Accutane (isotretinoin)

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Isotretinoin is administered orally with meals to maximize GI absorption. Isotretinoin should be administered in 2 divided doses. The manufacturers state that safety of once-daily dosing of isotretinoin has not been established and is not recommended.

To decrease the risk of esophageal irritation, isotretinoin capsules should be swallowed whole with a full glass of liquid. Patients should be instructed not to suck or chew the capsules.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Retinoids (Systemic)/Growth Hormone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic retinoids(1-8,11) and growth hormones(9-11) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(1-8) with growth hormones(9-10) may increase the risk of intracranial hypertension (pseudotumor cerebri). Early signs of intracranial hypertension include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(12)

PREDISPOSING FACTORS: Women of childbearing age with high body mass may have a higher risk of developing intracranial hypertension.(8)

PATIENT MANAGEMENT: The US manufacturer of tretinoin advises avoiding concomitant use of other products that can cause intracranial hypertension.(1) Patients who present with symptoms of intracranial hypertension should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(1-8)

DISCUSSION: Vitamin A derivatives and growth hormone have both been strongly associated with intracranial hypertension. A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 21 patients who developed intracranial hypertension while taking tretinoin, acitretin, or etretinate at prescribed doses. Symptom onset occurred at an average of 2-3 months after starting retinoid therapy and all except 3 cases resolved within a few months after discontinuing therapy.(8) In a systematic review of 580 reported cases of medication-induced intracranial hypertension between January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable cases of intracranial hypertension. Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred with excessive vitamin A supplementation. Growth hormone was implicated in 24 cases, all of which occurred in pediatric patients and involved frequent or higher doses of growth hormone.(12)

Selected Retinoids (Systemic)/Lithium

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic retinoids(1-7) and lithium(8-9) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(1-7) with lithium(8-9) may increase the risk of intracranial hypertension (pseudotumor cerebri). Early signs of intracranial hypertension include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(10)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(10)

PATIENT MANAGEMENT: The US manufacturer of tretinoin advises avoiding concomitant use of other products that can cause intracranial hypertension.(1) Patients who present with symptoms of intracranial hypertension should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(1-7)

DISCUSSION: Vitamin A derivatives and lithium have both been strongly associated with intracranial hypertension. In a systematic review of 580 reported cases of medication-induced intracranial hypertension between January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable cases of intracranial hypertension. Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred with excessive vitamin A supplementation. Lithium was implicated in 17 cases with lithium levels in therapeutic range.(10)

Selected Retinoids (Systemic)/Tetracyclines

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic tetracyclines(1-4,14) and systemic retinoids(5-14) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(5-12) with tetracyclines has been associated with pseudotumor cerebri (benign intracranial hypertension). Early signs of pseudotumor cerebri include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(15)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(15)

PATIENT MANAGEMENT: The UK(5) and US(6) manufacturers of acitretin state state that concurrent use with tetracyclines is contraindicated. The UK manufacturer of isotretinoin states that concurrent use with tetracyclines is contraindicated.(7) The US manufacturer of isotretinoin states that the concurrent use of tetracyclines should be avoided.(8) The US manufacturer of minocycline states that the administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.(2) The UK manufacturers of oral tretinoin and alitretinoin states that concurrent use with tetracyclines is contraindicated.(9,11) The Canadian manufacturer of palovarotene states that coadministration of tetracycline derivatives should be avoided.(12) Patients who present with symptoms of pseudotumor cerebri should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(5-13)

DISCUSSION: The concurrent use of isotretinoin and tetracyclines has been associated with pseudotumor cerebri.(5-13) A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 6 patients who developed intracranial hypertension while taking concurrent minocycline or tetracycline with tretinoin, acitretin, or etretinate.(13)

Selected Retinoids/Vitamin A

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The retinoids are structurally related to vitamin A. (1-6)

CLINICAL EFFECTS: Concurrent use of retinoids with vitamin A supplements may result in signs of vitamin A toxicity.(1-6) Symptoms of vitamin A toxicity include nausea, vomiting, loss of appetite, weakness, dry or itchy skin or lips, irritability, and hair loss.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acitretin states that concomitant use of vitamin A supplements should be avoided.(1) The manufacturer of bexarotene states that patients should be advised to limit vitamin A supplements. In clinical studies, patients were advised to limit their vitamin A intake to less than or equal to 15,000 International Units/day.(2) The manufacturer of isotretinoin states that patients should be advised against taking vitamin A supplements.(3) The manufacturer of palovarotene states that concomitant use of vitamin A must be avoided.(4) The manufacturer of tretinoin states that tretinoin must not be administered in combination with vitamin A.(5) The UK manufacturer of alitretinoin states that tretinoin must not be administered in combination with vitamin A.(6)

DISCUSSION: The retinoids are structurally related to vitamin A. The concurrent use of retinoids with vitamin A may result in signs and symptoms of vitamin A toxicity.(1-6)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Isotretinoin/Valoctocogene Roxaparvovec

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction has not been established.(1)

CLINICAL EFFECTS: Co-administration of valoctocogene roxaparvovec with isotretinoin resulted in decreased factor VIII activity, which may result in increased risk of bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of valoctocogene roxaparvovec states that co-administration with isotretinoin is not recommended in patients who are benefiting from valoctocogene roxaparvovec.(1)

DISCUSSION: In a patient treated with valoctocogene roxaparvovec and isotretinoin, decreased factor VIII activity without ALT elevation was noted after starting isotretinoin. The factor VIII activity recovered after isotretinoin was stopped.(1) In vitro studies indicate isotretinoin suppresses factor VIII transcription independent of hepatotoxicity, without impact of ALT, and expression was partially restored upon discontinuation.(1)

Selected Retinoids/Progestin-Only Oral Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use may result in increased progesterone levels and interference with the effect of the contraceptive. Major fetal abnormalities have been reported with the administration of acitretin(1) and isotretinoin.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use of "mini-pill" progestin preparations are not recommended. Patients on acitretin(1) or isotretinoin(2) therapy should be using two reliable methods of contraception and should be advised that progestin-only mini-pills may fail. Consider switching to a combination estrogen-progestin contraceptive agent; intrauterine device (IUD); or injected, implanted, or inserted hormonal birth control products. Two methods of contraception are still required.

DISCUSSION: According to the manufacturer of acitretin, this interaction has been documented in one patient who received concurrent therapy with acitretin and a progestin-only mini-pill.(1) Given the severe consequences of contraceptive failure during acitretin or isotretinoin therapy, caution is warranted. All females of reproductive age should use two reliable forms of contraception unless they have undergone a hysterectomy or practice abstinence.(1,2) In a study in 26 healthy women, concurrent use of isotretinoin and Ortho Novum 7/7/7 (ethinyl estradiol and norethindrone) resulted in small, inconsistent, although statistically significant, decreases in ethinyl estradiol (9%) and norethindrone (11%). However, there was large variability of pharmacokinetic and pharmacodynamic markers and the authors stressed that their results reinforced the need for additional contraceptive measures during therapy.(3)

There are no moderate interactions for this drug.

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• Acute pancreatitis
• Lactation
• Pregnancy

• Agranulocytosis
• Corneal opacity
• Depression
• Disease of liver
• Hearing loss
• Hypertriglyceridemia
• Idiopathic intracranial hypertension
• Inflammatory bowel disease
• Intracranial hypertension
• Neutropenic disorder
• Psychotic disorder
• Rectal bleeding
• Suicidal ideation
• Tinnitus

• Alcohol use disorder
• Anorexia nervosa
• Diabetes mellitus
• Keratoconjunctivitis sicca
• Obesity
• Osteomalacia
• Osteoporosis

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More Frequent

• Skin and skin structure infection

Less Frequent

• Hallucinations
• Osteopenia
• Panic disorder
• Psychiatric disorder

Rare or Very Rare

• Abnormal hepatic function tests
• Acute pancreatitis
• Aggressive behavior
• Agranulocytosis
• Anaphylaxis
• Anemia
• Bronchospastic pulmonary disease
• Cataracts
• Cerebrovascular accident
• Corneal opacity
• Depression
• Drug-induced psychosis
• Erythema multiforme
• Esophageal ulcer
• Glomerulonephritis
• Hearing loss
• Hematuria
• Hepatitis
• Hyperglycemia
• Hyperuricemia
• Idiopathic intracranial hypertension
• Inflammatory bowel disease
• Lymphadenopathy
• Neutropenic disorder
• Night blindness
• Optic neuritis
• Osteoporosis
• Pyogenic granuloma
• Rhabdomyolysis
• Seizure disorder
• Skeletal hyperostosis
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Tendonitis
• Thrombocytopenic disorder
• Thromboembolic disorder
• Toxic epidermal necrolysis

More Frequent

• Abnormal desquamation
• Alopecia
• Arthralgia
• Back pain
• Bone tenderness
• Cheilitis
• Cheilosis
• Dry eye
• Dry nose
• Dry skin
• Epistaxis
• Headache disorder
• Musculoskeletal pain
• Ocular irritation
• Pharyngitis
• Reduced visual acuity
• Skin inflammation
• Skin photosensitivity
• Skin rash
• Upper respiratory infection
• Xerostomia

Less Frequent

• Muscle rigidity
• Nausea
• Neck pain

Rare or Very Rare

• Acquired chromatopsia
• Acute abdominal pain
• Anorexia
• Blurred vision
• Conjunctivitis
• Dizziness
• Drowsy
• Dyschromia
• Eczema
• Edema
• Erectile dysfunction
• Eye tearing
• Eyelid edema
• Fatigue
• Gingival bleeding
• Gingivitis
• Hirsutism
• Hyperhidrosis
• Hyperlipidemia
• Hypertriglyceridemia
• Impaired wound healing
• Irregular menstrual periods
• Irritability
• Libido changes
• Malaise
• Menstrual disorder
• Mood changes
• Myalgia
• Nervousness
• Ocular inflammation
• Ocular itching
• Ocular redness
• Palpitations
• Paronychia
• Photophobia
• Premature epiphyseal closure
• Proteinuria
• Pruritus of skin
• Skin hypopigmentation
• Symptoms of anxiety
• Tachycardia
• Tinnitus
• Vaginal dryness
• Weight loss

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Isotretinoin is a known human teratogen, and can cause severe, life-threatening birth defects or fetal death if taken during pregnancy. Since the risks clearly outweigh any possible benefits in female patients who are or may become pregnant or who intend to become pregnant during treatment, female patients of childbearing potential should not receive isotretinoin until pregnancy is excluded and other conditions of use have been met. (See Teratogenicity Contraindications and Precautions under Cautions: Precautions and Contraindications.) There is an extremely high risk that severe birth defects will result if pregnancy occurs while receiving isotretinoin in any amount even for short periods of time. There are no accurate means of determining whether an exposed fetus has been affected following isotretinoin exposure. Therefore, patients who become pregnant, miss their expected menstrual period, stop using birth control, or have sexual intercourse without the use of 2 separate contraceptive measures should immediately discontinue isotretinoin and notify their clinician. Such patients should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Clinicians must immediately report any suspected fetal exposure during or up to 1 month following therapy to the US Food and Drug Administration (FDA) Medwatch Program at 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or through the program's website (http://www.ipledgeprogram.com). The iPLEDGE Program Pregnancy Registry collects data on pregnancies that occur in female patients who become pregnant while taking isotretinoin or within 1 month after the last dose. Data from this registry are used to evaluate further ways to reduce fetal exposure to isotretinoin; the information gathered in the registry will be used for statistical purposes only and will be held in the strictest confidence.

Since becoming commercially available in the US in 1982, isotretinoin has been labeled as being contraindicated during pregnancy, with warnings that use in women of childbearing potential be initiated only after advising them of the teratogenic risks, excluding the possibility of pregnancy, and ensuring the use of an effective means of contraception during isotretinoin therapy. Despite the stated contraindication and warnings and subsequent strengthening of precautionary information in the drug's labeling, the FDA, the US Centers for Disease Control and Prevention (CDC), and the manufacturer of Accutane(R) continued to receive reports of infants with congenital abnormalities born to women who had received isotretinoin during pregnancy. FDA states that there is some evidence that overprescribing (e.g., for patients without severe, recalcitrant nodular acne) for women of childbearing potential is partly responsible for such continued reports. However, because isotretinoin has been proven to be uniquely effective for use in severe, recalcitrant nodular acne, with therapeutic benefits for this condition that exceed those of other currently available drugs, FDA, at the recommendation of its Dermatologic Drugs Advisory Group, decided that the drug can remain available for use in the US once the manufacturer of Accutane(R) adopted the recommendations made by this Group and the FDA Fertility and Maternal Health Drugs Advisory Committee for a pregnancy prevention program that included changes in the professional labeling, patient labeling, and packaging; initiation of strengthened education of the patient that includes written informed consent and supervised viewing of an educational videocassette at the time of prescribing; expansion of patient referrals to obstetrician-gynecologists for pregnancy testing; and ensurance by the manufacturer that all unused isotretinoin be returned by the patient. Unfortunately, suboptimal participation (40% or less of women who received isotretinoin) and substantial noncompliance with critical elements of the manufacturer-supported pregnancy prevention program (e.g., 25% did not receive a pregnancy test prior to treatment and 33% initiated therapy prior to receiving their pregnancy test results) has been reported to the FDA. Of the 1995 documented cases of isotretinoin-exposed pregnancies reported by the manufacturer of Accutane(R), 958 pregnancies were identified after the previous pregnancy prevention program was in place. According to a 1999 report to the FDA by this manufacturer, approximately 11% of the pregnant women identified by a patient survey conducted by the Slone Epidemiology Unit of Boston University School of Public Health were pregnant at initiation of isotretinoin therapy and another 14% became pregnant during the first 3 weeks of treatment. Because of such limitations in the previous pregnancy prevention program, the manufacturer of Accutane(R), working with the FDA, developed a restricted distribution system, the System to Manage Accutane Related Teratogenicity (SMART), as an additional component of a risk management program to prevent fetal exposure to isotretinoin. As nonproprietary (generic) isotretinoin preparations became commercially available, additional restricted distribution programs were developed by other manufacturers. The SMART program included mandatory contraceptive measures for women, as well as mandatory pregnancy testing to confirm that a woman is not pregnant before isotretinoin therapy is initiated and does not become pregnant during or immediately after therapy with the drug.

Existing restricted distribution programs designed to reduce the risk of fetal exposure to isotretinoin, including the SMART program, were assessed in 2004 by FDA, and the results of this assessment were presented at a joint meeting of the Drug Safety and Risk Management and Dermatologic and Ophthalmic Drugs Advisory Committees. Those committees strongly recommended the need for improvements in the isotretinoin risk management program to strengthen processes to ensure pregnancy testing and counseling of patients prior to and during therapy to reduce the risk of fetal exposure in the US. The resulting FDA-approved iPLEDGE risk management program is a single, mandatory, computer-based, closed system of registered wholesalers, prescribers, pharmacies, and patients for all commercially available isotretinoin preparations. The iPLEDGE program links access to isotretinoin by female patients of childbearing potential with negative results of pregnancy testing to lower the risk of possible fetal exposure to the drug during pregnancy.

Although isotretinoin has been found in the semen of male patients taking the drug, the amount delivered to a female partner has been found to be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid-exposed fetuses. However, 2 of these reports were incomplete, and 2 had other possible explanations for the defects observed. Nevertheless, clinicians should report any pregnancy in the partner of a male patient receiving the drug to the iPLEDGE program. (See Dosage and Administration: Restricted Distribution Program.)

It is not known whether isotretinoin is distributed into milk. Because of the potential for serious adverse reactions to isotretinoin in nursing infants, isotretinoin should not be administered to women who are breast-feeding.

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