VA Class:AP101

AHFS Class:

• Antimalarials 8:30.08

Generic Name(s):

• quiNINE Sulfate

Chemical Name:

• (1) Cinchonan-9-ol, 6'-methoxy-, (8α,9R)-, sulfate (2:1) (salt), dihydrate

Molecular Formula:

• C₂₀H₂₄N₂O₂)₂ • H₂SO₄ • 2H₂O

Quinine, an alkaloid obtained from the bark of the cinchona tree and the levorotatory isomer of quinidine, is an antimalarial agent.185

Malaria

Treatment of Uncomplicated Malaria

Oral quinine sulfate is used for the treatment of uncomplicated malaria caused by Plasmodium falciparum .134,143,144,180,183,186 Oral quinine sulfate also is used for the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax †134,143,144,173 and for the treatment of uncomplicated malaria when the plasmodial species has not been identified†.134,143,144,173

Oral quinine sulfate is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of malaria.179 Since malaria is a life-threatening infection, the FDA states that the potential benefits of the drug outweigh the associated risks and justify its use for the treatment of malaria.182

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or the treatment of uncomplicated malaria when the plasmodial species has not been identified, the US Centers for Disease Control and Prevention (CDC) recommends the fixed combination of atovaquone and proguanil (atovaquone/proguanil), the fixed combination of artemether and lumefantrine (artemether/lumefantrine), or a regimen that includes quinine sulfate in conjunction with doxycycline, tetracycline, or clindamycin.143,144 Although mefloquine is another option for treatment in these patients,143,144 the CDC recommends that it be used only when other recommended treatment regimens cannot be used.143 If a quinine regimen is used, concomitant doxycycline or tetracycline generally is preferred instead of concomitant clindamycin since more efficacy data exist regarding antimalarial regimens that include tetracyclines.143

For the treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum , P. malariae , or P. knowlesi or the treatment of uncomplicated malaria when the plasmodial species has not been identified and the infection was acquired in areas where chloroquine resistance has not been reported, the CDC recommends chloroquine (or hydroxychloroquine).143,144 Alternatively, the CDC states that any of the regimens recommended for the treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.143,144

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax †, the CDC recommends a regimen of quinine sulfate and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine.144,143 Because quinine sulfate, doxycycline (or tetracycline), atovaquone/proguanil, and mefloquine are active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), a 14-day regimen of primaquine is indicated to prevent delayed primary attacks or relapse and provide a radical cure whenever any of these drugs is used for treatment of P. vivax or P. ovale malaria.134,143 (See Primaquine Phosphate 8:30.08.)

Pediatric patients with uncomplicated malaria generally can receive the same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143,144 For the treatment of uncomplicated chloroquine-resistant P. falciparum in children younger than 8 years of age, the CDC recommends atovaquone/proguanil or artemether/lumefantrine; mefloquine can be considered if no other options are available.144 Because children younger than 8 years of age† generally should not receive tetracyclines, the CDC states that if a quinine-based regimen is used for the treatment of uncomplicated malaria in such children, a 7-day regimen of quinine sulfate alone can be used (regardless of where the infection was acquired) or quinine sulfate can be given in conjunction with clindamycin.143 In rare instances, doxycycline or tetracycline can be used in conjunction with quinine sulfate in children younger than 8 years of age if other treatment options are not available or not tolerated and if potential benefits of using a tetracycline outweigh risks.143 For the treatment of chloroquine-resistant P. vivax malaria in children younger than 8 years of age who should not receive tetracyclines, the CDC recommends mefloquine given in conjunction with primaquine.143,144 Alternatively, if mefloquine is not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.143,144

Pregnant women with uncomplicated malaria caused by P. malariae , P. vivax , P. ovale , or chloroquine-susceptible P. falciparum should receive prompt treatment with chloroquine (or hydroxychloroquine).143 The CDC recommends that pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum receive prompt treatment with either mefloquine or a regimen of quinine sulfate and clindamycin;143 mefloquine is recommended for those with uncomplicated malaria caused by chloroquine-resistant P. vivax .143 Alternatively, atovaquone/proguanil or artemether/lumefantrine can be considered for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in pregnant women when other treatment options are not available or not tolerated and if potential benefits outweigh risks.143 Although tetracyclines generally are contraindicated in pregnant women, in rare circumstances when other treatment options are not available or not tolerated and if potential benefits outweigh risks, the CDC states that quinine sulfate may be used in conjunction with doxycycline (or tetracycline) for the treatment of uncomplicated malaria in pregnant women.143 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144

Clinical Experience

Quinine has been used for centuries for the treatment of malaria worldwide, and has been effective in geographic regions where chloroquine resistance has been documented.180,183,186 Oral quinine used alone or in conjunction with other antimalarial agents for the treatment of uncomplicated P. falciparum malaria has been evaluated in at least 21 randomized, active-controlled studies in more than 2900 patients from malaria-endemic areas; over 1400 such patients received treatment with oral quinine.180,183,186 Review of data from these trials indicates that a regimen containing oral quinine is effective for the treatment of uncomplicated P. falciparum malaria.180,183,186 In areas of increasing multidrug-resistant P. falciparum (e.g., Southeast Asia), cure rates (cure defined as initial clearing of parasitemia within 7 days after initiation of treatment without recrudescence by day 28) were at least 80% following a 7-day regimen of oral quinine monotherapy and greater than 90% following a 7-day regimen of oral quinine in conjunction with either tetracycline or clindamycin.180,183,186 In areas with less widespread multidrug-resistant P. falciparum , cure rates ranged from 86-100% following 7 days of quinine monotherapy.180,183,186

Intolerance to quinine may prevent completion of a full 7-day regimen of oral quinine and a shorter regimen (e.g., 3 days) of oral quinine in conjunction with another antimalarial (tetracycline, doxycycline, or clindamycin) has been used.180,183,186 However, data from randomized, controlled clinical trials evaluating these shorter regimens for the treatment of uncomplicated P. falciparum malaria are limited and such regimens may be less effective than the usual 7-day regimen.180,183,186

P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh; quinine treatment may be less effective in these areas.180,183,186

Treatment of Severe Malaria

Although quinine sulfate is not approved by the FDA for the treatment of severe or complicated malaria†,180,183,186 the CDC states that oral quinine sulfate can be used in conjunction with doxycycline, tetracycline, or clindamycin for follow-up treatment after an appropriate initial parenteral regimen.143,144

For the treatment of severe malaria in adults or children, the CDC recommends an initial regimen of IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin initiated as soon as possible after the diagnosis.143,144 (See Uses: Malaria, in Quinidine 24:04.04.04.) The CDC states that after parasitemia is reduced to less than 1% and oral therapy is tolerated, IV quinidine gluconate therapy can be discontinued and oral quinine sulfate initiated to complete 7 or 3 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).143,144

In the past, IV quinine dihydrochloride was considered the drug of choice for the treatment of severe malaria (e.g., cerebral malaria) caused by chloroquine-susceptible or -resistant P. falciparum ;107 however, delivery of emergency supplies for specific patient needs frequently required 24-36 hours149 because the drug was available in the US only from the Parasitic Diseases Drug Service of the CDC.107,131 Because severe P. falciparum malaria can be fatal if therapy is not initiated promptly, IV quinidine gluconate became the drug of choice for initial parenteral treatment of severe malaria in the US since it is more readily available.112,129,130,132,143,148,149,150 IV quinine dihydrochloride is no longer available for use in the US, either commercially or from CDC.148,149

If IV quinidine gluconate cannot be used for initial treatment because of adverse effects or contraindications or because it is unavailable locally and cannot be obtained quickly, parenteral artesunate is available from the CDC under an investigational new drug (IND) protocol for emergency initial treatment of severe malaria.143,144

Assistance with diagnosis or treatment of malaria or assistance obtaining quinidine gluconate or artesunate for treatment of severe malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143

Presumptive Self-treatment of Malaria

Although some clinicians have suggested that a regimen of oral quinine sulfate in conjunction with oral doxycycline may be used for presumptive self-treatment of malaria† in travelers,134 quinine sulfate is not approved by the FDA for presumptive self-treatment of malaria180,183,186 and is not recommended by CDC for such treatment.115

For presumptive self-treatment of malaria in travelers, the CDC and other experts recommend atovaquone/proguanil or artemether/lumefantrine.115,134

Prevention of Malaria

Quinine sulfate is not approved by the FDA for prevention of malaria.180,183,186 The CDC and other clinicians usually recommend use of other antimalarial agents (e.g., chloroquine [or hydroxychloroquine], atovaquone/proguanil, doxycycline, mefloquine) for prevention or chemoprophylaxis of malaria caused by susceptible plasmodia.115,134

Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention are available from the CDC at [Web] and [Web].115

Babesiosis

Oral quinine sulfate is used in conjunction with IV or oral clindamycin for the treatment of babesiosis† caused by Babesia microti .102,103,105,134,178,181

Although several species of Babesia can infect humans, B. microti is the most common cause of babesiosis in the US.178 B. microti is transmitted by Ixodes scapularis ticks, which also may be simultaneously infected with and transmit Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]).105,178 Therefore, the possibility of coinfection with B. burgdorferi and/or A. phagocytophilum should be considered in patients who have severe or persistent symptoms despite appropriate anti-infective treatment for babesiosis.178 (See Lyme Disease under Uses: Spirochetal Infections and see Uses: Ehrlichiosis and Anaplasmosis, in the Tetracyclines General Statement 8:12.24.)

The Infectious Diseases Society of America (IDSA) states that all patients with active babesiosis (i.e., symptoms of viral-like infection and identification of babesial parasites in blood smears or by polymerase chain reaction [PCR] amplification of babesial DNA) should receive anti-infective treatment because of the risk of complications; however, symptomatic patients whose serum contains antibody to babesia but whose blood lacks identifiable babesial parasites on smear or babesial DNA by PCR should not receive treatment.178 In addition, treatment is not recommended initially for asymptomatic individuals, regardless of the results of serologic examination, blood smears, or PCR, but should be considered if parasitemia persists for longer than 3 months.178

When anti-infective treatment of babesiosis is indicated, the IDSA and other clinicians recommend that either a regimen of quinine and clindamycin or a regimen of atovaquone and azithromycin be used.105,134,178,181 The quinine and clindamycin regimen may be preferred in those with severe babesiosis.178 However, there is some evidence that, in patients with mild or moderate illness, the atovaquone and azithromycin regimen may be as effective and better tolerated than the quinine and clindamycin regimen.105,134,178,181 Patients with moderate to severe babesiosis should be monitored closely during treatment to ensure clinical improvement.178 Exchange transfusions have been used successfully in asplenic patients with life-threatening babesiosis and should be considered, especially in severely ill patients with high levels of parasitemia (10% or more), significant hemolysis, or compromised renal, hepatic, or pulmonary function.105,134,178

Nocturnal Recumbency Leg Muscle Cramps

Quinine sulfate is not approved by the FDA for the treatment or prevention of nocturnal leg cramps†, and the drug should not be used in the management of this or related conditions (e.g., restless legs syndrome†).180,182,185,187,201

Although quinine sulfate has been used in the past for the prevention and treatment of nocturnal recumbency leg muscle cramps† (night cramps)175,176,177,182,184,185,198 and results of some uncontrolled or placebo-controlled studies suggest the drug may provide relief of cramps in some patients,114,119,122,175,176,198 there are no adequate and well-controlled studies evaluating efficacy and safety for this use.119,120,121,122,124,154,155,184,185

Quinine sulfate has a narrow margin of safety and may cause unpredictable serious and life-threatening hypersensitivity reactions, QT interval prolongation, serious cardiac arrhythmias (including torsades de pointes), serious hematologic reactions (including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura [HUS/TTP]), and other serious adverse events (e.g., blindness, deafness) requiring medical intervention and hospitalization.180,184,185,187,188,191,193,201 Fatalities associated with use of the drug have been reported.180,185,187,201 The known risks associated with the use of quinine sulfate, in the absence of evidence of safety and efficacy of the drug for the treatment or prevention of nocturnal leg cramps†, outweigh any potential benefits for this benign, self-limiting condition.180,184,185,187 (See Cautions.)

The FDA has determined that quinine preparations (including preparations containing any quinine salt alone or in fixed combination with vitamin E) are not generally recognized as safe and effective for treatment or prevention of nocturnal leg muscle cramps†.185 Promotion of quinine for self-medication of nocturnal leg cramps† has been prohibited in the US since February 1995 because of safety concerns.154,155,184,185 In addition, the FDA ordered firms involved in the marketing of unapproved quinine preparations to discontinue marketing such preparations on December 11, 2006.182,185 (See Preparations.)

Administration

Quinine sulfate is administered orally.180,183,186

Although quinine has been administered by slow IV infusion as quinine dihydrochloride, a parenteral preparation of the drug is no longer is available for use in the US, either commercially or from the US Centers for Disease Control and Prevention (CDC).148,149 When parenteral antimalarial therapy is indicated, IV quinidine gluconate should be used.143,144,148,149 (See Quinidine in 24:04.04.04.)

Quinine sulfate should be administered with food to minimize possible GI irritation.180,183,186

Patients should be advised to take quinine sulfate exactly as prescribed and to contact their clinicians if they have questions regarding the prescribed dosage regimen, including missed doses.180,183,186 If a patient misses a dose, they should be advised not to double the next dose; if more than 4 hours have elapsed following a missed dose, the patient should not take the missed dose and should take the next dose as previously scheduled.180,183,186

Dosage

Dosage of quinine sulfate is expressed in terms of the salt.180,183,186

The only FDA-approved preparations of quinine sulfate currently commercially available in the US are capsules containing 324 mg of quinine sulfate (Qualaquin^®; generic);180,183,185,186 the drug was previously available in the US as capsules containing 325 mg.185 This difference in quinine sulfate preparations may result in minor disparities between some published dosage recommendations that were based on the previously available 325-mg capsules and dosage recommendations for the currently available 324-mg capsules.

Malaria

Treatment of Uncomplicated Malaria Caused by Chloroquine-resistant P. falciparum or Unidentified Plasmodial Species

For the treatment of uncomplicated malaria caused by Plasmodium falciparum , the manufacturers recommend that adults receive oral quinine sulfate in a dosage of 648 mg every 8 hours for 7 days.180,183,186 The manufacturers caution that although shorter regimens (3 days) have been used, data regarding these regimens are limited and they may be less effective than a 7-day regimen.180,183,186

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or the treatment of uncomplicated malaria when the plasmodium species has not been identified† and the disease was acquired in areas with chloroquine resistance, the CDC and other clinicians recommend that adults receive oral quinine sulfate in a dosage of 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by the geographic origin of the infecting parasites (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with a 7-day regimen of oral doxycycline, tetracycline, or clindamycin.134,144 For treatment of these infections in pregnant women, the CDC recommends that the usual adult dosage of oral quinine sulfate be given in conjunction with a 7-day regimen of oral clindamycin144 or, alternatively, if benefits outweigh risks, given in conjunction with a 7-day regimen of oral doxycycline or tetracycline.144

For the treatment of uncomplicated malaria in children 8 years of age or older† caused by chloroquine-resistant P. falciparum or when the plasmodium species has not been identified, the CDC and other clinicians recommend that oral quinine sulfate be given in a dosage of 10 mg/kg 3 times daily for 7 or 3 days (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with a 7-day regimen of oral doxycycline, tetracycline, or clindamycin.134,144 Pediatric dosage should not exceed the usual adult dosage.143,144

If a quinine regimen is used in children younger than 8 years of age† for the treatment of chloroquine-resistant P. falciparum malaria, the CDC states that monotherapy with oral quinine sulfate may be given for 7 days or oral quinine sulfate can be given in conjunction with clindamycin for the usually recommended duration.143 In rare circumstances, the CDC states that a regimen of oral quinine sulfate and oral doxycycline or tetracycline can be considered in children younger than 8 years of age.143 (See Treatment of Uncomplicated Malaria under Uses: Malaria.)

Treatment of Uncomplicated Malaria Caused by Chloroquine-resistant P. vivax

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax † in adults, the CDC and other clinicians recommend that oral quinine sulfate be administered in a dosage of 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with a 7-day regimen of oral doxycycline or tetracycline and a 14-day regimen of oral primaquine phosphate.134,144 Primaquine is necessary to provide a radical cure and prevent relapse of P. vivax malaria.134,143,144 (See Primaquine Phosphate 8:30.08.)

For pregnant women with uncomplicated malaria caused by chloroquine-resistant P. vivax †, the CDC recommends that the usual adult dosage of oral quinine sulfate be given for 7 days (regardless of where the infection was acquired)143,144 or, if benefits outweigh risks, used in conjunction with oral doxycycline or tetracycline.144 Because primaquine (to provide a radical cure of P. vivax malaria) should not be administered during pregnancy, the CDC recommends that these pregnant women receive prophylaxis with chloroquine (300 mg [500 mg of chloroquine phosphate] once weekly) for the duration of the pregnancy and that use of primaquine be deferred until after delivery and after the women has been tested and determined not to have glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.143,144

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax † in children 8 years of age or older†, the CDC and other clinicians recommend that oral quinine sulfate be given in a dosage of 10 mg/kg 3 times daily for 7 or 3 days (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with a 7-day regimen of oral doxycycline or tetracycline and a 14-day regimen of oral primaquine phosphate.134,144 Pediatric dosage should not exceed the usual adult oral dosage.143,144 Primaquine is necessary to provide a radical cure and prevent relapse of P. vivax malaria.134,143,144 (See Primaquine Phosphate 8:30.08.)

Treatment of Severe Malaria

For the treatment of severe malaria†, oral quinine sulfate is administered after an initial regimen of IV quinidine gluconate and is given in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin (administered IV or orally as tolerated).143,144 (See Uses: Malaria, in Quinidine 24:04.04.04.) After parasitemia is reduced to less than 1% with the IV quinidine gluconate regimen and oral therapy is tolerated, IV quinidine gluconate can be discontinued and oral quinine sulfate substituted to complete 7 or 3 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).143,144

The dosage of oral quinine sulfate recommended by the CDC for follow-up in the treatment of severe malaria† in adults is 650 mg (two 324-mg capsules) every 8 hours.144 For follow-up in the treatment of severe malaria in children†, oral quinine sulfate has been given in a dosage of 10 mg/kg 3 times daily.199 Pediatric dosage should not exceed the usual adult dosage.143,144

Presumptive Self-treatment of Malaria

As an alternative for presumptive self-treatment of malaria† during travel, some clinicians recommend that adults receive oral quinine sulfate in a dosage of 650 mg every 8 hours given for 7 or 3 days (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with oral doxycycline (100 mg twice daily for 7 days).134 For presumptive self-treatment of malaria in children†, these clinicians recommend a quinine dosage of 30 mg/kg daily given in 3 equally divided doses for 7 or 3 days (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with oral doxycycline (4 mg/kg daily given in 2 doses for 7 days).134

Quinine is not included in current CDC recommendations for presumptive self-treatment of malaria.115 If quinine is used for such treatment, travelers should be advised to keep a sufficient amount of quinine and doxycycline in their possession during travel and to take the drugs promptly in the event of a febrile illness if professional medical care is not readily available.134 Presumptive self-treatment of a possible malarial infection is only a temporary measure and it is imperative that a professional medical evaluation be obtained as soon as possible.115

Babesiosis

For the treatment of babesiosis† caused by Babesia microti , the Infectious Diseases Society of America (IDSA) and other clinicians recommend that adults receive oral quinine sulfate in a dosage of 650 mg every 6-8 hours in conjunction with clindamycin (300-600 mg IV every 6 hours or 600 mg orally every 8 hours) given for 7-10 days.134,178

For the treatment of babesiosis† in pediatric patients, the IDSA recommends oral quinine sulfate in a dosage of 8 mg/kg (up to 650 mg) every 8 hours in conjunction with clindamycin (7-10 mg/kg [up to 600 mg] IV or orally every 6-8 hours) given for 7-10 days.178 Other clinicians recommend that pediatric patients receive oral quinine sulfate in a dosage of 30 mg/kg daily given in 3 divided doses for 7-10 days in conjunction with clindamycin (20-40 mg/kg daily given orally in 3 divided doses) for 7-10 days.134

Patients with mild to moderate babesiosis should have clinical improvement within 48 hours after treatment is initiated; symptoms should resolve completely within 3 months.178 Patients with severe babesiosis should receive IV clindamycin rather than oral clindamycin.178 Some patients may have persistent low-grade parasitemia for months after anti-infective treatment.178 Regardless of the presence or absence of symptoms, the IDSA suggests that retreatment be considered if babesial parasites or amplifiable babesial DNA is detected in blood 3 months or longer after initial treatment.178

Dosage in Renal and Hepatic Impairment

Renal Impairment

When quinine sulfate is used for the treatment of acute uncomplicated malaria in adults with severe chronic renal failure, computer models indicate that the dosage regimen should be modified to include a loading dose of 648 mg followed 12 hours later by maintenance doses of 324 mg every 12 hours.180,183,186 This dosage modification is based on data indicating that, in patients with severe chronic renal failure (mean serum creatinine 9.6 mg/dL) who were not receiving any type of dialysis and had no other serious illness, the median plasma quinine exposure (area under the plasma concentration-time curve [AUC]) was increased by 195% compared with that observed in adults with normal renal function.180,183,186

The effects of mild or moderate renal impairment on the pharmacokinetics and safety of quinine sulfate have not been determined to date.180,183,186

Hepatic Impairment

Quinine sulfate should not be used in patients with severe hepatic impairment (Child-Pugh class C).180,183,186

When quinine is used in patients with mild to moderate hepatic impairment (Child-Pugh class A or B), dosage adjustments are not required but such patients should be monitored closely for adverse effects associated with quinine.180,183,186 Data from patients with Child-Pugh class B hepatic impairment and no other serious illness indicate that the quinine AUC is increased by 55% compared with that observed in healthy adults with normal liver function.180,183,186 (See Pharmacokinetics: Elimination.)

The most common adverse effects of oral quinine sulfate are a cluster of symptoms referred to as “cinchonism.”180,183,186 These effects occur to some degree in almost all patients receiving quinine, and most symptoms are reversible and resolve when the drug is discontinued.180,183,186 (See Cautions: Cinchonism.) However, quinine can cause adverse effects on almost all body systems and some of these may be serious and life-threatening (e.g., hematologic reactions including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura [HUS/TTP], cardiac arrhythmias, severe hypersensitivity).180,182,183,185,186,187,201

From 1969 through September 2006, the US Food and Drug Administration (FDA) received 665 reports of serious adverse effects associated with quinine, including 93 deaths.182,185 Because of serious safety concerns, the FDA initiated several regulatory actions in December 2006 to remove unapproved quinine preparations from the US market.182,185,187 Despite these efforts, quinine still is being prescribed for uses other than malaria, and the FDA continues to receive reports of serious adverse effects associated with the drug.187 From April 2005 to October 2008, the FDA Adverse Event Reporting System (AERS) received 38 reports of serious adverse events associated with quinine (e.g., hematologic events, cardiovascular events, GI symptoms, hearing loss, rash, electrolyte imbalance, drug interactions).187,201 The majority of these reports (66%) involved patients who used quinine for unlabeled indications (prevention or treatment of leg cramps or restless leg syndrome†),187,201 and most (63%) involved serious or potentially fatal hematologic events.201 (See Cautions: Hematologic Effects.)

Because malaria is a life-threatening infection, the FDA states that the potential benefits of quinine outweigh the associated risks and justify its use for the treatment of malaria.182 However, the risks associated with use of the drug for unlabeled indications (prevention or treatment of leg cramps or restless leg syndrome†) outweigh any potential benefits and may expose patients to substantial and unnecessary risk.180,182,184,185,187 (See Uses: Nocturnal Recumbency Leg Muscle Cramps.)

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), angioedema, facial edema, bronchospasm, and pruritus, have been reported with quinine.180,183,185,186,191 In addition, thrombocytopenia, HUS/TTP, immune thrombocytopenic purpura, blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis have been reported and may also be due to hypersensitivity reactions to the drug.21,180,183,185,186,174,191,194,195 (See Cautions: Hematologic Effects.)

If evidence of hypersensitivity occurs during quinine therapy, the drug should be discontinued.180,183,186 (See Cautions: Precautions and Contraindications.)

Cinchonism

A cluster of symptoms referred to as “cinchonism” occurs in practically all patients receiving quinine.180,183,186 Most manifestations of cinchonism are reversible and resolve following discontinuance of quinine.180,183,186

Manifestations of mild cinchonism include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception.180,183,186 More severe cinchonism manifests as vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction.180,183,186

Hematologic Effects

Serious, life-threatening, and sometimes fatal hematologic reactions, including thrombocytopenia108,180,183,186,188,201 and HUS/TTP,180,183,186,201 have been reported in patients receiving quinine, especially patients using the drug for unlabeled indications (prevention or treatment of leg cramps or restless leg syndrome†).187,201 Subsequent development of chronic renal impairment has occurred in patients with quinine-associated TTP.180,183,186,201

Data from 24 patients who developed serious hematologic reactions while receiving quinine indicate that the median time to onset of these reactions was approximately 2 weeks after initiation of the drug.201 While most of these patients recovered when quinine was discontinued and other therapeutic interventions initiated, there were 2 fatalities (one related to TTP and the other related to hemolysis).201 If thrombocytopenia occurs, quinine should be discontinued since continued therapy puts the patient at risk for fatal hemorrhage.180,183,186 Thrombocytopenia usually resolves within 1 week after the drug is discontinued.180,183,186 The mechanism of quinine-induced thrombocytopenia appears to be the formation of drug-antibody complexes with an affinity for some component of the platelet membrane.180,183,186 Since quinine-induced thrombocytopenia is immune-mediated, re-exposure of the patient to quinine from any source may result in a more rapid and more severe course of thrombocytopenia compared to the original episode.180,183,186

Other adverse hematologic effects that have been reported in patients receiving quinine include agranulocytosis,180,183,186 hypoprothrombinemia,180,183,186 disseminated intravascular coagulation,158,180,183,186,195 hemolytic anemia,180 idiopathic thrombocytopenic purpura,180,183,186,188 petechiae,180,183,186 ecchymosis,180,183,186 hemorrhage,180,183,186 coagulopathy,156,157,180,183,186 blackwater fever,180,183,186 leukopenia,108,180,183,186 neutropenia,180,183,186 pancytopenia,156,157,180,183,186 aplastic anemia,180,183,186 and lupus anticoagulant have been reported with quinine therapy.180,183,186

Hemolysis, with the potential for hemolytic anemia, has been reported when quinine was administered to patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.180,183,186 (See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

QT interval prolongation has been a consistent finding in studies evaluating electrocardiographic (ECG) changes in individuals receiving oral or parenteral quinine.180,183,186 These ECG changes occur independent of the individual's age, clinical status, or disease severity,180,183,186 and maximal increases in QT interval correlate with peak plasma concentrations of quinine.180,183,186 Concentration-dependent prolongation of the PR and QRS intervals also has been reported in patients receiving oral quinine sulfate.180,183,186 Patients with underlying structural heart disease and preexisting conduction system abnormalities, geriatric patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia, and patients receiving drugs known to prolong the PR interval (e.g., verapamil) or QRS interval (e.g., flecainide, quinidine) are at particular risk.180,183,186

Potentially fatal cardiac arrhythmias, including torsades de pointes and ventricular fibrillation, have been reported rarely during quinine therapy.180,183,186 At least 1 case of fatal ventricular arrhythmia has been reported in a geriatric patient with preexisting prolonged QT interval treated with IV quinine sulfate for P. falciparum malaria.180,183,186

In a double-blind, multiple-dose, placebo- and positive-controlled crossover study in adults 20-78 years of age who received oral quinine sulfate (648 mg 3 times daily for 7 days), the maximum mean difference in QT interval corrected for rate (QT_c) from placebo after baseline correction was 27.7 msec and the maximum mean difference in PR and QRS intervals from placebo after baseline correction was 14.5 msec and 11.5 msec, respectively.180,183,186

Quinine should not be used in patients receiving other drugs known to cause QT interval prolongation, including class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide) and class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide).180,183,186 In addition, quinine should be avoided in patients receiving drugs known to be cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) substrates and for which increased plasma concentrations may be associated with prolonged QT interval (e.g., cisapride [available in the US only under a limited-use protocol], pimozide, halofantrine [an antimalarial not available in the US], quinidine).180,183,186 (See Drug Interactions.)

A paradoxical increase in ventricular response rate may occur with quinine, similar to that observed with quinidine.180,183,186 Rapid IV administration of quinine dihydrochloride (no longer available in the US either commercially or from the Parasitic Diseases Drug Service of the CDC) has resulted in severe hypotension, arrhythmias, and acute circulatory failure.

Chest pain,180,183,186 vasodilatation,180,183,186 hypotension,180,183,186 postural hypotension,180,183,186 tachycardia,180,183,186 bradycardia,180,183,186 palpitations,180,183,186 syncope,180,183,186 atrioventricular block,180,183,186 atrial fibrillation,180,183,186 irregular rhythm,180,183,186 unifocal premature ventricular contractions,180,183,186 nodal escape beats,180,183,186 U waves,180,183,186 ventricular tachycardia,180,183,186 and cardiac arrest180,183,186 also have been reported in patients receiving quinine.

Nervous System Effects

Quinine possesses neuromuscular blocking activity and the drug may exacerbate muscle weakness in patients with myasthenia gravis.180,183,186 (See Cautions: Precautions and Contraindications.)

Asthenia,180,183,186 headache,180,183,186 diplopia,180,183,186 confusion,180,183,186 altered mental status,180,183,186 seizures, 180,183,186 coma,180,183,186 disorientation,180,183,186 tremors,180,183,186 restlessness,180,183,186 ataxia,180,183,186 acute dystonic reaction,180,183,186 aphasia,180,183,186 and suicide180,183,186 have been reported with quinine therapy.

Quinine can affect the retina and optic nerve, and visual disturbances reported with quinine therapy include blurred vision with scotomata,180,183,186 sudden loss of vision,180,183,186 photophobia,180,183,186 diplopia,180,183,186 night blindness,180,183,186 diminished visual fields,180,183,186 fixed pupillary dilatation,180,183,186 disturbed color vision,180,183,186 optic neuritis,180,183,186 and blindness.180,183,186,193

Quinine has also caused vertigo,180,183,186 tinnitus,180,183,186 hearing impairment,180,183,186 and deafness.180,183,186

Dermatologic Effects

Cutaneous rashes (e.g., urticarial, papular, scarlatinal),180,183,186 pruritus,180,183,186 bullous dermatitis,180,183,186 exfoliative dermatitis,180,183,186 erythema multiforme,180,183,186 Stevens-Johnson syndrome,180,183,186 toxic epidermal necrolysis,180,183,186 fixed drug eruption,180,183,186 photosensitivity reactions,180,183,186,197 allergic contact dermatitis,180,183,186 acral necrosis,180,183,186 and cutaneous vasculitis180,183,186 have been reported with quinine therapy.

Respiratory Effects

Asthma,180,183,186 dyspnea,180,183,186 and pulmonary edema180,183,186,192 have been reported with quinine therapy.

GI Effects

GI effects including nausea,180,183,186 vomiting,180,183,186 diarrhea,180,183,186 abdominal pain,180,183,186 gastric irritation,180,183,186 esophagitis,180,183,186 and anorexia180,183,186 have been reported in patients receiving quinine.

Hepatic Effects

Granulomatous hepatitis,21,180,183,186 hepatitis,180,183,186 jaundice,180,183,186 and abnormal liver function tests180,183,186 have been reported in patients receiving quinine.180 In at least one patient who was receiving quinine for the treatment of nocturnal leg muscle cramps, granulomatous hepatitis was reported and was manifested as fever, malaise, nausea, vomiting, polyarthralgia, and increased serum concentrations of AST and ALT.21 Hepatocellular cholestatic hepatotoxicity, which appeared to be a hypersensitivity reaction to oral quinine, has been reported in at least one patient.136

Renal Effects

Hemoglobinuria,180,183,186 renal failure,180,183,186 renal impairment,180,183,186 and acute interstitial nephritis180,183,186 have been reported in patients receiving quinine.

Other Adverse Effects

Quinine stimulates release of insulin from the pancreas,180,183,186 and quinine-induced hypoglycemia has been reported.101,135,180,183,186,196 Clinically important hypoglycemia may occur, especially in pregnant women.180,183,186

Renal failure, associated with coagulopathy and quinine-dependent antibodies, has been reported.156

Fever,180,183,186 chills,180,183,186 sweating,180,183,186 flushing,180,183,186 and a lupus-like syndrome180,183,186 have been reported in patients receiving quinine.

Myalgias180,183,186 and muscle weakness180,183,186 have been reported in patients receiving quinine.

Precautions and Contraindications

Quinine is contraindicated in patients who are hypersensitive to the drug, as well as in patients with a history of potential hypersensitivity reactions associated with previous quinine use, including (but not limited to) HUS/TTP, idiopathic thrombocytopenic purpura, thrombocytopenia, or blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia).180,183,186

Quinine is contraindicated in patients with known hypersensitivity to mefloquine or quinidine because cross-sensitivity to quinine has been reported.180,183,186

Quinine is contraindicated in patients with prolonged QT interval.180,183,186 The drug should be avoided in patients with clinical conditions known to prolong the QT interval (e.g., uncorrected hypokalemia, bradycardia, certain cardiac conditions) and should not be used concomitantly with other drugs known to cause QT interval prolongation.180,183,186 (See Drug Interactions: Drugs That Prolong the QT Interval.)

Quinine is contraindicated in patients with G-6-PD deficiency, myasthenia gravis, or optic neuritis.180,183,186

Quinine should be used with caution in patients with atrial fibrillation or atrial flutter.180,183,186 A paradoxical increase in ventricular response rate may occur with quinine, similar to that observed with quinidine.180,183,186 The patient should be monitored closely if digoxin is used to prevent a rapid ventricular response.180,183,186 (See Drug Interactions: Digoxin.)

Quinine sulfate is not approved by the FDA for the treatment or prevention of nocturnal leg cramps†, and the drug should not be used in the management of this or related conditions (e.g., restless legs syndrome†)180,182,183,185,186,187,201 since the known risks outweigh any potential benefits.180,183,184,185,186,187 (See Uses: Nocturnal Recumbency Leg Muscle Cramps.)

When quinine is used for the treatment of malaria, patients should be advised to contact their clinician immediately if their malarial symptoms worsen or do not improve within 2 days of initiating quinine therapy or if fever recurs following completion of antimalarial therapy.180,183,186

Patients should be advised to contact their clinician immediately if symptoms of hypersensitivity (e.g., rash, hives, severe itching, severe flushing, facial swelling, difficulty breathing), bleeding problems (e.g., easy bruising, severe nose bleed, bleeding gums, blood in urine or stool, unusual purple, brown, or red skin spots indicating bleeding under the skin), or heart problems (e.g., chest pain, rapid heartbeat, irregular heart rhythm, weakness, sweating, nervousness) occur.180,183,186

Quinine should not be used in patients with severe hepatic impairment (Child-Pugh class C) since oral clearance is decreased, volume of distribution is increased, and half-life of the drug is prolonged relative to individuals with normal hepatic function.180,183,186 When quinine is used in patients with mild to moderate hepatic impairment (Child-Pugh class A or B), dosage adjustments are not necessary but patients should be monitored closely for adverse effects associated with quinine.180,183,186

Pediatric Precautions

The safety and efficacy of quinine in patients younger than 16 years of age have not been established.180,183,186

Oral quinine sulfate is included in CDC recommendations for the treatment of uncomplicated malaria in pediatric patients†.143,144 (See Treatment of Uncomplicated Malaria under Uses: Malaria.) The drug also has been used for follow-up after an initial parenteral antimalarial regimen in children with severe malaria†.199 (See Treatment of Severe Malaria under Uses: Malaria.)

Geriatric Precautions

Clinical studies evaluating quinine did not include sufficient numbers of individuals 65 years of age and older to determine whether they respond differently than younger adults.180,183,186 Other reported clinical experience has not identified differences in responses between geriatric adults and younger patients.180,183,186 However, geriatric patients receiving quinine should be closely monitored for adverse effects.180,183,186

Mutagenicity and Carcinogenicity

Carcinogenicity studies of quinine have not been conducted.180,183,186 Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice.180,183,186 There was no evidence of genotoxicity in the sex-linked recessive lethal test performed in Drosophila , in the in vivo mouse micronucleus assay, and in the chromosomal aberration assay in mice and Chinese hamsters.180,183,186

Pregnancy, Fertility, and Lactation

Pregnancy

The manufacturers state that quinine should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.180,183,186

The CDC recommends oral quinine sulfate and clindamycin as a regimen of choice for the treatment of uncomplicated chloroquine-resistant P. falciparum in pregnant women.143,144 (See Treatment of Uncomplicated Malaria under Uses: Malaria.)

Although published data on more than 1000 quinine pregnancy exposures (majority of exposures occurred after the first trimester) did not show an increased risk of teratogenic effects compared with the background rate in the general population, there are few well-controlled studies to date evaluating quinine in pregnant women.180,183,186

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, especially in pregnant women.180,183,186 In one study in women in the third trimester of pregnancy with severe P. falciparum malaria who received IV quinine dihydrochloride (no longer available in the US either commercially or from the Parasitic Diseases Drug Service of the CDC) in the recommended dosage, there was no apparent adverse effect on the fetuses; however, these women appeared to be particularly susceptible to the hypoglycemic effects of quinine.116

There is no evidence to date that quinine causes uterine contractions at dosages recommended for the treatment of malaria.180,183,186 However, doses severalfold higher than those used to treat malaria may stimulate the pregnant uterus.180,183,186

Quinine crosses the placenta resulting in measurable blood concentrations in the fetus.180,183,186 In a small number of women who delivered live infants 1-6 days after starting quinine therapy, placental cord plasma quinine concentrations were 1-4.6 mg/L (mean: 2.4 mg/L) and the mean ratio of cord plasma to maternal plasma quinine concentrations ranged from 0.18-0.46 mg/L (within 1 standard deviation).180,183,186 Such placental cord plasma quinine concentrations may not result in therapeutic fetal plasma quinine concentrations.180,183,186 If congenital malaria is suspected, the infant should be evaluated after delivery and treated with antimalarial agents if appropriate.180,183,186

Animal developmental studies have been conducted in multiple species using subcutaneous or IM quinine dosages similar to the maximum recommended human dosage (MRHD) of 32 mg/kg daily based on body surface area (BSA) comparisons.180,183,186 Teratogenic and fetotoxic effects were observed in rabbits (e.g., death in utero, degenerated auditory nerve and spiral ganglion, CNS anomalies [anencephaly, microcephaly]), dogs (e.g., death in utero), and guinea pigs (e.g., hemorrhage, mitochondrial change in cochlea).180,183,186 There were no teratogenic effects observed in rats or monkeys given the drug at dosages corresponding to 1 or 2 times the MRHD, respectively.180,183,186 In a pre- postnatal study in rats, oral quinine sulfate at a dosage corresponding to approximately 0.1 times the MRHD based on BSA comparison resulted in offspring with impaired growth, lower body weights at birth and during the lactation period, and delayed physical development of teeth eruption and eye opening during the lactation period.180,183,186

Deafness and optic nerve hypoplasia have been reported rarely in children exposed in utero when the mother received high-dose quinine therapy during pregnancy.180,183,186 Quinine reportedly has caused congenital malformations in humans when used in large doses (up to 30 g) for attempted abortion. Deafness related to auditory nerve hypoplasia was reported in about half of these cases; limb anomalies, visceral defects, and visual changes have also been reported. No clinically important difference in the rate of stillbirths at greater than 28 weeks of gestation was reported in women in Thailand with P. falciparum malaria treated with 10 mg/kg of quinine orally 3 times daily for 7 days during various stages of pregnancy (1.6%) compared with the rate of stillbirths reported in women without malaria or treatment with antimalarial agents during pregnancy (1.8%).180,183,186 In addition, the overall rate of congenital malformations (1.4%) was similar in pregnant women who received quinine compared with the rate observed in those who did not receive the drug (1.7%), and the rate of spontaneous abortion was higher in the women without malaria or treatment with antimalarial agents during pregnancy (10.9%) than in women treated with quinine during gestation (3.5%).180,183,186 There was no increased risk of structural birth defects reported in an epidemiologic survey that included 104 mother-child pairs exposed to quinine during the initial 4 months of gestation.180,183,186

Malaria infection in pregnant women is associated with high risks of both maternal and perinatal morbidity and mortality.143,180,183,186 Pregnant women with P. falciparum malaria have an increased incidence of fetal loss (e.g., spontaneous abortion, stillbirth), preterm labor and delivery, intrauterine growth retardation, low birth weight, and maternal death.180,183,186 Therefore, prompt treatment of malaria during pregnancy is important.180,183,186

Fertility

Data from a study in 5 men receiving quinine (600 mg 3 times daily for 1 week) indicate that sperm motility was decreased and the percentage of sperm with abnormal morphology was increased.180,183,186

Animal studies indicate that quinine produces testicular toxicity (e.g., atrophy or degeneration of seminiferous tubules, decreased sperm count and motility, decreased testosterone concentrations in serum and testes) when given intraperitoneally in mice or IM in rats at dosages corresponding to approximately 0.75 or 0.05 times the MRHD of 32 mg/kg daily, respectively, based on BSA comparisons.180,183,186 There was no effect on testes weight in mice or rats receiving oral dosages corresponding to approximately 1.2 or 3.5 times the MRHD, respectively, based on BSA comparisons.180,183,186

Lactation

Although quinine generally is considered compatible with breast-feeding, the risks and benefits to the infant and mother should be assessed and the drug should be used with caution in nursing women.180,183,186

Data to date are limited regarding the safety of quinine in breast-fed infants.180,183,186 In a single study of nursing women who received 10 mg/kg of quinine orally every 8 hours for 1-10 days, there was no evidence of infant toxicity.180,183,186 Estimates from this study indicate that breast-fed infants are exposed to less than 2-3 mg of quinine base (less than 0.4% of the maternal dose) daily through breast milk.180,183,186 (See Pharmacokinetics: Distribution.)

Plasma quinine concentrations may not be therapeutic in infants of nursing mothers receiving quinine.180,183,186 If malaria is suspected in the infant, appropriate evaluation and treatment should be provided.180,183,186

Drugs That Prolong the QT Interval

Because quinine prolongs the QT interval, an additive effect on the QT interval might occur if the drug is administered with other agents that prolong the QT interval.180,183,186 The manufacturers state that quinine should not be used concomitantly with other drugs known to cause QT interval prolongation, including class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide) and class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide).180,183,186 (See Cautions: Cardiovascular Effects.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vivo drug interaction studies suggest that quinine may inhibit the metabolism of drugs that are substrates of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) and CYP2D6.180,183,186

Quinine may inhibit the metabolism of other drugs known to cause QT interval prolongation that are substrates for CYP3A4, including astemizole and terfenadine (drugs no longer commercially available in the US), cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, halofantrine (an antimalarial not available in the US), or quinidine.159,161,163,180,183,186 Concurrent use of quinine with these drugs or any other drugs that are CYP3A4 substrates and have the potential to cause QT interval prolongation should be avoided.180,183,186 Elevated plasma astemizole concentrations were reported in a patient receiving chronic therapy with 10 mg of astemizole daily who developed torsades de pointes after receiving 3 doses of quinine for nocturnal leg cramps.180,183,186 During postmarketing surveillance, adverse cardiac effects that included cardiac arrest, ventricular tachycardia, syncope, and torsades de pointes were reported in at least one patient receiving terfenadine and quinine as components of multiple-drug therapy.161 Although not studied clinically, in vitro using human liver microsomes indicate that quinine inhibits the metabolism of halofantrine.180,183,186 The concurrent use of quinine sulfate and halofantrine may result in electrocardiographic abnormalities, including QT interval prolongation, and increase the risk for torsades de pointes or other serious ventricular arrhythmias.180,183,186

Quinine may affect the pharmacokinetics of drugs that are CYP2D6 substrates.180,183,186 There is evidence that quinine decreased the metabolism of desipramine (a CYP2D6 substrate) in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers.180,183,186 (See Drug Interactions: Desipramine.) Although low doses of quinine (80-400 mg) did not significantly affect the pharmacokinetics of some other CYP2D6 substrates (debrisoquine, dextromethorphan, methoxyphenamine),180,183,186 it is possible that higher quinine doses (600 mg or more) may inhibit the metabolism of these and other CYP2D6 substrates (e.g., flecainide, metoprolol, paroxetine).180,183,186 Patients receiving quinine concomitantly with drugs that are CYP2D6 substrates should be monitored closely for adverse effects of these drugs.180,183,186

Drugs Affecting or Affected by P-glycoprotein Transport

Quinine is a substrate for and an inhibitor of P-glycoprotein, and has the potential to affect the transport of drugs that are P-glycoprotein substrates.180,183,186

Antacids

Concomitant use of antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine.180,183,186 Concomitant use of such antacids with quinine should be avoided.180,183,186

Anticoagulants

Cinchona alkaloids, including quinine, may depress the hepatic synthesis of vitamin K-dependent coagulation factors, and the resulting hypoprothrombinemic effect may enhance the action of warfarin and other oral anticoagulants.180,183,186 In patients receiving these anticoagulants and concomitant therapy with quinine, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalized ratio (INR) should be closely monitored as indicated.180,183,186

Quinine may interfere with the anticoagulant action of heparin.180,183,186

Anticonvulsants

Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults, increases in the mean peak plasma concentration and area under the concentration-time curve (AUC) of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) were observed; pharmacokinetics of a single oral dose of phenytoin (200 mg) were not affected.180,183,186 Increases in the mean AUC of carbamazepine, phenobarbital, and phenytoin were 104, 81, and 4%, respectively, and mean increases in peak plasma concentration were 56, 53, and 4%, respectively.180,183,186 Mean urinary recoveries of these anticonvulsant agents over 24 hours were also profoundly increased by quinine.180,183,186 In addition, carbamazepine, phenobarbital, and phenytoin are inducers of CYP3A4 and may decrease quinine plasma concentrations if used concomitantly with quinine.180,183,186

If concomitant therapy with carbamazepine or phenobarbital cannot be avoided, anticonvulsant drug concentrations should be monitored frequently and the patient monitored closely for anticonvulsant adverse effects.180,183,186

Antifungal Agents

Although ketoconazole is an inhibitor of CYP3A4, quinine dosage adjustment is not required in patients receiving the drugs concomitantly; however, patients should be monitored closely for adverse effects associated with quinine.180,183,186 In a crossover study following oral administration of a single 500-mg dose of quinine hydrochloride (not commercially available in the US) used concomitantly with ketoconazole (100 mg twice daily for 3 days), the mean quinine AUC was increased by 45% and the clearance of quinine was decreased by 31% compared with that observed after quinine alone.180,183,186

Antilipemic Agents

Concomitant use of quinine and atorvastatin may increase plasma concentrations of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor and increase the risk of myopathy or rhabdomyolysis.180,183,186 Rhabdomyolysis with acute renal failure secondary to myoglobinuria was reported in a patient taking atorvastatin who received a single dose of quinine.180,183,186

If concomitant use of quinine and atorvastatin or other HMG-CoA reductase inhibitors that are CYP3A4 substrates (e.g., simvastatin, lovastatin) is being considered, the potential benefits and risks of each drug should be carefully weighed.180,183,186 If the drugs are used concomitantly, lower starting and maintenance dosages of the antilipemic agent should be considered and the patient monitored closely for signs or symptoms of muscle pain, tenderness, or weakness, especially during initial therapy.180,183,186 The HMG-CoA reductase inhibitor should be discontinued if plasma creatine kinase (CK, creatine phosphokinase, CPK) concentrations are markedly elevated or if myopathy (defined as muscle aches or weakness in conjunction with CPK concentrations more than 10 times the upper limit of normal) is diagnosed or suspected.180,183,186

Antimalarial Agents

Mefloquine

Concomitant use of mefloquine and quinine may result in potentially serious electrocardiographic (ECG) abnormalities, including prolonged QT interval corrected for rate (QT_c), and may increase the risk for torsades de pointes or other serious ventricular arrhythmias.145,180,183,186 (See Cautions: Cardiac Effects.) Concomitant use may also increase the risk of seizures.145,180,183,186

In healthy adults who received 750 mg of mefloquine 24 hours before 600 mg of oral quinine sulfate, the AUC of mefloquine was increased by 22% compared with that observed in those who received mefloquine alone and the QT_c was prolonged to a clinically important extent.180,183,186

Mefloquine should not be used concomitantly with quinine,134 and the drugs should be used sequentially with caution.134 Because mefloquine has a long terminal elimination half-life (see Pharmacokinetics: Elimination, in Mefloquine 8:30.08), quinine therapy for treatment of severe malaria should be initiated with caution in patients who were receiving mefloquine for prophylaxis.134 If quinine is used for initial treatment of severe malaria, mefloquine should not be administered for follow-up treatment until at least 12 hours after the last quinine dose.145

Antimycobacterial Agents

Isoniazid

Pretreatment for 7 days with 300 mg of isoniazid daily did not result in clinically important alterations in the pharmacokinetics of quinine.180,183,186 Quinine dosage adjustment is not required in patients receiving concomitant isoniazid.180,183,186

Rifampin

Rifampin is an inducer of CYP3A4 and plasma concentrations of quinine are decreased in patients receiving concomitant therapy with rifampin.180,183,186 In patients with uncomplicated P. falciparum malaria receiving concomitant therapy with 10 mg/kg of quinine sulfate and 15 mg/kg of rifampin daily for 7 days, the median AUC of quinine between days 3 and 7 of therapy was 75% lower compared to that observed in patients receiving quinine alone.180,183,186 Healthy adults pretreated with 600 mg of rifampin daily for 14 days and then given a single oral 600-mg dose of quinine sulfate experienced a decrease in the mean AUC and peak plasma concentration of quinine of 85 and 55%, respectively.180,183,186

Because reduced quinine concentrations may result in treatment failures, concomitant therapy with rifampin should be avoided.180,183,186

Antiretroviral Agents

Nevirapine

Concomitant use of quinine and nevirapine decreases the AUC, peak plasma concentration, and elimination half-life of quinine and increases the AUC and peak plasma concentration of 3-hydroxyquinine, the major metabolite of quinine.190 Adjustment of quinine dosage may be necessary in patients receiving nevirapine.190

Ritonavir

Compared with administration of quinine alone, administration of a single 600-mg dose of quinine sulfate in healthy individuals who were receiving ritonavir (200 mg every 12 hours) resulted in an increased quinine mean elimination half-life (11.2 hours versus 13.4 hours) and a fourfold increase in quinine peak plasma concentrations and AUC;180,183,186 concomitant administration of the drugs did not have a clinically important effect on ritonavir pharmacokinetics.180,183,186

The manufacturers of quinine state that concomitant use with ritonavir should be avoided.180,183,186 If the drugs are used concomitantly, the manufacturer of ritonavir states that quinine dosage may need to be reduced.203

Cholestyramine

Quinine pharmacokinetics were not altered in healthy adults who received concomitant therapy with 600 mg of quinine sulfate and 8 grams of cholestyramine.180,183,186

Cigarette Smoking

When a single dose of quinine (600 mg) was given to healthy males who were heavy cigarette smokers, mean quinine AUC was 44% lower, mean peak quinine plasma concentration was 18% lower, and the elimination half-life of the drug was shorter (7.5 hours versus 12 hours) compared with results attained in nonsmokers.180,183,186 In malaria patients who received a 7-day regimen of quinine, median quinine AUC was 25% lower and median peak quinine plasma concentration was 16.5% lower in cigarette smokers.180,183,186 The manufacturers of quinine suggest that reduced clearance of quinine in patients with acute malaria (see Pharmacokinetics: Elimination) could have diminished the metabolic induction effect of smoking.180,183,186

The manufacturers state that smoking does not appear to influence the therapeutic outcome in malaria patients, and quinine dosage does not need to be increased when treating acute malaria in heavy cigarette smokers.180,183,186

Desipramine

Desipramine is a substrate of CYP2D6.180,183,186 Quinine (750 mg daily for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers.180,183,186 Patients receiving quinine concomitantly with desipramine should be monitored closely for desipramine adverse effects.180,183,186

Digoxin

In 4 healthy adults receiving digoxin (0.5-0.75 mg daily) concomitantly with quinine (750 mg daily), a 33% increase in mean steady-state AUC of digoxin and a 35% reduction in steady-state biliary clearance of digoxin were observed compared to that observed in adults receiving digoxin alone.180,183,186 Plasma concentrations of digoxin should be closely monitored in patients receiving quinine and the digoxin dose adjusted, as necessary.180,183,186

Grapefruit Juice

Administration of a single 600-mg dose of quinine sulfate with grapefruit juice (full-strength or half-strength) in healthy adults did not alter the pharmacokinetics of quinine; therefore, the drug may be taken with grapefruit juice.180,183,186

Histamine H2-Receptor Antagonists

Cimetidine, but not ranitidine, has reduced the clearance and prolonged the elimination half-life of quinine sulfate in healthy adults,125,126,180,183,186 probably via cimetidine-induced inhibition of hepatic microsomal enzyme systems.125,126,183,186 Healthy adults given a single oral 600-mg dose of quinine sulfate following 7 days of pretreatment with cimetidine (200 mg 3 times daily and 400 mg at bedtime) experienced a decrease in the clearance and an increase in the mean elimination half-life of quinine; however, such effects on quinine pharmacokinetics were not observed following 7 days of pretreatment with ranitidine (150 mg twice daily).180,183,186 The mean AUC of quinine in adults receiving cimetidine or ranitidine pretreatment increased by 42 or 20%, respectively, compared with that in healthy adults not receiving such pretreatment; peak plasma quinine concentration was not altered.180,183,186

In patients receiving quinine who require concomitant therapy with a histamine H₂-receptor antagonist, ranitidine is preferred.180,183,186 If cimetidine is used concomitantly with quinine, patients should be monitored closely for quinine adverse effects.125,126,180,183,186

Macrolides

Because macrolide antibiotics inhibit CYP3A4, concurrent use of these drugs with quinine could result in increased quinine plasma concentrations.180,183,186 In vitro studies using human liver microsomes indicate that erythromycin inhibits the metabolism of quinine.180,183,186 Concomitant use of erythromycin with quinine is likely to result in increased plasma quinine concentrations.180,183,186 The use of macrolide antibiotics, including erythromycin, should be avoided in patients receiving quinine sulfate.180,183,186 Although a causal relationship between a specific drug and fatal arrhythmia was not established, fatal torsades de pointes has been reported in a geriatric patient who was receiving concomitant therapy with quinine, erythromycin, and dopamine.180,183,186

Concomitant use of quinine and troleandomycin (not commercially available in the US), another macrolide antibiotic, also has been shown to increase quinine exposure; such concomitant therapy should be avoided.180,183,186 In healthy adults receiving a single oral 600-mg dose of quinine sulfate and troleandomycin (500 mg every 8 hours), mean quinine AUC was increased by 87%, quinine clearance was decreased by 45%, and formation of the main quinine metabolite, 3-hydroxyquinine, was decreased by 81% compared with that observed when quinine was given alone.180,183,186

Midazolam

In 23 healthy individuals, quinine sulfate in a dosage of 324 mg every 8 hours for 7 days did not induce the metabolism of a single 2-mg dose of midazolam.180,183,186

Neuromuscular Blocking Agents

The use of neuromuscular blocking agents should be avoided in patients receiving quinine sulfate.180,183,186 Potentiated neuromuscular blockade (e.g., respiratory depression, apnea) has been reported in at least one patient who received quinine (1800 mg daily) 3 hours after having received intraoperative pancuronium.180,183,186 Although there have been no reports to date of similar respiratory difficulties with concurrent use of quinine and succinylcholine or tubocurarine (not commercially available in the US), quinine may also potentiate neuromuscular blockade when used with these neuromuscular blocking agents.180,183,186

Oral Contraceptives

The pharmacokinetics of a single 600-mg dose of quinine sulfate was similar in a small number of healthy females receiving concomitant oral contraceptive therapy (progestin alone or estrogen in combination with progestin) compared with age-matched females receiving quinine alone.180,183,186

Tetracycline

Tetracycline may be used concomitantly with quinine; however, patients should be closely monitored for adverse effects associated with quinine.180,183,186 Patients with acute uncomplicated P. falciparum malaria who received quinine sulfate (600 mg orally every 8 hours for 7 days) in conjunction with tetracycline (250 mg orally every 6 hours for 7 days) had mean plasma quinine concentrations twofold higher than those observed in patients receiving quinine alone.180,183,186

Theophyllines

Theophylline and aminophylline are substrates of CYP1A2.180,183,186 In healthy individuals receiving quinine sulfate in a dosage of 648 mg every 8 hours for 7 days, a single 300-mg dose of theophylline increased quinine AUC and peak plasma concentrations by 14 and 13%, respectively, and decreased the theophylline AUC by 10%.180,183,186 Although quinine dosage does not need to be adjusted in patients receiving concomitant therapy with theophylline or aminophylline, patients should be monitored closely for quinine adverse effects and plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations.180,183,186

Urinary Alkalizers

Increased plasma concentrations of quinine may result if agents that increase urinary pH (e.g., sodium bicarbonate, acetazolamide) are administered during quinine therapy.180,183,186

Laboratory Test Interferences

Urinary Steroids and Catecholamines

Quinine causes falsely elevated results for urinary 17-hydroxycorticosteroids when a modification of the Reddy-Jenkins-Thorn procedure is used, but apparently does not affect the modified Porter-Silber method. Quinine also causes falsely elevated results for 17-ketogenic steroids when the Zimmermann method is used.180,183,186

Quinine interferes with the Sobel and Henry modification of the trihydroxyindole method for determining urinary catecholamines, resulting in falsely increased concentrations.

Acute Toxicity

Manifestations

Overdosage of quinine may be associated with serious complications, including visual impairment, hypoglycemia, cardiac arrhythmias, and death.180,183,185,186 Visual impairment may range from blurred vision and defective color perception to visual field constriction and permanent blindness.104,113,180,183,186,193 Virtually all patients with quinine overdosage develop cinchonism with manifestations ranging from headache, nausea, vomiting, abdominal pain, diarrhea, tinnitus, vertigo, hearing impairment, sweating, flushing, and blurred vision to deafness, blindness, serious cardiac arrhythmias, hypotension, and circulatory collapse.180,183,185,186 CNS toxicity (e.g., drowsiness, disturbances of consciousness, ataxia, convulsions, respiratory depression, coma) also has been reported.180,183,186 In addition, pulmonary edema and adult respiratory distress syndrome have been reported with quinine overdosage.180,183,186

Most toxic effects of quinine are dose related, although idiosyncratic reactions also occur as a result of variation in patient sensitivity to the drug's toxic effects.180,183,185,186 The lethal dose of quinine has not been clearly defined; however, fatalities have been reported in adults after the ingestion of 2-8 g.127,133,180,183,186

Quinine, like quinidine, has class I antiarrhythmic effects.180,183,186 Quinine cardiotoxicity is a result of the drug's negative inotropic effect and its effect on cardiac conduction that result in decreases in the rates of depolarization and conduction and increases in action potential and effective refractory period.180,183,186 Electrocardiogram (ECG) changes have been observed with overdosage of quinine, including sinus tachycardia, PR prolongation, T wave inversion, bundle branch block, prolongation of the QT interval, and widening of the QRS complex.180,183,186 Quinine's α-blocking properties may result in hypotension and additional myocardial depression via decreased coronary perfusion.180,183,186 Overdosage of quinine also has been associated with hypotension, cardiogenic shock, and circulatory collapse, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, and torsades de pointes; as well as bradycardia and atrioventricular block. 180,183,186

Treatment

Quinine is rapidly absorbed, and attempts to remove residual quinine from the stomach by gastric lavage may not be effective.180,183,186 Multiple-dose activated charcoal has been shown to decrease plasma quinine concentrations.180,183,186 (See Pharmacokinetics: Elimination.)

Forced acid diuresis, hemodialysis, charcoal column hemoperfusion, and plasma exchange were not found to be effective in significantly increasing quinine elimination in a case series of overdosages of quinine.180,183,186

Mechanism of Action

Although the exact mechanism of antimalarial activity of quinine sulfate has not been determined, the drug inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes.180,183,186

Quinine has several effects on skeletal muscle. Quinine increases the tension response to a single maximum stimulus to muscle which is received either directly or through a nerve; however, the drug increases the refractory period of the muscle by a direct action on the muscle fiber so that the response to tetanic stimulation is diminished. Quinine has a curare-like effect and decreases the excitability of the motor endplate so that responses to repetitive nerve stimulation or acetylcholine are reduced. The drug also appears to affect the distribution of calcium within muscle fiber.

Quinine has a local anesthetic action and analgesic, antipyretic, and oxytocic effects. Quinine also has cardiovascular effects similar to those of quinidine.

Spectrum

Quinine is a blood schizonticidal agent and is active against the asexual erythrocytic forms of Plasmodium falciparum ,180,183,186 P. malariae , P. ovale , and P. vivax .189 The drug is not active against sporozoites or pre-erythrocytic or exoerythrocytic forms of plasmodia.180,183,186 Quinine is not gametocidal against P. falciparum .180,183,186

Resistance

Plasmodium falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.180,183,186 Strains of P. falciparum with decreased susceptibility to quinine also can be selected in vivo.180,183,186 Cross-resistance has been reported between mefloquine and quinine.145 Although cross-resistance has been demonstrated between quinine and 4-aminoquinoline derivatives (chloroquine, hydroxychloroquine), quinine may be active against some strains of P. falciparum that are resistant to chloroquine.

Pharmacokinetics

Absorption

Oral bioavailability of quinine is 76-88% in health adults.180,183,186 Quinine exposure is higher in patients with malaria than in healthy adults,180,183,186 possibly because malaria may cause impaired hepatic function, which results in decreased total body clearance of quinine and decreased volume of distribution of the drug.106,107,183,186

Following a single oral dose of quinine sulfate capsules in healthy adults (648 mg [approximately 8.7 mg/kg]) or patients with uncomplicated Plasmodium falciparum malaria (10 mg/kg), the mean time to peak quinine plasma concentrations was longer (5.9 versus 2.8 hours) and the mean area under the plasma concentration-time curve (AUC) and mean peak plasma concentrations (8.4 versus 3.2 mcg/mL) were higher in patients with uncomplicated P. falciparum malaria than in the healthy adults.180,183,186

The pharmacokinetics of quinine in children 1.5-12 years of age with uncomplicated P. falciparum malaria appear to be similar to that observed in adults with uncomplicated malaria.180,183,186 Following oral administration of a single dose of 10 mg/kg of quinine sulfate in healthy children or children 1.5-12 years of age with uncomplicated P. falciparum malaria, the mean time to peak quinine concentration was longer (4 versus 2 hours) and the mean peak plasma concentration was higher (7.5 versus 3.4 mcg/mL) in children with uncomplicated P. falciparum malaria than in the healthy children.180,183,186

Following oral administration of a single 600-mg dose of quinine sulfate in healthy geriatric adults 65-78 years of age, the mean AUC was approximately 38% higher than in younger adults 20-35 years of a 180,183,186 the mean time to peak quinine concentrations and mean peak quinine plasma concentrations were similar in both age groups.180,183,186 There were no differences in the rate and extent of absorption or clearance of quinine sulfate between geriatric adults 65-78 years of age and younger adults 20-39 years of age following a single 648-mg oral dose of the drug or at steady-state following a dosage of 648 mg 3 times daily for 7 days.180,183,186

Following oral administration of a single 600-mg dose of quinine sulfate in adults with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine 9.6 mg/dL) and adults with normal renal function (mean serum creatinine 1 mg/dL), the median AUC and mean peak plasma concentration were increased by 195 and 79%, respectively, in the adults with severe chronic renal failure.180,183,186 The effect of mild or moderate renal impairment on the pharmacokinetics of quinine sulfate has not been determined to date.180,183,186 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Following oral administration of a single 600-mg dose of quinine sulfate in otherwise healthy adults with moderate hepatic impairment (Child-Pugh class B), the mean AUC was increased by 55% compared with that in healthy adults with normal hepatic function; mean peak plasma concentrations were similar in both groups.180,183,186 Quinine absorption is prolonged in adults with hepatitis.180,183,186

When a single 324-mg oral dose of quinine sulfate capsules was administered with a high-fat meal in healthy adults, the time to peak concentrations was prolonged to approximately 4 hours; however, the mean peak plasma concentration and AUC from 0-24 hours were similar to those achieved following oral administration of the drug under fasted conditions.180,183,186 Although quinine sulfate may be administered without regard to meals, the manufacturers recommend that the drug be taken with food to minimize possible GI irritation.180,183,186 (See Dosage and Administration: Administration.)

Distribution

Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults, the mean volume of distribution ranged from 2.5-7.1 L/kg.180,183,186 The volume of distribution of quinine is lower in patients with malaria than in healthy individuals or patients convalescing from malaria.106 The volume of distribution decreases with increasing severity of malarial infection.180,183,186 In one study, the volume of distribution of the drug averaged 1.2-1.7 L/kg in adults with cerebral or moderate malaria and 2.7 L/kg in convalescing adults.106

Following oral administration of a single dose of 10 mg/kg of quinine sulfate in healthy children or pediatric patients 1.5-12 years of age with uncomplicated P. falciparum , the volume of distribution of quinine is reduced in those with malaria compared with that observed in healthy children (0.87 versus 1.43 L/kg).180,183,186 In children 1-12 years of age, the volume of distribution of quinine reportedly averages 0.8 L/kg in those with moderate malaria compared with 1.1 L/kg in convalescing children.106

Intra-erythrocytic quinine concentrations are approximately 30-50% of plasma concentrations.180,183,186 Small amounts of the drug are distributed into bile and saliva.

Quinine penetrates relatively poorly into the CSF in patients with cerebral malaria;180,183,186 CSF quinine concentrations are reported to be 2-7% of concurrent plasma concentrations of the drug.106,107,180,183,186

Quinine readily crosses the placenta180,183,186 and is distributed into milk.180,183,186 In one study, quinine concentrations in placental cord blood and breast milk were approximately 32 and 31%, respectively, of maternal plasma quinine concentrations.180,183,186 The estimated total amount of quinine distributed into breast milk daily was less than 2-3 mg.180,183,186 (See Cautions: Pregnancy, Fertility, and Lactation.)

Quinine is approximately 69-92% bound to plasma proteins in healthy adults.106,180,183,186 During active malarial infection, protein binding of quinine is increased to 78-95%, which correlates with increases in α-1-acid glycoprotein that occur during malarial infection.180,183,186 In one study, quinine was approximately 93% bound to plasma proteins in patients with cerebral malaria and approximately 90% bound in patients with uncomplicated malaria or in patients convalescing from the disease.106

Elimination

Quinine sulfate is metabolized almost exclusively via hepatic oxidative cytochrome P-450 (CYP) pathways into 4 primary metabolites (3-hydroxyquinine, 2'-quinone, O -desmethylquinine, and 10,11-dihydroxydihydroquinine) and 6 secondary metabolites resulting from further biotransformation of the primary metabolites.180,183,186 The major metabolite, 3-hydroxyquinine, is less active than the parent drug.180,183,186

In vitro studies indicate quinine is metabolized principally by CYP isoenzyme 3A4 (CYP3A4).180,183,186 Other CYP enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, also may play a role in metabolism of the drug.180,183,186 Concurrent use of drugs that inhibit or induce CYP3A4 may result in increased or decreased plasma quinine concentrations, respectively.180,183,186 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Approximately 20% of quinine is excreted unchanged in urine.180,183,186 Reabsorption of quinine is increased when urine is alkaline; the rate of renal excretion of the drug is doubled when the urine is acidic compared to when the urine is alkaline.180,183,186

Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults, the mean plasma clearance was 0.08-0.47 L/hour per kg (median: 0.17 L/hour per kg) and the mean plasma elimination half-life was 9.7-12.5 hours.180,183,186 Following oral administration of 10 mg/kg of quinine sulfate in patients with uncomplicated malaria, mean total clearance of quinine was decreased (approximately 0.09 L/hour per kg) during the acute phase of the infection and increased (approximately 0.16 L/hour per kg) during the recovery or convalescent phase.180,183,186 The plasma elimination half-life of quinine reportedly averages 8-21 hours in adults with malaria and 7-12 hours in healthy or convalescing adults.106,107

Following oral administration of a single dose of 10 mg/kg of quinine sulfate in healthy children or pediatric patients 1.5-12 years of age with uncomplicated P. falciparum malaria, the mean total clearance (0.06 versus 0.3 L/hour per kg) is reduced and the plasma elimination half-life increased (12.1 versus 3.21 hours) in pediatric patients with malaria as compared to that observed in healthy children.180,183,186 In children 1-12 years of age, the plasma elimination half-life of quinine reportedly averages 11-12 hours in those with malaria and 6 hours in those convalescing from the disease.106

Following oral administration of a single 600-mg dose of quinine sulfate in geriatric and younger adults, the mean clearance of the drug was decreased (0.06 versus 0.08 L/hour per kg) and the mean elimination half-life was significantly increased (18.4 versus 10.5 hours) in geriatric adults compared with younger adults.180,183,186 Although renal clearance of quinine was similar in geriatric and younger adults, geriatric adults excreted a larger proportion of the dose in urine as unchanged drug compared with younger adults (16.6 versus 11.2%).180,183,186 The steady-state pharmacokinetics after a quinine sulfate dosage of 648 mg 3 times daily for 7 days were similar in healthy geriatric adults 65-78 years of age and healthy younger adults 20-39 years of a however, the mean elimination half-life was 24 hours in the geriatric individuals compared with 20 hours in the younger adults.180,183,186

Following oral administration of a single 600-mg dose of quinine sulfate in adults with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine 9.6 mg/dL) and adults with normal renal function (mean serum creatinine 1 mg/dL), the mean plasma half-life was prolonged (26 versus 9.7 hours) in those with severe chronic renal impairment compared with those with no renal impairment.180,183,186 The effects of mild and moderate renal impairment on the pharmacokinetics and safety of quinine sulfate have not been determined to date.180,183,186 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

In otherwise healthy individuals with mild hepatic impairment (Child-Pugh class A) who received a single 500-mg dose of quinine sulfate, the pharmacokinetics of quinine and exposure to the major metabolite (3-hydroxyquinine) were similar to those reported for healthy individuals with normal hepatic function.180,183,186 In individuals with severe hepatic impairment (Child-Pugh class C), oral clearance of the drug and formation of the major metabolite (3-hydroxyquinine) were decreased and the volume of distribution and plasma elimination half-life were increased.180,183,186 In individuals with hepatitis, the apparent volume of distribution and elimination half-life are increased, but weight-adjusted clearance is not altered.180,183,186 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults who received four 50 g-doses of activated charcoal (the first dose of activated charcoal was given 4 hours after the oral quinine dose, with 3 additional doses given over the next 12 hours), the mean quinine elimination half-life decreased from 8.2 to 4.6 hours and the mean quinine clearance increased by 56% (from 11.8 L/hour to 18.4 L/hour).180,183,186 In symptomatic patients with acute quinine poisoning given multiple-dose activated charcoal (50 grams every 4 hours), the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in such patients who did not receive activated charcoal.180,183,186 In patients with quinine poisoning, forced acid diuresis did not alter the half-life of quinine elimination (25.1 versus 26.5 hours) or the amount of unchanged quinine recovered in the urine when compared to patients who did not undergo such diuresis.180,183,186

Negligible to minimal amounts of quinine are removed by hemodialysis or hemofiltration.180,183,186 In individuals with chronic renal failure undergoing hemodialysis, only about 6.5% of quinine is removed following 1 hour of hemodialysis.180,183,186 In patients with chronic renal failure, plasma quinine concentrations are not affected during or shortly after hemofiltration.180,183,186

Chemistry and Stability

Chemistry

Quinine is an alkaloid obtained from the bark of the cinchona tree and is the levorotatory isomer of quinidine.185 Quinine is commercially available for oral use as the sulfate salt.180,183,186

Quinine sulfate occurs as a white, crystalline powder;180,183,186 the drug is odorless and has a persistent and very bitter taste.180,183,186 Quinine sulfate is only slightly soluble in water, alcohol, chloroform, and ether.180,183,186

Stability

Quinine sulfate capsules should be stored in a tight, light-resistant container at 20-25°C.180,183,186 Quinine sulfate darkens on exposure to light.180,183,186

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