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| ====Dosing Information==== | | ====Dosing Information==== |
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| * Treatment of Uncomplicated [[P. falciparum Malaria]] | | * Treatment of Uncomplicated [[P. falciparum malaria]] |
| * For treatment of uncomplicated [[P. falciparum malaria]] in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days. | | * For treatment of uncomplicated [[P. falciparum malaria]] in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days. |
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| * Quinine sulphate should be taken with food to minimize [[gastric upset]]. | | * Quinine sulphate should be taken with food to minimize [[gastritis|gastric upset]]. |
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| =====Renal Impairment===== | | =====Renal Impairment===== |
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| * Adjustment of the recommended dose is not required in mild ([[Child-Pugh A]]) or moderate ([[Child-Pugh B]]) [[hepatic impairment]], but patients should be monitored closely for adverse effects of quinine. Quinine should not be administered in patients with severe ([[Child-Pugh C]]) [[hepatic impairment]]. | | * Adjustment of the recommended dose is not required in mild ([[Child-Pugh A]]) or moderate ([[Child-Pugh B]]) [[hepatic impairment]], but patients should be monitored closely for adverse effects of quinine. Quinine should not be administered in patients with severe ([[Child-Pugh C]]) [[hepatic impairment]]. |
| |offLabelAdultGuideSupport=* [[Babesiosis]] | | |offLabelAdultGuideSupport=There is limited information regarding off-label use and dosage for adults. |
| | |offLabelAdultNoGuideSupport=* [[Babesiosis]] |
| * [[Malaria]], Uncomplicated, [[Plasmodium vivax]] | | * [[Malaria]], Uncomplicated, [[Plasmodium vivax]] |
| |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Quinine sulphate in adult patients.
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| :* [[Myasthenia gravis]]. Quinine has [[neuromuscular]] blocking activity, and may exacerbate muscle weakness. | | :* [[Myasthenia gravis]]. Quinine has [[neuromuscular]] blocking activity, and may exacerbate muscle weakness. |
| :* [[Optic neuritis]]. Quinine may exacerbate active [[optic neuritis]] | | :* [[Optic neuritis]]. Quinine may exacerbate active [[optic neuritis]] |
| |warnings=====Use of Quinine for Treatment or Prevention of Nocturnal Leg Cramps:===== | | |warnings=====Use of Quinine for Treatment or Prevention of Nocturnal Leg Cramps:==== |
| * Quinine sulphate may cause unpredictable serious and life-threatening [[hematologic]] reactions including [[thrombocytopenia]] and [[hemolytic-uremic syndrome]]/[[thrombotic thrombocytopenic purpura]] ([[HUS]]/[[TTP]]) in addition to [[hypersensitivity]] reactions, [[QT prolongation]], serious [[cardiac arrhythmias]] including [[torsades de pointes]], and other serious adverse events requiring medical intervention and hospitalization. Chronic [[renal impairment]] associated with the development of [[TTP]], and fatalities have also been reported. The risk associated with the use of Quinine sulphate in the absence of evidence of its effectiveness for treatment or prevention of nocturnal [[leg cramps]], outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition. | | * Quinine sulphate may cause unpredictable serious and life-threatening [[hematologic]] reactions including [[thrombocytopenia]] and [[hemolytic-uremic syndrome]]/[[thrombotic thrombocytopenic purpura]] ([[HUS]]/[[TTP]]) in addition to [[hypersensitivity]] reactions, [[QT prolongation]], serious [[cardiac arrhythmias]] including [[torsades de pointes]], and other serious adverse events requiring medical intervention and hospitalization. Chronic [[renal impairment]] associated with the development of [[TTP]], and fatalities have also been reported. The risk associated with the use of Quinine sulphate in the absence of evidence of its effectiveness for treatment or prevention of nocturnal [[leg cramps]], outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition. |
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| =====Hypoglycemia===== | | =====Hypoglycemia===== |
| * Quinine stimulates release of [[insulin]] from the [[pancreas]], and patients, especially [[pregnant]] women, may experience clinically significant [[hypoglycemia]]. | | * Quinine stimulates release of [[insulin]] from the [[pancreas]], and patients, especially [[pregnant]] women, may experience clinically significant [[hypoglycemia]]. |
| |clinicalTrials=====Overall===== | | |clinicalTrials=====Overall==== |
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| * Quinine can adversely affect almost every body system. The most common adverse events associated with quinine use are a cluster of symptoms called "[[cinchonism]]", which occurs to some degree in almost all patients taking quinine. Symptoms of mild [[cinchonism]] include headache, [[vasodilation]] and [[sweating]], [[nausea]], [[tinnitus]], [[hearing impairment]], [[vertigo]] or [[dizziness]], [[blurred vision]], and disturbance in color perception. More severe symptoms of [[cinchonism]] are [[vomiting]], [[diarrhea]], [[abdominal pain]], [[deafness]], [[blindness]], and disturbances in [[cardiac rhythm]] or conduction. Most symptoms of [[cinchonism]] are reversible and resolve with discontinuation of quinine. | | * Quinine can adversely affect almost every body system. The most common adverse events associated with quinine use are a cluster of symptoms called "[[cinchonism]]", which occurs to some degree in almost all patients taking quinine. Symptoms of mild [[cinchonism]] include headache, [[vasodilation]] and [[sweating]], [[nausea]], [[tinnitus]], [[hearing impairment]], [[vertigo]] or [[dizziness]], [[blurred vision]], and disturbance in color perception. More severe symptoms of [[cinchonism]] are [[vomiting]], [[diarrhea]], [[abdominal pain]], [[deafness]], [[blindness]], and disturbances in [[cardiac rhythm]] or conduction. Most symptoms of [[cinchonism]] are reversible and resolve with discontinuation of quinine. |
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| =====Hematologic:===== | | =====Hematologic:===== |
| * [[Agranulocytosis]], [[hypoprothrombinemia]], [[thrombocytopenia]], [[disseminated intravascular coagulation,]] [[hemolytic anemia]]; [[hemolytic uremic syndrome]], [[thrombotic thrombocytopenic purpura]], [[idiopathic thrombocytopenic purpura]], [[petechiae]], [[ecchymosis]], [[hemorrhage]], [[coagulopathy]], [[blackwater]] [[fever]], [[leukopenia]], [[neutropenia]], [[pancytopenia]], [[aplastic anemia]], and [[lupus anticoagulant]]. | | * [[Agranulocytosis]], [[hypoprothrombinemia]], [[thrombocytopenia]], [[DIC|disseminated intravascular coagulation,]] [[hemolytic anemia]]; [[hemolytic uremic syndrome]], [[thrombotic thrombocytopenic purpura]], [[idiopathic thrombocytopenic purpura]], [[petechiae]], [[ecchymosis]], [[hemorrhage]], [[coagulopathy]], [[blackwater]] [[fever]], [[leukopenia]], [[neutropenia]], [[pancytopenia]], [[aplastic anemia]], and [[lupus anticoagulant]]. |
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| =====Neuropsychiatric:===== | | =====Neuropsychiatric:===== |
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| * Visual disturbances, including [[blurred vision]] with [[scotomata]], sudden [[loss of vision]], [[photophobia]], [[diplopia]], [[night blindness]], diminished [[visual fields]], fixed [[pupillary dilatation]], disturbed [[color vision]], [[optic neuritis]], [[blindness]], [[vertigo]], [[tinnitus]], [[hearing impairment]], and [[deafness]]. | | * Visual disturbances, including [[blurred vision]] with [[scotomata]], sudden [[loss of vision]], [[photophobia]], [[diplopia]], [[night blindness]], diminished [[visual fields]], fixed [[pupillary dilatation]], disturbed [[color vision]], [[optic neuritis]], [[blindness]], [[vertigo]], [[tinnitus]], [[hearing impairment]], and [[deafness]]. |
| |postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of Quinine sulphate in the drug label. | | |postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of Quinine sulphate in the drug label. |
| |drugInteractions=====Effects of Drugs and Other Substances on Quinine Pharmacokinetics=====
| | |alcohol=Alcohol-Quinine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |
| * Quinine is a P-gp substrate and is primarily metabolized by [[CYP3A4]]. Other [[enzymes]], including [[CYP1A2]], [[CYP2C8]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], and [[CYP2E1]] may contribute to the [[metabolism]] of quinine.
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| * Antacids:
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| :* [[Antacids]] containing [[aluminum]] and/or [[magnesium]] may delay or decrease absorption of quinine. Concomitant administration of these [[antacids]] with Quinine sulphate should be avoided.
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| * [[Antiepileptics]] (AEDs) ([[carbamazepine]], [[phenobarbital]], and [[phenytoin]]):
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| :* [[Carbamazepine]], [[phenobarbital]], and [[phenytoin]] are [[CYP3A4]] inducers and may decrease quinine [[plasma]] concentrations if used concurrently with Quinine sulphate.
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| * Cholestyramine:
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| :* In 8 healthy subjects who received quinine sulfate 600 mg with or without 8 grams of [[cholestyramine]] resin, no significant difference in quinine [[pharmacokinetic]] parameters was seen.
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| * [[Cigarette Smoking]] ([[CYP1A2]] inducer):
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| :* In healthy male heavy smokers, the mean quinine AUC following a single 600 mg dose was 44% lower, the mean [[Cmax]] was 18% lower, and the [[elimination half-life]] was shorter (7.5 hours versus 12 hours) than in their non-smoking counterparts. However, in [[malaria]] patients who received the full 7-day course of quinine therapy, [[cigarette smoking]] produced only a 25% decrease in median quinine AUC and a 16.5% decrease in median [[Cmax]], suggesting that the already reduced clearance of quinine in acute [[malaria]] could have diminished the [[metabolic]] induction effect of smoking. Because smoking did not appear to influence the [[therapeutic]] outcome in malaria patients, it is not necessary to increase the dose of quinine in the treatment of [[acute malaria]] in heavy [[cigarette smoking|cigarette smokers]].
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| * Grapefruit juice (P-gp/[[CYP3A4 inhibitor]]):
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| :* In a [[pharmacokinetic]] study involving 10 healthy subjects, the administration of a single 600 mg dose of quinine sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the [[pharmacokinetic]] parameters of quinine. Quinine sulphate may be taken with grapefruit juice.
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| * [[H2 antagonist|Histamine H2-receptor blockers]] [[[cimetidine]], [[ranitidine]] (nonspecific [[CYP450 inhibitors|CYP450 inhibitors]]:
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| :* In healthy subjects who were given a single oral 600 mg dose of quinine sulfate after pretreatment with [[cimetidine]] (200 mg three times daily and 400 mg at bedtime for 7 days) or [[ranitidine]] (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean elimination half-life increased significantly when given with [[cimetidine]] but not with [[ranitidine]]. Compared to untreated controls, the mean AUC of quinine increased by 20% with [[ranitidine]] and by 42% with [[cimetidine]] (p<0.05) without a significant change in mean quinine [[Cmax]]. When quinine is to be given concomitantly with a [[H2 antagonist|Histamine H2-receptor blockers]], the use of [[ranitidine]] is preferred over [[cimetidine]]. Although [[cimetidine]] and [[ranitidine]] may be used concomitantly with Quinine sulphate, patients should be monitored closely for adverse events associated with quinine.
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| * Isoniazid:
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| :* [[Isoniazid]] 300 mg/day pretreatment for 1 week did not significantly alter the [[pharmacokinetic]] parameter values of quinine. Adjustment of Quinine sulphate dosage is not necessary when [[isoniazid]] is given concomitantly.
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| * Ketoconazole ([[CYP3A4]] inhibitor):
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| :* In a crossover study, healthy subjects (N=9) who received a single oral dose of [[quinine hydrochloride]] (500 mg) concomitantly with [[ketoconazole]] (100 mg twice daily for 3 days) had a mean quinine AUC that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving [[quinine]] alone. Although no change in the Quinine sulphate dosage regimen is necessary with concomitant [[ketoconazole]], patients should be monitored closely for [[adverse reactions]] associated with quinine.
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| * [[Macrolide]] [[antibiotics]] ([[erythromycin]], [[troleandomycin]]) ([[CYP3A4]] inhibitors):
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| :* In a [[crossover study]] (N=10), healthy subjects who received a single oral 600 mg dose of quinine sulfate with the [[macrolide antibiotic]], [[troleandomycin]] (500 mg every 8 hours) exhibited a 87% higher mean quinine AUC, a 45% lower mean oral clearance of quinine, and a 81% lower formation clearance of the main [[metabolite]], 3-hydroxyquinine, than when quinine was given alone.
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| :* [[Erythromycin]] was shown to inhibit the in vitro [[metabolism]] of quinine in human [[liver]] [[microsomes]], an observation confirmed by an in vivo interaction study. In a crossover study (N=10), healthy subjects who received a single oral 500 mg dose of quinine sulfate with [[erythromycin]] (600 mg every 8 hours for four days) showed a decrease in quinine oral clearance (CL/F), an increase in half-life, and a decreased [[metabolite]] (3-hydroxyquinine) to quinine [[AUC]] ratio, as compared to when quinine was given with [[placebo]].
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| :* Therefore, concomitant administration of [[macrolide antibiotics]] such as [[erythromycin]] or [[troleandomycin]] with Quinine sulphate should be avoided.
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| * [[Oral contraceptives]] ([[estrogen]], [[progestin]]):
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| :* In 7 healthy females who were using single-ingredient [[progestin]] or combination estrogen-containing [[oral contraceptives]], the [[pharmacokinetic]] parameters of a single 600 mg dose of quinine sulfate were not altered in comparison to those observed in 7 age-matched female control subjects not using [[oral contraceptives]].
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| * [[Rifampin]] ([[CYP3A4]] inducer):
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| :* In patients with uncomplicated [[P. falciparum malaria]] who received quinine sulfate 10 mg/kg concomitantly with [[rifampin]] 15 mg/kg/day for 7 days (N=29), the [[AUC|median AUC]] of quinine between days 3 and 7 of therapy was 75% lower as compared to those who received quinine [[monotherapy]]. In healthy subjects (N=9) who received a single oral 600 mg dose of quinine sulfate after 2 weeks of pretreatment with [[rifampin]] 600 mg/day, the mean quinine AUC and [[Cmax]] decreased by 85% and 55%, respectively. Therefore, the concomitant administration of [[rifampin]] with Quinine sulphate should be avoided.
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| * Ritonavir:
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| :* In healthy subjects who received a single oral 600 mg dose of quinine sulfate with the 15th dose of [[ritonavir]] (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean quinine AUC and [[Cmax]], and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when quinine was given alone. Therefore, the concomitant administration of [[ritonavir]] with Quinine sulphate capsules should be avoided.
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| * [[Tetracycline]]:
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| :* In 8 patients with acute uncomplicated [[P. falciparum malaria]] who were treated with oral quinine sulfate (600 mg every 8 hours for 7 days) in combination with oral [[tetracycline]] (250 mg every 6 hours for 7 days), the mean [[plasma]] quinine concentrations were about two-fold higher than in 8 patients who received quinine [[monotherapy]]. Although [[tetracycline]] may be concomitantly administered with Quinine sulphate, patients should be monitored closely for adverse reactions associated with quinine sulfate.
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| * [[Theophylline]] or [[aminophylline]]:
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| :* In 20 healthy subjects who received multiple doses of Quinine sulphate (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of [[theophylline]], the quinine mean [[Cmax]] and AUC were increased by 13% and 14% respectively. Although no change in the Quinine sulphate dosage regimen is necessary with concomitant [[theophylline]] or [[aminophylline]], patients should be monitored closely for adverse reactions associated with quinine.
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| * Urinary alkalizers ([[acetazolamide]], [[sodium bicarbonate]]):
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| :* Urinary alkalinizing agents may increase plasma quinine concentrations.
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| =====Effects of Quinine on the Pharmacokinetics of Other Drugs:=====
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| * Results of in vivo [[drug interaction]] studies suggest that quinine has the potential to inhibit the [[metabolism]] of drugs that are substrates of [[CYP3A4]] and [[CYP2D6]]. Quinine inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates.
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| * [[Anticonvulsants]] ([[carbamazepine]], [[phenobarbital]], and [[phenytoin]]):
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| :* A single 600 mg oral dose of quinine sulfate increased the mean plasma [[Cmax]], and AUC0–24 of single oral doses of [[carbamazepine]] (200 mg) and [[phenobarbital]] (120 mg) but not [[phenytoin]] (200 mg) in 8 healthy subjects. The mean [[AUC]] increases of [[carbamazepine]], [[phenobarbital]] and [[phenytoin]] were 104%, 81% and 4%, respectively; the mean increases in [[Cmax]] were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three [[antiepileptics]] over 24 hours were also profoundly increased by quinine. If concomitant administration with [[carbamazepine]] or phenobarbital cannot be avoided, frequent monitoring of [[anticonvulsant]] drug concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these [[anticonvulsants]].
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| * [[Astemizole]] ([[CYP3A4]] substrate):
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| :* Elevated [[plasma]] [[astemizole]] concentrations were reported in a subject who experienced [[torsades de pointes]] after receiving three doses of quinine sulfate for [[nocturnal]] [[leg cramps]] concomitantly with chronic [[astemizole]] 10 mg/day. The concurrent use of Quinine sulphate with [[astemizole]] and other [[CYP3A4]] substrates with [[QT prolongation]] potential (e.g., [[cisapride]], [[terfenadine]], [[halofantrine]], [[pimozide]] and [[quinidine]]) should also be avoided.
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| * [[Atorvastatin]] ([[CYP3A4]] substrate):
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| :* [[Rhabdomyolysis]] with [[acute renal failure]] secondary to [[myoglobinuria]] was reported in a patient taking [[atorvastatin]] administered with a single dose of quinine. Quinine may increase plasma [[concentrations]] of [[atorvastatin]], thereby increasing the risk of [[myopathy]] or [[rhabdomyolysis]]. Thus, clinicians considering combined therapy of Quinine sulphate with [[atorvastatin]] or other [[HMG-CoA reductase|HMG-CoA reductase inhibitors]] ("[[statins]]") that are [[CYP3A4]] substrates (e.g., [[simvastatin]], [[lovastatin]]) should carefully weigh the potential benefits and risks of each medication. If Quinine sulphate is used concomitantly with any of these [[statins]], lower starting and maintenance doses of the [[statin]] should be considered. Patients should also be monitored closely for any signs or symptoms of [[muscle pain]], [[tenderness]], or weakness, particularly during initial therapy. If marked [[creatine phosphokinase]] ([[CPK]]) elevation occurs or [[myopathy]] (defined as [[muscle aches]] or [[muscle weakness]] in conjunction with [[CPK]] values >10 times the upper limit of normal) is diagnosed or suspected, [[atorvastatin]] or other [[statin]] should be discontinued.
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| * [[Desipramine]] ([[CYP2D6]] substrate):
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| :* [[Quinine]] (750 mg/day for 2 days) decreased the metabolism of [[desipramine]] in patients who were extensive [[CYP2D6]] metabolizers, but had no effect in patients who were poor [[CYP2D6]] metabolizers. Lower doses (80 mg to 400 mg) of quinine did not significantly affect the [[pharmacokinetics]] of other [[CYP2D6]] substrates, namely, [[debrisoquine]], [[dextromethorphan]], and [[methoxyphenamine]]. Although clinical drug interaction studies have not been performed, [[antimalarial]] doses (greater than or equal to 600 mg) of quinine may inhibit the [[metabolism]] of other drugs that are [[CYP2D6]] substrates (e.g., [[flecainide]], [[debrisoquine]], [[dextromethorphan]], [[metoprolol]], [[paroxetine]]). Patients taking medications that are [[CYP2D6]] substrates with Quinine sulphate should be monitored closely for adverse reactions associated with these medications.
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| * [[Digoxin]] (P-gp substrate):
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| :* In 4 healthy subjects who received [[digoxin]] (0.5 to 0.75 mg/day) during treatment with quinine (750 mg/day), a 33% increase in mean steady state AUC of [[digoxin]] and a 35% reduction in the steady state [[biliary]] clearance of [[digoxin]] were observed compared to [[digoxin]] alone. Thus, if Quinine sulphate is administered to patients receiving [[digoxin]], plasma [[digoxin]] concentrations should be closely monitored, and the [[digoxin]] dose adjusted, as necessary.
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| * [[Halofantrine]]:
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| :* Although not studied clinically, quinine was shown to inhibit the metabolism of [[halofantrine]] in vitro using human liver [[microsomes]]. Therefore, concomitant administration of Quinine sulphate is likely to increase plasma [[halofantrine]] concentrations.
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| * [[Mefloquine]]:
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| :* In 7 healthy subjects who received [[mefloquine]] (750 mg) at 24 hours before an oral 600 mg dose of quinine sulfate, the [[AUC]] of [[mefloquine]] was increased by 22% compared to [[mefloquine]] alone. In this study, the [[QTc interval]] was significantly prolonged in the subjects who received [[mefloquine]] and quinine sulfate 24 hours apart. The concomitant administration of [[mefloquine]] and Quinine sulphate may produce [[electrocardiographic]] abnormalities (including [[QT prolongation|QTc prolongation]]) and may increase the risk of [[seizures]].
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| * [[Midazolam]] ([[CYP3A4]] substrate):
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| :* In 23 healthy subjects who received multiple doses of Quinine sulphate 324 mg three times daily × 7 days with a single oral 2 mg dose of [[midazolam]], the mean AUC and [[Cmax]] of [[midazolam]] and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Quinine sulphate 324 mg every 8 hours did not induce the [[metabolism]] of [[midazolam]].
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| * [[Neuromuscular blocking agents]] ([[pancuronium]], [[succinylcholine]], [[tubocurarine]]):
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| :* In one report, quinine potentiated [[neuromuscular junction|neuromuscular blockade]] in a patient who received [[pancuronium]] during an operative procedure, and subsequently (3 hours after receiving [[pancuronium]]) received quinine 1800 mg daily. Quinine may also enhance the [[neuromuscular junction|neuromuscular blockade]] of [[succinylcholine]] and [[tubocurarine]].
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| * [[Ritonavir]]:
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| :* In healthy subjects who received a single oral 600 mg dose of quinine sulfate with the 15th dose of [[ritonavir]] (200 mg every 12 hours for 9 days), the mean [[ritonavir]] AUC, [[Cmax]], and elimination half-life were slightly but not significantly increased compared to when [[ritonavir]] was given alone. However, due to the significant effect of [[ritonavir]] on quinine [[pharmacokinetics]], the concomitant administration of Quinine sulphate capsules with [[ritonavir]] should be avoided.
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| * [[Theophylline]] or [[aminophylline]] ([[CYP1A2]] substrate):
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| :* In 19 healthy subjects who received multiple doses of Quinine sulphate 648 mg every 8 hours x 7 days with a single 300 mg oral dose of [[theophylline]], the mean [[theophylline]] [[AUC]] was 10% lower than when [[theophylline]] was given alone. There was no significant effect on mean [[theophylline]] [[Cmax]]. Therefore, if Quinine sulphate is co-administered to patients receiving [[theophylline]] or [[aminophylline]], plasma [[theophylline]] concentrations should be monitored frequently to ensure [[therapeutic]] concentrations.
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| * [[Warfarin]] and oral [[anticoagulants]]:
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| :* [[Cinchona alkaloids]], including quinine, may have the potential to depress [[hepatic]] [[enzyme]] synthesis of [[vitamin K|vitamin K-dependent]] [[coagulation]] pathway [[proteins]] and may enhance the action of [[warfarin]] and other oral [[anticoagulants]]. Quinine may also interfere with the [[anticoagulant]] effect of [[heparin]]. Thus, in patients receiving these [[anticoagulants]], the [[prothrombin time]] ([[PT]]), [[partial thromboplastin time]] ([[PTT]]), or [[international normalization ratio]] ([[INR]]) should be closely monitored as appropriate, during concurrent therapy with Quinine sulphate.
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| =====Drug/Laboratory Interactions:=====
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| * Quinine may produce an elevated value for [[steroids|urinary 17-ketogenic steroids]] when the Zimmerman method is used.
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| * Quinine may interfere with urine [[qualitative dipstick protein assays]] as well as quantitative methods (e.g., [[pyrogallol]] red-molybdate).
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| |FDAPregCat=C
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| |useInPregnancyFDA=* There are extensive published data but few well-controlled studies of Quinine sulphate in [[pregnant]] women. Published data on over 1,000 [[pregnancy]] exposures to quinine did not show an increase in [[teratogenic]] effects over the background rate in the general [[population]]; however, the majority of these exposures were not in the first [[trimester]]. In developmental and [[reproductive]] [[toxicity]] studies, [[central nervous system]] ([[CNS]]) and ear abnormalities and increased [[fetal]] deaths occurred in some species when [[pregnant]] animals received quinine at doses about 1 to 4 times the human clinical dose. Quinine should be used during [[pregnancy]] only if the potential benefit justifies the potential risk to the fetus.
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| * [[P. falciparum malaria]] carries a higher risk of [[morbidity]] and mortality in [[pregnant]] women than in the general population. [[Pregnant]] women with [[P. falciparum malaria]] have an increased incidence of [[fetal]] loss (including spontaneous [[abortion]] and [[stillbirth]]), [[preterm labor]] and [[delivery]], [[intrauterine growth retardation]], [[low birth weight]], and [[maternal death]]. Therefore, treatment of [[malaria]] in [[pregnancy]] is important.
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| * [[Hypoglycemia]], due to increased [[pancreatic]] secretion of [[insulin]], has been associated with quinine use, particularly in [[pregnant]] women.
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| * Quinine crosses the [[placenta]] with measurable bloo[[d]] concentrations in the [[fetus]]. In 8 women who delivered live infants 1 to 6 days after starting quinine therapy, [[umbilical cord]] [[plasma]] quinine concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to [[maternal]] [[plasma]] quinine concentrations was 0.32 ± 0.14. Quinine levels in the fetus may not be [[therapeutic]]. If [[congenital]] [[malaria]] is suspected after [[delivery]], the [[infant]] should be evaluated and treated appropriately.
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| * A study from Thailand (1999) of women with [[P. falciparum malaria]] who were treated with oral quinine sulfate 10 mg/kg 3 times daily for 7 days at anytime in [[pregnancy]] reported no significant difference in the rate of [[stillbirths]] at >28 weeks of [[gestation]] in women treated with quinine (10 of 633 women [1.6%]) as compared with a control group without [[malaria]] or exposure to [[antimalarial]] drugs during [[pregnancy]] (40 of 2201 women [1.8%]). The overall rate of [[congenital malformations]] (9 of 633 offspring [1.4%]) was not different for women who were treated with quinine sulfate compared with the [[control group]] (38 of 2201 offspring [1.7%]). The [[spontaneous abortion]] rate was higher in the control group (10.9%) than in women treated with quinine sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An [[epidemiologic]] survey that included 104 mother-child pairs exposed to quinine during the first 4 months of [[pregnancy]], found no increased risk of structural [[birth defects]] was seen (2 fetal [[malformations]] [1.9%]). Rare and isolated case reports describe deafness and [[optic nerve hypoplasia]] in children exposed in [[utero]] due to [[maternal]] [[ingestion]] of high doses of quinine.
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| * In animal developmental studies conducted in multiple animal species, [[pregnant]] animals received quinine by the [[subcutaneous]] or [[intramuscular]] route at dose levels similar to the maximum recommended human dose ([[MRHD]]; 32 mg/kg/day) based on body surface area (BSA) comparisons. There were increases in [[fetal]] death in [[utero]] in rabbits at maternal doses ≥ 100 mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels approximately 0.5 and 0.25 times the [[MRHD]] respectively based on BSA comparisons. Rabbit [[offspring]] had increased rates of degenerated [[auditory nerve]] and [[spiral ganglion]] and increased rates of [[CNS anomalies]] such as [[anencephaly]] and [[microcephaly]] at a dose of 130 mg/kg/day corresponding to a maternal dose approximately 1.3 times the [[MRHD]] based on BSA comparison. Guinea pig offspring had increased rates of [[hemorrhage]] and [[mitochondrial]] change in the [[cochlea]] at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the [[MRHD]] based on BSA comparison. There were no [[teratogenic]] findings in rats at [[maternal]] doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the [[MRHD]] respectively based on BSA comparisons.
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| * In a pre- [[postnatal]] study in rats, an estimated oral dose of quinine sulfate of 20 mg/kg/day corresponding to approximately 0.1 times the [[MRHD]] based on BSA comparison resulted in offspring with impaired growth, lower body weights at [[birth]] and during the [[lactation]] period, and delayed physical development of [[teeth|teeth eruption]] and eye opening during the [[lactation]] period.
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| |useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
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| | |
| There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Quinine sulphate in women who are pregnant.
| |
| |useInLaborDelivery=* There is no evidence that quinine causes uterine contractions at the doses recommended for the treatment of [[malaria]]. In doses several-times higher than those used to treat [[malaria]], quinine may stimulate the [[pregnant]] [[uterus]].
| |
| |useInNursing=* There is limited information on the safety of quinine in [[breastfeeding|breastfed]] infants. No toxicity was reported in infants in a single study where oral quinine sulfate (10 mg/kg every 8 hours for 1 to 10 days) was administered to 25 [[lactating]] women. It is estimated from this study that [[breastfeeding|breastfed]] [[infants]] would receive less than 2 to 3 mg per day of quinine base (< 0.4% of the maternal dose) via [[breast milk]].
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| | |
| * Although quinine is generally considered compatible with [[breastfeeding]], the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a [[nursing]] woman.
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| | |
| * If [[malaria]] is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma quinine levels may not be [[therapeutic]] in [[infants]] of [[nursing]] mothers receiving Quinine sulphate.
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| |useInPed=There is no FDA guidance on the use of Quinine sulphate with respect to pediatric patients.
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| |useInGeri=There is no FDA guidance on the use of Quinine sulphate with respect to geriatric patients.
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| |useInGender=There is no FDA guidance on the use of Quinine sulphate with respect to specific gender populations.
| |
| |useInRace=There is no FDA guidance on the use of Quinine sulphate with respect to specific racial populations.
| |
| |useInRenalImpair=* Clearance of quinine is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced
| |
| |useInHepaticImpair=* In patients with severe [[hepatic impairment]] ([[Child-Pugh C]]), quinine oral clearance (CL/F) is decreased, volume of distribution (Vd/F) is increased, and half-life is prolonged, relative to subjects with normal [[liver function]]. Therefore, quinine is not indicated in patients with severe [[hepatic impairment]] and alternate therapy should be administered.
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| | |
| * Close monitoring is recommended for patients with mild ([[Child-Pugh A]]) or moderate ([[Child-Pugh B]]) [[hepatic impairment]], as exposure to quinine may be increased relative to subjects with normal [[liver function]]
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| |useInReproPotential=There is no FDA guidance on the use of Quinine sulphate in women of [[reproductive]] potentials and males.
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| |useInImmunocomp=There is no FDA guidance one the use of Quinine sulphate in patients who are immunocompromised.
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| | |
| <!--Administration and Monitoring-->
| |
| |administration=* [[Oral]]
| |
| |monitoring=====Hepatic Impairment=====
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| | |
| * Adjustment of the recommended dose is not required in mild ([[Child-Pugh A]]) or moderate ([[Child-Pugh B]]) [[hepatic impairment]], but patients should be monitored closely for adverse effects of quinine. Quinine should not be administered in patients with severe ([[Child-Pugh C]]) [[hepatic impairment]].
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| | |
| * In otherwise healthy subjects with mild [[hepatic impairment]] ([[Child-Pugh A]]; N=10), who received a single 500 mg dose of quinine sulfate, there was no significant difference in quinine [[pharmacokinetic]] parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate [[hepatic impairment]] ([[Child-Pugh B]]; N=9) who received a single oral 600 mg dose of quinine sulfate, the mean [[AUC]] increased by 55% without a significant change in mean [[Cmax]], as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of quinine was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate [[hepatic impairment]], dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine.
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| | |
| =====Atrial Fibrillation and Flutter=====
| |
| * Quinine sulphate should be used with caution in patients with [[atrial fibrillation]] or [[atrial flutter]]. A paradoxical increase in [[ventricular]] response rate may occur with quinine, similar to that observed with [[quinidine]]. If [[digoxin]] is used to prevent a rapid [[ventricular]] response, serum [[digoxin]] levels should be closely monitored, because [[digoxin]] levels may be increased with use of quinine
| |
| | |
| =====Histamine H2-receptor blockers i.e cimetidine, ranitidine (nonspecific CYP450 inhibitors)======
| |
| * In healthy subjects who were given a single oral 600 mg dose of quinine sulfate after pretreatment with [[cimetidine]] (200 mg three times daily and 400 mg at bedtime for 7 days) or [[ranitidine]] (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean elimination half-life increased significantly when given with cimetidine but not with [[ranitidine]]. Compared to untreated controls, the mean AUC of quinine increased by 20% with [[ranitidine]] and by 42% with [[cimetidine]] (p<0.05) without a significant change in mean quinine [[Cmax]]. When quinine is to be given concomitantly with a [[histamine antagonist|histamine H2-receptor blocker]], the use of [[ranitidine]] is preferred over [[cimetidine]]. Although [[cimetidine]] and [[ranitidine]] may be used concomitantly with Quinine sulphate, patients should be monitored closely for adverse events associated with quinine.
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| | |
| =====Ketoconazole (CYP3A4 inhibitor)=====
| |
| * In a [[crossover study]], healthy subjects (N=9) who received a single oral dose of [[quinine hydrochloride]] (500 mg) concomitantly with [[ketoconazole]] (100 mg twice daily for 3 days) had a mean quinine [[AUC]] that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving quinine alone. Although no change in the Quinine sulphate dosage regimen is necessary with concomitant [[ketoconazole]], patients should be monitored closely for adverse reactions associated with quinine.
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| | |
| * [[Tetracycline]]: In 8 patients with acute uncomplicated [[P. falciparum malaria]] who were treated with oral quinine sulfate (600 mg every 8 hours for 7 days) in combination with oral [[tetracycline]] (250 mg every 6 hours for 7 days), the mean [[plasma]] quinine [[concentrations]] were about two-fold higher than in 8 patients who received quinine monotherapy. Although [[tetracycline]] may be concomitantly administered with Quinine sulphate, patients should be monitored closely for adverse reactions associated with quinine sulfate.
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| | |
| * [[Theophylline]] or [[aminophylline]]: In 20 healthy subjects who received multiple doses of Quinine sulphate (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of [[theophylline]], the quinine mean [[Cmax]] and [[AUC]] were increased by 13% and 14% respectively. Although no change in the Quinine sulphate dosage regimen is necessary with concomitant [[theophylline]] or [[aminophylline]], patients should be monitored closely for adverse reactions associated with quinine.
| |
| | |
| * [[Anticonvulsants]] ([[carbamazepine]], [[phenobarbital]], and [[phenytoin]]): A single 600 mg oral dose of quinine sulfate increased the mean [[Cmax|plasma Cmax]], and AUC0–24 of single oral doses of [[carbamazepine]] (200 mg) and [[phenobarbital]] (120 mg) but not [[phenytoin]] (200 mg) in 8 healthy subjects. The mean [[AUC]] increases of [[carbamazepine]], [[phenobarbital]] and [[phenytoin]] were 104%, 81% and 4%, respectively; the mean increases in [[Cmax]] were 56%, 53%, and 4%, respectively. Mean [[urinary]] recoveries of the three [[antiepileptics]] over 24 hours were also profoundly increased by quinine. If concomitant administration with [[carbamazepine]] or [[phenobarbital]] cannot be avoided, frequent monitoring of [[anticonvulsant drug]] concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these [[anticonvulsants]].
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| | |
| * [[Atorvastatin]] ([[CYP3A4]] substrate): [[Rhabdomyolysis]] with [[acute renal failure]] secondary to [[myoglobinuria]] was reported in a patient taking [[atorvastatin]] administered with a single dose of quinine. Quinine may increase [[plasma]] concentrations of [[atorvastatin]], thereby increasing the risk of [[myopathy]] or [[rhabdomyolysis]]. Thus, clinicians considering combined therapy of Quinine sulphate with [[atorvastatin]] or other [[Statin|HMG-CoA reductase inhibitors]] ("[[statins]]") that are [[CYP3A4]] substrates (e.g., [[simvastatin]], [[lovastatin]]) should carefully weigh the potential benefits and risks of each medication. If Quinine sulphate is used concomitantly with any of these [[statins]], lower starting and maintenance doses of the [[statin]] should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, [[tenderness]], or [[weakness]], particularly during initial therapy. If marked [[creatine phosphokinase]] ([[CPK]]) elevation occurs or [[myopathy]] (defined as [[muscle aches]] or [[muscle weakness]] in conjunction with [[CPK]] values >10 times the upper limit of normal) is diagnosed or suspected, [[atorvastatin]] or other [[statin]] should be discontinued.
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| | |
| * [[Desipramine]] ([[CYP2D6]] substrate): Quinine (750 mg/day for 2 days) decreased the [[metabolism]] of [[desipramine]] in patients who were extensive [[CYP2D6]] [[metabolism|metabolizers]], but had no effect in patients who were poor [[CYP2D6]] [[metabolism|metabolizers]]. Lower doses (80 mg to 400 mg) of quinine did not significantly affect the [[pharmacokinetics]] of other [[CYP2D6]] substrates, namely, [[debrisoquine]], [[dextromethorphan]], and [[methoxyphenamine]]. Although clinical [[drug interaction]] studies have not been performed, [[antimalarial]] doses (greater than or equal to 600 mg) of quinine may inhibit the [[metabolism]] of other drugs that are [[CYP2D6]] substrates (e.g., [[flecainide]], [[debrisoquine]], [[dextromethorphan]], [[metoprolol]], [[paroxetine]]). Patients taking medications that are [[CYP2D6]] substrates with Quinine sulphate should be monitored closely for adverse reactions associated with these medications.
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| | |
| * [[Digoxin]] (P-gp substrate): In 4 healthy subjects who received [[digoxin]] (0.5 to 0.75 mg/day) during treatment with quinine (750 mg/day), a 33% increase in mean steady state [[AUC]] of [[digoxin]] and a 35% reduction in the steady state [[biliary]] clearance of [[digoxin]] were observed compared to [[digoxin]] alone. Thus, if Quinine sulphate is administered to patients receiving [[digoxin]], plasma [[digoxin]] concentrations should be closely monitored, and the [[digoxin]] dose adjusted, as necessary.
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| | |
| * [[Theophylline]] or [[aminophylline]] ([[CYP1A2]] substrate): In 19 healthy subjects who received multiple doses of Quinine sulphate 648 mg every 8 hours x 7 days with a single 300 mg oral dose of [[theophylline]], the mean [[theophylline]] [[AUC]] was 10% lower than when [[theophylline]] was given alone. There was no significant effect on mean [[theophylline]] [[Cmax]]. Therefore, if Quinine sulphate is co-administered to patients receiving theophylline or [[aminophylline]], plasma [[theophylline]] concentrations should be monitored frequently to ensure [[therapeutic]] concentrations.
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| | |
| * [[Warfarin]] and oral [[anticoagulants]]: [[Cinchona|Cinchona alkaloids]], including quinine, may have the potential to depress [[liver|hepatic enzyme synthesis]] of [[vitamin K]]-dependent [[coagulation]] pathway [[proteins]] and may enhance the action of [[warfarin]] and other oral [[anticoagulants]]. Quinine may also interfere with the [[anticoagulant]] effect of [[heparin]]. Thus, in patients receiving these [[anticoagulants]], the [[prothrombin time]] ([[PT]]), [[partial thromboplastin time]] ([[PTT]]), or [[international normalization ratio]] ([[INR]]) should be closely monitored as appropriate, during concurrent therapy with Quinine sulphate.
| |
| |IVCompat=There is limited information regarding <i>IV Compatibility</i> of Quinine sulphate in the drug label.
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| | |
| <!--Overdosage-->
| |
| |overdose=* Quinine overdose can be associated with serious complications, including [[visual impairment]], [[hypoglycemia]], [[cardiac arrhythmias]], and [[death]]. [[Visual impairment]] can range from [[blurred vision]] and defective [[color perception]], to [[visual field]] constriction and [[blindness|permanent blindness]]. [[Cinchonism]] occurs in virtually all patients with quinine overdose. Symptoms range from [[headache]], [[nausea]], [[vomiting]], [[abdominal pain]], [[diarrhea]], [[tinnitus]], [[vertigo]], [[hearing impairment]], [[sweating]], [[flushing]], and [[blurred vision]], to [[deafness]], [[blindness]], serious [[cardiac arrhythmias]], [[hypotension]], and [[Circulatory arrest|circulatory collapse]]. [[Central nervous system]] toxicity ([[drowsiness]], disturbances of [[consciousness]], [[ataxia]], [[convulsions]], [[respiratory depression]] and coma) has also been reported with quinine [[overdose]], as well as [[pulmonary edema]] and adult [[respiratory distress syndrome]].
| |
| | |
| * Most [[toxic]] reactions are dose-related; however, some reactions may be idiosyncratic because of the variable sensitivity of patients to the toxic effects of quinine. A [[lethal dose]] of quinine has not been clearly defined, but [[fatal|fatalities]] have been reported after the [[ingestion]] of 2 to 8 grams in adults.
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| | |
| * Quinine, like quinidine, has [[antiarrhythmic|Class I antiarrhythmic]] properties. The [[cardiotoxicity]] of quinine is due to its [[negative inotropic]] action, and to its effect on [[Electrical conduction system of the heart|cardiac conduction]], resulting in decreased rates of [[depolarization]] and [[conduction]], and increased [[action potential]] and effective [[refractory period]]. [[ECG]] changes observed with quinine [[overdose]] include [[sinus tachycardia]], [[PR prolongation]], [[T wave inversion]], [[bundle branch block]], and [[QT prolongation|increased QT interval]], and a [[widening of the QRS complex]]. Quinine's [[alpha-blocking]] properties may result in [[hypotension]] and further exacerbate [[myocardial depression]] by decreasing [[coronary perfusion]]. Quinine [[overdose]] has been also associated with [[hypotension]], [[cardiogenic shock]], and [[circulatory collapse]], [[ventricular arrhythmias]], including [[ventricular tachycardia]], [[ventricular fibrillation]], [[idioventricular rhythm]], and [[torsades de pointes]], as well as [[bradycardia]], and [[atrioventricular block]].
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| | |
| * Quinine is rapidly absorbed, and attempts to remove residual quinine sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease [[plasma]]quinine concentrations.
| |
| | |
| * Forced acid [[diuresis]], [[hemodialysis]], [[charcoal]] column [[hemoperfusion]], and [[plasma]] exchange were not found to be effective in significantly increasing quinine elimination in a series of 16 patients.
| |
| |drugBox={{Distinguish|quinidine|quinone}}
| |
| {{drugbox2
| |
| | Verifiedfields = changed
| |
| | Watchedfields = changed
| |
| | verifiedrevid = 441980057
| |
| | IUPAC_name = (''R'')-(6-Methoxyquinolin-4-yl)((2''S'',4''S'',8''R'')-8-vinylquinuclidin-2-yl)methanol
| |
| | image = Quinine.png
| |
| | width = 160px
| |
| | image2 = Quinine-3D-balls.png
| |
| | width2 = 200px
| |
| | |
| <!--Clinical data-->
| |
| | tradename = Quinine sulphate, Quinate, Quinbisul
| |
| | Drugs.com = {{drugs.com|monograph|quinine-sulfate}}
| |
| | licence_US = Quinine
| |
| | MedlinePlus = a682322
| |
| | pregnancy_AU = D
| |
| | pregnancy_US = C
| |
| | legal_AU = S4
| |
| | legal_CA = Rx-only
| |
| | legal_UK = POM
| |
| | legal_US = Rx-only
| |
| | routes_of_administration = Oral, [[intravenous therapy|intravenous]]
| |
| | |
| <!--Pharmacokinetic data-->
| |
| | bioavailability =
| |
| | protein_bound = 70-95%<ref name = MSR>{{cite web|title=Quinine sulphate (quinine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=29 January 2014|url=http://reference.medscape.com/drug/Quinine sulphate-quinine-342696#showall}}</ref>
| |
| | metabolism = [[Liver|Hepatic]] (mostly [[CYP3A4]] and [[CYP2C19]]-mediated)
| |
| | elimination_half-life = 8-14 hours (adults), 6-12 hours (children)<ref name = MSR/>
| |
| | excretion = [[Kidney|Renal]] (20%)
| |
| | |
| <!--Identifiers-->
| |
| | CASNo_Ref = {{cascite|correct|CAS}}
| |
| | CAS_number_Ref = {{cascite|correct|??}}
| |
| | CAS_number = 130-95-0
| |
| | ATC_prefix = M09
| |
| | ATC_suffix = AA01
| |
| | ATC_supplemental = {{ATC|P01|BC01}}
| |
| | ChEBI_Ref = {{ebicite|changed|EBI}}
| |
| | ChEBI = 15854
| |
| | PubChem = 8549
| |
| | IUPHAR_ligand = 2510
| |
| | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| |
| | DrugBank = DB00468
| |
| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| |
| | ChemSpiderID = 84989
| |
| | UNII_Ref = {{fdacite|correct|FDA}}
| |
| | UNII = A7V27PHC7A
| |
| | KEGG_Ref = {{keggcite|correct|kegg}}
| |
| | KEGG = D08460
| |
| | ChEMBL_Ref = {{ebicite|correct|EBI}}
| |
| | ChEMBL = 170
| |
| | |
| <!--Chemical data-->
| |
| | C=20 | H=24 | N=2 | O=2
| |
| | molecular_weight = 324.417 [[Gram|g]]/[[Mole (unit)|mol]]
| |
| | smiles = O(c4cc1c(nccc1[C@@H](O)[C@H]2N3CC[C@@H](C2)[C@@H](/C=C)C3)cc4)C
| |
| | InChI = 1/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1
| |
| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| |
| | StdInChI = 1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1
| |
| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| |
| | StdInChIKey = LOUPRKONTZGTKE-WZBLMQSHSA-N
| |
| | melting_point = 177
| |
| }}
| |
| |mechAction=* Quinine is an antimalarial agent
| |
| | |
| <!--Structure-->
| |
| |structure=* Quinine sulphate (quinine sulfate) is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C20H24N2O2)2•H2SO4•2H2O and a molecular weight of 782.96.
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| | |
| The structural formula of quinine sulfate is:
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| | |
| [[File:Quinine structure.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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| | |
| <!--Pharmacodynamics-->
| |
| |PD=* QTc interval prolongation was studied in a [[double-blind]], multiple dose, placebo- and positive-controlled [[crossover study]] in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with Quinine sulphate 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms.
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| | |
| * [[PR prolongation|Prolongation of the PR]] and [[QRS prolongation|QRS interval]] was also noted in subjects receiving Quinine sulphate. The maximum mean (95% upper confidence bound) difference in PR from [[placebo]] after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms.
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| |PK=====Absorption:=====
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| | |
| * The oral [[bioavailability]] of quinine is 76 to 88% in healthy adults. Quinine exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of quinine sulfate, the mean quinine Tmax was longer, and mean AUC and Cmax were higher in patients with uncomplicated [[P. falciparum malaria]] than in healthy subjects, as shown in Table 1 below.
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| | |
| [[File:Quinine Pharmacokinetics table01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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| | |
| * Quinine sulphate capsules may be administered without regard to meals. When a single oral 324 mg capsule of Quinine sulphate was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of quinine was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when Quinine sulphate capsule was given under fasted conditions.
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| | |
| =====Distribution:=====
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| | |
| * In patients with [[malaria]], the volume of distribution (Vd/F) decreases in proportion to the severity of the [[infection]]. In published studies with healthy subjects who received a single oral 600 mg dose of quinine sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.
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| | |
| * Quinine is moderately protein-bound in [[blood]] in healthy subjects, ranging from 69 to 92%. During active [[malarial]] [[infection]], [[protein]] binding of quinine is increased to 78 to 95%, corresponding to the increase in α1-acid [[glycoprotein]] that occurs with [[malaria]] [[infection]].
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| | |
| * Intra-erythrocytic levels of quinine are approximately 30 to 50% of the plasma concentration.
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| | |
| * Quinine penetrates relatively poorly into the [[cerebrospinal fluid]] ([[CSF]]) in patients with cerebral malaria, with [[CSF]] [[concentration]] approximately 2 to 7% of [[plasma]] [[concentration]].
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| | |
| * In one study, quinine [[concentrations]] in [[placental cord]] [[blood]] and [[breast milk]] were approximately 32% and 31%, respectively, of quinine [[concentrations]] in maternal [[plasma]]. The estimated total dose of quinine secreted into breast milk was less than 2 to 3 mg per day.
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| | |
| =====Metabolism:=====
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| | |
| * Quinine is metabolized almost exclusively via [[hepatic]] oxidative [[cytochrome P450]] (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further [[biotransformation]] of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.
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| | |
| * In vitro studies using human [[liver]] [[microsomes]] and [[P450|recombinant P450 enzymes]] have shown that quinine is metabolized mainly by [[CYP3A4]]. Depending on the in vitro experimental conditions, other [[enzymes]], including [[CYP1A2]], [[CYP2C8]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], and [[CYP2E1]] were shown to have some role in the [[metabolism]] of quinine.
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| | |
| =====Elimination/Excretion:=====
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| | |
| * Quinine is eliminated primarily via [[hepatic]] [[biotransformation]]. Approximately 20% of quinine is excreted unchanged in [[urine]]. Because quinine is reabsorbed when the [[urine]] is [[alkaline]], [[renal]] excretion of the drug is twice as rapid when the urine is acidic than when it is [[alkaline]].
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| | |
| * In various published studies, healthy subjects who received a single oral 600 mg dose of quinine sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours.
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| | |
| * In 15 patients with uncomplicated [[malaria]] who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/h/kg) during the [[acute phase]] of the [[infection]], and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase.
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| | |
| * [[Extracorporeal]] Elimination:
| |
| :* Administration of multiple-dose [[activated charcoal]] (50 grams administered 4 hours after quinine dosing followed by 3 further doses over the next 12 hours) decreased the mean quinine [[elimination half-life]] from 8.2 to 4.6 hours, and increased the mean quinine clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of quinine sulfate. Likewise, in 5 symptomatic patients with acute quinine [[poisoning]] who received multiple-dose [[activated charcoal]] (50 grams every 4 hours), the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive [[activated charcoal]].
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| | |
| :* In 6 patients with quinine poisoning, forced acid diuresis did not change the half-life of quinine elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged quinine recovered in the [[urine]], in comparison to 8 patients not treated in this manner.
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| | |
| * Specific Populations:
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| | |
| :* [[Pediatric]] Patients:
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| :** The [[pharmacokinetics]] of quinine in children (1.5 to 12 years old) with uncomplicated [[P. falciparum malaria]] appear to be similar to that seen in adults with uncomplicated ma[[l]]aria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of quinine were reduced in [[pediatric]] patients with [[malaria]] as compared to the healthy [[pediatric]] controls. Table 2 below provides a comparison of the mean ± SD [[pharmacokinetic]] parameters of quinine in [[pediatric]] patients vs. healthy [[pediatric]] controls.
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| | |
| [[File:Quinine Pharmacokinetics table02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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| :* Geriatric Patients:
| |
| :** Following a single oral dose of 600 mg quinine sulfate, the mean [[AUC]] was about 38% higher in 8 healthy [[elderly]] subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean [[Tmax]] and [[Cmax]] were similar in elderly and younger subjects after a single oral dose of quinine sulfate 600 mg. The mean oral clearance of quinine was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of quinine between the two age groups, elderly subjects excreted a larger proportion of the dose in [[urine]] as unchanged drug than younger subjects (16.6% vs. 11.2%).
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| :** After a single 648 mg dose or at steady state, following quinine sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of [[absorption]] or clearance of quinine was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state [[Cmax]] (±SD) and [[AUC0]]-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral quinine sulfate 648 mg three times daily. The steady state [[pharmacokinetic]] parameters in healthy elderly subjects were similar to the [[pharmacokinetic]] parameters in healthy young subjects.
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| | |
| :* [[Renal Impairment]]:
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| :** Following a single oral 600 mg dose of quinine sulfate in otherwise healthy subjects with severe [[chronic renal failure]] not receiving any form of dialysis (mean [[serum creatinine]] = 9.6 mg/dL), the median [[AUC]] was higher by 195% and the median [[Cmax]] was higher by 79% than in subjects with normal [[renal function]] (mean [[serum creatinine]] = 1 mg/dL). The mean plasma half-life in subjects with severe [[chronic renal impairment]] was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with [[malaria]] and severe [[chronic renal failure]], a dosage regimen consisting of one loading dose of 648 mg Quinine sulphate followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine. The effects of mild and moderate renal impairment on the [[pharmacokinetics]] and safety of quinine sulfate are not known.
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| :** Negligible to minimal amounts of circulating quinine in the blood are removed by [[hemodialysis]] or [[hemofiltration]]. In subjects with [[chronic renal failure]] ([[CRF]]) on [[hemodialysis]], only about 6.5% of quinine is removed in 1 hour. [[Plasma]] quinine concentrations do not change during or shortly after [[hemofiltration]] in subjects with [[CRF]].
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| :* [[Hepatic Impairment]]:
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| :** In otherwise healthy subjects with mild [[hepatic impairment]] ([[Child-Pugh A]]; N=10), who received a single 500 mg dose of quinine sulfate, there was no significant difference in quinine [[pharmacokinetic]] parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate [[hepatic impairmenT]] ([[Child-Pugh B]]; N=9) who received a single oral 600 mg dose of quinine sulfate, the mean [[AUC]] increased by 55% without a significant change in mean [[Cmax]], as compared to healthy volunteer controls (N=6). In subjects with [[hepatitis]], the [[absorption]] of quinine was prolonged, the elimination half-life was increased, the apparent [[volume of distribution]] was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine.
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| :** In subjects with severe [[hepatic impairment]] ([[Child-Pugh C]]; N=10), quinine oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, quinine is not indicated in this population and alternate therapy should be administered.
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| |nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====
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| * Carcinogenesis:
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| :* [[Carcinogenicity]] studies of quinine have not been conducted.
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| * Mutagenesis:
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| :* [[Genotoxicity]] studies of quinine were positive in the Ames [[bacterial]] mutation assay with [[metabolic]] activation and in the sister [[chromatid exchange]] assay in mice. The sex-linked recessive lethal test performed in [[Drosophila]], the in vivo mouse [[micronucleus]] assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.
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| * Impairment of Fertility:
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| :* Published studies indicate that quinine produces testicular toxicity in mice at a single [[intraperitoneal]] dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose ([[MRHD]]; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the [[MRHD]] based on body surface area (BSA) comparisons. The findings include [[atrophy]] or degeneration of the [[seminiferous tubules]], decreased [[sperm count]] and [[motility]], and decreased [[testosterone]] levels in the [[serum]] and [[testes]]. There was no effect on [[testes]] weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the [[MRHD]] respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of quinine TID for one week, [[sperm motility]] was decreased and percent [[sperm]] with abnormal [[morphology]] was increased; [[sperm count]] and serum [[testosterone]] were unaffected.
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| |clinicalStudies=* Quinine has been used worldwide for hundreds of years in the treatment of [[malaria]]. Thorough searches of the published literature identified over 1300 references to the treatment of [[malaria]] with quinine, and from these, 21 [[randomized]], [[active-controlled]] studies were identified which evaluated oral quinine [[monotherapy]] or combination therapy for treatment of uncomplicated [[P. falciparum malaria]]. Over 2900 patients from [[malaria|malaria-endemic areas]] were enrolled in these studies, and more than 1400 patients received oral quinine. The following conclusions were drawn from review of these studies:
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| * In areas where multi-drug resistance of [[P. falciparum]] is increasing, such as Southeast Asia, cure rates with 7 days of oral quinine [[monotherapy]] were at least 80%; while cure rates for 7 days of oral quinine combined with an [[antimicrobial]] agent ([[tetracycline]] or [[clindamycin]]) were greater than 90%. In areas where [[multi-drug resistance]] of the [[parasite]] was not as widespread, cure rates with 7 days of quinine [[monotherapy]] ranged from 86 to 100%. Cure was defined as initial clearing of [[parasitemia]] within 7 days without recrudescence by day 28 after treatment initiation. [[P. falciparum malaria]] that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh, and quinine may not be as effective in those areas.
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| * Completion of a 7-day oral quinine treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of quinine combination therapy have been used. However, the published data from randomized, controlled [[clinical trials]] for shorter regimens of oral quinine in conjunction with [[tetracycline]], [[doxycycline]], or [[clindamycin]] for treatment of uncomplicated [[P. falciparum malaria]] is limited, and these shorter course combination regimens may not be as effective as the longer regimens.
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| |howSupplied=* Quinine sulphate capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:
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| [[File:Quinine how supplied table.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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| <!--Patient Counseling Information-->
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| |storage=* Store at 20° to 25°C (68° to 77°F).
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| |fdaPatientInfo======Dosing Instructions=====
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| * Patients should be instructed to:
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| :* Take all of the medication as directed.
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| :* Take no more of the medication than the amount prescribed.
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| :* Take with food to minimize possible gastrointestinal irritation.
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| :* If a dose is missed, patients should also be instructed not to double the next dose. If more than 4 hours has elapsed since the missed dose, the patient should wait and take the next dose as previously scheduled.
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| <!--Precautions with Alcohol-->
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| |alcohol=* Alcohol-Quinine sulphate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. | |
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| <!--Brand Names-->
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| |brandNames=* Quiphile®
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| * Quinamm®
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| * Qualaquin®
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| }}
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| <!--Category-->
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| [[Category:Drug]]
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