levonorgestrel oral/ethinylestradiol/ferrous bisglycinate (Rx)

Brand and Other Names:Balcoltra
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Dosing & Uses

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Dosage Forms and Strengths

levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

tablet, monophasic

  • 0.1mg/0.02mcg (21 tabs) plus 36.5mg ferrous bisglycinate (7 tabs)

Oral Contraception

Indicated for use by females of reproductive potential to prevent pregnancy

Follow manufacturer's color-coding for sequence

1 active tab PO qDay for 21 days, then 1 Fe tab PO qDay on Days 22-28

Take tablets in the order directed on the blister pack

Also see Administration

Dosage Modifications

Drug interactions

  • Drugs or herbal products that may decrease the effectiveness of hormonal contraceptives (eg, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, products containing St. John’s wort): Use an alternative method of contraception or a back-up method and continue backup contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability
  • Coadministration with colesevelam: Separate doses by 4 hr
  • Discontinue levonorgestrel oral/ethinylestradiol/ferrous bisglycinate prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; restart therapy ~2 weeks following completion of hepatitis C treatment (see Contraindications)
  • Also see Warnings

Discontinue if these adverse reactions occurs

  • Arterial thrombotic event or venous thromboembolic event occurs
  • Unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occurs
  • Jaundice develops

Hepatic impairment

  • Pharmacokinetics of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate have not been studied in women with hepatic impairment
  • Steroid hormones may be poorly metabolized in patients with hepatic impairment
  • See Contraindications and Warnings

Dosing Considerations

Switching to levonorgestrel oral/ethinylestradiol/ferrous bisglycinate from another contraceptive method

  • Transdermal patch: Start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate on the next scheduled application
  • Vaginal ring: Start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate on the day when next insertion would have been scheduled
  • Injection: Start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate on the day when next injection would have been scheduled
  • Intrauterine contraceptive (IUD): Start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate on the day of removal; if IUD is not removed on first day of the patient’s menstrual cycle, additional nonhormonal contraceptive (eg, condoms, spermicide) is needed for the first 7 days of the first cycle pack
  • Implant: Start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate on the day of removal

After abortion or miscarriage during first trimester

  • After a first-trimester abortion or miscarriage, start levonorgestrel oral/ethinylestradiol/ferrous bisglycinate immediately
  • Initiating within 5 days after pregnancy termination: No additional method of contraception is needed
  • Initiating >5 days after termination of pregnancy: Additional nonhormonal contraception (eg, condoms, spermicide) required for the first 7 days of first cycle pack
  • Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to increased risk of thromboembolic disease; start therapy following instructions for Day 1 or Sunday start, as desired; if using Sunday start, use additional non-hormonal contraception (such as condoms or spermicide) for first seven days of patient’s first cycle pack of contraceptive therapy

After childbirth

  • Do not start until 4 weeks after delivery owing to increased risk of thromboembolic disease
  • Start contraceptive therapy following instructions for women not currently using hormonal contraception
  • If woman has not yet had a period postpartum, consider possibility of ovulation and conception occurring prior to use of contraceptive therapy
  • CDC guidelines recommend waiting 3 weeks after delivery in postpartum women with no venous thromboembolism (VTE) risks and 3-6 weeks in postpartum women with additional VTE risks (Morbidity and Mortality Weekly; July 29, 2016)

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

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            Adverse Effects

            >10%

            Headache (14%)

            1-10%

            Metrorrhagia (8%)

            Dysmenorrhea (7%)

            Nausea (7%)

            Abdominal pain (4%)

            Breast pain (4%)

            Emotional lability (3%)

            Acne (3%)

            Depression (2%)

            Amenorrhea (2%)

            Vaginal moniliasis (2%)

            <1%

            Hypertension

            Hypercholesterolemia

            Weight gain

            Dysmenorrhea

            Flatulence

            Postmarketing Reports

            Cardiac disorder: Chest pain, dyspnea, palpitations

            Gastrointestinal disorders: Abdominal pain, nausea, vomiting, diarrhea

            General disorders and administration site conditions: Chest pain, fatigue, pain, malaise, injection site pain or erythema, feeling abnormal, pyrexia, condition aggravated, asthenia

            Immune system disorders: Hypersensitivity reactions, including pruritus, rash, urticaria, erythema

            Injury, poisoning, and procedural complications: Injury

            Investigations: Decreased weight

            Musculoskeletal and connective-tissue disorders: Pain in extremity, arthralgia, back pain, muscle spasm

            Nervous system disorders: Headache, migraine, dizziness, hypoesthesia, paresthesia

            Psychiatric disorders: Depression, insomnia, anxiety

            Reproductive system and breast disorders: Metrorrhagia, menorrhagia, hot flush, vaginal hemorrhage

            Respiratory, thoracic, and mediastinal disorders: Nasopharyngitis, cough

            Sleep disorders and disturbances: Somnolence

            Vascular disorders: Deep vein thrombosis, pulmonary embolism

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            Warnings

            Black Box Warnings

            Cigarette smoking & risk of cardiovascular disease

            • Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use
            • This risk increases with age (>35 years) and with heavy smoking (15 or more cigarettes/day)
            • For this reason, combined hormonal contraceptives (CHCs) are contraindicated in women aged >35 years who smoke

            Contraindications

            Liver tumors, benign or malignant, or liver disease (acute viral hepatitis or severe, decompensated, cirrhosis of the liver)

            Undiagnosed abnormal uterine bleeding

            Pregnancy (no reason to use CHCs during pregnancy)

            History or current breast cancer or other estrogen- or progestin-sensitive cancer

            Hypersensitivity

            Coadministration with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

            High risk of arterial or venous thrombotic disease

            • Smoking, if older than 35 years (see Black Box Warnings)
            • History or current deep vein thrombosis or pulmonary embolism
            • Inherited or acquired hypercoagulopathies
            • Cerebrovascular disease
            • Coronary artery disease
            • Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation)
            • Uncontrolled hypertension
            • Diabetes mellitus with vascular disease
            • Headaches with focal neurological symptoms or have migraine headaches with aura
            • Women over age 35 with any migraine headaches

            Cautions

            Risk of postpartum VTE decreases after third postpartum week, whereas risk of ovulation increases after third postpartum week; start contraceptive therapy no earlier than 4 weeks after delivery, in women who are not breastfeeding

            Acute or chronic disturbances of liver function may necessitate the discontinuation of CHCs use until liver function resolves to normal and CHC causation has been excluded

            Hepatic adenomas are associated with CHCs use; studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) combined oral contraceptive (COC) users (see Contraindications)

            Studies suggest a small increased relative risk of developing gallbladder disease among CHC users; use of CHCs may worsen existing gallbladder disease; past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use; women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis

            CHCs may decrease glucose tolerance; carefully monitor in prediabetes and diabetes

            Consider alternative contraception for women with uncontrolled dyslipidemia

            Small proportion of women will have adverse lipid changes while on CHCs; women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs

            If new headaches that are recurrent, persistent, or severe develop in women taking the drug, evaluate the cause and discontinue therapy if indicated (see Contraindications)

            This product contains FD&C yellow no. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons

            Carefully observe women with a history of depression, and discontinue therapy if depression recurs to a serious degree

            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 light

            Bleeding irregularities and amenorrhea

            • Unscheduled (breakthrough or intracyclic) bleeding and spotting may occur, especially during the first 3 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 contraceptive product
            • If scheduled (withdrawal) bleeding does not occur, consider possibility of pregnancy; if patient has not adhered to prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider possibility of pregnancy at time of first missed period and take appropriate diagnostic measures; if patient has adhered to prescribed regimen and misses two consecutive periods, rule out pregnancy
            • In clinical trial, 2.6% of the evaluable cycles were amenorrheic; women may experience amenorrhea or oligomenorrhea after discontinuation of CHCs, especially when such a condition was preexistent

            Thrombotic disorders and other vascular problems

            • Use of CHCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events
            • CHCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes)
            • If feasible, discontinue CHC at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE, as well as during the following prolonged immobilization
            • An increase in blood pressure has been reported in women taking CHCs, and this increase is more likely in older women with extended duration of use (see Contraindications); incidence of hypertension increases with increasing concentrations of progestin; monitor blood pressure periodically; stop therapy in women with well-controlled hypertension if blood pressure rises significantly

            Drug interactions overview

            • During clinical trials with the hepatitis C combination drug regimen containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, incidences of elevated ALT >5x ULN, including some cases >20x ULN, were significantly more frequent in women using ethinyl estradiol (EE)-containing medications, such as CHCs (see Contraindications)
            • Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding
            • Coadministration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 20-25%
            • Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation CYP3A4 inhibitors (eg, itraconazole, voriconazole, fluconazole, grapefruit juice, ketoconazole) may increase plasma hormone concentrations
            • Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of coadministration with HIV/HCV protease inhibitors and nonnucleoside reverse-transcriptase inhibitors CHCs containing EE may inhibit the metabolism of other compounds (eg, cyclosporine, prednisolone, theophylline, tizanidine, voriconazole) and increase their plasma concentrations
            • CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam, and lamotrigine; significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation
            • Estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin; dose of replacement thyroid hormone or cortisol therapy may need to be increased
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            Pregnancy & Lactation

            Pregnancy

            Contraindicated in pregnancy because there is no reason to use combined hormonal contraceptives (CHCs) in pregnancy (see Contraindications)

            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 CHCs before conception or during early pregnancy

            Lactation

            Combined hormonal contraceptives (CHCs) and/or metabolites are present in human milk and in breastfed infants

            CHCs, including levonorgestrel oral/ethinylestradiol/ferrous bisglycinate, can reduce milk production in breastfeeding females; reduction can occur at any time but is less likely to occur once breastfeeding

            Advise nursing female to use other methods of contraception until she discontinues breastfeeding

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Ethinyl Estradiol (EE): Reduces luteinizing hormone-releasing hormone release from hypothalamus; reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

            Levonorgestrel: Synthetic progestin; ovulation is inhibited from a negative feedback mechanism on hypothalamus, leading to reduced secretion of follicle-stimulating hormone and luteinizing hormone and LH

            Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation

            Absorption

            AUC: 41.7 ng·hr/mL (levonorgestrel); 1167 pg·hr/mL (EE)

            Peak plasma concentration: 4.4 ng/mL (levonorgestrel); 115 pg/mL (EE)

            Bioavailability after first-pass metabolism: ~100% (levonorgestrel); 38-48% (EE)

            Peak plasma time, single dose of two levonorgestrel and EE: 1 hr (levonorgestrel); 1.5 hr (EE)

            Distribution

            Protein bound (albumin): ~97% (EE)

            Metabolism

            Levonorgestrel

            • Most important metabolic pathway occurs in the reduction of the delta, 4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation
            • Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides
            • Some of the parent levonorgestrel also circulates as 17β-sulfate

            Ethinyl estradiol

            • CYP3A4 in the liver is responsible for the 2-hydroxylation that is the major oxidative reaction
            • 2-Hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion
            • CYP3A levels vary widely among individuals and can explain the variation in rates of EE 2-hydroxylation
            • EE is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation

            Elimination

            Half-life: 34 hr (single dose levonorgestrel); 17 hr (EE)

            Excretion: 40-68% (urine); 16-48% (feces)

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            Administration

            Oral Administration

            Starting CHCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start)

            • Tablet color
              • Active tablets: Orange (Day 1-21)
              • Placebo tablet: Blue (Day 22-28)
            • Day 1 start
              • Administer 1 tablet qDay at the same time each day
              • Take 1 orange tablet on the first day of period; take subsequent orange tablets once daily for a total of 21 days
              • Take 1 blue tablet daily for 7 days
              • Begin each subsequent pack on the same day of the week as the first cycle pack (eg, on the day after taking the last blue placebo tablet)
            • Sunday start
              • Administer 1 tablet qDay at the same time each day
              • Take first orange tablet on the first Sunday after the onset of menses
              • Owing to the potential risk of becoming pregnant, use additional nonhormonal contraception (eg, condoms or spermicide) for the first 7 days of the patient’s first cycle pack
              • Take subsequent orange tablets once daily for a total of 21 days
              • Take 1 blue tablet daily for the following 7 days
              • Begin each subsequent pack on the same day of the week as the first cycle pack

            Missed dose

            • If one orange tablet is missed in Weeks 1, 2, or 3: Take orange tablet as soon as possible; continue taking 1 tablet qDay until the pack is finished
            • If two orange tablets are missed in Week 1 or 2: Take 2 missed tablets as soon as possible and the next 2 orange tablets the next day; continue taking 1 tablet qDay until the pack is finished; additional nonhormonal contraception (eg, condoms or spermicide) should be used as backup if the patient has sex within 7 days after missing tablets
            • If two orange tablets are missed in Week 3 or ≥3 orange tablets are missed in a row in Weeks 1, 2, or 3
              • Day 1 start: Throw out remaining pack and start a new pack that same day
              • Sunday start: Continue taking 1 tablet qDay until Sunday, then throw out the remaining pack and start a new pack that same day; additional nonhormonal contraception (such as condoms or spermicide) should be used as backup if the patient has sex within 7 days after missing tablets
            • Gastrointestinal disturbances
              • In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken
              • If vomiting or diarrhea occurs within 3-4 hr after taking an orange tablet, handle this as a missed dose

            Storage

            Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Protect from light

            Keep out of the reach of children

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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