In this study, we collected porphyria AEs from 1470 reporters on the FAERS using four algorithms “ROR”, “PRR,” “BCPNN,” and “MGPS”; 406 drugs were obtained by combining different trade names and generic names representing the same drug, 52 drugs with signals were identified by all four algorithms. Anti-infective, antitumor and immune, digestive system, nervous system, cardiovascular system, urogenital system, dermatological system, hematological system, and musculoskeletal system drugs had high signals. Therefore, extreme caution must be taken to ensure that porphyrinogenic drugs are not prescribed to carriers of porphyria genetic mutations.

Porphyrinogenic drugs are potentially life-threatening to patients with hepatic porphyria and should thus be contraindicated. Early identification and removal of the offending drug, along with immediate treatment, are life-saving [23]. Development of photosensitivity or production of dark urine during drug therapy suggests the possibility of drug-induced PCT, which may respond to cessation of the offending drug [24]. However, these drugs are chemically unique and apparently structurally unrelated, making it difficult to pinpoint the culprit due to conflicting results published in the literature. Thunell et al. [9, 25]. developed a risk assessment model for individual patients receiving a drug, which formed the basis of the www.drugs-porphyria.org database where information on more than 1000 drugs is available for review. Although drug porphyrogenicity prediction can guide drug prescription and reduce drug risk, its accuracy requires verification in clinical practice. The FAERS collects ADR data from the United States and Europe through the MedWatch reporting system [26] and provides an opportunity to perform real-world studies on drug toxicity monitoring [27].

From our analysis, 1470 cases were reported with porphyria AEs in the FAERS, and 406 drugs were obtained by combining the trade names and generic names. The most common patient age was 18–44 years, with more cases involving females than males. Porphyria typically occurs in women between 20 and 30 years of age and 2–4 days prior to menstruation, as ovarian hormones, particularly progesterone, are potent inducers on ALAS1 [28, 29]. Young women are also at high risk for drug-induced porphyria, as shown in this study. Regarding elderly patients, porphyria AEs were frequently reported due to the higher number of drugs prescribed for multiple comorbidities, increasing the risk of encountering porphyrinogenic drugs. Approximately 90% of acute attacks related to AIP occur in women [30]. However, in this study, only 47.07% of cases were reported to have occurred in women. This may be explained in part by male patients carrying porphyria genetic mutations seldomly receiving early diagnosis or drug prescription.

The interval between drug initiation and onset of porphyria as an AE varies greatly, with 1 month (106; 39.70%) as the most common duration. Various drugs have been implicated in exacerbating acute attacks [31], i.e., porphyrinogenic drugs [32]. These drugs deplete the heme pool by inducing or inhibiting cytochrome enzymes (CYP), or abnormally degrading heme [12, 33]. In this study, antiviral drugs were the most common signaling drugs. In a previous study, the association between HIV and HCV infection with PCT was well established [34]. The high dosage of ribavirin could increase hepatic iron levels via hemolysis. The excess of iron in the cytosol of hepatocytes can reduce the action of uroporphyrinogen decarboxylase (UROD) and cause accumulation of its precursor [35]. Moreover, certain antiretroviral drugs also precipitate acute porphyria, such as atazanavir and ritonavir, which inhibit CYP-3A4, leading to heme depletion in hepatocytes, leading to compensatory activation of heme synthesis and toxic accumulation of ALA and PBG precursors in patients who are carriers of acute porphyria genetic mutations [36]. Appropriate antiretroviral regimens should be prescribed with vigilance to these patients. When patients who have been prescribed antiretroviral drugs experience unexplained abdominal pain or skin-photosensitivity symptoms, physicians must consider and closely monitor drug-induced porphyria.

The anti-tuberculosis drug rifampin and anti-fungal drug voriconazole induce or inhibit CYP-450 and provoke a porphyria attack [37]. In 2017, Zaman Babar et al [38]. reported pure motor axonal neuropathy, the peripheral neuropathy of AIP, triggered by anti-tuberculous therapy in an undiagnosed case of acute intermittent porphyria. Most first-line anti-tuberculous drugs are associated with acute attacks of porphyria, its mechanism of action includes: (1) activation of ALAS1 transcription and translation by inducing CYP expression; (2) irreversible inhibition of CYP and compensative activation of heme synthesis; (3) ALAS1 expression induction. Therefore, to prevent the acute onset of latent porphyria, anti-tuberculosis drugs should be used with caution.

Many people develop phototoxicity after using voriconazole [28, 39]. Voriconazole intake is subject to hepatic metabolism by CYP-450 enzymes. Voriconazole serum concentrations maintained between 1.5 and 4 µg/mL are generally safe; however, the possibility of hepatotoxicity cannot be excluded [40], with carriers of porphyria genes being at a greater risk.

Many psychotropic drugs have been implicated in exacerbating acute attacks [41, 42]. However, antipsychotics are often used in acute attacks of porphyria as agents for neuropathic abdominal pain.

This study suggests that immunomodulating agent drugs, like Leflunomide, are associated with porphyria attacks. System lupus erythematosus (SLE) has been associated with porphyria since 1952 [43]. Hydroxychloroquine (HCQ) is often prescribed to patients with SLE to reduce flares; chloroquine and hydroxychloroquine may induce AIP in these patients. Moreover, the use of medium–high doses (250–500 mg/d chloroquine and 200–400 mg/d HCQ) may cause liver toxicity in patients with PCT [44]. However, the mechanism by which immunomodulatory drugs induce porphyria attacks is not well understood. In clinical practice, clinicians should monitor for acute attacks of porphyria when patients using immunomodulators have severe abdominal pain and neuropsychiatric manifestations [24].

Previous studies have reported on the relationship between antitumor drugs and porphyria. Imatinib mesylate is a tyrosine kinase inhibitor [45] that is primarily used to treat chronic myelogenous leukemia (CML). Cutaneous adverse events associated with imatinib are common, while the pathogenesis of pseudoporphyria is unclear. Mahon et al. [45]. speculated that the mechanism of imatinib may be associated with the modulation of c-Kit pathways, disrupting normal melanocyte biology and impairing photoprotective mechanisms. A possible relationship between chemotherapeutic agents and the occurrence of PCT has been discussed in case reports on varying drugs [44]. Manzione et al. speculate that certain chemotherapeutics may induce ALAS1 expression by inhibiting CYP450, which increases heme and porphyrin precursors [46].

Small interfering RNA (givosiran) [47] and hemin are agents without porphyrinogens that are used to stop acute porphyria attacks. Meanwhile, patients who receive givosiran or hemin are at increased risk of disease exacerbation. Consequently, these drugs have been designated as causative agents due to this indication bias when in fact they may not be. Indication of prescription drugs as an error reported as an AE may also occur in this self-reporting system [48]. Interferon (IFN)-α was frequently reported, likely due to its combination with porphyrinogenic antiviral drugs. Such drugs without porphyrinogens must be manually removed from the signaling drugs. Regarding other signal drugs that were predicted as NP, PNP, or NC in the porphyria network drug database, more information is needed to redefine their porphyrinogen status and classification.

This study has certain limitations. First, the FAERS technology does not address all challenges regarding the detection and analysis of adverse drug reaction signs. Hence, the signals from FAERS were used only for qualitative research. Second, false reporting, incomplete reporting, underreporting, and arbitrariness are also included in the data. Third, patients who develop an acute attack may have been simultaneously exposed to multiple drugs and infection or stress, rendering the attribution of blame uncertain. Further research is needed to address these limitations of FAERS.