QUININE SULFATE

1 INDICATIONS AND USAGE Quinine sulfate is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Quinine sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ] . Limitations of Use: Quinine sulfate capsules are not approved for: Treatment of severe or complicated P. falciparum malaria. Prevention of malaria. Treatment or prevention of nocturnal leg cramps [see Warnings and Precautions (5.1) ] . Quinine sulfate is an antimalarial indicated for treatment of uncomplicated Plasmodium falciparum malaria. (1) Limitations of Use: Quinine sulfate capsules are not approved for: Treatment of severe or complicated P. falciparum malaria. Prevention of malaria. Treatment or prevention of nocturnal leg cramps

2 DOSAGE AND ADMINISTRATION Adults (≥ 16 years of age): 648 mg (two capsules) every 8 hours for 7 days. (2.1) Patients with Severe Chronic Renal Impairment: One loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days. (2.2) 2.1 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 [see Clinical Studies (14) ] . Quinine sulfate capsules should be taken with food to minimize gastric upset [see Clinical Pharmacology (12.3) ] . 2.2 Renal Impairment In patients with acute uncomplicated malaria and severe chronic renal impairment, the following dosage regimen is recommended: one loading dose of 648 mg quinine sulfate followed 12 hours later by maintenance doses of 324 mg every 12 hours. The effects of mild and moderate renal impairment on the safety and pharmacokinetics of quinine sulfate are not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.3 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 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

4 CONTRAINDICATIONS Quinine sulfate capsules are contraindicated in patients with the following: Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received quinine sulfate intravenously for P. falciparum malaria [see Warnings and Precautions (5.4) ] . Known hypersensitivity reactions to quinine. These include, but are not limited to, the following [see Warnings and Precautions (5.7) ] : Thrombocytopenia Idiopathic thrombocytopenia purpura (ITP) and thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS) Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia) Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to quinine has been documented [see Warnings and Precautions (5.7) ] . Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness. Optic neuritis. Quinine may exacerbate active optic neuritis [see Adverse Reactions (6.1) ] . Quinine sulfate capsules are contraindicated in patients with the following: Prolongation of QT interval. (4) Myasthenia gravis. (4) Known hypersensitivity to quinine, mefloquine, or quinidine. (4) Optic neuritis. (4)

5 WARNINGS AND PRECAUTIONS Thrombocytopenia, including ITP and HUS/TTP, has been reported. Discontinue drug. (5.2) Hemolytic Anemia: Monitor hemoglobin and hematocrit. Discontinue drug if hemolytic anemia occurs. (5.3) QT Prolongation and Ventricular Arrhythmias: Avoid concomitant use with drugs known to prolong QT interval. (5.4) Avoid concomitant use with rifampin. Quinine sulfate treatment failures have been reported. (5.5) Avoid concomitant use with neuromuscular blocking agents. Quinine sulfate may potentiate neuromuscular blockade and cause respiratory depression. (5.6) Serious and Life-Threatening Hypersensitivity Reactions: Discontinue drug. (4 , 5.7) Atrial Fibrillation and Flutter: Paradoxical increase in ventricular rate may occur. Closely monitor digoxin levels if used concomitantly. (5.8) Hypoglycemia: Monitor for signs and symptoms. (5.9) 5.1 Use of Quinine Sulfate for Treatment or Prevention of Nocturnal Leg Cramps Quinine sulfate 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 sulfate 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 [see Boxed Warning and Contraindications (4) ] . 5.2 Thrombocytopenia Quinine-induced thrombocytopenia is an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported, including cases of HUS/TTP. Chronic renal impairment associated with the development of TTP has also been reported. Thrombocytopenia usually resolves within a week upon discontinuation of quinine. If quinine is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to quinine from any source, a patient with quinine-dependent antibodies could develop thrombocytopenia that is more rapid in onset and more severe than the original episode. 5.3 Hemolytic Anemia Acute hemolytic anemia has been reported in patients receiving quinine for treatment of malaria, including patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The cause for the acute hemolytic anemia in quinine-treated patients with malaria and its potential relationship with G6PD deficiency has not been determined. Closely monitor hemoglobin and hematocrit during quinine treatment. Quinine should be discontinued if patients develop acute hemolytic anemia. 5.4 QT Prolongation and Ventricular Arrhythmias QT interval prolongation has been a consistent finding in studies which evaluated electrocardiographic changes with oral or parenteral quinine administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak quinine plasma concentration [see Clinical Pharmacology (12.2) ] . Quinine sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation. Quinine sulfate has been shown to cause concentration-dependent prolongation of the PR and QRS interval. At particular risk are patients with underlying structural heart disease and preexisting conduction system abnormalities, elderly patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (e.g., verapamil) or QRS interval (e.g., flecainide or quinidine) [see Clinical Pharmacology (12.2) ] . Quinine sulfate is not recommended for use with other drugs known to cause QT prolongation, including Class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), and Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide). The use of macrolide antibiotics such as erythromycin should be avoided in patients receiving quinine sulfate. Fatal torsades de pointes was reported in an elderly patient who received concomitant quinine, erythromycin, and dopamine. Although a causal relationship between a specific drug and the arrhythmia was not established in this case, erythromycin is a CYP3A4 inhibitor and has been shown to increase quinine plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase quinine exposure in a pharmacokinetic study [see Drug Interactions (7) ] . Quinine may inhibit the metabolism of certain drugs that are CYP3A4 substrates and are known to cause QT prolongation, e.g., astemizole, cisapride, terfenadine, pimozide, halofantrine and quinidine. Torsades de pointes has been reported in patients who received concomitant quinine and astemizole. Therefore, concurrent use of quinine sulfate with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7) ] . Concomitant administration of quinine sulfate with the antimalarial drugs, mefloquine or halofantrine, may result in electrocardiographic abnormalities, including QT prolongation, and increase the risk for torsades de pointes or other serious ventricular arrhythmias. Concurrent use of quinine sulfate and mefloquine may also increase the risk of seizures [see Drug Interactions (7) ] . Quinine sulfate should also be avoided in patients with known prolongation of QT interval and in patients with clinical conditions known to prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and certain cardiac conditions [see Contraindications (4) ] . 5.5 Concomitant Use of Rifampin Treatment failures may result from the concurrent use of rifampin with quinine sulfate, due to decreased plasma concentrations of quinine, and concomitant use of these medications should be avoided [see Drug Interactions (7) ] . 5.6 Concomitant Use of Neuromuscular Blocking Agents The use of neuromuscular blocking agents should be avoided in patients receiving quinine sulfate. In one patient who received pancuronium during an operative procedure, subsequent administration of quinine resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, quinine may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions (7) ] . 5.7 Hypersensitivity Serious hypersensitivity reactions reported with quinine sulfate include anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, and pruritus. A number of other serious adverse reactions reported with quinine, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), thrombocytopenia, immune thrombocytopenic purpura (ITP), blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis may also be due to hypersensitivity reactions. Quinine sulfate should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ] . 5.8 Atrial Fibrillation and Flutter Quinine sulfate 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 [see Drug Interactions (7) ] . 5.9 Hypoglycemia Quinine stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.

7 DRUG INTERACTIONS Table 1 below presents clinically significant drug interactions with quinine sulfate. Table 1: Clinically Significant Drug Interactions with Quinine Sulfate Drug(s) Clinical Impact Recommendation Effects of Drugs and Other Substances on Quinine Pharmacokinetics Antacids Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with quinine sulfate should be avoided. Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin) Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with quinine sulfate. 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. Histamine H 2 -receptor blockers [cimetidine, ranitidine (nonspecific CYP450 inhibitors)] When quinine is to be given concomitantly with a histamine H 2 -receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with quinine sulfate [see Clinical Pharmacology (12.3) ] . Patients should be monitored closely for adverse events associated with quinine. Ketoconazole (CYP3A4 inhibitor) No change in the quinine sulfate dosage regimen is necessary with concomitant ketoconazole [see Clinical Pharmacology (12.3) ] . Patients should be monitored closely for adverse reactions associated with quinine. Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors) Increased quinine plasma levels have been observed when used concomitantly [see Clinical Pharmacology (12.3) ] . Concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with quinine sulfate should be avoided [see Warnings and Precautions (5.4) ] . Rifampin (CYP3A4 inducer) Decreased quinine plasma levels have been observed when used concomitantly [see Clinical Pharmacology (12.3) ] . Concomitant administration of rifampin with quinine sulfate should be avoided [see Warnings and Precautions (5.5) ] . Ritonavir Increased quinine plasma levels have been observed when used concomitantly [see Clinical Pharmacology (12.3) ] . Concomitant administration of ritonavir with quinine sulfate should be avoided. Tetracycline Tetracycline may be concomitantly administered with quinine sulfate [see Clinical Pharmacology (12.3) ] . Patients should be monitored closely for adverse reactions associated with quinine sulfate. Theophylline or aminophylline No change in the quinine sulfate dosage regimen is necessary with concomitant theophylline or aminophylline [see Clinical Pharmacology (12.3) ] . Patients should be monitored closely for adverse reactions associated with quinine. Urinary alkalizers (acetazolamide, sodium bicarbonate) Urinary alkalinizing agents may increase plasma quinine concentrations. Use caution if using concomitantly. Effects of Quinine on the Pharmacokinetics of Other Drugs Anticonvulsants (carbamazepine, phenobarbital, and phenytoin) Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with quinine sulfate [see Clinical Pharmacology (12.3) ] . If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of anticonvulsant drug concentrations is recommended. Patients should be monitored closely for adverse reactions associated with these anticonvulsants. Astemizole (CYP3A4 substrate) 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 sulfate with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided [see Warnings and Precautions (5.4) ] . 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 sulfate with atorvastatin or other 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 sulfate 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. Desipramine (CYP2D6 substrate) Quinine may inhibit the metabolism of drugs that are CYP2D6 substrates if used at antimalarial doses (greater than or equal to 600 mg) [see Clinical Pharmacology (12.3) ] . Patients taking medications that are CYP2D6 substrates with quinine sulfate should be monitored closely for adverse reactions associated with these medications. Digoxin (P-gp substrate) Digoxin levels may be increased with use of quinine [see Clinical Pharmacology (12.3) ] . If quinine sulfate is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary [see Warnings and Precautions (5.8) ] . Mefloquine The concomitant administration of mefloquine and quinine sulfate may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see Clinical Pharmacology (12.3) ] . Avoid concomitant use [see Warnings and Precautions (5.4) ] . Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine) Quinine may also enhance the neuromuscular blocking effects of succinylcholine and tubocurarine [see Clinical Pharmacology (12.3) ] . Avoid concomitant use [see Warnings and Precautions (5.6) ] . Ritonavir Ritonavir has significant effect on quinine pharmacokinetics [see Clinical Pharmacology (12.3) ] . The concomitant administration of quinine sulfate with ritonavir should be avoided. Theophylline or aminophylline (CYP1A2 substrate) Increased quinine plasma levels when used concomitantly [see Clinical Pharmacology (12.3) ] . If quinine sulfate is co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations. Warfarin and oral anticoagulants Cinchona alkaloids, including quinine, may have the potential to depress 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. 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 sulfate. Drug/Laboratory Interactions Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used. Quinine may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate). Special attention to patients using quinine is needed to minimize errors in the interpretation of laboratory results. Interacting Drug Interaction Drugs known to prolong QT interval (e.g., Class 1A and Class III antiarrhythmic agents) Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use. (5.4) Other antimalarials (e.g., halofantrine, mefloquine) ECG abnormalities including QT prolongation. Avoid concomitant use. (5.4 , 7) CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse reactions of quinine. (7) CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse reactions of the co-administered drug. (7) Digoxin Increased digoxin plasma concentration. (5.8 , 7) See full prescribing information for a complete list of reported and potential interactions.

6 ADVERSE REACTIONS Most common adverse reactions are a cluster of symptoms called “cinchonism”, which occurs to some degree in almost all patients taking quinine: headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, disturbance in color perception, vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Overall 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. The following adverse reactions have been reported with quinine sulfate. Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General: fever, chills, sweating, flushing, asthenia, lupus-like syndrome, and hypersensitivity reactions. 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. Neuropsychiatric: headache, diplopia, confusion, altered mental status, seizures, coma, disorientation, tremors, restlessness, ataxia, acute dystonic reaction, aphasia, and suicide. Dermatologic: cutaneous rashes, including urticarial, papular, or scarlatinal rashes, pruritus, bullous dermatitis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption, photosensitivity reactions, allergic contact dermatitis, acral necrosis, and cutaneous vasculitis. Respiratory: asthma, dyspnea, pulmonary edema. Cardiovascular: chest pain, vasodilatation, hypotension, postural hypotension, tachycardia, bradycardia, palpitations, syncope, atrioventricular block, atrial fibrillation, irregular rhythm, unifocal premature ventricular contractions, nodal escape beats, U waves, QT prolongation, ventricular fibrillation, ventricular tachycardia, torsades de pointes, and cardiac arrest. Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric irritation, and esophagitis. Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests. Metabolic: hypoglycemia and anorexia. Musculoskeletal: myalgias and muscle weakness. Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis. Special Senses: 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.

8 USE IN SPECIFIC POPULATIONS Renal Impairment: Reduce dose and dosing frequency for patients with severe chronic renal impairment. (2.2 , 8.6 , 12.3) Hepatic Impairment: Closely monitor for adverse reactions. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment. (2.3 , 8.7 , 12.3) 8.1 Pregnancy Risk Summary Prolonged experience with quinine in pregnant women over several decades, based on published prospective and retrospective observational studies, surveys, safety and efficacy studies, review articles, case reports and case series have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data) . In animal reproduction studies, administration of quinine by multiple routes of administration to pregnant rabbits, dogs, guinea pigs, rats, and monkeys during the period of organogenesis at doses of 0.25 to 2 times the maximum recommended human dose (MRHD) based on body surface area (BSA), produced embryo-fetal toxicity including malformations. Offspring of pregnant rats administered oral quinine sulfate during mating, gestation, and lactation at a dose approximately equivalent to 0.1 times the MRHD based on BSA comparison experienced impaired growth and delayed physical development (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Malaria during and after pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth retardation, congenital malaria, and maternal and neonatal mortality. Maternal adverse reactions An increased incidence of hypoglycemia, due to increased pancreatic secretion of insulin, has been reported with quinine use, in pregnant women, especially during the third trimester 1 . Monitor glucose levels in pregnant woman taking quinine. Tinnitus, vomiting, dizziness, and nausea are commonly reported adverse reactions in pregnant women taking quinine. Pregnant women are also at risk for a rare triad of complications: massive hemolysis, hemoglobinemia, and hemoglobinuria 2 . Labor or delivery In doses several times higher than those used to treat malaria, quinine may cause uterine contractions; however, there is no evidence that quinine causes uterine contractions at the doses recommended for the treatment of malaria. Data Human Data Quinine crosses the placenta with measurable blood 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 mg/L 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. Adverse outcomes have been identified in the post-marketing experience with quinine during pregnancy. Because these outcomes are reported from varied data sources and have inconsistent findings and/or important methodological limitations, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In studies in which more than 893 pregnant women were treated with quinine for malaria in the first trimester, no quinine-associated increases in the incidence of congenital anomalies were observed compared with other antimalarial drugs 3 . A retrospective study of women with P. falciparum malaria who were treated with oral quinine sulfate 10 mg/kg 3 times daily for 7 days at any time 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 to 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%]). Case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of quinine. Animal Data In animal developmental studies conducted in multiple animal species 4 , pregnant animals received quinine by the subcutaneous, intramuscular, and oral routes at doses 0.25 to 2 times the maximum recommended human dose (MRHD) based on body surface area (BSA). Increases in fetal death were observed in utero in pregnant rabbits at maternal doses ≥ 100 mg/kg/day and in pregnant 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 cochlear hemorrhage at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. No fetal malformations were observed in rats at maternal doses up to 300 mg/kg/day and in monkeys at maternal doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons. In a pre-postnatal study, pregnant rats received quinine sulfate in feed beginning two weeks prior to mating, through gestation, and lactation. 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 eruption and eye opening during the lactation period. 8.2 Lactation Risk Summary Quinine is present in human milk. It is estimated that breastfed infants would receive less than 2 to 3 mg per day of quinine base (< 0.4% of the maternal dose) via breast milk (see Data) . There are no data on the effects of quinine on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for quinine sulfate and any potential adverse effects on the breastfed child from quinine sulfate or from the underlying maternal condition. Data 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. Quinine concentrations in breast milk are approximately 31% of quinine concentrations in maternal plasma. 8.3 Females and Males of Reproductive Potential Infertility In a published study 5 in 5 men receiving oral tablets of 600 mg quinine three times a day for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased, but sperm count and serum testosterone were unaffected. Based on findings from animal studies, quinine sulfate may impair fertility [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and efficacy of quinine sulfate in pediatric patients under the age of 16 has not been established. 8.5 Geriatric Use Clinical studies of quinine sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond to treatment differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Renal Impairment Clearance of quinine is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh C), quinine oral clearance (CL/F) is decreased, volume of distribution (V d /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 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] .