The stomach must be evacuated immediately, within an hour after ingestion, either by emesis or gastric lavage. Finely powdered activated charcoal at a dose of at least five times the overdose, can inhibit further absorption if it is introduced into the stomach through a tube after washing and within 30 minutes of ingestion of the overdose.
Parenteral diazepam administration should be considered in cases of overdose; It has been shown to be beneficial in reversing chloroquine cardiotoxicity.
Respiratory support may be needed and the need for incubation or tracheostomy may be considered. Shock should be treated by administration of fluid (with plasma expanders if necessary) with monitoring of central venous pressure. In severe cases, dopamine administration should be considered.
A patient who endures the intense stage and is asymptomatic ought to be firmly noticed for at any rate 6 hours.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: antirheumatic and antiprotozoal drugs, ATC code: P01BA02
Antimalarial agents such as chloroquine and hydroxychloroquine have several pharmacological actions that may be involved in their therapeutic effect in the treatment of rheumatic disease, but the role of each is not known. These include interaction with sulfhydryl groups, interference with enzyme activity (including phospholipase, NADH - cytochrome C reductase, cholinesterase, proteases, and hydrolases), DNA binding, stabilization of lysosomal membranes, inhibition of prostaglandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin-1 production from monocytes and inhibition of superoxide release from neutrophils
5.2. Pharmacokinetic properties
Absorption
Hydroxychloroquine is rapidly absorbed after oral administration. The average bioavailability is approximately 74%.
Distribution
Distribution takes place throughout the body, accumulation occurs in blood cells and tissues such as the liver, lungs, kidneys, and eyes. The proportion found in plasma is approximately 50% bound to plasma proteins.
Biotransformation
It is partially metabolized in the liver to ethylated active metabolites and elimination occurs mainly through the kidneys (23-25% unchanged), but also through the bile.
Elimination
Elimination is slow, the terminal elimination half-life is approximately 50 days (whole blood) and 32 days (plasma). Hydroxychloroquine crosses the placenta and is probably excreted in human milk.
5.3. Preclinical safety data
There are no relevant non-clinical studies available.
o 6. PHARMACEUTICAL INFORMATION
o 6.1. List of excipients
o Tablet core:
Corn starch, calcium hydrogen phosphate dihydrate (E341), colloidal anhydrous silica (E551), polysorbate 80 (E433), dried corn starch, talc (E553B), magnesium stearate (E470b).
Covering:
Hypromellose 15 cps (E464), talc (E553B), macrogol 6000 and titanium dioxide (E171)
6.2. Incompatibilities
Not applicable.
6.3. Period of validity
3 years
6.4. Special precautions for storage
Store in the first holder to shield from light.
6.5. Nature and contents of container
Pack sizes
PVC/Alu rankle packs of 30 and 100 film-covered tablets.
Only some pack sizes may be marketed.
6.6. Special precautions for disposal and other handling
Disposal of unused medicine and all materials that have been in contact with it will be done in accordance with local regulations.
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