WARNINGS
Use of Qualaquin for Treatment or Prevention of Nocturnal Leg Cramps
Qualaquin may cause unpredictable serious and life-threatening hypersensitivity reactions, QT prolongation, serious cardiac arrhythmias including torsades de pointes, and other serious adverse events requiring medical intervention and hospitalization. Fatalities have also been reported. The risk associated with the use of Qualaquin 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 CONTRAINDICATIONS, PRECAUTIONS, and ADVERSE REACTIONS).
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/Electrocardiogram). Quinine sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.
Qualaquin 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).
Quinine may also inhibit the metabolism of other drugs that are CYP3A4 substrates known to cause QT prolongation, such as 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 Qualaquin with these medications, or drugs with similar properties, should be avoided (See PRECAUTIONS/Drug Interactions).
Concomitant administration of Qualaquin 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 Qualaquin and mefloquine may also increase the risk of seizures (See PRECAUTIONS/Drug Interactions).
The use of macrolide antibiotics such as erythromycin should be avoided in patients receiving Qualaquin. 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 could potentially increase quinine plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has been shown to increase quinine exposure in a pharmacokinetic study (See PRECAUTIONS/Drug Interactions).
Qualaquin should also be avoided in patients with known prolongation of QT interval (See CONTRAINDICATIONS), in elderly patients, and in patients with clinical conditions known to prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and certain cardiac conditions.
Concomitant Use of Rifampin
Treatment failures may result from the concurrent use of rifampin with Qualaquin, due to decreased plasma concentrations of quinine, and concomitant use of these medications should be avoided (See PRECAUTIONS/Drug Interactions).
Glucose-6-Phosphate Dehydrogenase (G-6-PD) Deficiency
Hemolysis and hemolytic anemia can occur in patients with G-6-PD deficiency who receive quinine. Qualaquin should be stopped immediately upon the appearance of evidence of hemolysis (See CONTRAINDICATIONS).
Myasthenia Gravis
Quinine sulfate has neuromuscular blocking activity, and may exacerbate muscle weakness in patients with myasthenia gravis (See CONTRAINDICATIONS).
Neuromuscular Blocking Agents
The use of neuromuscular blocking agents should also be avoided in patients receiving Qualaquin. 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 PRECAUTIONS/Drug Interactions).
PRECAUTIONS
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 (See CONTRAINDICATIONS).
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. Qualaquin should be discontinued in case of any signs or symptoms of hypersensitivity (See CONTRAINDICATIONS).
Atrial Fibrillation and Flutter
Qualaquin 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 PRECAUTIONS/Drug Interactions).
Hypoglycemia
Quinine stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.
Information for Patients
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. (See Patient Package Insert.)
Drug Interactions
Effects of Drugs and Other Agents on Quinine Pharmacokinetics
Quinine undergoes hepatic metabolism primarily by CYP3A4 and to a lesser extent CYP1A2. In vivo drug interactions have been observed with drugs that induce or inhibit CYP3A4. Similarly, other in vivo drug interactions have been reported with drugs that inhibit or induce a wide range of CYP enzymes that may contribute to the metabolism of quinine such as CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Concomitant administration of drugs that inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 would be expected to increase quinine plasma concentrations and thereby increase the risk of quinine-associated adverse events such as cinchonism (see ADVERSE REACTIONS). Clinicians need to monitor for adverse events and consider cessation of these concomitant drugs if quinine-associated toxicities occur. When quinine is co-administered with potent inducers of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, quinine plasma concentrations would be expected to decrease. Clinicians should discontinue potent inducers of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 when treating malaria patients with quinine in order to achieve maximal therapeutic benefit.
Antacids
Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with Qualaquin should be avoided.
Cholestyramine
In 8 healthy volunteers who received quinine sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in quinine pharmacokinetic parameters was seen.
CYP1A2 substrates or inhibitors (e.g., fluoroquinolones, fluvoxamine)
The role of CYP1A2 in the metabolism of quinine is confirmed by in vitro experiments and the observation that smoking induces the clearance of quinine. Patients taking medications that are CYP1A2 substrates or inhibitors with Qualaquin should be monitored closely for adverse reactions associated with these medications.
Erythromycin (CYP3A4 inhibitor)
Erythromycin was shown to inhibit the metabolism of quinine in vitro using human liver microsomes. Therefore, concomitant administration of erythromycin with Qualaquin is likely to increase plasma quinine concentrations, and should be avoided (See WARNINGS).
Grapefruit juice (CYP3A4 inhibitor)
In a pharmacokinetic study involving 10 healthy volunteers, 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. Qualaquin may be taken with grapefruit juice.
Histamine H2-receptor blockers (cimetidine, ranitidine)
In healthy volunteers 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 (a non-specific inhibitor of several isoenzymes including CYP1A2, CYP2C19, CYP2D6, and CYP3A4) but not with ranitidine (a CYP2D6 inhibitor). Compared to untreated controls, the mean AUC of quinine increased by only 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 may be used concomitantly with Qualaquin, 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 parameters of quinine. Adjustment of Qualaquin 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 Qualaquin dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with quinine.
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 volunteers (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 Qualaquin should be avoided (See WARNINGS).
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 Qualaquin, patients should be monitored closely for adverse reactions associated with quinine sulfate.
Troleandomycin (CYP3A4 inhibitor)
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. Therefore, concomitant administration of troleandomycin with Qualaquin should be avoided (See WARNINGS).
Urinary alkalizers (acetazolamide, sodium bicarbonate)
Urinary alkalinizing agents may increase plasma quinine concentrations.
Effect of Quinine on the Pharmacokinetics of Other Drugs
Results of in vivo and in vitro drug interaction studies suggest that quinine has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6, as well as inhibit the biliary excretion of drugs like digoxin. A recent in vitro study using accepted methodology demonstrates quinine inhibits only CYP2C8 and CYP2D6. Thus, quinine may increase the plasma concentration of drugs that are substrates of either enzyme.
In an in vitro induction study using human hepatocytes, quinine (5 to 30 µM) increased the metabolic activities of CYP1A2 and CYP3A4. Quinine did not significantly induce the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
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. Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with Qualaquin.
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 Qualaquin with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided (See WARNINGS).
CYP2C8 substrates (e.g., paclitaxel, repaglinide)
Although not reported in the published literature, coadministration of known CYP2C8 substrates and quinine, a CYP2C8 inhibitor, may increase plasma concentrations of these drugs, thereby increasing the risk of serious adverse effects. Patients taking medications that are CYP2C8 substrates with Qualaquin should be monitored closely for adverse reactions associated with these medications.
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 Qualaquin should be monitored closely for adverse reactions associated with these medications.
Digoxin
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 Qualaquin is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary (See PRECAUTIONS).
Halofantrine
Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Qualaquin is likely to increase plasma halofantrine concentrations (See WARNINGS).
HMG-CoA reductase inhibitors (CYP3A4 substrates)
Rhabdomyolysis was reported to occur in a patient taking atorvastatin administered a single dose of quinine sulfate. Thus, clinicians considering combined therapy with atorvastatin or other HMG-CoA reductase inhibitors that are CYP3A4 substrates (e.g., lovastatin or simvastatin) and quinine, also a CYP3A4 substrate, should weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. There is no assurance that monitoring creatinine phosphokinase (CPK) will prevent the occurrence of severe myopathy.
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 Qualaquin may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures (See WARNINGS).
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).
Theophylline or aminophylline (CYP1A2 substrate)
Although not studied clinically, quinine has been shown to induce the activity of CYP1A2 in vitro using human hepatocytes. Therefore, concomitant administration of Qualaquin and theophylline or aminophylline is likely to decrease the plasma theophylline concentrations, possibly reducing the effect of theophylline or aminophylline. Plasma theophylline concentrations should be monitored frequently during concurrent therapy with theophylline or aminophylline and Qualaquin.
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 Qualaquin.
Drug/Laboratory Interactions
Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies of quinine have not been conducted.
Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. There were non-positive genotoxicity findings in the sex-linked recessive lethal test performed in Drosophila, in the in vivo mouse micronucleus assay, and in the chromosomal aberration assay in mice and Chinese hamsters.
Studies to evaluate the effect of quinine upon fertility in animals or in humans have not been conducted.
Pregnancy
Category C
There are no adequate and well-controlled studies in pregnant women.
Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, particularly in pregnant women.
Quinine crosses the placenta and gives measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting quinine therapy, placental 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 (See CLINICAL PHARMACOLOGY). Quinine levels in the fetus may not be therapeutic. If congenital malaria is suspected after delivery, the infant should be evaluated and treated appropriately.
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.
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].
In an epidemiologic survey that included 104 mother-child pairs exposed to quinine during the first 4 months of pregnancy, no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]).
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. Qualaquin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The risks and benefits of alternative treatments should be considered. If Qualaquin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazards to the fetus.
Teratogenic effects have been demonstrated in some animal species but not in others when quinine was given by the subcutaneous or intramuscular route at dose levels in the same range as the maximum recommended human dose. Teratogenic effects were observed in rabbits (death in utero, degenerated auditory nerve and spiral ganglion, and CNS anomalies such as anencephaly and microcephaly), dogs (death in utero), guinea pigs (hemorrhage and mitochondrial change in cochlea), and chinchillas (death and growth suppression in utero and CNS anomalies, such as anencephaly and microcephaly). There were no teratogenic findings in mice, rats, and monkeys.
Labor and Delivery
There is no evidence that quinine causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, quinine may stimulate the pregnant uterus.
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).
Although quinine is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed.
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 Qualaquin.
Pediatric Use
The safety and efficacy of Qualaquin in pediatric patients under the age of 16 has not been established.
Geriatric Use
Clinical studies of quinine sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
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