Aralen; Primaquine

Chloroquine Phosphate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Aralen; Primaquine (Chloroquine Phosphate) reviews

INDICATIONS AND USAGE

Aralen; Primaquine (Chloroquine Phosphate) Phosphate Tablets are indicated for 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; Primaquine (Chloroquine Phosphate) Phosphate Tablets do 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.

CONTRAINDICATIONS

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.

WARNINGS

It has been found that certain strains of P. falciparum have become resistant to 4-aminoquinoline compounds and hydroxychloroquine). Aralen; Primaquine (Chloroquine Phosphate) 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 basin ¹.

Before using Aralen; Primaquine (Chloroquine Phosphate) for prophylaxis, it should be ascertained whether Aralen; Primaquine (Chloroquine Phosphate) is appropriate for use in the region to be visited by the traveler. Aralen; Primaquine (Chloroquine Phosphate) should not be used for treatment of P. falciparum infections acquired in areas of Aralen; Primaquine (Chloroquine Phosphate) resistance or malaria occurring in patients where Aralen; Primaquine (Chloroquine Phosphate) 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 Aralen; Primaquine (Chloroquine Phosphate), sometimes in relatively small doses (0.75 g or 1 g Aralen; Primaquine (Chloroquine Phosphate) 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; Primaquine (Chloroquine Phosphate) Phosphate Tablets 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 Aralen; Primaquine (Chloroquine Phosphate) 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 body ². There are no adequate and well-controlled studies evaluating the safety and efficacy of Aralen; Primaquine (Chloroquine Phosphate) in pregnant women. Usage of Aralen; Primaquine (Chloroquine Phosphate) during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgement of the physician the benefit outweighs the potential risk to the fetus.

PRECAUTIONS

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 deficiency.

Auditory Effects:

In patients with preexisting auditory damage, Aralen; Primaquine (Chloroquine Phosphate) should be administered with caution. In case of any defects in hearing, Aralen; Primaquine (Chloroquine Phosphate) should be immediately discontinued, and the patients closely observed.

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 a history of epilepsy should be advised about the risk of Aralen; Primaquine provoking seizures.

Drug Interactions:

Antacids and kaolin: Antacids and kaolin can reduce the absorption of Aralen; Primaquine (Chloroquine Phosphate); an interval of at least 4 hours between intake of these agents and Aralen; Primaquine (Chloroquine Phosphate) should be observed.

Cimetidine: Cimetidine can inhibit the metabolism of Aralen; Primaquine (Chloroquine Phosphate), increasing its plasma level. Concomitant use of cimetidine should be avoided.

Ampicillin: In a study of healthy volunteers, Aralen; Primaquine (Chloroquine Phosphate) significantly reduced the bioavailability of ampicillin. An interval of at least two hours between intake of this agent and Aralen; Primaquine (Chloroquine Phosphate) should be observed.

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

Mefloquine: Co-administration of Aralen; Primaquine (Chloroquine Phosphate) and mefloquine may increase the risk of convulsions.

The blood concentrations of Aralen; Primaquine (Chloroquine Phosphate) and desethylchloroquine (the major metabolite of Aralen; Primaquine (Chloroquine Phosphate), which also has antimalarial properties) were negatively associated with log antibody titers. Aralen; Primaquine (Chloroquine Phosphate) taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine.

Pregnancy:

See WARNINGS, Usage in Pregnancy.

Nursing Mothers:

Because of the potential for serious adverse reactions in nursing infants from Aralen; Primaquine, 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.

The excretion of Aralen; Primaquine (Chloroquine Phosphate) and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single dose of Aralen; Primaquine (Chloroquine Phosphate) (600 mg base). The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for the infant is required. See DOSAGE AND ADMINISTRATION.

Pediatric Use:

See WARNINGS and DOSAGE AND ADMINISTRATION.

Geriatric Use:

Clinical studies of Aralen; Primaquine (Chloroquine Phosphate) Phosphate Tablets 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.

ADVERSE REACTIONS

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. Reversible corneal opacities have also been reported.

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

Skin and appendages: Rare reports of erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis and similar desquamation-type events. Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, urticaria, anaphylactic/anaphylactoid reaction including angioedema, photosensitivity and hair loss and bleaching of hair pigment.

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

Nervous system: Convulsive seizures, mild and transient headache, polyneuritis. Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, 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.

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Symptoms: Aralen; Primaquine (Chloroquine Phosphate) is very rapidly and completely absorbed after ingestion. Toxic doses of Aralen; Primaquine (Chloroquine Phosphate) 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. Hypokalemia has been observed with arrythmias in cases of intoxication. 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 Aralen; Primaquine (Chloroquine Phosphate) 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.

Intervention options can involve: diazepam for life-threatening symptoms, seizures and sedation, epinephrine for treatment of vasodilation and myocardial depression, potassium replacement with close monitoring of serum potassium levels.

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.

DOSAGE AND ADMINISTRATION

The dosage of Aralen; Primaquine phosphate is often expressed in terms of equivalent Aralen; Primaquine (Chloroquine Phosphate) base. Each 250 mg tablet of Aralen; Primaquine (Chloroquine Phosphate) phosphate is equivalent to 150 mg base and each 500 mg tablet of Aralen; Primaquine (Chloroquine Phosphate) phosphate is equivalent to 300 mg 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 Aralen; Primaquine (Chloroquine Phosphate) phosphate of 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.

HOW SUPPLIED

Aralen; Primaquine (Chloroquine Phosphate) Phosphate Tablets USP 500 mg: Pink Color, Round Tablets Debossed "WW 125".

Bottles of 10 and 40 tablets.

Store at 20-25°C (68-77°F)..

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

REFERENCES

• Malaria Deaths Following Inappropriate Malaria Chemoprophylaxis – United States, 2001, MMWR Weekly, 2001; 50(28): 597-599.
• Ullberg S, Lindquist N G, Sjostrand S E: Accumulation of chorioretinotoxic drugs in the foetal eye. Nature 1970; 227: 1257.

Manufactured by:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised May 2010

Primaquine Phosphate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Clinical studies
• References
• Aralen; Primaquine (Primaquine Phosphate) reviews

DESCRIPTION

Aralen; Primaquine (Primaquine Phosphate) is 8-[(4-amino-1-methylbutyl)amino]-6-methoxyquinoline phosphate, a synthetic compound with potent antimalarial activity. Each tablet contains 26.3 mg of Aralen; Primaquine (Primaquine Phosphate) (equivalent to 15 mg of primaquine base). The dosage is customarily expressed in terms of the base.

Inactive Ingredients: Carnauba Wax, Hydroxypropyl Methylcellulose, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 400, Polysorbate 80, Pregelatinized Starch, Red Ferric Oxide, Talc, Titanium Dioxide.

CLINICAL PHARMACOLOGY

Aralen; Primaquine (Primaquine Phosphate) is an 8-amino-quinoline compound which eliminates tissue (exoerythrocytic) infection. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which are responsible for relapses in vivax malaria. Aralen; Primaquine (Primaquine Phosphate) is also active against gametocytes of Plasmodium falciparum.

INDICATIONS AND USAGE

Aralen; Primaquine (Primaquine Phosphate) is indicated for the radical cure (prevention of relapse) of vivax malaria.

CONTRAINDICATIONS

Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Pregnant women.

Aralen; Primaquine (Primaquine Phosphate) is contraindicated in acutely ill patients suffering from systemic disease manifested by tendency to granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. The drug is also contraindicated in patients receiving concurrently other potentially hemolytic drugs or depressants of myeloid elements of the bone marrow.

Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. Similarly, primaquine should not be administered to patients who have received quinacrine recently, as toxicity is increased.

WARNINGS

Hemolytic anemia and G6PD deficiency

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing has to be performed before using primaquine. Due to the limitations of G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk should be available.

Primaquine should not be prescribed for patients with severe G6PD deficiency.

In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of using primaquine. If primaquine administration is considered, baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring (e.g. at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should be available.

When the G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of using primaquine. Risk factors for G6PD deficiency or favism must be assessed. Baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring (e.g. at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should be available.

Discontinue the use of Aralen; Primaquine (Primaquine Phosphate) promptly if signs suggestive of hemolytic anemia occur (darkening of the urine, marked fall of hemoglobin or erythrocytic count).

Hemolytic reactions (moderate to severe) may occur in individuals with G6PD deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G6PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency of erythrocytic G6PD) while receiving primaquine and related drugs.

Usage in Pregnancy

Safe usage of this preparation in pregnancy has not been established. Primaquine is contraindicated in pregnant women. Even if a pregnant woman is G6PD normal, the fetus may not be. Animal data show toxicity to reproduction.

Nonclinical data from studies conducted in bacteria and in animals treated with primaquine show evidence of gene mutations and chromosomal/DNA damage, teratogenicity, and injury to embryos and developing fetuses when primaquine is administered to pregnant animals. Patients must be informed of the potential for adverse genetic and reproductive effects associated with primaquine treatment.

Use in Females and Males of Reproductive Potential

Pregnancy Testing

Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with primaquine.

Contraception

Patients should avoid pregnancy during treatment. The use of effective contraception is recommended during treatment and after the end of treatment as follows: Advise sexually active females of childbearing potential to use effective contraception when using primaquine and after stopping treatment until completion of an ongoing ovulatory cycle (e.g., up to next menses). Advise treated males whose partners may become pregnant to use a condom while on treatment and for 3 months after stopping treatment with primaquine.

Lactation

It is not known whether primaquine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from primaquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PRECAUTIONS

Blood Monitoring

Since anemia, methemoglobinemia, and leukopenia have been observed following administration of large doses of primaquine, the adult dosage of 1 tablet daily for fourteen days should not be exceeded. In G6PD normal patients it is also advisable to perform routine blood examinations (particularly blood cell counts and hemoglobin determinations) during therapy.

If Aralen; Primaquine (Primaquine Phosphate) is prescribed for an individual who has shown a previous idiosyncratic reaction to Aralen; Primaquine (Primaquine Phosphate) as manifested by hemolytic anemia, methemoglobinemia, or leukopenia; an individual with a family or personal history of hemolytic anemia or nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency, the person should be observed closely. In all patients, the drug should be discontinued immediately if marked darkening of the urine or sudden decrease in hemoglobin concentration or leukocyte count occurs.

Potential Prolongation of QT Interval

Due to potential for QT interval prolongation, monitor ECG when using primaquine in patients with cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT interval prolonging agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with primaquine. No fertility studies have been conducted with primaquine. Primaquine is reported in the literature to be a weak genotoxic agent which elicits both gene mutations,¹ chromosomal damage and DNA strand breaks.² The publications reported positive results in the in vitro reverse gene mutation assays using bacteria ^3,4 and in the 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).^2,5 The genotoxicity data obtained in vitro and in rodent models are suggestive of a human risk for genotoxicity with primaquine administration.

Animal Pharmacology and/or Animal Toxicology

Literature data on reproductive toxicology identified embryo-fetal development toxicity. In studies in rats, teratogenic effects on fetus were observed.

In the first reproductive toxicity study,⁶ primaquine was administered orally to rats between gestation day (GD) 6 and GD15 at dose levels of 10.3, 30.8 and 61.5 mg/kg/day (as base) (representing approximatively 7, 20 and 40 times the human dose [HD] on a body surface area comparison) when considering a human body weight of 60 kg). High dose levels induced death of pregnant females in almost all cases, while lower dose levels caused maternal toxicity. At cesarean section, embryo resorption, a decrease in fetal survival rate and body size, internal abnormalities (including hydrocephalia, heterotaxia), and an increase in skeletal variations were observed at the mid dose level. There were no fetal abnormalities at the low dose level providing a potential safety margin of at least 7 times the recommended clinical dose.

For the second reproductive toxicity study,⁷ 6 to10 animals per group were used. Dose levels of 0.57, 5.7, 11.4 and 34 mg/kg/day of primaquine (as base) (representing approximatively 0.4, 4, 7 and 22 times the HD on a body surface area comparison) were administered orally to Sprague Dawley rats between GD8 and GD16, or of 57 mg/kg only once on GD13 (representing more than 37 times the HD on a body surface area comparison). A total of 1/7 and 4/6 pregnant females at 34 mg/kg/day and at 57 mg/kg, respectively, died. Primaquine-associated teratogenic malformations (including cleft palate and small chin) were observed in 4/54 fetuses in the 57 mg/kg single-dose group.

Drug Interactions

Caution is advised if primaquine is used concomitantly with other drugs that prolong the QT interval.

Geriatric Use

Clinical studies of primaquine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Gastrointestinal: Nausea, vomiting, epigastric distress, and abdominal cramps.

Hematologic: Leukopenia, hemolytic anemia in G6PD deficient individuals, and methemoglobinemia in nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficient individuals.

Cardiac: Cardiac arrhythmia and QT interval prolongation.

Nervous System: Dizziness.

Skin and Soft Tissue: Rash, pruritus.

OVERDOSAGE

Symptoms of overdosage of Aralen; Primaquine (Primaquine Phosphate) include abdominal cramps, vomiting, burning epigastric distress, central nervous system and cardiovascular disturbances, including cardiac arrhythmia and QT interval prolongation, cyanosis, methemoglobinemia, moderate leukocytosis or leukopenia, and anemia. The most striking symptoms are granulocytopenia and acute hemolytic anemia in G6PD deficient patients. Acute hemolysis occurs, but patients recover completely if the dosage is discontinued.

DOSAGE AND ADMINISTRATION

Aralen; Primaquine (Primaquine Phosphate) is recommended only for the radical cure of vivax malaria, the prevention of relapse in vivax malaria, or following the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemic. Patients suffering from an attack of vivax malaria or having parasitized red blood cells should receive a course of chloroquine phosphate, which quickly destroys the erythrocytic parasites and terminates the paroxysm. Aralen; Primaquine (Primaquine Phosphate) should be administered concurrently in order to eradicate the exoerythrocytic parasites in a dosage of 1 tablet (equivalent to 15 mg base) daily for 14 days.

HOW SUPPLIED

Aralen; Primaquine (Primaquine Phosphate) is supplied as pink, convex, discoid, film-coated tablets of 26.3 mg (= 15 mg base), printed with a "W" and "P97" on one side.

Available in bottles of 100. (NDC 0024-1596-01)

Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F)

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

CLINICAL STUDIES

Persons with acute attacks of vivax malaria, provoked by the release of erythrocytic forms of the parasite, respond readily to therapy, particularly to chloroquine phosphate. Primaquine eliminates tissue (exoerythrocytic) infection and prevents relapses in experimentally induced vivax malaria in human volunteers and in persons with naturally occurring infections and is a valuable adjunct to conventional therapy in vivax malaria.

REFERENCES

1. Shubber EK, Jacobson-Kram D, Williams JR. Comparison of the Ames assay and the induction of sister chromatid exchanges: results with ten pharmaceuticals and five selected agents. Cell Biol Toxicol. 1986;2:379–99.

2. Chatterjee T, Muhkopadhyay A, Khan KA, Giri AK. Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine. Mutagenesis. 1998;13:619–24.

3. Marss TC. Bright JE, Morris BC. Methemoglobinogenic potential of primaquine and its mutagenicity in the Ames test. Toxicol Lett. 1987;36:281–7.

4. Ono T, Norimatsu M, Yoshimura H. Mutagenic evaluation of primaquine, pentaquine and pamaquine in the Salmonella/mammalian microsome assay. Mutat Res. 1994;325:7–10.

5. Giovanella F, Ferreira GK, de Prá1 SDT, et al. Effects of primaquine and chloroquine on oxidative stress parameters in rats. An Acad Bras Cienc (Annals of the Brazilian Academy of Sciences). 2015;87:1487–1496.

6. Trutter JA, Reno FE, Durloo RS. Teratogenicity studies with a candidate antileishmanial drug. The Toxicologist. 1983;3:65.

7. Beveridge E, Caldwell IC, Latter VS, Neal RA, Udall V, Waldron MM. The activity against Trypanosoma cruzi and cutaneous leishmaniasis, and toxicity, of moxipraquine (349C59). Trans R Soc Trop Med Hyg. 1980;74:43–51.

Revised July 2017

Manufactured for:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

©2017 sanofi-aventis U.S. LLC

P-425

NDC 0024-1596-01

Rx only

Aralen; Primaquine (Primaquine Phosphate)

Tablets, USP

26.3 mg (=15 mg base)

Store at 25° C (77° F); excursions

permitted to 15° C - 30° C

(59° F - 86° F) [see USP Controlled

Room Temperature].

NSN 6505-01-348-2465

100 tablets

SANOFI