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

ARALEN 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 500 mg of chloroquine phosphate USP, equivalent to 300 mg chloroquine base.

Inactive Ingredients: Carnauba Wax, Colloidal Silicon Dioxide, Dibasic Calcium Phosphate, Hydroxypropyl Methylcellulose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80, Pregelatinized Starch, Sodium Starch Glycolate, Stearic Acid, Titanium Dioxide.

ARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis.

ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. 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.

The dosage of chloroquine phosphate is often expressed in terms of equivalent chloroquine base. Each 500 mg tablet of ARALEN contains the equivalent of 300 mg chloroquine base. In infants and children the dosage is preferably calculated by body weight.

Malaria: Suppression - Adult Dose: 500 mg (= 300 mg base) on exactly the same day of each week.

Pediatric Dose: The weekly suppressive dosage is 5 mg calculated as base, per kg of body weight, but should not 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.

For Treatment of Acute Attack.

Adults: An initial dose of 1 g (= 600 mg base) followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days.

The dosage for adults of low body weight and for infants and children should be determined as follows:

First dose: 10 mg base per kg (but not exceeding a single dose of 600 mg base).

Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base).

Third dose: (24 hours after first dose) 5 mg base per kg.

Fourth dose: (36 hours after first dose) 5 mg base per kg.

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

Extraintestinal Amebiasis: Adults,1 g (600 mg base) daily for two days, followed by 500 mg (300 mg base) daily for at least two to three weeks. Treatment is usually combined with an effective intestinal amebicide.

Geriatric Use

See PRECAUTIONS, Geriatric Use.

Tablets containing 500 mg chloroquine phosphate USP, equivalent to 300 mg of chloroquine base, bottles of 25 (NDC 0024-0084-01).

White, film-coated convex, discoid tablet, 1/2 inch in diameter with an uncoated core, printed in black ink with a stylized "W" on one side and an "A77" on the other side.

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

Store at 25° C (77° F); excursions permitted to 15°- 30°C (59° - 86°F) [see USP Controlled Room Temperature]

Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Revised March 2007 © 2007 sanofi-aventis U.S. LLC. FDA Rev date: 6/13/2003

Special Senses: Ocular: 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.

Auditory: Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage.

Musculoskeletal system: Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, which may be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve conduction, have been noted.

Gastrointestinal system: Anorexia, nausea, vomiting, diarrhea, abdominal cramps.

Skin and appendages: Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, photosensitivity and hair loss and bleaching of hair pigment.

Hematologic system: Rarely, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia.

Central Nervous system: Convulsive seizures. Mild and transient headache. Neuropsychiatric changes including psychosis, delirium, personality changes and depression.

Cardiovascular system: Rarely, hypotension, electrocardiographic change (particularly, inversion or depression of the T-wave with widening of the QRS complex), and cardiomyopathy.

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. An interval of at least two hours between intake of this agent and chloroquine should be observed.

Cyclosporine: After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued.

It has been found that certain strains of P. falciparum have become resistant to 4-aminoquinoline compounds (including chloroquine and hydroxychloroquine). Chloroquine resistance is widespread and, at present, is particularly prominent in various parts of the world including sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and over large portions of South America, including the Amazon basin¹.

Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Chloroquine should not be used for treatment of P. falciparum infections acquired in areas of chloroquine resistance or malaria occurring in patients where chloroquine prophylaxis has failed.

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.

Irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy. Retinopathy has been reported to be dose related.

When prolonged therapy with any antimalarial compound is contemplated, initial (base line) and periodic ophthalmologic examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests) should be performed.

If there is any indication (past or present) 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) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress even after cessation of therapy.

All patients on long-term therapy with this preparation 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.

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 this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds.

Use of ARALEN in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The drug should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the potential risks.

Usage in Pregnancy: Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body². There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the potential risk to the fetus.

Hematological Effects/Laboratory Tests

Complete blood cell counts should be made periodically if patients are given prolonged therapy. If any severe blood disorder appears which is not attributable to the disease under treatment, discontinuance of the drug should be considered.

The drug should be administered with caution to patients having G-6-PD (glucose-6 phosphate dehydrogenase) deficiency.

Auditory Effects

In patients with preexisting auditory damage, chloroquine should be administered with caution. In case of any defects in hearing, chloroquine should be immediately discontinued, and the patient closely observed (see ADVERSE REACTIONS).

Hepatic Effects

Since this drug is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs.

Central Nervous System Effects

Patients with history of epilepsy should be advised about the risk of chloroquine provoking seizures.

Pregnancy

See WARNINGS, Usage in Pregnancy.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from chloroquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential clinical benefit of the drug to the mother.

Pediatric Use

See WARNINGS and DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of ARALEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

REFERENCES

1. Malaria Deaths Following Inappropriate Malaria Chemoprophylaxis - United States, 2001. MMWR Weekly, 2001; 50(28): 597-599.

2. Ullberg S, Lindquist N G, Sjostrand S E: Accumulation of chorioretinotoxic drugs in the foetal eye. Nature 1970; 227: 1257.

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. These consist of headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, shock and convulsions followed by sudden and early respiratory and cardiac arrest. The electrocardiogram 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 stomach tube, after lavage, and within 30 minutes after ingestion of the antimalarial, 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 chloroquine ingested.

Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultra short-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen administration and artificial respiration. Monitor ECG. In shock with hypotension, a potent vasopressor should be administered. Replace fluids and electrolytes as needed. Cardiac compressing or pacing may be indicated to sustain the circulation. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary. Peritoneal dialysis and exchange transfusions have also been suggested to reduce the level of the drug in the blood.

A patient who survives the acute phase and is asymptomatic should be closely observed for at least six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine to help promote urinary excretion in cases of both overdosage or sensitivity.

Use of this drug is contraindicated in the presence of retinal or visual field changes either attributable to 4-aminoquinoline compounds or to any other etiology, and in patients with known hypersensitivity to 4-aminoquinoline compounds. However, in the treatment of acute attacks of malaria caused by susceptible strains of plasmodia, the physician may elect to use this drug after carefully weighing the possible benefits and risks to the patient.

Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only a small proportion of the administered dose is found in the stools. Approximately 55% of the drug in the 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 considerable amounts. 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, in contrast, contain only 10 to 30 times the amount present in plasma.

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

Microbiology

Mechanism of Action: Chloroquine is an antimalarial agent. While the drug can inhibit certain enzymes, its effect is believed to result, at least in part, from its interaction with DNA. However, the mechanism of plasmodicidal action of chloroquine is not completely certain.

Activity in vitro and in vivo: Chloroquine is active against the erythrocytic forms of Plasmodium vivax. Plasmodium malariae, and susceptible strains of Plasmodium falciparum (but not the gametocytes of P. falciparum). It is not effective against exoerythrocytic forms of the parasite.

In vitro studies with trophozoites of Entamoeba histolytica have demonstrated that chloroquine also possesses amebicidal activity comparable to that of emetine.

Drug Resistance: Resistance of Plasmodium falciparum to chloroquine is widespread and cases of Plasmodium vivax resistance have been reported.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CHLOROQUINE - ORAL

(KLOR-oh-kwin)

COMMON BRAND NAME(S): Aralen

USES: This medication is used to prevent certain types of malaria, a parasite infection, when traveling to certain areas that have malaria. Another drug may be used instead if you are going to an area with resistant malaria. Chloroquine may also be used with other medications to treat certain less severe (uncomplicated) types of malaria or a spreading infection with another parasite (ameba). Chloroquine is an amebicide and antimalarial drug. It works by killing ameba and the form of the malaria parasite that infects the red blood cells.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat certain immune diseases (e.g., rheumatoid arthritis, lupus).

HOW TO USE: Take this medication by mouth with or without food. If stomach upset occurs, take with a meal. For prevention of malaria, take chloroquine exactly as directed by your doctor, usually once weekly on the same day each week. Start this medication usually 1 to 2 weeks before you enter the malaria area, and continue to take it during your stay and for 4 weeks after leaving the area, or as directed by your doctor.

For treatment of a sudden/severe attack of malaria, take this medication as directed, usually 4 doses over 3 days. The first dose is larger and is followed by 3 smaller doses. On day 1 take the large dose followed 6 hours later with a smaller dose, then take the next smaller doses on days 2 and 3.

For treatment of ameba, take this medication as directed, usually once daily for 2 to 3 weeks. The first 2 doses are larger.

If you are taking any antacid, do not take chloroquine within 4 hours before or after the antacid.

Dosage is based on your body weight, medical condition, and response to treatment.

It is very important to continue taking this medication exactly as prescribed by your doctor. This medication works best when taken exactly as directed. If you are taking this drug once a week, it may help to mark your calendar or travel schedule with a reminder.

Do not take more or less of this drug than prescribed. Do not stop taking it before completing treatment, even if you feel better, unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause prevention treatment to be ineffective, cause the amount of parasite to increase, make the infection more difficult to treat (resistant), or worsen side effects.

No drug treatment is completely effective in preventing malaria. Therefore, seek immediate medical attention if you develop symptoms of malaria (e.g., fever, chills, headache, other flu-like symptoms), especially for 2 months after completing this prescription.

It is important to prevent mosquito bites (e.g., using appropriate insect repellents, wearing clothes that cover most of the body, remaining in air-conditioned or well-screened areas, using mosquito nets, using insect-killing spray). Buy insect repellent before traveling. The most effective insect repellents contain diethyltoluamide (DEET). Ask your doctor or pharmacist to recommend the appropriate strengths of mosquito repellent for you/your children.

SIDE EFFECTS: Blurred vision, stomach pain, nausea, vomiting, abdominal cramps, mild headache, and diarrhea may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mouth sores, ringing in the ears, darkening of skin, darkening of the tissue inside of the mouth, sun sensitivity.

Tell your doctor immediately if any of these rare but very serious side effects occur: seizures, signs of serious infection (e.g., high fever, severe chills, persistent sore throat), signs of decreased red blood cells (e.g., tiredness, pale lips/nails/skin, fast heartbeat/breathing with normal activity level), easy bruising/bleeding, mental/mood changes (e.g., confusion, personality changes, unusual thoughts/behavior, depression).

Seek immediate medical attention if any of these rare but very serious side effects occur: severe dizziness, fainting, fast/slow/irregular heartbeat.

Some side effects only occur rarely with daily, long-term use (over weeks to years) and may include: signs of a poorly pumping heart (e.g., tiredness, shortness of breath, swelling legs/ankles), muscle weakness, loss of muscle size, hair loss, bleaching of hair color, more severe vision changes (e.g., sparkles/blank spots in vision, difficulty reading, complete vision loss), hearing loss.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking chloroquine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: problems with the retina of the eye, vision problems, chloroquine-resistant malaria, a very severe form of a blood enzyme deficiency (non-spherocytic hemolytic anemia with G6PD deficiency), certain heart problems (QT prolongation in the EKG, previous torsade de pointes), low levels of potassium or magnesium in the blood.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: certain other heart problems (slow heartbeat, heart failure), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death), less severe G6PD deficiency, psoriasis, a certain liver condition (porphyria), other liver problems, alcoholism, kidney problems, seizures, hearing loss.

This drug may rarely make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

Caution is advised when using this drug in the elderly because they may experience increased side effects.

During pregnancy, this medication should be used only when clearly needed. While you are pregnant, traveling to an area with malaria places you and your infant at much higher risk of death and other problems. Discuss the risks and benefits of malaria prevention with your doctor.

This drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also How to Use section.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: cimetidine, agalsidase, artemether-lumefantrine.

This drug should generally not be used with the following medications because very serious interactions may occur: disopyramide, amiodarone, quinidine, quinine, procainamide, flecainide, propafenone, sotalol, ibutilide, droperidol, bepridil, ziprasidone, dofetilide, cisapride, arbutamine, pimozide, astemizole, halofantrine, mefloquine, penicillamine, ranolazine.

These drugs, among others, may affect the heart rhythm (QT prolongation in the EKG). Before using chloroquine, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting chloroquine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: cyclosporine, ampicillin, praziquantel, sulfadoxine/pyrimethamine, certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).

Although no longer available in the United States, a certain rabies vaccine (HDCV) may not work as well if given while you are taking chloroquine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: headache, drowsiness, vision problems, nausea, vomiting, sudden fainting, seizures, very slow breathing.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., eye exams, reflex tests, liver blood tests, blood cell counts) should be performed periodically to monitor your progress or check for side effects if you are taking chloroquine for long periods. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.