Mylan-Hydroxychloroquine Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

Mylan-Hydroxychloroquine (Hydroxychloroquine sulfate) belongs to the 4-aminoquinoline class. Mylan-Hydroxychloroquine has been beneficial for patients with rheumatoid arthritis and lupus erythematosus, especially chronic discoid lupus. The exact mode of action in controlling these diseases is unknown. The action of this compound against malarial parasites is similar to that of chloroquine phosphate.

INDICATIONS AND CLINICAL USE

MYLAN-HYDROXYCHLOROQUINE (hydroxychloroquine sulfate) is indicated for the treatment of rheumatoid arthritis, and discoid and systemic lupus erythematosus, in patients who have not responded satisfactorily to drugs with less potential for serious side effects.

It is also indicated for the suppressive treatment and treatment of acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is not active against the exo-erythrocytic forms of P. vivax, P. malariae and P. ovale and therefore will neither prevent infection due to these organisms when given prophylactically, nor prevent relapse of infection due to these organisms. It is highly effective as a suppressive agent in patients with vivax or malariae malaria in terminating acute attacks and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria, it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum.

CONTRAINDICATIONS

• pre-existing retinopathy of the eye
• patients with known hypersensitivity to 4-aminoquinoline compounds

• use in children below 6 years of age (200 mg tablets not adapted for weight <35 kg)

  (see WARNINGS AND PRECAUTIONS, Special Populations – Pediatric Use).

WARNINGS AND PRECAUTIONS

General:

Observe caution in patients with gastrointestinal or neurological disorders, in those with sensitivity to quinine, and in porphyria.

Effects on Ability to Drive and Use Machinery:

Patients should be warned about driving and operating machinery since Mylan-Hydroxychloroquine can impair accommodation and cause blurring of vision. If the condition is not self-limiting, dosage may need to be temporarily reduced.

Malaria:

Hydroxychloroquine sulfate tablets is not effective against chloroquine-resistant strains of P. falciparum and is not active against the exo-erythrocytic forms of P. vivax, P. ovale and P. malarias and therefore will neither prevent infection due to these organisms when given prophylactically, nor prevent relapse of infection due to these organisms.

Carcinogenesis and Mutagenesis:

Non-clinical studies showed a potential risk of chloroquine inducing gene mutations. Long term studies in animals have not been conducted to evaluate the carcinogenic potential (see TOXICOLOGY). In humans, there are insufficient data to rule out an increased risk of cancer in patients receiving-long term treatment.

Cardiovascular:

Cases of cardiomyopathy resulting in cardiac failure, in some cases with a fatal outcome, have been reported in patients treated with Mylan-Hydrochloroquine. Mylan-Hydrochloroquine should be discontinued if signs and symptoms of cardiomyopathy develop. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed (see ADVERSE REACTIONS and SYMPTOMS AND TREATMENT OF OVERDOSAGE).

Mylan-Hydroxychloroquine may induce cardiac arrhythmia (see DRUG INTERACTIONS and SYMPTOMS AND TREATMENT OF OVERDOSAGE).

Hydroxychloroquine sulfate prolongs the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking hydroxychloroquine sulfate (see OVERDOSAGE). Therefore, Mylan-Hydrochloroquine should not be administered with other drugs that have the potential to prolong the QT interval. Mylan-Hydrochloroquine should be used with caution in individuals with known heart disease, a family history of sudden unexplained death consistent with cardiac arrhythmias, and risk factors for drug-induced QT/QTc prolongation (see DRUG INTERACTIONS, ADVERSE REACTIONS, and SYMPTOMS AND TREATMENT OF OVERDOSAGE).

Endocrine and Metabolism:

Mylan-Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic medications. Patients treated with Mylan-Hydroxychloroquine should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with Mylan-Hydroxychloroquine should have their blood glucose level checked and the need for Mylan-Hydroxychloroquine treatment reviewed as necessary. In cases of severe hypoglycemia, Mylan-Hydroxychloroquine should be discontinued and alternative therapy considered. If patients use Mylan-Hydroxychloroquine concomitantly with antidiabetic drugs, a decrease in doses of insulin or antidiabetic drugs may be required as Mylan-Hydroxychloroquine may enhance the effects of hypoglycemic treatment (see DRUG INTERACTIONS and ADVERSE REACTIONS).

Hematologic:

Periodic blood counts should be obtained in patients requiring prolonged therapy due to the risk of bone marrow depression (see ADVERSE REACTIONS). If any severe blood disorder appears that is not attributable to the disease under treatment, the drug should be discontinued.

Observe caution in patients with blood disorders or glucose-6-phosphate dehydrogenase deficiency.

Musculoskeletal:

All patients on long term therapy with this preparation should be questioned and examined periodically, including the examination of skeletal muscle function and tendon reflexes, testing of knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the drug (see ADVERSE REACTIONS).

Neurologic:

Extrapyramidal reactions have been reported in patients taking Mylan-Hydroxychloroquine (see ADVERSE REACTIONS). Symptoms may persist in some patients after discontinuation of therapy.

Ophthalmologic:

Irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy for discoid and systemic lupus erythematosus, or rheumatoid arthritis. Before starting a long term treatment, both eyes should be examined by careful ophthalmoscopy for visual acuity, central visual field and color vision, and fundoscopy. Then, the examination should be repeated at least annually.

Retinal toxicity is largely dose-related. The risk of retinal damages is small with daily doses of up to 6.5 mg/kg ideal (lean) body weight. Exceeding the recommended daily dose sharply increases the risk of retinal toxicity. Significant risk factors for toxic retinopathy reported during long-term (≥5 years) treatment with hydroxychloroquine include daily doses greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, subnormal glomerular filtration rate, durations of use longer than five years, and concurrent treatment with tamoxifen citrate. Concomitant use of Mylan-Hydroxychloroquine with drugs known to induce retinal toxicity, such as tamoxifen, is not recommended.

Careful ophthalmologic examination should be more frequent and adapted to the patient, in the following situations:

• daily doses exceeding 6.5 mg (salt form)/kg ideal (lean) body weight. Absolute body weight used as a guide to dosage, could result in an overdosage in the obese;
• renal insufficiency;
• cumulative dose more than 200 g (salt form);
• elderly;
• impaired visual acuity.

If there is any indication of abnormality in the visual acuity, visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks, abnormal colour vision) that are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be stopped immediately. The patient should be closely observed for possible progression of the abnormality. Retinal changes (and visual disturbances) may progress even after cessation of the therapy (see ADVERSE REACTIONS).

Methods recommended for early diagnosis of retinopathy consist of (1) funduscopic examination of the macula for fine pigmentary disturbances or loss of the foveal reflex and (2) examination of the central visual field with a small red test object for pericentral or paracentral scotoma or determination of retinal thresholds to red. Any unexplained visual symptoms, such as light flashes or streaks also should be regarded with suspicion as possible manifestations of retinopathy.

Psychiatric:

Suicidal behaviour has been reported in patients treated with hydroxychloroquine (see ADVERSE REACTIONS).

Skin:

Dermatological reactions to hydroxychloroquine sulfate tablets may occur. It is not recommended for the treatment of psoriasis or porphyria as these conditions may be exacerbated by its use. Observe caution in patients with psoriasis.

Sexual Health:

Fertility

Animal studies showed an impairment of male fertility with chloroquine treatment (see TOXICOLOGY, Reproductive and development toxicity). There are no data in humans.

Special Populations

Pregnancy:

Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. Hydroxychloroquine sulfate tablets should be avoided in pregnancy. It should be noted that the 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 to the foetus.

Embryonic deaths and ocular malformations in the offspring have been reported when pregnant rats received large doses of chloroquine (see TOXICOLOGY, Reproductive and development toxicity).

Nursing Mothers:

Careful consideration should be given to using hydroxychloroquine during lactation, since it has been known 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.

Pediatric Use:

Safety and efficacy has not been established in rheumatoid arthritis or systemic lupus erythematosus in children. Children are especially sensitive to the 4-aminoquinoline compounds. The most reported fatalities follow the accidental ingestion of chloroquine, sometimes in small doses. Patients should be strongly warned to keep these drugs out of the reach of children (see CONTRAINDICATIONS).

Hepatic Impairment:

Hydroxychloroquine sulfate tablets should be used with caution in patients with hepatic disease or alcoholism, in whom a reduction in dosage may be necessary, or in conjunction with known hepatotoxic drugs. Isolated cases of abnormal liver function tests have been reported; fulminant hepatic failure has also been reported.

Renal Impairment:

Observe caution in patients with renal disease, in whom a reduction in dosage may be necessary, as well as in those taking medicines known to affect this organ.

DRUG INTERACTIONS

A table with potential drug interaction with Hydroxychloroquine is included below. Mylan-Hydroxychloroquine should also be used with caution in patients taking medicines which may cause adverse ocular or skin reactions (see WARNINGS AND PRECAUTIONS).

ADVERSE REACTIONS

The following Council for International Organizations of Medical Sciences (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, anemia, aplastic anemia, agranulocytosis, leucopenia, thrombocytopenia (see WARNINGS AND PRECAUTIONS).

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 discontinuation may lead to recovery (see WARNINGS AND PRECAUTIONS, SYMPTOMS AND TREATMENT OF OVERDOSAGE).

Hydroxychloroquine prolongs the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking Hydroxychloroquine (see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and SYMPTOMS AND TREATMENT OF OVERDOSAGE).

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Not known: Hearing loss including cases of irreversible hearing loss.

Eye disorders

Common: Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible (see WARNINGS AND PRECAUTIONS).

Uncommon: Maculopathies which may be irreversible.

Retinopathy with changes in pigmentation and visual field defects. In its early form it appears reversible upon discontinuation of the drug. If allowed to develop however, 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, abnormal colour visions, reduction in visual acuity, night blindness, difficulty reading and skipping words.

Corneal changes including edema and opacities. They are either symptomless or may cause disturbances such as halos around lights especially at night, blurring of vision or photophobia. They may be transient or are reversible upon discontinuation of therapy (see WARNINGS AND PRECAUTIONS).

Not known: Macular degeneration which may be irreversible.

Gastrointestinal disorders

Very common: Abdominal pain, nausea

Common: Diarrhea, vomiting

These symptoms usually resolve immediately upon reducing the dose or upon stopping the treatment.

Hepatobiliary disorders

Uncommon: Abnormal liver function tests

Not known: Fulminant hepatic failure (see WARNINGS AND PRECAUTIONS)

Immune system disorders

Not known: Urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders

Common: Anorexia (usually resolves immediately upon reducing the dose or upon stopping the treatment).

Not known: hypoglycemia (see WARNINGS AND PRECAUTIONS).

Mylan-Hydroxychloroquine may exacerbate porphyria (see WARNINGS AND PRECAUTIONS).

Musculoskeletal and connective tissue disorders

Uncommon: Sensory motor disorders

Not known: Skeletal muscle palsies or skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups. Depression of tendon reflexes, abnormal results of nerve conduction tests. Myopathy may be reversible after drug discontinuation, but recovery may take many months (see WARNINGS AND PRECAUTIONS).

Nervous system disorders

Common: Headache

Uncommon: Dizziness

Not known: Convulsions. Extrapyramidal reactions such as: akathisia, dystonia, dyskinesia, gait disturbance, tremor.

Psychiatric disorders

Common: Affect lability

Uncommon: Nervousness

Not known: Psychosis, suicidal behavior.

Skin and subcutaneous tissue disorders

Common: Skin rash, pruritus

Uncommon: Pigmentary changes in skin and mucous membranes, bleaching of hair, alopecia. These usually resolve readily upon cessation of therapy.

Not known: Bullous eruptions (including urticarial, morbilliform, lichenoid, maculopapular, purpuric, erythema annulare centrifugum), toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), photosensitivity, exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP).

AGEP has to be distinguished from psoriasis, although Mylan-Hydroxychloroquine may precipitate attacks of psoriasis. It may be associated with fever and hyperleukocytosis. Outcome is usually favorable after discontinuation of drug.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2 grams having proved fatal.

Symptoms:

The 4-aminoquinoline compounds are very rapidly and completely absorbed following ingestion and in accidental overdosage toxic symptoms may occur within 30 minutes. These consist of headache, drowsiness, visual disturbances, cardiovascular collapse, hypokalemia and convulsions, rhythm and conduction disorders, including QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation, followed by sudden potentially fatal respiratory and cardiac arrest. Immediate medical attention is required, as these effects may appear shortly after overdose. The ECG may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest.

Treatment:

Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis (at home, before transportation to the hospital), or gastric lavage until the stomach is completely emptied. If finely powdered activated charcoal is introduced by the stomach tube, after lavage and within 30 minutes after ingestion of the tablets, it may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least five times the estimated dose of ingested hydroxychloroquine. Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultrashort-acting barbiturate may be tried but, if due to anoxia, convulsions should be corrected by oxygen administration, artificial respiration or, in shock with hypotension, by vasopressor therapy. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, has also been advised. Exchange transfusions have been used to reduce the level of 4-aminoquiolines in the blood.

Consideration should be given to administering diazepam parenterally since studies have reported it beneficial in reversing chloroquine cardiotoxicity.

A patient who survives the acute phase and is asymptomatic should be closely observed for at least 6 hours. Fluids may be forced, and sufficient ammonium chloride may be administered for a few days to acidify the urine to help promote urinary excretion.

If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that ammonium chloride (8 g daily in divided doses for adults) three or four days a week be administered for several months after therapy has been stopped, as acidification of the urine increases renal excretion of the 4-aminoquinoline compounds by 20 to 90 percent. However, caution must be exercised in patients with impaired renal function and/or metabolic acidosis.

For management of a suspected drug overdose, contact your regional Poison Control Centre immediately.

DOSAGE AND ADMINISTRATION

Absolute body weight used as a guide to dosage could result in an overdosage; daily doses should not exceed 6.5 mg (salt form)/kg ideal (lean) body weight. Exceeding the recommended daily dose sharply increase the risk of retinal toxicity.

The dosages cited below are stated in terms of hydroxychloroquine sulfate. One 200 mg tablet is equivalent to 155 mg base. Each dose should be taken with a meal or a glass of milk.

Rheumatoid Arthritis:

The compound is cumulative in action and will require several weeks to exert its beneficial therapeutic effects, whereas minor side effects may occur somewhat early. Several months of therapy may be required before maximum effects can be obtained. If objective improvement (such as reduced joint swelling, increased mobility) does not occur within six months, the drug should be stopped. Safe use of the drug in the treatment of juvenile rheumatoid arthritis has not been established.

Initial dosage - In adults, from 400 to 600 mg daily. In a few patients, the side effects may require temporary reduction of the initial dosage. Generally, after five to ten days the dose may be gradually increased to the optimum response level, frequently, without return of side effects.

Maintenance dosage - When a good response is obtained (usually in four to twelve weeks), the dosage is reduced by 50 percent and continued at an acceptable maintenance level of 200 to 400 mg daily. The incidence of retinopathy has been reported to be higher when the maintenance dose is exceeded.

If a relapse occurs after medication is withdrawn, therapy may be resumed or continued on an intermittent schedule if there are no ocular contraindications.

Use in Combination Therapy: Mylan-Hydroxychloroquine (hydroxychloroquine sulfate) may be used safely and effectively in combination with corticosteroids, salicylates, NSAIDS, and methotrexate and other second line therapeutic agents. Corticosteroids and salicylates can generally be decreased gradually in dosage or eliminated after the drug has been used for several weeks. When gradual reduction of steroid dosage is suggested, it may be done by reducing every four to five days, the dose of cortisone by no more than 5 to 15 mg; of hydrocortisone from 5 to 10 mg; of prednisolone and prednisone from 1 to 2.5 mg; of methylprednisolone and triamcinolone from 1 to 2 mg and dexamethasone from 0.25 to 0.5 mg. Regimens of treatment using other agents than steroids and NSAIDS are under development. No definitive dose combinations have been established.

Lupus Erythematosus:

Initially, the average adult dose is 400 mg once or twice daily. This may be continued for several weeks or months, depending upon the response of the patient. For prolonged maintenance therapy, a smaller dose, from 200 to 400 mg daily will suffice. The incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded.

Malaria:

Suppression - In adults, 400 mg on exactly the same day of each week. In children (6 years of age and older), the weekly suppressive dose is 5 mg base/kg, but should not exceed the adult dose regardless of body weight.

Suppressive therapy should begin two weeks before exposure. When not administered before exposure, give an initial loading dose of 800 mg to adults, or 10 mg base/kg to children in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area.

Treatment of the acute attack -In adults, an initial loading dose of 800 mg followed by 400 mg in six to eight hours. This is followed by 400 mg on each of the next two days for a total of 2 g of hydroxychloroquine sulfate or 1.55 g base. Alternatively, the administration of a single dose of 800 mg has also proved effective. The dosage for adults may also be calculated by body weight.

For children (6 years of age and older) - dosage calculated by body weight is preferred. A total dose representing 25 mg of base/kg is administered over three days as follows:

First dose: 10 mg base/kg (not to exceed 620 mg base)

Second dose: 5 mg base/kg 6 hours after the first dose (not to exceed 310 mg base)

Third dose: 5 mg base/kg 18 hours after the second dose

Fourth dose: 5 mg base/kg 24 hours after the third dose

For radical cure of vivax and malariae malaria - concomitant therapy with an 8-aminoquinoline compound is necessary.

STORAGE AND STABILITY

Store between 15°C - 30°C.

Keep in a safe place out of reach of children.

AVAILABILITY OF DOSAGE FORMS

Each white, film-coated, peanut-shaped tablet, with “HQ 200" debossed on one side and “G” debossed on the other side, is available in bottles of 100 tablets.

The non-medicinal ingredients are maize (corn) starch, calcium hydrogen phosphate dihydrate DC, sodium starch glycollate (Type A), magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400, polyethylene glycol 8000.

TOXICOLOGY

Only limited preclinical data are available for hydroxychloroquine, therefore chloroquine data are considered due to the similarity of structure and pharmacological properties between the 2 products.

Genotoxicity

There are limited data on hydroxychloroquine genotoxicity.

Chloroquine is reported in the literature to be a weak genotoxic agent which may elicit both gene mutations and chromosomal/DNA breaks. Mechanisms may involve DNA intercalation or induction of oxidative stress. Positive and negative results in in vitro reverse gene mutation assays using bacteria (Ames test) and in in vivo studies using rodents (mouse bone marrow cell sister chromatid exchange, mouse bone marrow cell chromosome abnormality, and rat DNA strand-breaks in multiple organs when animals were dosed by intraperitoneal route).

Carcinogenicity

There are no data on hydroxychloroquine carcinogenicity from animal studies and insufficient data on carcinogenicity is available for chloroquine. Both drugs are not classifiable as to their carcinogenicity to humans.

Reproductive and developmental toxicity

There are limited data on hydroxychloroquine teratogenicity.

Supratherapeutic doses of chloroquine resulted in a fetal mortality rate of 25% and ocular malformations in 45% of fetuses. Autoradiographic studies have shown that when administered at the start or the end of gestation, chloroquine accumulates in the eyes and ears.

There are no data on hydroxychloroquine action on fertility.

A study in male rats after 30 days of oral treatment at 5 mg/day of chloroquine showed a decrease in fertility rate, testosterone levels, weight of testes, epididymis, seminal vesicles and prostate, and caused production of abnormal sperm.