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Active ingredient: Quinine Dihydrochloride

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Quinine Dihydrochloride uses


WARNING:

Quinine Dihydrochloride® 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 Dihydrochloride use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Quinine Dihydrochloride® 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 Dihydrochloride use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

Dose and Administration
Hepatic Impairment (2.3) 4/2013
Warnings and Precautions
QT Prolongation and Ventricular Arrhythmias (5.3) 9/2012
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1 INDICATIONS AND USAGE

Quinine Dihydrochloride (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Quinine Dihydrochloride sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ].

Quinine Dihydrochloride oral capsules are not approved for:


Quinine Dihydrochloride® (quinine sulfate) is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria (1).

2 DOSAGE AND ADMINISTRATION

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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride sulfate are not known [see Use in Specific Populations, 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 Dihydrochloride. Quinine Dihydrochloride should not be administered in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) ].

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3 DOSAGE FORMS AND STRENGTHS

324 mg capsules - hard gelatin, clear cap/clear body, imprinted with 'AR 102'

4 CONTRAINDICATIONS

Quinine Dihydrochloride is contraindicated in patients with the following:


Quinine Dihydrochloride is contraindicated in patients with the following:

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5 WARNINGS AND PRECAUTIONS

5.1 Use of Quinine Dihydrochloride for Treatment or Prevention of Nocturnal Leg Cramps

Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride. If Quinine Dihydrochloride is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to Quinine Dihydrochloride 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 Dihydrochloride administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak Quinine Dihydrochloride plasma concentration [see Clinical Pharmacology ]. Quinine Dihydrochloride sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.

Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride. Fatal torsades de pointes was reported in an elderly patient who received concomitant Quinine Dihydrochloride, 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 Dihydrochloride plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase Quinine Dihydrochloride exposure in a pharmacokinetic study [see Drug Interactions (7.1) ].

Quinine Dihydrochloride 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 Dihydrochloride and astemizole. Therefore, concurrent use of Quinine Dihydrochloride with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2) ].

Concomitant administration of Quinine Dihydrochloride 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 Dihydrochloride and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Quinine Dihydrochloride 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 Dihydrochloride, due to decreased plasma concentrations of Quinine Dihydrochloride, 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 Dihydrochloride. In one patient who received pancuronium during an operative procedure, subsequent administration of Quinine Dihydrochloride resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, Quinine Dihydrochloride may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions ].

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Quinine Dihydrochloride 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 Dihydrochloride, 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 Dihydrochloride should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ].

5.7 Atrial Fibrillation and Flutter

Quinine Dihydrochloride should be used with caution in patients with atrial fibrillation or atrial flutter. A paradoxical increase in ventricular response rate may occur with Quinine Dihydrochloride, 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 Dihydrochloride [see Drug Interactions ].

5.8 Hypoglycemia

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

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6 ADVERSE REACTIONS

Most common adverse reactions are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Quinine Dihydrochloride: 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.

To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or drugsafetyQuinine Dihydrochlorideurlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

Quinine Dihydrochloride can adversely affect almost every body system. The most common adverse events associated with Quinine Dihydrochloride use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Quinine Dihydrochloride. 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 Dihydrochloride.

The following ADVERSE REACTIONS have been reported with Quinine Dihydrochloride 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

Interacting Drug Interaction
Drugs known to prolong QT interval. Quinine Dihydrochloride prolongs 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 Dihydrochloride concentration. Monitor for lack of efficacy or increased adverse events of Quinine Dihydrochloride (7.1).
CYP3A4 and CYP2D6 substrates Quinine Dihydrochloride is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).

7.1 Effects of Drugs and Other Substances on Quinine Dihydrochloride Pharmacokinetics

Quinine Dihydrochloride 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 Dihydrochloride [see Clinical Pharmacology (12.3) ].

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of Quinine Dihydrochloride. Concomitant administration of these antacids with Quinine Dihydrochloride should be avoided.

Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin): Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease Quinine Dihydrochloride plasma concentrations if used concurrently with Quinine Dihydrochloride.

Cholestyramine: In 8 healthy subjects who received Quinine Dihydrochloride sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in Quinine Dihydrochloride pharmacokinetic parameters was seen.

Cigarette Smoking (CYP1A2 inducer): In healthy male heavy smokers, the mean Quinine Dihydrochloride 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 Dihydrochloride therapy, cigarette smoking produced only a 25% decrease in median Quinine Dihydrochloride AUC and a 16.5% decrease in median Cmax, suggesting that the already reduced clearance of Quinine Dihydrochloride 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 Dihydrochloride in the treatment of acute malaria in heavy cigarette smokers.

Grapefruit juice (P-gp/CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy subjects, the administration of a single 600 mg dose of Quinine Dihydrochloride sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of Quinine Dihydrochloride. Quinine Dihydrochloride may be taken with grapefruit juice.

Histamine H2-receptor blockers [cimetidine, ranitidine (nonspecific CYP450 inhibitors)]: In healthy subjects who were given a single oral 600 mg dose of Quinine Dihydrochloride sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for 7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of Quinine Dihydrochloride 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 Dihydrochloride increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean Quinine Dihydrochloride Cmax. When Quinine Dihydrochloride 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 Dihydrochloride, patients should be monitored closely for adverse events associated with Quinine Dihydrochloride.

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of Quinine Dihydrochloride. Adjustment of Quinine Dihydrochloride 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 Dihydrochloride hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean Quinine Dihydrochloride AUC that was higher by 45% and a mean oral clearance of Quinine Dihydrochloride that was 31% lower than after receiving Quinine Dihydrochloride alone. Although no change in the Quinine Dihydrochloride dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with Quinine Dihydrochloride.

Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors): In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of Quinine Dihydrochloride sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean Quinine Dihydrochloride AUC, a 45% lower mean oral clearance of Quinine Dihydrochloride, and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when Quinine Dihydrochloride was given alone.

Erythromycin was shown to inhibit the in vitro metabolism of Quinine Dihydrochloride 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 Dihydrochloride sulfate with erythromycin (600 mg every 8 hours for four days) showed a decrease in Quinine Dihydrochloride oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to Quinine Dihydrochloride AUC ratio, as compared to when Quinine Dihydrochloride was given with placebo.

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

Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single-ingredient progestin or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of Quinine Dihydrochloride sulfate were not altered in comparison to those observed in 7 age-matched female control subjects not using oral contraceptives.

Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received Quinine Dihydrochloride sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of Quinine Dihydrochloride between days 3 and 7 of therapy was 75% lower as compared to those who received Quinine Dihydrochloride monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of Quinine Dihydrochloride sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the mean Quinine Dihydrochloride AUC and Cmax decreased by 85% and 55%, respectively. Therefore, the concomitant administration of rifampin with Quinine Dihydrochloride should be avoided [see Warnings and Precautions (5.4) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Quinine Dihydrochloride sulfate with the 15th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean Quinine Dihydrochloride AUC and Cmax, and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when Quinine Dihydrochloride was given alone. Therefore, the concomitant administration of ritonavir with Quinine Dihydrochloride capsules should be avoided [see also Drug Interactions (7.2) ].

Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with oral Quinine Dihydrochloride 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 Dihydrochloride concentrations were about two-fold higher than in 8 patients who received Quinine Dihydrochloride monotherapy. Although tetracycline may be concomitantly administered with Quinine Dihydrochloride, patients should be monitored closely for adverse reactions associated with Quinine Dihydrochloride sulfate.

Theophylline or aminophylline: In 20 healthy subjects who received multiple doses of Quinine Dihydrochloride (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of theophylline, the Quinine Dihydrochloride mean Cmax and AUC were increased by 13% and 14% respectively. Although no change in the Quinine Dihydrochloride dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with Quinine Dihydrochloride.

Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma Quinine Dihydrochloride concentrations.

7.2 Effects of Quinine Dihydrochloride on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that Quinine Dihydrochloride has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Quinine Dihydrochloride inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates.

Anticonvulsants : A single 600 mg oral dose of Quinine Dihydrochloride sulfate increased the mean plasma Cmax, and AUC0–24 of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine, phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in Cmax were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by Quinine Dihydrochloride. 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 Dihydrochloride sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Quinine Dihydrochloride 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 Dihydrochloride. Quinine Dihydrochloride may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride (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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride should be monitored closely for adverse reactions associated with these medications.

Digoxin (P-gp substrate): In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with Quinine Dihydrochloride (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 Dihydrochloride 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 Dihydrochloride was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Quinine Dihydrochloride is likely to increase plasma halofantrine concentrations [see Warnings and Precautions (5.3) ].

Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose of Quinine Dihydrochloride 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 Dihydrochloride sulfate 24 hours apart. The concomitant administration of mefloquine and Quinine Dihydrochloride 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 Dihydrochloride 324 mg three times daily × 7 days with a single oral 2 mg dose of midazolam, the mean AUC and Cmax of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Quinine Dihydrochloride 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, Quinine Dihydrochloride potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received Quinine Dihydrochloride 1800 mg daily. Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride pharmacokinetics, the concomitant administration of Quinine Dihydrochloride capsules with ritonavir should be avoided [see also Drug Interactions (7.1) ].

Theophylline or aminophylline (CYP1A2 substrate): In 19 healthy subjects who received multiple doses of Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride, 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 Dihydrochloride 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 Dihydrochloride.

7.3 Drug/Laboratory Interactions

Quinine Dihydrochloride may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

Quinine Dihydrochloride 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 Dihydrochloride in pregnant women. Published data on over 1,000 pregnancy exposures to Quinine Dihydrochloride 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 Dihydrochloride at doses about 1 to 4 times the human clinical dose. Quinine Dihydrochloride 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 Dihydrochloride use, particularly in pregnant women.

Quinine Dihydrochloride crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting Quinine Dihydrochloride therapy, umbilical cord plasma Quinine Dihydrochloride concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to maternal plasma Quinine Dihydrochloride concentrations was 0.32 ± 0.14. Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride (10 of 633 women [1.6%]) as compared with a control group without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201 women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with Quinine Dihydrochloride sulfate compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with Quinine Dihydrochloride sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to Quinine Dihydrochloride during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of Quinine Dihydrochloride.

In animal developmental studies conducted in multiple animal species, pregnant animals received Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, Quinine Dihydrochloride may stimulate the pregnant uterus.

8.3 Nursing Mothers

There is limited information on the safety of Quinine Dihydrochloride in breastfed infants. No toxicity was reported in infants in a single study where oral Quinine Dihydrochloride sulfate 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 Dihydrochloride base (< 0.4% of the maternal dose) via breast milk [see Clinical Pharmacology (12.3) ].

Although Quinine Dihydrochloride is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman.

If malaria is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma Quinine Dihydrochloride levels may not be therapeutic in infants of nursing mothers receiving Quinine Dihydrochloride.

8.4 Pediatric Use

The safety and efficacy of Quinine Dihydrochloride in pediatric patients under the age of 16 has not been established.

8.5 Geriatric Use

Clinical studies of Quinine Dihydrochloride 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 Dihydrochloride is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see Dosage and Administration, Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh C), Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride may be increased relative to subjects with normal liver function [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride. A lethal dose of Quinine Dihydrochloride has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Quinine Dihydrochloride, like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride is rapidly absorbed, and attempts to remove residual Quinine Dihydrochloride sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma Quinine Dihydrochloride 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 Dihydrochloride elimination in a series of 16 patients.

11 DESCRIPTION

Quinine Dihydrochloride (quinine sulfate) is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C20H24N2O2)2-H2SO4-2H2O and a molecular weight of 782.96.

The structural formula of Quinine Dihydrochloride sulfate is:

Quinine Dihydrochloride sulfate 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, alcohol, chloroform, and ether.

Quinine Dihydrochloride is supplied for oral administration as capsules containing 324 mg of the active ingredient Quinine Dihydrochloride sulfate USP, equivalent to 269 mg free base. Inactive ingredients: corn starch, magnesium stearate, and talc.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Quinine Dihydrochloride is an antimalarial agent [see Clinical Pharmacology ].

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

Prolongation of the PR and QRS interval was also noted in subjects receiving Quinine Dihydrochloride. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [see Warnings and Precautions (5.3) ].

12.3 Pharmacokinetics

Absorption

The oral bioavailability of Quinine Dihydrochloride is 76 to 88% in healthy adults. Quinine Dihydrochloride exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Quinine Dihydrochloride sulfate, the mean Quinine Dihydrochloride 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.

Healthy Subjects

Mean ± SD

 Uncomplicated P. falciparum Malaria Patients

(N = 15)

Mean ± SD
Dose (mg/kg)Quinine Dihydrochloride 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) 28.0 73.0

Quinine Dihydrochloride capsules may be administered without regard to meals. When a single oral 324 mg capsule of Quinine Dihydrochloride was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of Quinine Dihydrochloride was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when Quinine Dihydrochloride 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 Dihydrochloride sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.

Quinine Dihydrochloride is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of Quinine Dihydrochloride is increased to 78 to 95%, corresponding to the increase in α1-acid glycoprotein that occurs with malaria infection.

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

Quinine Dihydrochloride 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 Dihydrochloride concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of Quinine Dihydrochloride concentrations in maternal plasma. The estimated total dose of Quinine Dihydrochloride secreted into breast milk was less than 2 to 3 mg per day [see Use in Specific Populations (8.1, 8.3) ].

Metabolism

Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride.

Elimination/Excretion

Quinine Dihydrochloride is eliminated primarily via hepatic biotransformation. Approximately 20% of Quinine Dihydrochloride is excreted unchanged in urine. Because Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride sulfate, the mean total clearance of Quinine Dihydrochloride 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 Dihydrochloride dosing followed by 3 further doses over the next 12 hours) decreased the mean Quinine Dihydrochloride elimination half-life from 8.2 to 4.6 hours, and increased the mean Quinine Dihydrochloride clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of Quinine Dihydrochloride sulfate. Likewise, in 5 symptomatic patients with acute Quinine Dihydrochloride poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean Quinine Dihydrochloride 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 6 patients with Quinine Dihydrochloride poisoning, forced acid diuresis did not change the half-life of Quinine Dihydrochloride elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged Quinine Dihydrochloride recovered in the urine, in comparison to 8 patients not treated in this manner [see Overdosage (10) ].

Specific Populations

Pediatric Patients: The pharmacokinetics of Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride in pediatric patients vs. healthy pediatric controls.

Healthy Pediatric Controlsage 1.5 to 12 years

(N = 5)

Mean ± SD

 P. falciparum Malaria Pediatric Patients

(N = 15)

Mean ± SD
Tmax (h) 2.0 4.0
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

Geriatric Patients: Following a single oral dose of 600 mg Quinine Dihydrochloride sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean Tmax and Cmax were similar in elderly and younger subjects after a single oral dose of Quinine Dihydrochloride sulfate 600 mg. The mean oral clearance of Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Quinine Dihydrochloride was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state Cmax (±SD) and AUC0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral Quinine Dihydrochloride sulfate 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects.

Renal Impairment: Following a single oral 600 mg dose of Quinine Dihydrochloride 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 Dihydrochloride followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Quinine Dihydrochloride [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Quinine Dihydrochloride sulfate are not known.

Negligible to minimal amounts of circulating Quinine Dihydrochloride in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of Quinine Dihydrochloride is removed in 1 hour. Plasma Quinine Dihydrochloride concentrations do not change during or shortly after hemofiltration in subjects with CRF [see Overdosage (10) ].

Hepatic Impairment: In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of Quinine Dihydrochloride sulfate, there was no significant difference in Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride sulfate is not completely understood.

Activity In Vitro and In Vivo

Quinine Dihydrochloride 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 Dihydrochloride can be selected in vivo. P. falciparum malaria that is clinically resistant to Quinine Dihydrochloride 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 Dihydrochloride have not been conducted.

Mutagenesis

Genotoxicity studies of Quinine Dihydrochloride 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 Dihydrochloride produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of Quinine Dihydrochloride 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 Dihydrochloride has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with Quinine Dihydrochloride, and from these, 21 randomized, active-controlled studies were identified which evaluated oral Quinine Dihydrochloride monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral Quinine Dihydrochloride. 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 Dihydrochloride monotherapy were at least 80%; while cure rates for 7 days of oral Quinine Dihydrochloride 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 Dihydrochloride 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 Dihydrochloride has been reported in some areas of South America, Southeast Asia, and Bangladesh, and Quinine Dihydrochloride may not be as effective in those areas.

Completion of a 7-day oral Quinine Dihydrochloride treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of Quinine Dihydrochloride combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral Quinine Dihydrochloride 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 Dihydrochloride capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:

Bottles of 30 NDC 13310-153-07
Bottles of 100 NDC 13310-153-01
Bottles of 500 NDC 13310-153-05
Bottles of 1000 NDC 13310-153-10

16.2 Storage

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

17.1 Dosing Instructions

Patients should be instructed to:


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 Dihydrochloride®

(kwol-a-kwin)

(Quinine sulfate) Capsules

Read the Medication Guide that comes with Quinine Dihydrochloride ® 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 Dihydrochloride ® when you start taking it and at regular checkups. Quinine Dihydrochloride ® is not approved for the treatment of night-time leg cramps.

What is the most important information I should know about Quinine Dihydrochloride®?

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


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 Dihydrochloride® 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 Dihydrochloride ® 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 Dihydrochloride® 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 Dihydrochloride® and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What is Quinine Dihydrochloride®?

Quinine Dihydrochloride ® is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Quinine Dihydrochloride® is Not approved to:


It is not known if Quinine Dihydrochloride® is safe and works in children younger than 16 years old.

Who should not take Quinine Dihydrochloride®?

Do not take Quinine Dihydrochloride® if you have:


What should I tell my healthcare provider before starting Quinine Dihydrochloride®?

Before you take Quinine Dihydrochloride®, tell your healthcare provider if you:


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

How should I take Quinine Dihydrochloride®?


Call your healthcare provider right away if:


What are the possible side effects of Quinine Dihydrochloride®?

Quinine Dihydrochloride® may cause serious side effects.


Common side effects with Quinine Dihydrochloride ® 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 Dihydrochloride ® . 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 Dihydrochloride®?


Keep Quinine Dihydrochloride® and all medicines out of the reach of children.

General Information about Quinine Dihydrochloride®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Quinine Dihydrochloride ® for a condition for which it was not prescribed. Do not give Quinine Dihydrochloride ® 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 Dihydrochloride ® . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Quinine Dihydrochloride ® that is written for healthcare professionals.

For more information, go to www. QUALAQUIN.com or call 1-888-351-3786.

What are the ingredients in Quinine Dihydrochloride®?

Active Ingredients: Quinine Dihydrochloride Sulfate, USP

Inactive Ingredients: Corn starch, magnesium stearate, talc

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

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 23, April 2013

PRINCIPAL DISPLAY PANEL - 324 mg Capsule Bottle Label

100 CAPSULES

NDC 13310-153-01

Quinine Dihydrochloride ®

Quinine Dihydrochloride sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Quinine Dihydrochloride available forms, composition, doses:


Indications and Usages:

ATC codes:


ICD-10 codes:


Quinine Dihydrochloride destination | category:


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Drugs with same active ingredients (Pharmaceutical companies):


References

  1. Dailymed."QUININE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Quinine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Quinine". http://www.drugbank.ca/drugs/DB0046... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Quinine Dihydrochloride?

Depending on the reaction of the Quinine Dihydrochloride after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Quinine Dihydrochloride not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Quinine Dihydrochloride addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Quinine Dihydrochloride, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Quinine Dihydrochloride consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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No survey data has been collected yet

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Visitor reported frequency of use

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Visitor reported doses

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Visitor reported administration

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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