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.

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.
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.

Retinopathy
The occurrence of retinopathy is very uncommon if the recommended daily dose is not
exceeded. The administration of doses in excess of the recommended maximum is likely to
increase the risk of retinopathy, and accelerate its onset.
All patients should have an ophthalmological examination before initiating treatment with
Hydroxychloroquine. Thereafter, ophthalmological examinations must be repeated at least
every 12 months.
The examination should include testing visual acuity, careful ophthalmoscopy, fundoscopy
and central visual field testing with a red target, and colour vision.
This examination should be more frequent and adapted to the patient in the following
situations:
- daily dosage exceeds 6.5mg/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.
- concomitant use of hydroxychloroquine sulfate with drugs known to induce retinal
toxicity, such as tamoxifen.

Hydroxychloroquine should be discontinued immediately in any patient who develops a
pigmentary abnormality, visual field defect, or any other abnormality not explainable by
difficulty in accommodation or presence of corneal opacities. Patients should continue to be
observed for possible progression of the changes.
Patients should be advised to stop taking the drug immediately and seek the advice of their
prescribing doctor if any disturbances of vision are noted, including abnormal colour vision.
 

Extrapyramidal disorders
Extrapyramidal disorders may occur with Hydroxychloroquine sulfate (see section 4.8).
 

Hypoglycaemia
Hydroxychloroquine has been shown to cause severe hypoglycaemia including loss of
consciousness that could be life threatening in patients treated with and without antidiabetic
medications. Patients treated with hydroxychloroquine should be warned about the risk of
hypoglycaemia and the associated clinical signs and symptoms. Patients presenting with
clinical symptoms suggestive of hypoglycaemia during treatment with hydroxychloroquine
should have their blood glucose level checked and treatment reviewed as necessary.
 

QT interval prolongation
Hydroxychloroquine has the 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 section 4.5)
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.
 

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 (see section 4.8 and 4.9).
Clinical monitoring for signs and symptoms of cardiomyopathy is advised and with
hydroxychloroquine sulfate should be discontinued if cardiomyopathy develops. Chronic
toxicity should be considered when conduction disorders (bundle branch block / atrioventricular
heart block) as well as biventricular hypertrophy are diagnosed (see section 4.8).
 

Bone marrow depression
Although the risk of bone marrow depression is low, periodic blood counts are advisable as
anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells, and
thrombocytopenia have been reported. Hydroxychloroquine should be discontinued if
abnormalities develop.
 

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 section 4.8).
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 section
4.8)
 

Potential carcinogenic risk
Experimental data showed a potential risk if inducing gene mutations. Animal carcinogenicity
data is only available for one species for the parent drug chloroquine and this study was
negative (see section 5.3). In humans, there is insufficient data to rule out an increased risk of
cancer in patients receiving long-term treatment.
Hydroxychloroquine sulphate should be used with caution in patients taking medicines which
may cause adverse skin reactions.
Caution should also be applied when it is used in the following:
• patients with hepatic or renal disease, and in those taking drugs 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.
• 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.
 

Paediatric populations

Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore
patients should be warned to keep Hydroxychloroquine out of the reach of children.
 

Dermatological reactions
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) have been reported with the use of Hydroxychloroquine.
Patients should be advised of the signs and symptoms and monitored closely for skin
reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal
lesions) are present, Hydroxychloroquine treatment should be discontinued.
The best results in managing SJS and TEN come from early diagnosis and immediate
discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
If the patient has developed SJS or TEN with the use of Hydroxychloroquine,
Hydroxychloroquine must not be re-started in this patient at any time.
 

Suicidal behaviour and psychiatric disorders
Suicidal behaviour and psychiatric disorders have been reported in some patients treated with
hydroxychloroquine (see section 4.8). Psychiatric side effects typically occur within the first
month after the start of treatment with hydroxychloroquine and have been reported also in
patients with no prior history of psychiatric disorders. Patients should be advised to seek
medical advice promptly if they experience psychiatric symptoms during treatment.
Carefully consider the benefits and risks before prescribing hydroxychloroquine for any
patients taking azithromycin or other macrolide antibiotics, because of the potential for an
increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).

Digoxin
Hydroxychloroquine sulfate has been reported to increase plasma digoxin levels: Serum
digoxin levels should be closely monitored in patients receiving concomitant treatment.
 

Anti-diabetics
As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in
doses of insulin or antidiabetic drugs may be required.
 

Drugs known to prolong the 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 sections 4.4 and 4.9).
Halofantrine should not be administered with hydroxychloroquine. There may be an increased
risk of inducing ventricular arrhythmias if hydroxychloroquine is used concomitantly with other
arrhythmogenic drugs, such as amiodarone and moxifloxacin.
Ciclosporin
An increased plasma ciclosporin level was reported when ciclosporin and hydroxychloroquine
were co-administered.
 

Tamoxifen
Concomitant use of drugs known to induce retinal toxicity e.g. tamoxifen and
hydroxychloroquine, is not recommended (see section 4.4).
 

Agalsidase
There is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when
hydroxychloroquine is co-administered with agalsidase.
 

Drugs affecting the convulsive threshold

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.
 

Anti-epileptics
Also, the activity of antiepileptic drugs might be impaired if co-administered with
hydroxychloroquine.
Hydroxychloroquine sulfate may also be subject to several of the known interactions of
chloroquine even though specific reports have not appeared. These include:
• potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics
• inhibition of its metabolism by cimetidine which may increase plasma concentration of the
antimalarial
• antagonism of effect of neostigmine and pyridostigmine

• reduction of the antibody response to primary immunisation with intradermal human diploidcell rabies vaccine.
As with chloroquine, antacids may reduce absorption of hydroxychloroquine so it is advised
that a 4 hour interval be observed between hydroxychloroquine sulfate and antacid dosing.
 

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. Per extrapolation, due to the similarities in structure and
pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect
may be expected for hydroxychloroquine.
Observational data have shown that co-administration of hydroxychloroquine with
azithromycin in patients with rheumatoid arthritis is associated with an increased risk of
cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits
and risks before prescribing hydroxychloroquine for any patients taking azithromycin. Similar
careful consideration of the balance of benefits and risk should also be undertaken before
prescribing hydroxychloroquine for any patients taking other macrolide antibiotics, such as
clarithromycin or erythromycin, because of the potential for a similar risk when
hydroxychloroquine is co-administered with these medicines.

Pregnancy
A moderate amount of data on pregnant women (between 300 – 1000 pregnancy outcomes),
including prospective studies in long-term use with large exposure, have not observed a
significant increased risk of congenital malformations or poor pregnancy outcomes.
Hydroxychloroquine crosses the placenta. 4-aminoquinolines in therapeutic doses caused
damage to the central nervous system, including ototoxicity (auditory and vestibular toxicity,
congenital deafness), retinal haemorrhages and abnormal retinal pigmentation.
In animal studies, reproduction toxicity was found with chloroquine, a substance related to
hydroxychloroquine, following high maternal exposition (see section 5.3).
Only limited non-clinical data are available for hydroxychloroquine, data on chloroquine have
shown developmental toxicity at high supratherapeutic doses and a potential risk of
genotoxicity in some test systems (see section 5.3).
Therefore, hydroxychloroquine sulfate should be avoided in pregnancy (see section 4.3)
except when, in the judgement of the physician, the individual potential benefits outweigh the
potential hazards. Before treatment is started a pregnancy has to be excluded.

Breast-feeding
Hydroxychloroquine is excreted in breast milk (less than 2% of the maternal dose after
bodyweight correction). 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.
 

Fertility
Animal studies showed an impairment of male fertility for chloroquine (see section 5.3). There
are no data in humans.
 

Contraception
During treatment with hydroxychloroquine and for at least 3 months after treatment
termination, a pregnancy should be strictly avoided

Impaired 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.

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

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.

Pharmacotherapeutic group: Antimalarials, Aminoquinolines
ATC Code: P01BA02
 

Mechanism of action
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.

Absorption
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.

Only limited preclinical data are available for hydroxychloroquine, therefore 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.

• HYPROMELLOSE,SUBSTITUTION GRADE 2910 (TYLOPUR 603) EP
• LACTOSE MONOHYRATE (PHARMATOSE 200M) EP
• MAIZE STARCH (CORN STARCH) USP
• SODIUM HYDROXIDE PELLETS USP
• PURIFIED WATER USP
• CROSPOVIDONE
• MAGNESIUM STEARATE
• OPADRY WHAITE

Not applicable.

Store below 30 ºC

Vasrasti are white to off-white, round shaped, biconvex film-coated tablets debossed JS46 on
one side and plain on other side.
Vasrasti pack as 60 film-coated tablets per pack (10 Tablets per blister – SIX blisters per Pack).

Any unused medicinal product or waste material should be disposed of in accordance with
local requirements, Keep out of the reach & sight of children