Super Bioavailable (SUBA) Itraconazole-Induced Galactorrhea—Could it be due to Hydroxypropyl Methylcellulose Phthalate?

Dear Editor,

Drug-induced hyperprolactinemia is one of the important causes of non-physiological galactorrhea.[1] The varied drugs implicated are antipsychotics, antidepressants, estrogen-containing drugs, prokinetics, antihypertensives, and opioids which can increase prolactin, secretion or increase the sensitivity of breast tissue to prolactin. We report a case of galactorrhea consequent to Super Bioavailable (SUBA) itraconazole. An 18-year-old unmarried female patient with no comorbidities, presented with tinea corporis et cruris [Figure 1] and was started on SUBA itraconazole 100 mg once a day (OD) due to the prevalent resistance to terbinafine.[2] Within 5 days of starting the drug, she developed a milky white discharge from both breasts with no associated pain or tenderness. There was no history of menstrual irregularities, persistent headache, seizure, vision changes, or facial deviation during the episode. While a more common cause is believed to be a physiological variation, the problem persisted, and on day 7, SUBA itraconazole was withheld and a serum prolactin level was ordered which revealed raised prolactin levels (33 ng/ml, reference range 3.20–18.55). The galactorrhea resolved within 8 days of stopping the drug and the serum prolactin was normalized (3.3 ng/ml). Adverse drug reaction probability scale (Naranjo) was applied giving a possible (score of 4) causative link for SUBA-induced galactorrhea.

Figure 1.

Before treatment with griseofulvin

She was consequently initiated on griseofulvin 500 mg OD, which led to visible improvement in 2 weeks [Figure 2]. There was a marked and remarkable correlation of hyperprolactinemia with SUBA itraconazole, and complete resolution on stopping the drug. A challenge in such cases is converse to medical ethics and very distressing to the patient and was not contemplated.

Figure 2.

After treatment with griseofulvin

Galactorrhea with the rise in serum prolactin levels can be physiological, pharmacological, and pathological. A large group of medications can raise prolactin levels [Table 1].[1] The varying mechanisms include action as false dopamine precursors, inhibition of L-aromatic amino acid decarboxylase, dopamine receptor antagonism, enhanced serotoninergic neurotransmission, direct and indirect serotonin agonism, blocking serotonin reuptake, and histamine H2 receptor antagonism.

Table 1.

Drugs implicated in galactorrhea[1]

Class of drug	Examples
Antipsychotics	Typical: Haloperidol, chlorpromazine, thioridazine
	Atypical: Risperidone, amisulpride
Antidepressants	Tricyclics: Amitriptyline, desipramine, clomipramine
	SSRI: Sertraline, Fluoxetine, paroxetine
	MAOI: Pargyline, clorgyline
Psychotropics	Buspirone, alprazolam
Prokinetics	Metoclopramide, domperidone
Antihypertensive	Alpha-methyldopa, reserpine, verapamil
Opiates	Morphine
H2 Antagonists	Cimetidine, ranitidine

SSRI=Selective serotonin reuptake inhibitors , MAOI= Monoamine oxidase inhibitors

The hyperprolactinemia in drug-induced hyperprolactinemia is usually mild [25–100 ng/ml] and the levels usually fall to normal levels within a week of stopping the drug.[1] The rising incidence of antifungal resistance to terbinafine leads to the use of conventional itraconazole (C ITZ), which has been replaced by SUBA itraconazole, due to quality variations in pellet technology and bioavailability of C ITZ and is used for tinea corporis et cruris in India.[3] Despite the widespread prescription of C ITZ since 2016 in India, this drug has not been reported to cause galactorrhea, and except for rare reports of gynecomastia, there is no previous report of this side effect to the best of our knowledge. This specific side effect of SUBA formulation could be attributed to the polymer hypromellose phthalate (HPMCP) as opposed to hydroxypropyl methylcellulose (HPMC) used in C ITZ. The use of this polymer (HPMCP) enables better absorption and increased bioavailability in the basic pH of the intestine, which ensures higher and consistent bioavailability as compared to C ITZ.[4] Phthalates have been known to be endocrine disruptors and can also impact on mammary function.[5] While a study has implicated phthalates as a cause of hyperprolactinemia[6], more data are awaited with SUBA ITZ. The prompt reversal of the galactorrhea and prolactin levels proves the association in our singular case and the rising use of SUBA ITZ may lead to similar cases and thus can shed more light on this purported link.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.