Document: spc-doc_PL 17907-0486 change

• spc-doc_PL 17907-0486
• spc-doc_PL 17907-0487

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Chloroquine Phosphate 250 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg Chloroquine phosphate as an active ingredient. Excipient with known effect: also contains Lactose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

a)    Treatment of malaria.

b)    Prophylaxis and suppression of malaria.

c)    Treatment of amoebic hepatitis and abscess.

d)    Treatment of discoid and systemic lupus erythematosus.

e)    Treatment of rheumatoid arthritis

4.2    Posology and method of administration

Posology

a.    Treatment of malaria:

i) P. falciparum and P. malariae infections

Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days.

Paedriatric population: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days.

Age (years)	Initial dose	Second dose 6 hours after first	Dose on each of the two subsequent days
1 - 4	1 Tablet	/ Tablet	/Tablet
5 - 8	2 Tablets	1 Tablet	1 Tablet
9 -14	3 Tablets	1/ Tablets	1/ Tablets

ii) P. vivax and P. ovale infections

Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.

Paedriatric population: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Chloroquine phosphate to patients with renal disease or hepatic disease.

b) Prophylaxis and suppression of malaria

Adults: Two tablets taken once a week, on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.

Paediatric population: A single dose of 5mg chloroquine base/kg per week on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.

For practical purposes, children aged over 14 years may be treated as adults. The dose given to infants and children should be calculated on their body weight and must not exceed the adult dose regardless of weight.

1 - 4 years / tablet 5 - 8 years 1 tablet 9 - 14 years 1/ tablets

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Chloroquine phosphate to patients with renal disease or hepatic disease.

c)    Amoebic hepatitis

Adults: Four tablets daily for two days followed by one tablet twice daily for two or three weeks.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Chloroquine phosphate to patients with renal disease or hepatic disease.

d)    Lupus erythematosus

Adults: One tablet twice daily for one to two weeks followed by a maintenance dosage of one tablet daily.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Chloroquine phosphate to patients with renal disease or hepatic disease.

e)    Rheumatoid arthritis

Adults: The usual dosage is one tablet daily.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Chloroquine phosphate to patients with renal disease or hepatic disease.

Method of administration

The dose should be taken after food.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients listed section 6.1 Concomitant use with amiodarone (see section 4.5).

4.4    Special warnings and precautions for use

When used as malaria prophylaxis official guidelines and local information on prevalence to resistance to anti-malarial drugs should be considered.

Chloroquine 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 chloroquine 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 chloroquine should have their blood glucose level checked and treatment reviewed as necessary.

Caution is necessary when giving Chloroquine to patients with impaired hepatic function, particularly when associated with cirrhosis.

Caution is also necessary in patients with porphyria. Chloroquine may precipitate severe constitutional symptoms and an increase in the amount of porphyrins excreted in the urine. This reaction is especially apparent in patients with high alcohol intake.

A small number of cases of diffuse parenchymal lung disease have been identified in patients taking chloroquine. A response after therapy with steroids has been observed in some of these cases.

Cases of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been identified in patients taking chloroquine alone or in combination with proguanil. Recovery after discontinuation of treatment and response after therapy with steroids has been observed.

Caution is necessary when giving Chloroquine to patients with renal disease. Chloroquine should be used with care in patients with a history of epilepsy. Potential risks and benefits should be carefully evaluated before use in subjects on anticonvulsant therapy or with a history of epilepsy as rare cases of convulsions have been reported in association with chloroquine (see section 4.5).

The use of Chloroquine in patients with psoriasis may precipitate a severe attack

Caution is advised in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDD), as there may be a risk of haemolysis.

Considerable caution is needed in the use of Chloroquine for long-term high dose therapy and such use should only be considered when no other drug is available. Patients on long-term therapy should also be monitored for cardiomyopathy and prolongation of QTc interval (see section 4.8). Such use should only be considered if no drug is available.

Irreversible retinal damage and corneal changes may develop during longterm therapy and after the drug has been stopped. Ophthalmic examination prior to and at 3-6 monthly intervals during use is required if patients are receiving chloroquine

-    at continuous high doses for longer than 12 months

-    as weekly treatment for longer than 3 years

-    when total consumption exceeds 1.6g/Kg (cumulative dose

100g)

Full blood counts should be carried out regularly during extended treatment as bone marrow suppression may occur rarely. Caution is required if drugs known to induce blood disorders are used concurrently.

Acute extrapyramidal disorders (see section 4.8) have been reported during treatment with chloroquine, usually disappearing on discontinuation of treatment and /or on symptomatic treatment.

This medicine contains Lactose:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

There is an increased risk of inducing ventricular arrhythmias if chloroquine is used with halofantrine or other arrhythmogenic drugs such as moxifloxacin. In particular, amiodarone should not be used and its use is contraindicated. Antacids (aluminium, calcium and magnesium salts) and adsorbents (e.g. kaolin) may reduce the absorption of chloroquine, so should be taken well separated from Chloroquine (at least four hours apart).

If the patient is taking ciclosporin then chloroquine may cause an increase in ciclosporin levels.

Chloroquine should be used with caution with drugs known to prolong QT interval or with potential to induce cardiac arrhytmias.

Pre-exposure intra-dermal human diploid-cell rabies vaccine should not be administered to patients takingchloroquine as this may suppress the antibody response. When vaccinated against rabies, that vaccine should precede the start of the antimalarial dosing, otherwise the effectiveness of the vaccine might be reduced. Chloroquine significantly reduces levels of praziquantel. Caution is therefore advised during co-administration. Prescribers may consider increasing the dose of praziquantel if the patient does not respond to the initial dose.

Other antimalarials:    increased risk of convulsion with mefloquine.

Cardiac glycosides:    hydroxychloroquine and possibly chloroquine

increase plasma concentration of digoxin. Parasympathomimetics: chloroquine and hydroxychloroquine have potential

to increase symptoms of myasthenia gravis and thus diminish effect of neostigmine and pyridostigmine.

Ulcer healing drugs: cimetidine inhibits metabolism of chloroquine

(increased plasma concentration).

In vitro work has shown that the concomitant use of drugs such as multidrug and toxin extrusion protein (MATE1) inhibitors (e.g., ciprofloxacin, cimetidine, omeprazole, pyrimethamine) may impact the renal clearance of chloroquine, which could theoretically lead to increased levels of chloroquine and potentially overdosage (see section 4.9). In addition, care should be taken when alkalinization of urine occurs as this may reduce chloroquine renal excretion.

Chloroquine may lower the convulsive threshold and thus antagonise the actions of antiepileptics (See section 4.4).

Thyroid medication: increased Thyroid Stimulating Hormone levels have been observed with the concomitant use of levothyroxine, dosage adjustment of thyroid medication may be necessary.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Chloroquine should not be used during pregnancy unless in the judgement of the physician, potential benefit outweighs the risk.

Long-term high dose:

There is evidence to suggest that Chloroquine given to women in high doses throughout pregnancy can give rise to foetal abnormalities including visual loss, ototoxicity and cochlear-vestibular dysfunction.

Short-term malaria prophylaxis:

Malaria in pregnant women increases the risk of maternal death, miscarriages, still births and low birth weight infants with the associated risk of neonatal death. Travel to malarious areas should be avoided during pregnancy but if this is not possible women should receive effective prophylaxis.

Breast-feeding

Although Chloroquine is excreted in breast milk, the amount is too small to be harmful when used for malaria prophylaxis but as a consequence, is insufficient to confer any benefit on the infant. Separate chemoprophylaxis for the infant is required. However, when long-term high doses are used for rheumatoid disease, breast feeding is not recommended.

4.7 Effects on ability to drive and use machines

Defects in visual accommodation may occur on first taking Chloroquine and patients should be warned regarding driving or operating machinery.

4.8 Undesirable effects

Summary of safety profile:

The adverse reactions which may occur at doses used in the prophylaxis or treatment of malaria are generally not of a serious nature. Where prolonged high dosage is required, i.e. in the treatment of rheumatoid arthritis, adverse reactions can be of a more serious nature.

Undesirable effects are listed by MedDRA System Organ Classes. Assessment of undesirable effects is based on the following frequency groupings:

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

Tabulated list of adverse reactions:

System Organ Class	Undesirable Effect and Frequency
Blood and lymphatic system disorders	Not known Bone marrow failure Aplastic anaemia Agranulocytosis Thrombocytopenia Neutropenia Pancytopenia
Immune system disorders	Not known Hypersensitivity and anaphylactic reactions, including urticaria, angioedema and vasculitis.
Metabolism and nutrition disorders	Not known Hypoglycaemia (see section 4.4).
Psychiatric Disorders	Rare Hallucinations Not known Psychotic disorder including anxiety,

	personality change Insomnia Confusion Depression
Nervous system disorders	Not known Convulsion (see section 4.4) Visual field defects Headache Neuromyopathy Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) (see section 4.4)
Eye disorders	Not known Retinal degeneration Macular defects of colour vision Pigmentation Optic atrophy scotomas Blindness Corneal opacity and pigmented deposits Vision blurred Accommodation disorder Diplopia
Ear and labyrinth disorders	Not known Tinnitus Hypoacusis Deafness neurosensory
Cardiac disorders	Rare Cardiomyopathy (see section 4.4) Not Known Atrioventricular block QT prolongation
Vascular Disorders	Not known Hypotension
Respiratory, thoracic and mediastinal	Not known Diffuse parenchymal lung disease
Gastrointestinal disorders:	Not known Gastrointestinal disorder Nausea Vomiting Diarrhoea Abdominal pain

Hepatobiliary disorders	Rare Changes in liver function, including hepatitis and abnormal liver function tests
Skin and subcutaneous tissue disorders	Not known Macular, urticarial and purpuric skin eruptions Alopecia Erythema multiforme Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN) Precipitation of psoriasis Pruritus Photosensitivity reaction Lichenoid keratosis Pigmentation disorder * Exfoliative dermatitis Acute generlised exanthematous pustulosis (AGEP)
Musculoskeletal and connective tissue disorders	Not known Myopathy
Investigations	Not known Electrocardiogram change**
* Long term use **At high doses

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.

4.9 Overdose

Symptoms:

Chloroquine is highly toxic in overdose and children are particularly susceptible. The chief symptoms of overdosage include circulatory collapse due to a potent cardiotoxic effect, respiratory arrest, and coma. Cardiovascular adverse reactions may occur with serious intoxication.

Symptoms may progress rapidly and include:

General features include nausea and vomiting. Hypokalemia is common in severe poisoning and metabolic acidosis may also develop. Rarely hepatotoxicity, nephritis, gastric haemorrhage, haematological abnormalities and psychiatric features may occur.

-    Neurological features include headache, dizziness, drowsiness, blurred vision, diplopia and, rarely, blindness, may precede restlessness, increased excitability and convulsions. Coma is less common.

-    Cardiac features often appear at an early stage. Cardiac arrest may be a presenting feature. Hypotension is very common and may progress to cardiogenic shock and pulmonary oedema. Intraventricular conduction defects with a wide QRS, and prolongation of the QT interval are more common than A-V (atrioventricular) conduction defects. Ventricular tachycardia and fibrillation tend to occur early while torsade de pointes develops after about 8 hours.

Management:

Acute overdose with chloroquine can be rapidly lethal and intensive supportive treatment should be started immediately.

Death may result from circulatory or respiratory failure or cardiac arrhythmia but is usually due to cardiac arrest related to the direct effects on the myocardium. If there is no demonstrable cardiac output due to arrhythmias, asystole or electromechanical dissociation, external chest compression should be persisted with for as long as necessary, or until adrenaline and diazepam can be given (see below).

Firstly, maintain a clear airway and ensure adequate ventilation. The benefit of gastric decontamination is uncertain, but activated charcoal can be considered for adults and children aged over 5 years, within 1 hour of ingestion of more than 10 mg/kg of chloroquine base as a single dose or for any amount in a child aged 5 years and under, as it may reduce absorption of any remaining chloroquine from the gut. Activated charcoal should also be considered within 1 hour of ingestion of a weekly dose taken on 2 or more consecutive days. Alternatively, gastric lavage may be considered in adults within 1 hour of a potentially life threatening overdose. There is a risk of cardiac arrest following aspiration of gastric contents in more serious cases.

Monitor circulatory status (with central venous pressure measurement), cardiac rhythm, respiration, conscious level and urinary output. Check urea & electrolytes, liver function and full blood count in symptomatic patients. Consider arterial blood gas analysis in patients who have a reduced level of consciousness or have reduced oxygen saturation on pulse oximetry.

It is not clear if correction of hypokalaemia is essential but it may have a protective effect and should not be corrected in the early stages of poisoning. The degree of hypokalaemia may be correlated with the severity of chloroquine intoxication. If it persists beyond 8 hours, cautious correction should be undertaken with frequent biochemical monitoring of progress. Rebound hyperkalaemia is a risk during recovery.

In case of persistent metabolic acidosis consider intravenous sodium bicarbonate. Rapid correction is particularly important if there is prolongation of the QRS interval. DC (direct current) shock is indicated for ventricular tachycardia and ventricular fibrillation.

Cardiac arrhythmias should be treated with caution. The use of anti-arrhythmic drugs (such as those with quinidine-like effects) is best avoided since they may depress the myocardium further and exacerbate hypotension.

Early administration of the following has been shown to improve survival in cases of serious poisoning:

1.    Adrenaline infusion until adequate systolic blood pressure (more than 100mg/Hg) is restored; adrenaline reduces the effects of chloroquine on the heart through its inotropic and vasoconstrictor effects.

2.    Diazepam infusion; diazepam may decrease the cardiotoxicity of chloroquine.

Acidification of the urine, haemodialysis, peritoneal dialysis or exchange transfusion have not been shown to be of value in treating chloroquine poisoning. Chloroquine is excreted very slowly therefore cases of overdosage require observation for several days.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiprotozoals, Antimalarials ATC code: P01B A01.

Mechanism of action:

The mode of action of chloroquine on plasmodia has not been fully elucidated. Chloroquine binds to and alters the properties of DNA. Chloroquine also binds to ferriprotoporphyrin IX and this leads to lysis of the plasmodial membrane.

In suppressive treatment, chloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitised erythrocytes may account for the selective toxicity against the erythrocytic stages of plasmodial infection.

5.2 Pharmacokinetic properties

Absorption:

Studies in volunteers using single doses of chloroquine phosphate equivalent to 300mg base have found peak plasma levels to be achieved within one to six hours. These levels are in the region of 54 - 102microgram/litre, the concentration in whole blood being some 4 to 10 times higher. Following a single dose, chloroquine may be detected in plasma for more than four weeks. Mean bioavailability from tablets of chloroquine phosphate is 89%.

Distribution:

Chloroquine is widely distributed in body tissues such as the eyes, kidneys, liver, and lungs where retention is prolonged.

Biotransformation:

Approximately 50-70% of chloroquine in plasma is bound to the plasma proteins.

The principal metabolite is monodesethylchloroquine, which reaches a peak concentration of 10-20 microgram/litre within a few hours.

Elimination:

The elimination of chloroquine is slow, with a multi exponential decline in plasma concentration. The initial distribution phase has a half-life of 2-6 days while the terminal elimination phase is 10-60 days. Mean urinary recovery, within 3-13 weeks, is approximately 50% of the administered dose, most being unchanged drug and the remainder as metabolite. Chloroquine may be detected in urine for several months.

5.3 Preclinical safety data

None stated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Starch

Sodium Starch Glycollate Stearic Acid Magnesium Stearate

6.2    Incompatibilities

None

6.3    Shelf life

60 months.

6.4    Special precautions for storage

Protect from light and moisture.

6.5    Nature and contents of container

PVC/Alu blister packs containing 10, 12, 20, 24, 30, 36, 40, 48, 50, 60, 70, 72, 80, 84, 90, 96 and 100 tablets.

Securitainer details

High density polypropylene container with a low density polyethylene closure. Pack sizes: 100, 250, 500 and 1000 tablets.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Bristol Laboratories Limited Unit-3, Canalside Northbridge Road Berkhamsted