The use of systemic drugs in seborrheic dermatitis treatment is aimed at acute cases, large areas of involvement, resistant forms associated with HIV, and neurological disorders. Systemic therapy aims to reduce acute symptoms, while topical therapy is for prevention and maintenance.

The antifungal medicinal effect is direct against Malassezia and is anti-inflammatory. The systemic antifungal agents used in treating seborrheic dermatitis are:
  • triazole (itraconazole and fluconazole), 
  • diazol (ketoconazole), 
  • and allylamine (terbinafine) groups.

Azole and terbinafine inhibit the synthesis of ergosterol (a key component of cell membranes). Diazol and triazole inhibit the 14 α sterol demethylase enzyme, which causes the accumulation of 14 α methyl sterol resulting in inhibition of fungal growth. Terbinafine inhibits the synthesis of the enzyme squalane 2,3 epoxidase. It is affecting ergosterol metabolism and squalane accumulation, which causes fungal cell death. Terbinafine has additional mechanisms such as neutrophil modulation, scavenger effect on reactive oxygen species (ROS), and sebum secretion modulation.

Ketoconazole was the first systemic antifungal used to treat seborrheic dermatitis. Currently, ketoconazole is only used topically because of its hepatotoxicity. Itraconazole is currently considered the first choice for systemic therapy of seborrheic dermatitis, both acute and relapsed. Itraconazole undergoes cytochrome P450 metabolism in the liver. In plasma, It circulates as an active metabolite.

Drugs metabolized by cytochrome P450 interact with other drugs, either increasing their toxicity or decreasing their efficacy. Itraconazole has a good level of safety at a dose of 200 mg/day. The most common side effects during itraconazole therapy are:
  • Hepatotoxicity, 
  • epigastric pain, 
  • heart rhythm disturbances, 
  • hypokalemia, 
  • hypertriglyceridemia, 
  • and elevated transaminases.

 The therapeutic efficacy of itraconazole is supported by evidence that it is secreted with sebum in the stratum corneum, where the colonization of Malassezia is located. Its lipophilic molecular nature causes the agent to stay longer on the skin even after no longer taking it.

A study conducted by Kose et all; on 20 patients with Seborrheic Dermatitis showed a reduction in inflammation and improvement in DS symptoms after administration of systemic itraconazole at a dose of 200 mg/day for a week followed by administration of the drug at a dose of 200 mg/day for the first two days of each month for the following two months.

Meanwhile, a study by Caputo et al. proved the itraconazole effectiveness as maintenance therapy. One hundred sixty patients who had been treated for seven days with 200 mg of itraconazole per day. Furthermore, given a 200 mg/day dose on the first two days per month for eight months. There were no recurrences during the observation period.

Fluconazole has the characteristic of being well absorbed by the gastrointestinal tract regardless of acidity or diet. Fluconazole significantly increases plasma concentrations of several drugs such as warfarin, cyclosporine, tacrolimus, and theophylline. Rifampin lowers blood levels of fluconazole.

A randomized controlled trial evaluated fluconazole and placebo's short-term therapeutic efficacy in 63 patients with seborrheic dermatitis. These regiments were given to 27 patients at a dose of 300 mg per week for two weeks. Significant clinical improvement was achieved in patients on fluconazole at the end of the study, while patients on placebo showed no improvement.

Terbinafine is a lipophilic molecule that can be deposited on the skin to maintain effective drug concentrations. Even therapy has been stopped.

Terbinafine has a safe and well-tolerated pharmacological profile with a low side effects incidence. Side effects include epigastric pain, hepatotoxicity, neutropenia, rash, and Steven Johnson syndrome.

Scaparno et al. performed a multicentre randomized study to evaluate terbinafine's efficacy versus moisturizing ointment at a dose of 250 mg/day over four weeks.

Terbinafine significantly relieved the seborrheic dermatitis symptoms, such as erythema, scale, and itching (p <0.0001).

A multicentre randomized trial evaluated the efficacy of terbinafine versus placebo in treating seborrheic dermatitis. In this trial, patients were divided into two groups based on the lesions' location, namely the face area and the body and scalp area. Both groups took the drug for six weeks at a daily dose of 250 mg/day. The result was a clinical and subjective improvement in patients given the treatment and placebo and only in the group with closed lesion sites.

In a large study, 661 moderate-severe seborrheic dermatitis patients who did not respond to conventional therapy were studied by Cassano and colleagues to assess terbinafine's effectiveness in treating seborrheic dermatitis. There was a significant clinical improvement and a drastic reduction in relapses after discontinuation of the drug. This progress occurred in the group using terbinafine 250 mg/day for the first 12 days of the month for three consecutive months. The intermittent regimen is well-tolerated, improves compliance, and is affordable.