Qualaquin

Dosage Forms & Strengths

capsule

• 324mg

Malaria

Uncomplicated (P. falciparum)

• 648 mg PO q8hr x 7 days

Chloroquine -Resistant (P. falciparum)

• 648 mg PO q8hr x 3-7 days with concomitant tetracycline, doxycycline, or clindamycin

Chloroquine-Resistant (P. vivax)

• 648 mg PO q8hr x 3-7 days with concomitant doxycycline (or tetracycline) and PO primaquine

Babesiosis

648 mg PO q8hr x 7 days, with concomitant PO or IV clindamycin

Dosage Modifications

Severe, chronic renal impairment: 648 mg PO once, then 324 mg PO q12hr

Hepatic impairment

• Mild or moderate (Child-Pugh A or B): No dosage adjustment required; monitor closely
• Severe (Child-Pugh C): Do not administer

Dosage Forms & Strengths

capsule

• 324mg

Malaria

Uncomplicated (P. falciparum)

• 30 mg/kg/day PO divided TID x 3–7 days  
• Should not exceed the usual adult PO dosage.

Chloroquine-Resistant (P. falciparum)

• 30 mg/kg/day PO divided TID x3-7 days, with concomitant doxycycline, tetracycline or clindamycin
• Should not exceed the usual adult PO dosage.

Chloroquine-Resistant (P. vivax)

• 30 mg/kg/day PO TID x 3–7 days, with concomitant doxycyline & PO primaquine
• Should not exceed the usual adult PO dosage.

Babesiosis (Off-label)

25 mg/kg/day PO divided TID x7 days, with concomitant oral clindamycin 

Quinine comes as a capsule to take by mouth. It usually is taken with food three times a day (every 8 hours) for 3 to 7 days. Take quinine at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take quinine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole; do not open, chew, or crush them. Quinine has a bitter taste.

You should begin to feel better during the first 1-2 days of your treatment. Call your doctor if your symptoms do not improve or if they get worse. Also call your doctor if you have a fever soon after you finish your treatment. This could be a sign that you are experiencing a second episode of malaria.

Take quinine until you finish the prescription, even if you feel better. If you stop taking quinine too soon or if you skip doses, your infection may not be completely treated and the organisms may become resistant to antimalarials.

Quinine is also sometimes used to treat babesiosis (a serious or life-threatening illness that is transmitted from animals to humans by ticks). Talk to your doctor about the risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Qualaquin is part of the drug class:

• Methanolquinolines

Avoid taking other anti-malaria medications without your doctor's advice. This includes chloroquine, halofantrine, and mefloquine.

Avoid using antacids without your doctor's advice. Use only the type of antacid your doctor recommends. Some antacids can make it harder for your body to absorb quinine.

Quinine may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Do not use quinine to treat any condition that has not been checked by your doctor.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• fever, chills, body aches, flu symptoms, sores in your mouth and throat;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;

• sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with balance;

• chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• problems with vision or hearing;

• pain, swelling, warmth, or redness in one or both legs;

• severe pain in your side or lower back, blood in your urine, little or no urine;

• low blood sugar (more common in pregnant women)--headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery;

• loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• headache, blurred vision, changes in color vision;

• sweating or flushing (warmth, redness, or tingly feeling);

• mild dizziness, spinning sensation, ringing in your ears; or

• upset stomach, vomiting, stomach pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Absorption

Bioavailability

Oral bioavailability is 76–88% in healthy adults.180 183 186 Quinine exposure higher in patients with malaria than in healthy adults,180 183 186 possibly because malaria may cause impaired hepatic function, which results in decreased quinine total body clearance and volume of distribution.106 107

In adults with uncomplicated P. falciparum malaria, mean AUC and peak plasma concentrations higher and time to peak concentration longer than that reported in healthy adults.180 183 186 Following a single oral dose, mean time to peak serum concentrations is 5.9 hours in adults with uncomplicated P. falciparum malaria compared with 2.8 hours in healthy adults.180 183 186

Food

When a single 324-mg dose of oral quinine sulfate capsules was administered with a high-fat meal in healthy adults, the time to peak concentrations was prolonged to approximately 4 hours; however, mean peak plasma concentration and AUC from 0–24 hours were similar to those achieved following oral administration of the drug under fasted conditions.180 183 186

Special Populations

Pharmacokinetics in children 1.5–12 years of age with uncomplicated P. falciparum malaria appear to be similar to that observed in adults with uncomplicated malaria.180 183 186 Following a single dose of 10 mg/kg of oral quinine sulfate in healthy children or children 1.5–12 years of age with uncomplicated P. falciparum malaria, mean time to peak quinine concentration was longer (4 versus 2 hours) and mean peak plasma concentration was higher (7.5 versus 3.4 mcg/mL) in children with uncomplicated P. falciparum malaria than in healthy children.180 183 186

Following a single 600-mg dose of oral quinine sulfate, mean AUC in healthy geriatric adults 65–78 years of age is approximately 38% higher than in younger adults 20–35 years of age;180 183 186 mean time to peak quinine concentrations and mean peak plasma concentrations are similar in both age groups.180 183 186

Following a single 600-mg dose of oral quinine sulfate in adults with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine 9.6 mg/dL), median AUC and mean peak plasma concentration increased by 195 and 79%, respectively, compared with adults with normal renal function.180 183 186 Effect of mild or moderate renal impairment on pharmacokinetics of quinine sulfate not determined to date.180 183 186

Following a single 600-mg oral dose of quinine sulfate in otherwise healthy adults with moderate hepatic impairment (Child-Pugh class B), mean AUC increased 55% compared with healthy adults with normal hepatic function; mean peak plasma concentrations similar in both groups.180 183 186 Quinine absorption prolonged in adults with hepatitis.180 183 186 Pharmacokinetic data not available to date for patients with severe hepatic impairment (Child-Pugh class C).180 183 186

Distribution

Extent

Volume of distribution lower in patients with malaria than in healthy individuals or patients convalescing from malaria.106 Volume of distribution decreases with increasing severity of malarial infection.180 183 186

Intra-erythrocytic quinine concentrations are approximately 30–50% of plasma concentrations.180 183 186 Small amounts distributed into bile and saliva.a

Penetrates relatively poorly into CSF in patients with cerebral malaria;180 183 186 CSF quinine concentrations reported to be 2–7% of concurrent plasma concentrations.106 107 180 183 186

Readily crosses the placenta.180 183 186 In a small number of women who delivered live infants 1–6 days after starting quinine therapy, placental cord plasma quinine concentrations were 1–4.6 mg/L (mean: 2.4 mg/L) and mean ratio of cord plasma to maternal plasma quinine concentrations was 0.32.180 Such placental cord concentrations may not result in therapeutic fetal plasma quinine concentrations.180 183 186

Distributed into milk.180 183 186

Plasma Protein Binding

Approximately 69–92% in healthy adults.106 180 183 186

During active malarial infection, protein binding increased to 78–95%, which correlates with increases in α-1-acid glycoprotein that occur during malarial infection.180 183 186 In one study, quinine was approximately 93% bound to plasma proteins in patients with cerebral malaria and approximately 90% bound in patients with uncomplicated malaria or in patients convalescing from the disease.106

Elimination

Metabolism

Metabolized almost exclusively via hepatic oxidative (CYP) pathways into 4 primary metabolites (3-hydroxyquinine, 2′-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine) and 6 secondary metabolites resulting from further biotransformation of the primary metabolites.180 183 186

The major metabolite, 3-hydroxyquinine, is less active than parent drug.180 183 186

In vitro studies indicate quinine is metabolized principally by CYP3A4 and may also be metabolized by other CYP enzymes, including 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1.180

Elimination Route

Approximately 20% of a dose excreted unchanged in urine.180 183 186 Reabsorption of quinine is increased when urine is alkaline; rate of renal excretion of the drug is doubled when urine is acidic compared with when urine is alkaline.180

Negligible to minimal amounts removed by hemodialysis or hemofiltration.180 183 186

Half-life

Adults: 8–21 hours in those with malaria and 7–12 hours in those who are healthy or convalescing from the disease.106 107

Children 1–12 years of age: 11–12 hours in those with malaria and 6 hours in those convalescing from the disease.106

Geriatric adults: Mean elimination half-life after single dose is increased to 18.4 hours.180 183 186 At steady-state, mean elimination half-life is 24 hours in geriatric adults compared with 20 hours in younger adults.180 183 186 Although renal clearance of quinine is similar in geriatric and younger adults, geriatric adults excrete a larger proportion of the dose in urine as unchanged drug compared with younger adults.180 183 186

Special Populations

Plasma concentrations are higher and plasma half-life may be prolonged in patients with malaria.106 107

Adults with hepatitis: Elimination half-life and apparent volume of distribution are increased, but weight-adjusted clearance not altered.180 183 186

Otherwise healthy individuals with mild hepatic impairment (Child-Pugh class A): Quinine pharmacokinetics and exposure to 3-hydroxyquinine are similar to that in healthy individuals with normal hepatic function.180 183 186

Individuals with severe hepatic impairment (Child-Pugh class C): Oral clearance of quinine and formation of 3-hydroxyquinine decreased; volume of distribution and plasma elimination half-life increased.180 183 186

Adults with severe chronic renal failure: Mean plasma half-life prolonged to 26 hours.180 Effects of mild and moderate renal impairment on pharmacokinetics and safety not determined to date.180 183 186

In the U.S.

• Qualaquin
• Quinamm
• Quiphile

Available Dosage Forms:

• Tablet, Extended Release
• Tablet
• Capsule

Therapeutic Class: Musculoskeletal Agent

Chemical Class: Cinchona Alkaloid

• It is used to treat or prevent malaria.
• It may be given to you for other reasons. Talk with the doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Qualaquin affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Do not take antacids with this medicine.
• Avoid foods or drinks that have quinine, such as tonic water.
• If you are diabetic, you will need to monitor blood sugars very closely.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Qualaquin.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Qualaquin while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

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)].

Qualaquin should be taken with food to minimize gastric upset [see Clinical Pharmacology (12.3)].

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 Qualaquin 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)].

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)].

324 mg capsules - hard gelatin, clear cap/clear body, imprinted with 'AR 102'

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 Qualaquin 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 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 [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 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 [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 Qualaquin 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 Qualaquin 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 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 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 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 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 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 [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 Qualaquin 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 Qualaquin 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 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 [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 Qualaquin capsules 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 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).