Use of Topical Tazarotene for the Treatment of Acne Vulgaris in Pregnancy: A Literature Review

Abstract

A concern with the increasing use of prescription drugs during pregnancy is teratogenic risk. This risk is undetermined for most drugs approved in the United States (US) from 2000 to 2010. Acne and psoriasis are chronic diseases that typically occur during the child-bearing years, and as topical retinoids are recommended for both acne and psoriasis treatment, is it possible for women to be exposed to a topical retinoid during pregnancy. Pharmacokinetic studies show relatively low systemic exposure from topical retinoids, but the exposure levels that could lead to teratogenicity in humans are unknown. Tazarotene, a topical retinoid, was US Food and Drug Administration (FDA) approved for both acne and psoriasis using pharmacokinetic data from psoriasis studies, which estimated the data based on use of tazarotene on up to 20% body surface area. As such, under both the previous and current FDA pregnancy labeling, tazarotene is not recommended for use during pregnancy. The goal of this literature review was to provide historical context for the pregnancy labeling rule for tazarotene compared with other approved retinoids and gather available data on tazarotene- and retinoid-related pregnancy outcomes. While there are case reports of topical tretinoin and adapalene exposure in utero, it is unclear if either affected fetal development. In terms of topical tazarotene, there are currently limited data regarding pregnancy outcomes after in-utero exposure. Additional case reports and outcomes studies are needed to further explore the safety of topical tazarotene in pregnancy.

Tazarotene is a topical retinoid approved in the United States (US) for the treatment of acne and psoriasis,1–3 both chronic diseases that typically occur during the child-bearing years. While pharmacokinetic studies show relatively low systemic exposure from topical tazarotene,4,5 the levels that could lead to teratogenicity in humans are unknown.1,5

Tazarotene was approved by the US Food and Drug Administration (FDA) for both acne and psoriasis using pharmacokinetic data from psoriasis studies; these studies estimated the pharmacokinetic data based on the use of tazarotene on up to 20 percent of the body surface area, whereas the face accounts for only two percent of the body surface area.1,5 As such, under the previous FDA pregnancy labeling, topical tazarotene was contraindicated for use during pregnancy (Category X).5

The goal of this review is to provide the historical context for the pregnancy labeling rule for tazarotene compared with other approved retinoids and to briefly summarize the pharmacokinetics of topical retinoids as well as the available data on tazarotene- and retinoid-exposure and pregnancy outcomes.

PRESCRIPTION DRUG USE DURING PREGNANCY

The use of prescription drugs during pregnancy has been increasing.6 According to data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006, 22 percent of pregnant women and 47 percent of non-pregnant women of childbearing age (15–44 years) reported using prescription medications in the past 30 days.7 Another study using data from two large registries found that 50 to 70 percent of women interviewed after delivery reported having taken at least one prescription medication while pregnant; in addition, 29 to 49 percent reported using these medications in the first trimester and the use of four or more medications (prescribed or over the counter) during the first trimester has tripled, from 9.9 percent to 27.6 percent.6

Use of medications during pregnancy is concerning, as some drugs could cause abnormal embryo or fetal development. Drugs with this potential are called teratogens.8 Whether a drug can exert teratogenic effects is dependent on the conditions of gestational exposure (e.g., timing, duration, frequency, drug dose, and the chemical characteristics of the drug).8 The task of determining efficacy, safety (including teratogenic potential), and dosing when prescribing medications to women who might become, or already are, pregnant is left to clinicians.9,10

FDA DRUG LABELING AND CLASSIFICATION

In 1979, the FDA implemented regulations for prescription drugs requiring a label summarizing available safety and efficacy information; part of these requirements included providing information regarding use during pregnancy, labor/delivery, and lactation.11 Unless a drug was known to not have any systemic absorption nor any potential for indirect fetal harm, it was required to be classified based on the risk of reproductive or developmental effects, whether the maternal benefits outweighed the possible risks to the fetus, and if experimental data were available from humans and/or animals.11 Drugs were categorized using one of five letters: A, B, C, D, or X (Table 1).11 Any drug in Category A was considered to have a low teratogenic potential and any drug Categorized as X was not recommended for use during pregnancy.

TABLE 1.

Original FDA pregnancy labeling for prescription drugs11

FDA CATEGORY	DESCRIPTION	EXAMPLES
A	Adequate, well-controlled studies in pregnant women showed no evidence of risk to the fetus in the first trimester of pregnancy or in later trimesters	Levothyroxine42
B	Animal reproduction studies did not show fetal risk and there were no adequate, well-controlled studies in pregnant women	Amoxicillin, insulin,42topical clindamycin, azelaic acid31
C	Animal reproduction studies have shown adverse effects on the fetus, there are no adequate, well-controlled human studies, and the drug benefits in pregnant women may be acceptable despite potential risks	Albuterol,42topical tretinoin, adapalene31
D	Positive evidence in humans of fetal risk based on adverse events data from investigational or marketing experience or studies in humans but the potential benefits in pregnant women may be acceptable despite potential risks	Paroxetine,42diazepam, lisinopril43
X	Studies in humans or animals have shown fetal abnormalities or there is positive evidence of fetal risk based on adverse event reports from investigational or marketing experience, or both are true, and the risk clearly outweighs any benefits to pregnant women	Progestins/progesterone,42isotretinoin, topical tazarotene31

FDA: Food and Drug Administration

After the initial labeling requirements were developed, there were concerns that the labeling was unclear, with insufficient information about potential developmental risks and potential effects of drug discontinuation during pregnancy on the mother and/or fetus.9,12 Additional concerns included: the lack of information to assist clinicians in determining the relevance of data from animal studies; the appearance that different drugs in the same letter category had comparable risks and benefits when they did not; the appearance that inclusion into a category was based solely on risk; and the lack of procedures in place for updating the label if new safety data became available.9 In response to these concerns, the FDA changed the pregnancy labeling in 2014 now referred to as the Pregnancy and Lactation Labeling Rule. The letter categories were removed and the narrative subsections in the “Use in Specific Populations” section were revised (Figure 1); these subsections now include pregnancy (Section 8.1), lactation (Section 8.2), and a new section on females and males of reproductive potential (Section 8.3).13,14 Furthermore, labels are now required to be updated if new information causes the current label to be “inaccurate, false, or misleading”. These changes went into effect in June 2015.

FIGURE 1.

Pregnancy and lactation labeling changes.13,14

While the label changes provide a more clinically relevant summary of the data, teratogenic risk is still undetermined for 98 percent of the drugs approved by the FDA between 2000 and 2010; furthermore, almost 75 percent of these drugs had no human data available regarding safety in pregnancy.15 This is due to the exclusion of pregnant women and those planning to become pregnant from clinical drug trials for ethical concerns.9,10 As such, potential teratogenic risks are determined primarily through preclinical toxicity studies in animals9,10 and post-marketing data from voluntary case reports and registries.10 Neither are ideal ways to determine teratogenic risk. Animal toxicity studies do not present clear information regarding teratogenic risks, as effects in animals are not necessarily predictive of the same effects in humans.16 Additionally, it can be difficult for clinicians to determine the relevance of animal data and interpretation may vary.9 Finally, teratogenic risk may not be determined for years or decades after human data from case reports and registries become available.10

RETINOIDS AND TAZAROTENE

As noted previously, prescription medications are frequently used by women of reproductive age and during pregnancy. Acne vulgaris and psoriasis are both chronic, inflammatory skin diseases that typically occur during the reproductive years and can negatively impact quality of life.17,18 Acne is a common disease, occurring in 85 percent of adolescents in the US; it also currently affects up to 12 percent of adult women18 and prevalence in adults appears to be increasing. Psoriasis is less common, occurring in 2 to 3 percent of the global population, with an onset typically between the ages of 18 to 39 years.19

Topical treatments in the form of lotions, creams, gels, and foams provide localized drug delivery, which decreases systemic exposure;5,20 these are standard-of-care for treating mild-to-moderate disease.17,20 Topical retinoids are recommended for both acne and psoriasis treatment.17,18 Retinoids are vitamin A derivatives that vary in terms of efficacy and tolerability as a result of binding to different retinoic acid receptors.18 Four topical retinoids and one oral retinoid are FDA-approved for acne treatment: tretinoin, adapalene, tazarotene, trifarotene, and oral isotretinoin.18,21,22 Tazarotene is also approved for the treatment of plaque psoriasis on up to 20 percent of body surface area.1,2,17 As retinoid use is limited by irritation, treatments are available in one or more dosages and formulations (i.e., gel, cream, foam, lotion).18,21 Studies have shown that topical tazarotene is safe and effective for the treatment of psoriasis (dosages: 0.1%; 0.01%; 0.05%; 0.045%)23–25 and acne (0.1%; 0.05%; 0.045%).26–30 As acne is a very common disease in women of child-bearing age and topical retinoids are a typical treatment, it is possible for women to be exposed to a topical retinoid during pregnancy.

TAZAROTENE PREGNANCY LABELING

Under previous FDA pregnancy-labeling rules, topical tretinoin and adapalene were considered Category C and topical tazarotene was considered Category X (Table 1), even though resulting plasma retinoid levels from treatment with each were all similarly low (Table 2).5,31 One reason for differences in labeling is that tazarotene received simultaneous FDA-approval for the treatment of acne and psoriasis using pharmacokinetic data from psoriasis studies rather than from acne studies.5 Psoriasis studies estimated pharmacokinetic data based on use of tazarotene on up to 20-percent body surface area, whereas the face accounts for only two percent of the entire body surface area.5 The revised FDA pregnancy and lactation labeling note that tazarotene gel is contraindicated in pregnancy, but it is also noted that exposure levels that could lead to teratogenicity in humans are unknown.1 In males of reproductive potential, no guidance is provided. Furthermore, the effects of topical tazarotene on fertility in human males are unknown; studies in animals, however, show no detrimental effects.2,3

TABLE 2.

Pharmacokinetics of tretinoin, adapalene, and tazarotene

DRUG (INITIAL US APPROVAL)	STUDY POPULATION	DOSAGE	MEAN Cmax, ng/mL	MEAN AUC0-24, ng*h/mL
Tretinoin (1971)44	44 healthy participants	0.1% gel (500mg) as single- and repeated-daily doses for 28 days	1–3a	NR
Adapalene (1996)45	16 patients with acne	0.3% gel (2g) applied to face, chest, and back once daily for 10 days (~2mg/cm2)	0.553	8.37
	78 patients with acne	0.3% or 0.1% gel applied to face (optionally to trunk) once daily for 12 weeks (~1g/day average)	<0.15 (n=75)b <0.25 (n=3)b	NR
Tazarotenec (1997)1–3,34	8 female patients with acne	0.1% cream applied to face once daily for 29 days	0.10	1.54
	10 female patients with acne	0.1% cream applied to ~15% BSA once daily for 29 days	1.20	17.01
	48 patients with facial acne	0.1% cream applied to face once daily for 12 weeks	0.073 (Week 4)b 0.052 (Week 8)b	NR
	9 patients with psoriasis	0.1% cream applied to 5 to 35% BSAd once daily for 14 days	2.31	31.2e
	Female patients with acne	0.1% gel applied to ~15% BSA once daily for 41 days	4.84 (Day 15f)	44.6
	24 healthy participants	0.1% gel applied to 20% BSA once daily for seven days	0.72	10.1
	5 patients with psoriasis	0.1% cream applied to 8–18% BSAg once daily for 14 daysh	12.0	105
	28 patients with acne	0.045% lotion (4g) applied to face, neck, upper chest, and upper back once daily for 14 days	0.365 (Day 14)	5.72 (Day 15)

^aPlasma concentration for tretinoin and its metabolites (13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid).

^bValues reported as plasma concentration (not specifically C_max).

^cPharmacokinetic data shown for tazarotenic acid, the active metabolite of tazarotene.

^dMean BSA was 14%.

^eOn Day 15 in five participants who were administered clinical doses of 2mg cream/cm2.

^fMean C_max values were 1.81ng/mL on Day 8, 2.44ng/mL on Day 28, and 1.95ng/mL on Day 42.

^gMean BSA was 13%.

^hStudy protocol dictated exaggerated and precise dosage conditions.4

AUC_0–24: area under the plasma concentration time curve from 0 to 24 hours; BSA: body surface area; C_max: maximum plasma concentration; NR: not reported; US: United States

PHARMACOKINETICS OF TAZAROTENE

Low systemic exposure to a drug may reduce the potential risk of teratogenicity.5 Topical tazarotene has limited percutaneous penetration, rapid metabolism to hydrophilic metabolites (preventing accumulation in adipose tissue), and rapid elimination, all of which contribute to a low systemic exposure (Figure 2).4,32 Tazarotene has a mean half-life of 17 to 18 hours.4 Systemic bioavailability with 0.1% monotherapy dosing was 1% in healthy participants after single and multiple applications; in patients with psoriasis, bioavailability was one percent and there was an increase to five percent by Week 2, but this decreased by Week 12.4 This increase in bioavailability may have been due to a compromised epidermal barrier that occurs in patients with psoriasis; in addition, initial tazarotene treatment can thin psoriatic plaques and further reduce the skin barrier. After 12 weeks, skin barrier properties may have been reestablished, reducing permeability to tazarotene. In patients with acne and psoriasis treated with 0.1% tazarotene cream, tazarotenic acid plasma levels were similar to endogenous retinoid levels measured in healthy volunteers and lower than in healthy volunteers dosed with vitamin A (Figure 3).5,33,34 Single 40mg or 80mg doses of oral isotretinoin, by comparison, had similar or slightly longer half-lives of 18 or 21 hours than topical tazarotene but 30 to 70 times greater mean plasma concentrations, respectively (Figure 3). Overall, these data indicate that systemic exposure from topical tazarotene 0.1% is generally low and similar to endogenous retinoid levels.

FIGURE 2.

Distribution of tazarotene-treated patients by tazarotenic acid plasma concentrations; adapted from Tang-Liu et al.4 Data shown for the distribution of tazarotenic acid plasma concentration (ng/mL) in 601 patients with psoriasis treated with tazarotene 0.05% and 0.1% gel once daily for up to one year. BLQ: below the limit of quantitation

FIGURE 3.

Maximum plasma concentrations^a from topical tazarotene, oral vitamin A, no treatment (endogenous levels) or oral isotretinoin.1,32,33,35,52 Tazarotenic acid is a metabolite of tazarotene; trans-retinoic acid is a metabolite of vitamin A. Oral isotretinoin was provided under fed conditions (high fat standardized meals). ^aData for endogenous and oral vitamin A were provided as “plasma concentrations” and did not specify mean maximum plasma concentrations.33 ^bStudy protocol dictated exaggerated and precise dosage condition.4 BSA: body surface area; NR: not reported

While topical retinoids provide low systemic exposure and have demonstrated a positive safety profile in acne and psoriasis clinical trials, topical or oral retinoid use during pregnancy is not recommended. Retinoid-associated malformations and developmental delays have been observed in the offspring of rats and rabbits given oral retinoids during pregnancy.1,2,5,32 There have also been reports of retinoid-associated abnormalities in humans. The oral retinoid isotretinoin was approved for the treatment of severe recalcitrant nodular acne in the US in 1982; in the years since approval, there have been confirmed reports of major congenital malformations, some leading to death, in children who were exposed in utero.35,36 Women taking isotretinoin are also at increased risk for spontaneous abortions and premature births. For tazarotene, oral and topical formulations have shown teratogenic effects in pregnant rats and rabbits treated with doses greater than the maximum recommended human dose,1 but as noted previously, the level of exposure that could lead to teratogenicity in humans is unknown.1,5

PREGNANCY OUTCOMES WITH TAZAROTENE

Data from FDA New Drug Applications, global surveillance, and FDA reporting indicate that there have been 76 reports of pregnancies in clinical trials and post-marketing surveillance of topical tazarotene, though it is unknown if any of these reports overlap and represent the same pregnancies (Table 3).1,37–39 Unfortunately, limited details regarding the outcomes were reported. Further, the extent and timing of drug exposure was unknown or not provided for most patients. Of the 76 pregnancies, the most common outcomes reported were unknown/lost to follow-up (n=31), healthy or caesarian delivery (n=21), spontaneous abortion (n=12), and termination/planned termination of pregnancy (n=8). Given the lack of information on timing and extent of exposure to tazarotene during pregnancy—as well as exposure to any other medicines during that time—the significance of the outcomes is unknown.1,5

TABLE 3.

Pregnancy reporting for topical tazarotene from clinical trials and global surveillance

DRUGS AND DATA SOURCES	NO. PREGNANCIES	NO. TAZAROTENE-TREATED	OUTCOMES AT TIME OF REPORTING
TAZAROTENE GEL/CREAM, FDA NDAs37–39
Global surveillance	7	7a	6 unknown
			1 terminationb
Clinical trials (cream)	9	7c	2 healthy/full term deliveries
			2 terminations
			1 currently pregnant
			1 planning termination
			1 lost to follow-up
Clinical trials (gel)	6	6	6 healthy/full term deliveries
Clinical trials (foam)	5	1	1 healthy, full term delivery
TAZAROTENE GEL
Clinical trials, US PI1	13	9	8 healthy deliveries
			1 terminationd
FAERS, 2001 to 2019 [data on file]e	46	46f	24 unknown
			12 spontaneous abortiong
			4 cesarean section deliveriesh
			3 terminations
			2 neonatal disordersi
			2 pre-eclampsiasj

Note: The extent and timing of drug exposure is unknown or not provided for most patients and the reports from the clinical trials might overlap.

^a All patients discontinued tazarotene use when pregnancy became known.

^b Fetus had trisomy 18; the extent of the relationship to tazarotene was unknown and the patient reported the use of etretinate 10 years prior.

^c Five patients discontinued tazarotene use when pregnancy became known; pregnancy became known at exit visit for two patients.

^d Noted as non-medical reasons/unrelated to treatment.

^e Summary reports available upon request from the FDA.

^f In 15 of these 46 pregnancies, one or more other prescription or over-the-counter drugs were reported in addition to tazarotene.

^g One was noted as anencephaly.

^h One premature labor, one prolonged labor and anemia, one breech presentation with neonatal disorder, nail discoloration, and onychomadesis.

ⁱ One patient was also reported under cesarean section deliveries.

^j One patient had a single umbilical artery.

FAERS: FDA Adverse Event Reporting System; FDA: Food and Drug Administration; NDA: new drug application; PI: prescribing information; US: United States

PREGNANCY OUTCOMES WITH RETINOID EXPOSURE

Limited pregnancy outcomes data have been published on topical tazarotene specifically, with most articles focusing on tretinoin or other retinoids. A large retrospective analysis using data from US healthcare claims databases from 2011–2015 examined 86,834 isotretinoin-exposed, 973,587 tretinoin-exposed, and 5,302,105 unexposed matched pregnancies.40 Risk of spontaneous abortions was similar across groups and rates of pregnancy terminations were higher in isotretinoin-exposed pregnancies (28%) than tretinoin-exposed (10%) or unexposed pregnancies (6%). Malformations occurred at similar rates between the tretinoin-exposed (4.5%) and unexposed pregnancies (4.2%); malformation rates in the isotretinoin group were too low to assess.

A meta-analysis of outcomes in pregnancies with first trimester retinoid exposure employed a search of multiple databases up to the year 2014.41 The meta-analysis included 590 infants born to 654 pregnant women who were exposed to a topical retinoid during pregnancy, as well as 1,278 infants born to 1,375 unexposed women (control group). No significant differences between the exposed versus unexposed groups were found for major congenital malformations (odds ratio [95% confidence interval]: 1.22 [0.65−2.29]), spontaneous abortions (1.02 [0.64−1.63]), stillbirths (2.06 [0.43−9.86]), elective terminations (1.89 [0.52–6.80]), low birthweight (1.01 [0.31–3.27])or prematurity (0.69 [0.39–1.23]).

CASE STUDIES OF IN UTERO RETINOID EXPOSURE

Presented in Table 4 are outcomes from six case studies of in utero topical tretinoin or adapalene exposure. All exposure occurred prior to conception as well as during the first trimester. There were three live births and one termination. It is unclear to what extent, if any, retinoid exposure affected fetal development in these cases.

TABLE 4.

Outcomes from case studies of in uteroretinoid exposure

DRUG (STUDY)	IN UTERO EXPOSURE	GESTATIONAL AGE (WK)	BIRTH WEIGHT (G)	OUTCOMES
Tretinoin 0.025% (Selcen 2000)46	Prior to conception and first 2–3 months	41	4,090	Absence of the right ear and external auditory canal. Brain scans indicated right posterior hemisphere cerebral calcification, right parietooccipital lobe encephalomalacia, and a basal ganglia infarct.
Tretinoin 0.05% (Camera 1992)47	1 month prior to conception and first 11 weeks	41	2,620	Crumpled hypoplastic ear and external auditory meatus atresia on the right side.
Tretinoin 0.05% (Lipson 1993)48	Prior to conception and first 5 weeks	NR	NR	Supraumbilical exomphalos, an anterior diaphragmatic hernia, an inferior pericardial defect, dextroposition of the heart, a right-side upper limb reduction defect, and a mildly hypoplastic hand with a small thumb and fifth digit.
Adapalene 0.1% (Autret 1997)49	1 month prior to conception and first 13 weeks	NA	NA	Optic chiasm anophthalmia and agenesis was discovered at 22 weeks. Pregnancy was terminated.
Tretinoin 0.05% (Navarre-Belhassen 1998)50	Prior to conception and first 8 weeksa	40	2,800	Hand and heart malformations detected at 5 months gestation. Infant born with coarctation of the aorta, hypoplastic left hand, hypertelorism, and small ear canals.
Tretinoin 0.05% (Colley 1998)51	Throughout pregnancy	NR (born at term)	NR	Severe craniofacial and central nervous malformations, consistent with deranged cranial neural crest cell migration.

^a The mother was also using topical benzoyl peroxide 2.5% for facial acne during the same time period.

NA: not applicable; NR: not reported

CONCLUSION

As acne is a very common disease in women of child-bearing age and topical retinoids are a typical treatment, it is possible that some of these women will be exposed to a topical retinoid during pregnancy. Pharmacokinetic studies show relatively low systemic exposure from topical tazarotene, similar to that of endogenous retinoids. While there are case reports of topical tretinoin and adapalene exposure in utero, it is unclear if either affected fetal development. In terms of topical tazarotene, there is little published data on pregnancy outcomes in patients exposed to topical tazarotene. Additional case reports and outcomes studies are needed to further explore the safety of topical tazarotene in pregnancy.

ACKNOWLEDEMENTS

Medical writing support was provided by Lynn M. Anderson, PhD, and Jaqueline Benjamin, PhD, of Prescott Medical Communications Group (Chicago, Ilinois) with financial support from Ortho Dermatologics. Ortho Dermatologics is a division of Bausch Health US, LLC.