Chloroquine phosphate tablets 250 mg, chloroquine phosphate, USP, is a 4-aminoquinoline compound for oral administration. It is a white, odorless, bitter tasting, crystalline substance, freely soluble in water.

Chloroquine phosphate is an antimalarial and amebicidal drug.

Chemically, it is 7-chloro-4-[[4- (diethylamino)-1-methylbutyl]amino] quinoline phosphate (1:2) and has the following structural formula:

Each tablet contains 250 mg of chloroquine phosphate USP, equivalent to 150 mg chloroquine base.

Inactive Ingredients: Colloidal silicon dioxide, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.

Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only asmall proportion of the administered dose is found in the stools. Approximately 55% of the drug inthe plasma is bound to nondiffusible plasma constituents. Excretion of chloroquine is quite slow,but is increased by acidification of the urine. Chloroquine is deposited in the tissues in considerableamounts. In animals, from 200 to 700 times the plasma concentration may be found in the liver,spleen, kidney, and lung; leukocytes also concentrate the drug. The brain and spinal cord, incontrast, contain only 10 to 30 times the amount present in plasma.

Chloroquine undergoes appreciable degradation in the body. The main metabolite isdesethylchloroquine, which accounts for one fourth of the total material appearing in the urine;bisdesethylchloroquine, a carboxylic acid derivative, and other metabolic products as yetuncharacterized are found in small amounts. Slightly more than half of the urinary drug productscan be accounted for as unchanged chloroquine.

Chloroquine phosphate is indicated for the:

• Treatment of uncomplicated malaria due to susceptible strains of P. falciparum, P.malariae, P. ovale, and P.vivax.
• Prophylaxis of malaria in geographic areas where resistance to chloroquine is not present.
• Treatment of extraintestinal amebiasis.

Chloroquine phosphate tablets do not prevent relapses in patients with vivax or ovale malaria because it is not effective against exoerythrocytic forms of the parasites.

Limitations of Use in Malaria:

• Do not use chloroquine phosphate tablets for the treatment of complicated malaria (high-grade parasitemia and/or complications e.g., cerebral malaria or acute renal failure).
• Do not use chloroquine phosphate tablets for malaria prophylaxis in areas where chloroquine resistance occurs, Resistance to chloroquine phosphate tablets is widespread in P. falciparum, and is reported in P.vivax (see WARNINGS).
• Concomitant therapy with an 8-aminoquinoline drug is necessary for treatment of the hypnozoite liver stage forms of P.vivax and P.ovale (see DOSAGE AND ADMINISTRATION).

Use of chloroquine phosphate tablets for indications other than acute malaria is contraindicated in the presence of retinal or visual field changes of any etiology.

Use of chloroquine phosphate tablets is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.

Chloroquine-Resistant Malaria

Chloroquine phosphate tablets are not effective against chloroquine-or hydroxychloroquine resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY, Microbiology). Chloroquine resistance is widespread in P. falciparum and is reported in P. vivax. Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Information regarding the geographic areas where resistance to chloroquine occurs, is available at the Centers for Disease Control and Prevention (www.cdc.gov\malaria).

Patients infected with a resistant strain of plasmodia as shown by the fact that normally adequate doses have failed to prevent or cure clinical malaria or parasitemia should be treated with another form of antimalarial therapy.

Treatment of Exo-Erythocytic Forms of Malaria

Chloroquine does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to P. vivax or P. ovale. Additional treatment with an anti-malarial agent active against these forms, such as an 8-aminoquinoline, is required for the treatment of infections with P. vivax and P. ovale.

Cardiac Effects

Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have

been reported in patients treated during long term therapy at high doses with chloroquine (see

ADVERSE REACTIONS and OVERDOSAGE). Monitor for signs and symptoms of cardiomyopathy and discontinue chloroquine if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of chloroquine may prevent life-threatening complications. QT interval prolongation, torsades de pointes, and ventricular arrhythmias have been reported. The risk is greater if chloroquine is administered at high doses. Fatal cases have been reported. Chloroquine should be used with caution in patients with cardiac disease, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT interval prolonging agents due to potential for QT interval prolongation (see WARNINGS, PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and OVERDOSAGE)

Hypoglycemia

Chloroquine has been shown to cause severe hypoglycemia including loss of consciousness

that could be life-threatening in patients treated with or without antidiabetic medications (see

PRECAUTIONS, Drug Interactions). Patients treated with chloroquine phosphate tablets 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 chloroquine should have their blood glucose level checked and treatment reviewed as necessary.

Retinopathy1

Irreversible retinal damage has been observed in some patients who had received chloroquine. Significant risk factors for retinal damage include daily doses of chloroquine phosphate greater than 2.3 mg/kg of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate (see PRECAUTIONS), and concurrent macular disease.

A baseline ophthalmological examination should be performed within the first year of starting

chloroquine phosphate tablets. The baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain optical coherence tomography (SD-OCT). For individuals with significant risk factors (daily dose of chloroquine phosphate greater than 2.3 mg/kg of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SDOCT.

For individuals without significant risk factors, annual exams (including BCVA, VF and SD-OCT) can usually be deferred until five years of treatment.

In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees.

It is recommended that chloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy.

Central Nervous System Effects

Acute extrapyramidal disorders may occur with chloroquine (see PRECAUTIONS, ADVERSE

REACTIONS and OVERDOSAGE). These adverse reactions usually resolve after treatment

discontinuation and/or symptomatic treatment.

Muscular Weakness

All patients on long-term therapy with chloroquine should be questioned and examined periodically, including testing knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the drug.

Pediatric Accidental Ingestion

A number of fatalities have been reported following the accidental ingestion of chloroquine,

sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep chloroquine phosphate tablets out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds (see OVERDOSAGE and ADVERSE REACTIONS).

Worsening of Psoriasis and Porphyria

Use of chloroquine phosphate tablets in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. Chloroquine phosphate tablets should not be used in these conditions unless the benefit to the patient outweighs the potential risks.

The following adverse reactions have been identified during post-approval use of chloroquine

or other 4-aminoqunoline compounds. Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ocular disorders: Maculopathy and macular degenration have been reported and may be irreversible (see WARNINGS), irreversible retinal damage in patients receiving long-term or high-dosage 4-aminoquinoline therapy; visual disturbances (blurring of vision and difficulty of focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas, e.g., difficulty in reading with words tending to disappear, seeing half an object, misty vision, and fog before the eyes. Reversible corneal opacities have also been reported.

Immune system disorders: Urticaria, anaphylactic reaction including angioedema.

Ear and labyrinth disorders: Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage.

Musculoskeletal and connective tissue-disorders: Sensorimotor disorders, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction.

Gastrointestinal disorders: Hepatitis, increased liver enzymes, anorexia, nausea, vomiting, diarrhea, abdominal cramps.

Skin and subcutaneous tissue disorders: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis. Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus,; drug rash with eosinophilia and systemic symptoms (DRESS syndrome); photosensitivity and hair loss and bleaching of hair pigment.

Blood and lymphatic system disorders: Pancytopenia, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia. Hemolytic anemia in G6PD deficient patients (see PRECAUTIONS).

Nervous system disorders: Convulsions, mild and transient headache, polyneuropathy, acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) (see WARNINGS and OVERDOSAGE).

Neuropsychiatric disorders: Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, depression, and suicidal behavior.

Cardiac disorders: Hypotension, electrocardiographic changes (particularly, inversion or depression of the T-wave with widening of the QRS complex), and cardiomyopathy (which may result in cardiac failure and in some cases a fatal outcome). Cardiac arrhythmias, conduction disorders such as bundle branch block / atrio-ventricular block, QT interval 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 (see WARNINGS, Cardiac Effects and OVERDOSAGE).

Metabolic and Nutritional disorders: Hypoglycemia (see WARNINGS).

Signs and Symptoms: Chloroquine is very rapidly and completely absorbed after ingestion. Toxic doses of chloroquine can be fatal. As little as 1 g may be fatal in children. Toxic symptoms can occur within minutes. The symptoms of overdosage may include nausea, vomiting, headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades 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 the overdose. Cases of extrapyramidal disorders have also been reported in the context of chloroquine overdose (see WARNINGS and ADVERSE REACTIONS).

Treatment: Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis or gastric lavage followed by treatment with activated charcoal. Chloroquine overdose is a life-threatening emergency and should be managed with cardio-respiratory and hemodynamic support, monitoring of potassium along with management of arrhythmias and convulsions, as necessary. A patient who survives the acute phase and is asymptomatic should be closely observed until all clinical features of toxicity resolve.

The dosage of chloroquine phosphate is often expressed in terms of equivalent chloroquine base. Each 250 mg tablet of chloroquine phosphate contains the equivalent of 150 mg chloroquine base. In infants and children the dosage is preferably calculated by body weight.

Prophylaxis against chloroquine-sensitive Plasmodium species

Adult Dose: The dosage for prophylaxis is 250 mg (= 150 mg base) administered once per week on exactly the same day of each week.

Pediatric Dose: The dosage for prophylaxis is 5 mg calculated as base, per kg of body weight, administered once per week on exactly the same day of each week. The pediatric dose should never exceed the adult dose regardless of weight.

If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (= 600 mg base), or in children 10 mg base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area.

Tablets containing 250 mg chloroquine phosphate USP, equivalent to 150 mg of chloroquine base

Bottle of 50 (NDC 64980-177-50)

Bottle of 100 (NDC 64980-177-01)

Bottle of 500 (NDC 64980-177-05)

Bottle of 1000 (NDC 64980-177-10)

Chloroquine phosphate tablets are white to off-white colour round, bi-convex tablets, debossed with 'CN 250' on one side and score line on the other side.

Dispense in tight, light-resistant container as defined in the USP/NF.

Store at 20-25°C (68-77° F) [See USP Controlled Room Temperature]. Protect from light and moisture.

1. Marmor MF, Kellner U, and Lai TY, et al. Recommendations on Screening for Chloroquine
   
   and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology 2016. Doi10.1016./
   
   jophtha.2016.01.058
2. Ullberg S, Lindquist N G, Sjostrand S E: Accumulation of chorioretinotoxic drugs in the foetal eye. Nature 1970; 227: 1257.

Rx Only

Manufactured by:

NATCO PHARMA LIMITED

Kothur- 509 228,

India.

Manufactured for:

Rising Pharmaceuticals Inc.

Saddle Brook, NJ 07663



Rev: 02-Feb/2018

346151

Rising® NDC 64980-177-50

Chloroquine Phosphate

Tablets, USP

250 mg *

(Equivalent to 150 mg Chloroquine base)

For use in Malaria and

Extraintestinal Amebiasis Only

50 Tablets    Rx Only