Mechanism of effect
Synthetic progestin, ovulation is inhibited from a negative feedback mechanism on hypothalamus, leading to reduced secretion of FSH and LH
Pharmacodynamic
Levonorgestrel: Progestin; inhibits secretion of gonadotropins from pituitary; prevents follicular maturation and ovulation; stimulates growth of mammary tissues
Ethinyl estradiol: Reduces release of luteinizing hormone-releasing hormone (LHRH) from hypothalamus; reduces release of gonadotropin from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues
Pharmacokinetics
Absorption
Bioavailability (levonorgestrel): Nearly 100%; rapidly and almost completely absorbed; not subject to first-pass metabolism; (ethinyl estradiol): 43%; rapidly and almost completely absorbed from gastrointestinal (GI) tract; subject to first-pass metabolism in gut mucosa and liver
Distribution
Protein bound (levonorgestrel): 97.5-99% (principally to sex hormone-binding globulin [SHBG] and, to a lesser extent, to serum albumin); (ethinyl estradiol): 95-97% (to serum albumin)
Vd (levonorgestrel): 1.8 L/kg; (ethinyl estradiol): 4.3 L/kg
Metabolism
Levonorgestrel: Forms conjugated metabolites
Ethinyl estradiol: Metabolized in liver by CYP3A4 to estriol and estrone
Elimination
Half-life (levonorgestrel): 22-49 hr (after single dose); (ethinyl estradiol): 12-23 hr
Excretion (levonorgestrel and metabolites): Urine (40-68%) and feces (16-48%), mostly as glucuronide conjugates; (ethinyl estradiol): Urine and feces, as glucuronide and sulfate conjugates
Drug indications
ContraceptiveDosage
(Regimens vary; see package inserts (follow manufacturer's color-coding for sequence
Missed Active Contraceptive Dose
One active tablet missed
- Take 1 tablet as soon as possible, or take 2 tablets on following day
- Alternatively, take 1 tablet, discard missed tablet, and continue taking subsequent tablets as scheduled
- Use other forms of contraception for next 7 days after missed dose or until menses occur
Two active tablets missed consecutively
- Take 2 tablets as soon as remembered and continue taking as scheduled
- Alternatively, take 2 tablets daily for the next 2 days and continue taking as scheduled
- Missed 3rd week of cycle and patient is Sunday Starter: Take 1 pill every day until Sunday; discard rest of pack, and start new pack that same day
- Missed 3rd week of cycle and patient is day-1 starter: Discard rest of pack, and start new pack that same day
- Use other forms of contraception for next 7 days after missed dose or until menses occur
- Menses may not occur this month; if menses do not occur for 2 consecutive months, contact healthcare provider about possibility of pregnancy
Three active tablets missed consecutively
- Sunday starter: Take 1 pill every day until Sunday; discard rest of pack, and start new pack that same day
- Day-1 starter: Discard rest of pack, and start new pack that same day
- Use other forms of contraception for next 7 days after missed dose or until menses occur
- Menses may not occur this month; if menses do not occur for 2 consecutive months, contact healthcare provider about possibility of pregnancy
Drug contraindications
liver failure , renal failure , Hypersensitivity to this drug , acute arterial thrombi and embolism , Coronary Artery Disease (CAD , the acute treatment of migraine with or without aura in adults , adrenal insufficiencySide effects
Migraine , Headache , Angioedema , urticaria , Hypertension , pulmonary embolism , hemorrhage , hirsutism , flatulence , local thrombophlebitis , acute arterial thrombi and embolismArterial thromboembolism
Interactions
Exemestane , Enoxaparin , Oxecarbazepin , Bosentan , Protamine sulfat , Primidone , calaspargase , sugammadex sodium , lesinurad , fondaparinux , st. john's wort , Eslicarbazepine acetate , voxelotor , tucatinib , Ombitasvir, Paritaprevir, and Ritonavir , elagolix , Pretomanid , Fedratinib , ivosidenib , Bemiparin , Elvitegravir , Butabarbital , Antithrombin alfa , Secobarbital , Apalutamide , encorafenib , pexidartinib , Dalteparin , Efavirenz , Tipranavir , lumacaftor and Ivacaftor , Antithrombin III , Perampanel , Metyrapone , Lopinavir , Indinavir , Armodafinil , Idelalisib , brigatinib , nelfinavir , nevirapine , Fosamprenavir , Phenindione , Bivalirudin , Argatroban , Darunavir , Quinidine , Pentobarbital , Amobarbital , ritonavir , saquinavir , Carbamazepine , Chloramphenicol , Rifabutin , Rifapentine , Atazanavir , Ranolazine , Griseofulvin , Letrozole , Mycophenolate mofetil , Modafinil , Heparin , Warfarin , Tranexamic acid , Topiramate , Dexamethasone , Rifampin , Phenobarbital , Phenytoin , sirukumabAlerts
Use caution in patients with family history of breast cancer, DVT/PE, or both; current or previous depression, endometriosis, diabetes mellitus, hypertension, bone mineral density changes, renal or hepatic impairment, bone metabolic disease, systemic lupus erythematosus (SLE); conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy)
Risk of VTE is highest during first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer; risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued; use of COCs increases risk of arterial thromboses that result in strokes and myocardial infarctions, especially in women with other risk factors for these events; COCs have been shown to increase both relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes); risk increases with age, particularly in women over 35 years of age who smoke
Discontinue therapy if an arterial thrombotic event or venous thromboembolic (VTE) event occurs; if feasible, stop therapy 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 and following prolonged immobilization; initiate therapy no earlier than 4 weeks after delivery in women who are not breastfeeding; risk of postpartum VTE decreases after third postpartum week, whereas risk of ovulation increases after third postpartum week
Discontinue if the following develop: Jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery
Discontinue 4 weeks before major surgery or prolonged immobilization
Discontinue drug prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; therapy can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen
Use of warfarin or other oral anticoagulants (increase in anticoagulant dose may be warranted)
Estrogen component of COCs may raise 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
Some studies link oral contraceptive use with increased risk of breast cancer, whereas others do not; risk depends on conditions where naturally high hormone levels persist for long periods, including early-onset menstruation (age <12 years), late-onset menopause (age >55 years), first child after age 30 years, nulliparity
Increased risk of cervical cancer with oral contraceptive use, however, human papillomavirus (HPV) remains primary risk factor for this cancer
Discontinue hormonal therapy prior to starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; may restart approximately 2 weeks following completion of treatment with combination drug regimen
Long-term (≥5 years) use of oral contraceptives may be associated with increased risk
Increased risk of liver cancer with oral contraceptive use; risk increases with duration of use
CDC guidelines recommend waiting ≥3 weeks after vaginal birth or ≥6 weeks after cesarean section to decrease risk of VTE before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum status) should not use combined hormonal contraceptives
Scheduled withdrawal bleeding does not occur with therapy; the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize; if pregnancy suspected, a pregnancy test should be performed
Benign hepatic adenomas are associated with oral contraceptive use; rupture of rare, benign, hepatic adenomas may cause death through intraabdominal hemorrhage
Retinal thrombosis associated with use of oral contraceptives that may lead to partial or complete loss of vision reported; oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions; appropriate diagnostic and therapeutic measures should be undertaken immediately
Increased risk of myocardial infarction attributed to oral contraceptive use; risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes
An increased risk of venous thromboembolic and thrombotic disease associated with use of oral contraceptives is well established; the excess risk is highest during the first year a woman ever uses a combined oral contraceptive
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 receiving therapy
Oral contraceptives have been shown to increase both relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, risk is greatest among older (>35 years), hypertensive women who also smoke
Not for use in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver; acute or chronic disturbances of liver function may necessitate discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded; discontinue therapy if jaundice develops
Women with migraine (particularly migraine/ headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at increased risk of stroke
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease
A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents; a decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease; 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 control of hyperlipidemias more difficult; nonhormonal contraception should be considered in women with uncontrolled dyslipidemias; persistent hypertriglyceridemia may occur; elevations of plasma triglycerides may lead to pancreatitis and other complications
Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations
Increase in blood pressure reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use; women with history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception; if women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued
Onset or exacerbation of migraine or development of headache with new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause
The convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures
Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care
For women with well-controlled hypertension, monitor blood pressure and stop treatment if blood pressure rises significantly
Studies suggest a small increased relative risk of developing gallbladder disease among COC users; use of COCs may worsen existing gallbladder disease; a past history of COC-related cholestasis predicts an increased risk with subsequent COC use; women with a history of pregnancy-related cholestasis may be at increased risk for COC related cholestasis
If a woman receiving therapy develops new headaches that are recurrent, persistent, or severe, evaluate cause and discontinue therapy if indicated; consider discontinuation in case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event)
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
Women receiving therapy may experience amenorrhea, absence of withdrawal bleeding, even if they are not pregnant; 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
Points of recommendation
Cigarette smoking & risk of cardiovascular disease
- Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use
- Risk increases with age (>35 years) and with heavy smoking (≥15 cigarettes/day)
- Advise women who use hormonal oral contraceptives not to smoke
- Not for the treatment of patients who use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations
Pregnancy level
There is little or no increased risk of birth defects in women who inadvertently use combination oral contraceptives during early 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 low dose combination oral contraceptives prior to conception or during early pregnancy
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