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Quinine Sulfate

Mylan Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use quinine sulfate capsules safely and effectively. See full prescribing information for quinine sulfate capsules. Quinine Sulfate Capsules, USP for oral useInitial U.S. Approval: 2005BOXED WARNING (See full prescribing information for complete boxed warning.)RECENT MAJOR CHANGESDosage and Administration Hepatic Impairment (2.3) 4/2013Warnings and Precautions     QT Prolongation and Ventricular Arrhythmias (5.3)     9/2012BOXED WARNINGWARNING: Quinine sulfate capsules use for the treatment or prevention of nocturnal leg cramps may result in serious and life threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with quinine sulfate capsules use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit (see WARNINGS). INDICATIONS AND USAGEQuinine sulfate is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria. (1)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) DOSAGE FORMS AND STRENGTHS •324 mg buff opaque cap and buff opaque body, hard-shell gelatin capsules axially printed with MYLAN over QS 324 in black ink on cap and body. CONTRAINDICATIONSQuinine sulfate capsules are contraindicated in patients with the following: •Prolongation of QT interval (4) •Glucose-6-phosphate dehydrogenase (G6PD) deficiency (4) •Myasthenia gravis (4) •Known hypersensitivity to quinine, mefloquine, or quinidine (4) •Optic neuritis (4) WARNINGS AND PRECAUTIONS •Not indicated for the prevention or treatment of nocturnal leg cramps. Risk of serious and life threatening adverse reactions. (1, 5.1) •Thrombocytopenia, including ITP and HUS/TTP, has been reported. Discontinue drug. (5.2) •QT prolongation and ventricular arrhythmias. Avoid concomitant use with drugs known to prolong QT interval. (5.3) •Avoid concomitant use with rifampin. Quinine sulfate capsules treatment failures have been reported. (5.4) •Avoid concomitant use with neuromuscular blocking agents. Quinine sulfate capsules may potentiate neuromuscular blockade and cause respiratory depression. (5.5) •Serious and life threatening hypersensitivity reactions. Discontinue drug. (4, 5.6) •Atrial fibrillation and flutter. Paradoxical increase in ventricular rate may occur. Closely monitor digoxin levels if used concomitantly. (5.7) •Hypoglycemia. Monitor for signs and symptoms. (5.8) Side EffectsMost 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. DRUG INTERACTIONS Interacting Drug Interaction Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de pointes. Avoid concomitant use. (5.3) Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use. (5.3, 7.2) CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine. (7.1) CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug. (7.2) Digoxin Increased digoxin plasma concentration. (5.8, 7.1)  See full prescribing information for a complete list of reported and potential interactions.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 events. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment. (2.3, 8.7, 12.3) •Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk. (8.1) •Nursing Mothers: Exercise caution when administering to a nursing woman. (8.3)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

WARNING

Quinine sulfate capsules use for the treatment or prevention of nocturnal leg cramps may result in serious and life threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with quinine sulfate capsules use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit (see WARNINGS).

1 INDICATIONS AND USAGE

Quinine sulfate capsules are 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)].

Quinine sulfate oral 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Treatment of Uncomplicated 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 capsules 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) ] .

3 DOSAGE FORMS AND STRENGTHS

324 mg capsules – hard-shell gelatin, buff opaque cap and buff opaque body, axially printed with MYLAN over QS 324 in black ink on cap and body.

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 (5.3)].
  • •Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • •Hemolysis can occur in patients with G6PD deficiency receiving quinine.
  • •Known hypersensitivity reactions to quinine.
    • •These include, but are not limited to, the following [see Warnings and Precautions (5.6)]:
      • •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 (5.6)].
    • •Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness.
    • •Optic neuritis. Quinine may exacerbate active optic neuritis [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Use of Quinine Sulfate Capsules for Treatment or Prevention of Nocturnal Leg Cramps

Quinine sulfate capsules 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 capsules 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 reexposure 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 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 capsules have 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 capsules are 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 capsules. 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 (7.1)].

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 capsules with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2)].

Concomitant administration of quinine sulfate capsules 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 (7.2)].

Quinine sulfate capsules 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)].

5.4 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 (7.1)].

5.5 Concomitant Use of Neuromuscular Blocking Agents

The use of neuromuscular blocking agents should be avoided in patients receiving quinine sulfate capsules. 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 (7.2)].

5.6 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 capsules should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4)].

5.7 Atrial Fibrillation and Flutter

Quinine sulfate capsules 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 (7.2)].

5.8 Hypoglycemia

Quinine stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.

6 ADVERSE REACTIONS

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. Most of these reactions are thought to be uncommon, but the actual incidence is unknown:

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.

7 DRUG INTERACTIONS

7.1 Effects of Drugs and Other Substances on Quinine Pharmacokinetics

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 [see Clinical Pharmacology (12.3)].

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.

Cholestyramine

In eight 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.

Cigarette Smoking (CYP1A2 Inducer)

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 smokers.

Grapefruit Juice (P-gp/CYP3A4 Inhibitor)

In a pharmacokinetic study involving ten 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 sulfate capsules may be taken with grapefruit juice.

Histamine H-Receptor Blockers [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 3 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 H2-receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with quinine sulfate, patients should be monitored closely for adverse events associated with quinine.

Isoniazid

Isoniazid 300 mg/day pretreatment for one week did not significantly alter the pharmacokinetic parameter values of quinine. Adjustment of quinine sulfate dosage is not necessary when isoniazid is given concomitantly.

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 sulfate dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with quinine.

Macrolide Antibiotics (Erythromycin, Troleandomycin) (CYP3A4 Inhibitors)

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.

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 4 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.

Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with quinine sulfate should be avoided [see Warnings and Precautions (5.3)].

Oral Contraceptives (Estrogen, Progestin)

In seven 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 seven age-matched female control subjects not using oral contraceptives.

Rifampin (CYP3A4 Inducer)

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 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 sulfate should be avoided [see Warnings and Precautions (5.4)].

Ritonavir

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 sulfate capsules should be avoided [see Drug Interactions (7.2)].

Tetracycline

In eight 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 2-fold higher than in eight patients who received quinine monotherapy. Although tetracycline may be concomitantly administered with quinine sulfate, patients should be monitored closely for adverse reactions associated with quinine sulfate.

Theophylline or Aminophylline

In 20 healthy subjects who received multiple doses of quinine sulfate (648 mg every 8 hours x 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 sulfate dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with quinine.

Urinary Alkalizers (Acetazolamide, Sodium Bicarbonate)

Urinary alkalinizing agents may increase plasma quinine concentrations.

7.2 Effects of Quinine on the Pharmacokinetics of Other Drugs

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.

Anticonvulsants (Carbamazepine, Phenobarbital, and Phenytoin)

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 eight 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.

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 (5.3)].

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 (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 sulfate should be monitored closely for adverse reactions associated with these medications.

Digoxin (P-gp Substrate)

In four 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 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 (5.7)].

Halofantrine

Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of quinine sulfate is likely to increase plasma halofantrine concentrations [see Warnings and Precautions (5.3)].

Mefloquine

In seven 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 sulfate may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see Warnings and Precautions (5.3)].

Midazolam (CYP3A4 Substrate)

In 23 healthy subjects who received multiple doses of quinine sulfate 324 mg 3 times daily x 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 sulfate 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular Blocking Agents (Pancuronium, Succinylcholine, Tubocurarine)

In one report, quinine potentiated 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 blocking effects of succinylcholine and tubocurarine [see Warnings and Precautions (5.5)].

Ritonavir

 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 sulfate capsules with ritonavir should be avoided [see Drug Interactions (7.1)].

Theophylline or Aminophylline (CYP1A2 Substrate)

In 19 healthy subjects who received multiple doses of quinine sulfate 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 sulfate is coadministered 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. 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 sulfate.

7.3 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).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are extensive published data but few well controlled studies of quinine sulfate 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.

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.

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, particularly in pregnant women.

Quinine crosses the placenta with measurable blood concentrations in the fetus. In eight women who delivered live infants 1 to 6 days after starting quinine therapy, umbilical cord plasma quinine concentrations were between 1 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.

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 2,201 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 2,201 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 (two 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.

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.

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 eruption and eye opening during the lactation period.

8.2 Labor and Delivery

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.

8.3 Nursing Mothers

There is limited information on the safety of quinine in 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 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 Clinical Pharmacology (12.3)].

Although quinine is generally considered compatible with breast-feeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman.

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 sulfate.

8.4 Pediatric Use

The safety and efficacy of quinine sulfate capsules 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), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In patients with severe hepatic renal 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 [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)].

10 OVERDOSAGE

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 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 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 fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Quinine, like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of quinine is due to its negative inotropic action, and to its effect on 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, an 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 [see Warnings and Precautions (5), Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

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.

11 DESCRIPTION

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 782.94.

The structural formula of quinine sulfate is:

Quinine sulfate, USP occurs as a white or almost white powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform, and ether.

Quinine sulfate capsules, USP supplied for oral administration as capsules containing 324 mg of the active ingredient quinine sulfate, equivalent to 269 mg free base. Inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, gelatin, magnesium stearate, povidone, pregelatinized starch, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

The imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Quinine is an antimalarial agent [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

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 sulfate 648 mg 3 times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms.

Prolongation of the PR and QRS interval was also noted in subjects receiving quinine sulfate capsules. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [See Warnings and Precautions (5.3).]

12.3 Pharmacokinetics

Absorption

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.

Table 1: Pharmacokinetic Parameters of Quinine in Healthy Subjects and Patients with Uncomplicated P. falciparum Malaria after a Single DoseQuinine sulfate dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria. of Oral Quinine Sulfate Capsules

Healthy Subjects

(N = 23)

Mean ± SD

Uncomplicated
P. falciparum Malaria Patients

(N = 15)

Mean ± SD

Dose (mg/kg)Quinine sulfate dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria.

8.7

10

Tmax (h)

2.8 ± 0.8

5.9 ± 4.7

Cmax (mcg/mL)

3.2 ± 0.7

8.4

AUC0-12 (mcg*h/mL)

28

73

Quinine sulfate capsules may be administered without regard to meals. When a single oral 324 mg capsule of quinine sulfate was administered to healthy subjects (N = 26) with a standardized high fat breakfast, the mean Tmax of quinine was prolonged to about 4 hours, but the mean Cmax and AUC0-24h were similar to those achieved when quinine sulfate capsule was given under fasted conditions [see Dosage and Administration (2.1)].

Distribution

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.

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.

Intra-erythrocytic levels of quinine are approximately 30% to 50% of the plasma concentration.

Quinine penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2% to 7% of plasma concentration.

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 mg to 3 mg per day [see Use in Specific Populations (8.1, 8.3)].

Metabolism

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.

In vitro studies using human liver microsomes and 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.

Elimination/Excretion

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.

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.

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.

Extracorporeal Elimination

Administration of multiple-dose activated charcoal (50 grams administered 4 hours after quinine dosing followed by three 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 seven healthy adult subjects who received a single oral 600 mg dose of quinine sulfate. Likewise, in five 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 [see Overdosage (10)].

In six 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 eight patients not treated in this manner [see Overdosage (10)].

Specific Populations

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 malaria. 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.

Table 2: Quinine Pharmacokinetic Parameters Following the First 10 mg/kg Quinine Sulfate Oral Dose in Healthy Pediatric Controls and Pediatric Patients with Acute Uncomplicated P. falciparum Malaria

Healthy Pediatric Controls age 1.5 to 12 years

(N = 5)

Mean ± SD

P. falciparum Malaria
Pediatric Patients age 1.5 to 12 years

(N = 15)

Mean ± SD

Tmax (h)

2

4

Cmax (mcg/mL)

3.4 ± 1.18

7.5 ± 1.1

Half-life (h)

3.2 ± 0.3

12.1 ± 1.4

Total CL (L/h/kg)

0.30 ± 0.04

0.06 ± 0.01

Vd (L/kg)

1.43 ± 0.18

0.87 ± 0.12

Following a single oral dose of 600 mg quinine sulfate, the mean AUC was about 38% higher in eight 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%).

After a single 648 mg dose or at steady-state, following quinine sulfate 648 mg given 3 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 hours) than in younger subjects (20 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 3 times daily. The steady-state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects.

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 sulfate followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine [see Dosage and Administration (2.2)]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of quinine sulfate are not known.

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 one hour. Plasma quinine concentrations do not change during or shortly after hemofiltration in subjects with CRF [see Overdosage (10)].

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 [see Use in Specific Populations (8.7)].

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 [see Dosage and Administration (2.3)].

12.4 Microbiology

Mechanism of Action

Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of quinine sulfate is not completely understood.

Activity In Vitro and In Vivo

Quinine sulfate acts primarily on the blood schizont form of P. falciparum. It is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to quinine can be selected in vivo. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of quinine have not been conducted.

Mutagenesis

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.

Impairment of Fertility

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 five 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.

14 CLINICAL STUDIES

Quinine has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1,300 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 2,900 patients from malaria-endemic areas were enrolled in these studies, and more than 1,400 patients received oral quinine. The following conclusions were drawn from review of these studies:

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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Quinine Sulfate Capsules, USP are available containing 324 mg of quinine sulfate, USP.

The 324 mg capsule is a buff opaque cap and buff opaque body, hard-shell gelatin capsule filled with white to off-white powder. The capsule is axially printed with MYLAN over QS 324 in black ink on cap and body. They are available as follows:

NDC 0378-7180-93
bottles of 30 capsules

NDC 0378-7180-01
bottles of 100 capsules

NDC 0378-7180-05
bottles of 500 capsules

16.2 Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide (17.2)

17.1 Dosing Instructions

Patients should be instructed to:

  • •Take all of the medication as directed.
  • •Take no more of the medication than the amount prescribed.
  • •Take with food to minimize possible gastrointestinal irritation.

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.

17.2 FDA-Approved Medication Guide

     

MEDICATION GUIDE
QUININE SULFATE CAPSULES, USP
(kwye′ nine sul′ fate)
324 mg

Read the Medication Guide that comes with quinine sulfate capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about quinine sulfate capsules when you start taking it and at regular checkups. Quinine sulfate capsules are not approved for the treatment of night-time leg cramps.

What is the most important information I should know about quinine sulfate capsules?

Quinine sulfate capsules used to treat or prevent leg cramps may cause serious side effects or even death.

  • •Quinine sulfate capsules may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen.
  • •Quinine sulfate capsules may cause problems with your heart rhythm that can lead to death.
  • •Quinine sulfate capsules may cause serious allergic reactions.

Call your healthcare provider right away if you have:

  • •easy bruising
  • •severe nose bleed
  • •blood in urine or stool
  • •bleeding gums
  • •appearance of unusual purple, brown or red spots on your skin (bleeding under your skin)
  • •rash
  • •hives
  • •severe itching
  • •severe flushing
  • •swelling of your face
  • •trouble breathing
  • •chest pain
  • •rapid heartbeat
  • •irregular heart rhythm
  • •weakness
  • •sweating
  • •nervousness

Taking quinine sulfate capsules with some other medicines can increase the chance of serious side effects. Tell your healthcare provider if you take any other medicines.

Certain medicines can cause the blood levels of quinine sulfate capsules to be too high or too low in your body. It is important for you to tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Quinine sulfate capsules and other medicines may affect each other causing serious side effects or death. Even medicines that you may take for a short period of time, such as antibiotics, can mix in your blood with quinine sulfate and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What are quinine sulfate capsules?

Quinine sulfate capsules are a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Quinine sulfate capsules are not approved to:

  • •Prevent malaria
  • •Treat severe or complicated malaria
  • •Prevent or treat night-time leg cramps

It is not known if quinine sulfate capsules are safe and work in children younger than 16 years old.

Who should not take quinine sulfate capsules?

Do not take quinine sulfate capsules if you have:

  • •certain heart rhythm problems (atrial fibrillation) or abnormal electrocardiogram (ECG) (QT prolongation).
  • •low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G6PD).
  • •an autoimmune disease (myasthenia gravis) that leads to muscle weakness.
  • •had allergic reactions to quinine, quinidine, or mefloquine (Lariam®*).
  • •had serious side effects to quinine (quinine sulfate capsules), such as low platelets, which are necessary for your blood to clot.
  • •an inflammation of the nerve important for vision (optic neuritis).

What should I tell my healthcare provider before starting quinine sulfate capsules?

Before you take quinine sulfate capsules, tell your healthcare provider if you:

  • •Have heart problems.
  • •Have kidney problems.
  • •Have liver problems.
  • •Have any other medical condition.
  • •Are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your healthcare provider can tell you more about the benefits and risks of taking this medication during pregnancy. Low blood sugar (hypoglycemia) can be seen in pregnant women while taking quinine sulfate capsules. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if quinine sulfate capsules are right for you.
  • •Are breast-feeding. Small amounts of quinine sulfate can pass into your breast milk. You and your healthcare provider can decide if you should breast-feed while taking quinine sulfate capsules.

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins and herbal supplements.

How should I take quinine sulfate capsules?

  • •Take quinine sulfate capsules exactly as your healthcare provider tells you to take it.
  • •Your healthcare provider will tell you how many quinine sulfate capsules to take and when to take them.
  • •To lower the chance of stomach upset, take quinine sulfate capsules with food.
  • •Finish all the quinine sulfate capsules that are prescribed even if you feel better. Do not stop taking the medication without talking to your healthcare provider.
  • • Do not take more than the amount prescribed. Do not take more than two capsules at one time or more than three doses in one day. If you take more than the prescribed dose, call your healthcare provider right away.
  • •If you forget to take quinine sulfate capsules, do not double the next dose. If it has been more than 4 hours since the missed dose, just wait and take the regular dose at the next scheduled time. Call your healthcare provider if you are not sure what to do.
  • •If you take too much quinine sulfate capsules call your healthcare provider or go to the nearest emergency room right away.

Call your healthcare provider right away if:

  • •If you feel worse, or if you do not start feeling better within 1 or 2 days of starting to take quinine sulfate capsules.
  • •If your fever comes back after finishing treatment with quinine sulfate capsules.

What are the possible side effects of quinine sulfate capsules?

Quinine sulfate capsules may cause serious side effects.

  • •See “What is the most important information I should know about quinine sulfate capsules?” section.
  • •Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion.

Common side effects with quinine sulfate capsules include:

  • •headache
  • •sweating
  • •flushing
  • •nausea
  • •ringing in your ears
  • •diarrhea
  • •deafness
  • •hearing loss
  • •dizziness (vertigo)
  • •blurred vision
  • •changes in how you see color
  • •vomiting
  • •stomach pain
  • •blindness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of quinine sulfate capsules. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store quinine sulfate capsules?

  • •Keep the capsules in a tightly closed container.
  • •Do not refrigerate or freeze.
  • •Store at 20° to 25°C (68° to 77°F).

Keep quinine sulfate capsules and all medicines out of the reach of children.

General information about quinine sulfate capsules 

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use quinine sulfate capsules for a condition for which it was not prescribed. Do not give quinine sulfate capsules to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about quinine sulfate capsules. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about quinine sulfate capsules that is written for healthcare professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in quinine sulfate capsules?

Active ingredients: Quinine Sulfate

Inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, gelatin, magnesium stearate, povidone, pregelatinized starch, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

The imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brand listed is a registered trademark of its respective owner.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED APRIL 2013
QUNE:R3mmt

PRINCIPAL DISPLAY PANEL - 324 mg

NDC 0378-7180-93

Quinine
Sulfate
Capsules, USP
324 mg

PHARMACIST: Dispense the accompanying
Medication Guide to each patient.

Rx only 30 Capsules

Each capsule contains:
Quinine sulfate, USP 324 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: Two capsules every
8 hours for 7 days. See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM7180H1

Quinine Sulfate

quinine sulfate CAPSULE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:0378-7180
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Quinine Sulfate QUININE 324 mg

Inactive Ingredients

Ingredient Name Strength
SILICON DIOXIDE
STARCH, CORN
CROSCARMELLOSE SODIUM
GELATIN
MAGNESIUM STEARATE
POVIDONES
ferric oxide red
SODIUM LAURYL SULFATE
titanium dioxide
FERRIC OXIDE YELLOW
AMMONIA
FERROSOFERRIC OXIDE
propylene glycol
SHELLAC

Product Characteristics

Color Size Imprint Code Shape
WHITE (buff opaque) 23 mm MYLAN;QS;324 CAPSULE

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:0378-7180-93 30 in 1 BOTTLE, PLASTIC
2 NDC:0378-7180-01 100 in 1 BOTTLE, PLASTIC
3 NDC:0378-7180-05 500 in 1 BOTTLE, PLASTIC

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202581 2012-12-14


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Be sure to consult your doctor before taking any medication!
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