Aflukin - General Information
An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Aflukin is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Aflukin is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood.
Pharmacology of Aflukin
Aflukin is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. Aflukin acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.
Aflukin for patients
324 mg Capsules
This leaflet contains a summary of the most important information about Quinine Sulfate capsules and should be read completely before starting your treatment. This leaflet does not replace talking to your doctor or health care provider about your treatment or medical condition. If you have any questions about your treatment or medical condition, ask your doctor. Only your doctor or other health care provider can prescribe Quinine Sulfate and determine if it is right for you.
Malaria is a serious infection, and if not treated, can be life-threatening. Quinine Sulfate has been used for many years as an effective treatment for uncomplicated malaria caused by the parasite Plasmodium falciparum.
What is Quinine Sulfate?
Quinine Sulfate is a prescription medication used in the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Quinine Sulfate is NOT approved for the prevention of malaria or for the prevention or treatment of night-time leg cramps.
Who should not take Quinine Sulfate?
Do not take Quinine Sulfate if you:
·Had previous allergic reactions to quinine, quinidine, or mefloquine (Lariam).
· Had previous serious side effects to quinine, such as decreased platelets, which are components of blood necessary for clotting.
·Have low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G-6-PD).
·Have myasthenia gravis.
·Have optic neuritis, which is an inflammation of the nerve important for vision.
·Have certain heart rhythm problems or certain inherited abnormalities on your electrocardiogram (ECG). Your doctor will tell you whether your ECG has these abnormalities.
What should I tell my doctor or health care provider before taking Quinine Sulfate?
Tell your doctor or health care provider:
·About all your medical conditions, including any heart, kidney, or liver problems.
·About all the prescription and non-prescription medications you are taking, including vitamins and herbal medications.
·If you are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your doctor can tell you more about the benefits and risks of taking this medication during pregnancy for uncomplicated malaria. You and your doctor can decide if Quinine Sulfate is right for you.
·If you are breast-feeding. Small amounts of Quinine Sulfate can pass into the breast milk, but no problems with this medicine have been reported in nursing babies. Discuss with your doctor whether you should breastfeed while taking Quinine Sulfate.
How should I take Quinine Sulfate?
·Take Quinine Sulfate exactly as prescribed.
·Quinine is a clear capsule that is taken by mouth.
·Unless directed otherwise by your doctor, the usual dose is 648 mg (two 324 mg capsules) of Quinine Sulfate every 8 hours by mouth at the same time every day for 7 days.
·To lower the chance of stomach upset, take this medication WITH FOOD.
·Finish all the Quinine Sulfate that is prescribed even if you feel better. Do not stop taking the medication without talking to your doctor.
·Do not take more than the amount prescribed. Do not take more than 2 capsules at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your doctor right away.
What should I do if I miss a dose?
If you forget to take Quinine Sulfate, do NOT double the next dose. If it has been more than 4 hours since the missed dose, WAIT and take the regular dose at the next scheduled time. Call your doctor if you are not sure what to do.
What are the possible side effects of Quinine Sulfate?
The most common side effects that you may have when taking Quinine Sulfate are not usually serious, and will usually get better when Quinine Sulfate is stopped. Common side effects with Quinine Sulfate include:
·Ringing in your ears ·Mild hearing loss
·Dizziness · Blurred vision
·Change in color vision
Occasionally, more severe symptoms such as vomiting, diarrhea, and abdominal pain may occur. Rarely, rapid or irregular heart beat, severe hearing loss, or blindness, may occur. If you experience any severe side effects, call your doctor.
Some patients may experience low blood sugar (hypoglycemia) while taking Quinine Sulfate. Symptoms of low blood sugar include lightheadedness, dizziness, sweating, confusion, shakiness, anxiety, and weakness. If you experience symptoms of low blood sugar, drink some fruit juice or eat a snack, and call your doctor.
Elderly patients may be more sensitive to the side effects of quinine than younger patients, and should quickly report any side effects to their doctor.
Quinine Sulfate has other less common side effects that are not listed here. For a complete list of side effects, ask your doctor. If you notice any side effects not mentioned in this leaflet, or if you have any concerns about a side effect you are having, talk to your doctor.
Quinine Sulfate is NOT approved for the treatment of leg cramps because quinine has not been proven to work for this condition, and may cause serious or life-threatening side effects. Some of the more serious side effects of quinine are blindness, deafness, and abnormal heart rhythm. Your doctor can tell you additional information about serious side effects reported with Quinine Sulfate.
Call your doctor or health care provider right away if:
·You feel worse; or if you do not start feeling better within a day or two of taking Quinine Sulfate.
·If your fevers come back after completing treatment with Quinine Sulfate, call your doctor to make sure that the malaria has not returned.
·You experience serious problems such as:
o Serious allergic reactions : rash, hives, severe itching, severe flushing, trouble breathing.
o Eyesight problems: blurred vision, double vision, blindne ss.
o Heart problems: chest pain, rapid heart beats, abnormal heart rhythm.
o Other reactions: dizziness, confusion, lightheadedness, fainting, seizure.
o Other problems: abnormal bleeding (such as severe nosebleed, and blood in the urine, or stool), severe bruising, or the appearance of unusual purple-brown or red spots on your skin.
What about other medications I am taking?
·Tell your doctor about all other prescription and non-prescription medications
you are taking, including vitamins and herbal supplements.
·Certain medications should be avoided when you are taking Quinine Sulfate.
·Your doctor has a list of medications that should be avoided or which may require special precautions while taking Quinine Sulfate.
How do I store Quinine Sulfate?
Keep Quinine Sulfate out of reach of children. Keep the capsules in a tightly closed container. Do not refrigerate or freeze. Store at room temperature; 25-30°C (77-86°F).
General advice about Quinine Sulfate:
Do not use Quinine Sulfate for a condition for which it was not prescribed. Do NOT give Quinine Sulfate to other people, even if they have the same symptoms, because it may be harmful.
This leaflet highlights the most important information about Quinine Sulfate. For more information, you should talk with your doctor or health care provider.
Active Ingredients: Quinine Sulfate, USP
Inactive Ingredients: Corn starch, magnesium stearate, talc
Effects of Drugs and Other Agents on Quinine Pharmacokinetics
Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with quinine 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.
Erythromycin (CYP3A4 inhibitor): Erythromycin was shown to inhibit the metabolism of quinine in vitro using human liver microsomes. Therefore, concomitant administration of erythromycin with quinine sulfate is likely to increase plasma quinine concentrations, and should be avoided.
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. Quinine sulfate 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 but not with ranitidine. 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 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 parameters of quinine. Adjustment of quinine 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 dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactio ns associated with quinine sulfate.
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 quinine sulfate 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 quinine sulfate, 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 quinine sulfate should be avoided.
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.
Anticonvulsants (carbamazepine, phenobarbital, and phenytoin): A single 600 mg oral dose of quinine sulfate increased the mean plasma C max, 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 C max 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, phe nobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with quinine sulfate.
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 quinine with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide, and quinidine ) should also be avoided
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 quinine sulfate should be monitored closely for adverse reactions a sociated 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 quinine is administered to patients receiving digo xin, 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 quinine sulfate 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 quinine may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures.
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.
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 quinine.
Drug/Laboratory Interactions: Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.
Quinine is contraindicated in patients with known hypersensitivity, in pregnancy, in women of child bearing potential, in patients with glucose-6-phosphate dehydrogenase deficiency, in patients with tinnitus, or optic neuritis, and in patients with a history of blackwater fever.
Additional information about Aflukin
Aflukin Indication: For the treatment of malaria and leg cramps
Mechanism Of Action: The theorized mechanism of action for quinine and related anti-malarial drugs is that these drugs are toxic to the malaria parasite. Specifically, the drugs interfere with the parasite's ability to break down and digest hemoglobin. Consequently, the parasite starves and/or builds up toxic levels of partially degraded hemoglobin in itself.
Drug Interactions: Anisindione Aflukin/quinidine increases the anticoagulant effect
Acenocoumarol Aflukin/quinidine increases the anticoagulant effect
Dicumarol Aflukin/quinidine increases the anticoagulant effect
Warfarin Aflukin/quinidine increases the anticoagulant effect
Digoxin Aflukin/quinidine increases the effect of digoxin
Digitoxin Aflukin/quinidine increases the effect of digoxin
Vecuronium The quinine derivative increases the effect of the muscle relaxant
Succinylcholine The quinine derivative increases the effect of the muscle relaxant
Pancuronium The quinine derivative increases the effect of the muscle relaxant
Metocurine The quinine derivative increases the effect of the muscle relaxant
Gallamine Triethiodide The quinine derivative increases the effect of the muscle relaxant
Atracurium The quinine derivative increases the effect of the muscle relaxant
Astemizole Increased risk of cardiotoxicity and arrhythmias
Atomoxetine The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Food Interactions: Not Available
Generic Name: Quinine
Synonyms: 6'-Methoxycinchonidine; 6'-Methoxycinchonine; Quinine, Anhydrous; Quinineanhydrous; Quinoline Alkaloid; Quinine sulfate
Drug Category: Analgesics, Non-Narcotic; Muscle Relaxants, Central; Antimalarials
Drug Type: Small Molecule; Approved
Other Brand Names containing Quinine: Aflukin; Chinin; Chinine; Coco-Quinine; None; Quinine Dab;
Absorption: 76 - 88%
Toxicity (Overdose): Not Available
Protein Binding: Approximately 70%
Biotransformation: Hepatic, over 80% metabolized by the liver.
Half Life: Approximately 18 hours
Dosage Forms of Aflukin: Solution / drops Oral
Chemical IUPAC Name: (R)-[(5R,7S)-5-ethenyl-1-azabicyclo[2.2.2]octan-7-yl]-(6-methoxyquinolin-4-yl)methanol
Chemical Formula: C20H24N2O2
Quinine on Wikipedia: http://en.wikipedia.org/wiki/Quinine
Organisms Affected: Humans and other mammals