Quinine Sulfate 324 MG Oral Capsule

Generic Name: QUININE SULFATE
Brand Name: Quinine Sulfate
  • Substance Name(s):
  • QUININE SULFATE

DRUG INTERACTIONS

7 Interacting Drug Interaction Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).

Quinine sulfate capsules, USP 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 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 co-administered 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.

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 capsules, USP 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 capsules, USP.

Cholestyramine: In 8 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 10 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, USP 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 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 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 capsules, USP, patients should be monitored closely for adverse events associated with quinine.

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of quinine.

Adjustment of quinine sulfate capsules, USP 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 capsules, USP 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 four 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 capsules, USP 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 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 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 capsules, USP 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, USP 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 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 two-fold higher than in 8 patients who received quinine monotherapy.

Although tetracycline may be concomitantly administered with quinine sulfate capsules, USP, 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 capsules, USP (648 mg every 8 hours × 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 capsules, USP 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 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.

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 capsules, USP 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 capsules, USP 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 capsules, USP are 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 capsules, USP 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 (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 capsules, USP are 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 capsules, USP 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 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 capsules, USP 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 capsules, USP 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 sulfate capsules, USP 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, USP 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 sulfate capsules, USP 648 mg every 8 hours × 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 capsules, USP are co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations.

Warfarin and oral anticoagulants: Cinchona alkaloids, including quinine, may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin and other oral anticoagulants.

Quinine may also interfere with the anticoagulant effect of heparin.

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 capsules, USP.

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).

OVERDOSAGE

10 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.

DESCRIPTION

11 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 sulfate is: Quinine 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 sulfate capsules, USP are supplied for oral administration as capsules containing 324 mg of the active ingredient quinine sulfate USP, equivalent to 269 mg free base.

Inactive ingredients: corn starch, magnesium stearate, and talc.

Chemical Structure

CLINICAL STUDIES

14 Quinine 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, 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 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 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.

HOW SUPPLIED

16 / STORAGE AND HANDLING 16.1 How Supplied Quinine sulfate capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102: Bottles of 30 NDC 53489-700-07 Bottles of 100 NDC 53489-700-01 16.2 Storage Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature] Dispense in a tight container as defined in the USP.

GERIATRIC USE

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.

DOSAGE FORMS AND STRENGTHS

3 324 mg capsules – hard gelatin, clear cap/clear body, imprinted with ‘AR 102’ 324 mg hard gelatin, clear cap/clear body capsules, imprinted with ‘AR 102’ (3).

MECHANISM OF ACTION

12.1 Mechanism of Action Quinine is an antimalarial agent [see Clinical Pharmacology (12.4) ].

INDICATIONS AND USAGE

1 Quinine sulfate capsules, USP 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) ].

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

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of quinine sulfate capsules, USP in pediatric patients under the age of 16 has not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category C There are extensive published data but few well-controlled studies of quinine sulfate capsules, USP 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 8 women who delivered live infants 1 to 6 days after starting quinine therapy, umbilical cord plasma quinine 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 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 2201 women [1.8%]).

The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with quinine sulfate compared with the control group (38 of 2201 offspring [1.7%]).

The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with quinine sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7].

An epidemiologic survey that included 104 mother-child pairs exposed to quinine during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]).

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.

NUSRING MOTHERS

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 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 levels may not be therapeutic in infants of nursing mothers receiving quinine sulfate capsules, USP.

BOXED WARNING

WARNING: HEMATOLOGIC REACTIONS Quinine sulfate capsules, USP 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, USP use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit [see Warnings and Precautions (5.1) ].

WARNING: HEMATOLOGIC REACTIONS See full prescribing information for complete boxed warning Quinine sulfate capsules, USP 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, USP use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit (5.1).

WARNING AND CAUTIONS

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 capsules, USP treatment failures have been reported (5.4).

Avoid concomitant use with neuromuscular blocking agents.

Quinine sulfate capsules, USP 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 Capsules, USP for Treatment or Prevention of Nocturnal Leg Cramps Quinine sulfate capsules, USP 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, USP 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 capsules, USP 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, USP 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, USP.

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

Concomitant administration of quinine sulfate capsules, USP 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 capsules, USP and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Quinine sulfate capsules, USP 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 capsules, USP, 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, USP.

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

5.7 Atrial Fibrillation and Flutter Quinine sulfate capsules, USP 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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) 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.

Distributed by: Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512 Rev 03, December 2014

DOSAGE AND ADMINISTRATION

2 Adults (≥ 16 years of age): 648 mg (two capsules) every 8 hours for 7 days (2.1).

Patients with severe chronic renal impairment: one loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days (2.2).

2.1 Treatment of Uncomplicated P.

falciparum Malaria For treatment of uncomplicated P.

falciparum malaria in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days [see Clinical Studies (14) ].

Quinine sulfate capsules, USP 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, USP 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), 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), Clinical Pharmacology (12.3) ].