ZAFEMY: Package Insert and Label Information (Page 3 of 6)

5.11 Depression

Carefully observe women with a history of depression and discontinue ZAFEMY if depression recurs to a serious degree.

5.12 Malignant Neoplasms

Breast Cancer

ZAFEMY is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)]. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].

Cervical Cancer

Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.13 Effect on Binding Globulins

The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

5.14 Monitoring

A woman who is taking hormonal contraceptive should have routine visits with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.15 Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.16 Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using ZAFEMY.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of combination hormonal contraceptives, including ZAFEMY, are discussed elsewhere in the labeling:

Adverse reactions commonly reported by users of combination hormonal contraceptives are:

  • Irregular uterine bleeding
  • Nausea
  • Breast tenderness
  • Headache

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to ZAFEMY in 3,330 sexually active women (3,322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (ZAFEMY or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%).

The most common adverse reactions (≥ 5%) reported during clinical trials were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability.

Adverse drug reactions reported by ≥ 2.5% of ZAFEMY-treated subjects in these trials are shown in Table 3.

Table 3: Adverse Drug Reactions Reported by ≥ 2.5% of ZAFEMY-treated Subjects in Three Phase 3 Clinical Trials

System/Organ Class* Adverse reaction

ZAFEMY (n=3,322)

Reproductive system and breast disorders

Breast symptoms

22.4%

Dysmenorrhea

7.8%

Vaginal bleeding and menstrual disorders

6.4%

Gastrointestinal disorders

Nausea

16.6%

Abdominal pain

8.1%

Vomiting

5.1%

Diarrhea

4.2%

Nervous system disorders

Headache

21.0%

Dizziness

3.3%

Migraine

2.7%

General disorders and administration site conditions

Application site disorder

17.1%

Fatigue

2.6%

Psychiatric disorders

Mood, affect and anxiety disorders

6.3%

Skin and subcutaneous tissue disorders

Acne

2.9%

Pruritus

2.5%

Infections and infestations

Vaginal yeast infection

3.9%

Investigations

Weight increased

2.7%

* MedDRA version 10.0

Represents a bundle of similar terms

Additional adverse drug reactions that occurred in < 2.5% of ZAFEMY-treated subjects in the above clinical trials datasets are:

  • Gastrointestinal disorders: Abdominal distension
  • General disorders and administration site conditions: Fluid retention1 , malaise
  • Hepatobiliary disorders: Cholecystitis
  • Investigations: Blood pressure increased, lipid disorders1
  • Musculoskeletal and connective tissue disorders: Muscle spasms
  • Psychiatric disorders: Insomnia, libido decreased, libido increased
  • Reproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness
  • Respiratory, thoracic and mediastinal disorders: Pulmonary embolism
  • Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation

1 Represents a bundle of similar terms

6.2 Postmarketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 2).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use.

Figure 2:

1
(click image for full-size original)

RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.
The following adverse reactions (Table 4) have been identified during post-approval use of ZAFEMY. 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.

Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ZAFEMY by System Organ Class*

System Organ Class

Adverse Drug Reactions

Cardiac disorders

Myocardial infarction

Endocrine disorders

Hyperglycemia, insulin resistance

Eye disorders

Contact lens intolerance or complication

Gastrointestinal disorders

Colitis

General disorders and administration site conditions

Application site reaction , edema

Hepatobiliary disorders

Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased

Immune system disorders

Allergic reaction , urticaria

Investigations

Blood glucose abnormal, blood glucose decreased

Metabolism and nutrition disorders

Increased appetite

Neoplasms benign, malignant and unspecified (Incl. cysts and polyps)

Breast cancer , cervix carcinoma, hepatic adenoma, hepatic neoplasm

Nervous system disorders

Dysgeusia, migraine with aura

Psychiatric disorders

Anger, emotional disorder, frustration, irritability

Reproductive system and breast disorders

Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder , suppressed lactation, uterine leiomyoma

Skin and subcutaneous tissues disorders

Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash , seborrheic dermatitis, skin reaction

Vascular disorders

Arterial thrombosis , cerebrovascular accident , deep vein thrombosis , hemorrhage intracranial , hypertension, hypertensive crisis, pulmonary embolism , thrombosis

* MedDRA version 10.0

Represents a bundle of similar terms

7 DRUG INTERACTIONS

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives

Substances Decreasing the Plasma Concentrations of CHCs and Potentially Diminishing the Efficacy of CHCs:

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances Increasing the Plasma Concentrations of CHCs:

Co-administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 20% to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors:

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

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