ALTRENO- tretinoin lotion

Baus ch Health US, LLC

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HIGHLIGHT S OF PRESCRIBING INFORMAT ION

T hese hig hlig hts do no t include all the info rmatio n needed to use ALT RENO safely and effectively. See full
prescribing info rmatio n fo r ALT RENO.
ALT RENO ® (tretino in) lo tio n, fo r to pical use
Initial U.S. Appro val: 19 73
INDICAT IONS AND USAGE
ALTRENO is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. (1)
DOSAGE AND ADMINIST RAT ION

• Apply a thin layer of ALTRENO to affected areas once daily. Avoid eyes, mouth, paranasal creases, and mucous
membranes. (2)
• Not for ophthalmic, oral, or intravaginal use. (2)

DOSAGE FORMS AND ST RENGT HS

Lotion, 0.05% (3)
Each gram of ALTRENO contains 0.5 mg (0.05%) tretinoin. (3)
CONT RAINDICAT IONS
None. (4)
WARNINGS AND PRECAUT IONS

• Skin Irritation: Dryness, pain, erythema, irritation and exfoliation may occur with use of ALTRENO. (5.1)
• Ultraviolet Light and Environmental Exposure: Minimize exposure to sunlight and sunlamps. Use sunscreen and
protective clothing when sun exposure cannot be avoided. (5.2)
• Fish Allergies: Use ALTRENO with caution if allergic to fish due to potential for allergenicity to fish protein. Advise
patients to contact their healthcare provider if they develop pruritus or urticaria. (5.3)

ADVERSE REACT IONS

• The most common adverse reactions occurring in ≥1% of subjects and greater than vehicle were dryness, pain,
erythema, irritation and exfoliation (all at the application site). (6.1)

T o repo rt SUSPECT ED ADVERSE REACT IONS, co ntact Bausch Health US, LLC at 1-8 0 0 -321-4 576 o r FDA at 1-
8 0 0 -FDA-10 8 8 o r www.fda.g o v/medwatch.
See 17 fo r PAT IENT COUNSELING INFORMAT ION and FDA-appro ved patient labeling .
Revised: 3/20 20

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Skin Irritation
5.2 Ultraviolet Light and Environmental Exposure
5.3 Fish Allergies
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
 8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ALTRENO ® (tretinoin) lotion, 0.05% is indicated for the topical treatment of acne vulgaris in patients 9
years of age and older.

2 DOSAGE AND ADMINISTRATION

Apply a thin layer of ALTRENO to the affected areas once daily. Avoid the eyes, mouth, paranasal
creases, and mucous membranes.
ALTRENO is for topical use only. Not for ophthalmic, oral, or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

Lotion, 0.05%
Each gram of ALTRENO contains 0.5 mg (0.05%) tretinoin in an opaque, pale yellow topical lotion.

4 CONTRAINDICATIONS
None.

5 WARNINGS AND PRECAUTIONS

5.1 Skin Irritation

Patients using ALTRENO may experience application site dryness, pain, erythema, irritation, and
exfoliation. Depending upon the severity of these adverse reactions, instruct patients to use a
moisturizer, reduce the frequency of the application of ALTRENO, or discontinue use. Avoid
application of ALTRENO to eczematous or sunburned skin.

5.2 Ultraviolet Light and Environmental Expos ure

Minimize unprotected exposure to ultraviolet light including sunlight and sunlamps during the use of
ALTRENO. Warn patients who normally experience high levels of sun exposure and those with
inherent sensitivity to sun to exercise caution. Use sunscreen products and protective clothing over
treated areas when sun exposure cannot be avoided.

5.3 Fis h Allergies

ALTRENO contains soluble fish proteins. Use with caution in patients with known sensitivity or allergy
to fish. Advise patients to contact their healthcare provider if they develop pruritus or urticaria.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.
In 2 randomized, double-blind, vehicle-controlled trials, subjects age 9 years and older applied
ALTRENO or vehicle once daily for 12 weeks. The majority of subjects were White (74%) and female
(55%). Approximately 47% were Hispanic/Latino and 45% were younger than 18 years of age. Adverse
reactions reported by ≥1% of subjects treated with ALTRENO and more frequently than vehicle are
summarized in Table 1.

Table 1: Advers e Reactions Reported by ≥1% of Subjects Treated with ALTRENO and More
Frequently than Vehicle
Advers e Reactions
n (%)
ALTRENO Vehicle
N=767 N=783
Application site dryness 29 (4) 1 (<1)
Application site pain* 25 (3) 3 (<1)
Application site erythema 12 (2) 1 (<1)
Application site irritation 7 (1) 1 (<1)

3 (<1)
Application site exfoliation 6 (1)
* Application site pain defined as application site stinging, burning or pain.

Skin irritation was evaluated by active assessment of erythema, scaling, hypopigmentation,

hyperpigmentation, itching, burning and stinging. The percentage of subjects who were assessed to
have these signs and symptoms at any post baseline visit are summarized in Table 2.

Table 2: Application Site Tolerability Reactions at Any Pos t Bas eline Vis it
ALTRENO Vehicle
N=760 N=782
Mild/Mod/Severe Mild/Mod/Severe
Erythema 51% 44%
Scaling 49% 30%
Hypopigmentation 12% 10%
Hyperpigmentation 35% 35%
Itching 35% 28%
Burning 30% 14%
Stinging 21% 8%
8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
Available data from published observational studies of topical tretinoin in pregnant women have not
established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal
outcomes. There are no data on ALTRENO use in pregnant women.
The systemic levels following topical administration are lower than with administration of oral
tretinoin; however, absorption of this product may result in fetal exposure. There are reports of major
birth defects similar to those seen in infants exposed to oral retinoids, but these case reports do not
establish a pattern or association with tretinoin-related embryopathy (see Data).
Animal reproduction studies have not been conducted with ALTRENO. Topical administration of
tretinoin in a different formulation to pregnant rats during organogenesis was associated with
malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in
ossification, and increased supernumerary ribs) at doses up to 0.5 mg tretinoin/kg/day, approximately 2
times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison
and assuming 100% absorption. Oral administration of tretinoin to pregnant cynomolgus monkeys during
organogenesis was associated with malformations at 10 mg/kg/day (approximately 100 times the MRHD
based on BSA comparison and assuming 100% absorption) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse
outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% and of
miscarriage is 15 to 20% of clinically recognized pregnancies.
Data
Human Data
While available studies cannot definitively establish the absence of risk, published data from multiple
prospective controlled observational studies on the use of topical tretinoin products during pregnancy
have not identified an association with topical tretinoin and major birth defects or miscarriage. The
available studies have methodologic limitations, including small sample size and in some cases, lack of
physical exam by an expert in birth defects. There are published case reports of infants exposed to
topical tretinoin during the first trimester that describe major birth defects similar to those seen in
infants exposed to oral retinoids; however, no pattern of malformations has been identified and no causal
association has been established in these cases. The significance of these spontaneous reports in terms
of risk to the fetus is not known.
Animal Data
Tretinoin in a 0.05% gel formulation was topically administered to pregnant rats during organogenesis
at doses of 0.1, 0.3 and 1 g/kg/day (0.05, 0.15, 0.5 mg tretinoin/kg/day). Possible tretinoin malformations
(craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and
increased supernumerary ribs) were observed at maternal doses of 0.5 mg tretinoin/kg/day
(approximately 2 times the MRHD based on BSA comparison and assuming 100% absorption). These
findings were not observed in control animals. Other maternal and reproductive parameters in tretinoin-
treated animals were not different from control. For purposes of comparison of the animal exposure to
human exposure, the MRHD is defined as 4 g of ALTRENO applied daily to a 60 kg person.
Other topical tretinoin embryofetal development studies have generated equivocal results. There is
evidence for malformations (shortened or kinked tail) after topical administration of tretinoin to pregnant
Wistar rats during organogenesis at doses greater than 1 mg/kg/day (approximately 5 times the MRHD
based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%,
os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 50
times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to
pregnant rats during organogenesis. Supernumerary ribs have been a consistent finding in rat fetuses
when pregnant rats were treated topically or orally with retinoids.
Oral administration of tretinoin during organogenesis has been shown to induce malformations in rats,
mice, rabbits, hamsters, and nonhuman primates. Fetal malformations were observed when tretinoin was
orally administered to pregnant Wistar rats during organogenesis at doses greater than 1 mg/kg/day
(approximately 5 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal
malformations were reported when an oral dose of 10 mg/kg/day was administered to pregnant monkeys
during organogenesis (approximately 100 times the MRHD based on BSA comparison). No fetal
malformations were observed at an oral dose of 5 mg/kg/day (approximately 50 times the MRHD based
on BSA comparison). Increased skeletal variations were observed at all doses in this study and dose-
related increases in embryo lethality and abortion were reported in this study. Similar results have also
been reported in pigtail macaques.
Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 10 times the MRHD
based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when
administered at doses 4 times the MRHD based on BSA comparison.

8.2 Lactation
Risk Summary
There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the
breastfed infant, or the effects on milk production. It is not known whether topical administration of
tretinoin could result in sufficient systemic absorption to produce detectable concentrations in human
milk. The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for ALTRENO and any potential adverse effects on the breastfed child from
ALTRENO.

8.4 Pediatric Us e
Safety and effectiveness of ALTRENO for the topical treatment of acne vulgaris have been established
in pediatric patients age 9 years to less than 17 years based on evidence from two multicenter,
randomized, double-blind, parallel-group, vehicle-controlled, 12-week trials and an open-label
pharmacokinetic study. A total of 318 pediatric subjects aged 9 to less than 17 years received
ALTRENO in the clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
The safety and effectiveness of ALTRENO in pediatric patients below the age of 9 years have not been
established.

8.5 Geriatric Us e
Clinical trials of ALTRENO did not include any subjects age 65 years and older to determine whether
they respond differently from younger subjects.

11 DESCRIPTION
ALTRENO (tretinoin) lotion is an opaque, pale yellow lotion containing 0.05% tretinoin by weight for
topical administration.
Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-
cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds and a
metabolite of vitamin A. Tretinoin has the following chemical structure:
Molecular Formula: C20 H 28 O 2 Molecular Weight: 300.44
Each gram of ALTRENO contains 0.5 mg (0.05%) of tretinoin in an opaque, pale yellow lotion base
consisting of benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen TR-1),
carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-9,
purified water, sodium hyaluronate, soluble collagen and trolamine.

12 CLINICAL PHARMACOLOGY

12.1 Mechanis m of Action

Tretinoin is a metabolite of vitamin A that binds with high affinity to specific retinoic acid receptors
located in both the cytosol and nucleus.
Tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and
RARγ) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth
and differentiation. It has not been established whether the clinical effects of tretinoin are mediated
through activation of retinoic acid receptors, other mechanisms, or both.
Although the exact mode of action of tretinoin in acne treatment is unknown, current evidence suggests
that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo
formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular
epithelial cells causing extrusion of the comedones.

12.2 Pharmacodynamics
The pharmacodynamics of ALTRENO in the treatment of acne vulgaris are unknown.

12.3 Pharmacokinetics
Plasma concentrations of tretinoin and its major metabolites (isotretinoin and 4-oxo-isotretinoin) were
evaluated in 20 subjects in an open-label, randomized, pharmacokinetic study. Subjects aged 10 years to
less than 17 years old with acne vulgaris applied approximately 3.5 g of ALTRENO to the skin of the
entire face (excluding eyes and lips), neck, upper chest, upper back and shoulders once daily for 14
days. Single-dose pharmacokinetic (PK) characteristics were determined from samples drawn on Days 1
and 2 of dosing and steady-state PK characteristics were determined from samples drawn on Days 14
and 15 under maximal use conditions. The mean baseline corrected Cmax and AUC0-t of tretinoin and its
metabolites after once daily application of ALTRENO for 14 days are shown below:

Mean (±SD) C max Mean (±SD) AUC 0 -t

Compound
(ng/mL) (ng*h/mL)
Tretinoin 0.33 (0.33) 6.46 (5.15)
 Isotretinoin 0.49 (0.66) 9.30 (9.95)
4-oxo-isotretinoin 0.57 (0.82) 14.51 (18.28)

The mean concentrations of tretinoin and its metabolites (isotretinoin and 4 oxo isotretinoin) remain
relatively stable and unchanged over the 24 hour period after both the Day 1 dose and the Day 14 dose.
Systemic concentrations of tretinoin appear to be at or near steady state by Day 14. Mean accumulation
ratios of the baseline corrected AUC between Day 14 and Day 1 were 1.5, 4.5 and 7.3 for tretinoin,
isotretinoin, and 4-oxo-isotretinoin, respectively.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility

A 2-year dermal mouse carcinogenicity study was conducted with topical administration of 0.005%,
0.025% and 0.05% of a tretinoin gel formulation. Although no drug-related tumors were observed in
surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data
interpretation and reducing the biological significance of these results.
Studies in hairless albino mice with a different formulation suggest that concurrent exposure to tretinoin
may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar
simulator. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not
overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of
these studies to humans is not clear, patients should minimize exposure to sunlight or artificial
ultraviolet irradiation sources.
The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro
chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests
were negative.
In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant)
decreases in sperm count and motility were seen at 0.5 mg/kg/day (approximately 2 times the MRHD
based on BSA comparison and assuming 100% absorption), and slight (not statistically significant)
increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and
above (approximately the MRHD based on BSA comparison and assuming 100% absorption) were
observed.

14 CLINICAL STUDIES
The safety and efficacy of once daily use of ALTRENO for the treatment of acne vulgaris were
assessed in two multicenter, randomized, double-blind clinical trials enrolling 1640 subjects age 9
years and older with acne vulgaris. Enrolled subjects had a score of moderate (3) or severe (4) on the
Evaluator’s Global Severity Score (EGSS), 20 to 40 inflammatory lesions (papules, pustules, and
nodules), 20 to 100 non-inflammatory lesions (open and closed comedones) and two or fewer facial
nodules. The coprimary efficacy endpoints of success on the EGSS, absolute change in
noninflammatory lesion count, and absolute change in inflammatory lesion count were assessed at Week
12. Success on the EGSS was defined as at least a 2-grade improvement from Baseline and an EGSS
score of clear (0) or almost clear (1). Table 3 lists the efficacy results for trials 1 (NCT02491060) and
2 (NCT02535871).

Table 3: Efficacy Res ults at Week 12

Trial 1 ALTRENO Vehicle
N=406 N=414
EGSS
Clear or Almost Clear and 16.5% 6.9%
2-Grade Reduction from
Baseline
Non-Inflammatory Facial
Les ions
Mean Absolute Reduction 17.8 10.6
Mean Percent Reduction 47.5% 27.3%
Inflammatory Facial Les ions
Mean Absolute Reduction 13.1 10.2
Mean Percent Reduction 50.9% 40.4%
Trial 2 ALTRENO Vehicle
N=413 N=407
EGSS
Clear or Almost Clear and 19.8% 12.5%
2-Grade Reduction from
Baseline
Non-Inflammatory Facial
Les ions
Mean Absolute Reduction 21.9 13.9
Mean Percent Reduction 45.6% 31.9%
Inflammatory Facial Les ions
Mean Absolute Reduction 13.9 10.7
Mean Percent Reduction 53.4% 41.5%

16 HOW SUPPLIED/STORAGE AND HANDLING

ALTRENO (tretinoin) lotion, 0.05% is an opaque, pale yellow topical lotion and available as:

• 45 g tube (NDC 0187-0005-45)

• 20 g tube (NDC 0187-0005-20)
• 50 g pump (NDC 0187-0005-50)

Storage and Handling Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. Protect from freezing.
Store pump upright.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Warn patients of the potential for skin irritation during treatment.

• Advise patients to minimize exposure to sunlight and sunlamps; recommend the use of sunscreen
products and protective apparel (e.g., hat) when sun exposure cannot be avoided.

Dis tributed by:

Bausch Health US, LLC
Bridgewater, NJ 08807 USA
Manufactured by:
Bausch Health Companies Inc.
Laval, Quebec H7L 4A8, Canada

ALTRENO is a trademark of Bausch Health Companies Inc. or its affiliates.

© 2020 Bausch Health Companies Inc. or its affiliates
9650303

Patient Package Ins ert

PATIENT INFORMATION
ALTRENO ® (al-TREN-oh)
(tretinoin) lotion, 0.05%
for topical use
Important information: ALTRENO is for use on skin only. Do not use ALTRENO in your eyes,
mouth, the corners of your nose, or vagina.
What is ALTRENO?
ALTRENO is a prescription medicine used on the skin (topical) to treat people with acne. Acne is a
condition in which the skin has blackheads, whiteheads, and other pimples.
It is not known if ALTRENO is safe and effective in children under 9 years of age.
Before us ing ALTRENO, tell your healthcare provider about all your medical conditions ,
including if you:

• are allergic to fish. ALTRENO contains fish proteins. Tell your healthcare provider if you get
hives or itching while using ALTRENO.
• have eczema or any other skin problems.
• have a sunburn.
• are pregnant or plan to become pregnant. It is not known if ALTRENO will harm your unborn
baby.
• are breastfeeding or plan to breastfeed. It is not known if ALTRENO passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them
to show your healthcare provider and pharmacist when you get a new medicine.
How s hould I us e ALTRENO?

• Use ALTRENO exactly as your healthcare provider tells you to use it.
• Apply a thin layer of ALTRENO to cover the affected areas 1 time each day.

Applying ALTRENO:

• ALTRENO comes in a tube and a pump. If you have been prescribed the:

Tube: Squeeze the lotion from the tube onto a fingertip. Apply a thin layer to cover the affected areas,
as prescribed by your doctor. Spread ALTRENO evenly over the affected areas.
Pump: Fully depress the pump to dispense ALTRENO onto a fingertip. Apply a thin layer to cover the
affected areas, as prescribed by your doctor. Spread ALTRENO evenly over the affected areas.

• Wash your hands after applying ALTRENO.

What s hould I avoid while us ing ALTRENO?

• You should avoid sunlamps, tanning beds, and ultraviolet light during treatment with ALTRENO.
• Minimize exposure to sunlight.
• If you have to be in the sunlight or are sensitive to sunlight, use a sunscreen with an SPF (sun
protection factor) of 15 or more and wear protective clothing and a wide-brimmed hat to cover the
treated areas.

What are the pos s ible s ide effects of ALTRENO?

ALTRENO may caus e s erious s ide effects , including:
Skin irritation. ALTRENO may cause irritation including skin dryness, pain, redness, excessive flaking
or peeling. If you develop these symptoms, your healthcare provider may tell you to use a moisturizer,
decrease the number of times you apply ALTRENO, or completely stop treatment with ALTRENO.
Avoid applying ALTRENO to skin that is affected by eczema or sunburned skin.
These are not all the possible side effects of ALTRENO.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088.
How s hould I s tore ALTRENO?

• Store ALTRENO at room temperature between 68° to 77°F (20° to 25°C).

• Do not freeze.
• Store ALTRENO pump upright.

Keep ALTRENO and all medicines out of the reach of children.

General information about the s afe and effective us e of ALTRENO
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
Do not use ALTRENO for a condition for which it was not prescribed. Do not give ALTRENO to
other people, even if they have the same symptoms that you have. It may harm them. You can ask your
pharmacist or healthcare provider for information about ALTRENO that is written for health
professionals.
What are the ingredients in ALTRENO?
Active ingredient: tretinoin
Inactive ingredients : benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen
TR-1), carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-
9, purified water, sodium hyaluronate, soluble collagen and trolamine.
Dis tributed by:
Bausch Health US, LLC, Bridgewater, NJ 08807 USA
Manufactured by:
Bausch Health Companies Inc., Laval, Quebec H7L 4A8, Canada
For more information, call 1-800-321-4576.
ALTRENO is a trademark of Bausch Health Companies Inc. or its affiliates.
© 2020 Bausch Health Companies Inc. or its affiliates
This Patient Information has been approved by the U.S. Food and Drug Administration.
9650303
Revised: 03/2020