Quinine

Interacting Drug Interaction Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate 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 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. 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 C max 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 C max , 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 may be taken with grapefruit juice.

Histamine H 2 -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 C max .

When quinine is to be given concomitantly with a histamine H 2 -receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with quinine sulfate, 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 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 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 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 C max decreased by 85% and 55%, respectively. Therefore the concomitant administration of rifampin with quinine sulfate 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 15 th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean quinine AUC and C max , 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 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, 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 (648 mg every 8 hours x 7 days) with a single 300 mg oral dose of theophylline, the quinine mean C max and AUC were increased by 13% and 14% respectively. Although no change in the quinine sulfate 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 C max , and AUC 0–24 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…