ORATANE™ 20MG

Indications

• Severe acne (such as nodular or conglobate acne) resistant to adequate courses of systemic antibacterials and topical therapy
• Acne associated with psychological problems
• Acne with scarring
• Systemic treatment of nodulo-cystic and conglobate acne

Dosage

Children: Child 12-17 years:

Adults: Initially 500 micrograms/kg daily in 1-2 divided doses, increased if necessary to 1 mg/kg daily until a total cumulative dose of 120-150 mg/kg is reached. Treatment may be repeated after at least 8 weeks if relapse occurs.

Mechanism of action

Isotretinoin alters cell cycle progression, differentiation, survival, and apoptosis. It significantly reduces sebum production and prevents pore blockage, thereby inhibiting the growth of acne-causing bacteria. It induces apoptosis in sebocytes, decreases hyperkeratinization, and modifies immune responses, which collectively contribute to its therapeutic effects in acne treatment.

Pharmacodynamics

The pharmacodynamics of isotretinoin are not fully elucidated, but it is known to significantly influence sebaceous gland activity and reduce inflammation associated with acne. It has minimal affinity for retinol binding proteins and retinoic acid nuclear receptors, yet it might interact with various cellular pathways to exert its effects.

Pharmacokinetics

Isotretinoin is well absorbed from the gastrointestinal tract and is metabolized predominantly in the liver. It has a half-life of approximately 10-20 hours and undergoes extensive hepatic metabolism, primarily to its active metabolite, 4-oxo-isotretinoin. The drug is excreted mainly in urine and feces. Due to its lipophilic nature, isotretinoin is best absorbed when taken with food.

Contra-indications

• Pregnancy due to high risk of serious congenital malformations
• Hypersensitivity to isotretinoin or any of its excipients
• Liver disease
• Hyperlipidaemia

Adverse effects

• Dry skin
• Chapped lips
• Nosebleeds
• Eye irritation
• Headaches
• Muscle and joint pain
• Mood changes, including depression and suicidal ideation
• Erectile dysfunction
• Decreased libido

Interactions

• Tetracyclines may increase the risk of intracranial hypertension
• Vitamin A supplements may increase the risk of hypervitaminosis A
• Alcohol may increase the risk of liver toxicity
• Hormonal contraceptives may be less effective while taking isotretinoin

Precautions

• Monitor for signs of depression or suicidal thoughts
• Women of childbearing potential must use effective contraception
• Caution in patients with a history of depression
• Use sunscreen to protect against sun exposure

Pregnancy

Isotretinoin is contraindicated in pregnancy due to a high risk of serious congenital malformations. Women must adhere to strict pregnancy prevention measures.

Breast-feeding

The amount of isotretinoin in breast milk is probably too small to be harmful; however, it is advised to ensure that the infant does not come in contact with treated areas.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Capsules
• Oral solution
• Topical cream
• Topical gel

Mechanism of action

Isotretinoin produces its effects through altering progress through the cell cycle, cell differentiation, survival, and apoptosis. These actions reduce sebum production, preventing the blockage of pores, and growth of acne causing bacteria. Isotretinoin and 4-oxo-isotretinoin both significantly reduce the production of sebum. Isotretinoin has little to no affinity for retinol binding proteins (RBPs) and retinoic acid nuclear receptors (RARs). Tretinoin and 4-oxo-tretinion bind to the RAR-γ receptor, which is suspected to be part of the action of acne treatment by isotretinoin. Isotretinoin induces apoptosis in sebocytes, leading to a decrease in sebum production. Isotretinoin also reduces the formation of comedones by reducing hyperkeratinization through an unknown mechanism. Isotretinoin does not directly kill bacteria but it does reduce the size of sebum ducts and makes the microenvironment less hospitable to acne causing bacteria. It may also increase immune mechanisms and alter chemotaxis of monocytes to reduce inflammation. There is preliminary evidence suggesting isotretinoin may interact with FoxO1, which may explain a substantial number of isotretinoin's unexplained actions. This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.

Pharmacodynamics

The pharmacodynamics of isotretinoin are poorly understood.