Pyrimethamine

Limits on what this shows

• Null findings: A cyclic low-dose regimen (6.25 mg three times a week, about 2.7 mg/day) in 4 adults with late-onset Tay-Sachs disease, with 5 mg/day folic acid, reported no hematologic or clinical evidence of folate deficiency over a mean 82.8 weeks; no numeric counts given [13]. Weekly Fansidar (25 mg pyrimethamine with 500 mg sulfadoxine) versus chloroquine for one year in 105 workers (57 and 48): no significant blood-count changes reported, folate not measured [14]. A phase I study of 12.5 to 50 mg/day in 16 patients with relapsed leukemia reported no significant drug-related toxicity; the record read lacks a title and does not mention folate [15]. Measured-folate null: Fuller 1988 [39], Gambian children aged 3 months to 5 years in a malaria chemoprophylaxis trial, Maloprim (pyrimethamine plus dapsone, given every two weeks at one quarter or one half of the adult dose) versus chlorproguanil versus placebo, about 20% with red cell folate under 100 ng/ml at baseline; without folate supplements, mean red cell folate did not differ significantly among Maloprim, chlorproguanil and placebo, and with folate supplements Maloprim and placebo were similar (sample sizes, means and p values were not in the abstract paraphrase read). Co-drug is dapsone, and the regimen is low and intermittent, so it bounds the folate finding to treatment-range or continuous exposure rather than refuting it.
• At-risk subgroups: Documented or probable folate deficiency, malabsorption, alcoholism, pregnancy [2][3]; co-prescription of trimethoprim-sulfamethoxazole or methotrexate [3][8]; infants and children, who are "extremely susceptible" to overdose [2]; malnourished children (lower weight Z-score) [11]; high-dose regimens [2].

Direction

Functional antagonism (drug mechanism and toxicity). Not depletion by loss, not dietary shortfall (Hard Rule 2, Hard Rule 5).

Regulatory status

US label: contraindicated in documented megaloblastic anemia due to folate deficiency; doses used for toxoplasmosis "may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, neutropenia"; concurrent folinic acid "strongly recommended in all patients"; semiweekly blood counts at high dosage [1][2]. UK SmPC: all patients should receive calcium folinate; pancytopenia responsive to folate reported in probable pre-existing folate deficiency; anaemia listed very common [3]. Label cautions apply to malabsorption, alcoholism and pregnancy [2]. The combination product Fansidar carries the same folic acid antagonist language [4][5].

Population evidence

Carellos 2017 [11]: cohort of children from neonatal screening in Minas Gerais, 190 diagnosed with congenital toxoplasmosis, 171 with treatment data, on sulfadiazine, pyrimethamine and folinic acid. Hematologic events (macrocytic anemia, neutropenia, thrombocytopenia) in 44%; neutropenia 31%; resolved after folinic acid was increased in 25.7% and after temporary suspension in 1.8%; macrocytic anemia associated with lower weight Z-score (P = 0.03). Ben-Harari 2017 [10]: systematic review, 31 studies, 2,975 patients; bone marrow suppression up to 50% (congenital), up to 42.7% (toxoplasmic encephalitis), up to 9.0% (ocular); toxoplasmic encephalitis anemia 138/323 (42.7%), leukopenia 75/323 (23.2%); folate levels not reported in the content read. Corvaisier 2004 [12]: 32 children on pyrimethamine and sulfadoxine every 10 days for a year with weekly folinic acid; treatment interrupted in 2 for moderate neutropenia; folate not measured. Direct human folate: Stürchler and Holzer 1980 [16], title "Low serum folate among persons taking Fansidar (pyrimethamine plus sulfadoxine) for prophylaxis of malaria", indexed with folic acid and dose-response terms; no abstract in the PubMed record (re-checked 2026-10-10, same result). Metz 2007, a narrative review that cites it [38], states that in healthy subjects taking prophylactic sulfadoxine-pyrimethamine mean serum folate was significantly lower than in controls; the review gives no n, values, CI or doses, so the effect size remains unretrieved and the primary paper was not opened. The Stürchler study is therefore known to this dossier only through that secondary sentence. The combination partner sulfadoxine is also folate-pathway active.

Mechanism

Named. Inhibition of dihydrofolate reductase. Recombinant human DHFR IC50 reported as 4.49 uM in a preprint [30]. Low-dose folinic acid and high-dose folic acid fully reversed pyrimethamine effects on DNA-synthesis markers in human lymphocytes in vitro [19]. In pregnant rats pyrimethamine halved folate in embryonic tissue while maternal folate was unchanged [17]. In rats it also competitively inhibited intestinal folate transport, weakly (listing-level summary only) [18]. The 1969 NEJM human marrow work (Herbert and Waxman) was found as a record without abstract [21].

Counter-evidence held on record

Counter-evidence and confounding Hematologic toxicity in these regimens is shared with sulfadiazine or sulfadoxine, so the pyrimethamine fraction is not separable in [10][11][12]. Folate itself was not measured in the large hematologic datasets. Active infection can lower serum folate independent of the drug (Plasmodium falciparum patients had lower serum folate than healthy controls in a 27-patient abstract [20]), and the 1980 report studied a prophylaxis population where that confounder is smaller [16]. Weekly low-dose prophylaxis showed no significant count changes in one trial [14]. Red is withheld because only one source reports a drug-associated fall in measured folate and its size is unknown, and the second directly measured pyrimethamine cohort found no change in red cell folate [39]. A Burkina Faso cross-sectional study of 201 pregnant women (146 of 201 reported SP-IPT) found 62% with serum folate under 7.7 ng/mL, but reported no folate comparison by SP status and cannot attribute the low folate to the drug [43]. Framing caution A monitoring and prescriber matter. A person taking pyrimethamine should not infer a need for extra dietary folate or a folic acid supplement from this entry. Folic acid is not interchangeable with folinic acid here [3], and high-dose folic acid blunted sulfadoxine-pyrimethamine in malaria trials (see the folic acid entry).

Limits on what this shows

• Null findings: Mbaye 2006, 1,035 Gambian primigravidae: failure 5.7% (0.5 mg) versus 4.9% (1.5 mg), no difference [22]. Moya-Alvarez 2018, 318 Beninese pregnant women on SP IPTp plus 5 mg folic acid daily: high folate not associated with malaria infection (adjusted OR 0.51, 95% CI 0.17 to 1.56) [25].
• At-risk subgroups: Patients treated for toxoplasmosis who self-start folic acid; pregnant women given folic acid and pyrimethamine regimens; malaria prevention settings with high-dose folic acid [22][23].

Direction

Nutrient affects drug (Hard Rule 4). Pharmacodynamic competition at the parasite, so a time-separation interval does not apply; the control is the prescriber choosing folinic acid.

Regulatory status

UK SmPC: "calcium folinate should be used because folic acid does not correct folate deficiency" [3]. US label specifies folinic acid (leucovorin) for rescue [1][2].

Population evidence

Malaria trials of sulfadoxine-pyrimethamine (pyrimethamine in the cohort; indication Plasmodium, not Toxoplasma), summarized in a narrative review [22]: Ouma 2006, 488 pregnant women, day-14 failure 13.9% (placebo), 14.5% (0.4 mg folic acid), 27.1% (5 mg), adjusted hazard ratio 2.19 for 5 mg versus placebo (p = 0.005), day-14 hemoglobin not different from placebo (abstract and results text opened [41]); Carter 2005, 303 patients, 5 mg reduced efficacy versus placebo, 2.5 mg did not differ; Mulenga 2006, 183 Zambian children, 1 mg for 14 days increased failure; van Hensbroek, 600 Gambian children, folic acid with SP had higher failure than SP with placebo. van Eijk 2008, 467 pregnant women: high baseline folate, 5 mg folic acid and high day-7 folate were independent risk factors for failure [23]. Dzinjalamala 2005, Malawian children: higher blood folate in late treatment failure [24]. A Cochrane evidence summary of folic acid in people taking antifolate antimalarials (SP in five of eight trials) states that most trials used folic acid above 1 mg daily and found more treatment failures, while the one 400 ug trial showed little to no difference [42]. For toxoplasmosis no trial was opened; a Tier D page rates the folic acid interaction "Evidence D, anecdotal" [26].

Mechanism

Present. Exogenous reduced folate competes with the antifolate effect; supported in human lymphocytes in vitro, where high-dose folic acid reversed pyrimethamine effects [19].

Counter-evidence held on record

Counter-evidence and confounding The dose-response is not uniform across trials (5 mg harmful, 0.4 to 1.5 mg often not) and the trial results come from a different indication than toxoplasmosis. Two of the sources are reviews or secondary summaries [22][26]. The drug was in every cohort cited as part of sulfadoxine-pyrimethamine, so this is not class extrapolation, but the sulfadoxine partner is also folate-pathway active. Framing caution Not a deficiency claim. Do not recommend folic acid or any folate supplement from this entry; whether and which folate form to give with pyrimethamine is a prescriber decision.

Limits on what this shows

• Null findings: None sought beyond the label text; no study showing no interaction was found.
• At-risk subgroups: Patients on chronic antacids or kaolin products with pyrimethamine for toxoplasmosis [3].

Direction

Co-ingested mineral product reduces drug absorption. No effect on mineral status is claimed.

Regulatory status

UK SmPC 4.5: "antacid salts and the anti-diarrhoeal agent kaolin reduce the absorption of pyrimethamine" [3]. No antacid statement was found in the US label text retrieved [1][2]. The newborn monograph gives no antacid guidance [6].

Population evidence

No pharmacokinetic study was opened and no magnitude is given in [3]. The Ontario HIV pharmacy fact sheet (secondary, derived from the manufacturer monograph) advises avoiding these agents or taking them at least 2 hours after the pyrimethamine dose [7].

Mechanism

Not stated in the retrieved sources. The sources say "antacid salts" without naming magnesium, aluminium or calcium.

Counter-evidence held on record

Counter-evidence and confounding Size of the effect is unknown, so clinical importance is unquantified. The 2-hour interval comes from a secondary fact sheet, not the label, and should be confirmed with a pharmacist. Framing caution A timing prompt only: separate antacid or kaolin products to at least 2 hours after the pyrimethamine dose pending pharmacist confirmation. Not a mineral deficiency or a reason to change mineral intake.

Limits on what this shows

• Why no grade: Dual condition met on the sources actually read: no Tier B or C evidence and no circulating claim. The unread 1953 monkey study (nutrient-to-drug direction) is disclosed and could change this entry to yellow if its content supports it. Genuine gap for read sources (homocysteine listing searched, no pyrimethamine-effect study; B12 never measured in the one SP cohort found); tooling-limited for the 1953 record.

What was searched

Web search "pyrimethamine homocysteine": results were generic homocysteine pages and patents, none about pyrimethamine. Label and monograph text read (US label, SmPC, MSF monograph, Fansidar label): megaloblastic anemia is attributed to folate deficiency; no B12 or homocysteine statement. A 1953 record "The effect of vitamin B12 on the toxicity of pyrimethamine (Daraprim) in the monkey" (Indian Journal of Malariology) was found; the repository holds no abstract or full text, so its content is unknown [33]. Repair pass 2026-10-10: PubMed listing "pyrimethamine homocysteine" returned 3 records. Two were not usable (a 1976 B12-folate review that names pyrimethamine as a DHFR inhibitor causing megaloblastic anemia without data, and a malaria drug-target database). The third, Douamba 2012 [43], was opened in full: 201 pregnant women in Ouagadougou, 146 of 201 with SP-IPT by Table 3 (the text says 27%, an internal conflict), mean homocysteine about 10.5 umol/L, 90% (181/201) normal at 12 umol/L or below, 9% (18) moderate and 1% (2) at 30 or above, 62% (125/201) with low folate (under 7.7 ng/mL), B12 not measured, and no homocysteine or folate comparison by SP status. It is a cross-sectional pregnancy cohort with confounding by indication and no unexposed comparator, so it cannot show a drug effect and does not support even a yellow grade.

Channel outcomes

PubMed term listing: 429 rate limit on repeat attempts (one listing page returned a partial summary); PubMed and PMC article pages: reCAPTCHA bot verification; OpenAlex single-record lookups worked for some PMIDs; Crossref title search: 429; shared web-search budget exhausted before the last planned queries. The 1953 record could not be read, which is a tooling limit. Repair pass: PubMed homocysteine listing worked; an OpenAlex title search for the 1953 paper returned a fetch error; web search budget exhausted.