Included as part of the "PRECAUTIONS" Section
Risk Of Embryofetal Toxicity
Based on findings in animal studies, Solagé may cause fetal harm. Avoid use in pregnant women [see Use In Specific Populations].
Phototoxicity And Risk Of Sunburn
Because of heightened burning susceptibility, avoid or minimize exposure to sunlight (including sunlamps) to treated areas during the use of Solagé. Patients must be advised to use protective clothing and comply with a comprehensive sun avoidance program (including using sunscreen) when using Solagé. Patients with sunburn should be advised not to use Solagé until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using Solagé.
Solagé should not be administered if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity.
Local Adverse Reactions
Solagé is a dermal irritant and the results of continued irritation of the skin for greater than 52 weeks in chronic, long-term use are not known.
Tretinoin has been reported to cause severe irritation of eczematous skin, including the development of skin fissures. Solagé should be used with caution in patients with this condition.
Solagé may cause skin irritation, erythema, burning, stinging or tingling, peeling, and pruritis. If the degree of such local irritation warrants, patients should be directed to use less medication, decrease the frequency of application, discontinue use temporarily, or discontinue use altogether. The efficacy at reduced frequencies of application has not been established.
Avoid concomitant use of other potentially irritating topical products (such as products with high concentration of alcohol, astringents, spices or lime, medicated soaps or shampoos, permanent wave solutions, electrolysis, hair depilatories or waxes, or products with a strong skin drying effect). Weather extremes, such as wind or cold may be more irritating to patients using Solagé.
Hypopigmentation has occurred with Solagé use. Solagé should be used with caution by patients with a history, or family history, of vitiligo, as they might be more susceptible to hypopigmentation, which can also be more severe in these patients.
Keep away from heat and open flame.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Risk Of Embryofetal Toxicity
Based on findings in animal studies, Solagé may cause fetal harm. Avoid use in pregnant women.
Photosensitivity And Risk Of Sunburn
Advise patients to avoid excessive sun exposure and to use of sunscreens and protective measures (hat, visor). Advise patients to avoid using Solagé if also taking other medicines may increase sensitivity to sunlight.
Advise a woman to use Solagé on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Solagé directly to the nipple and areola to avoid direct infant exposure.
Important Administration Instructions
Advise patients of the following:
- Use Solagé twice daily, morning and evening at least 8 hours apart.
- Apply Solagé to the solar lentigines using the applicator tip while avoiding application to the surrounding skin.
- Do not apply to non-intact skin.
- Avoid concomitant use of topical products with a strong drying or irritating effect.
- Advise patients not to use more than the recommended amount and not to apply more than twice daily as this will not produce faster or better results but may increase irritation and hypopigmentation.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
A dermal carcinogenicity study in mice demonstrated that Solagé applied topically at daily doses up to 80 and 0.4 mg/kg or 240 and 1.2 mg/m2 of mequinol and tretinoin, respectively, was not carcinogenic.
Mequinol was non-mutagenic in the Ames/Salmonella assay using strains TA98, TA100, TA1535, and TA1537, all of which are insensitive to mutagenic effects of structurally-related quinones. Solagé was non-genotoxic in an in vivo dermal micronucleus assay in rats, but exposure of bone marrow to drug was not demonstrated.
No impairment of fertility was observed in rats dosed topically with Solagé at a daily dose of 80 and 0.4 mg/kg or 480 and 2.4 mg/m2 of mequinol and tretinoin, respectively.
Use In Specific Populations
Solagé should be avoided by pregnant women. Solagé contains tretinoin and ethyl alcohol. The systemic levels of ethyl alcohol were not assessed and the systemic levels for tretinoin following topical administration are lower than with oral tretinoin, however absorption of this product may result in fetal exposure. Available data from published observational studies of topical tretinoin in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are case reports of major birth defects observed with the use of other topical tretinoin products that were similar to those seen in fetuses exposed to oral retinoids, but these case reports do not establish a pattern or association with tretinoin-related embryopathy. There are no data on mequinol or Solagé use in pregnant women.
In animal reproduction studies with pregnant rabbits dosed topically with Solagé during organogenesis, there were incidences of known retinoid malformations, including hydrocephaly, cleft palate and appendicular skeletal defects (see Data). The available data do not support relevant comparisons of systemic mequinol and tretinoin exposures achieved in the animal studies to exposures observed in humans after topical use of Solagé.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%20%, respectively.
Topical administration of mequinol and tretinoin or tretinoin alone to pregnant rabbits during organogenesis was associated with marked hydrocephaly with visible doming of the head observed in one mid-dose litter (12 and 0.06 mg/kg or 132 and
0.66 mg/m2 of mequinol and tretinoin, respectively) and two fetuses in one high dose litter (40 and 0.2 mg/kg or 440 and 2.2 mg/m2 of mequinol and tretinoin, respectively) treated with Solagé, and two high-dose litters treated with tretinoin (0.2 mg/kg, 2.2 mg/m2). These malformations were considered to be treatment related and due to the known effects of tretinoin. This was further supported by coincident appearance of other malformations associated with tretinoin, such as cleft palate and appendicular skeletal defects. No effects attributed to treatment were observed in rabbits in that study treated topically with mequinol alone (dose 40 mg/kg, 440 mg/m2). A no-observed-effect level (NOEL) for malformations in rabbits was established at 4 and 0.02 mg/kg or 44 and 0.22 mg/m2 mequinol and tretinoin, respectively. Plasma tretinoin concentrations were not raised above endogenous levels, even at doses where malformations were observed.
In a repeated study in pregnant rabbits administered the same topical dose levels as the study described above, additional precautionary measures were taken to prevent ingestion, although there is no evidence to confirm that ingestion occurred in the initial study. Precautionary measures additionally limited transdermal absorption to a six hour exposure period, or approximately one-fourth of the human clinical daily continuous exposure time. This study did not show any significant malformations at doses up to 40 and 0.2 mg/kg or 440 and 2.2 mg/m2 of mequinol and tretinoin, respectively. However, a concurrent tretinoin dose group (0.2 mg/kg/day) did include two litters with limb malformations.
Topical administration of Solagé to pregnant rats during organogenesis did not cause malformations at doses of 80 and 0.4 mg/kg mequinol and tretinoin, or 480 and 2.4 mg/m2.
There are no data on the presence of topical tretinoin, mequinol or their metabolites in human milk, the effects on the breastfed infant or the effects on milk production. It is possible that topical administration of large amounts of Solagé could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Solagé and any potential adverse effects on the breastfed infant from Solagé or from the underlying maternal condition.
To minimize potential exposure to the breastfed infant via breast milk, use Solagé on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Solagé directly to the nipple and areola to avoid direct infant exposure.
The safety and effectiveness of Solagé have not been established in pediatric patients.
Of the total number of subjects in clinical studies of Solagé, approximately 43% were 65 and older, while approximately 8% were 75 and over. No overall differences in effectiveness or safety were observed between these patients and younger patients.