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Topical Antineoplastic Retinoids
Retinoid; a synthetic version of 9-cis-retinoic acid.; used topically in patients with failed or refractory cutaneous Kaposi's sarcoma. An oral formulation is under investigation.
Panretin Topical Gel: 0.1%
Apply a generous amount to cover the lesions twice daily. Gradually, increase frequency of application to 3—4 times daily according to individual tolerance. A response may be seen within 2 weeks of starting therapy, but most patients require more time to respond. Treatment should continue as long as the patient is receiving benefit. In clinical trials, alitretinoin gel was applied for up to 96 weeks. If toxicity occurs at the application site, the frequency of application may be decreased and/or therapy held until symptoms resolve. NOTE: Topical alitretinoin is not indicated when systemic therapy is required (e.g., > 10 new lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary disease or visceral involvement).
In phase II trials, alitretinoin 60—100 mg/m2/day PO in divided doses has been studied. Higher doses (up to 140 mg/m2/day) have been associated with an increased risk of toxicity. Responses have been seen in patients refractory to prior chemotherapy with an overall response rate of 37%.
4 applications topically per lesion/day.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Apply a generous coating of gel to lesions. The gel should be allowed to dry 3—5 minutes before covering with clothing. Do not rub the gel into the lesion. Proper application should leave some gel visible on the surface of the lesion. Do not cover the treated area with an occlusive dressing.Wait 20 minutes after a shower or bath before applying alitretinoin gel. Do not shower, swim or bathe for at least 3 hours after application.Avoid contact with unaffected skin due to irritation. Also, avoid application on or near mucosal surfaces such as eyes, nostrils, mouth lips, vagina, tip of penis, rectum or anus.Wipe your finger(s) used to apply the gel with a disposable tissue and wash hands using soap and water following application.
Panretin:- Store at 77 degrees F; excursions permitted to 59-86 degrees F
Alitretinoin gel may cause fetal harm if absorbed in significant amounts and is considered a pregnancy category D agent. Oral 9-cis-retinoic acid has been associated with teratogenesis in animal models. There are no adequate, well-controlled studies of alitretinoin gel in pregnant women. If alitretinoin gel is used during pregnancy or the patient becomes pregnant while using the gel, the potential risks should be discussed with the patient. Women of child-bearing potential should not become pregnant while using alitretinoin gel.
According to the manufacturer, alitretinoin should not be used during breast-feeding. It is not known whether alitretinoin or its metabolites are excreted into breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The safety and efficacy of alitretinoin gel in children and geriatric patients > 65 years of age have not been established.
Retinoids have been associated with photosensitivity. Although there were no reports of photosensitivity during the clinical trials with alitretinoin gel, 9-cis-retinoic acid is a weak photosensitizer. Patients should be instructed to avoid sunlight (UV) exposure, sunlamps and tanning beds while using alitretinoin.
Do not use an occlusive dressing with alitretinoin gel.
exfoliative dermatitis / Delayed / 3.0-9.0
edema / Delayed / 3.0-8.0erythema / Early / Incidence not known
rash / Early / 25.0-77.0paresthesias / Delayed / 3.0-22.0pruritus / Rapid / 8.0-11.0
There are no drug interactions associated with Alitretinoin products.
Mechanism of Action: Retinoids are intracrine or paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Depending upon the action required, cells regulate the formation of specific retinoid isomers. Physiologically, 9-cis-retinoic acid is an isomer of all-trans-retinoic acid (ATRA).Retinoids exert their effects through binding to specific intracellular receptors. Intracellular retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These proteins are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. 9-cis-retinoic acid binds to all retinoic acid receptors (RAR-alpha, beta, gamma and RXR-alpha, beta, gamma) while all-trans-retinoic acid binds only to the RARs. The 9-cis-retinoic acid isomer is 50 times more potent than all-trans-retinoic acid at binding to RXR but equipotent at activating RAR-alpha. As opposed to other currently available retinoids, alitretinoin binds to all 6 retinoid receptor subtypes. RAR-alpha is found in the cerebellum, adrenal gland, testis, and hematopoeitic cells; RAR-beta is found in the kidney, prostate, and cerebral cortex; and RAR-gamma is located in the skin. RXR is located primarily in visceral organs such as the liver and kidney. The RAR subtypes bind to specific DNA sites and act as transcription factors, which control target gene expression. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and epidermal malignancies, respectively. Activated RXRs form heterodimers (RAR/RXR) or homodimers (RXR/RXR) that bind to DNA at retinoic acid response elements. These receptors have a role in modifying retinoid responses in the cell.The role of retinoids in fetal development is to specify positional information for cells in developing limbs and possibly in the nervous system. Retinoids are required for normal growth and proliferation of epithelial tissues. Dysregulation of retinoids may contribute to lung, gastric, uterine, bladder, testicular, breast, prostate, pancreatic, and skin cancers.
Alitretinoin is currently available as a topical preparation and is under investigation as an oral formulation. Intracellular isomerases convert all-trans-retinoic acid to 9-cis, 11-cis or 13-cis-retinoic acid. The major metabolite of 9-cis-retinoic acid is 4-oxo-9-cis-retinoic acid. Studies indicate 9-cis-retinoic acid is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, and 1A2 enzymes. In lower doses (< 140 mg/m2/day), 9-cis-retinoic acid does not appear to induce its own metabolism as is seen with other retinoids. The elimination half-life of alitretinoin appears to be 1.1—2.4 hours.
Following oral absorption of retinol (vitamin A) from the GI tract, all-trans-retinoic acid (ATRA) is formed intracellularly via oxidation.
There have been no pharmacokinetic studies of topical alitretinoin; however, there appears to be no extensive systemic absorption. In patients receiving chronic, multiple daily applications of alitretinoin gel, the plasma levels of 9-cis-retinoic acid is in the range of naturally occurring 9-cis-retinoic acid in untreated healthy volunteers.