Quinine Sulfate drug interactions

# Drug Interactions

## 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 .

### Antacids
Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with QUALAQUIN should be avoided.

### Antiepileptics (AEDs)
Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with QUALAQUIN.

### 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. QUALAQUIN may be taken with grapefruit juice.

### Histamine H2-receptor blockers 
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 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 parameter values 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.

### 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 QUALAQUIN should be avoided .

### 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 QUALAQUIN should be avoided .

### 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 QUALAQUIN capsules should be avoided .

### 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.

### Theophylline or aminophylline
In 20 healthy subjects who received multiple doses of QUALAQUIN (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 QUALAQUIN 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.

## 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 AUC024 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 QUALAQUIN with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided .

### 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 QUALAQUIN 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 QUALAQUIN is used concomitantly with any of these statins, lower starting and maintenance doses of the statin should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. If marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values >10 times the upper limit of normal) is diagnosed or suspected, atorvastatin or other statin should be discontinued.

### Desipramine (CYP2D6 substrate)
Quinine (750 mg/day for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers. Lower doses (80 mg to 400 mg) of quinine did not significantly affect the pharmacokinetics of other CYP2D6 substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies have not been performed, antimalarial doses (greater than or equal to 600 mg) of quinine may inhibit the metabolism of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol, paroxetine). Patients taking medications that are CYP2D6 substrates with QUALAQUIN 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 QUALAQUIN is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary .

### 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 .

### 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 .

### Midazolam (CYP3A4 substrate)
In 23 healthy subjects who received multiple doses of QUALAQUIN 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 QUALAQUIN 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 .

### 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 QUALAQUIN capsules with ritonavir should be avoided .

### Theophylline or aminophylline (CYP1A2 substrate)
In 19 healthy subjects who received multiple doses of QUALAQUIN 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 QUALAQUIN 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, 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.
Quinine may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate).