QUININE SULFATE

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 (C 20 H 24 N 2 O 2 )2•H 2 SO 4 •2H 2 O and a molecular weight of 782.96. The structural formula of quinine sulfate is: Quinine sulfate, USP occurs as a white, crystalline powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, sparingly soluble in boiling water and in alcohol, practically insoluble in ether. Quinine sulfate capsules, USP are supplied for oral administration containing 324 mg of the active ingredient, quinine sulfate, USP, equivalent to 269 mg free base. Inactive ingredients: corn starch, croscarmellose sodium, gelatin, magnesium stearate, microcrystalline cellulose, povidone and silicon dioxide. The capsules also use a monogramming ink which contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. df

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

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) ] .

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)

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.

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.