SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nivaquine 68mg/5ml Syrup

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

In terms of the active ingredient:-Chloroquine Sulphate BP 68 mg/5 ml.

3.    PHARMACEUTICAL FORM

Syrup.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nivaquine is a 4-aminoquinoline compound which has a high degree of activity against the asexual erythrocytic forms of all species of malaria parasites.

It is indicated for the prevention of malaria.

Route of administration: oral.

4.2    Posology and method of administration Prevention of malaria

Adults:6 x 5 ml Nivaquine Syrup (300 mg chloroquine base) to be taken once a week on the same day each week.

Infants and children up to 12 years: 5 mg chloroquine base per kg bodyweight to be taken once a week on the same day each week.

It is advisable to start taking Nivaquine 1 week before entering an endemic area and to continue for 4 weeks after leaving.

4.3. Contraindications

The use of chloroquine is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.

Nivaquine is generally contraindicated in pregnancy. However, clinicians may decide to administer Nivaquine to pregnant women for the prevention or treatment of malaria. Ocular or inner ear damage may occur in infants born of mothers who receive high doses of chloroquine throughout pregnancy.

4.4 Special warnings and precautions for use

Nivaquine should be used with care in patients with a history of epilepsy as it has been reported to provoke seizures. Caution is advised in cases of porphyria (precipitated disease may be especially apparent in patients with a high alcohol intake), hepatic disease (particularly cirrhosis) or renal disease, severe gastrointestinal, neurological and blood disorders and in patients receiving anticoagulant therapy.

Nivaquine should be used with care in patients with psoriasis as the condition may be exacerbated.

Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with chloroquine (see SPC section 4.8 and SPC section 4.9). Clinical monitoring for signs and symptoms of cardiomyopathy is advised and Nivaquine should be discontinued if cardiomyopathy develops.

Chloroquine should be used with caution in patients with cardiac disease, a history of ventricular dysrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT interval prolonging agents (see SPC section 4.5 and SPC section 4.8 and SPC section 4.9)

(due to potential for QT prolongation)

Retinopathy/maculopathy, as well as macular degeneration have been reported (see section 4.8 Undesirable effects) and irreversible retinal damage may occur in patients with prolonged treatment. Therefore, ophthalmological examinations should be performed before starting and regularly during therapy.

Risk factors for the development of retinopathy include age, duration of treatment, high daily and/or cumulated doses.

If any visual disturbances indicative of retinopathy/ maculopathy occur during treatment, chloroquine should be immediately discontinued and the patient observed for possible progression. Retinal changes (and visual disturbances) may progress even after cessation of therapy. Therefore, patients should be advised to discontinue the medication and seek immediate medical advice if they notice any deterioration in their vision which persists for more than 48 hours. Ophthalmological examination should always be carried out before and regularly (3-6 monthly intervals) during prolonged treatment. Retinal damage is particularly likely to occur if treatment has been given for longer than one year, or if the total dosage has exceeded 1.6 g/kg bodyweight. These precautions also apply to patients receiving chloroquine continuously at weekly intervals as a prophylactic against malarial attack for more than three years.

Bone marrow depression, including aplastic anaemia occurs rarely. Full blood counts should therefore be carried out regularly during extended treatment. Caution is required if drugs known to induce blood disorders are used concurrently.

Resistance of Plasmodium falciparum to chloroquine is well documented. When used as malaria prophylaxis official guidelines and local information on prevalence of resistance to anti-malarial drugs should be taken into consideration.

Acute extrapyramidal disorders may occur with Nivaquine (see Section 4.8 undesirable effects and 4.9 overdose). These adverse reactions usually resolve after treatment discontinuation and/or symptomatic treatment. Treatment continuation should be based on benefit vs. the risk to the patient.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of chloroquine with magnesium-containing antacids or kaolin may result in reduced absorption of chloroquine. Chloroquine should, therefore, be administered at least two hours apart from antacids or kaolin.

Concomitant use of cimetidine and chloroquine may result in an increased half-life and a decreased clearance of chloroquine.

As chloroquine may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

Halofantrine prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias, including chloroquine. Also, there may be an increased risk of inducing ventricular arrhythmias if chloroquine is used concomitantly with other arrhythmogenic drugs, such as amiodarone and moxifloxacin.

Chloroquine and mefloquine can lower the convulsive threshold. Co-administration of chloroquine and mefloquine may increase the risk of convulsions. Also, the activity of antiepileptic drugs might be impaired if co-administered with chloroquine.

There have been isolated case reports of an increased plasma ciclosporin level when ciclosporin and chloroquine were co-administered.

Chloroquine may affect the antibody response to rabies vaccine (HDCV).

In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel.

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

Caution is advised in patients receiving anticoagulant therapy.

Co-administration of chloroquine and other drugs that have arrhythmogenic potential (e.g. amiodarone) may increase the risk of cardiac arrhythmias.

Concomitant administration of chloroquine and digoxin may increase plasma concentrations of digoxin.

Concomitant use of chloroquine with neostigmine or pyridostigmine has the potential to increase the symptoms of myasthenia gravis and thus diminish the effects of neostigmine and pyridostigmine.

4.6. Pregnancy and lactation

Nivaquine is generally contraindicated in pregnancy. However, clinicians may decide to administer Nivaquine to pregnant women for the prevention or treatment of malaria. Ocular or inner ear damage may occur in infants born of mothers who receive high doses of chloroquine throughout pregnancy.

Although chloroquine is excreted in breast milk, the amount is insufficient to confer any benefit on the infant. Separate chemoprophylaxis for the infant is required. When used for rheumatoid disease breast feeding is not recommended.

4.7. Effects on ability to drive and use machines

Nivaquine has a temporary effect on visual accommodation and patients should be warned that they should not drive or operate machinery if they are affected.

4.8 Undesirable effects

The following CIOMS frequency rating is used when applicable:

Very common > 10%; Common > 1 and < 10%; Uncommon > 0.1 and < 1%; Rare > 0.01 and < 0.1%; Very rare < 0.01%; Not known (frequency cannot be estimated from available data)

Cardiac disorders

-    Uncommon: cardiomyopathy has been reported during long term therapy at high doses, which may result in cardiac failure and in some cases a fatal outcome

-    Rare: cardiac arrhythmias, including QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation have been reported with therapeutic doses of chloroquine as well as with overdose. The risk is greater if chloroquine is administered at high doses. Fatal cases have been reported.

-    Not known - hypotension.

Nervous system disorders (See Section 4.4)

-    Very common: headache

-    Common: convulsions have been reported rarely (these may result from cerebral malaria. Such patients should receive an injections of phenobarbital to prevent seizures, in a dose of 3.5mg/kg in addition to intravenous administration of Nivaquine),

-    Uncommon: neuropathy

-    Rare: polyneuropathy

-    Not known: acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) (see Section 4.4 and Section 4.9).

Psychiatric disorders

-    Very common: insomnia

-    Common: depression

-    Rare: psychiatric disorders such as anxiety, agitation, confusion, hallucinations, delirium

-    Not known: suicidal behaviour

Eye disorders (See Sections 4.4 and 4.7)

-    Common: transient blurred vision

-    Rare: reversible corneal opacity, cases of retinopathy as well as cases of irreversible retinal damage have been reported during long term, high dose therapy.

-    Not known: maculopathy and macular degeneration have been reported and may be irreversible (see also Section 4.4).

-    macular defects of colour vision, optic atrophy, scotomas, field defects, blindness and pigmented deposits, difficult in focusing, diplopia.

Gastro-intestinal disorders

-    Very common: gastrointestinal disturbances such as nausea, vomiting, diarrhoea.

-    Not known: abdominal cramps

Blood and lymphatic system disorders (See Section 4.4)

-    Rare: bone marrow depression, including aplastic anaemia, agranulocytosis, pancytopenia, thrombocytopenia, neutropenia

Hepatobiliary disorders

-    Rare: changes in liver function, including hepatitis and abnormal liver function tests

Immune system disorders

-    Common: allergic and anaphylactic reactions, including angioedema

Ear and labyrinth disorders

-    Uncommon: ototoxicity such as tinnitus, hypoacusis, nerve deafness.

Musculoskeletal and connective tissue disorders

-    Uncommon: myopathy

Skin and subcutaneous tissue disorders (See Section 4.4)

-    Very common: pruritis,

-    Common: skin eruptions, urticaria

-    Uncommon: alopecia, bluish-black pigmentation of the nails and mucosae (long term use).

-    Rare: exacerbation of psoriasis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

-    Very rare: exfoliative dermatitis and similar desquamation-type events.

-    Not known: depigmentation, photosensitivity, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)

Metabolism and nutrition disorders

-    Not known: hypoglycaemia (see section 4.4).

4.9 Overdose

Signs and symptoms

Chloroquine is rapidly absorbed and is highly toxic in overdosage; children are particularly susceptible to toxic doses of chloroquine. The chief symptoms of overdose include cardiovascular collapse due to a potent cardiotoxic effect, respiratory arrest and coma. Symptoms may progress rapidly after initial headache, drowsiness, visual disturbances nausea and vomiting. Symptoms of overdose may include rhythm and conduction disorders, including QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation. Hypokalaemia can occur, possibly due to an extracellular to intracellular potassium shift, and may increase the risk of cardiac dysrhythmia. Death may result from acute cardiac or respiratory failure or cardiac dysrhythmia.

Cases of extrapyramidal disorders have also been reported in the context of chloroquine overdose (see also SPC section 4.4 and SPC section 4.8)

Management

Gastric lavage should be carried out urgently, first protecting the airways and instituting artificial ventilation where necessary. There is a risk of cardiac arrest following aspiration of gastric contents in more serious cases. Activated charcoal left in the stomach may reduce absorption of any remaining chloroquine from the gut. Circulatory status (with central venous pressure measurement), respiration, plasma electrolytes and blood gases should be monitored, with correction of hypokalaemia and acidosis if indicated. Cardiac arrhythmias should not be treated unless life threatening; drugs with quinidine-like effects should be avoided.

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

1) Adrenaline infusion (0.25 micrograms/kg/min initially, with increments of 0.25 micrograms/kg/min until adequate systolic blood pressure (more than 100 mm mercury) is restored; adrenaline reduces the effects of chloroquine on the heart through its inotropic and vasoconstrictor effects.

2) Diazepam infusion (2 mg/kg over 30 minutes as a loading dose, followed by 1-2 mg/kg/day for up to 2-4 days). Diazepam may minimise cardiotoxicity.

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

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antimalarials, Aminoquinolines ATC code: P01B A01

Chloroquine is used for the prevention of malaria. It has rapid schizonticidal effect and appears to affect cell growth by interfering with DNA; its activity also seems to depend on preferential accumulation in the infected erythrocyte. Chloroquine kills the erythrocytic forms of malaria parasites at all stages of development.

5.2. Pharmacokinetic properties

Chloroquine is readily absorbed from the gastro-intestinal tract and about 55% in the circulation is bound to plasma proteins. It accumulates in high concentrations in some tissues, such as kidneys, liver, lungs and spleen and is strongly bound in melanin containing cells such as those in the eyes and the skin; it is also bound to double stranded DNA, present in red blood cells containing schizonts. Chloroquine is eliminated very slowly from the body and it may persist in tissues for a long period. Up to 70% of a dose may be excreted unchanged in urine and up to 25% may be excreted also in the urine as the desethyl metabolite. The rate of urinary excretion of chloroquine is increased at low pH values.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose,

Monosodium glutamate, Saccharin sodium,

Propylene glycol,

Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Peppermint Oil,

Pineapple flavour,

Caramel,

Purified water

6.2. Incompatibilities

None known.

6.3. Shelf life

36 months.

6.4. Special precautions for storage

Nivaquine should be stored below 25°C, protected from light.

6.5    Nature and contents of container

Amber glass bottle containing either 60 or 100 ml. Either with rolled on pilfer proof aluminium cap and PVDC emulsion coated wad, or HDPE/polypropylene child resistant cap with a tamper evident band.

6.6    Special precautions for disposal

None stated.

7    MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited One Onslow Street Guildford Surrey

Or trading as:-

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. MARKETING AUTHORISATION NUMBER

PL 04425/0329

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06 March 2003

10 DATE OF REVISION OF THE TEXT

14/05/2014