Quinine Sulfate

5 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 treatment failures have been reported ( 5.4 ). Avoid concomitant use with neuromuscular blocking agents. Quinine sulfate 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 ). 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 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 ( 7.1 )] . 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 with these medications, or drugs with similar properties, should be avoided [see DRUG INTERACTIONS ( 7.2 )] . 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 ( 7.2 )] . 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 )] . 5.4 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. 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 should be discontinued in case of any signs or symptoms of hypersensitivity [see CONTRAINDICATIONS ( 4 )] . 5.7 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 ( 7.2 )] . 5.8 Hypoglycemia Quinine stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.