Isotretinoin

Usage

Isotretinoin is primarily prescribed for the treatment of severe recalcitrant nodular acne that is resistant to other conventional therapies, including systemic antibiotics and topical medications. It’s particularly effective for acne with scarring or cystic acne. It belongs to the retinoid class of medications, which are structurally related to vitamin A. Isotretinoin works by reducing sebum production, shrinking sebaceous glands, inhibiting inflammation, and reducing the colonization of Propionibacterium acnes (formerly P. acnes) bacteria within the sebaceous glands.

Alternate Names

While “isotretinoin” is the generic name, it’s widely recognized by its former brand name, Accutane (now discontinued). Other brand names include Absorica, Amnesteem, Claravis, Myorisan, Sotret, and Zenatane. Isotrex and Isotrexin were brand names for the topical gel formulation, which are no longer available.

How It Works

Pharmacodynamics: Isotretinoin’s primary effect is a significant reduction in sebum production. This is achieved through shrinking the sebaceous glands, which are responsible for producing sebum. It also exhibits anti-inflammatory properties, diminishing the inflammatory component of acne. Furthermore, it hinders the growth and colonization of P. acnes within the sebaceous glands.

Pharmacokinetics: Isotretinoin is well-absorbed orally and ideally taken with food for optimal bioavailability. It’s highly lipophilic, meaning it readily dissolves in fats and accumulates in fatty tissues. Isotretinoin is metabolized in the liver, primarily to 4-oxo-isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. It is excreted through both renal (kidneys) and hepatic (liver) routes. Elimination half-life is approximately 90 hours.

Mechanism of Action: Isotretinoin acts by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in the cell nucleus. This binding modulates gene expression, affecting cell differentiation, proliferation, and apoptosis, ultimately leading to reduced sebum production, decreased inflammation, and normalization of follicular keratinization.

Dosage

Standard Dosage

Adults:

• Conventional Capsules: The initial dose is typically 0.5 to 1 mg/kg of body weight per day, divided into two doses, taken with food. The dosage can be adjusted up to a maximum of 2 mg/kg/day for severe cases, particularly those with scarring or truncal acne, as tolerated.

• Absorica LD Capsules: The recommended dosage is 0.4 to 0.8 mg/kg/day, administered in two divided doses with or without meals. Doses may be adjusted up to 1.6 mg/kg/day for patients with severe acne or scarring.

• Micronized Capsules: The dosage typically ranges from 0.4 to 0.8 mg/kg/day, divided into two doses.

Children (12 years and older):

Dosing in children (12 years and older) is similar to the adult recommendations, based on body weight. Safety and efficacy in children younger than 12 have not been established.

Special Cases:

• Elderly Patients: Start with a lower dose and adjust as tolerated, considering age-related changes in renal and hepatic function.

• Patients with Renal Impairment: Initiate treatment at a reduced dose (e.g., 10 mg daily for severe impairment) and titrate cautiously based on patient tolerance and renal function.

• Patients with Hepatic Dysfunction: Isotretinoin is contraindicated in patients with active liver disease.

• Patients with Comorbid Conditions: Careful monitoring is recommended for patients with diabetes, depression, or a history of mood disorders.

Clinical Use Cases

Isotretinoin is not typically indicated for clinical use cases like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is severe acne unresponsive to other treatments.

Dosage Adjustments

Dosage adjustments are individualized based on patient response, tolerance, and the presence of renal impairment, or other relevant conditions. Regular monitoring of liver enzymes and lipid levels is essential during treatment.

Side Effects

Common Side Effects:

Dry skin, lips, eyes, and mucous membranes (cheilitis, xerosis, conjunctivitis), nosebleeds (epistaxis), muscle aches, joint pain (arthralgia), and elevated triglycerides.

Rare but Serious Side Effects:

Depression, suicidal ideation, pseudotumor cerebri (increased intracranial pressure), pancreatitis, inflammatory bowel disease (IBD) exacerbations, severe allergic reactions, and hepatotoxicity.

Long-Term Effects:

Potential long-term side effects include dry eye syndrome (sometimes irreversible), decreased night vision, and musculoskeletal issues.

Adverse Drug Reactions (ADR):

Serious ADRs requiring urgent medical attention include Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, and severe hepatitis.

Contraindications

• Pregnancy: Isotretinoin is absolutely contraindicated in pregnancy due to the high risk of teratogenicity.
• Breastfeeding: Isotretinoin is contraindicated during breastfeeding.
• Known hypersensitivity to isotretinoin or parabens.
• Severe hepatic impairment.
• Concurrent use with tetracyclines.
• Patients with markedly elevated triglyceride levels.
• Patients receiving vitamin A supplements.

Drug Interactions

Isotretinoin interacts with several medications, including:

• Vitamin A supplements: Increased risk of vitamin A toxicity.
• Tetracyclines: Increased risk of pseudotumor cerebri.
• Corticosteroids: Increased risk of osteoporosis.
• Microdose progestin-only (‘mini-pill’) oral contraceptives: Reduced contraceptive efficacy.
• Medications that affect liver enzymes: May alter isotretinoin metabolism.
• St. John’s wort, phenytoin, some antiretrovirals can reduce efficacy of hormonal contraceptives.
• Alcohol

Pregnancy and Breastfeeding

Isotretinoin is highly teratogenic and absolutely contraindicated during pregnancy and breastfeeding. Females of reproductive potential must participate in the iPLEDGE program, which mandates strict contraception before, during, and after treatment.

Drug Profile Summary

• Mechanism of Action: Reduces sebum production, shrinks sebaceous glands, anti-inflammatory, and reduces P. acnes colonization.
• Side Effects: Dry skin, mucous membranes, cheilitis, myalgia, arthralgia, increased triglycerides; rarely: depression, suicidal ideation, pseudotumor cerebri, pancreatitis, hepatotoxicity.
• Contraindications: Pregnancy, breastfeeding, hepatic impairment, hypersensitivity to isotretinoin or parabens, concurrent tetracycline use, hypervitaminosis A.
• Drug Interactions: Vitamin A supplements, tetracyclines, microdose progestin (‘mini-pill’), medications affecting liver enzymes.
• Pregnancy & Breastfeeding: Absolutely contraindicated.
• Dosage: 0.5-1 mg/kg/day divided BID, up to 2 mg/kg/day in severe cases, adjusted for renal impairment; lower doses for Absorica LD and micronized formulations.
• Monitoring Parameters: Liver enzymes (ALT, AST), triglycerides, cholesterol levels, blood glucose.

Popular Combinations

Isotretinoin is sometimes used in combination with topical antibiotics for initial management of inflammatory acne before starting isotretinoin monotherapy. However, combined use with oral tetracyclines is contraindicated.

Precautions

• General Precautions: Baseline and periodic liver function tests, lipid profile, and blood glucose monitoring. Psychiatric evaluation for history of depression or mood disorders.
• Specific Populations: Contraindicated in pregnancy and breastfeeding. Caution in patients with diabetes, renal impairment, and history of depression.
• Lifestyle Considerations: Avoid excessive sun exposure, use sunscreen. Limit alcohol consumption. Temporary visual disturbances, particularly at night, may affect driving ability.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isotretinoin?

A: The standard dosage is 0.5-1 mg/kg/day, divided into two doses, taken with meals, for 15-20 weeks. Absorica LD and micronized formulations have lower recommended starting doses. Dosage can be adjusted based on response and tolerance, up to a maximum of 2 mg/kg/day for conventional capsules.

Q2: What are the most common side effects?

A: Dry skin, chapped lips, dry eyes, nosebleeds, muscle aches, and joint pain.

Q3: Is Isotretinoin safe during pregnancy?

A: No, Isotretinoin is absolutely contraindicated during pregnancy due to its high teratogenic potential.

Q4: What are the serious side effects that I should watch for?

A: Signs of depression, suicidal thoughts, severe headaches, blurred vision, nausea and vomiting (pseudotumor cerebri), severe abdominal pain (pancreatitis), and signs of allergic reactions.

Q5: How does Isotretinoin interact with other medications?

A: Isotretinoin can interact with vitamin A supplements, tetracycline antibiotics, certain hormonal contraceptives, and medications that affect liver enzymes. Always inform your patients to disclose all medications and supplements they are taking.

Q6: What precautions should patients take while on Isotretinoin?

A: Avoid excessive sun exposure, use sunscreen, limit alcohol intake, and avoid cosmetic procedures like waxing, dermabrasion, and laser treatments during treatment and for several months afterward. Do not donate blood during treatment and for at least one month after stopping isotretinoin.

Q7: Can Isotretinoin be used in patients with liver disease?

A: No, isotretinoin is contraindicated in patients with active liver disease. Close monitoring of liver function is necessary in all patients receiving isotretinoin.

Q8: How long does a typical course of Isotretinoin treatment last?

A: A typical course lasts 15-20 weeks, although some patients may require a second course after a period off the medication.

Q9: What monitoring is required for patients taking Isotretinoin?

A: Baseline and periodic liver function tests (ALT, AST), triglyceride and cholesterol levels, and possibly blood glucose, especially in patients with diabetes or at risk for diabetes.

Q10: Can male patients father children while on Isotretinoin?

A: While isotretinoin doesn’t appear to damage sperm or significantly affect male fertility, it is crucial that female partners avoid pregnancy due to the risk of fetal exposure. Appropriate contraceptive measures must be taken if the partner is of childbearing potential.