Brand name: Qualaquin
Drug class: Antimalarials
VA class: AP101
Chemical name: (8S,9R)-6′-Methoxycinchonan-9-ol
Molecular formula: C₂₀H₂₄N₂O₂
CAS number: 60-93-5

Medically reviewed by Drugs.com on Feb 26, 2024. Written by ASHP.

Introduction

Antimalarial; alkaloid obtained from bark of the cinchona tree.¹⁸⁵

Uses for quiNINE

Treatment of Uncomplicated Malaria

Treatment of uncomplicated malaria caused by Plasmodium falciparum.^{134 143 144 180 183 186} Also used for treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax^{† [off-label]134 143 144 173} and treatment of uncomplicated malaria when plasmodial species not identified^{† [off-label]}.^{134 143 144 173}

Designated an orphan drug by FDA for treatment of malaria.¹⁷⁹ Since malaria is a life-threatening infection, FDA states that potential benefits of the drug outweigh associated risks and justify its use for treatment of malaria.¹⁸²

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or treatment of uncomplicated malaria when plasmodial species not identified, CDC recommends fixed combination of atovaquone and proguanil (atovaquone/proguanil), fixed combination of artemether and lumefantrine (artemether/lumefantrine), or regimen of quinine in conjunction with doxycycline, tetracycline, or clindamycin.^{143 144} If quinine regimen used, concomitant doxycycline or tetracycline generally preferred instead of concomitant clindamycin since more efficacy data exist regarding antimalarial regimens that include tetracyclines.¹⁴³

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

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax^{† [off-label]}, CDC recommends regimen of quinine 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, doxycycline (or tetracycline), atovaquone/proguanil, and mefloquine active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), 14-day regimen of primaquine indicated to prevent delayed primary attacks or relapse and provide a radical cure whenever any of these drugs used for treatment of P. vivax or P. ovale malaria.^{134 143}

Pediatric patients with uncomplicated malaria generally can receive same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.^{143 144} For treatment of uncomplicated chloroquine-resistant P. falciparum in children <8 years of age, atovaquone/proguanil or artemether/lumefantrine usually recommended; mefloquine can be considered if no other options available.¹⁴⁴ If a quinine regimen used in children <8 years of age, CDC states a 7-day regimen of quinine alone can be used (regardless of where infection was acquired) or quinine can be given in conjunction with clindamycin, since children <8 years of age generally should not receive tetracyclines.¹⁴³ In rare instances, doxycycline or tetracycline can be used in conjunction with quinine in children <8 years of age if other treatment options not available or not tolerated and if potential benefits of including a tetracycline outweigh risks.¹⁴³ For treatment of chloroquine-resistant P. vivax malaria in children <8 years of age, CDC recommends mefloquine given in conjunction with primaquine.^{143 144} Alternatively, if mefloquine 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 CDC recommends that pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum receive prompt treatment with mefloquine or a regimen of quinine and clindamycin;¹⁴³ mefloquine recommended for those with uncomplicated malaria caused by chloroquine-resistant P. vivax.¹⁴³ Although tetracyclines generally contraindicated in pregnant women, in rare circumstances when other treatment options not available or not tolerated and if potential benefits outweigh risks, CDC states that regimen of quinine and doxycycline (or tetracycline) may be used.¹⁴³ (See Pregnancy under Cautions.) Alternatively, atovaquone/proguanil or artemether/lumefantrine can be considered for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in pregnant women when other treatment options not available or not tolerated and if potential benefits outweigh risks.¹⁴³ Pregnant women with P. vivax or P. ovale malaria should receive chloroquine prophylaxis for the duration of the pregnancy and receive primaquine after delivery to provide a radical cure.^{143 144}

Assistance with diagnosis or treatment of malaria available from 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 CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.^{143 144}

Treatment of Severe Malaria

Used in conjunction with doxycycline, tetracycline, or clindamycin for follow-up treatment of severe or complicated malaria^†.^{143 144}

Severe malaria usually caused by P. falciparum and requires initial aggressive treatment with a parenteral antimalarial regimen initiated as soon as possible after diagnosis.^{143 144 200}

For treatment of severe malaria in adults and children, CDC recommends an initial regimen of IV quinidine in conjunction with doxycycline, tetracycline, or clindamycin (administered orally or IV as tolerated).^{143 144} After parasitemia reduced to <1% and oral therapy tolerated, IV quinidine can be discontinued and oral quinine initiated to complete 7 or 3 days of total quinidine and quinine therapy as determined by geographic origin of infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).^{143 144}

If IV quinidine unavailable or cannot be used for initial treatment because of adverse effects or contraindications, parenteral artesunate may be available from CDC under an investigational new drug (IND) protocol for emergency initial treatment of severe malaria.^{143 144}

Assistance with diagnosis or treatment of malaria and assistance obtaining quinidine or artesunate for treatment of severe malaria is available by contacting 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 CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.¹⁴³

Presumptive Self-treatment of Malaria

Regimen of quinine in conjunction with doxycycline has been recommended by some clinicians for presumptive self-treatment of malaria^† in travelers.¹³⁴

Not approved by FDA for presumptive self-treatment of malaria in travelers¹⁸⁰ and not recommended by CDC for such treatment.¹¹⁵

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

Prevention of Malaria

Not approved by FDA for prevention (prophylaxis) of malaria¹⁸⁰ and not included in current CDC recommendations for prevention of malaria.¹¹⁵

CDC and other clinicians recommend other antimalarials (e.g., chloroquine [or hydroxychloroquine], atovaquone/proguanil, doxycycline, mefloquine) for prevention of malaria caused by susceptible plasmodia.^{115 134}

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

Babesiosis

Treatment of babesiosis^† caused by Babesia microti.^{102 103 105 134 178 181}

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 Treatment not recommended initially for asymptomatic individuals, regardless of results of serologic examination, blood smears, or PCR, but should be considered if parasitemia persists for >3 months.¹⁷⁸

When anti-infective treatment of babesiosis indicated, IDSA and other clinicians recommend a regimen of quinine and clindamycin or a regimen of atovaquone and azithromycin.^{105 134 178 181}

The quinine and clindamycin regimen may be preferred for 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} Consider use of exchange transfusions, especially in severely ill patients with high levels of parasitemia (≥10%), significant hemolysis, or compromised renal, hepatic, or pulmonary function.^{105 134 178}

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} Consider possibility of coinfection with B. burgdorferi and/or A. phagocytophilum in patients who have severe or persistent symptoms despite appropriate anti-infective treatment for babesiosis.¹⁷⁸

Nocturnal Recumbency Leg Muscle Cramps

Not approved by FDA for the treatment or prevention of nocturnal leg cramps^†.^{180 182 185 187} Should not be used in the management of this or related conditions (e.g. restless legs syndrome^†).^{180 182 185 187 201}

Although quinine 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} 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 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 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} (See Cautions.) The known risks associated with the use of quinine, 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}

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, FDA ordered that marketing of all unapproved quinine preparations be discontinued as of December 11, 2006.¹⁸² (See Preparations.)

quiNINE Dosage and Administration

Administration

Quinine is administered orally as quinine sulfate.^{180 183 186}

Although quinine has been administered by slow IV infusion as quinine dihydrochloride, a parenteral preparation of the drug no longer available for use in the US, either commercially or from CDC.^{148 149} When parenteral antimalarial therapy indicated, use IV quinidine gluconate.^{148 149 143 144}

Oral Administration

Administer orally.^{180 183 186}

Take with food to minimize possible GI irritation.^{134 180 183 186}

Dosage

Available as quinine sulfate; dosage expressed in terms of the salt.^{180 183 186}

The only FDA-approved preparations of quinine currently commercially available in US are capsules containing 324 mg of quinine sulfate (Qualaquin, generic);^{180 183 186} the drug was previously available in US as capsules containing 325 mg.¹⁸⁵ This difference in quinine 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.^a

Pediatric Patients

Malaria

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

Oral

Children ≥8 years of age^†: 10 mg/kg 3 times daily for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).¹³⁴ Use in conjunction with a 7-day regimen of oral doxycycline, tetracycline, or clindamycin.^{134 144}

Children <8 years of age^†: If quinine regimen used, CDC states quinine monotherapy may be given for 7 days or quinine can be given in conjunction with clindamycin for the usually recommended duration.¹⁴³ In rare circumstances, a regimen of quinine and doxycycline or tetracycline can be considered.¹⁴³ (See Treatment of Uncomplicated Malaria under Uses.)

Do not exceed usual adult dosage.^{143 144}

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

Oral

Children ≥8 years of age^†: 10 mg/kg 3 times daily for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).¹³⁴ Do not exceed usual adult dosage.^{143 144}

Use in conjunction with 7-day regimen of oral doxycycline or tetracycline.^{134 144} A 14-day regimen of primaquine also indicated to provide a radical cure and prevent delayed attacks or relapse of P. vivax malaria.^{134 143 144}

Treatment of Severe Malaria†

Oral

10 mg/kg 3 times daily to complete 7 or 3 days of total IV quinidine and oral quinine therapy as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).¹⁹⁹ Do not exceed usual adult dosage.¹⁴³

IV quinidine gluconate must be used initially; after ≥24 hours and after parasitemia reduced to <1% and oral therapy tolerated, oral quinine may be substituted.¹⁴⁴

Use quinidine/quinine regimen in conjunction with 7-day regimen of doxycycline, tetracycline, or clindamycin (administered IV or orally as tolerated).¹⁴⁴

Presumptive Self-treatment of Malaria†

Oral

10 mg/kg 3 times daily for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere) given in conjunction with a 7-day regimen of oral doxycycline.¹³⁴

Not included in current CDC recommendations for presumptive self-treatment of malaria in travelers.¹¹⁵

Babesiosis†

Oral

IDSA recommends 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 30 mg/kg daily in 3 divided doses given for 7–10 days in conjunction with oral clindamycin (20–40 mg/kg daily in 3 divided doses for 7–10 days).¹³⁴

For mild to moderate babesiosis, clinical improvement should be evident within 48 hours after initiation of treatment and symptoms should resolve completely within 3 months.¹⁷⁸ Low-grade parasitemia may persist in some patients for months after completion of treatment.¹⁷⁸ Regardless of presence or absence of symptoms, IDSA suggests that retreatment be considered if babesial parasites or amplifiable babesial DNA detected in blood ≥3 months after initial treatment.¹⁷⁸

Adults

Malaria

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

Oral

Manufacturers recommend 648 mg every 8 hours for 7 days for P. falciparum malaria.^{180 183 186} Manufacturers caution that shorter regimens (3 days) have been used, but data regarding these regimens limited and they may be less effective than a 7-day regimen.^{180 183 186}

CDC and other clinicians recommend 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).^{134 144} Use in conjunction with 7-day regimen of oral doxycycline, tetracycline, or clindamycin.^{134 143 144}

Pregnant women: CDC recommends 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).¹⁴⁴ Use in conjunction with 7-day regimen of oral clindamycin.^{143 144} Alternatively, if benefits outweigh risks, used in conjunction with oral doxycycline or tetracycline.¹⁴⁴

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

Oral

650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).^{134 144} Use in conjunction with 7-day regimen of oral doxycycline or tetracycline.^{134 143} A 14-day regimen of primaquine also indicated to provide a radical cure and prevent delayed attacks or relapse of P. vivax malaria.^{134 143 144}

Pregnant women: CDC recommends 650 mg (two 324-mg capsules) every 8 hours for 7 days (regardless of where infection was acquired).¹⁴⁴ Used alone^{143 144} or, if benefits outweigh risks, used in conjunction with oral doxycycline or tetracycline.¹⁴⁴ Then, give chloroquine (300 mg [500 mg of chloroquine phosphate] once weekly) as prophylaxis for the duration of the pregnancy until primaquine can be given after delivery to provide a radical cure and prevent relapse.^{143 144}

Treatment of Severe Malaria†

Oral

650 mg (two 324-mg capsules) every 8 hours to complete 7 or 3 days of total IV quinidine and oral quinine therapy as determined by geographic origin of infecting parasite (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere).¹⁴⁴

IV quinidine gluconate must be used initially; after ≥24 hours and after parasitemia reduced to <1% and oral therapy tolerated, oral quinine may be substituted.¹⁴⁴

Use quinidine/quinine regimen in conjunction with 7-day regimen of doxycycline, tetracycline, or clindamycin (administered IV or orally as tolerated).¹⁴⁴

Presumptive Self-treatment of Malaria†

Oral

650 mg every 8 hours given for 7 or 3 days (7 days if malaria acquired in Southeast Asia or 3 days if acquired elsewhere) in conjunction with a 7-day regimen of oral doxycycline.¹³⁴

Not included in current CDC recommendations for presumptive self-treatment of malaria in travelers.¹¹⁵

Babesiosis†

Oral

IDSA and other clinicians recommend 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 mild to moderate babesiosis, clinical improvement should be evident within 48 hours after initiation of treatment and symptoms should resolve completely within 3 months.¹⁷⁸ Low-grade parasitemia may persist in some patients for months after completion of treatment.¹⁷⁸ Regardless of presence or absence of symptoms, IDSA suggests that retreatment be considered if babesial parasites or amplifiable babesial DNA detected in blood ≥3 months after initial treatment.¹⁷⁸

Prescribing Limits

Pediatric Patients

Treatment of Uncomplicated or Severe Malaria

Oral

Do not exceed usual adult dosage.^{143 144}

Babesiosis

Oral

Maximum 650 mg per dose.¹⁷⁸

Special Populations

Hepatic Impairment

Treatment of Uncomplicated Malaria

Mild to moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustment not necessary;^{180 183 186} monitor closely for adverse effects.^{180 183 186}

Severe hepatic impairment (Child-Pugh class C): Do not use.^{180 183 186} (See Hepatic Impairment under Cautions.)

Renal Impairment

Treatment of Uncomplicated Malaria

Severe chronic renal failure: 648-mg loading dose followed 12 hours later by maintenance doses of 324 mg given every 12 hours; dosage based on computer models.^{180 183 186}

Mild or moderate renal impairment: Safety and pharmacokinetics not determined to date.^{180 183 186}

Geriatric Adults

Treatment of Uncomplicated Malaria

Dosage adjustment not necessary.^{180 183 186}

Cautions for quiNINE

Contraindications

• Hypersensitivity to quinine.^{180 183 186}

• History of potential hypersensitivity reactions associated with previous quinine use, including (but not limited to) thrombocytopenia, TTP, idiopathic thrombocytopenic purpura (ITP), HUS, or blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia).^{180 183 186} (See Hypersensitivity Reactions under Cautions.)

• Hypersensitivity to mefloquine or quinidine.^{180 183 186} (See Hypersensitivity Reactions under Cautions.)

• Prolonged QT interval.^{180 183 186} (See QT Prolongation and Other Cardiovascular Effects under Cautions.)

• Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.^{180 183 186} (See G-6-PD Deficiency under Cautions.)

• Myasthenia gravis.^{180 183 186} (See Myasthenia Gravis under Cautions.)

• Optic neuritis.^{180 183 186}

Warnings/Precautions

Warnings

Use for Treatment or Prevention of Nocturnal Leg Cramps†

Quinine 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 HUS/TTP), and other serious adverse events (e.g., blindness, deafness) requiring medical intervention and hospitalization.^{180 183 184 185 186 187 193 201} Fatalities reported.^{180 183 185 186 201}

Quinine not approved by FDA for treatment or prevention of nocturnal leg cramps^†, and should not be used in the management of this or related conditions (e.g., restless legs syndrome^†).^{180 182 183 185 186 187 201} The known risks associated with use of quinine, in the absence of evidence of safety and efficacy of the drug for treatment or prevention of nocturnal leg cramps^†, outweigh any potential benefits for this benign, self-limiting condition.^{180 183 184 185 186 187}

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}

Because of serious safety concerns, 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 being prescribed for uses other than malaria, and 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 Hematologic Effects under Cautions.)

Hematologic Effects

Serious, life-threatening, and sometimes fatal hematologic reactions, including thrombocytopenia^{108 180 183 186 188 201} and HUS/TTP,^{180 201} have been reported in patients receiving quinine, especially those 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}

In 24 reported cases of serious hematologic reactions, median time to onset was approximately 2 weeks after initiation of quinine.²⁰¹ Most recovered when the drug was discontinued and other therapeutic interventions initiated, but there were 2 fatalities (one related to TTP and the other related to hemolysis).²⁰¹

If thrombocytopenia occurs, discontinue quinine since continued therapy puts patient at risk for fatal hemorrhage.^{180 183 186} Thrombocytopenia usually resolves within 1 week after quinine discontinued.¹⁸⁰ Quinine-induced thrombocytopenia is immune-mediated and re-exposure to quinine from any source may result in a more rapid and more severe course of thrombocytopenia compared to original episode.^{180 183 186}

QT Prolongation and Other Cardiovascular Effects

QT interval prolongation has been a consistent finding in studies evaluating ECG changes in individuals receiving oral or parenteral quinine and has occurred independent of age, clinical status, or disease severity.^{180 183 186} Maximal increases in QT interval correlate with peak plasma quinine concentrations.^{180 183 186}

Concentration-dependent prolongation of PR and QRS intervals also reported in patients receiving oral quinine.^{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, reported.^{180 183 186} At least 1 case of fatal ventricular arrhythmia reported in a geriatric patient with preexisting prolonged QT interval who received IV quinine sulfate for treatment of P. falciparum malaria.^{180 183 186}

Do not use in patients with known prolonged QT interval.^{180 183 186} Avoid use in patients with clinical conditions known to prolong the QT interval (e.g., uncorrected hypokalemia, bradycardia, certain cardiac conditions).^{180 183 186}

Use 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} Monitor closely if digoxin used to prevent a rapid ventricular response.^{180 183 186} (See Digoxin under Interactions.)

Do not use 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 Drugs That Prolong the QT Interval under Interactions.)

Avoid use with drugs that are CYP3A4 substrates and are known to cause QT prolongation (e.g., cisapride [available in the US only under a limited-use protocol], pimozide, halofantrine [not commercially available in the US], quinidine).^{180 183 186} (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

G-6-PD Deficiency

Potential for hemolysis and hemolytic anemia if used in patients with G-6-PD deficiency.^{180 183 186} Discontinue immediately if evidence of hemolysis occurs.^{180 183 186}

Do not use in patients with G-6-PD deficiency.^{180 183 186}

Myasthenia Gravis

Has neuromuscular blocking activity and may exacerbate muscle weakness if used in patients with myasthenia gravis.^{180 183 186}

Do not use in patients with myasthenia gravis.^{180 183 186}

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic shock, anaphylactoid reactions, urticaria, serious rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), angioedema, facial edema, bronchospasm, and pruritus, reported.^{180 183 185 186 191}

Other serious adverse reactions also reported and may be due to hypersensitivity, including thrombocytopenia, HUS/TTP, ITP, blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis.^{180 183 185 186 191 194 195} (See Hematologic Effects under Cautions.)

Cross-sensitivity to quinine has been documented in individuals hypersensitive to mefloquine or quinidine.^{180 183 186}

Discontinue quinine if there are signs or symptoms of hypersensitivity (rash, hives, severe itching, severe flushing, trouble breathing).^{180 183 186}

Photosensitivity Reactions

Photosensitivity reported.^{180 183 186 197}

General Precautions

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}

Hypoglycemia

Quinine stimulates release of insulin from the pancreas,^{180 183 186} and quinine-induced hypoglycemia has been reported.^{180 183 186 196}

Clinically important hypoglycemia may occur, especially in pregnant women.^{180 183 186}

Male Fertility

Decreased sperm motility and increased percentage of sperm with abnormal morphology reported from a study in 5 men receiving quinine (600 mg 3 times daily for 1 week).^{180 183 186} Testicular toxicity (e.g., atrophy or degeneration of seminiferous tubules, decreased sperm count and motility, decreased testosterone concentrations in serum and testes) reported in animals.^{180 183 186}

Specific Populations

Pregnancy

Category C.^{180 183 186}

Manufacturers states quinine should be used during pregnancy only if potential benefits justify potential risks to the fetus.^{180 183 186}

CDC recommends quinine and clindamycin as a regimen of choice for treatment of uncomplicated chloroquine-resistant P. falciparum malaria in pregnant women.^{143 144} (See Treatment of Uncomplicated Malaria under Uses.)

Crosses the placenta.^{180 183 186} Although quinine concentrations may be measurable in the fetus and cord blood of women who received the drug near the time of delivery (see Distribution under Pharmacokinetics), such concentrations may not be therapeutic for the fetus.^{180 183 186} If congenital malaria suspected, evaluate infant after delivery and treat with antimalarial agents if appropriate.^{180 183 186}

Deafness and optic nerve hypoplasia reported rarely in children exposed in utero when the mother received high-dose quinine therapy during pregnancy.^{180 183 186}

Although published data of >1000 pregnancies exposed to quinine (majority of exposures occurred after first trimester) have not shown an increase in teratogenic effects over background rates in the general population, there are few well-controlled studies to date evaluating the drug in pregnant women.^{180 183 186}

In animal studies evaluating sub-Q or IM quinine, teratogenic or fetotoxic effects (e.g., death in utero, degenerated auditory nerve and spiral ganglion, CNS anomalies, hemorrhage, mitochondrial changes in cochlea) demonstrated in some species.^{180 183 186}

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, especially in pregnant women.^{180 183 186}

No evidence to date that quinine causes uterine contractions at dosages recommended for the treatment of malaria;^{180 183 186} doses several fold higher than those used to treat malaria may stimulate the pregnant uterus.^{180 183 186}

Lactation

Distributed into milk.^{180 183 186}

Only limited information available regarding safety of quinine in breast-fed infants.^{180 183 186} Although quinine generally considered compatible with breast-feeding, assess the risks and benefits to the infant and mother and use with caution in nursing women.^{180 183 186}

Plasma quinine concentrations may not be therapeutic in infants of nursing mothers receiving quinine.^{180 183 186} If malaria suspected in the infant, provide appropriate evaluation and treatment.^{180 183 186}

Pediatric Use

Safety and efficacy not established in children <16 years of age.^{180 183 186}

Quinine is included in CDC recommendations for treatment of uncomplicated malaria in pediatric patients^†.^{143 144} (See Treatment of Uncomplicated Malaria under Uses.) The drug also is used for follow-up after an initial parenteral antimalarial regimen in children with severe malaria^†.^{199 200} (See Treatment of Severe Malaria under Uses.)

Geriatric Use

Clinical studies did not include sufficient numbers of individuals ≥65 years of age 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}

Closely monitor geriatric patients for adverse effects.^{180 183 186}

Hepatic Impairment

If used in adults with mild to moderate hepatic impairment (Child-Pugh class A or B), monitor closely for adverse effects associated with quinine.^{180 183 186}

Do not use in patients with severe hepatic impairment (Child-Pugh class C); oral clearance is decreased, volume of distribution increased, and half-life of the drug prolonged relative to individuals with normal hepatic function.^{180 183 186}

Renal Impairment

Reduced dosage recommended when used for treatment of acute uncomplicated malaria in adults with severe chronic renal failure.^{180 183 186} (See Renal Impairment under Dosage and Administration.) The effects of mild or moderate renal impairment on safety and pharmacokinetics not determined to date.^{180 183 186}

Common Adverse Effects

Mild cinchonism, manifested as headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception, occurs in most patients.^{180 183 186} More severe cinchonism, manifested as vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction, also reported.^{180 183 186}

Drug Interactions

Metabolized principally by CYP3A4; may also be metabolized by other CYP enzymes, including 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1.¹⁸⁰

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 drugs that prolong the QT interval.^{180 183 186} Concomitant use of quinine and other drugs known to cause QT prolongation, including class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide) and class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide), not recommended.^{180 183 186}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vivo and in vitro drug interaction studies suggest quinine may inhibit metabolism of drugs that are substrates of CYP3A4 and 2D6.^{180 183 186}

Avoid use with drugs that are CYP3A4 substrates and are known to cause QT prolongation (e.g., cisapride [available in the US only under a limited-use protocol], pimozide, halofantrine [not commercially available in the US], quinidine).^{180 183 186}

Quinine has been shown to decrease metabolism of desipramine in some patients (see Desipramine under Interactions) and may decrease metabolism of some other drugs that are CYP2D6 substrates (e.g., debrisoquine [not commercially available in the US], dextromethorphan, flecainide, methoxyphenamine [not commercially available in the US], metoprolol, paroxetine).^{180 183 186} If used concomitantly with a CYP2D6 substrate, monitor closely for adverse effects associated with the CYP2D6 substrate.^{180 183 186}

Drugs Affecting or Affected by P-glycoprotein Transport

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

Specific Drugs and Laboratory Tests

quiNINE Pharmacokinetics

Absorption

Bioavailability

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

In adults with uncomplicated P. falciparum malaria, mean AUC and peak plasma concentrations higher and time to peak concentration longer than that reported in healthy adults.^{180 183 186} Following a single oral dose, mean time to peak serum concentrations is 5.9 hours in adults with uncomplicated P. falciparum malaria compared with 2.8 hours in healthy adults.^{180 183 186}

Food

When a single 324-mg dose of oral 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, 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}

Special Populations

Pharmacokinetics 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 a single dose of 10 mg/kg of oral quinine sulfate in healthy children or children 1.5–12 years of age with uncomplicated P. falciparum malaria, mean time to peak quinine concentration was longer (4 versus 2 hours) and mean peak plasma concentration was higher (7.5 versus 3.4 mcg/mL) in children with uncomplicated P. falciparum malaria than in healthy children.^{180 183 186}

Following a single 600-mg dose of oral quinine sulfate, mean AUC in healthy geriatric adults 65–78 years of age is approximately 38% higher than in younger adults 20–35 years of age;^{180 183 186} mean time to peak quinine concentrations and mean peak plasma concentrations are similar in both age groups.^{180 183 186}

Following a single 600-mg dose of oral quinine sulfate in adults with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine 9.6 mg/dL), median AUC and mean peak plasma concentration increased by 195 and 79%, respectively, compared with adults with normal renal function.^{180 183 186} Effect of mild or moderate renal impairment on pharmacokinetics of quinine sulfate not determined to date.^{180 183 186}

Following a single 600-mg oral dose of quinine sulfate in otherwise healthy adults with moderate hepatic impairment (Child-Pugh class B), mean AUC increased 55% compared with healthy adults with normal hepatic function; mean peak plasma concentrations similar in both groups.^{180 183 186} Quinine absorption prolonged in adults with hepatitis.^{180 183 186} Pharmacokinetic data not available to date for patients with severe hepatic impairment (Child-Pugh class C).^{180 183 186}

Distribution

Extent

Volume of distribution lower in patients with malaria than in healthy individuals or patients convalescing from malaria.¹⁰⁶ Volume of distribution decreases with increasing severity of malarial infection.^{180 183 186}

Intra-erythrocytic quinine concentrations are approximately 30–50% of plasma concentrations.^{180 183 186} Small amounts distributed into bile and saliva.^a

Penetrates relatively poorly into CSF in patients with cerebral malaria;^{180 183 186} CSF quinine concentrations reported to be 2–7% of concurrent plasma concentrations.^{106 107 180 183 186}

Readily crosses the placenta.^{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 mean ratio of cord plasma to maternal plasma quinine concentrations was 0.32.¹⁸⁰ Such placental cord concentrations may not result in therapeutic fetal plasma quinine concentrations.^{180 183 186}

Distributed into milk.^{180 183 186}

Plasma Protein Binding

Approximately 69–92% in healthy adults.^{106 180 183 186}

During active malarial infection, protein binding 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

Metabolism

Metabolized almost exclusively via hepatic oxidative (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 parent drug.^{180 183 186}

In vitro studies indicate quinine is metabolized principally by CYP3A4 and may also be metabolized by other CYP enzymes, including 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1.¹⁸⁰

Elimination Route

Approximately 20% of a dose excreted unchanged in urine.^{180 183 186} Reabsorption of quinine is increased when urine is alkaline; rate of renal excretion of the drug is doubled when urine is acidic compared with when urine is alkaline.¹⁸⁰

Negligible to minimal amounts removed by hemodialysis or hemofiltration.^{180 183 186}

Half-life

Adults: 8–21 hours in those with malaria and 7–12 hours in those who are healthy or convalescing from the disease.^{106 107}

Children 1–12 years of age: 11–12 hours in those with malaria and 6 hours in those convalescing from the disease.¹⁰⁶

Geriatric adults: Mean elimination half-life after single dose is increased to 18.4 hours.^{180 183 186} At steady-state, mean elimination half-life is 24 hours in geriatric adults compared with 20 hours in younger adults.^{180 183 186} Although renal clearance of quinine is similar in geriatric and younger adults, geriatric adults excrete a larger proportion of the dose in urine as unchanged drug compared with younger adults.^{180 183 186}

Special Populations

Plasma concentrations are higher and plasma half-life may be prolonged in patients with malaria.^{106 107}

Adults with hepatitis: Elimination half-life and apparent volume of distribution are increased, but weight-adjusted clearance not altered.^{180 183 186}

Otherwise healthy individuals with mild hepatic impairment (Child-Pugh class A): Quinine pharmacokinetics and exposure to 3-hydroxyquinine are similar to that in healthy individuals with normal hepatic function.^{180 183 186}

Individuals with severe hepatic impairment (Child-Pugh class C): Oral clearance of quinine and formation of 3-hydroxyquinine decreased; volume of distribution and plasma elimination half-life increased.^{180 183 186}

Adults with severe chronic renal failure: Mean plasma half-life prolonged to 26 hours.¹⁸⁰ Effects of mild and moderate renal impairment on pharmacokinetics and safety not determined to date.^{180 183 186}

Stability

Storage

Oral

Capsules

20–25°C in tight, light-resistant container.^{180 183 186} Drug darkens on exposure to light.^{180 183 186}

Actions and Spectrum

• An alkaloid obtained from the bark of the cinchona tree; the levorotatory isomer of quinidine.¹⁸⁵

• Has several effects on skeletal muscle.^a Increases the refractory period of muscle by a direct action on muscle fiber so that the response to tetanic stimulation is diminished;^a has a curare-like effect and decreases the excitability of the motor endplate so that responses to repetitive nerve stimulation or acetylcholine are reduced;^a and affects the distribution of calcium within muscle fiber.^a

• Has cardiovascular effects similar to those of quinidine.^{180 183 186}

• Exact mechanism of antimalarial activity not determined.^{180 183 186} Inhibits nucleic acid synthesis, protein synthesis, and glycolysis in P. falciparum and can bind with hemazoin in parasitized erythrocytes.^{180 183 186}

• A blood schizonticidal agent active against the asexual erythrocytic forms of P. falciparum,^{180 183 186} P. malariae,^a P. ovale,^a and P. vivax.¹⁸⁹ Not gametocidal against P. falciparum.^{180 183 186} Inactive against sporozoites or pre-erythrocytic or exoerythrocytic forms of plasmodia.^{180 183 186}

• P. falciparum malaria 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 rarely between quinine and 4-aminoquinoline derivatives, quinine may be active against some strains of P. falciparum resistant to chloroquine.^a

Advice to Patients

• Importance of taking the drug exactly as prescribed.^{180 183 186} Advise patients not to double the next dose if a dose is missed; if >4 hours has elapsed since the missed dose, patient should not take the missed dose and should take the next dose as previously scheduled.^{180 183 186}

• Importance of taking with food to minimize possible GI irritation.^{180 183 186}

• Importance of immediately contacting a clinician if 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}

• Importance of immediately contacting a clinician if symptoms of hypersensitivity (e.g., rash, hives, severe itching, severe flushing, facial swelling, difficulty breathing), bleeding (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}

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{180 183 186}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{180 183 186}

• Importance of advising patients of other important precautionary information.^{180 183 186} (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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