indication

For the the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant); For the topical treatment of acne vulgaris, flat warts and other skin conditions (psoriasis, ichthyosis congenita, icthyosis vulgaris, lamellar icthyosis, keratosis palmaris et plantaris, epidermolytic hyperkeratosis, senile comedones, senile keratosis, keratosis follicularis (Darier's disease), and basal cell carcinomas.); For palliative therapy to improve fine wrinkling, mottled hyperpigmentation, roughness associated with photodamage.

pharmacology

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A (retinol). Retinoids such as tretinoin are important regulators of cell reproduction, proliferation, and differentiation and are used to treat acne and photodamaged skin and to manage keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin also represents the class of anticancer drugs called differentiating agents and is used in the treatment of acute promyelocytic leukemia (APL).

mechanism of action

Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. Although the exact mechanism of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced. Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. When Tretinoin is given systemically to APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

biotransformation

Hepatic

absorption

1-31% (topical)

half life

0.5-2 hours

drug interactions

Atazanavir: The strong CYP2C8 inhibitor, Atazanavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Atazanavir is initiated, discontinued to dose changed.

Carbamazepine: The strong CYP2C8 inducer, Carbamazepine, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Carbamazepine is initiated, discontinued or dose changed.

Celecoxib: The moderate CYP2C8 inhibitor, Celecoxib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Celecoxib is initiated, discontinued to dose changed.

Demeclocycline: Demeclocycline may increase the adverse effects of oral Tretinoin. Increased risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Desogestrel: Oral Tretinoin may decrease the effect of oral contraceptive, Desogestrel. An alternate form of contraception should be used during concomitant therapy.

Doxycycline: Doxycycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Drospirenone: Oral Tretinoin may decrease the effect of oral contraceptive, Drospirenone. An alternate form of contraception should be used during concomitant therapy.

Ethinyl Estradiol: Oral Tretinoin may decrease the effect of the oral contraceptive, Ethinyl Estradiol. An alternate form of contraception should be used during concomitant therapy.

Ethynodiol Diacetate: Oral Tretinoin may decrease the effect of oral contraceptive, Ethynodiol Diacetate. An alternate form of contraception should be used during concomitant therapy.

Etonogestrel: Oral Tretinoin may decrease the effect of oral contraceptive, Etonogestrel. An alternate form of contraception should be used during concomitant therapy.

Felodipine: The moderate CYP2C8 inhibitor, Felopidine, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Felopidine is initiated, discontinued to dose changed.

Fosphenytoin: The strong CYP2C8 inducer, Fosphenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Fosphenytoin is initiated, discontinued or dose changed.

Gemfibrozil: The strong CYP2C8 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Gemfibrozil is initiated, discontinued to dose changed.

Irbesartan: The moderate CYP2C8 inhibitor, Irbesartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Irbesartan is initiated, discontinued to dose changed.

Lapatinib: The moderate CYP2C8 inhibitor, Lapatinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Lapatinib is initiated, discontinued to dose changed.

Levonorgestrel: Oral Tretinoin may decrease the effect of oral contraceptive, Levonorgestrel. An alternate form of contraception should be used during concomitant therapy.

Losartan: The moderate CYP2C8 inhibitor, Losartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Losartan is initiated, discontinued to dose changed.

Mestranol: Oral Tretinoin may decrease the effect of oral contraceptive, Mestranol. An alternate form of contraception should be used during concomitant therapy.

Minocycline: Minocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Natalizumab: Oral tretinoin may increase the adverse/toxic effects of Natalizumab. Concurrent therapy should be avoided.

Nilotinib: The moderate CYP2C8 inhibitor, Nilotinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Nilotinib is initiated, discontinued to dose changed.

Norethindrone: Oral Tretinoin may decrease the effect of oral contraceptive, Norethindrone. An alternate form of contraception should be used during concomitant therapy.

Norgestimate: Oral Tretinoin may decrease the effect of oral contraceptive, Norgestimate. An alternate form of contraception should be used during concomitant therapy.

Oxytetracycline: Oxytetracycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Phenobarbital: The strong CYP2C8 inducer, Phenobarbital, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenobarbital is initiated, discontinued or dose changed.

Phenytoin: The strong CYP2C8 inducer, Phenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenytoin is initiated, discontinued or dose changed.

Pioglitazone: The moderate CYP2C8 inhibitor, Pioglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Pioglitazone is initiated, discontinued to dose changed.

Primidone: The strong CYP2C8 inducer, Primidone, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Primidone is initiated, discontinued or dose changed.

Quinine: The moderate CYP2C8 inhibitor, Quinine, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Quinine is initiated, discontinued to dose changed.

Rabeprazole: The moderate CYP2C8 inhibitor, Rabaprazole, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rabaprazole is initiated, discontinued to dose changed.

Rifampin: The strong CYP2C8 inducer, Rifampin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rifampin is initiated, discontinued or dose changed.

Rifapentine: The strong CYP2C8 inducer, Rifapentine, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rifapentine is initiated, discontinued or dose changed.

Ritonavir: The strong CYP2C8 inhibitor, Ritonavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Ritonavir is initiated, discontinued to dose changed.

Rosiglitazone: The moderate CYP2C8 inhibitor, Rosiglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rosiglitazone is initiated, discontinued to dose changed.

Secobarbital: The strong CYP2C8 inducer, Secobarbital, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Secobarbital is initiated, discontinued or dose changed.

Sorafenib: The strong CYP2C8 inhibitor, Sorafenib, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Sorafenib is initiated, discontinued to dose changed.

Tamoxifen: The moderate CYP2C8 inhibitor, Tamoxifen, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Tamoxifen is initiated, discontinued to dose changed.

Tetracycline: Demeclocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Tigecycline: Demeclocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided.

Trastuzumab: Increased risk of leukopenia and anemia due to synergistic effects. Monitor for signs and symptoms of adverse events during concomitant therapy.

Trimethoprim: The moderate CYP2C8 inhibitor, Trimethoprim, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Trimethoprim is initiated, discontinued to dose changed.

Vitamin A: Tretinoin increases the risk of vitamin A toxicity. Avoid vitamin A supplementation while taking systemic tretinoin.