Quinine (Systemic)


VA CLASSIFICATION
Primary: AP101
Secondary: MS900

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiprotozoal—

antimyotonic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Malaria (treatment)—Quinine is indicated in conjunction with doxycycline, clindamycin, or sulfadoxine/pyrimethamine combination in the treatment of uncomplicated chloroquine-resistant malaria caused by Plasmodium falciparum and [Plasmodium vivax] {02} {07} {19}.

Note: The treatment of chloroquine-resistant malaria caused by P. vivax requires higher doses of quinine {02}. Therefore, if quinine is considered for the treatment of chloroquine-resistant malaria caused by P. vivax , expert advice from an infectious or tropical disease specialist should be sought {02}.


[Leg cramps (prophylaxis and treatment)]—Quinine is indicated in the prophylaxis and treatment of nocturnal recumbency leg muscle cramps {02} {11}, including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis, and static foot deformities.

[Babesiosis (treatment)]1—Quinine is used concurrently with clindamycin in the treatment of severe babesiosis caused by Babesia microti {44} {45} {46}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    782.96

Mechanism of action/Effect:

Antiprotozoal—The precise mechanism of action of quinine in malaria has not been determined but may be based on its ability to concentrate in parasitic acid vesicles, causing an elevation of pH in intracellular organelles. This is thought to disrupt the intracellular transport of membrane components and macromolecules, and phospholipase activity {14}. Quinine has a schizonticidal action. Its ability to concentrate in parasitized erythrocytes may account for its selective toxicity against the erythrocytic stages of the four malarial parasites, including Plasmodium falciparum strains resistant to chloroquine. The drug is also gametocidal against Plasmodium vivax and Plasmodium malariae {14} {47}.

Antimyotonic—Quinine increases the refractory period of skeletal muscle by direct action on the muscle fiber and the distribution of calcium within the muscle fiber, thereby diminishing the response to tetanic stimulation. It also decreases the excitability of the motor end-plate region, reducing the responses to repetitive nerve stimulation and to acetylcholine.

Absorption:

Rapidly and almost completely absorbed. Bioavailability is approximately 80% in healthy subjects {38}.

Distribution:

Distribution of quinine may vary depending on the degree of illness; the volume of distribution is smaller in patients with cerebral malaria and increases with recovery. Children and pregnant women have a smaller volume of distribution than do nonpregnant female adults and male adults. Plasma and red blood cell (RBC) concentrations appear to be similar before infection; however, during a malaria attack, plasma concentrations are considerably higher than RBC concentrations. Quinine does not freely cross the blood-brain barrier; the cerebrospinal fluid to plasma ratio is approximately 7%. Quinine crosses the placenta and is distributed into breast milk; peak concentrations are reached in breast milk approximately 90 minutes after oral administration {03} {13} {17}.


Vol D:


Adults—

Cerebral malaria—Approximately 1.2 liters per kg {13}.

Uncomplicated malaria—Approximately 1.7 liters per kg {13}.



Children—


Uncomplicated malaria—

Approximately 0.8 liter per kg {13}.




Protein binding:

Higher (> 90%) in patients with cerebral malaria, pregnant women, and children {14}; approximately 85 to 90% in patients with uncomplicated malaria {13}; and approximately 70% in healthy adults {01}.

Biotransformation:

Hepatic; > 80% metabolized by the liver {16}. Metabolites have less activity than the parent drug {13}.

Half-life:


Adults:

Cerebral malaria: Approximately 18 hours.

Uncomplicated malaria: Approximately 16 hours.

Healthy persons: Approximately 11 hours.



Children:

Uncomplicated malaria: Approximately 12 hours.



Acute overdose:

Approximately 26 hours {32}.


Time to peak serum concentration

Acute malaria—Approximately 5.9 hours {38}.

Convalescence—Approximately 3.2 hours {38}.

Mean serum concentration

Approximately 7 mcg per mL, following chronic administration of total daily doses of 1 gram. Plasma concentrations are higher in patients with cerebral malaria due to reduced clearance and volume of distribution; concentrations decrease as patient recovers {13}.

Elimination:
    Primarily renal, with about 20% excreted as unchanged drug. Excretion of quinine is increased in acidic urine {13}.
    Dialysis—Exchange transfusion, hemodialysis, peritoneal dialysis, and hemofiltration have little effect on plasma quinine concentrations {16} {32}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to quinidine may be hypersensitive to this medication also.

Carcinogenicity

A study in rats given quinine sulfate in drinking water at a concentration of 0.1% for up to 20 months has not shown that quinine is carcinogenic {01}.

Mutagenicity

Micronucleus tests in male and female mice given 2 intraperitoneal injections of quinine dihydrochloride 24 hours apart in doses of 0.5 millimole per kg of body weight have not shown that quinine is mutagenic. Direct Salmonella typhimurium tests were also negative. However, when mammalian liver homogenate was added, positive results were obtained.

Sister chromatid exchange (SCE) tests, micronucleus tests, and chromosome aberration tests in Chinese hamsters given quinine hydrochloride orally in doses of 100 mg per kg of body weight (mg/kg) have not shown that quinine is mutagenic.

Micronucleus tests and chromosome aberration tests in mice given quinine hydrochloride orally in doses of 100 mg/kg have not shown that quinine is mutagenic. However, the SCE test showed an increase in SCEs per cell. Tests were repeated in two inbred strains of mice, using oral doses of 55, 75, and 110 mg of quinine hydrochloride per kg of body weight. The effects were more pronounced in these mice and the increase in SCEs per cell demonstrated a linear dose relationship. One of the inbred strains of mice showed positive micronucleus test results. The chromosome aberration tests also showed an increase in chromatid breaks. In addition, the Ames test was negative for point mutation {01}.

Pregnancy/Reproduction
Fertility—
No information is available on the effect of quinine on fertility in animals or humans.

Pregnancy—
Quinine crosses the placenta; one study found the cord plasma concentration to be approximately one third the concentration of quinine in maternal plasma {17}. Quinine has been used to treat patients with Plasmodium falciparum malaria in the third trimester of pregnancy {13}. However, the risk of quinine to the fetus must be balanced against the danger of P. falciparum malaria, which is potentially life-threatening, especially during pregnancy. Studies in humans have shown that quinine causes congenital malformations, especially when given in large doses (e.g., up to 30 grams for attempted abortion). These malformations include deafness related to auditory nerve hypoplasia, limb anomalies, visceral defects, and visual changes. In addition, quinine may have an oxytoxic action on the uterus and has been shown to cause abortion when taken in toxic amounts. Stillbirths have also been reported in mothers taking quinine during pregnancy {01}.

Studies in rabbits and guinea pigs have shown that quinine is teratogenic. However, no teratogenic effects were seen in mice, rats, dogs, or monkeys.

FDA Pregnancy Category X.

Breast-feeding

Quinine is distributed into breast milk in small amounts {01}. One study suggests that a breast-fed infant will receive approximately 1.5 to 3 mg per day of quinine base from maternal therapy {17}. Problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of quinine for use as an antimyotonic have not been performed in the pediatric population. Antimalarial studies performed to date have shown that children have a decreased elimination half-life and volume of distribution; however, pediatrics-specific problems that would limit the usefulness of quinine in children have not been documented {15}.


Geriatrics


No information is available on the relationship of age to the effects of quinine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antacids, aluminum-containing    (concurrent use of aluminum-containing antacids with quinine may decrease or delay the absorption of quinine {03} {11})


Anticoagulants, coumarin- or indandione-derivative    (hypoprothrombinemic effects may be increased when these agents are used concurrently with quinine because of decreased hepatic synthesis of procoagulant factors; hypoprothrombinemia can be prevented by coadministration of vitamin K; dosage adjustments may be necessary during and after quinine therapy {18})


Antimyasthenics    (concurrent use of medications with neuromuscular blocking action may antagonize the effect of antimyasthenics on skeletal muscle; temporary dosage adjustments of antimyasthenics may be necessary to control symptoms of myasthenia gravis during and following concurrent use)


Cimetidine    (concurrent use of cimetidine with quinine may reduce the clearance of quinine {05})


Digitoxin or
Digoxin    (concurrent use of digoxin with quinine may result in increased digoxin serum concentrations and increased digoxin effect by decreasing the nonrenal clearance of digoxin; concurrent use of quinidine with digitoxin has been reported to result in increased digitoxin serum concentrations and increased digitoxin effect as well; because of the similarities of the digitalis glycosides and the similarities of quinine and quinidine, serum digoxin and digitoxin concentrations should be monitored periodically during concurrent therapy with quinine, and dosage adjustments made as indicated {01} {04} {18})


Hemolytics, other (see Appendix II ) or
Neurotoxic medications, other (see Appendix II ) or
Ototoxic medications, other, (see Appendix II )    (concurrent use of these medications with quinine may increase the potential for toxicity)


» Mefloquine    (concurrent use with quinine may result in an increased incidence of seizures and of electrocardiogram abnormalities, predisposing the patient to arrhythmias; it is recommended that mefloquine be administered at least 12 hours after the last dose of quinine {20} {21} {22})

    (patients taking weekly mefloquine prophylaxis may be found to have mefloquine-resistant malaria that requires treatment with quinine; because mefloquine has a very long half-life [approximately 20 days], it will remain in the body long after the drug has been discontinued. Although there is insufficient information available, it is recommended that if quinine must be given, the patient be hospitalized, if possible, and monitored for QT prolongation and possible rhythm disturbances. Seizure activity also may be potentiated in these patients. In patients considered to be at high risk for a seizure, additional precautions and interventions may be indicated {07})


Neuromuscular blocking agents    (neuromuscular blockade may be potentiated when these agents are used concurrently with quinine {18})


Quinidine    (concurrent use with quinine may increase the possibility of QT prolongation or cinchonism)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
17-ketogenic steroid, urinary    (quinine may cause increased values for urinary 17-ketogenic steroids when the metyrapone or Zimmerman method is used {01} {23} {34})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Blackwater fever, history of    (interrupted or recurrent quinine therapy in patients with Plasmodium falciparum infections may predispose them to the complications of blackwater fever, including anemia and hemolysis with renal failure {01} {14} {31})


Cardiac arrhythmias, history of, or QT prolongation    (a prolonged QT interval has been noted in patients being treated for cerebral malaria, without correlation with plasma quinine concentration; patients with a history of cardiac arrhythmias or QT prolongation may be at risk for arrhythmias while taking quinine {35})


Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (hemolysis or hemolytic anemia may occur in G6PD-deficient patients; however, quinine has been given safely in therapeutic doses to patients with G6PD deficiency {01} {43})


» Hypersensitivity to quinine or quinidine
» Hypoglycemia    (quinine stimulates release of insulin from the pancreas; hypoglycemia may also be a complication of severe P. falciparum malaria, especially in children and during pregnancy {04} {06} {07})


» Myasthenia gravis    (quinine may exacerbate muscle weakness in myasthenia gravis due to its neuromuscular blocking effects {01})


» Purpura, thrombocytopenic, or history of    (quinine may cause thrombocytopenic purpura, especially in highly sensitive patients or in patients with a previous history of this reaction to quinine {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Gastrointestinal disturbances (abdominal or stomach cramps or pain; diarrhea; nausea; vomiting){02}


Note: Symptoms of gastrointestinal disturbances, such as nausea and vomiting, may be related to central nervous system (CNS) effects of quinine {02}.

Incidence less frequent
    
Blood dyscrasias such as agranulocytosis, leukopenia, and/or thrombocytopenia (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; sore throat; unusual bleeding or bruising; unusual tiredness or weakness){02}
    
hypoglycemia (anxiety; behavior change, similar to drunkenness; blurred vision; cold sweats; confusion; convulsions or coma; cool pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; unusual tiredness or weakness){02}

Note: Hypoglycemia, which may be severe and recurrent, has been reported in some patients with severe malaria caused by Plasmodium falciparum who received quinine therapy, and there was some evidence that quinine-induced insulin secretion may have been one of several possible precipitating factors {02}.


Incidence rare
    
Cinchonism (abdominal pain; blurred vision; change in color vision; diarrhea; headache; nausea; ringing or buzzing in ears; vomiting)
    
hemolytic uremic syndrome (abdominal pain; bruising; fever or chills; increased sweating; muscle aches; nausea; vomiting)
    
hypersensitivity reactions (abdominal pain; difficulty in breathing and/or swallowing; fever; hives; nausea; reddening of the skin, especially around ears; swelling of eyes, face, or inside of nose; unusual tiredness or weakness)
    
hypoprothrombinemia (unusual bleeding or bruising){01}{02}
    
visual disturbances (blurred vision; disturbed color perception; double vision; night blindness){02}

Note: Hemolytic uremic syndrome (HUS) is a multi-system disorder that is characterized by hemolytic anemia, thrombocytopenia, disseminated intravascular coagulation (DIC), and acute renal failure {01}. This reaction may occur within hours of a single ingestion of quinine {01}. Several case reports have been published describing patients who have had an acute hypersensitivity reaction to quinine that resulted in adult HUS {01}.
Hypoprothrombinemia may be reversed with vitamin K administration {01}.




Those indicating need for medical attention if they occur or progress after medication is discontinued
    
Blurred vision or any other change in vision {02}




Overdose
For specific information on the agents used in the management of quinine overdose, see:
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • Ipecac (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Cardiovascular toxicity (blurred vision; chest pain; confusion; dizziness; fainting; lightheadedness; rapid or irregular heartbeat; unusual tiredness or weakness)
    
central nervous system toxicity (coma; confusion; restlessness; seizures; shortness of breath or troubled breathing; sleepiness)
    
cinchonism (abdominal pain; blurred vision; change in color vision; diarrhea; headache; nausea; ringing or buzzing in ears; vomiting)
    
visual disturbances (blurred vision; complete blindness; double vision)—blindness usually is transitory, but rarely may be permanent{02}


Treatment of overdose

Note: Treatment is mostly symptomatic with attention to maintaining blood pressure, renal function, and respiration, and treating arrhythmias {02}.

Recommended treatment consists of the following:


To decrease absorption:
Using gastric lavage or inducing emesis with ipecac syrup to remove residual quinine from the stomach. Repeated dosing of activated charcoal every 4 hours may be beneficial in shortening the half-life of quinine in an overdose {02} {25} {26} {27}.



To enhance elimination:
Although excretion of quinine is increased in acidic urine, administration of forced acid diuresis has had little impact on quinine elimination by the kidney, which accounts for only 20% of the total body clearance. Peritoneal dialysis, hemodialysis, exchange transfusion, charcoal hemoperfusion, resin hemoperfusion, and plasmapheresis have not been found to be effective in the management of quinine overdose {02} {28} {29} {30}.



Specific treatment:
Stellate ganglionic block has not been shown to be of value in treating quinine-induced blindness and may cause an increase in complications. Caution should be used in administration of antiarrhythmics since quinine has class 1 antiarrhythmic properties that can be potentiated {31} {32} {33}.



Supportive care:
Supportive measures such as maintaining an open airway, respiration, and circulation may be administered. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Quinine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to quinine

Pregnancy—Quinine has been found to be teratogenic; it has also caused stillbirths and abortions in pregnant women





Breast-feeding—Quinine is distributed into breast milk
Other medications, especially mefloquine
Other medical problems, especially a history of blackwater fever, hypoglycemia, myasthenia gravis, and a history of thrombocytopenic purpura

Proper use of this medication
» Importance of not taking more medication than the amount recommended

» Taking medication with or after meals to minimize possible gastrointestinal irritation

» Compliance with full course of therapy in malaria

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Caution if blurred vision or change in color vision occurs


Side/adverse effects
Signs of side effects, especially gastrointestinal disturbances; blood dyscrasias such as agranulocytosis, leukopenia, and/or thrombocytopenia; hypoglycemia; cinchonism; hemolytic uremic syndrome; hypersensitivity reactions; hypoprothrombinemia; and visual disturbances


General Dosing Information
This medication should be taken with or after meals to minimize gastrointestinal irritation.

In the treatment of chloroquine-resistant Plasmodium falciparum malaria, quinine is given concurrently with tetracycline, clindamycin, or pyrimethamine in combination with sulfadiazine or sulfadoxine {14} {19}.

In the treatment of nocturnal recumbency leg cramps, quinine may be discontinued if leg cramps do not occur after several consecutive nights of therapy, to determine if continued therapy is needed {01}.

Plasma concentrations above 10 mg per 100 mL may cause severe symptoms of cinchonism.

Bioequivalence information
Bioavailability of quinine is extensive and rapid in healthy subjects. Studies using various salts of quinine have indicated no marked difference in the rate and extent of absorption of quinine in the capsule and plain tablet dosage forms {08} {12}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling. The dosing and dosage forms available are expressed in terms of quinine sulfate (salt). Bioavailability studies have indicated no marked difference in the rate and extent of absorption of quinine in the capsule and plain tablet dosage forms {08} {12}.

QUININE SULFATE CAPSULES USP

Usual adult and adolescent dose
Malaria, Plasmodium falciparum , chloroquine-resistant (treatment)
Oral, 600 to 650 mg every eight hours for at least three days in most areas of the world (seven days in Southeast Asia) with concurrent administration of 250 mg of tetracycline every six hours for seven days; or concurrent administration of 100 mg of doxycycline every twelve hours for seven days; or concurrent administration of 1.5 grams of sulfadoxine and 75 mg of pyrimethamine combination as a single dose; or concurrent administration of 900 mg of clindamycin three times a day for three days {19}.

[Antimyotonic (treatment)]
Nocturnal recumbency leg cramps: Oral, 200 to 300 mg at bedtime; if an additional dose of 200 to 300 mg is needed, it may be taken following the evening meal {11}.

[Babesiosis (treatment)]1
Oral, 650 mg three or four times a day with concurrent intravenous administration of 300 to 600 mg clindamycin four times a day for seven to ten days {45} {46}.


Usual pediatric dose
Malaria, Plasmodium falciparum , chloroquine-resistant (treatment)
Oral, 8.3 mg per kg of body weight every eight hours for at least three days in most areas of the world (seven days in Southeast Asia) with concurrent administration of 5 mg per kg of body weight of tetracycline every six hours for seven days in children older than 8 years of age; or concurrent administration of 6.7 to 13.3 mg per kg of body weight of clindamycin three times a day for three days; or concurrent administration of 1.25 mg per kg of body weight of pyrimethamine in combination with 25 mg per kg of body weight of sulfadoxine as a single dose {14} {19}.

[Antimyotonic (treatment)]
Dosage has not been established.

[Babesiosis (treatment)]1
Dosage has not been established; however, based on one case report in an infant, the suggested dose is: Oral, 25 mg per kg of body weight per day with concurrent intravenous or intramuscular administration of 20 mg per kg of body weight per day of clindamycin for seven to ten days {44}.


Strength(s) usually available
U.S.—


200 mg (Rx)[Generic]{09}{36}


300 mg (Rx)[Generic]{09}{36}


325 mg (Rx)[Generic]{09}{36}

Canada—


200 mg (Rx)[Generic]{10}{37}


300 mg (Rx)[Generic]{10}{37}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause vision problems.
   • Continue medication for full time of treatment.


QUININE SULFATE TABLETS USP

Usual adult and adolescent dose
See Quinine Sulfate Capsules USP {19}.

Usual pediatric dose
See Quinine Sulfate Capsules USP {14} {19}.

Strength(s) usually available
U.S.—


260 mg (Rx)[Generic]{09}{36}


325 mg (Rx)[Generic]{09}{36}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause vision problems.
   • Continue medication for full time of treatment.



Parenteral Dosage Forms

QUININE DIHYDROCHLORIDE INJECTION

Note: The dosing and strengths of the dosage form are expressed in terms of quinine dihydrochloride (salt) {02}.


Usual adult and adolescent dose
Malaria, Plasmodium falciparum , severe (treatment)
Intravenous (if an infusion pump is available), 7 mg per kg of body weight over thirty minutes followed immediately by 10 mg per kg of body weight diluted in 10 mL per kg isotonic fluid over four hours; repeated every eight hours until oral treatment can be instituted {02}.

or

Intravenous (if an infusion pump is not available), 20 mg per kg of body weight over four hours followed immediately by 10 mg per kg of body weight diluted in 10 mL per kg isotonic fluid over four hours; repeated every eight hours until oral treatment can be instituted {02}.


Note: The two dosage regimens listed above are equally effective {02}. Either regimen should be administered in conjunction with doxycycline, clindamycin, or sulfadoxine/pyrimethamine combination {02}. Treatment should be switched to oral quinine sulfate when the patient can swallow, to complete a seven-day treatment course {02}. If parenteral treatment is required for more than forty-eight hours, the maintenance dose of quinine should be reduced by one third to one half {02}.


Usual pediatric dose
See Usual adult and adolescent dose {02}.

Strength(s) usually available

Note: Quinine dihydrochloride injection is not commercially available in the U.S. or Canada. However, quinine dihydrochloride injection can be obtained in the U.S. from the Parasitic Diseases Drug Service of the Centers for Disease Control and Prevention (CDC), and in Canada from the Special Access Program, Health Canada {02}.

U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.



Revised: 05/24/1999



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