ALTAVERA: Package Insert and Label Information

ALTAVERA- levonorgestrel and ethinyl estradiol
Xiromed, LLC.

levo-altaveraethinyl-e-altaverafigure1-altaaltavera-labelalta-boxpatient-guide-chart

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including Altavera, are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS and WARNINGS (1)].

DESCRIPTION

Altavera (levonorgestrel and ethinyl estradiol tablets) is a combination oral contraceptive (COC) consisting of 21 peach active tablets, each containing 0.15 mg of levonorgestrel, a synthetic progestin and 30 mcg of ethinyl estradiol, an estrogen, and 7 white inert tablets (without hormones).

The structural formulas for the active components are:

levo-altavera
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Levonorgestrel C21 H28 O2 MW: 312.4

ethinyl-e-altavera
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Ethinyl Estradiol C20 H24 O2 MW: 296.4

Ethinyl Estradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol.

Each peach active tablet contains the following inactive ingredients: lactose anhydrous, iron oxide black, iron oxide red, iron oxide yellow, magnesium stearate, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, povidone, talc, titanium dioxide.

Each white inert tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, povidone, talc, titanium dioxide.

CLINICAL PHARMACOLOGY

Combination oral contraceptives prevent pregnancy primarily by suppressing ovulation.

INDICATIONS AND USAGE

Altavera is indicated for use by females of reproductive potential to prevent pregnancy.

CONTRAINDICATIONS

Altavera is contraindicated in females who are known to have the following conditions:

  • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
    • Smoke, if over age 35 [see BOXED WARNING and WARNINGS (1)].
    • Have current or history of deep vein thrombosis or pulmonary embolism [see WARNINGS (1)].
    • Have cerebrovascular disease [see WARNINGS (1)].
    • Have coronary artery disease [see WARNINGS (1)].
    • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS (1)].
    • Have inherited or acquired hypercoagulopathies [see (1)].
    • Have uncontrolled hypertension or hypertension with vascular disease [see WARNINGS (3)].
    • Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see WARNINGS (7)].
    • Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see WARNINGS (8)].
  • Current or history of breast cancer or other estrogen- or progestin-sensitive cancer.
  • Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see WARNINGS (2)].
  • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see WARNINGS (5)].
  • Undiagnosed abnormal uterine bleeding [see WARNINGS (9)].
  • Pregnancy, because there is no reason to use COCs during pregnancy [see PRECAUTIONS (6)].

WARNINGS

1. Thromboembolic Disorders and Other Vascular Conditions

  • Stop Altavera if an arterial or venous thrombotic/thromboembolic event occurs.
  • Stop Altavera if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
  • Discontinue Altavera during prolonged immobilization. If feasible, stop Altavera at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism.
  • Start Altavera no earlier than four weeks after delivery in females who are not breast-feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.
  • Before starting Altavera evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Altavera is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases (see CONTRAINDICATIONS).

Arterial Events
COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.

Altavera is contraindicated in women over 35 years of age who smoke (see CONTRAINDICATIONS). Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs (see CONTRAINDICATIONS). While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years.

The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1. Likelihood of Developing a VTE

figure1-alta
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2. Liver Disease

Elevated Liver Enzymes
Altavera is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of liver (see CONTRAINDICATIONS). Discontinue Altavera if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of COC use until the liver tests return to normal and COC causation has been excluded.

Liver Tumors
Altavera is contraindicated in females with benign or malignant liver tumors (see CONTRAINDICATIONS). COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users.

3. Hypertension

Altavera is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease (see CONTRAINDICATIONS). For all females, including those with well- controlled hypertension, monitor blood pressure at routine visits and stop Altavera if blood pressure rises significantly.

An increase in blood pressure has been reported in females using COCs, and this increase is more likely in older women with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

4. Age-related Considerations

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see CONTRAINDICATIONS and WARNINGS (1) ]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a COC for women over 35 years, such as:

  • Hypertension
  • Diabetes
  • Dyslipidemia
  • Obesity

5. 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 Altavera prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Altavera can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6. Gallbladder Disease

Studies suggest an increased risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC- related cholestasis.

7. Adverse Carbohydrate and Lipid Metabolic Effects
Hyperglycemia
Altavera is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration (see CONTRAINDICATIONS). Altavera may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using Altavera.

Dyslipidemia
Consider alternative contraception for females with uncontrolled dyslipidemia. Altavera may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using Altavera, which may increase the risk of pancreatitis.

8. Headache
Altavera is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura (see CONTRAINDICATIONS).

If a woman using Altavera develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Altavera if indicated. Consider discontinuation of Altavera if there is an increased frequency or severity of migraines during COC use (which may be prodromal of a cerebrovascular event).

9. Bleeding Irregularities and Amenorrhea
Unscheduled Bleeding and Spotting
Females using Altavera may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

In two clinical trials of Altavera (1084 subjects reporting for a total of 8186 treatment cycles and 238 subjects reporting for a total of 1102 treatment cycles), breakthrough bleeding occurred in 6.9% and 8.1% of reported cycles, and spotting occurred in 8.6% and 7.9% of reported cycles over the total study duration, respectively. In the two trials, intermenstrual bleeding (i.e., breakthrough bleeding and/or spotting) occurred in 13.1% and 12.9% of reported cycles over the total study duration, respectively. In one trial, 33 subjects out of 1084 (3.0%) discontinued due to bleeding irregularities (i.e., breakthrough bleeding and spotting); in the other trial, 6 subjects out of 238 (2.5%) discontinued due to bleeding irregularities.

Amenorrhea and Oligomenorrhea
Females who use Altavera may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. In two clinical trials of Altavera, one including 8186 reported treatment cycles, and the other including 1102 reported treatment cycles, amenorrhea occurred in 1.5% of treatment cycles in each trial.

If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two 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 perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy.

After discontinuation of a COC, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

10. Depression
Carefully observe females with a history of depression and discontinue Altavera if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.

11. Cervical Cancer
Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

12. Effect on Binding Globulins
The estrogen component of Altavera 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.

13. Hereditary Angioedema
In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

14. Chloasma
Chloasma may occur with Altavera use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using Altavera.

PRECAUTIONS

1. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult [see WARNINGS (7)].

In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.

2. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

3. Gastrointestinal Motility
Diarrhea and/or vomiting may reduce hormone absorption (see DOSAGE AND ADMINISTRATION).

4. Drug InteractionsThe sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.

Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations .

No drug-drug interaction studies were conducted with Altavera.

4.1 Effects of Other Drugs on Combined Oral Contraceptives

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

Table 1 includes substances that demonstrated an important drug interaction with Altavera.

Table 1: Significant Drug Interactions Involving Substances That Affect COCs

Metabolic Enzyme Inducers
Clinical effect
  • Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs.
  • Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding.
Prevention or management
  • Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs.
  • Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.
Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s worta , and certain protease inhibitors (see separate section on protease inhibitors below).
Colesevelam
Clinical effect
  • Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinylestradiol.
  • Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC.
Prevention or management Administer 4 or more hours apart to attenuate this drug interaction.

a Induction potency of St. John’s wort may vary widely based on preparation.

Substances increasing the systemic exposure of COCs:
Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non­ nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

4.2 Effects of Combined Oral Contraceptives on Other Drugs

Table 2 provides significant drug interaction information for drugs co-administered with Altavera.

Table 2: Significant Drug Interaction Information for Drugs Co-Administered With COCs

Lamotrigine
Clinical effect
  • Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation.
  • Decreased systemic exposure of lamotrigine may reduce seizure control.
Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine.
Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy
Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid- binding and cortisol-binding globulin (see Warnings, EFFECT ON BINDING GLOBULINS).
Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use (see Warnings, EFFECT ON BINDING GLOBULINS).
Other Drugs
Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol­ containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole).
Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.

4.3 Effect on Laboratory Tests
The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

5. Carcinogenesis
See WARNINGS (11).

6. Pregnancy
Risk Summary
Altavera is contraindicated in pregnancy because there is no reason to use COCs in pregnancy. Discontinue Altavera if pregnancy occurs. 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 COCs before conception or during early pregnancy. Animal studies to evaluate embryo/fetal toxicity were not conducted.

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.

7. Lactation
Risk Summary
Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding. (see DOSAGE AND ADMINISTRATION). The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Altavera and any potential adverse effects on the breast-fed child from Altavera or from the underlying maternal condition.

8. Pediatric Use
Safety and efficacy of Altavera have been established in females of reproductive potential. Use of Altavera before menarche is not indicated.

9. Geriatric Use
Altavera has not been studied in postmenopausal women and is not indicated in this population.

10. PATIENT COUNSELING INFORMATION

  • Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.
  • Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
  • Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed.
  • Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.
  • Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established.
  • Counsel any patient who starts Altavera postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a light-orange tablet for 7 consecutive days.
  • Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.
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