G6PD Deficiency and Medications: How to Prevent Hemolysis

Imagine taking a common medication for an infection, only to have your red blood cells start breaking down hours later. For someone with G6PD deficiency, this isn’t hypothetical-it’s a real and dangerous risk. Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects around 400 million people worldwide, and many don’t even know they have it until they’re exposed to a trigger. The good news? Hemolysis from G6PD deficiency is almost always preventable-if you know which medications to avoid and how to act before they’re prescribed.

What Is G6PD Deficiency, Really?

G6PD deficiency is a genetic condition where your red blood cells can’t handle oxidative stress. Think of it like a car without enough antifreeze: under normal conditions, it runs fine. But when things get hot-like when you take certain drugs-the system overheats and breaks down. The enzyme G6PD helps protect red blood cells from damage caused by free radicals. Without enough of it, those cells rupture, leading to hemolytic anemia. This isn’t a slow, chronic problem like sickle cell disease. It’s sudden, sharp, and can drop your hemoglobin by half in just a few days.

This condition is most common in people with ancestry from malaria-prone regions: sub-Saharan Africa, the Mediterranean, and Southeast Asia. That’s not a coincidence. The same genetic mutation that causes G6PD deficiency also offers some protection against malaria. But today, with malaria controlled in many places, the main danger isn’t the parasite-it’s the medicine.

Which Medications Can Trigger Hemolysis?

Not all drugs are dangerous, but a surprising number are. The World Health Organization lists 87 medications that can cause hemolysis in G6PD-deficient individuals. Here are the big ones you need to know:

• Rasburicase: Used to treat tumor lysis syndrome. This drug always causes severe hemolysis in G6PD-deficient patients. The FDA requires testing before use-yet cases still happen because providers forget to check.
• Methylene blue: Given for methemoglobinemia. In G6PD-deficient people, it doesn’t fix the problem-it makes it worse. One case reported a hemoglobin drop from 14.2 to 5.8 g/dL in 48 hours.
• Primaquine: Used to prevent malaria relapse. It’s a major trigger, especially in Mediterranean and Asian variants. Even one dose can cause acute hemolysis.
• Dapsone: Used for leprosy and some skin conditions. Doses over 50mg daily are risky. Many patients aren’t warned because the warning isn’t always on the label.
• Sulfonamides: Antibiotics like sulfamethoxazole. Not all sulfa drugs are dangerous, but many are. Don’t assume safety just because it’s common.

Here’s what’s scary: many of these drugs are still prescribed without testing. A 2022 survey of over 1,200 G6PD-deficient patients found that 68% had experienced at least one hemolytic episode-and 42% said their doctors didn’t know about the risks.

Safe Alternatives Exist

You don’t have to go without treatment. There are safe options for nearly every condition. For example:

• For malaria prevention: Use atovaquone-proguanil (Malarone) instead of primaquine. It’s just as effective and completely safe for G6PD-deficient travelers.
• For malaria treatment: Artemisinin-based combination therapies (ACTs) are safe across all G6PD classes. WHO recommends them as first-line.
• For methemoglobinemia: Instead of methylene blue, use ascorbic acid (vitamin C) or exchange transfusion if needed.
• For gout or tumor lysis: Use allopurinol instead of rasburicase. It’s slower but safe.

And here’s an important update: tafenoquine is now approved for malaria radical cure-but only if you’ve been tested and confirmed to have normal G6PD activity. It’s not a replacement for testing. It’s a replacement for primaquine only after testing.

Testing Is the Key-But Timing Matters

Testing for G6PD deficiency isn’t optional. It’s essential. But here’s the catch: if you’ve had a recent hemolytic episode, your test will be wrong. After red blood cells break down, your body releases younger cells with higher enzyme levels. That can make you look normal when you’re not.

Wait at least three months after a hemolytic crisis before testing. That’s when your red blood cell population has fully turned over. The best test is a quantitative enzyme assay-measuring activity in units per gram of hemoglobin. A result below 10% of normal means you’re at high risk.

Point-of-care tests now exist. The STANDARD G6PD Test System, approved by the FDA in January 2024, gives accurate results in under 8 minutes. Hospitals in high-risk areas are using them in emergency rooms and clinics. No more waiting days for lab results before giving a life-saving drug.

Who’s at Risk? It’s Not Just Men

For decades, doctors thought only men got G6PD deficiency because it’s X-linked. That’s outdated. About 15% of women with one mutated gene still have low enough enzyme levels to be at risk. Why? Because of X-chromosome inactivation-random silencing of one X chromosome in each cell. Some women end up with patches of red blood cells that are severely deficient.

A 2020 Lancet study showed that women with G6PD deficiency can and do experience hemolysis. If your mother or maternal uncle had the condition, you could be a carrier. Testing shouldn’t be based on gender. It should be based on ancestry and risk.

What About Newborns?

In the U.S., only 12 states require newborn G6PD screening. But the American Academy of Pediatrics says it should be universal in areas where prevalence exceeds 5%. That’s over 127 countries worldwide. Saudi Arabia implemented mandatory newborn screening in 2010-and saw hemolytic crisis admissions drop by 78% over 10 years.

Early detection saves lives. A baby with G6PD deficiency who avoids certain medications in the first weeks of life won’t have a single hemolytic episode. Simple blood spot tests can be done at birth. If your hospital doesn’t offer it, ask. Demand it.

Real-World Impact: What Works

In Thailand, Mahidol University implemented a rule: no primaquine without a G6PD test. They treated over 4,000 malaria patients between 2018 and 2022. Before the rule, 15.2% had hemolytic crises. After? Just 0.3%. That’s a 98% reduction.

At UCSF, their electronic health system now flags 87 high-risk drugs automatically when G6PD status is known. In a 12-month pilot, inappropriate prescribing dropped by 89%. That’s not just better care-it’s a system change that prevents errors before they happen.

And it’s not just hospitals. The Global Fund has invested $127 million from 2023 to 2025 to bring G6PD testing to 32 malaria-endemic countries. The goal? Prevent 15,000 hemolytic crises annually.

What You Can Do

If you or someone you care about has G6PD deficiency:

1. Get tested if you haven’t already-especially if you’re from a high-risk region.
2. Keep a printed list of unsafe medications. Carry it with you. Show it to every doctor, pharmacist, and ER nurse.
3. Ask: “Is this drug on the G6PD risk list?” Don’t take “I’ve never heard of it” as an answer.
4. For travelers: Use Malarone, not primaquine. Check the CDC’s travel guidelines before you go.
5. If you’ve had unexplained jaundice, dark urine, or fatigue after taking a new drug, suspect G6PD deficiency. Get tested.

Education works. The NIH found that 92% of patients who received detailed avoidance training had no hemolytic episodes over five years. Those who didn’t? Only 38% stayed safe.

The Future Is Better

Research is moving fast. A 2024 study in Blood Advances showed that N-acetylcysteine (NAC) can protect red blood cells from oxidative damage-even when paired with primaquine. It’s not standard yet, but it’s a promising shield.

And in late 2024, Phase I trials will begin for a recombinant human G6PD enzyme replacement therapy. This could one day cure the deficiency itself.

Right now, though, prevention is still the only reliable tool. The technology exists. The guidelines are clear. The data is overwhelming. What’s missing is awareness-and action.