Save up to 80% by drug discount in your pharmacy with "Pharmacy Near Me - National Drug Discount Card"
You can scan QR Code(just open camera on your phone/scan by application) from the image on prescription drug discount card to save it to your mobile phone. Or just click on image if you're on mobile phone.
| Product NDC Code | 68968-6650 | ||||
|---|---|---|---|---|---|
| Drug Name | Minivelle |
||||
| Type | Brand | ||||
| Pharm Class | Estradiol Congeners [CS], Estrogen Receptor Agonists [MoA], Estrogen [EPC] |
||||
| Active Ingredients |
|
||||
| Route | TRANSDERMAL | ||||
| Dosage Form | FILM, EXTENDED RELEASE | ||||
| RxCUI drug identifier | 241946, 242891, 242892, 248478, 1149632, 1356979, 1356997, 1357007, 1357009, 1551622 |
||||
| Application Number | NDA203752 | ||||
| Labeler Name | Noven Therapeutics, LLC | ||||
| Packages |
|
||||
| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Minivelle
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of MINIVELLE therapy with institution of appropriate symptomatic care.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warning , Warning and Precaution, ( 5.1 )] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions ( 5.2 )] The most common adverse reactions (greater than or equal to 5 percent) with MINIVELLE are: headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1-800-455-8070 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. There were no clinical trials conducted with MINIVELLE. MINIVELLE is bioequivalent to Vivelle ® . The following adverse reactions are reported with Vivelle therapy: Table 1: Summary of Most Frequently Reported Adverse Reactions (Vivelle versus Placebo) Regardless of Relationship Reported at a Frequency ≥5 Percent † Represents milligrams of estradiol delivered daily by each system * NOS represents not otherwise specified ** NEC represents not elsewhere classified *** Application site erythema and application site irritation were observed in 3.2% or less of patients across treatment groups. Vivelle 0.025 mg/day † (N=47) N (%) Vivelle 0.0375 mg/day † (N=130) N (%) Vivelle 0.05 mg/day † (N=103) N (%) Vivelle 0.075 mg/day † (N=46) N (%) Vivelle 0.1 mg/day † (N=132) 2 N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 (4.3) 5 (3.8) 4 (3.9) 3 (6.5) 2 (1.5) 4 (2.5) Dyspepsia 4 (8.5) 12 (9.2) 3 (2.9) 2 (4.3) 0 10 (6.4) Nausea 2 (4.3) 8 (6.2) 4 (3.9) 0 7 (5.3) 5 (3.2) General disorders and administration site conditions *** Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS* 0 8 (6.2) 0 2 (4.3) 7 (5.3) 7 (4.5) Infections and infestations Influenza 4 (8.5) 4 (3.1) 6 (5.8) 0 10 (7.6) 14 (8.9) Nasopharyngitis 3 (6.4) 16 (12.3) 10 (9.7) 9 (19.6) 11 (8.3) 24 (15.3) Sinusitis NOS* 4 (8.5) 17 (13.1) 13 (12.6) 3 (6.5) 7 (5.3) 16 (10.2) Upper respiratory tract infection NOS* 3 (6.4) 8 (6.2) 11 (10.7) 4 (8.7) 6 (4.5) 9 (5.7) Investigations Weight increased 4 (8.5) 5 (3.8) 2 (1.9) 2 (4.3) 0 3 (1.9) Musculoskeletal and connective tissue disorders Arthralgia 0 11 (8.5) 4 (3.9) 2 (4.3) 5 (3.8) 9 (5.7) Back pain 4 (8.5) 10 (7.7) 9 (8.7) 4 (8.7) 14 (10.6) 10 (6.4) Neck pain 3 (6.4) 4 (3.1) 4 (3.9) 0 6 (4.5) 2 (1.3) Pain in limb 0 10 (7.7) 7 (6.8) 2 (4.3) 6 (4.5) 9 (5.7) Nervous system disorders Headache NOS* 7 (14.9) 35 (26.9) 32 (31.1) 23 (50.0) 34 (25.8) 37 (23.6) Sinus headache 0 12 (9.2) 5 (4.9) 5 (10.9) 2 (1.5) 8 (5.1) Psychiatric disorders Anxiety NEC ** 3 (6.4) 5 (3.8) 0 0 2 (1.5) 4 (2.5) Depression 5 (10.6) 4 (3.1) 7 (6.8) 0 4 (3.0) 6 (3.8) Insomnia 3 (6.4) 6 (4.6) 4 (3.9) 2 (4.3) 2 (1.5) 9 (5.7) Reproductive system and breast disorders Breast tenderness 8 (17.0) 10 (7.7) 8 (7.8) 3 (6.5) 17 (12.9) 0 Dysmenorrhea 0 0 0 3 (6.5) 0 0 Intermenstrual bleeding 3 (6.4) 9 (6.9) 6 (5.8) 0 14 (10.6) 7 (4.5) Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS* 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS* 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) During the clinical pharmacology studies with MINIVELLE, 35 percent or less of subjects experienced barely perceptible erythema. No transdermal systems were removed due to irritation. Three subjects (2.2 percent) reported mild discomfort while wearing MINIVELLE (N=136). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MINIVELLE. 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. Breast Breast enlargement Cardiovascular Palpitations, angina unstable Gastrointestinal Hemorrhage, diarrhea Skin Application site reactions, erythema, rash, hyperhidrosis, pruritis, urticaria Central Nervous System Dizziness, paresthesia, migraine, mood swings, emotional disorder, irritability, nervousness Miscellaneous Portal vein thrombosis, dyspnea, malaise, fatigue, peripheral edema, muscle spasms, paresthesia oral, swollen tongue, lip swelling, pharyngeal edema
| † Represents milligrams of estradiol delivered daily by each system | ||||||
| *NOS represents not otherwise specified | ||||||
| **NEC represents not elsewhere classified | ||||||
| ***Application site erythema and application site irritation were observed in 3.2% or less of patients across treatment groups. | ||||||
| Vivelle 0.025 mg/day † (N=47) N (%) | Vivelle 0.0375 mg/day † (N=130) N (%) | Vivelle 0.05 mg/day † (N=103) N (%) | Vivelle 0.075 mg/day † (N=46) N (%) | Vivelle 0.1 mg/day † (N=132) 2 N (%) | Placebo (N=157) N (%) | |
| Gastrointestinal disorders | ||||||
| Constipation | 2 (4.3) | 5 (3.8) | 4 (3.9) | 3 (6.5) | 2 (1.5) | 4 (2.5) |
| Dyspepsia | 4 (8.5) | 12 (9.2) | 3 (2.9) | 2 (4.3) | 0 | 10 (6.4) |
| Nausea | 2 (4.3) | 8 (6.2) | 4 (3.9) | 0 | 7 (5.3) | 5 (3.2) |
| General disorders and administration site conditions *** | ||||||
| Influenza-like illness | 3 (6.4) | 6 (4.6) | 8 (7.8) | 0 | 3 (2.3) | 10 (6.4) |
| Pain NOS* | 0 | 8 (6.2) | 0 | 2 (4.3) | 7 (5.3) | 7 (4.5) |
| Infections and infestations | ||||||
| Influenza | 4 (8.5) | 4 (3.1) | 6 (5.8) | 0 | 10 (7.6) | 14 (8.9) |
| Nasopharyngitis | 3 (6.4) | 16 (12.3) | 10 (9.7) | 9 (19.6) | 11 (8.3) | 24 (15.3) |
| Sinusitis NOS* | 4 (8.5) | 17 (13.1) | 13 (12.6) | 3 (6.5) | 7 (5.3) | 16 (10.2) |
| Upper respiratory tract infection NOS* | 3 (6.4) | 8 (6.2) | 11 (10.7) | 4 (8.7) | 6 (4.5) | 9 (5.7) |
| Investigations | ||||||
| Weight increased | 4 (8.5) | 5 (3.8) | 2 (1.9) | 2 (4.3) | 0 | 3 (1.9) |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0 | 11 (8.5) | 4 (3.9) | 2 (4.3) | 5 (3.8) | 9 (5.7) |
| Back pain | 4 (8.5) | 10 (7.7) | 9 (8.7) | 4 (8.7) | 14 (10.6) | 10 (6.4) |
| Neck pain | 3 (6.4) | 4 (3.1) | 4 (3.9) | 0 | 6 (4.5) | 2 (1.3) |
| Pain in limb | 0 | 10 (7.7) | 7 (6.8) | 2 (4.3) | 6 (4.5) | 9 (5.7) |
| Nervous system disorders | ||||||
| Headache NOS* | 7 (14.9) | 35 (26.9) | 32 (31.1) | 23 (50.0) | 34 (25.8) | 37 (23.6) |
| Sinus headache | 0 | 12 (9.2) | 5 (4.9) | 5 (10.9) | 2 (1.5) | 8 (5.1) |
| Psychiatric disorders | ||||||
| Anxiety NEC ** | 3 (6.4) | 5 (3.8) | 0 | 0 | 2 (1.5) | 4 (2.5) |
| Depression | 5 (10.6) | 4 (3.1) | 7 (6.8) | 0 | 4 (3.0) | 6 (3.8) |
| Insomnia | 3 (6.4) | 6 (4.6) | 4 (3.9) | 2 (4.3) | 2 (1.5) | 9 (5.7) |
| Reproductive system and breast disorders | ||||||
| Breast tenderness | 8 (17.0) | 10 (7.7) | 8 (7.8) | 3 (6.5) | 17 (12.9) | 0 |
| Dysmenorrhea | 0 | 0 | 0 | 3 (6.5) | 0 | 0 |
| Intermenstrual bleeding | 3 (6.4) | 9 (6.9) | 6 (5.8) | 0 | 14 (10.6) | 7 (4.5) |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Sinus congestion | 0 | 4 (3.1) | 3 (2.9) | 3 (6.5) | 6 (4.5) | 7 (4.5) |
| Vascular disorders | ||||||
| Hot flushes NOS* | 3 (6.4) | 0 | 3 (2.9) | 0 | 0 | 6 (3.8) |
| Hypertension NOS* | 2 (4.3) | 0 | 3 (2.9) | 0 | 0 | 2 (1.3) |
Minivelle Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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 may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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, 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated concentrations of these hormones seen in postmenopausal women. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to MINIVELLE nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid. 12.3 Pharmacokinetics Absorption In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, MINIVELLE (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC 0-84 ) and estradiol peak concentration (C max ) following a single-dose on the lower abdomen for 84 hours. Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years). MINIVELLE transdermal systems delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2 . AUC and C max are dose proportional from 0.025 mg to 0.1 mg per day. Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of MINIVELLE (N=36) a Median (minimum-maximum) Parameter 0.1 mg/day 0.05 mg/day 0.025 mg/day AUC 84 (pg·hr/mL) 5875 (1857) 3057 (980) 1763 (600) AUC 120 (pg·hr/mL) 6252 (1938) 3320 (1038) 1979 (648) C max (pg/mL) 117 (39.3) 56.6 (17.6) 30.3 (11.1) T max (hr) a 24.0 (8-60) 24.0 (8-60) 36.0 (8-84) Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of MINIVELLE at three different strengths. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of MINIVELLE 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36) Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean half-life values of estradiol calculated from treatment groups in the bioequivalence study and dose-proportionality study after dosing with MINIVELLE ranged from 6.2 to 7.9 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline concentrations within 24 hours. Adhesion and Adhesive Residue Based on combined data from bioequivalence and dose proportionality studies consisting of 208 MINIVELLE observations, approximately 98 percent of the observations had an adhesion score of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour wear period. One woman had a complete detachment during the wear period. Approximately 65 percent of the transdermal systems evaluated in these studies were with MINIVELLE 0.1 mg per day (6.6 cm 2 active surface area). After removal of MINIVELLE, women had either no adhesive residue (score of 0) or light adhesive residue (score of 1). No woman had medium adhesive residue. Of the 208 MINIVELLE observations, 54 percent had light adhesive residue and 46 percent had no adhesive residue. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of MINIVELLE 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (
| a Median (minimum-maximum) | |||
| Parameter | 0.1 mg/day | 0.05 mg/day | 0.025 mg/day |
| AUC 84 (pg·hr/mL) | 5875 (1857) | 3057 (980) | 1763 (600) |
| AUC 120 (pg·hr/mL) | 6252 (1938) | 3320 (1038) | 1979 (648) |
| C max (pg/mL) | 117 (39.3) | 56.6 (17.6) | 30.3 (11.1) |
| T max (hr) a | 24.0 (8-60) | 24.0 (8-60) | 36.0 (8-84) |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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, 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated concentrations of these hormones seen in postmenopausal women.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to MINIVELLE nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, MINIVELLE (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC 0-84 ) and estradiol peak concentration (C max ) following a single-dose on the lower abdomen for 84 hours. Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years). MINIVELLE transdermal systems delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2 . AUC and C max are dose proportional from 0.025 mg to 0.1 mg per day. Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of MINIVELLE (N=36) a Median (minimum-maximum) Parameter 0.1 mg/day 0.05 mg/day 0.025 mg/day AUC 84 (pg·hr/mL) 5875 (1857) 3057 (980) 1763 (600) AUC 120 (pg·hr/mL) 6252 (1938) 3320 (1038) 1979 (648) C max (pg/mL) 117 (39.3) 56.6 (17.6) 30.3 (11.1) T max (hr) a 24.0 (8-60) 24.0 (8-60) 36.0 (8-84) Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of MINIVELLE at three different strengths. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of MINIVELLE 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36) Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean half-life values of estradiol calculated from treatment groups in the bioequivalence study and dose-proportionality study after dosing with MINIVELLE ranged from 6.2 to 7.9 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline concentrations within 24 hours. Adhesion and Adhesive Residue Based on combined data from bioequivalence and dose proportionality studies consisting of 208 MINIVELLE observations, approximately 98 percent of the observations had an adhesion score of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour wear period. One woman had a complete detachment during the wear period. Approximately 65 percent of the transdermal systems evaluated in these studies were with MINIVELLE 0.1 mg per day (6.6 cm 2 active surface area). After removal of MINIVELLE, women had either no adhesive residue (score of 0) or light adhesive residue (score of 1). No woman had medium adhesive residue. Of the 208 MINIVELLE observations, 54 percent had light adhesive residue and 46 percent had no adhesive residue. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of MINIVELLE 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (
| a Median (minimum-maximum) | |||
| Parameter | 0.1 mg/day | 0.05 mg/day | 0.025 mg/day |
| AUC 84 (pg·hr/mL) | 5875 (1857) | 3057 (980) | 1763 (600) |
| AUC 120 (pg·hr/mL) | 6252 (1938) | 3320 (1038) | 1979 (648) |
| C max (pg/mL) | 117 (39.3) | 56.6 (17.6) | 30.3 (11.1) |
| T max (hr) a | 24.0 (8-60) | 24.0 (8-60) | 36.0 (8-84) |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS MINIVELLE is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Breast cancer or a history of breast cancer [see Warnings and Precautions ( 5.2 )] . Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )] . Active DVT, PE, or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Known anaphylactic reaction, angioedema, or hypersensitivity to MINIVELLE Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or a history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to MINIVELLE ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION MINIVELLE (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of MINIVELLE are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active surface area of 1.65, 2.48, 3.30, 4.95, or 6.6 cm 2 and contains 0.41, 0.62, 0.83, 1.24, or 1.65 mg of estradiol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The structural formula is The molecular formula of estradiol is C 18 H 24 0 2 . The molecular weight is 272.39 MINIVELLE is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a polyolefin laminate backing (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. Estradiol USP Layers of MINIVELLE
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus, does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Start therapy with MINIVELLE® 0.0375 mg per day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause. Dosage adjustment should be guided by the clinical response ( 2.1 ) Start therapy with MINIVELLE 0.025 mg per day applied to the skin twice weekly for the prevention of postmenopausal osteoporosis. The dose may be adjusted as necessary ( 2.2 ) Place MINIVELLE on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply MINIVELLE to the breasts ( 2.3 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with MINIVELLE 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on clinical response. Attempt to taper or discontinue MINIVELLE at 3 to 6 month intervals. 2.2 Prevention of Postmenopausal Osteoporosis due to Menopause 2.3 Application Instructions Place the adhesive side of MINIVELLE on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply MINIVELLE to the breasts. Replace MINIVELLE twice weekly (every 3-4 days). Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area for application that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact with the skin, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location. In either case, continue the original treatment schedule. If a woman has forgotten to apply MINIVELLE, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking MINIVELLE might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day. Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE MINIVELLE is indicated for: MINIVELLE® is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) Prevention of postmenopausal osteoporosis ( 1.2 ) Limitations of Use When prescribing solely for the treatment of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.
1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.
Spl product data elements
Usually a list of ingredients in a drug product.Minivelle estradiol DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 ESTRADIOL ESTRADIOL Minivelle estradiol DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 ESTRADIOL ESTRADIOL Minivelle estradiol DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 ESTRADIOL ESTRADIOL Minivelle estradiol DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 ESTRADIOL ESTRADIOL Minivelle estradiol DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 ESTRADIOL ESTRADIOL
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Package Label - Principal Display Panel – 0.025mg Trade Carton NDC 68968-6625-8 0.025 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.025 mg/day Twice-Weekly Rx Only Includes 8 Systems Open Here Contents: 8 Systems Rx Only Each 1.65 cm 2 system contains 0.41 mg of estradiol USP. Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner. For Transdermal Use Only Important: Package not child-resistant. Apply immediate upon removal from pouch. Do not store unpouched. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dosage and Administration: Apply twice-weekly. See package insert. N3 68968-6625-8 7 302348-3 Noven Your application schedule Determine which 2 days of the week you will change your patch and then mark them on this calender º Sunday/Wednesday º Thursday/Sunday º Monday/Thursday º Friday/Monday º Tuesday/Friday º Saturday/Tuesday º Wednesday/Saturday As a handy reminder of your application schedule, keep this tear out with you Pull here for your Minivelle ® patches 0.025 mg/day Mfd. by: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. by: Noven Therapeutics, LLC Miami, Florida 33186 0.025 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.025 mg/day 01440 30248-3 LOT/EXP GTIN: 00368968662587 trade carton 0.025mg
Package Label - Principal Display Panel – 0.0375mg Carton NDC 68968-6637-8 0.0375 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.0375 mg/day Twice-Weekly Rx Only Includes 8 Systems Open Here Contents: 8 Systems Rx Only Each 2.48 cm 2 system contains 0.62 mg of estradiol USP. Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner. For Transdermal Use Only Important: Package not child-resistant. Apply immediate upon removal from pouch. Do not store unpouched. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dosage and Administration: Apply twice-weekly. See package insert. N3 68968-6637-8 2 302360-4 Noven Your application schedule Determine which 2 days of the week you will change your patch and then mark them on this calender º Sunday/Wednesday º Thursday/Sunday º Monday/Thursday º Friday/Monday º Tuesday/Friday º Saturday/Tuesday º Wednesday/Saturday As a handy reminder of your application schedule, keep this tear out with you Pull here for your Minivelle ® patches 0.0375 mg/day Mfd. by: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. by: Noven Therapeutics, LLC Miami, Florida 33186 0.0375 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.025 mg/day 01440 30248-3 LOT/EXP GTIN: 00368968663782 CARTON 0.0375mg
Package Label - Principal Display Panel – 0.05mg Carton NDC 68968-6650-8 0.05 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.05 mg/day Twice-Weekly Rx Only Includes 8 Systems Open Here Contents: 8 Systems Rx Only Each 3.3 cm 2 system contains 1.83 mg of estradiol USP. Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner. For Transdermal Use Only Important: Package not child-resistant. Apply immediate upon removal from pouch. Do not store unpouched. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dosage and Administration: Apply twice-weekly. See package insert. N3 68968-6650-8 3 302360-4 Noven Your application schedule Determine which 2 days of the week you will change your patch and then mark them on this calender º Sunday/Wednesday º Thursday/Sunday º Monday/Thursday º Friday/Monday º Tuesday/Friday º Saturday/Tuesday º Wednesday/Saturday As a handy reminder of your application schedule, keep this tear out with you Pull here for your Minivelle ® patches 0.05 mg/day Mfd. by: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. by: Noven Therapeutics, LLC Miami, Florida 33186 0.05 mg/day Minivelle® (estradiol transdermal system) Delivers 0.025 mg/day 01440 30248-3 LOT/EXP GTIN: 00368968665083 CARTON 0.05mg
Package Label - Principal Display Panel – 0.075mg Carton NDC 68968-6675-8 0.075 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.05 mg/day Twice-Weekly Rx Only Includes 8 Systems Open Here Contents: 8 Systems Rx Only Each 4.95 cm 2 system contains 1.24 mg of estradiol USP. Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner. For Transdermal Use Only Important: Package not child-resistant. Apply immediate upon removal from pouch. Do not store unpouched. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dosage and Administration: Apply twice-weekly. See package insert. N3 68968-6675-8 2 302360-4 Noven Your application schedule Determine which 2 days of the week you will change your patch and then mark them on this calender º Sunday/Wednesday º Thursday/Sunday º Monday/Thursday º Friday/Monday º Tuesday/Friday º Saturday/Tuesday º Wednesday/Saturday As a handy reminder of your application schedule, keep this tear out with you Pull here for your Minivelle ® patches 0.075 mg/day Mfd. by: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. by: Noven Therapeutics, LLC Miami, Florida 33186 0.05 mg/day Minivelle® (estradiol transdermal system) Delivers 0.025 mg/day 01440 302357-3 LOT/EXP GTIN: 003689686637582 CARTON 0.075mg
Package Label - Principal Display Panel – 0.1mg Carton NDC 68968-6610-8 0.1 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.05 mg/day Twice-Weekly Rx Only Includes 8 Systems Open Here Contents: 8 Systems Rx Only Each 6.6 cm 2 system contains 1.65 mg of estradiol USP. Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner. For Transdermal Use Only Important: Package not child-resistant. Apply immediate upon removal from pouch. Do not store unpouched. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dosage and Administration: Apply twice-weekly. See package insert. N3 68968-6610-8 5 302360-4 Noven Your application schedule Determine which 2 days of the week you will change your patch and then mark them on this calender º Sunday/Wednesday º Thursday/Sunday º Monday/Thursday º Friday/Monday º Tuesday/Friday º Saturday/Tuesday º Wednesday/Saturday As a handy reminder of your application schedule, keep this tear out with you Pull here for your Minivelle ® patches 0.1 mg/day Mfd. by: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. by: Noven Therapeutics, LLC Miami, Florida 33186 0.1 mg/day Minivelle ® (estradiol transdermal system) Delivers 0.025 mg/day 01440 302351-4 LOT/EXP GTIN: 00368968661085 CARTON 0.1mg
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 02/2024
| Warnings and Precautions, Malignant Neoplasms ( | 02/2024 |
Minivelle: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Vaginal Bleeding Inform postmenopausal women to report unusual vaginal bleeding to their healthcare providers as soon as possible [see Warnings and Precautions ( 5.2 )] Possible Serious Adverse Reactions with Estrogen–Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warning and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Common Adverse Reactions with Estrogen–Alone Therapy Inform postmenopausal women of less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.
Instructions for use
Information about safe handling and use of the drug product.INSTRUCTIONS FOR USE MINIVELLE ® (MIN-ee-vell) (estradiol transdermal system) Read this PATIENT INFORMATION before you start using MINIVELLE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. You will need the following supplies (See Figure A) . Figure A Step 1: Pick the days you will change your patch. You will need to change your patch 2 times a week or every 3 to 4 days. Use the calendar printed inside your carton to choose the 2 days you will change your patch (See Figure B) . Remember to change your patch on the same 2 days you marked on your calendar. If you forget to change your patch on the correct date, apply a new patch as soon as you remember, and continue to follow your original schedule Figure B Step 2. Remove the MINIVELLE patch from the pouch. Remove the patch from its protective pouch by tearing at the notch ( do not use scissors, See Figure C ). Do not remove your patch from the protective pouch until you are ready to apply it Figure C Step 3. Remove half of the adhesive liner (See Figure D). Figure D Step 4. Placing the patch on your skin. Hold the part of the patch that still has the adhesive liner on it Avoid touching the sticky half of the patch with your fingers Apply the exposed sticky half of the patch to 1 of the areas of skin shown below (See Figures E and F) . Note: Avoid the waistline, since clothing and belts may cause the patch to be rubbed off Do not apply the patch to your breasts Only apply the patch to skin that is clean, dry, and free of any powder, oil, or lotion You should not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy) Step 5: Press the patch firmly onto your skin. Remove the remaining half of the adhesive liner and press the entire patch into place with the palm of your hand for 10 seconds Rub the edges of the patch with your fingers to make sure that it will stick to your skin (See Figure G) . Figure G Note: Showering will not cause your patch to fall off If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area (See Figures E and D) and continue to follow your original placement schedule If you stop using your MINIVELLE patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and recurrence of symptoms Step 6: Throwing away your used patch. When it is time to change your patch, remove the old patch before you apply a new patch To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured by: Noven Pharmaceuticals Inc. Miami, FL 33186 Approved (02/2024) Figure A Figure B Figure C Figure D Figures E and F Figure G
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.PATIENT INFORMATION MINIVELLE (MIN-ee-vell) (estradiol transdermal system) Read this Patient Information before you start using MINIVELLE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about MINIVELLE (an estrogen hormone)? Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using MINIVELLE. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes, or dementia. Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of MINIVELLE will affect your chances of developing these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with MINIVELLE. What is MINIVELLE? MINIVELLE is a prescription medicine patch (transdermal system) that contains the estrogen hormone estradiol. When applied to the skin, estradiol is absorbed through the skin into the bloodstream. What is MINIVELLE ® used for? MINIVELLE is used after menopause to: Reduce moderate to severe hot flashes Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild and they will not need estrogens. In other women, symptoms can be more severe. Help reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use MINIVELLE only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue treatment with MINIVELLE. Who should not use MINIVELLE? Do not start using MINIVELLE if you: have unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have been diagnosed with a bleeding disorder currently have or have had certain cancers Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use MINIVELLE. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to MINIVELLE or the ingredients in it. See the list of ingredients in MINIVELLE at the end of this leaflet. Before you use MINIVELLE, tell your healthcare provider about all of your medical conditions, including if you: have any unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions that may become worse while you are using MINIVELLE Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), diabetes, epilepsy (seizures), migraine, endometriosis, lupus, angioedema (swelling of the face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop using MINIVELLE. are pregnant or think you may be pregnant. MINIVELLE is not for pregnant women. are breast feeding The hormone in MINIVELLE can pass 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. Some medicines may affect how MINIVELLE works. MINIVELLE may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use MINIVELLE? For detailed instructions, see the step-by-step instructions for using MINIVELLE at the end of this Patient Information Use MINIVELLE exactly as your healthcare provider tells you to use it MINIVELLE is for skin use only Change your MINIVELLE patch 2 times a week or every 3 to 4 days Apply your MINIVELLE patch to a clean, dry area on your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin Apply your MINIVELLE patch to a different area of your abdomen or your buttocks each time. Do not use the same application site 2 times in the same week. Do not apply MINIVELLE to your breasts If you forget to apply a new MINIVELLE patch, apply a new patch as soon as possible. You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with MINIVELLE. How to Change MINIVELLE When changing the patch, peel off the used patch slowly from the skin. After removal of MINIVELLE if any adhesive residue remains on your skin, allow the area to dry for 15 minutes. Then, gently rub the area with oil or lotion to remove the adhesive from your skin Apply the new patch to a different area of your abdomen or buttocks. This area must be clean, dry, cool and free of powder, oil or lotion. What are the possible side effects of MINIVELLE? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: heart attack stroke blood clots breast cancer cancer of the lining of the uterus (womb) cancer of the ovary dementia high or low blood calcium gallbladder disease visual abnormalities high blood pressure high levels of fat (triglyceride) in your blood liver problems changes in your thyroid hormone levels fluid retention cancer changes of endometriosis enlargement of benign tumors of the uterus (“fibroids”) worsening of swelling of face and tongue (angioedema) in women with a history of angioedema Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue swelling of face and tongue with or without red, itchy bumps Common side effects of MINIVELLE include: headache breast pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection redness and/or irritation at patch placement site These are not all the possible side effects of MINIVELLE. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to Noven at 1-800-455-8070 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with MINIVELLE? Talk with your healthcare provider regularly about whether you should continue using MINIVELLE. If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while using MINIVELLE. Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store and throw away used MINIVELLE patches? Store MINIVELLE at room temperature 68°F to 77°F (20°C to 25°C) Do not store MINIVELLE patches outside of their pouches. Apply immediately upon removal from the protective pouch Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet KEEP MINIVELLE and all other medicines out of the reach of children General information about safe and effective use of MINIVELLE Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use MINIVELLE for conditions for which it was not prescribed. Do not give MINIVELLE to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about MINIVELLE that is written for health professionals. You can get more information by calling Noven Pharmaceuticals, Inc. at 1-800-455-8070. What are the ingredients in MINIVELLE? Active ingredient: estradiol Inactive ingredients: Polyolefin laminate backing, acrylic and silicone adhesives, oleyl alcohol, NF, povidone, USP and dipropylene glycol and a polyester release liner
|
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women There have been no efficacy and safety trials conducted with MINIVELLE. In a pharmacokinetic study, MINIVELLE was shown to be bioequivalent to Vivelle. In two controlled clinical trials with Vivelle, in a total of 356 women, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Weeks 4, 8 and 12 of treatment. In these studies, the 0.0375 and 0.05 mg doses did not differ from placebo at Week 4, therefore, a third 12-week placebo-controlled study in 255 women was performed with Vivelle to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 women was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2. Figure 2: Mean (SD) change from baseline in mean daily number of hot flushes for Vivelle 0.0375 mg versus Placebo in a 12 week trial. The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Weeks 4, 8 and 12 of treatment. Figure 2: Mean (SD) change from baseline in mean daily number of hot flushes for Vivelle 0.0375 mg versus Placebo in a 12 week trial. 14.2 Effects on Bone Mineral Density in Postmenopausal Women There have been no bone efficacy and safety trials conducted with MINIVELLE. In a pharmacokinetic study, MINIVELLE was shown to be bioequivalent to Vivelle. Efficacy and safety of Vivelle in the prevention of postmenopausal osteoporosis have been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., ≥0.0827 g/cm 2 ) were enrolled in this study; 194 women were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 women to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study. The study population comprised naturally (82 percent) or surgically (18 percent) menopausal, hysterectomized (61 percent) or non-hysterectomized (39 percent) women with a mean age of 52.0 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89 percent) randomized women (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Women were given supplemental dietary calcium (100 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically significant differences in pairwise comparisons among the three lower doses (See Figure 3 ). Figure 3: Bone mineral density – AP Lumbar spine Least squares means of percentage change from baseline All randomized women with at least one post-baseline assessment available with last post-baseline observation carried forward Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant and non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three lower doses at this skeletal site (see Figure 4 ). Figure 4: Bone mineral density - Femoral neck Least squares means of percentage change from baseline All randomized women with at least one post-baseline assessment available with last post-baseline observation carried forward Figure 3: Bone mineral density – AP Lumbar spine Figure 4 Bone mineral density - Femoral neck 14.3 Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 3. Table 3: Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHI a a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events. invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE vs. Placebo (95% nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c Non-fatal MI c CHD death c 0.95 (0.78–1.16) 0.91 (0.73–1.14) 1.01 (0.71–1.43) 54 40 16 57 43 16 All Strokes c Ischemic stroke c 1.33 (1.15–1.68) 1.55 (1.19–2.01) 45 38 33 25 Deep vein thrombosis c,d 1.47 (1.06–2.06) 23 15 Pulmonary embolism c 1.37 (0.90–2.07) 14 10 Invasive breast cancer c 0.80 (0.62–1.04) 28 34 Colorectal cancer e 1.08 (0.75–1.55) 17 16 Hip fracture c 0.65 (0.45–0.94) 12 19 Vertebral fractures c,d 0.64 (0.44–0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47–0.72) 35 59 Total fractures c,d 0.71 (0.64–0.80) 144 197 Death due to other causes e,f 1.08 (0.88–1.32) 53 50 Overall mortality c,d 1.04 (0.88–1.22) 79 75 Global Index g 1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. ⁹ The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. ¹⁰ Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 4: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) CE/MPA (n = 8,506) Placebo (n = 8,102) Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99–1.53) 1.28 (1.00–1.63) 1.10 (0.70–1.75) 41 31 8 34 25 8 All strokes Ischemic stroke 1.31 (1.03–1.68) 1.44 (1.09–1.90) 33 26 25 18 Deep vein thrombosis d 1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancer e 1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancer d 0.81 (0.48–1.36) 6 7 Cervical cancer d 1.44 (0.47–4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fractures d 0.65 (0.46–0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59–0.85) 44 62 Total fractures d 0.76 (0.69–0.83) 152 199 Overall mortality f 1.00 (0.83–1.19) 52 52 Global Index g 1.13 (1.02–1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. 14.4 Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.5 )]. The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21- 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )]. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )].
| a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. | |||
| b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. | |||
| c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. | |||
| d Not included in “global index”. | |||
| e Results are based on an average follow-up of 6.8 years. | |||
| f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. | |||
| g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events. invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. | |||
| CHD events c | 0.95 (0.78–1.16) | 54 | 57 |
| All Strokes c | 1.33 (1.15–1.68) | 45 | 33 |
| Deep vein thrombosis c,d | 1.47 (1.06–2.06) | 23 | 15 |
| Pulmonary embolism c | 1.37 (0.90–2.07) | 14 | 10 |
| Invasive breast cancer c | 0.80 (0.62–1.04) | 28 | 34 |
| Colorectal cancer e | 1.08 (0.75–1.55) | 17 | 16 |
| Hip fracture c | 0.65 (0.45–0.94) | 12 | 19 |
| Vertebral fractures c,d | 0.64 (0.44–0.93) | 11 | 18 |
| Lower arm/wrist fractures c,d | 0.58 (0.47–0.72) | 35 | 59 |
| Total fractures c,d | 0.71 (0.64–0.80) | 144 | 197 |
| Death due to other causes e,f | 1.08 (0.88–1.32) | 53 | 50 |
| Overall mortality c,d | 1.04 (0.88–1.22) | 79 | 75 |
| Global Index g | 1.02 (0.92–1.13) | 206 | 201 |
| a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. | |||
| b Results are based on centrally adjudicated data. | |||
| c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. | |||
| d Not included in “global index”. | |||
| e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. | |||
| f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. | |||
| g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. | |||
| CHD events | 1.23 (0.99–1.53) | 41 | 34 |
| All strokes | 1.31 (1.03–1.68) | 33 | 25 |
| Deep vein thrombosis d | 1.95 (1.43–2.67) | 26 | 13 |
| Pulmonary embolism | 2.13 (1.45–3.11) | 18 | 8 |
| Invasive breast cancer e | 1.24 (1.01–1.54) | 41 | 33 |
| Colorectal cancer | 0.61 (0.42–0.87) | 10 | 16 |
| Endometrial cancer d | 0.81 (0.48–1.36) | 6 | 7 |
| Cervical cancer d | 1.44 (0.47–4.42) | 2 | 1 |
| Hip fracture | 0.67 (0.47–0.96) | 11 | 16 |
| Vertebral fractures d | 0.65 (0.46–0.92) | 11 | 17 |
| Lower arm/wrist fractures d | 0.71 (0.59–0.85) | 44 | 62 |
| Total fractures d | 0.76 (0.69–0.83) | 152 | 199 |
| Overall mortality f | 1.00 (0.83–1.19) | 52 | 52 |
| Global Index g | 1.13 (1.02–1.25) | 184 | 165 |
References
This field may contain references when prescription drug labeling must summarize or otherwise relay on a recommendation by an authoritative scientific body, or on a standardized methodology, scale, or technique, because the information is important to prescribing decisions.15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357–365. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women with Hysterectomy. JAMA. 2006;295:1647-1657. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing MINIVELLE to determine whether those over 65 years of age differ from younger subjects in their response to MINIVELLE. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (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 ( 14.3 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . 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 or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.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 MINIVELLE and any potential adverse effects on the breastfed child from MINIVELLE or from the underlying maternal condition.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use MINIVELLE is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary MINIVELLE is not indicated for use in pregnancy. There are no data with the use of MINIVELLE 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 (estrogens 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary MINIVELLE is not indicated for use in pregnancy. There are no data with the use of MINIVELLE 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 (estrogens 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 MINIVELLE and any potential adverse effects on the breastfed child from MINIVELLE or from the underlying maternal condition. 8.4 Pediatric Use MINIVELLE 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 MINIVELLE to determine whether those over 65 years of age differ from younger subjects in their response to MINIVELLE. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (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 ( 14.3 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . 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 or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied MINIVELLE (estradiol transdermal system), 0.025 mg per day - each 1.65 cm 2 system contains 0.41 mg of estradiol USP for nominal* delivery of 0.025 mg of estradiol per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 68968-6625-8 MINIVELLE (estradiol transdermal system), 0.0375 mg per day - each 2.48 cm 2 system contains 0.62 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 68968-6637-8 MINIVELLE (estradiol transdermal system), 0.05 mg per day - each 3.3 cm 2 system contains 0.83 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-6650-8 MINIVELLE (estradiol transdermal system), 0.075 mg per day - each 4.95 cm 2 system contains 1.24 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-6675-8 MINIVELLE (estradiol transdermal system), 0.1 mg per day - each 6.6 cm 2 system contains 1.65 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-6610-8 *See Description 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [ see USP Controlled Room Temperature ] Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.
Storage and handling
Information about safe storage and handling of the drug product.16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [ see USP Controlled Room Temperature ] Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.4 )]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.3 , 14.4 )]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other route of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )]. The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.4 )]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.3 , 14.4 )]. Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.3 )]. Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREST CANCER See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 ) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Estrogen Plus Progestin Therapy The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API