Summary of medicine characteristics - QUINORIC 200 MG FILM-COATED TABLETS, HYDROXYCHLOROQUINE SULFATE 200 MG FILM-COATED TABLETS
Hydroxychloroquine Sulfate 200 mg Film – Coated Tablets
Quinoric 200mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach film-coated tablet contains 200 mg Hydroxychloroquine Sulfate B.P.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
3 PHARMACEUTICAL FORMFilm coated tablet (tablet)
White, circular, biconvex film coated tablets debossed with ‘200’ on one side and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Posology
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 400mg 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 31kg.
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Method of administration
The 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.
4.3 Contraindications
4.7 Effects on ability to drive and use machines
4.7 Effects on ability to drive and use machinesImpaired visual accommodation soon after the start of treatment 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.
4.8 Undesirable effects
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 (frequency cannot be estimated from the available data).
Tabulated list of adverse reactions
| System Organ class | Frequency | Adverse reaction |
| Blood and lymphatic system disorders | Not known | Bone-marrow depression, anaemia, aplastic anaemia, agranulocytosis, leucopenia and thrombocytopenia |
| Immune system disorders | Not known | Urticaria, angioedema, bronchospasm |
| Metabolism and nutrition disorders | Common | Anorexia |
| Not known | Hypoglycaemia (see section 4.4) Hydroxychloroquine may precipitate or exacerbate porphyria | |
| Psychiatric disorders | Common | Affect liability |
| Uncommon | Nervousness | |
| Not known | Suicidal behaviour, psychosis, depression, hallucinations, anxiety, agitation, confusion, delusions, mania and sleep disorders | |
| Nervous system disorders | Common | headache |
| Uncommon | dizziness | |
| Not known | Convulsions have been reported with this class of drugs Extrapyramidal disorders such as dystonia, dyskinesia, tremor (see section 4.4) | |
| Eye disorders | Common | Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible |
| Uncommon | Retinopathy with changes in pigmentation and visual field defects can occur, but appears to be uncommon if the recommended daily dose is not exceeded. In its early form it appears reversible on discontinuation of hydroxychloroquine sulfate. If allowed to develop, there may be a risk of progression even after treatment withdrawal. |
| Patients with retinal changes may be asymptomatic initially, or may have scotomatous vision with paracentral, pericentral ring types, temporal scotomas and abnormal colour vision. Corneal changes including oedema and opacities have been reported. They are either symptomless or may cause disturbances such as haloes, blurring of vision or photophobia. They may be transient and are reversible on stopping treatment. | ||
| Not known | Cases of maculopathies and macular degeneration have been reported (the onset ranging from 3 months to several years of exposure to hydroxychloroquine) and may be irreversible | |
| Ear and labyrinth disorders | Uncommon | Vertigo, tinnitus |
| Not known | Hearing loss | |
| Skin and subcutaneous tissue disorders | Common | Skin rash, Pruritus |
| Uncommon | Pigmentation disorders in skin and mucous membranes, bleaching of hair, alopecia These usually resolve readily on stopping treatment. | |
| Not known | Bullous eruptions including erythema multiforme Stevens-Johnson syndrome and toxic epidermal necrolysis Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) photosensitivity exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although hydroxychloroquine may precipitate attacks of psoriasis. It may be associated with fever and hyperleukocytosis. Outcome is usually favourable after drug withdrawal. | |
| Gastrointestinal disorders | Very common | Abdominal pain, nausea |
| Common | diarrhoea, vomiting These symptoms usually resolve immediately on reducing the dose or on stopping treatment. | |
| Cardiac disorders | Not known | QT interval prolongation in patients with specific risk factors, which may lead to arrhythmia (torsade de pointes, ventricular tachycardia) (see sections 4.4 and 4.9). Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome (see section 4.4 and 4.9) Chronic toxicity should be considered when conduction disorders (bundle branch block/atrioventricular heart block) as well as biventricular hypertrophy are found. Drug withdrawal may lead to recovery. |
| Musculoskeletal and connective tissue disorders | Uncommon | Sensory motor disorders |
| Not known | Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups. Myopathy may be reversible after drug discontinuation, but recovery may take many months. Depression of tendon reflexes and abnormal nerve conduction studies. Phospholipidosis mimicking Fabry disease | |
| Hepatobiliary disorders | Uncommon | Abnormal liver function tests |
| Not known | Fulminant hepatic failure |
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
Overdose with the 4-aminoquinolines is dangerous particularly in infants, as little as 1–2g having proved fatal.
Symptoms
The symptoms of overdose may include headache, visual disturbances, cardiovascular collapse, convulsions and 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 potentially fatal respiratory and cardiac arrest. Immediate medical attention is required, as these effects may appear shortly after the overdose.
Management
The stomach should be immediately evacuated, either by emesis or gastric lavage. Finely powdered activated charcoal in a dose at least five times of the overdose 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 overdose; it has been shown to be beneficial in reversing chloroquine cardiotoxicity.
Respiratory support and shock management should be instituted as necessary.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
5.2 Pharmacokinetic properties
5.2 Pharmacokinetic propertiesAbsorption
Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a single dose of 400mg in healthy subjects ranged from 53–208ng/ml with a mean of 105ng/ml. The mean time to peak plasma concentration was 1.83 hours.
Distribution
The parent compound and metabolites are widely distributed in the body.
Metabolism
The metabolism of Hydroxychloroquine is similar to that of Chloroquine.
Elimination
The mean plasma elimination half-life varied, depending on the post-administration period, as follows; 5.9 hours (at C max- 10 hours), 26.1 hours (at 10–48 hours) and 229 hours (at 48–504 hours). Elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.
5.3. Preclinical safety data
Only limited preclinical data are available for hydroxychloroquine, therefor chloroquine data are considered due to the similarity of structure and pharmacological properties between the two products.
Genotoxicity:
There are limited data on hydroxychloroquine genotoxicity. Chloroquine is reported in the literature to elicit both gene mutations and chromosomal/DNA breaks in some in vitro systems in others and in in vivo studies using rodents when dosed via the intraperitoneal route. Chromosomal effects were not observed in vivo when chloroquine was administered orally.
Carcinogenicity:
There are no data on hydroxychloroquine carcinogenicity.
In a limited 2-years study in rats with chloroquine, no increase in neoplastic or proliferative changes was observed.
Development and reproductive toxicity
There are limited data on hydroxychloroquine teratogenicity. Chloroquine is teratogenic in rats after administration at very high, supratherapeutic doses, i.e. between 250 – 1500 mg/kg/day, showing a fetal mortality rate of 25% and ocular malformations (anophthalmia and microophthalmia) in 45% of foetuses in the 1000 mg/kg/day group. Auto-radiographic studies have shown that when administered at the start or the end of gestation, chloroquine accumulates in the eyes and ears of fetuses.
A study in male rats after 30 days of oral treatment at 5 mg/day of chloroquine showed a decrease in testosterone levels, weight of testes, epididymis, seminal vesicles and prostate. The fertility rate was also decreased in another rat study after 14 days of intraperitoneal treatment at 10mg/kg/day.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2. Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd.
Unit 3, Canalside, Northbridge Road,
Berkhamsted, Herts, HP4 1EG, United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0017
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
15/02/2007