Each film-coated tablet contains: Hydroxychloroquine sulfate 200 mg.
Pharmacology: Pharmacodynamics: Antimalarial agents like chloroquine and hydroxychloroquine have several pharmacological actions which 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 sulphydryl groups, interference with enzyme activity (including phospholipase, NADH - cytochrome C reductase, cholinesterase, proteases and hydrolases), DNA binding, stabilisation 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 neutrophil superoxide release.
Pharmacokinetics: Absorption: Following oral administration, peak blood concentration is achieved in approximately 4 hours. Oral absolute bioavailability is 79%.
Distribution: Hydroxychloroquine has a large volume of distribution due to extensive tissue accumulation (5500 L in blood, 44 000 L in plasma), and has been shown to accumulate in blood cells, with a blood to plasma ratio of 7.2. Approximately 50% of hydroxychloroquine is bound to plasma proteins.
Metabolism: Hydroxychloroquine is mainly metabolized to N-desethylhydroxychloroquine, and two other metabolites in common with chloroquine, desethylchloroquine and bidesethylchloroquine. It can be extrapolated from chloroquine, that hydroxychloroquine could be metabolized in vitro by the same CYPs as for chloroquine, i.e. CYP2C8 and CYP3A, and to a lesser extent by CYP2D6.
Elimination: Hydroxychloroquine presents a multi-phasic elimination profile with a long terminal half-life ranging from 30 to 60 days.
Toxicology: Preclinical safety data: Only limited preclinical data are available for hydroxychloroquine, therefore chloroquine data are considered due to the similarity of structure and pharmacological properties between the 2 products.
Genotoxicity/Carcinogenicity: There are limited data on hydroxychloroquine genotoxicity or carcinogenicity. Chloroquine, a substance related to hydroxychloroquine was genotoxic in non-GLP in-vitro tests. A non-GLP 2-year dietary administration carcinogenicity study of chloroquine in rats did not show any carcinogenic potential.
Reproductive and developmental toxicity: Hydroxychloroquine crosses the placenta. In non-GLP studies with mice and monkeys, transplacental transfer chloroquine, a substance related to hydroxychloroquine, was demonstrated with accumulation in foetal eye and ear tissue. High maternal doses of chloroquine were foetotoxic in rats and caused anophthalmia and microophthalmia. In studies in rats, chloroquine reduced the testosterone secretion, the weight of the testis and epididymis and caused production of abnormal sperm.
There are no preclinical safety data of relevance to the prescriber, which are additional to that already included in other sections of the package insert.
Adults: Treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight.
Paediatric population: Treatment of juvenile idiopathic arthritis (in combination with other therapies), discoid and systemic lupus erythematosus.
Plaquenil tablets are for oral administration. Each dose should be taken with a meal or glass of milk.
Hydroxychloroquine is cumulative in action and will require several weeks to exert its beneficial effects, whereas minor side effects may occur relatively early.
For rheumatic disease, treatment should be discontinued if there is no improvement by 6 months. In light-sensitive diseases, treatment should only be given during periods of maximum exposure to light.
Adults (including the elderly): The minimum effective dose should be employed. This dose should not exceed 6.5 mg/kg/day (calculated from ideal body weight and not actual body weight) and will be either 200 mg or 400 mg per day.
In patients able to receive 400 mg daily: Initially 400 mg daily in divided doses. The dose can be reduced to 200 mg when no further improvement is evident. The maintenance dose should be increased to 400 mg daily if the response lessens.
Paediatric population: The minimum effective dose should be employed and should not exceed 6.5 mg/kg/day based on ideal body weight. The 200 mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31 kg.
Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2 grams having proved fatal.
The symptoms of overdosage may include headache, visual disturbances, cardiovascular collapse, convulsions, hypokalaemia, rhythm and conduction disorders, including QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation, width-increased QRS complex, bradyarrhythmias, nodal rhythm, atrioventricular block, followed by sudden and potentially fatal respiratory and cardiac arrest. Immediate medical attention is required, as these effects may appear shortly after the overdose. The stomach should be immediately evacuated, either by emesis or by gastric lavage. Activated charcoal in a dose at least five times that of the overdosage may inhibit further absorption if introduced into the stomach by tube, following lavage, and within 30 minutes of ingestion of the overdose.
Consideration should be given to administration of parenteral diazepam in cases of overdosage; it has been shown to be beneficial in reversing chloroquine cardiotoxicity.
Respiratory support and shock management should be instituted as necessary.
Known hypersensitivity to 4-aminoquinoline compounds; Pre-existing maculopathy of the eye; Below 6 years of age (200 mg tablets not adapted for weight <35 kg) or for ideal body weight < 31 kg (see Dosage & Administration).
Retinopathy: All patients should have an ophthalmological examination before treatment with hydroxychloroquine sulfate (Plaquenil) is initiated. Thereafter, ophthalmological examinations must be repeated at least every 12 months.
Retinal toxicity is largely dose-related. The risk of retinal damage is small with daily doses of up to 6.5 mg/kg body weight. Exceeding the recommended dose sharply increase the risk of retinal toxicity.
The examination should include testing visual acuity and colour vision, careful ophthalmoscopy, fundoscopy and central visual field testing with a red target.
This examination should be more frequent and adapted to the patient in the following situations: daily dosage exceeds 6.5 mg/kg lean body weight. Absolute body weight used as a guide to dosage could result in an overdosage in the obese; renal insufficiency; visual acuity below 6/8; age above 65 years; cumulative dose more than 200 g.
Hydroxychloroquine sulfate (Plaquenil) should be discontinued immediately in any patient who develops a pigmentary abnormality, visual field defect or any other abnormalities not explained by difficulty in accommodation (see also Adverse Reactions). Patients should continue to be observed as retinal changes and visual disturbances may progress even after cessation of therapy (see also Adverse Reactions).
Concomitant use of hydroxychloroquine with drugs known to induce retinal toxicity, such as tamoxifen, is not recommended.
Hypoglycaemia: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic medications (see Interactions and Adverse Reactions). Patients treated with Hydroxychloroquine should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with Hydroxychloroquine should have their blood glucose level checked and treatment reviewed as necessary.
QT interval prolongation: Hydroxychloroquine has potential to prolong the QTc interval in patients with specific risks factors.
Hydroxychloroquine should be used with caution in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as: cardiac disease, e.g., heart failure, myocardial infarction; proarrhythmic conditions, e.g., bradycardia (< 50 bpm); a history of ventricular dysrhythmias; uncorrected hypokalemia and/or hypomagnesemia; during concomitant administration with QT interval prolonging agents (see Interactions) as this may lead to an increased risk for ventricular arrhythmias.
The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded (see also Interactions and Adverse Reactions).
If signs of cardiac arrhythmia occur during treatment with hydroxychloroquine, treatment should be stopped and an ECG should be performed.
Chronic cardiac toxicity: Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with Hydroxychloroquine sulfate (Plaquenil) (see Adverse Reactions and Overdosage). Clinical monitoring for signs and symptoms of cardiomyopathy is advised, and hydroxychloroquine sulfate (Plaquenil) should be discontinued if cardiomyopathy develops.
Chronic toxicity should be considered when conduction disorders (bundle branch block-/atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed (see Adverse Reactions).
Hydroxychloroquine sulfate (Plaquenil) should be used with caution in patients taking medicines which may cause adverse ocular or skin reactions. Caution should also be applied when it is used in the following: patients with hepatic or renal disease, and in those taking medicines known to affect those organs. Estimation of plasma hydroxychloroquine levels should be undertaken in patients with severely compromised renal or hepatic function, and dosage adjusted accordingly; patients with severe gastrointestinal, neurological, or blood disorders.
Suicidal behavior: Suicidal behavior has been reported in very rare cases in patients treated with Hydroxychloroquine.
Other monitoring on long-term treatments: Patients on long term therapy should have periodic full blood counts, and Hydroxychloroquine should be discontinued if abnormalities develop. (see Adverse Reactions).
All patients on long-term therapy should undergo periodic examination of skeletal muscle function and tendon reflexes. If weakness occurs, the drug should be withdrawn (see Adverse Reactions).
Potential carcinogenic risk: Experimental data showed a potential risk of inducing gene mutations. Animal carcinogenicity data is only available for one species for the parent drug chloroquine and this study was negative (see Pharmacology: Toxicology: Preclinical safety data under Actions). In humans, there are insufficient data to rule out an increased risk of cancer in patients receiving-long term treatment.
Extrapyramidal disorders: Extrapyramidal disorders may occur with hydroxychloroquine sulfate (Plaquenil) (see Adverse Reactions).
Other precautions: Caution is also advised in patients with a sensitivity to quinine, those with glucose-6-phosphate dehydrogenase deficiency, those with porphyria cutanea tarda which can be exacerbated by hydroxychloroquine, and in patients with psoriasis since it appears to increase the risk of skin reactions.
Small children are particularly sensitive to the toxic effects of 4-aminoquinolines therefore patients should be warned to keep hydroxychloroquine sulfate (Plaquenil) out of reach of children.
Patients with Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Malaria: Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum, and is not active against the exo-erythrocytic forms of P. vivax, P. ovale and P. malariae and therefore will neither prevent infection due to these organisms when given prophylactically, nor prevent relapse of infection due to these organisms.
Effects on ability to drive and use machines: Impaired visual accommodation soon after the start of treatment, which can cause blurring of vision, has been reported and patients should be warned regarding driving or operating machinery. If the condition is not self-limiting it will resolve on reducing the dose or stopping treatment.
Pregnancy: Only limited non-clinical data are available for hydroxychloroquine. In animal studies, reproduction toxicity was found with chloroquine, a substance related to hydroxychloroquine, following high maternal exposure. Chloroquine preclinical data show a potential risk of genotoxicity in some test systems (see Pharmacology: Toxicology: Preclinical safety data under Actions).
For hydroxychloroquine, when used on long-term therapy with high dosages for auto-immune diseases: Observational studies, as well as a meta-analysis including prospective studies in long-term use with large exposure have not observed a statistically significant increased risk of congenital malformations or poor pregnancy outcomes.
Hydroxychloroquine crosses the placenta. It should be noted that 4-aminoquinolines in therapeutic doses have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal hemorrhages and abnormal retinal pigmentation. These effects were not confirmed in larger series/observational studies. Observational studies, as well as a meta-analysis including prospective studies in long-term use with large exposure have not observed a statistically significant increased risk of congenital malformations or poor pregnancy outcomes.
Therefore hydroxychloroquine sulfate should be avoided in pregnancy except when, in the judgement of the physician, the individual potential benefits outweigh the potential hazards.
Fertility: There is no information available on the effect of Hydroxychloroquine sulfate on human fertility. In animal studies, chloroquine, a substance related to hydroxychloroquine, showed adverse effects on male fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Lactation: Hydroxychloroquine is excreted in breast milk (less than 2% of the maternal dose after bodyweight correction). Careful consideration should be given to long term treatment with hydroxychloroquine during lactation because of the slow elimination rate and the potential for accumulation of a toxic amount in the infant. It is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.
There are very limited data on the safety in the breastfed infant during hydroxychloroquine long-term treatment; the prescriber should assess the potential risks and benefits of use during breastfeeding, according to indication and duration of treatment.
The following CIOMS frequency rating is used, when applicable: 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), not known (cannot be estimated from the available data). (See table.)
Click on icon to see table/diagram/image
Pharmacodynamics interactions: Insulin and antidiabetic drugs: As Hydroxychloroquine may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.
Drugs known to prolong QT interval/with potential to induce cardiac arrhythmia: Hydroxychloroquine should be used with caution in patients receiving drugs known to prolong the QT interval, e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some anti-infectives due to increased risk of ventricular arrhythmia (see Precautions and Overdosage). Halofantrine should not be administered with hydroxychloroquine.
Antimalarials: Hydroxychloroquine can lower the convulsive threshold. Co-administration of Hydroxychloroquine with other antimalarials known to lower the convulsion threshold (e.g mefloquine) may increase the risk of convulsions.
Antiepileptic drugs: The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine.
Agalsidase: There is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.
Effects of other medicinal products on hydroxychloroquine: Antacids: Concomitant administration with magnesium-containing antacids or kaolin may result in reduced absorption of chloroquine. Per extrapolation, hydroxychloroquine should therefore be administered at least four hours apart from antacids or kaolin.
CYP inhibitors or inducers: Concomitant use of cimetidine, a moderate CYP2C8 and CYP3A4 inhibitor, resulted in a 2-fold increase of chloroquine exposure. Per extrapolation, due to the similarities in structure and metabolic elimination pathways between hydroxychloroquine and chloroquine, a similar interaction could be observed for hydroxychloroquine. Caution is advised (e.g. monitoring for adverse reactions) when CYP2C8 and CYP3A4 strong or moderate inhibitors (such as gemfibrozil, clopidogrel, ritonavir, itraconazole, clarithromycin, grapefruit juice) are concomitantly administered.
Lack of efficacy of hydroxychloroquine was reported when rifampicin, a CYP2C8 and CYP3A4 strong inducer, was concomitantly administered. Caution is advised (e.g. monitoring for efficacy) when CYP2C8 and CYP3A4 strong inducers (such as rifampicin, St. John's Wort, carbamazepine, phenobarbital) are concomitantly administered.
Effects of hydroxychloroquine on other medicinal products: P-gp substrates: The inhibitory potential of hydroxychloroquine on P-gp substrates has not been evaluated. In vitro observations show that all other aminoquinolines tested inhibit P-gp. Therefore, there is a potential for increased concentrations of P-gp substrates when hydroxychloroquine is concomitantly administered. An increased plasma ciclosporin level was reported when ciclosporin and hydroxychloroquine were co-administered. Increased digoxin serum levels were reported when digoxin and hydroxychloroquine were coadministered. Caution is advised (e.g. monitoring for adverse reactions or plasma concentrations as appropriate) when P-gp substrates with narrow therapeutic index (such as digoxin, ciclosporin, dabigatran) are concomitantly administered.
Praziquantel: In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel. It is not known if there is a similar effect when hydroxychloroquine and praziquantel are co-administered. It is not known if there is a similar effect when hydroxychloroquine and praziquantel are co-administered. Per extrapolation, due to the similarities in structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect may be expected for hydroxychloroquine.
Store at temperatures not exceeding 30°C.
P01BA02 - hydroxychloroquine ; Belongs to the class of aminoquinoline antimalarials.