Quinine (DB00468): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Quinine, a cinchona alkaloid identified by DrugBank ID DB00468 and CAS Number 130-95-0, represents a compound of profound historical significance and complex contemporary clinical relevance. Originally derived from the bark of the South American cinchona tree, its isolation in 1820 and subsequent use marked the first successful application of a chemical agent to combat an infectious disease, fundamentally altering the course of global health and geopolitics. While historically employed for a range of ailments, its therapeutic role in modern medicine has been sharply curtailed by a narrow therapeutic index and a well-documented profile of severe, sometimes fatal, toxicities.

The primary mechanism of its antimalarial action involves the disruption of the Plasmodium parasite's heme detoxification pathway, leading to the accumulation of cytotoxic heme within the parasite's food vacuole. Its pharmacokinetic profile is notably complex, as its absorption, distribution, and clearance are dynamically altered by the acute malarial state it is used to treat.

Currently, the sole indication for quinine sulfate approved by the U.S. Food and Drug Administration (FDA) is the treatment of uncomplicated Plasmodium falciparum malaria. Its use in babesiosis, in combination with clindamycin, represents another important therapeutic application. However, the legacy of its widespread, unapproved off-label use for nocturnal leg cramps has prompted stringent regulatory actions, including an FDA Boxed Warning. This warning highlights the risk of life-threatening hematologic reactions, such as thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), and unequivocally states that the risks of such use far outweigh any potential benefits.

This monograph provides a comprehensive examination of Quinine, synthesizing data on its chemical properties, pharmacology, clinical applications, extensive safety profile, and regulatory history. The analysis underscores that the appropriate use of Quinine in contemporary practice demands strict adherence to its approved indication, a thorough understanding of its significant risks and contraindications, and vigilant clinical monitoring.

Chemical Identity and Physicochemical Properties

Quinine is a naturally occurring small molecule classified as a cinchona alkaloid.[1] Its chemical structure is foundational to its biological activity and is characterized by a cinchonan skeleton, which comprises a quinoline functional group linked to an azabicyclo[2.2.2]octane (quinuclidine) moiety.[1] Specifically, it is a stereoisomer of cinchonidine wherein the hydrogen at the 6-position of the quinoline ring is substituted by a methoxy group.[2] This complex structure contains four defined atom stereocenters, making it a chiral molecule.[4] It is the laevorotatory stereoisomer of quinidine, a diastereomer with distinct primary therapeutic applications as a Class IA antiarrhythmic agent.[4] The subtle differences in the three-dimensional arrangement of these two molecules lead to their different primary clinical effects, yet they share overlapping toxicity profiles, particularly concerning cardiovascular effects and hypersensitivity reactions.

Quinine is identified by a comprehensive set of chemical descriptors that ensure its precise characterization for scientific, clinical, and regulatory purposes. Its International Union of Pure and Applied Chemistry (IUPAC) name is (R)-octan-2-yl]-(6-methoxyquinolin-4-yl)methanol.[2] It is also known by numerous synonyms, including (-)-Quinine and 6-Methoxy-α-(5-vinyl-2-quinuclidinyl)-4-quinolinemethanol.[1]

The molecular formula of Quinine is C20​H24​N2​O2​, with a calculated molecular weight of 324.42 g/mol.[1] Physically, it presents as a bulky, white, amorphous powder or as crystalline, triboluminescent orthorhombic needles.[4] The substance is noted to turn brown upon exposure to light and air, indicating a sensitivity that requires appropriate storage conditions.[2] It is odorless but possesses a persistent and intensely bitter taste, a characteristic that has influenced its historical use as a flavoring agent in tonic water and impacts patient compliance with oral formulations.[2]

Its solubility profile is critical for its formulation and absorption. It is poorly soluble in water (approximately 500 mg/L at 15 °C) but is highly soluble in organic solvents such as alcohol (1 g in 0.8 mL) and chloroform (1 g in 1.2 mL).[2] Its solubility in aqueous media increases with temperature and in acidic conditions due to the formation of salts.[4] The melting point is reported to be in the range of 173–177 °C, with some decomposition observed.[4]

Property	Value	Source(s)
IUPAC Name	(R)-octan-2-yl]-(6-methoxyquinolin-4-yl)methanol	2
Common Synonyms	(-)-Quinine, Qualaquin, 6'-Methoxycinchonidine	1
CAS Number	130-95-0	2
DrugBank ID	DB00468	1
Molecular Formula	C20​H24​N2​O2​	2
Molecular Weight	324.42 g/mol	7
Physical Appearance	White, crystalline powder or needles; turns brown on exposure to light	4
Solubility (Water)	500 mg/L at 15 °C; slightly soluble	2
Solubility (Alcohol)	1 g in 0.8 mL; highly soluble	4
Solubility (Chloroform)	1 g in 1.2 mL; highly soluble	4
Melting Point	173–177 °C (with decomposition)	4
pKa (Basic)	9.05	11
LogP (Octanol/Water)	3.44	4

Historical Significance: From Cinchona Bark to Modern Medicine

The history of Quinine is a remarkable narrative that traces its origins from a traditional remedy to a cornerstone of modern medicine, profoundly influencing global health, military strategy, and colonial history. Its story begins with the indigenous Quechua people of the Andean regions of Peru, Bolivia, and Ecuador, who utilized the bark of the cinchona tree as a muscle relaxant to control shivering.[3] To counteract the bark's intense bitterness, they would mix the ground powder with sweetened water, an early formulation that presaged the development of modern tonic water.[3]

The introduction of cinchona bark to Europe in the early 17th century by Spanish Jesuit missionaries marked a turning point in Western medicine.[3] By 1633, extracts of the bark were being used to treat malaria, a disease that was endemic throughout Europe, including Rome, and was a major cause of mortality.[1] The treatment of malaria with cinchona bark, and later its purified alkaloid, represents the first successful use of a chemical compound to combat an infectious disease, a landmark achievement that laid the groundwork for the field of chemotherapy.[3]

In 1820, a critical scientific advancement occurred when French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou successfully isolated the primary active alkaloid from the bark.[3] They named the substance "quinine," derived from the original Quechua word for the bark,

quina-quina, meaning "bark of bark".[3] This discovery allowed for standardized dosing and more potent treatment than was possible with crude bark preparations. The molecular formula of quinine was later determined by Adolph Strecker in 1854.[3]

The availability of an effective antimalarial had far-reaching geopolitical consequences. Quinine played a significant role in the European colonization of tropical regions, particularly in Africa and Southeast Asia.[3] By providing a means to mitigate the devastating impact of malaria on non-immune individuals, quinine was instrumental in transforming regions previously deemed the "white man's grave," thereby enabling deeper and more sustained colonial expansion.[3] Its strategic importance was acutely demonstrated during major global conflicts. During the American Civil War, the Union blockade of Southern ports created a desperate need for quinine in the Confederacy, prompting efforts to find local botanical substitutes.[14] Later, during World War II, the capture of the primary cinchona plantations on the island of Java by Japanese forces created a crisis for the Allied powers, spurring an urgent research effort to achieve its total chemical synthesis. This goal was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering, although isolation from natural sources remains the only economically viable method of production.[3]

Following World War II, the development of more effective and better-tolerated synthetic antimalarials, such as chloroquine, led to a decline in the use of quinine.[12] However, its story took another turn in the 1960s with the emergence and global spread of chloroquine-resistant strains of

Plasmodium falciparum. This development necessitated the clinical reinstatement of quinine, which remained effective against these resistant parasites. Despite its more significant toxicity profile, it once again became a critical therapeutic option for treating life-threatening malaria in many parts of the world, cementing its enduring, albeit complex, legacy in the fight against infectious diseases.[1]

Comprehensive Pharmacology

The pharmacological profile of Quinine is multifaceted, defined by its potent antimalarial activity, its direct effects on host physiological systems, and a complex pharmacokinetic profile that is uniquely influenced by the malarial disease state.

Mechanism of Action as an Antimalarial Agent

The primary antimalarial effect of Quinine is exerted during the intraerythrocytic stage of the Plasmodium life cycle. It acts as a blood schizonticide, targeting the parasites as they grow and replicate within red blood cells.[1] Its mechanism, while not fully elucidated in all aspects, is centered on the disruption of a critical detoxification pathway within the parasite.

Inhibition of Heme Detoxification and Hemozoin Formation

During its intraerythrocytic stage, the Plasmodium parasite digests large quantities of host hemoglobin to obtain essential amino acids.[1] This process releases vast amounts of heme (ferriprotoporphyrin IX), which is highly toxic to the parasite due to its ability to generate reactive oxygen species and disrupt membrane integrity.[17] To protect itself, the parasite has evolved a unique detoxification mechanism: it polymerizes the toxic heme into an inert, insoluble crystalline pigment known as hemozoin (also referred to as β-hematin or malaria pigment).[16] This biomineralization process is catalyzed by an enzymatic activity referred to as heme polymerase and occurs within the parasite's acidic food vacuole.[1]

Quinine, as a weak base, is protonated and becomes trapped within the acidic environment of the parasite's food vacuole, where it concentrates to high levels.[1] Here, it directly interferes with hemozoin formation.[1] The drug is believed to bind to heme molecules, forming a complex that prevents their incorporation into the growing hemozoin crystal.[17] This inhibition of heme polymerase activity leads to the accumulation of toxic, free heme within the parasite, causing oxidative stress, membrane damage, and ultimately, parasite death.[1]

Molecular Interactions: The "Step-Pinning" Model of Heme Crystal Growth Inhibition

The precise molecular interaction by which Quinine inhibits hemozoin formation has been further clarified by advanced imaging techniques such as atomic-force microscopy. This research has led to the "step-pinning" model of inhibition.[20] Hemozoin crystals grow as heme dimer "bricks" are added at specific growth sites, such as step edges and kink sites on the crystal surface. Some antimalarial agents act by a "kink-blocking" mechanism, binding only to the active kink sites where new units are added. Quinine, along with chloroquine, employs a more effective strategy. It binds not only to the kink sites but also broadly across the flat terrace faces of the growing crystal. This widespread binding effectively "pins" the growth steps, preventing further propagation and inhibiting crystal formation over a much larger surface area. This mechanism is considered more potent than simple kink-blocking and provides a molecular-level explanation for Quinine's efficacy.[20]

Ancillary Effects on Parasite Glycolysis and Nucleic Acid Synthesis

While the inhibition of heme detoxification is considered the principal mechanism of action, official prescribing information and other studies suggest that Quinine may have additional effects on the parasite's cellular machinery. It has been reported to inhibit nucleic acid synthesis, protein synthesis, and glycolysis in P. falciparum.[9] Some evidence also suggests it may intercalate into parasite DNA, disrupting replication and transcription.[22] This multi-targeted approach, combining a primary potent effect with several secondary disruptive actions, likely contributes to its overall antimalarial efficacy.[17]

Pharmacological Effects on Host Systems

In addition to its antiparasitic actions, Quinine exerts several direct pharmacological effects on human systems, which account for both its historical therapeutic uses and its significant toxicity profile.

Neuromuscular and Musculoskeletal Effects

Quinine has direct effects on skeletal muscle, acting on the muscle membrane and its sodium channels.[1] It increases the effective refractory period of the muscle and decreases the excitability of the motor end-plate.[2] This action reduces the response of the muscle to tetanic stimulation and repetitive nerve stimulation. These properties form the physiological basis for its historical, and now strongly discouraged, off-label use for treating nocturnal leg cramps and myotonia congenita.[1] Furthermore, Quinine possesses neuromuscular blocking activity, which can potentiate the effects of other neuromuscular blockers and exacerbate weakness in patients with myasthenia gravis, a condition in which it is contraindicated.[23]

Cardiovascular Electrophysiology

Quinine shares structural similarities with its diastereomer, quinidine, a well-known Class IA antiarrhythmic agent, and consequently exhibits similar effects on cardiac electrophysiology. It has a dose-dependent effect on the QT interval of the electrocardiogram (ECG).[25] By blocking cardiac potassium channels, it can prolong the QTc interval, which increases the risk of life-threatening ventricular arrhythmias, most notably Torsades de Pointes.[3] This cardiotoxicity is a primary safety concern and underlies many of its contraindications and drug interactions.

Antipyretic and Analgesic Properties

Quinine also functions as a mild antipyretic (fever-reducing) and non-narcotic analgesic (pain-relieving) agent.[1] These properties contribute to the symptomatic relief experienced by patients with malaria, who typically suffer from high fevers, chills, and muscle pain.[17] This also explains its historical inclusion in over-the-counter preparations for the common cold.[1]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The disposition of Quinine in the human body is characterized by rapid oral absorption, extensive protein binding, primary hepatic metabolism, and a pharmacokinetic profile that is significantly altered by the presence of acute malaria. This dynamic interplay between the drug and the disease state is a critical factor in its clinical use.

Bioavailability and Factors Affecting Absorption

Following oral administration, Quinine is readily and almost completely absorbed from the small intestine, with an absolute bioavailability reported to be between 76% and 88% in healthy individuals.[1] Peak plasma concentrations (Tmax) are typically reached within 1 to 3 hours of a single oral dose in healthy subjects.[10] Studies have shown that its absorption is both fast and reproducible, with low intra-subject variability.[31] Administration with food, particularly a high-fat meal, can delay the time to peak concentration but does not significantly affect the overall extent of absorption (Cmax or AUC), making co-administration with food a recommended practice to minimize gastric irritation.[33]

Protein Binding and Tissue Distribution: The Influence of Acute Malaria

Quinine is widely distributed into various tissues, including the liver, lungs, kidneys, and spleen.[10] A key feature of its pharmacokinetics is the profound impact of the acute malarial infection on its distribution and protein binding. In healthy individuals, Quinine is moderately protein-bound, with bound fractions ranging from 69% to 92%.[1] However, during an active malarial infection, protein binding increases significantly to 78–95%.[9] This change is primarily driven by a marked increase in the plasma concentration of the acute-phase reactant protein α1-acid glycoprotein (AAG), to which Quinine avidly binds.[36]

This increase in protein binding, coupled with other physiological changes during malaria, leads to a contraction of the apparent volume of distribution (Vd). For example, the Vd in pediatric patients with malaria (0.87 L/kg) is substantially lower than in healthy pediatric controls (1.43 L/kg).[1] The clinical consequence of this is that for a given dose, total plasma Quinine concentrations are higher during the acute phase of malaria than during convalescence or in healthy individuals. As the patient recovers and AAG levels normalize, the Vd expands, and plasma concentrations fall.[38] This dynamic shift is critical, as sub-therapeutic concentrations during the later stages of treatment can increase the risk of recrudescence.[38] Quinine also readily crosses the placenta and is secreted in small amounts into breast milk, with cord blood and milk concentrations reaching approximately 30% of maternal plasma levels.[9]

Hepatic Biotransformation: The Central Role of Cytochrome P450 Enzymes

Quinine is extensively metabolized, with over 80% of the drug eliminated via hepatic biotransformation.[1] This metabolism occurs almost exclusively through oxidative pathways mediated by the cytochrome P450 (CYP) enzyme system. The principal enzyme responsible for Quinine metabolism is

CYP3A4, which catalyzes the 3-hydroxylation of the quinuclidine ring to form the major metabolite, 3-hydroxyquinine.[40] This metabolite is less active than the parent compound.[9] While CYP3A4 is the dominant pathway, other CYP enzymes, including CYP2C19, CYP1A2, CYP2C9, and CYP2D6, have been shown to play minor roles in the formation of other secondary metabolites.[9] The heavy reliance on CYP3A4 for its clearance makes Quinine highly susceptible to clinically significant drug-drug interactions with inhibitors and inducers of this enzyme.

Elimination Pathways and Half-Life

The primary route of elimination for Quinine is through its hepatic metabolism. Less than 20% of an administered dose is excreted unchanged in the urine.[1] The renal excretion of unchanged Quinine is pH-dependent. Because Quinine is a weak base, it is reabsorbed in the renal tubules when the urine is alkaline. Consequently, its renal clearance is approximately twice as rapid when the urine is acidic compared to when it is alkaline.[9]

The elimination half-life of Quinine in healthy adults is approximately 11 to 18 hours.[1] This half-life is prolonged during acute malaria due to reduced systemic clearance.[9] For instance, the mean total clearance in malaria patients during the acute phase (approx. 0.09 L/h/kg) is significantly slower than during the recovery phase (approx. 0.16 L/h/kg).[9] The half-life is also significantly prolonged in patients with severe chronic renal impairment (up to 26 hours) and in elderly subjects (up to 18.4 hours).[9]

Pharmacokinetic Parameter	Healthy Subjects (Value)	Patients with Uncomplicated Malaria (Value)	Source(s)
Oral Bioavailability (%)	76–88	>85	1
Tmax (hours)	1–3	4–6	9
Volume of Distribution (L/kg)	2.5–7.1 (Adults) 1.43 (Pediatrics)	0.87 (Pediatrics)	1
Protein Binding (%)	69–92	78–95	1
Elimination Half-life (hours)	9.7–12.5	~12–18	1
Total Clearance (L/h/kg)	0.17	0.09 (Acute Phase)	1
Primary Metabolizing Enzyme	CYP3A4	CYP3A4	40
Fraction Excreted Unchanged (Urine, %)	<20	<20	1

Clinical Applications and Therapeutic Guidelines

The clinical use of Quinine has evolved dramatically over its long history. Once a panacea for fevers, its modern application is now highly circumscribed due to a significant potential for toxicity. Its therapeutic role is defined by a single FDA-approved indication, a valuable second-line use in another parasitic infection, and a strong regulatory prohibition against its most common historical off-label use.

FDA-Approved Indication: Treatment of Uncomplicated Plasmodium falciparum Malaria

The sole indication for which quinine sulfate (marketed in the U.S. as Qualaquin) is approved by the Food and Drug Administration (FDA) is the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum.[23]

Efficacy and Place in Therapy

Quinine's enduring value lies in its efficacy against strains of P. falciparum that have developed resistance to other antimalarial drugs, most notably chloroquine.[1] It functions as a blood schizonticide, effectively clearing the asexual erythrocytic stages of the parasite that are responsible for clinical illness.[1] However, it is not active against the dormant liver stages (hypnozoites) of

P. vivax and P. ovale, meaning that treatment for these species must be followed by a course of primaquine or tafenoquine to prevent relapse.[12]

Due to its toxicity profile and the availability of safer and better-tolerated alternatives, Quinine is no longer considered a first-line agent for uncomplicated malaria in most regions. The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend artemisinin-based combination therapies (ACTs) as the preferred treatment for uncomplicated P. falciparum malaria.[12] Quinine, typically in combination with an antibiotic such as doxycycline, tetracycline, or clindamycin, is reserved as a second-line or alternative treatment.[22]

Dosage and Administration

The dosing of Quinine requires careful attention to the specific salt form, patient age, and the geographic origin of the infection, which informs the necessary duration of therapy.

• Oral Administration (Adults): For the treatment of uncomplicated P. falciparum malaria in adults and children 16 years of age and older, the standard oral dosage is 648 mg of quinine sulfate (equivalent to 542 mg of quinine base, typically administered as two 324 mg capsules) every 8 hours.[23] The duration of treatment is typically 3 to 7 days. A 7-day course is specifically recommended for infections acquired in Southeast Asia, where parasite sensitivity to quinine is reduced.[51] To minimize gastric irritation, Quinine should be administered with food.[33]
• Oral Administration (Pediatrics): The CDC recommends a weight-based oral dose of 10 mg/kg of quinine sulfate salt (equivalent to 8.3 mg/kg of base) every 8 hours for 3 or 7 days.[51] The total daily dose should not exceed the adult dose. As the commercially available 324 mg capsules in the U.S. are not suitable for precise pediatric dosing, the use of a compounding pharmacy is often necessary to prepare appropriate formulations.[51]
• Intravenous Administration (Severe Malaria): In cases of severe malaria where the patient cannot tolerate oral medication, quinine dihydrochloride is administered by slow intravenous infusion. It must never be given as a rapid IV bolus injection due to the risk of severe hypotension and cardiac arrest.[56] The standard regimen involves a loading dose of 20 mg/kg of salt infused over 4 hours, followed 8 hours later by a maintenance dose of 10 mg/kg of salt infused over 4 hours, repeated every 8 hours.[56] The loading dose should be omitted if the patient has received quinine or mefloquine within the preceding 24 hours.[56] Intravenous therapy should be switched to an oral regimen as soon as the patient's condition allows. It is important to note that in the U.S. and Europe, intravenous artesunate is now the recommended first-line treatment for severe malaria, with IV quinine considered an alternative only when artesunate is unavailable.[61]

Treatment of Babesiosis

Quinine also has a therapeutic role in the treatment of babesiosis, a tick-borne parasitic infection caused by protozoa of the genus Babesia, most commonly Babesia microti.[1]

Rationale for Use and Combination Therapy

Quinine is recommended as an alternative, second-line therapy for babesiosis.[64] It is always administered in combination with the antibiotic clindamycin to enhance efficacy and prevent the development of resistance.[64] The preferred first-line regimen for babesiosis is the combination of atovaquone and azithromycin, which is generally better tolerated and associated with fewer adverse effects.[64] The quinine/clindamycin combination is typically reserved for patients who cannot tolerate the first-line regimen or in cases of severe disease.[65]

The mechanism by which Quinine acts against Babesia is distinct from its antimalarial action. Unlike Plasmodium, Babesia parasites do not digest hemoglobin and do not produce hemozoin, rendering the inhibition of heme polymerization irrelevant.[68] The anti-babesial activity is therefore thought to rely on other, less well-understood mechanisms, such as DNA intercalation or disruption of other essential parasite cellular functions.[68] This distinction is a clear example of how a drug's mechanism can be highly dependent on the specific pathogen being targeted.

Recommended Treatment Protocols

For the treatment of babesiosis in adults, the typical oral dosage of quinine sulfate is 650 mg three times a day, administered concurrently with clindamycin (e.g., 600 mg orally three times a day).[52] The standard duration of treatment is 7 to 10 days for immunocompetent patients.[65] In patients who are severely ill or immunocompromised, treatment may need to be initiated with intravenous clindamycin and may require a longer duration, often for 6 weeks or more, until parasitemia is cleared.[65]

The Off-Label Use for Nocturnal Leg Cramps: A Risk-Benefit Analysis

Historically, the most prevalent use of Quinine in the United States was not for malaria but for the treatment and prevention of idiopathic nocturnal leg cramps, an unapproved (off-label) indication.[69]

Historical Use and Evidence of Modest Efficacy

For decades, physicians prescribed Quinine at low doses (typically 200–300 mg at bedtime) for nocturnal leg cramps, based on its known effects on muscle excitability.[70] Multiple systematic reviews and meta-analyses have examined its efficacy for this condition. The consensus from these reviews is that Quinine is modestly effective, demonstrating a statistically significant but clinically small reduction in the frequency (by about 25%) and intensity (by about 10%) of leg cramps compared to placebo.[70]

Regulatory Stance and Clinical Recommendations

Despite this modest efficacy, the significant risk of severe and life-threatening adverse events has led regulatory bodies, particularly the U.S. FDA, to take a firm stance against this off-label use. The FDA has explicitly stated that the risk associated with using Quinine for a benign, self-limiting condition like nocturnal leg cramps unequivocally outweighs any potential benefit.[23]

This conclusion is based on a substantial body of evidence documenting rare but fatal hematologic and cardiovascular toxicities even at the low doses used for leg cramps. The regulatory actions have been escalating over several decades, from a 1994 ban on its over-the-counter sale for this purpose to the issuance of a Boxed Warning and the implementation of a Risk Evaluation and Mitigation Strategy (REMS) for the sole approved prescription product, Qualaquin.[69]

The persistence of this prescribing practice, despite strong regulatory warnings and clear evidence of harm, serves as a compelling case study in the challenges of de-implementing established medical practices. The inertia of physician and patient habits, combined with the lack of highly effective and safe alternatives for leg cramps, created a significant gap between evidence-based guidelines and real-world clinical behavior. Current clinical guidelines from major neurological and family practice associations strongly advise against the routine use of Quinine for leg cramps.[70] It should only be considered as a last-resort option for a short, four-week trial in fully informed patients who suffer from frequent, severe, and debilitating cramps that have failed to respond to all non-pharmacologic measures and other safer therapeutic options.[70]

Indication (Status)	Population	Route	Dosage Regimen	Duration	Key Remarks
Uncomplicated P. falciparum Malaria (FDA-Approved)	Adults (≥16 yrs)	Oral	648 mg quinine sulfate every 8 hours	3 or 7 days	Take with food. 7-day course required for infections from Southeast Asia. 23
Uncomplicated P. falciparum Malaria (FDA-Approved)	Pediatrics	Oral	10 mg/kg quinine sulfate salt every 8 hours	3 or 7 days	Do not exceed adult dose. May require compounding pharmacy. 51
Severe Malaria (Alternative Therapy)	Adults & Pediatrics	IV Infusion	Loading Dose: 20 mg/kg salt over 4 hrs. Maintenance: 10 mg/kg salt over 4 hrs, every 8 hrs.	Until oral therapy is tolerated	NEVER give as IV bolus. Omit loading dose if prior quinine/mefloquine use. 56
Babesiosis (Off-label, Alternative)	Adults	Oral	650 mg quinine sulfate every 8 hours	7–10 days	Always used in combination with clindamycin. Longer duration for immunocompromised patients. 52
Nocturnal Leg Cramps (Off-label, Not Recommended)	Adults	Oral	200–300 mg at bedtime	N/A	Use is strongly discouraged by FDA due to risk of serious adverse events. 49

Safety and Toxicology Profile

Quinine is characterized by a narrow therapeutic index and a significant potential for toxicity, which has led to stringent regulatory oversight and a restricted clinical role. The safety profile ranges from a common, dose-related syndrome of mild adverse effects to rare, unpredictable, and life-threatening reactions.

Boxed Warning: Hematologic Toxicity and Off-Label Use

The U.S. FDA has mandated a Boxed Warning on the prescribing information for quinine sulfate, which represents the agency's most serious safety alert.[23] The warning is unequivocal and has two primary components:

1. Risk of Off-Label Use: It explicitly warns against the use of Quinine for the treatment or prevention of nocturnal leg cramps.
2. Severe Hematologic Reactions: It highlights that such use may result in serious and life-threatening hematologic events, including thrombocytopenia, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), and associated chronic renal impairment.

The warning concludes that the risk associated with using Quinine for leg cramps, a benign condition, outweighs any potential benefit.[23]

Common Adverse Reactions and Cinchonism

The most frequently encountered adverse effects of Quinine are a collection of symptoms collectively known as cinchonism. This syndrome occurs to some degree in nearly all patients receiving therapeutic doses and is dose-related.[3]

• Mild Cinchonism: The characteristic symptoms include tinnitus (ringing in the ears), reversible high-frequency hearing loss, headache, nausea, flushing, sweating, dizziness or vertigo, and visual disturbances such as blurred vision and altered color perception.[3]
• Severe Cinchonism: At higher concentrations or in sensitive individuals, the syndrome can progress to include vomiting, diarrhea, abdominal pain, profound deafness, blindness, confusion, and disturbances in cardiac rhythm.[21] While most symptoms of cinchonism are reversible upon discontinuation of the drug, severe auditory and visual damage can be permanent.[21]

Serious and Life-Threatening Adverse Events

Beyond cinchonism, Quinine can cause unpredictable and severe toxicities affecting multiple organ systems.

Hematologic Disorders

Quinine can induce severe, idiosyncratic, and immune-mediated hematologic reactions, which are the primary focus of the FDA's Boxed Warning. These reactions are not necessarily dose-dependent and can occur even with small amounts of the drug, such as from tonic water.

• Thrombocytopenia: Quinine can induce the production of drug-dependent antibodies that target platelet glycoproteins (most commonly GPIb-IX complex), leading to rapid platelet destruction and a severe drop in platelet count.[1] This can result in life-threatening hemorrhage. The reaction typically resolves within a week of drug cessation, but re-exposure from any source can trigger a more rapid and severe recurrence.[3]
• Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP): These are severe forms of thrombotic microangiopathy, where small blood clots form in capillaries throughout the body. This process consumes platelets and red blood cells, leading to thrombocytopenia, microangiopathic hemolytic anemia, and organ damage, particularly acute kidney injury. These conditions are medical emergencies and can be fatal.[3]
• Hemolytic Anemia and Blackwater Fever: Quinine can trigger hemolysis, especially in individuals with a genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD).[23] A particularly severe form of acute intravascular hemolysis associated with malaria and quinine use is known as blackwater fever, characterized by the passage of dark urine due to massive hemoglobinuria, which can lead to acute renal failure.[23]

Cardiovascular Toxicity

• QT Prolongation and Arrhythmias: As previously noted, Quinine prolongs the QTc interval in a dose-dependent manner. This creates a significant risk for potentially fatal ventricular arrhythmias, including Torsades de Pointes and ventricular fibrillation, especially in patients with underlying cardiac conditions, electrolyte abnormalities, or those taking other QT-prolonging drugs.[3]

Severe Hypersensitivity and Dermatologic Reactions

Serious, life-threatening hypersensitivity reactions, including anaphylaxis, angioedema, and bronchospasm, can occur.[3] Additionally, severe cutaneous adverse reactions (SCARs) have been reported, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which are characterized by widespread blistering and sloughing of the skin and can be fatal.[26]

Other Serious Events

• Hypoglycemia: Quinine stimulates insulin release from pancreatic β-cells and can cause significant, sometimes severe, hypoglycemia. This risk is particularly elevated in pregnant women and in patients with severe malaria.[26]
• Hepatotoxicity: While rare, Quinine can cause hypersensitivity-mediated liver injury, often presenting as granulomatous hepatitis with fever, myalgias, and a cholestatic or mixed pattern of liver enzyme elevation.[81]
• Ocular and Auditory Toxicity: Severe overdose or idiosyncratic reactions can lead to optic neuritis and retinal damage, resulting in permanent blindness. Similarly, severe ototoxicity can cause irreversible deafness.[3]

Contraindications and Precautions

Due to its significant toxicity profile, Quinine is strictly contraindicated in several patient populations [24]:

• Known Hypersensitivity: Patients with a known hypersensitivity to Quinine, its diastereomer quinidine, or the related antimalarial mefloquine.[23]
• Prolonged QT Interval: Patients with a baseline prolonged QT interval or clinical conditions known to prolong it.[23]
• G6PD Deficiency: Due to the risk of hemolysis.[23]
• Myasthenia Gravis: As Quinine's neuromuscular blocking activity can exacerbate muscle weakness.[23]
• Optic Neuritis or Tinnitus: As Quinine can exacerbate these conditions.[23]
• Previous Adverse Hematologic Reaction: Any patient with a history of Quinine-induced thrombocytopenia, HUS/TTP, or blackwater fever should never be re-exposed to the drug.[23]

Use in Specific Populations

• Pregnancy: Malaria during pregnancy poses a significant risk to both the mother and fetus. While Quinine use carries potential for fetal harm, the benefits of treating malaria are generally considered to outweigh the risks. It is a recommended agent for treating uncomplicated malaria in the first trimester.[3] Pregnant women are at an increased risk for Quinine-induced hypoglycemia and should be monitored closely.[26]
• Lactation: Quinine is excreted into breast milk in small amounts. Studies suggest this poses a minimal risk to the nursing infant.[33]
• Renal Impairment: The clearance of Quinine is decreased in patients with severe chronic renal failure. A dose reduction is required for these patients (e.g., a loading dose of 648 mg followed by 324 mg every 12 hours).[23]
• Hepatic Impairment: No dose adjustment is typically needed for mild to moderate (Child-Pugh A or B) hepatic impairment, but patients should be monitored closely. Quinine should not be administered to patients with severe (Child-Pugh C) hepatic impairment.[23]

Clinically Significant Interactions

Quinine is involved in numerous clinically significant drug and food interactions, primarily driven by its effects on the cytochrome P450 (CYP) metabolic enzyme system and its own potential for toxicity. A thorough medication review is essential before initiating therapy. There are over 490 drugs known to interact with Quinine, with nearly 100 of these interactions classified as major.[85]

Drug-Drug Interactions

Interactions can be broadly categorized based on their pharmacodynamic or pharmacokinetic mechanisms.

Interactions via CYP450 Metabolism

Quinine's metabolism and its effects on other drugs are central to its interaction profile.

• Quinine as a Metabolic Substrate: Quinine is metabolized predominantly by CYP3A4.[40]
• CYP3A4 Inducers: Strong inducers of CYP3A4, such as rifampin, carbamazepine, phenobarbital, and phenytoin, can significantly increase the clearance of Quinine, leading to lower plasma concentrations and a high risk of therapeutic failure. The concomitant use of rifampin with Quinine should be avoided.[21]
• CYP3A4 Inhibitors: Strong inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, and macrolide antibiotics (e.g., erythromycin, clarithromycin), can decrease Quinine's metabolism, leading to elevated plasma concentrations and an increased risk of toxicity, particularly QT prolongation. The concomitant use of ritonavir and macrolide antibiotics with Quinine should be avoided.[21]
• Quinine as a Metabolic Inhibitor: Quinine itself is an inhibitor of other CYP enzymes.
• CYP2D6 Inhibition: Quinine is a potent inhibitor of CYP2D6.[3] It can significantly increase the plasma concentrations of drugs that are substrates of this enzyme, such as certain beta-blockers (e.g., metoprolol), antidepressants (e.g., desipramine, paroxetine), and antiarrhythmics (e.g., flecainide). Dose adjustments and careful monitoring for toxicity of the co-administered drug may be necessary.[23]
• CYP3A4 Inhibition: Quinine is also a moderate inhibitor of CYP3A4.[23] It can increase the plasma concentrations of CYP3A4 substrates, such as certain statins (e.g., atorvastatin, simvastatin, lovastatin), increasing the risk of myopathy and rhabdomyolysis. Lower doses of the statin or use of an alternative not metabolized by CYP3A4 should be considered.[23]

Interactions with QT-Prolonging Agents

Due to its intrinsic ability to prolong the QTc interval, Quinine has an additive pharmacodynamic effect when co-administered with other drugs that share this property. This combination significantly increases the risk of Torsades de Pointes and other fatal ventricular arrhythmias. Concomitant use with such agents should be avoided. These drugs include:

• Class IA and Class III antiarrhythmics (e.g., quinidine, amiodarone, sotalol, dofetilide).[21]
• Certain antipsychotics (e.g., thioridazine, pimozide, ziprasidone).[21]
• Certain antibiotics (macrolides, fluoroquinolones).[21]
• Other antimalarials like mefloquine and halofantrine.[23]

Other Significant Pharmacodynamic and Pharmacokinetic Interactions

• Anticoagulants: Quinine can enhance the hypoprothrombinemic effect of warfarin and other oral anticoagulants, possibly by depressing the hepatic synthesis of vitamin K-dependent clotting factors. Close monitoring of coagulation parameters (PT/INR) is required.[34]
• Digoxin: Quinine is an inhibitor of the P-glycoprotein (P-gp) efflux transporter. By inhibiting P-gp, Quinine can decrease the clearance of digoxin, leading to elevated plasma concentrations and an increased risk of digoxin toxicity. Digoxin levels should be monitored closely, and dose reduction may be necessary.[21]
• Neuromuscular Blocking Agents: Quinine can potentiate the effects of both depolarizing (e.g., succinylcholine) and non-depolarizing (e.g., pancuronium, tubocurarine) neuromuscular blockers, potentially leading to profound respiratory depression and apnea. Concomitant use should be avoided.[23]
• Antacids: Antacids containing aluminum and/or magnesium can delay or decrease the absorption of Quinine from the gastrointestinal tract. Administration should be separated by at least 2 hours.[21]

Food and Lifestyle Interactions

• Food: It is recommended to take Quinine with food or milk to minimize gastric upset and irritation.[33] Food, including high-fat meals, may delay the time to peak concentration but does not significantly impact the overall amount of drug absorbed.[34]
• Grapefruit Juice: Grapefruit juice is a well-known inhibitor of intestinal CYP3A4. However, multiple studies have shown that it does not significantly alter the pharmacokinetics of Quinine.[34] This lack of interaction is likely because Quinine has high oral bioavailability and does not undergo significant first-pass metabolism in the gut wall, which is the primary site of grapefruit juice's effect.[90] Therefore, patients can generally consume grapefruit juice while taking Quinine. However, caution is advised due to a single case report of Torsades de Pointes in a patient with underlying long QT syndrome who consumed excessive amounts of both grapefruit juice and tonic water.[87]
• Tobacco: Cigarette smoking is an inducer of CYP1A2 and has been shown to increase the clearance and reduce the plasma concentrations of Quinine in healthy volunteers. However, this effect is less pronounced in patients with acute malaria, and it does not appear to impact therapeutic outcomes. Therefore, dose adjustment for smokers is not recommended.[34]

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Effect	Clinical Recommendation/Management	Source(s)
CYP3A4 Inducers (e.g., Rifampin, Carbamazepine, Phenytoin)	Induction of CYP3A4, the primary metabolizing enzyme for Quinine.	Decreased plasma concentrations of Quinine, leading to potential therapeutic failure of malaria treatment.	Avoid concomitant use, especially with rifampin. If unavoidable, monitor for lack of efficacy.	23
CYP3A4 Inhibitors (e.g., Ketoconazole, Ritonavir, Macrolides)	Inhibition of CYP3A4 metabolism.	Increased plasma concentrations of Quinine, leading to an increased risk of toxicity, especially QT prolongation.	Avoid concomitant use with strong inhibitors like ritonavir and macrolides. Use with caution and monitor for toxicity with others.	23
QT-Prolonging Agents (e.g., Amiodarone, Sotalol, Mefloquine, certain antipsychotics)	Additive pharmacodynamic effect on cardiac repolarization.	Increased risk of significant QTc interval prolongation, Torsades de Pointes, and other life-threatening ventricular arrhythmias.	Avoid concomitant use. This combination is often contraindicated.	21
Digoxin	Inhibition of P-glycoprotein (P-gp) mediated efflux by Quinine.	Increased plasma concentrations of digoxin, leading to an increased risk of digoxin toxicity.	Monitor digoxin serum concentrations closely and adjust digoxin dose as necessary.	21
Warfarin	Pharmacodynamic interaction; potential depression of vitamin K-dependent clotting factors.	Enhanced anticoagulant effect of warfarin, leading to an increased risk of bleeding.	Monitor prothrombin time (PT) and International Normalized Ratio (INR) closely. Adjust warfarin dose as needed.	34
Neuromuscular Blocking Agents (e.g., Pancuronium, Succinylcholine)	Pharmacodynamic synergism; Quinine has intrinsic neuromuscular blocking activity.	Potentiation of neuromuscular blockade, leading to prolonged muscle paralysis and respiratory depression.	Avoid concomitant use.	23
CYP2D6 Substrates (e.g., Desipramine, Metoprolol)	Potent inhibition of CYP2D6 by Quinine.	Increased plasma concentrations of the co-administered drug, leading to an increased risk of its specific toxicities.	Monitor for adverse effects of the CYP2D6 substrate. Dose reduction of the substrate may be required.	23
Antacids (Aluminum/Magnesium-containing)	Decreased gastrointestinal absorption of Quinine.	Delayed or reduced absorption of Quinine, potentially affecting efficacy.	Avoid concomitant administration. If necessary, separate doses by at least 2-4 hours.	21

Regulatory Status and History

The regulatory history of Quinine in the United States is a compelling narrative of the FDA's efforts to balance the drug's historical legacy and therapeutic utility against significant safety concerns, particularly those arising from widespread off-label use.

United States Food and Drug Administration (FDA)

Quinine's journey through the U.S. regulatory landscape reflects the evolution of drug safety standards over the 20th and 21st centuries.

From Unapproved Drug to Orphan Drug Approval (Qualaquin)

Quinine, in the form of cinchona bark, was used in the United States long before the establishment of modern drug regulation with the 1938 Food, Drug, and Cosmetic Act.[92] For decades, numerous companies marketed unapproved Quinine products, both over-the-counter (OTC) and by prescription, for various indications without having undergone the rigorous FDA approval process for safety and efficacy.[94]

This unregulated market persisted until the early 21st century. Citing a significant number of serious adverse event reports—665 reports, including 93 deaths, between 1969 and 2006—the FDA took decisive action.[94] In 2006, the agency ordered all companies marketing unapproved Quinine drugs to cease their distribution, effectively clearing the market of these products.[73]

Prior to this, on August 12, 2005, the FDA approved a New Drug Application (NDA 21-799) from Mutual Pharmaceutical Company for a specific formulation of quinine sulfate in 324 mg capsules, which was subsequently marketed under the brand name Qualaquin.[92] This became the only FDA-approved Quinine product in the United States. The approved indication was strictly limited to the treatment of uncomplicated

P. falciparum malaria. Due to the relative rarity of malaria in the U.S., Qualaquin was granted orphan drug status, which provides incentives for the development of drugs for rare diseases.[95]

Regulatory Actions Against Off-Label Promotion and Use

The FDA's regulatory actions have been heavily focused on curtailing the pervasive and dangerous off-label use of Quinine for nocturnal leg cramps.

• 1994: The agency finalized a rule establishing that OTC drug products containing Quinine for the treatment or prevention of nocturnal leg cramps were not generally recognized as safe and effective (GRASE). This action effectively banned the OTC sale of Quinine for this indication.[73]
• 1998: The FDA extended this GRASE finding to OTC products labeled for the treatment and/or prevention of malaria, concluding that this serious disease requires the supervision of a healthcare professional.[95]
• 2006: In conjunction with the removal of unapproved products from the market, the FDA issued strong warnings against the use of any Quinine product for leg cramps, emphasizing that the risks of serious harm far outweighed any potential benefit.[97]

This series of escalating regulatory actions demonstrates a multi-decade campaign by the FDA to align the use of a legacy drug with modern evidence of its safety and efficacy. The initial OTC ban was insufficient to curb prescription use, and the subsequent crackdown on unapproved products did not prevent the off-label prescribing of the newly approved Qualaquin. This necessitated more direct interventions aimed at influencing prescriber and patient behavior.

Implementation of the Risk Evaluation and Mitigation Strategy (REMS)

Despite the approval of Qualaquin with a narrow indication, post-market surveillance revealed that the majority of its use continued to be for the unapproved indication of nocturnal leg cramps.[48] In response to continued reports of serious adverse events, the FDA took a further significant step. In July 2010, the agency approved a

Risk Evaluation and Mitigation Strategy (REMS) for Qualaquin.[72] The key components of this REMS included:

1. A Medication Guide: A mandatory patient-friendly leaflet to be dispensed with every prescription, clearly explaining what Qualaquin is and is not approved for, and detailing its potential serious side effects.
2. A Communication Plan: A plan to educate healthcare professionals about the serious risks associated with off-label use, particularly the hematologic toxicities.

This was accompanied by the addition of the Boxed Warning to the product's label, the FDA's strongest form of safety warning, to ensure the risks were prominently communicated.[69] The implementation of the REMS and Boxed Warning represents the culmination of the FDA's efforts to manage the risks of a drug with a deeply entrenched but dangerous off-label use, serving as a regulatory model for addressing similar public health challenges.

European Medicines Agency (EMA) and International Status

In the European Union, Quinine is authorized for the treatment of malaria and is available as a prescription-only medicine (POM) in countries like the United Kingdom.[3] However, its therapeutic role has been largely superseded by newer agents. The EMA has noted that intravenous artesunate is more effective than Quinine for the treatment of severe malaria.[62] In 2021, the European Commission granted marketing authorization for Artesunate Amivas, establishing it as a preferred treatment for severe malaria in the EU/EEA.[62]

The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) continues to actively monitor the safety of Quinine through Periodic Safety Update Reports (PSURs).[25] Based on ongoing safety assessments, the PRAC has recommended updates to the product information for Quinine-containing medicines to include warnings about the risk of atrioventricular block and dose-dependent QT prolongation, further underscoring the ongoing regulatory vigilance surrounding its use.[25]

Conclusion and Expert Recommendations

Quinine is a drug of immense historical importance, representing the first successful chemical therapy against an infectious disease. However, its place in contemporary medicine is sharply defined by a narrow therapeutic window and a significant profile of potential toxicities. Its clinical utility is now restricted to a very specific set of indications where its benefits are proven to outweigh its substantial risks. The extensive history of severe adverse events, particularly those linked to its widespread and inappropriate off-label use for nocturnal leg cramps, has culminated in unequivocal warnings and stringent regulatory controls from agencies like the U.S. FDA.

The pharmacological profile of Quinine is complex, with a unique antimalarial mechanism involving the inhibition of heme detoxification and a pharmacokinetic profile that is dynamically altered by the very disease it treats. This requires a sophisticated understanding for safe and effective administration. The risk of severe, life-threatening hematologic, cardiovascular, and hypersensitivity reactions necessitates careful patient selection and vigilant monitoring.

Based on a comprehensive analysis of the available evidence, the following expert recommendations are provided for clinicians:

1. Strict Adherence to Indication: The prescription of Quinine should be limited exclusively to its FDA-approved indication for the treatment of uncomplicated P. falciparum malaria or as a recognized alternative therapy for babesiosis in combination with clindamycin. Its use for nocturnal leg cramps is not supported by a favorable risk-benefit profile and is strongly contraindicated by regulatory guidance.
2. Thorough Patient Screening: Prior to initiating therapy, a meticulous patient history and assessment are imperative. Clinicians must screen for all contraindications, including a personal or family history of prolonged QT interval, known G6PD deficiency, myasthenia gravis, optic neuritis, and any prior history of an adverse hematologic reaction or hypersensitivity to Quinine or its diastereomer, quinidine.
3. Comprehensive Medication Review: A complete review of all concomitant medications is essential to prevent severe drug-drug interactions. Particular attention must be paid to other QT-prolonging agents, strong inducers and inhibitors of CYP3A4, substrates of CYP2D6, anticoagulants, and digoxin.
4. Informed Patient Counseling: Clinicians must adhere to the requirements of the FDA's REMS program by providing and reviewing the Medication Guide with every patient. Counseling should emphasize the approved use of the medication, the dangers of off-label use, and the critical signs and symptoms of serious adverse effects (e.g., unusual bruising or bleeding, dark urine, severe rash, palpitations, or visual changes), with clear instructions to seek immediate medical attention if they occur.
5. Vigilant Clinical Monitoring: Patients receiving Quinine should be monitored for adverse effects. In patients with cardiovascular risk factors or those on concomitant QT-prolonging drugs, baseline and follow-up ECGs should be considered. Clinicians should maintain a high index of suspicion for signs of hematologic toxicity, hypoglycemia (especially in pregnant patients), and cinchonism.

In conclusion, Quinine remains a valuable tool in the global fight against parasitic diseases, but it is a tool that must be wielded with great care, precision, and a profound respect for its potential to cause harm. Its safe use is contingent upon a modern, evidence-based approach that prioritizes patient safety above historical prescribing habits.

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