Zanika

Hydroxychloroquine sulfate is a colorless crystalline solid, soluble in water to at least 20 percent; chemically the drug is 2-[[4-[(7-Chloro-4-quinolyl)amino] pentyl] ethylamino] ethanol sulfate (1:1). It has an empirical formula of C₁₈H₂₈ClN₃O₅S, a molecular weight of 433.948 g/mol.
Each film-coated tablet contains: Hydroxychloroquine Sulfate USP 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: Following a single 200 mg oral dose of hydroxychloroquine sulfate to healthy males, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half-life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL reached in 3.74 hours with a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. The mean & action of the dose absorbed was 0.74. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months owing the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics.
Following chronic oral administration of hydroxychloroquine, significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BOCQ) have been found in plasma and blood, with DHCQ being the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue uptake rather than through decreased excretion. Peak plasma levels of hydroxychloroquine were seen in about 3 to 4 hours. Renal clearance in rheumatoid arthritis (RA) patients taking hydroxychloroquine sulfate for at least six months seemed to be similar to that of the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients with renal impairment. In RA patients, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Cellular levels of patients on daily hydroxychloroquine have been shown to be higher in mononuclear cells than polymorphonuclear leucocytes.
A single 200 mg oral dosage of Hydroxychloroquine has actions, pharmacokinetics and metabolism similar to those of chloroquine. Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a single dose of 400 mg in healthy subjects ranges from 53-208 ng/mL with a mean of 105 ng/mL.
The mean time to peak plasma concentration was 1.83 hours. The mean plasma elimination half-life varied, depending on the post administration period, as follows: 5.9 hours at Cmax-10 hours) 26.1 hours (at 10-48 hours and 299 hours (at 48-504 hours). The parent compound and metabolites are widely distributed in the body and elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.

For the treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis.
Therapeutic Conditions: 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.

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.
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. Each 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.
The tablets are for oral administration.

Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2 g having proved fatal. The symptoms of overdosage 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, followed by sudden potential headache.
Uncommon: Dizziness, 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 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 overdosage; it has been shown to be beneficial in reversing chloroquine cardiotoxicity.
Respiratory support and shock management should be instituted as necessary.

Use of Hydroxychloroquine sulfate is contraindicated in patient with known hypersensitivity to 4-aminoquinoline compounds.

General: 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 Zanika. Thereafter, ophthalmological examinations must be at least every 12 months. The examination should include testing visual activity, careful ophthalmoscopy, fundoscopy, 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 6.5 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 should be discontinued immediately in any patient who develops a pigmentary abnormality, visual field defect, or any other 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. Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, reported in patients treated with Zanika. Clinical monitoring for signs and symptoms of cardiomyopathy is advised and Zanika 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. Hydroxychloroquine sulfate 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 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.
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. Zanika should be discontinued if abnormalities develop. 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 sulfate and in the patients with psoriasis since it appears to increase the risk of skin reactions. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Small children are particularly sensitive to the toxic effects of 4-aminoquinolines. Therefore, patients should be warned to keep Hydroxychloroquine Sulfate out of the reach of the reach of children. All patients on long-term therapy should undergo periodic examination of skeletal muscle function reflexes. If weakness occurs, the drug should be withdrawn. Hydroxychloroquine has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic. 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. Extrapyramidal disorders may occur with Hydroxychloroquine sulfate.
Information for Patients: Patients should be informed of the early signs and symptoms of toxicity such as rash, visual changes. Patients must see their physicians promptly in case of the appearance of these or of any unusual effects. Periodic laboratory tests may be recommended in some patients.
Patients should be fully informed of the potential risks of the use of hydroxychloroquine sulfate, especially in pregnancy and in children.
Carcinogenesis, mutagenesis, impairment of fertility: Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of hydroxychloroquine sulfate.
The mutagenic potential of hydroxychloroquine sulfate was not evaluated. However, chloroquine has been shown to be a catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.

Pregnancy: Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. 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. Therefore, Zanika should not be used in pregnancy.
Lactation: Careful consideration should be given to using hydroxychloroquine during lactation, since it has been shown to be excreted in small amounts in human breast milk, and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

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).
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: Hypoglycemia.
Hydroxychloroquine may precipitate or exacerbate porphyria.
Psychiatric disorders: Common: Affect lability.
Uncommon: Nervousness.
Not known: Psychosis.
Nervous system disorders: Not known: Convulsions have been reported with this class of drugs. Extrapyramidal disorders such as dystonia, dyskinesia, tremor.
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 Zanika. 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.
Cardiac disorders: Not known: Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome.
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.
Gastrointestinal disorders: Very common: Abdominal pain, nausea.
Common: Diarrhoea, vomiting.
These symptoms usually resolve immediately on reducing the dose or on stopping treatment.
Hepatobiliary disorders: Uncommon: Abnormal liver function tests.
Not known: Fulminant hepatic failure.
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.
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.
General: Use with caution in patients with gastrointestinal, neurological, or blood disorders, and in those with a sensitivity to quinine.

Digoxin: Concomitant hydroxychloroquine sulfate and digoxin therapy may result in increased serum digoxin levels. Serum digoxin levels should be closely monitored in patients receiving combined therapy.
Insulin or antidiabetic drugs: As hydroxychloroquine sulfate may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.
Drugs that prolong QT interval and other arrhythmogenic drugs: Hydroxychloroquine sulfate prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias. Also, there may be an increased risk of inducing ventricular arrythmias if hydroxychloroquine sulfate is used concomitantly with other arrhythmogenic drugs.
Mefloquine and other drugs known to lower the convulsive threshold: Hydroxychloroquine sulfate can lower the convulsive threshold. Co-administration of hydroxychloroquine sulfate with other antimalarials known to lower the convulsion threshold (e.g., mefloquine) may increase the risk of convulsions.
Antiepileptics: The activity of antiepileptic drugs might be impaired when co-administered with hydroxychloroquine sulfate.
Methotrexate: Combined use of methotrexate with hydroxychloroquine sulfate has not been studied and may increase the incidence of adverse effects.
Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate were co-administered.
The following interactions have been observed on treatment with the structurally related substance chloroquine phosphate, and therefore cannot be ruled out for hydroxychloroquine.
Praziquantel: Chloroquine has been reported to reduce the bioavailability of praziquantel.
Antacids and kaolin: Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed.
Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided.
Ampicillin: In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin.

Store at temperature not exceeding 30°C.

Antimalarials / Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

P01BA02 - hydroxychloroquine ; Belongs to the class of aminoquinoline antimalarials.

Rx