Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme disorder that leaves red blood cells less able to handle oxidative stress. A handful of drugs can precipitate haemolytic anaemia in affected people — but far fewer than the classic teaching suggests. Dapsone is the one member of the sulfa family with strong evidence behind it. Sulfamethoxazole, sulfadiazine and sulfasalazine are now classified as low-to-no risk. The deficiency is more common in some Mediterranean, African, and South/Southeast Asian populations.

Educational reference — not medical advice. This page describes what is generally known about a drug family. It cannot account for your history, your other medicines, or your circumstances. Decisions about your own treatment belong with your doctor or pharmacist.

What G6PD does

Glucose-6-phosphate dehydrogenase catalyses the first step of the pentose phosphate pathway, generating NADPH. Red blood cells need NADPH to keep glutathione in its reduced form, and reduced glutathione is the cell's main defence against oxidative damage to hemoglobin and the cell membrane. Other cells have alternative ways of generating reducing power; the red cell, lacking a nucleus and most organelles, relies heavily on G6PD.

In G6PD deficiency, the enzyme works less efficiently, and the red cell's antioxidant capacity is reduced. Under normal conditions this is often clinically silent. Under oxidative stress — certain drugs, certain infections, fava beans, naphthalene exposure — hemoglobin is damaged, denatured proteins (Heinz bodies) form, and the affected cells are removed from the circulation, sometimes catastrophically.

Population prevalence

G6PD deficiency is one of the most common enzyme disorders in humans. Carrier rates are high in regions with historical malaria endemicity — partial protection against malaria has been the proposed evolutionary explanation. Estimates of population prevalence vary widely by region but are notably higher in Mediterranean (around the basin), Sub-Saharan African, Middle Eastern, and South/Southeast Asian populations than in Northern European populations. The variant phenotypes also differ: African variants tend to be milder than Mediterranean variants.

Because the gene sits on the X chromosome, severe deficiency is commoner in males, who carry only one copy. Females are more complicated than the word "carrier" suggests. Random X-inactivation gives a heterozygous woman a mosaic of normal and deficient red cells, in proportions that vary from person to person, so her enzyme activity can land anywhere between normal and as low as a deficient male's. A heterozygous woman can have a drug-induced haemolysis profile indistinguishable from a homozygote's, and genotype alone will not tell you which — that needs an enzyme activity assay. Around 443 million people worldwide carry a deficient variant, with allele frequencies peaking above 30% in parts of sub-Saharan Africa and the Arabian Peninsula.

Sulfa drugs and G6PD

This is the part where the textbook teaching and the evidence have parted company, and the gap is large enough to matter.

Dapsone is the genuine risk, and it is not a marginal one. In trials of dapsone in children with the G6PD A− variant, essentially all deficient boys developed acute haemolytic anaemia, around a tenth of them needing transfusion. Pre-prescription G6PD testing is standard before dapsone, particularly for long-term use in leprosy, dermatitis herpetiformis, or PCP prophylaxis. Dapsone-induced methaemoglobinaemia is a separate concern on top of that.

Sulfamethoxazole, sulfadiazine, and sulfasalazine sit in a different category. Current pharmacogenomic guidance places all three in the low-to-no risk tier, with the explicit note that the evidence tying sulfamethoxazole to haemolysis is weak — mostly case reports, and frequently confounded by the infection being treated, or by fava beans, or by another drug taken at the same time. Several studies show safe use. The guidance is that there is no reason to avoid a low-to-no-risk drug on G6PD status alone at standard doses.

Where the myth came from. Many drugs were blamed for haemolysis because they happened to be given to patients who were haemolysing for another reason — usually the infection itself, which is one of the most common triggers there is. A real-world study of nearly 32,000 people with G6PD deficiency found 71 hospitalised for major haemolysis. Fifty-one of those were caused by fava beans and six by infection; only three were plausibly attributed to any medication at all. Sulfamethoxazole, sulfasalazine and sulfacetamide were each prescribed safely to hundreds or thousands of people in that same cohort.

None of this makes sulfa antibiotics risk-free in an individual, and haemolysis is dose-related — higher doses generate more oxidative stress. It does mean that a G6PD-deficient patient who needs TMP-SMX for a good reason is not automatically barred from it, and that no guideline recommends G6PD screening before prescribing it. Screening is required before tafenoquine, primaquine, and rasburicase.

One irony worth flagging: nitrofurantoin, a common substitute for TMP-SMX in urinary infection, is rated higher risk in G6PD deficiency than the drug it replaces. Swapping one for the other on G6PD grounds can make things worse rather than better.

What hemolysis looks like

Drug-induced hemolysis in G6PD deficiency typically begins one to three days after starting the drug. Symptoms can include: pallor, fatigue, jaundice (yellow eyes and skin), dark urine (sometimes very dark — like cola), back or abdominal pain, breathing difficulty in severe cases. Laboratory findings include anemia, elevated indirect bilirubin, low haptoglobin, raised reticulocytes, and sometimes hemoglobinuria.

Severity varies widely. Mild cases self-limit when the drug is stopped. Severe cases may require transfusion. In neonates, hemolysis can contribute to severe jaundice with risk of kernicterus.

What to do

If G6PD deficiency is known: avoid dapsone where possible; for other drugs, the prescriber considers indication, alternatives, and the specific G6PD variant. Pre-prescription G6PD testing is appropriate in some settings, including before dapsone in many guidelines and before rasburicase (a non-sulfa drug used in tumour lysis syndrome).

If hemolysis is suspected on a drug — symptoms or laboratory findings consistent — the offending drug is stopped, and supportive care is given. Severe cases may need transfusion. The diagnosis is often reviewed and confirmed once the patient has recovered, because measuring G6PD activity during an acute hemolytic episode can give falsely normal results (the deficient older cells have already been destroyed; younger cells have higher activity).

If you have G6PD deficiency, this should be on your medical record. Carry it with you to clinical visits and emergency presentations. Medical ID covers wearable allergy alerts; G6PD deficiency is one of the conditions where a wearable can help.

Pediatric and family considerations

G6PD deficiency is heritable. Family screening may be appropriate after a new diagnosis, particularly for boys and for relatives planning pregnancy. Newborn screening for G6PD deficiency is performed in some countries, particularly those where it is common.

Other triggers — fava beans (favism), naphthalene exposure (mothballs), some food preservatives — are unrelated to drug therapy but worth being aware of for affected patients. Sulfa and G6PD deficiency covers the special-population considerations more fully.

G6PD deficiency and hemolysis.