Accutane (Isotretinoin) Complete Drug-Drug Interaction Profile

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What the two labels list

The Absorica and Absorica LD label carries a short drug interactions section with three entries: vitamin A, tetracyclines, and oral contraceptives [1]. The Accutane label, an older-format isotretinoin capsule label, covers more ground and adds micro-dosed progesterone preparations, norethindrone and ethinyl estradiol, St. John's Wort, phenytoin and systemic corticosteroids [2]. The two labels agree on the two avoid-list items [1][2].

Tetracyclines: avoid, but not a contraindication

The contraindications section of the isotretinoin label lists pregnancy and hypersensitivity to isotretinoin, vitamin A or any component. Tetracyclines are not there [1]. Tetracyclines are handled under Warnings and Precautions and Drug Interactions: avoid concomitant use, because isotretinoin has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved tetracyclines [1]. The Accutane label says the same thing [2].

The Accutane label lists early signs of pseudotumor cerebri: papilledema, headache, nausea and vomiting, and visual disturbances. It says patients with these symptoms should be screened for papilledema and, if it is present, told to stop Accutane and be referred to a neurologist [2].

Vitamin A

Both labels tell patients to avoid supplements that contain vitamin A [1][2]. The Absorica label gives the reason: isotretinoin is closely related to vitamin A, so taking them together may lead to isotretinoin-associated adverse reactions [1]. The Accutane label frames it as avoiding additive toxic effects [2].

Hormonal contraceptives: no pharmacokinetic change

The Absorica label states that isotretinoin did not cause clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when the two were used together as an oral contraceptive, and that an interaction with other oral contraceptives is not known [1]. The Accutane label describes the study behind that statement: 31 premenopausal women with severe recalcitrant nodular acne took Ortho-Novum 7/7/7 with isotretinoin 1 mg/kg/day, with no clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone or in serum progesterone, FSH and LH [2].

Two contraceptive caveats sit in the labels. Micro-dosed progesterone preparations without an estrogen (minipills) may be an inadequate method of contraception during treatment [2]. And the Accutane label notes reported pregnancies in people using combined oral contraceptives, as well as patch, injectable, implant and vaginal ring products, more often with a single method, and states that it is not known whether hormonal contraceptives differ in effectiveness when used with isotretinoin [2]. Every patient is enrolled in the iPLEDGE REMS, and patients who can get pregnant must use two forms of contraception or committed abstinence. Birth control pills do not replace those requirements [1].

Phenytoin: no pharmacokinetic change found

The Accutane label states that isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a study of seven healthy volunteers, consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit CYP2C9 [2]. The same label notes that no formal clinical studies have assessed whether the two drugs interact on bone loss, that phenytoin is known to cause osteomalacia, and that caution should be exercised when using them together [2].

Systemic corticosteroids: a bone caution

The Accutane label's entry is brief. Systemic corticosteroids are known to cause osteoporosis; no formal clinical studies have assessed whether their bone-loss effect interacts with isotretinoin's; caution should be exercised when using them together [2]. The label does not describe a pharmacokinetic interaction between the two.

St. John's Wort: the concern is contraception

The Accutane label cautions patients not to self-medicate with St. John's Wort, because a possible interaction with hormonal contraceptives has been suggested by reports of breakthrough bleeding shortly after starting it, and pregnancies have been reported by users of combined hormonal contraceptives who also used it [2]. Separately, a systematic review found that St. John's wort can lower the concentration or effect of several medicines, including oral contraceptives, probably through induction of CYP3A4, CYP2C9, CYP1A2 and P-glycoprotein [3]. The label's concern is hormonal-contraceptive effectiveness, not isotretinoin levels [2].

CYP pathways, and the drugs the labels do not name

In vitro, the primary P450 isoforms involved in isotretinoin metabolism are CYP2C8, CYP2C9, CYP3A4 and CYP2B6, and isotretinoin is more than 99.9% bound to plasma proteins [2]. Neither label's drug interactions section names methotrexate, warfarin, a statin, an SSRI, an NSAID or a CYP inhibitor or inducer as an interaction with isotretinoin [1][2].

Food and absorption

In 74 healthy adults given a single 80 mg dose, a high-fat meal more than doubled absorption: AUC was 10,004 ng·h/mL fed versus 3,703 ng·h/mL fasted, and Cmax was 862 versus 301 ng/mL, with a half-life of about 21 hours in both conditions [2]. The Accutane label says the drug should be taken with food, because failure to do so significantly decreases absorption [2]. The Absorica label says it can be taken with or without meals [1].

Alcohol and lipids

The Accutane label lists increased alcohol intake among the factors that call for especially careful risk-benefit consideration during treatment, alongside diabetes, obesity and lipid metabolism disorders. It also notes that some patients have reversed triglyceride elevation with weight reduction, restriction of dietary fat and alcohol, and a dose reduction while continuing treatment [2]. Marked triglyceride elevations occurred in approximately 25% of patients in clinical trials, and elevations above 800 mg/dL have been reported [2]. Cheilitis and hypertriglyceridemia are the two reactions the Absorica label calls dose related [1].