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Details with Side Effects
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
- Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Vascular events [see WARNINGS AND PRECAUTIONS]
- Liver disease [see WARNINGS AND PRECAUTIONS]
Adverse reactions commonly reported by COC users are:
- Irregular uterine bleeding
- Breast tenderness
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.
Contraception and Heavy Menstrual Bleeding Studies
A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Natazia were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Natazia as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Natazia in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology. [See Clinical Studies]
Adverse Reactions Leading to Study Discontinuation: 11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3% ); mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%); acne (1.1%), headache (including migraines) (1.1%), and weight increased (0.7 %).
Common Adverse Reactions ( ≥ 2%): headache (including migraines) (12.7%), breast pain, discomfort or tendernes s (7.0%), menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (depression, mood s wings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) and increased weight (2.9%).
Serious Adverse Reactions: myocardial infarction (2 cases), ruptured ovarian cyst (2 cases), deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis.
The following adverse reactions have been identified during post-approval use of Natazia. Because these reactions are reported voluntarily from a population of uncerta in size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: Hypersensitivity
Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia
Nervous system disorders: Dizziness
Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain)
Infections and infestations: Vulvovaginal candidiasis
Read the Natazia (estradiol valerate and estradiol valerate dienogest tablets) Side Effects Center for a complete guide to possible side effects
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Oral Contraceptives
Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Natazia.
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include barbiturates, bosentan, felbamate, griseofulvin, oxcarbazepine, and topiramate. Counsel women to use an alternative method of contraception or a back-up method when moderate or weak enzyme inducers are used with COCs, and t o continue back-up contraception for 28 days after discontinuing the enzymeinducer to ensure contraceptive reliability.
Dienogest is a substrate of CYP3A4. Women who take medications that are strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John's wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy.
The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate/dienogest tablets led to a 52 % and 83% decrease in the mean Cmax and AUC (0–24hr), respectively, for dienogest and a 25% and 44% decrease in Cmax and AUC (0–24hr), respectively, for estradiol at steady state.
Strong CYP3A4 Inhibitors
Strong CYP3A4 inhibitors such as ketoconazole increased hormone serum concentrations. In a study investigating the effect of ketoconazole on dienogest and estradiol pharmacokinetics, co-administration with the strong CYP3A4 inhibitor ketoconazole resulted in a 186% increase of AUC (0–24hr) at steady state for dienogest and a 57% increase for estradiol. There was also a 94% and 65% increase of Cmax at steady state for dienogest and estradiol when co-administered with ketoconazole.
Moderate CYP3A4 Inhibitors
The AUC (0–24hr) of dienogest and estradiol at steady state were increased by 62% and 33%, respectively, when co-administered with a moderate CYP3A4 inhibitor, erythromycin. There was also a 33% and 51% increase of Cmax at steady state for dienogest and estradiol, respectively, when co-administered with erythromycin.
Other known CYP3A4 inhibitors like azoleantifungals, cimetidine , verapamil, macrolides, diltiazem, antidepressants, and grapefruit juice may increase plasma concentrations of dienogest.
Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors
Significant changes (increase and decrease) in plasma concentrations of estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
Effects of Combined Oral Contraceptives on Other Drugs
COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
In vitro studies with human CYP enzymes did not indicate an inhibitory potential of dienogest at clinically relevant concentrations.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serumconcentrations of thyroid-binding globulin increase with use of COCs.
Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Read the Natazia Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 9/5/2013
This monograph has been modified to include the generic and brand name in many instances.
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