Tydemy Drug Information
Generic name: DROSPIRENONE, ETHINYL ESTRADIOL AND LEVOMEFOLATE CALCIUM AND LEVOMEFOLATE CALCIUM
Uses of Tydemy
Oral Contraceptive Tydemy TM is indicated for use by females of reproductive
potential to prevent pregnancy.
Folate Supplementation Tydemy is indicated in females of reproductive potential who choose
to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product.
Dosage & Administration of Tydemy
| If one orange active tablet is missed | Take it as soon as possible. Take the next tablet at the regular time. This means two tablets may be taken in one day. A back-up birth control method is not required if the patient has sex. |
|---|---|
| If two orange active tablets in a row are missed in Week 1 or Week 2 | Take two tablets as soon as possible and two tablets the next day. Then take one tablet a day until the pack is finished. |
| If two orange active tablets in a row are missed in Week 3 | Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. |
| If three or more orange active tablets in a row are missed during any week | Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. |
| If any of the seven light orange inactive tablets are missed in Week 4: | Throw away the tablets that were missed. Keep taking one tablet each day until the pack is empty. They do not need a back-up method. |
| Finally, if they are still not sure what to do about the tablets they have missed: |
Side Effects of Tydemy
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Contraception and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of Yasmin ® (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837) and folate supplementation (N=172). For contraception, the US pivotal clinical study (N=326) for the oral contraception indication for Yasmin ® was a multicenter, open-label trial in healthy women aged 18 to 35 who were treated with Yasmin ® for up to 13 cycles. The second contraceptive pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of Yasmin ® vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17 to 40 who were treated for up to 26 cycles.
The primary efficacy study using drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets for folate supplementation was a randomized, single-center European trial in 172 healthy, female subjects aged 18 to 40 years comparing the pharmacodynamic effects of Yasmin ® + 0.451 mg levomefolate calcium to Yasmin ® co-administered with folic acid during 24 weeks of treatment followed by 20 weeks of open-label Yasmin ®. The adverse reactions seen across the 2 indications overlapped and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%), and abdominal pain/discomfort/tenderness (2.2%). Adverse Reactions (≥ 1%) Leading to Study Discontinuation Contraception Clinical Trials Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%). Folate Clinical Trial There were no subjects who discontinued due to an adverse reaction. Serious Adverse Reactions: Contraception Clinical Trials : depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma.
Folate Supplementation Clinical Trial : none reported in the clinical trial
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 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). 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 - 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 8-10 years of COC use.
Figure 3: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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 have been identified during post-approval use of Yasmin ®. 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. Adverse reactions, including fatalities, are grouped into System Organ Classes and ordered by frequency.
Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Hyperkalemia Skin and subcutaneous tissue disorders: Chloasma Image
Warnings & Cautions for Tydemy
Thromboembolic Disorders and Other Vascular Problems Stop drospirenone, ethinyl estradiol and levomefolate
calcium tablets and levomefolate calcium tablets if an arterial or venous thrombotic (VTE) event occurs. Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, Yasmin ® ), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase.
Before initiating use of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs . A number of studies have compared the risk of VTE for users of Yasmin ® (which contains 0.03 mg of EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 2. Table 2: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Yasmin ® Compared to Users of Oral Contraceptives that Contain Other Progestins a) "New users" -no use of combination hormonal contraception for at least the prior 6 months b) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate c) Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone d) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product (all are low-dose COCs; with ≤ 0.04 mg of EE) Hazard Ratio (HR) (95% CI) i3 Ingenix (Seeger 2007) Initiators, including new users a All COCs available in the US during the conduct of the study b HR: 0.9 (0.5 to 1.6) EURAS (Dinger 2007) Initiators, including new users a All COCs available in Europe during the conduct of the study c HR: 0.9 (0.6 to 1.4) Levonorgestrel/EE HR: 1.0 (0.6 to 1.8) "FDA-funded study" New users a Other COCs available during the course of the study d HR: 1.8 (1.3 to 2.4) Levonorgestrel/0.03 mg EE HR: 1.6 (1.1 to 2.2) All users (i.e., initiation and continuing use of study combination hormonal contraception) Other COCs available during the course of the study d HR: 1.7 (1.4 to 2.1) Levonorgestrel/0.03 mg EE HR: 1.5 (1.2 to 1.8) In addition to these "regulatory studies," other studies of various designs have been conducted. Overall, there are two prospective cohort studies (see Table 2): the US post-approval safety study Ingenix, the European post-approval safety study EURAS (European Active Surveillance Study). An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk.
There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 2), and two from Denmark. There are two case-control studies: the Dutch MEGA study analysis and the German case-control study. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study and the GPRD study.
The results of all of these studies are presented in Figure 1. Figure 1: VTE Risk with Yasmin ® Relative to LNG-Containing COCs (adjusted risk # ) Risk ratios displayed on logarithmic scale; risk ratio < 1 indicates a lower risk of VTE for DRSP, > 1 indicates an increased risk of VTE for DRSP. * Comparator "Other COCs" including LNG- containing COCs † LASS is an extension of the EURAS study # Some adjustment factors are indicated by superscript letters: a) Current heavy smoking, b) hypertension, c) obesity, d) family history, e) age, f) BMI, g) duration of use, h) VTE history, i) period of inclusion, j) calendar year, k) education, l) length of use, m) parity, n) chronic disease, o) concomitant medication, p) smoking, q) duration of exposure, r) site (References: Ingenix 2, EURAS (European Active Surveillance Study) 3, LASS (Long-Term Active Surveillance Study), FDA-funded study 4, Danish 5, Danish re-analysis 6, MEGA study 7, German Case-Control study 8, PharMetrics 9, GPRD study 10 ) Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period (see Figure 2). The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use.
Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 2: Likelihood of Developing a VTE If feasible, stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.
COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
Hyperkalemia Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets
contains 3 mg of the progestin DRSP, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets is contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin–II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin.
Malignant Neoplasms Breast Cancer Drospirenone, ethinyl estradiol and levomefolate calcium tablets and
levomefolate calcium tablets is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive. 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. Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.
Liver Disease Discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate
calcium tablets if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.
Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis.
Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.
Risk of Liver Enzyme Elevations with
Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and
stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.
The incidence of hypertension increases with increasing concentration of progestin.
Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder
disease among COC users.
Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who
are taking drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemia.
A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Headache
If a woman taking drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.10 Bleeding Irregularities Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy.
If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Data from ten Yasmin ® contraceptive efficacy clinical trials (N=2,467) show that the percent of women who took Yasmin ® and experienced unscheduled bleeding decreased over time from 12% at cycle 2 to 6% (cycle 13). A total of 25 subjects out of 3,009 in the Yasmin ® and drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets trials (<1%) discontinued due to bleeding complaints. These are described as metrorrhagia, vaginal hemorrhage, menorrhagia, abnormal withdrawal bleeding, and menometrorrhagia. The average duration of scheduled bleeding episodes in the majority of subjects (86% to 88%) was 4 to 7 days.
Women who use drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from Yasmin ® contraceptive efficacy trials, during cycles 2 to 13, 1 to 11% of women per cycle experienced no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.
If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 5.11 Depression Women with a history of depression should be carefully observed and drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets discontinued if depression recurs to a serious degree. 5.12 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs . DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. Folates may mask vitamin B12 deficiency. 5.13 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.14 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 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 taking COCs. Image Image
Drug Interactions with Tydemy
Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy
of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (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 phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St.John's wort. Interactions between oral 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 COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin with certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.
In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly . 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 progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: 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 EE 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. COCs Increasing the Plasma Concentrations of CYP450 Enzymes : In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Potential to Increase Serum Potassium Concentration : There is a potential for an increase in serum potassium concentration in women taking Tydemy with other drugs that may increase serum potassium concentration.
Concomitant Use of
HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Tydemy with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations .
Effects of Folates on Other Drugs Folates may modify the pharmacokinetics or
pharmacodynamics of certain antifolate drugs, e.g., antiepileptics (such as phenytoin), methotrexate or pyrimethamine, and may result in a decreased pharmacological effect of the antifolate drug.
Effects of Other Drugs on Folates Several drugs have been reported to
reduce folate concentrations by inhibition of the dihydrofolate reductase enzyme (e.g., methotrexate and sulfasalazine) or by reducing folate absorption (e.g., cholestyramine), or via unknown mechanisms (e.g., antiepileptics such as carbamazepine, phenytoin, phenobarbital, primidone and valproic acid).
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. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. Folates may mask vitamin B12 deficiency .
Pregnancy Safety for Tydemy
Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs 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 percent and 15 to 20 percent, respectively.
Data Human Data A retrospective database study of women in Norway, that included 44,734 pregnancies of which 368 were women who inadvertently took drospirenone/ethinyl estradiol during the first trimester of a pregnancy, found there were no adverse effects on pre-term birth, small for gestational age, or birth weight Z-scores. Post-marketing adverse event data on the use of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population.
Pediatric Use of Tydemy
Pediatric Use Safety and efficacy of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Contraindications for Tydemy
Tydemy is contraindicated in females who are known to have or develop the following conditions: Renal impairment Adrenal insufficiency A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 Have deep vein thrombosis or pulmonary embolism, now or in the past Have cerebrovascular disease Have coronary artery disease Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) Have inherited or acquired hypercoagulopathies Have uncontrolled hypertension Have diabetes mellitus with vascular disease Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 Undiagnosed abnormal uterine bleeding Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive Liver tumor (benign or malignant) or liver disease Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations . Renal impairment Adrenal insufficiency A high risk of arterial or venous thrombotic diseases Undiagnosed abnormal uterine bleeding Breast cancer Liver tumors or liver disease Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir
Overdosage Information for Tydemy
There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. DRSP is a spironolactone analogue which has anti-mineralocorticoid properties.
Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose. Levomefolate calcium doses of 17 mg/day (37-fold higher than the levomefolate calcium dose of Tydemy) were well tolerated after long-term treatment up to 12 weeks.
Clinical Studies of Tydemy
Oral Contraceptive Clinical Trial
In the clinical efficacy studies of Yasmin ® (3 mg DRSP/0.03 mg EE) of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 ± 4.7 years. The age range was 16 to 37 years.
The racial demographic was: 83% Caucasian, 1% Hispanic, 1% Black, <1% Asian, <1% other, <1% missing data, 14% not inquired and <1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.
Folate Supplementation Clinical Trials
The development program for drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets (Yasmin ® + levomefolate calcium) consisted of two clinical trials. One study was a multicenter, randomized, double-blind, active-controlled, parallel group US study. Plasma folate and red blood cell folate levels were investigated during a 24-week treatment with 3 mg DRSP/0.02 mg EE (YAZ ® ) + 0.451 mg levomefolate calcium as compared to YAZ ® alone in a U.S. population that consumed folate fortified food.
A total of 379 healthy women between 18 and 40 years of age with no restrictions on folate supplementation received YAZ ® + levomefolate calcium (N= 285) or YAZ ® (N=94). The plasma and RBC folate concentrations at Week 24 were the co-primary endpoints. Figures 4 and 5 display the results for plasma and RBC folate concentrations, respectively, among evaluable subjects in each arm of the study. Figure 4: US Study: Mean trough concentration-time curves (and SD) of plasma folates after daily oral administration of YAZ ® + levomefolate calcium and YAZ ® Figure 5: US Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of YAZ ® + levomefolate calcium and YAZ ® In the second study, the pharmacodynamic effect on plasma folate, RBC folate, and the profile of circulating folate metabolites was assessed during 24 weeks of treatment with 0.451 mg levomefolate calcium or with 0.4 mg folic acid (equimolar dose to 0.451 mg levomefolate calcium), both in combination with 3 mg DRSP/0.03 mg EE (Yasmin ® ) followed by 20 weeks of open-label treatment with Yasmin ® only (elimination phase). One-hundred and seventy-two healthy women between 18 to 40 years of age from a German population that consumed food without folate fortification and without concomitant intake of folate supplements were randomized to one of the two treatments.
Figures 6 and 7 display the results for plasma and RBC folate concentrations, respectively, among evaluable subjects in the levomefolate arm of the study. Figure 6: German Study: Mean trough concentration-time curve (and SD) of plasma folates after daily oral administration of Yasmin ® + levomefolate calcium Figure 7: German Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of Yasmin® + levomefolate calcium The potential to reduce the incidence of neural tube defects (NTDs) with folate supplementation is well established based on a body of evidence derived from randomized, controlled trials, nonrandomized intervention trials, and observational studies using folic acid. Therefore, the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force recommend that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily 1, 6. Image Image Image Image
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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