Qualaquin (Quinine Sulfate) - Drug Interactions, Contraindications, Overdosage

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 C_max. 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 C_max 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.

OVERDOSAGE

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, PRECAUTIONS, and ADVERSE EVENTS).

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/Extracorporeal elimination).

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.

CONTRAINDICATIONS

Prolonged QT Interval

Qualaquin is contraindicated in patients with a prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received quinine sulfate intravenously for P. falciparum malaria (See WARNINGS).

Glucose-6-Phosphate Dehydrogenase Deficiency

Qualaquin is contraindicated in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (See WARNINGS).

Myasthenia Gravis

Qualaquin is contraindicated in patients with myasthenia gravis (See WARNINGS).

Hypersensitivity

Qualaquin is contraindicated in patients with known hypersensitivity to quinine. Qualaquin is also contraindicated in patients with known hypersensitivity to mefloquine or quinidine because cross-sensitivity to quinine has been documented (See PRECAUTIONS).

Qualaquin is contraindicated in patients with a history of potential hypersensitivity reactions associated with previous quinine use. These include, but are not limited to the following:

• Thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)
• Thrombocytopenia
• Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia)
  (See PRECAUTIONS).