Qualaquin - An Overview

Overview:

Qualaquin (Quinine sulfate) is a medication derived from the bark of the cinchona tree. Its chemical name is cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate. The chemical formula is (C20H24N2O2)2•H2SO4•2H2O, with a molecular weight of 782.96. Quinine sulfate is a white, crystalline powder that turns darker when exposed to light. It has no smell but a very bitter taste. It does not dissolve well in water, alcohol, chloroform, or ether. Qualaquin is available in capsule form for oral use, with each capsule containing 324 mg (milligrams) of Quinine sulfate, which is equivalent to 269 mg of the free base form of the drug. The inactive ingredients in the capsules include cornstarch, magnesium stearate, and talc. The United States Food and Drug Administration (USFDA) approved the drug in December 2005.

Available Doses and Dosage Forms:

• Capsule Qualaquin of 324 mg (milligrams) for uncomplicated (Plasmodium falciparum) malaria, take 648 mg by mouth every eight hours for seven days.

• For Chloroquine-resistant (P. falciparum), take 648 mg orally every eight hours for three to seven days, along with Tetracycline, Doxycycline, or Clindamycin.

• For Chloroquine-resistant (P. vivax), take 648 mg by mouth every eight hours for three to seven days, along with Doxycycline (or Tetracycline) and oral Primaquine.

• For Babesiosis (off-label use), take 648 mg by mouth every eight hours for seven days, along with oral or IV Clindamycin.

Dosage Adjustments

• For severe renal impairment, take 648 mg orally once, then 324 mg by mouth every 12 hours.

• For mild or moderate hepatic impairment (Child-Pugh A or B), no dosage adjustment is needed. However, close monitoring is required. In case of severe hepatic impairment, drug use is prohibited.

For Patients:

What Is Uncomplicated Malaria?

Uncomplicated malaria occurs when someone has malaria symptoms, but their vital organs remain unaffected. This means they feel sick and show signs of infection, like fever, chills, and fatigue, but no serious complications involve their major organs like the liver or kidneys. The illness is noticeable and uncomfortable, but it does not pose an immediate danger to their overall health.

How Does Qualaquin Work?

Qualaquin is used to kill the malarial parasites that are living inside the red blood cells. However, sometimes a person might need to take another medicine, like Primaquine and Qualaquin, to kill any malaria parasites hiding in other parts of the body. Taking both medicines might be necessary to fully eliminate the infection and stop its recurrence. This way, a person can ensure that all the parasites are eliminated and prevent any chance of a relapse.

How Effective Is Qualaquin?

Qualaquin is not suitable for treating severe malaria. It should not be used to prevent malaria. Some people have taken Qualaquin for leg cramps, but this use has not been approved by the FDA. Taking this medication incorrectly or without a doctor’s guidance can lead to serious side effects or even death.

How Is Qualaquin Administered?

• Swallow the medication after food to avoid stomach upset, as directed by the doctor. Usually, it needs to be taken every eight hours for three to seven days.

• Take Quinine for two to three hours, either before or after magnesium or aluminum antacids. These may impede the body's absorption of the medication.

• The dosage and duration of the medication depend on the medical condition, the site of infection, other malarial treatments, and how well the patient responds to the treatment. For children, the amount of medicine also depends on their weight.

• It is crucial to take Quinine precisely as the doctor prescribed. Do not take more or less than instructed, and do not skip any doses. The patient must complete the entire dose, even if they start feeling better. Stopping early could make the infection harder to treat and can lead to recurrence.

• Quinine works best when the amount in the body stays steady and, hence, must be taken every day at the same time.

• If a person does not feel better within one to two days of starting Quinine, tell the doctor. If their fever comes back after finishing the medication, contact the doctor to check if the malaria has returned.

What Are the Side Effects of Qualaquin?

Quinine can affect nearly every part of the body. The most common side effects are known as "cinchonism," which almost everyone taking Quinine experiences to some degree. Mild symptoms of cinchonism include headache, flushing and sweating, nausea, ringing in the ears, hearing problems, dizziness, blurred vision, and changes in color vision. More severe symptoms include vomiting, diarrhea, stomach pain, deafness, blindness, and heart rhythm issues. Most of these symptoms go away once a person stops taking Quinine. Other side effects reported with Quinine sulfate, though uncommon and with unknown frequency, include:

1. General: Fever, chills, sweating, flushing, weakness, lupus-like syndrome, and allergic reactions.

2. Blood-related: Severe reduction in white blood cells, low levels of clotting factors, low platelet count, blood clotting disorders, red blood cell destruction, HUS, TTP, ITP, small red or purple spots on the skin, bruising, bleeding, coagulation problems, blackwater fever, reduced white blood cells, low neutrophils, low blood cell counts, bone marrow failure, and lupus anticoagulant.

3. Neuropsychiatric: Headache, double vision, confusion, mental changes, seizures, coma, disorientation, tremors, restlessness, loss of coordination, muscle spasms, speech problems, and suicidal thoughts.

4. Skin-related: Various skin rashes, itching, blistering dermatitis, peeling skin conditions, severe allergic reactions, sun sensitivity, and skin inflammation.

5. Respiratory: Asthma, difficulty breathing, and fluid in the lungs.

6. Cardiovascular: Chest pain, blood vessel dilation, low blood pressure, fainting, rapid or slow heartbeat, palpitations, irregular heartbeats, heart block, atrial fibrillation, unusual heart rhythms, QT prolongation, dangerous heart arrhythmias, and cardiac arrest.

7. Digestive: Nausea, vomiting, diarrhea, stomach pain, irritation of the stomach lining, and esophagitis.

8. Liver-related: Inflammation of the liver, jaundice, and abnormal liver function tests.

9. Metabolic: Low blood sugar and loss of appetite.

10. Musculoskeletal: Muscle pain and weakness.

11. Kidney-related: Blood in the urine, kidney failure, kidney impairment, and kidney inflammation.

12. Special Senses: Vision problems, sudden vision loss, light sensitivity, double vision, night blindness, reduced visual fields, fixed pupil dilation, color vision disturbances, optic nerve inflammation, blindness, dizziness, ringing in the ears, hearing loss, and deafness.

Overdose:

Taking too much Quinine can cause severe complications, such as vision problems, low blood sugar, irregular heartbeats, and even death. Symptoms of overdose include blurred vision, nausea, vomiting, hearing loss, and cardiac issues like arrhythmias. Medical interventions like stomach pumping and activated charcoal may be used to reduce Quinine levels, but other treatments have shown limited effectiveness in speeding up elimination.

Storage:

Store Qualaquin capsules USP, 324 mg in a cool, dry place at room temperature between 68 to 77 degrees Fahrenheit (20 to 25 degrees Celsius). Keep them in a tightly sealed container as per standard guidelines for medication storage.

For Doctors:

Indication:

Qualaquin is a medication used to treat mild cases of malaria caused by the Plasmodium falciparum parasite. It works well in areas where the malaria parasite has become resistant to Chloroquine. Plasmodium capsules are not approved for:

• Treating severe or complicated cases of Plasmodium falciparum malaria.

• Preventing malaria.

• Treating or preventing nighttime leg cramps.

• It is important to use Qualaquin only for its approved purposes to avoid potential risks and side effects.

Dose:

The 324 mg capsules are made of hard gelatin and have a clear cap and clear body. They are marked with 'AR 102' on them.

Pharmacological Aspects of Qualaquin

• Pharmacodynamics: In a study with 24 healthy individuals, after taking single doses of Qualaquin (324 mg and 648 mg), the average maximum increase in QTc interval from baseline was 10 ± 19 msec and 12 ± 18 msec (milliseconds), respectively. No participants experienced a QTc interval longer than 500 msec or an increase in QTc interval greater than 60 msec, which are concerning levels associated with heart rhythm issues.

• Mechanism: Quinine works against malaria by interfering with the parasite's ability to make essential molecules like DNA, proteins, and energy. It also binds to a substance called hemozoin within infected red blood cells. However, the exact mechanism is not well understood. Quinine primarily targets the form of the malaria parasite found in red blood cells during its active stage. It does not affect the earlier stages of the parasite or the forms that spread from mosquitoes to humans. Some strains of the malaria parasite have developed reduced sensitivity to Quinine, especially in certain regions like parts of South America, Southeast Asia, and Bangladesh.

• Pharmacokinetics: Quinine, when taken orally, is absorbed well in healthy adults, with 76 to 88 percent reaching the bloodstream. Patients with malaria absorb more Quinine than healthy individuals, leading to higher levels in the body. Quinine is primarily metabolized in the liver and eliminated mostly through urine, with its effects lasting around 9.7 to 12.5 hours. Activated charcoal can help speed up the elimination of Quinine in cases of overdose, but other methods, like acid diuresis, are less effective.

Toxicity:

Carcinogenicity studies to determine if Quinine causes cancer have not been performed. In tests assessing genetic damage, Quinine showed some potential to cause mutations in bacteria when specific enzymes were present. However, it did not induce mutations in tests involving fruit flies or cause chromosomal abnormalities in mice and hamsters. No studies have been conducted to investigate how Quinine might affect fertility in animals or humans.

Clinical Studies:

Quinine has been widely used for centuries to treat malaria. Studies reviewed more than 1300 sources on its use, including 21 rigorous trials involving over 2900 patients in malaria-prone regions. In areas where malaria resistance is low, a seven-day course of Quinine alone or with antibiotics like Tetracycline cleared infections in over 80 to 100 percent of cases. However, in regions with high resistance, efficacy may be lower. Shorter treatment options, like three-day courses with Quinine and antibiotics, are used but may not be as effective based on limited clinical data.

Contraindications of Qualaquin

Qualaquin should not be used in patients with the following conditions:

• Prolonged QT Interval: Prolonged QT interval in the electrocardiogram can lead to death.

• G6PD Deficiency: Patients with this genetic condition can suffer from red blood cell breakdown (hemolysis) when taking Quinine.

• Allergies to Quinine: If a person has a known allergy to Quinine, they should not take Qualaquin. Allergic reactions can include low blood platelet count (thrombocytopenia), blood disorders like ITP and TTP, a serious condition called HUS, and blackwater fever.

• Allergies to Related Drugs: If a person is allergic to Mefloquine or Quinidine, they may also be allergic to Quinine.

• Myasthenia Gravis: This medication can worsen muscle weakness in people with this condition.

• Optic Neuritis: If a person is having optic neuritis, Quinine intake can make it worse.

Avoiding Qualaquin in these situations helps prevent serious side effects and complications.

Warnings and Precautions:

• Treatment or Prevention of Nocturnal Leg Cramps: Qualaquin is not recommended for treating or preventing leg cramps at night due to serious and potentially life-threatening side effects it can cause, such as blood-related issues (thrombocytopenia, hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura), allergic reactions, QT prolongation leading to severe heart rhythm problems like torsades de pointes, and other serious medical events. The risks associated with Qualaquin outweigh any potential benefits of treating this minor condition.

• Thrombocytopenia: This condition involves a low platelet count in the blood, which can be severe and even life-threatening. It typically resolves within a week after stopping Quinine, but in some cases, it can lead to serious kidney problems. Re-exposure to Quinine can worsen thrombocytopenia rapidly.

• QT Prolongation and Ventricular Arrhythmias: Quinine can prolong the QT interval, which is a risk factor for heart arrhythmias. It is not recommended to use Qualaquin with other medications that are known to prolong QT intervals or cause serious heart rhythm issues.

• Concomitant Use with Rifampin: Using Rifampin with Quinine can reduce Quinine levels in the blood, potentially leading to treatment failure for malaria.

• Neuromuscular Blocking Agents: The use of drugs like Pancuronium with Qualaquin can intensify muscle relaxation to the point of causing respiratory depression and difficulty breathing.

• Hypersensitivity: Serious allergic reactions have been reported with Qualaquin, including anaphylactic shock, severe skin rashes, swelling, difficulty breathing, and other severe immune responses. It should be discontinued immediately if any signs of hypersensitivity occur.

• Atrial Fibrillation and Flutter: Qualaquin may increase the heart rate in patients with atrial fibrillation or flutter, similar to effects seen with other medications like Quinidine. This can affect the use and monitoring of medications like digoxin.

• Hypoglycemia: Quinine can stimulate the release of insulin from the pancreas, potentially causing low blood sugar levels (hypoglycemia), especially in pregnant women.

These points underscore the serious nature of potential side effects associated with Qualaquin and emphasize the need for careful consideration and monitoring when using this medication.

Drug Interactions of Qualaquin

Quinine interacts with various drugs and substances, affecting how it works in the body and how other medications are metabolized:

• Antacids: Avoid taking aluminum or magnesium-containing antacids with Qualaquin, as they can affect how Quinine is absorbed.

• Antiepileptics (Carbamazepine, Phenobarbital, Phenytoin): These drugs can decrease Quinine levels in the blood when taken together.

• Cigarette Smoking: Smoking can reduce the effectiveness of Quinine in treating malaria, especially in heavy smokers.

• Grapefruit Juice: Drinking grapefruit juice does not significantly change how Quinine is processed in the body.

• Histamine H2-receptor Blockers (Cimetidine, Ranitidine): Cimetidine can increase Quinine levels significantly, while Ranitidine has a lesser effect.

• Ketoconazole: This medication increases Quinine levels in the body and requires close monitoring for potential side effects.

• Macrolide Antibiotics (Erythromycin, Troleandomycin): Troleandomycin significantly increases Quinine levels and should not be used together.

• Oral Contraceptives: The use of oral contraceptives does not affect how Quinine works in the body.

• Rifampin: Taking Rifampin significantly decreases Quinine levels and may reduce its effectiveness in treating malaria.

• Tetracycline: Using Tetracycline with Quinine increases Quinine levels in the blood and requires careful monitoring for side effects.

Specific Considerations:

• Pregnancy: Quinine (Pregnancy Category C) lacks extensive studies but shows no increased birth defect risk in over 1,000 pregnancies, though high doses in animals indicate potential abnormalities. Its use in treating severe P. falciparum malaria during pregnancy often outweighs the risks despite crossing the placenta.

• Labor and Delivery: Quinine does not cause uterine contractions at the recommended doses for treating malaria. However, at much higher doses, it may stimulate the uterus.

• Nursing Mothers: There is limited information on the safety of Quinine for breastfed infants. In a study of 25 lactating women taking Quinine, no toxicity was reported in their infants. Infants would receive a very small amount of Quinine through breast milk. Quinine is generally considered safe for breastfeeding, but the risks and benefits should be assessed. If malaria is suspected in the infant, they should be evaluated and treated appropriately.

• Pediatric Use: The safety and effectiveness of Qualaquin have not been established for children under 16 years old.

• Geriatric Use: There is not enough data to determine if older adults respond differently to Quinine compared to younger adults. Clinical experience has not identified any differences.

• Renal Impairment: People with severe kidney failure clear Quinine from their bodies more slowly, so the dosage and frequency should be reduced.

• Hepatic Impairment: Patients with liver problems should be closely monitored when taking Quinine, as impaired liver function can increase exposure to the drug.