DIVIGEL

RECENT MAJOR CHANGES Warnings and Precautions, Malignant Neoplasms (5.2)11/2023 Boxed Warning, Cardiovascular Disorders, Breast Cancer, Probable Dementia removed 2/2026 Dosage and Administration, Important Use Information ( 2.1 ) 2/2026 Contraindications ( 4 ) 2/2026 Warnings and Precautions, Cardiovascular Disorders ( 5.1 ) 2/2026 Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 2/2026 Warnings and Precautions, Risks Associated with Co-administration of Estrogen Plus Progesterone ( 5.3 ) 2/2026 Warnings and Precautions, Probable Dementia removed 2/2026 Warnings and Precautions, Addition of a Progestogen When a Woman Has Not Had a Hysterectomy removed 2/2026

1 INDICATIONS AND USAGE Divigel is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ). 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

2 DOSAGE AND ADMINISTRATION Daily administration of 0.25 to 1.25 grams of Divigel to the right or left upper thigh on alternating days. Women should be started with the lowest effective dose and the dose should be evaluated periodically ( 2 ). 2.1 Important Use Information The timing of Divigel initiation can affect the overall benefit-risk profile. Consider initiating Divigel in women <60 years old or <10 years since menopause onset [see Warnings and Precautions ( 5 ), Use in Specific Populations ( 8.5 ) and Clinical Studies ( 14 )]. When estrogen is prescribed for a menopausal woman with a uterus, the addition of a progestogen has been shown to reduce the risk of endometrial cancer. There are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. See prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized menopausal women receiving estrogens [see Warnings and Precautions ( 5.2 , 5.3 )] . Generally, a woman without a uterus, does not need to use a progestogen with estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may benefit from the addition of a progestogen [see Warnings and Precautions ( 5.13 )]. 2.2 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with the 0.25 grams applied once daily on the skin of either the right or left upper thigh. Adjust the dose up to a maximum of 1.25 grams, as needed. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, apply Divigel to the right or left upper thigh on alternating days. Do not apply Divigel on the face, breasts, or irritated skin or in or around the vagina. Allow gel to dry after application before dressing. Do not wash the application site within 1 hour after applying Divigel. Avoid contact of the gel with eyes. Wash hands after application.

3 DOSAGE FORMS AND STRENGTHS Divigel is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). Divigel is a clear, colorless gel, which is odorless when dry. Gel: 0.25, 0.5, 0.75, 1.0, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively ( 3 )

4 CONTRAINDICATIONS Divigel is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology [see Warning and Precautions ( 5.2 )] Current or history of breast cancer [see Warning and Precautions ( 5.2 )] Estrogen-dependent neoplasia [see Warning and Precautions ( 5.2 )] Active DVT, PE, or history of these conditions [see Warning and Precautions ( 5.1 )] Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warning and Precautions ( 5.1 )] Known anaphylactic reaction, angioedema, or hypersensitivity to Divigel Hepatic impairment or disease [see Warnings and Precautions ( 5.9 )] Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding ( 4 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to Divigel ( 4 ) Hepatic impairment or disease ( 4 , 5.9 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2 )] . The most common adverse reactions (incidence >5 percent and greater than placebo) in any Divigel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact VERTICAL PHARMACEUTICALS, LLC at 1-800-541-4802 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 practice. Divigel was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1. In a 12-week placebo-controlled study of Divigel, application site reactions were seen in <1 percent of participating women. DivigelTable1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Divigel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge Breasts Gynecomastia Cardiovascular Palpitations, ventricular extrasystoles Gastrointestinal Flatulence Skin Rash pruritic, urticaria Eyes Retinal vein occlusion Central Nervous System Tremor Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased

7 DRUG INTERACTIONS In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in adverse reactions. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration ( 7 ).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Divigel is not indicated for use in pregnant women. There are no data with the use of Divigel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well ­established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Divigel and any potential adverse effects on the breastfed child from Divigel or from the underlying maternal condition. 8.4 Pediatric Use Divigel is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Divigel to determine whether those over 65 years of age differ from younger subjects in their response to Divigel. The Women's Health Initiative Studies In the WHI estrogen-alone trial (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.2 )] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of probable dementia in women receiving estrogen-alone [see Clinical Studies ( 14.3 )] . Since the trial was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Clinical Studies ( 14.3 )]. The safety and efficacy of Divigel for the prevention of dementia has not been established.

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

11 DESCRIPTION Divigel (estradiol gel) 0.1 percent, is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm 2 ) of the thigh in a thin layer. Divigel is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). The active component of the topical gel is estradiol, an estrogen. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17ß-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: Divigel Chemical Structure The remaining components of the gel (carbomer, ethanol, propylene glycol, purified water, and triethanolamine) are pharmacologically inactive. Divigel contains 56% alcohol. Divigel Chemical Structure

10 OVERDOSAGE Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Divigel therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Divigel (estradiol gel) 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively. NDC 68025-065-30, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 68025-066-30, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 68025-083-30, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet NDC 68025-067-30, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet NDC 68025-086-30, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet Keep out of the reach of children. 16.2 Storage and Handling 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.]