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Primaquine Phosphate

Class: Antimalarials
VA Class: AP101
CAS Number: 63-45-6

Introduction

Antimalarial; 8-aminoquinoline derivative.100

Uses for Primaquine Phosphate

Malaria

Treatment of malaria caused by Plasmodium vivax or P. ovale.133 139 Provides a radical cure to prevent relapse of malaria caused by these Plasmodium.139 Not usually active against asexual erythrocytic forms of Plasmodium; a regimen that includes a blood schizonticidal agent (e.g., chloroquine, quinine with doxycycline or tetracycline, mefloquine, the fixed-combination of atovaquone and proguanil) always is given in conjunction with primaquine for treatment of P. ovale or P. vivax malaria.142

Terminal malaria prophylaxis in travelers who received chloroquine or other suitable antimalarials for prevention of malaria but are returning from areas where P. vivax or P. ovale are endemic.103 125 126 128 133 139 If primaquine prophylaxis is not used for terminal prophylaxis in individuals who may have been exposed to P. ovale or P. vivax malaria, delayed primary attacks or relapse caused by these Plasmodium can occur.103

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Prevention of malaria (primary prophylaxis).103 If primaquine is used for primary prophylaxis, the drug does not need to be used for terminal prophylaxis.103

Assistance with diagnosis or treatment of malaria available from CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.139 142

Detailed recommendations regarding prevention of malaria available from CDC 24 hours a day from the voice information service (877-394-8747) or at .103

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP); used in conjunction with clindamycin.109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 130 131 133 140 Designated an orphan drug by FDA for use in this condition.132

Co-trimoxazole is initial drug of choice for treatment in most adults, adolescents, and children, including HIV-infected patients; a regimen of clindamycin and primaquine is an alternative for adults or adolescents with mild to moderately severe PCP who had an inadequate response to co-trimoxazole or when co-trimoxazole is contraindicated or not tolerated.109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 140 141

Clindamycin in conjunction with primaquine has been used as an alternative for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) of PCP,114 123 but USPHS/IDSA states the regimen should only be considered for primary or secondary prophylaxis of PCP in unusual situations when the usually recommended agents (co-trimoxazole, dapsone, dapsone with pyrimethamine and leucovorin, aerosolized pentamidine, atovaquone) cannot be used.137

Primaquine Phosphate Dosage and Administration

General

  • Prior to use for treatment or prevention of malaria, CDC recommends appropriate laboratory tests to rule out glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.103

Administration

Oral Administration

Administer orally as a single dose at the same time each day.103 a

Administration with a meal may decrease adverse GI effects.a

Dosage

Available as primaquine phosphate; dosage usually expressed in terms of primaquine.100 Each 26.3 mg of primaquine phosphate is equivalent to 15 mg of primaquine.100

Pediatric Patients

Malaria
Radical Cure and Prevention of Delayed Attacks or Relapse of P. ovale or P. vivax Malaria
Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days.103 139 142 Pediatric dosage should not exceed usual adult dosage.

Terminal Prophylaxis to Prevent Delayed Primary Attacks or Relapse of P. ovale or P. vivax Malaria
Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days.103 Pediatric dosage should not exceed usual adult dosage.

When used in individuals who have left areas where P. ovale or P. vivax are endemic, administer primaquine during the last 2 weeks of, or immediately following, primary prophylaxis with chloroquine, doxycycline, or mefloquine.103 133 If fixed-combination of atovaquone and proguanil is used for primary prophylaxis, administer primaquine either during the last 7 days of atovaquone and proguanil prophylaxis and then for an additional 7 days, or alternatively, for 14 days after atovaquone and proguanil prophylaxis is discontinued.103

Primary Prophylaxis of Malaria )
Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily.103 Pediatric dosage should not exceed usual adult dosage. Initiate prophylaxis 1–2 days prior to entering a malarious area and continue for 7 days after leaving the area.103

Adults

Malaria
Radical Cure and Prevention of Delayed Attacks or Relapse of P. ovale or P. vivax Malaria
Oral

30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days recommended by CDC and others.103 133 139 Manufacturer recommends 15 mg of primaquine (26.3 mg of primaquine phosphate) once daily for 14 days.100

As an alternative to the daily regimen or in patients with borderline G-6-PD deficiency, CDC recommends 45 mg of primaquine (79 mg of primaquine phosphate) once weekly for 8 weeks.139 Consultation with an expert in infectious disease and/or tropical medicine is recommended if this alternative regimen is considered for individuals with borderline G-6-PD deficiency.139 (See Hematologic Effects under Cautions.)

Terminal Prophylaxis to Prevent Delayed Primary Attacks or Relapse of P. ovale or P. vivax Malaria
Oral

30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days recommended by CDC and others.103 133 Manufacturer recommends 15 mg of primaquine (26.3 mg of primaquine phosphate) once daily for 14 days.100

When used in individuals who have left areas where P. ovale or P. vivax are endemic, administer primaquine during the last 2 weeks of, or immediately following, prophylaxis with chloroquine, doxycycline, or mefloquine.103 133 If the fixed-combination atovaquone and proguanil is used for primary prophylaxis, administer primaquine either during the last 7 days of atovaquone and proguanil prophylaxis and then for an additional 7 days, or alternatively, for 14 days after atovaquone and proguanil prophylaxis is discontinued.103

Primary Prophylaxis of Malaria
Oral

30 mg of primaquine once daily.103 133 Initiate prophylaxis 1–2 days prior to entering a malarious area and continue for 7 days after leaving the area.103

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Treatment of Mild to Moderate Infections
Oral

15–30 mg of primaquine once daily for 21 days; used in conjunction with IV clindamycin (600–900 mg every 6–8 hours) or oral clindamycin (300–450 mg orally every 6–8 hours) given for 21 days.133 140

Prescribing Limits

Pediatric Patients

Pediatric dosage should not exceed usual adult dosage.103 139

Cautions for Primaquine Phosphate

Contraindications

  • Acutely ill patients who have systemic disease manifested by a tendency to develop granulocytopenia (e.g., rheumatoid arthritis, lupus erythematosus).a

  • Patients receiving other potentially hemolytic drugs or agents capable of depressing the myeloid elements of bone marrow.a

  • CDC states that use is contraindicated in individuals with G-6-PD deficiency, in pregnant women, and during lactation (unless the breast-fed infant has been determined not to have G-6-PD deficiency).103 139

Warnings/Precautions

Warnings

Hematologic Effects

Acute hemolytic anemia, possibly fatal, may occur if used in patients with G-6-PD deficiency.103 CDC recommends that appropriate laboratory testing be done to rule out G-6-PD deficiency before initiating primaquine prophylaxis.103 139

Hemolytic anemia may also occur if administered to individuals with other defects of the erythrocytic pentose phosphate pathway of glucose metabolism or in patients with certain hemoglobinopathies.a

The severity of hemolytic anemia depends on dosage and the specific genetic defect in the individual with G-6-PD deficiency.a In American and African Blacks with G-6-PD deficiency, hemolysis may be mild, self-limiting, and asymptomatic; in individuals of Mediterranean or certain Asian extractions, hemolysis may be severe.a

There is some evidence that a once-weekly (rather than daily) primaquine regimen may result in a lower incidence of hemolytic anemia in American Blacks who are sensitive to primaquine.a

Monitor closely if used in individuals who have had a previous idiosyncratic reaction to primaquine (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia), individuals with a personal or family history of favism, or individuals with G-6-PD deficiency or NADH methemoglobin reductase deficiency.a

Monitor CBCs periodically during therapy.a Do not exceed recommended dosage.a

Discontinue immediately if evidence of hemolytic anemia occurs (e.g., darkening of urine, marked fall in hemoglobin level or erythrocyte count).a

Specific Populations

Pregnancy

Category C.b

CDC and other experts state that use for malaria prophylaxis is contraindicated in pregnant women.103 133 139

If a pregnant women requires treatment of Plasmodium vivax or P. ovale malaria, CDC recommends use of oral chloroquine (300 mg once weekly) for prophylaxis for the duration of the pregnancy and deferral of primaquine (to provide a radical cure) until after delivery and after the women has been tested and determined not to have G-6-PD deficiency.139

Lactation

CDC states contraindicated during lactation, unless the breast-fed infant has been determined not to have G-6-PD deficiency.103 139

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.100

Select dosage with caution (starting at the low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.100

Common Adverse Effects

Hematologic effects (hemolytic anemia, leukocytosis, leukopenia); GI effects (nausea, vomiting, epigastric distress, abdominal cramps).a

Primaquine Phosphate Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract.a Peak plasma concentrations generally are attained within 6 hours; plasma concentrations may be negligible after 24 hours.a

Considerable interindividual variation in peak plasma concentrations reported.a

Distribution

Extent

Widely distributed following oral administration.101

Elimination

Metabolism

Extensively and rapidly metabolized in the liver.101 The principal metabolite is carboxyprimaquine; plasma concentrations of the metabolite greatly exceed those of unchanged primaquine.101

Elimination Route

Only small amounts excreted unchanged in urine.101

Half-life

3.7–9.6 hours in healthy adults.101

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C) in tight container.100

Actions and Spectrum

  • Tissue schizonticidal agent active against the preerythrocytic and exoerythrocytic forms of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax.a Also gametocytocidal against Plasmodium, especially the gametocytes of P. falciparum.a

  • Has some activity against the asexual erythrocytic forms of P. vivax, but generally inactive against the erythrocytic forms of Plasmodium.a

  • Mechanism of antimalarial activity appears to involve interference with Plasmodium DNA.a

Advice to Patients

  • Necessity of taking protective measures to reduce contact with mosquitoes (protective clothing, insect repellents, mosquito nets, remaining in air-conditioned or well-screened areas).103 133

  • Possibility of contracting malaria during travel, regardless of prophylactic regimen used.103 133

  • Importance of seeking medical attention as soon as possible if febrile illness develops during or after return from a malaria-endemic area and of informing clinician of possible malaria exposure.103 133

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.103 133

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Primaquine Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder*

Oral

Tablets

15 mg (of primaquine)

Primaquine Phosphate Tablets

Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Primaquine Phosphate 26.3MG Tablets (SANOFI-AVENTIS U.S.): 30/$58.31 or 90/$146.93

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Sanofi-Synthelabo. Primaquine phosphate tablets prescribing information. New York, NY; 2003 Apr.

101. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet. 1985; 10:187-215. [IDIS 202191] [PubMed 3893840]

103. Centers for Disease Control and Prevention. Health information for international travel, 2010. Atlanta, GA: US Department of Health and Human Services; 2010. Updates available from CDC website.

109. Ruf B, Pohle HD. Clindamycin/primaquine for Pneumocystis carinii pneumonia. Lancet. 1989; 2:626-7. [IDIS 259200] [PubMed 2570324]

110. Toma E, Fournier D, Poisson M et al. Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lancet. 1989; 1:1046-8. [IDIS 254599] [PubMed 2566001]

111. Black JR, Feinberg J, Fass RJ et al. Clindamycin plus primaquine as primary therapy for Pneumocystis carinii (PC) pneumonia in AIDS patients. Fifth International Conference on AIDS. Montreal; 1989:291. Abstract No. T.B.P.30.

112. Black JR, Feinberg J, Murphy RL et al. Clindamycin and primaquine as primary treatment for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS. Eur J Clin Microbiol Infect Dis. 1991; 10:204-7. [PubMed 2060532]

113. Joseph P, Marzouk J, Phelps R. Oral clindamycin plus primaquine for Pneumocystis carinii pneumonia. Sixth International Conference on AIDS. 1990:373. Abstract No. 2078.

114. Kay R, DuBois RE. Clindamycin/primaquine therapy and secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS. South Med J. 1990; 83:403-4. [IDIS 266040] [PubMed 2321069]

115. Ruf B, Rohde I, Pohle HD. Efficacy of clindamycin/primaquine (C/P) vs trimethoprim/sulfamethoxazole (TMP/SMZ) in acute treatment of Pneumocystis carinii pneumonia (PCP). Sixth International Conference on AIDS. 1990:221. Abstract No. Th.B.397.

116. Ruf B, Rohde I, Pohle HD. Efficacy of clindamycin/primaquine versus trimethoprim/sulfamethoxazole in primary treatment of Pneumocystis carinii pneumonia. Eur J Clin Microbiol Infect Dis. 1991; 10:207-10. [PubMed 2060533]

117. Toma E. Clindamycin/primaquine for treatment of Pneumocystis carinii pneumonia in AIDS. Eur J Clin Microbiol Infect Dis. 1991; 10:210-3. [PubMed 2060534]

118. Toma E, Fournier S, Morisset R et al. Clindamycin/primaquine vs trimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) in AIDS. Sixth International Conference on AIDS. 1990:221. Abstract No. Th.B.396.

119. Reviewers’ comments (personal observations).

120. Black JR, Akil B, Murphy R et al. Oral clindamycin plus primaquine therapy for Pneumocystis carinii pneumonia in AIDS patients. Seventh International Conference on AIDS. June 1991. Abstract No. Th.B.42.

121. Noskin GA, Murphy RL, Black JR et al. Salvage therapy with clindamycin/primaquine for Pneumocystis carinii pneumonia. Clin Infect Dis. 1992; 14:183-8. [IDIS 295061] [PubMed 1571426]

122. Vildé JL, Remington JS. Role of clindamycin with or without another agent for the treatment of pneumocystosis in patients with AIDS. J Infect Dis. 1992; 166:694-5. [IDIS 301385] [PubMed 1500762]

123. Smith D, Gazzard B. Treatment and prophylaxis of Pneumocystis carinii pneumonia. Drugs. 1991; 42:628-39. [PubMed 1723365]

125. World Health Organization. International travel and health: vaccination requirements and health advice. Geneva: World Health Organization; 2001. From WHO web site.

126. World Health Organization. WHO model prescribing information: drugs used in parasitic diseases. Geneva, Switzerland: WHO; 1990:22-4.

128. Wyler DJ. Malaria: overview and update. Clin Infect Dis. 1993; 16:449-58. [IDIS 312108] [PubMed 8513046]

130. Lane HC, Laughon BE, Falloon J et al. Recent advances in the management of AIDS-related opportunistic infections. Ann Intern Med. 1994; 120:945-55. [IDIS 330618] [PubMed 7909657]

131. Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med. 1994; 154:949-73. [IDIS 329350] [PubMed 8179453]

132. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

133. Anon. Drugs for parasitic infections. From the Medical Letter website. Aug 2008.

134. Fryauff DJ, Baird JK, Basri H et al. Randomised placebo-controlled trial of primaquine for prophylaxis of falciparum and vivax malaria. Lancet. 1995; 346:1190-3. [IDIS 355612] [PubMed 7475658]

135. Weiss WR, Oloo AJ, Johnson A et al. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil. J Infect Dis. 1995; 171:1569-75. [IDIS 348465] [PubMed 7769294]

137. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus. From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

138. Anon. Advice for travelers. Med Lett Drugs Ther. 2004; 2:33-40.

139. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2007 Mar. From the CDC website.

140. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(No. RR-15):1-112.

141. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(No. RR-14):1-92.

142. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States). From the CDC website. Accessed 2009 Jul 1.

a. AHFS Drug Information 2004. McEvoy GK, ed. Primaquine Phosphate. Bethesda, MD: American Society of Health-System Pharmacists; 2004:835-6.

b. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia; PA: Lippincott Wiliams & Wilkins; 2002:1154.

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