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ORAL CONTRACEPTIVES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Oral contraceptives are usually estrogen and progesterone combinations that are taken orally by women to prevent pregnancy.
    1) Combined, classical, or balanced contraceptive: a combination of an orally active progestin and estrogen.
    2) TRIPHASIC CONTRACEPTIVE:
    a) A combination of orally active progestin and estrogen with the dosage varied at different times in the cycle.
    3) SEQUENTIAL CONTRACEPTIVE: An estrogen is administered from the 5th to 20th or 21st day of menstrual cycle and then estrogen and progesterone for the next 5 to 7 days.

Specific Substances

    1) Contraceptives, oral
    1.2.1) MOLECULAR FORMULA
    1) DIENOGEST: C20H25NO2
    2) DROSPIRENONE: C24H30O3
    3) ESTRADIOL VALERATE: C23H32O3
    4) ETHINYL ESTRADIOL: C20H24O2

Available Forms Sources

    A) FORMS
    1) A large variety of prescription products is available--see individual products for specific names and/or ingredients. Some currently marketed iron-containing oral contraceptives are:
    1) Norlestrin FE 1/50(R), Parke-Davis
    2) Norlestrin FE 2.5/50(R), Parke-Davis
    3) Loestrin FE 1.5/50(R), Parke-Davis
    4) Loestrin FE 1/20(R), Parke-Davis
    2) COMMERCIALLY AVAILABLE COMBINATIONS
    a) Monophasic oral contraceptives
    Estrogen (mcg)Progestin (mg)
    Mestranol 100Norethynodrel 2.5
    Mestranol 100Norethindrone 2
    Mestranol 100Ethynodiol diacetate
    Mestranol 80Norethindrone 1
    Mestranol 75Norethynodrel 5
    Mestranol 50Norethindrone 1
    Ethinyl estradiol 50Norethindrone 1
    Ethinyl estradiol 50Norethindrone acetate 1
    Ethinyl estradiol 50Ethynodiol diacetate 1
    Ethinyl estradiol 50Norethindrone acetate 2.5
    Ethinyl estradiol 50Norgestrel 0.5
    Ethinyl estradiol 35Norethindrone 1
    Ethinyl estradiol 35Norethindrone 0.5
    Ethinyl estradiol 35Norethindrone 0.4
    Ethinyl estradiol 35Ethynodiol diacetate 1
    Ethinyl estradiol 30Norethindrone acetate 1.5
    Ethinyl estradiol 30Norgestrel 0.3
    Ethinyl estradiol 30Levonorgestrel 0.15
    Ethinyl estradiol 20Norethindrone acetate 1

    3) BIPHASIC ORAL CONTRACEPTIVES
    a) Phase 1 (10 tablets) contain:
    1) Ethinyl estradiol 35 mcg
    2) Norethindrone 0.5 mg
    b) Phase 2 (11 tablets) contain:
    1) Ethinyl estradiol 35 mcg
    2) Norethindrone 1 mg
    4) TRIPHASIC ORAL CONTRACEPTIVES
    a) Tri-Norinyl(R), Syntex
    1) phase 1 (7 tablets)
    2)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 0.5 mg
    3) phase 2 (9 tablets)
    4)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 1 mg
    5) phase 3 (5 tablets)
    6)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 0.5 mg
    b) Ortho Novum 7/7/7(R), Ortho
    1) phase 1 (7 tablets)
    2)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 0.5 mg
    3) phase 2 (7 tablets)
    4)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 0.75 mg
    5) phase 3 (7 tablets)
    6)
    a) ethinyl estradiol 35 mcg
    b) norethindrone 1 mg
    c) Tri-Levlen(R), Berlex and Triphasil(R), Wyeth-Ayerst
    1) phase 1 (6 tablets)
    2)
    a) ethinyl estradiol 30 mcg
    b) levonorgestrel 0.05 mg
    3) phase 2 (5 tablets)
    4)
    a) ethinyl estradiol 40 mcg
    b) levonorgestrel 0.075 mg
    5) phase 3 (10 tablets)
    6)
    a) ethinyl estradiol 30 mcg
    b) levonorgestrel 0.125 mg
    5) THIRD-GENERATION ORAL CONTRACEPTIVES
    a) Third-generation oral contraceptives include those containing either gestodene or desogestrel. Due to an increased risk of cerebral venous sinus thrombosis and venous thromboembolism, their use is limited (de Bruijn et al, 1998; Jick et al, 1998).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: To suppress the follicle-stimulating hormone luteinizing hormone sequence from the anterior pituitary, resulting in the suppression of ovulation and production of mucus that is less acceptable to spermatozoa.
    B) PHARMACOLOGY: An oral contraceptive acts by suppression of gonadotropins.
    C) TOXICOLOGY: There are no significant toxic effects from overdose.
    D) WITH THERAPEUTIC USE
    1) Abdominal pain, nausea, vomiting, headaches, breast tenderness, dysmenorrhea, arterial thromboembolism, hypertension, venous thrombosis, pulmonary embolus, cerebral thrombosis.
    E) WITH POISONING/EXPOSURE
    1) Nausea and vomiting with iron containing contraceptives in children, otherwise asymptomatic.
    0.2.20) REPRODUCTIVE
    A) Oral contraceptives and ethinyl estradiol are classified as FDA pregnancy category X. Oral contraceptives are contraindicated during pregnancy and there is no need for their use during pregnancy. Oral contraceptives are excreted into breast milk and may decrease the quantity and quality of breast milk.
    0.2.21) CARCINOGENICITY
    A) There is an increased risk of cervical cancer or intraepithelial neoplasia according to some studies. However, causality of combination oral contraceptives is controversial due to other competing factors, including differing sexual behaviors.
    B) Although past studies have shown a possible association between increased rates of breast cancer and combination oral contraceptive use, recent studies do not confirm this association.
    C) There is an increased risk of hepatocellular carcinoma with long-term (longer than 8 years) combination contraceptive use; however, attributable risk of hepatic cancers is less than one case per million combination oral contraceptive users.
    D) ESTRADIOL VALERATE/DIENOGEST
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of estradiol valerate/dienogest.

Laboratory Monitoring

    A) Concentrations of the hormones in oral contraceptives are not clinically useful.
    B) No routine laboratory studies are needed in most patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The vast majority of oral contraceptive overdoses require only supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity is not expected in single substance oral contraceptive ingestion.
    C) DECONTAMINATION
    1) There is no need for GI decontamination.
    D) AIRWAY MANAGEMENT
    1) Patients with single substance oral contraceptive ingestion will not require airway management.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis and hemoperfusion are not of value.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with inadvertent ingestions can be managed at home. If oral contraceptives containing iron are ingested, asymptomatic patients ingesting less than 40 mg/kg elemental iron can be managed at home.
    2) OBSERVATION CRITERIA: The following patients should be sent to a healthcare facility for evaluation: Patients with self-harm ingestions; patients ingesting iron-containing oral contraceptives at a dose of more than 40 mg/kg elemental iron or who have symptoms (nausea, vomiting, or other gastrointestinal complaints).
    3) ADMISSION CRITERIA: Patients with pure oral contraceptive overdoses do not need admission. Children with exposure to iron-containing products should follow the iron guidelines for admission.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients for any additional questions.
    H) PITFALLS
    1) Not identifying a possible iron exposure. Not identifying other co-ingestants that could cause toxicity. Not evaluating a patient for the possibility of thromboembolic complications when clinically indicated.
    I) PHARMACOKINETICS
    1) Oral bioavailability depends of the formulation of the product. Transdermal products are designed to release their formulation over a longer period of time. Injectable products can last several months. Always consult the package insert for specific information.
    J) TOXICOKINETICS
    1) Given the asymptomatic nature of overdoses, toxicokinetics are not well described.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other non-toxic ingestions, iron toxicity.

Range Of Toxicity

    A) TOXICITY: A human toxic dose has not been established. Significant toxicity has not been reported after overdose. THERAPEUTIC DOSE: Oral contraceptives are available in various brands, doses, and formulations.

Clinical Effects

Summary Of Exposure

    A) USES: To suppress the follicle-stimulating hormone luteinizing hormone sequence from the anterior pituitary, resulting in the suppression of ovulation and production of mucus that is less acceptable to spermatozoa.
    B) PHARMACOLOGY: An oral contraceptive acts by suppression of gonadotropins.
    C) TOXICOLOGY: There are no significant toxic effects from overdose.
    D) WITH THERAPEUTIC USE
    1) Abdominal pain, nausea, vomiting, headaches, breast tenderness, dysmenorrhea, arterial thromboembolism, hypertension, venous thrombosis, pulmonary embolus, cerebral thrombosis.
    E) WITH POISONING/EXPOSURE
    1) Nausea and vomiting with iron containing contraceptives in children, otherwise asymptomatic.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Abnormal ocular conditions have been reported in patients taking oral contraceptives chronically, including conditions affecting the CNS primarily and affecting the eyes secondarily, and those involving the optic nerve and retina. No cause and effect relationship has been established (Grant, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) THROMBOEMBOLIC DISEASE: An increased incidence of venous thrombosis, DVT, pulmonary embolism, thrombotic stroke, and cardiovascular disease has been associated with chronic oral contraceptive use (Prod Info femhrt(R) oral tablets, 2011; Anon, 1976).
    b) A case control study reported 34 out of 40 women (85%), ages 15 to 64 years, with diagnosed cerebral venous sinus thrombosis (CVST) had been using oral contraceptives at the time of CVST. Of these 34 women, 19 (56%) had taken third-generation (gestodene or desogestrel) contraceptives. The authors concluded that users of third-generation contraceptives were at an increased risk for CVST compared with users of other oral contraceptives (de Bruijn et al, 1998a).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) The use of oral contraceptives appears to contribute to the risk of myocardial infarction when other risk factors (cigarette smoking, hypertension, diabetes, hypercholesterolemia, toxemia of pregnancy, or obesity) were present (Mann, 1975).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Chronic use of oral contraceptives has been associated with the development of essential hypertension in some patients (Anon, 1976).
    D) CEREBROVASCULAR DISEASE
    1) WITH POISONING/EXPOSURE
    a) A 36 year old woman presented with headache, somnolence and left sided weakness. Evaluation revealed occlusion of the right common carotid artery and an ischemic stroke. Lipid profile, thyroid tests, serologic tests for HIV, syphilis and borreliosis, antithrombin III, protein C, protein S, lupus procoagulant, and antiphospholipid antibodies were all normal or negative. She smoked 20 cigarettes a day. The patient had used post coital contraception consisting of 5 pills daily for 3 days, each pill containing 50 mcg ethinylestradiol and 250 mcg levonorgestrel. This represents a 4 fold overdose and was felt to be responsible for her stroke (Sanchez-Ojanguren et al, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Subcortical disturbance was noted on a EEG performed on the first day following a single oral dose of 160 mg of estradiol valerate. The EEG one week after the overdose was normal (Punnonen & Salmi, 1983).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported with the use of ethinyl estradiol/norethindrone acetate oral contraceptive therapy (Prod Info Junel(R) 1/20 oral tablets, 2011; Prod Info Junel(R) 1.5/30 oral tablets, 2011; Prod Info LOESTRIN(R) 1/20 21 Day oral tablets, 2009; Prod Info LOESTRIN(R) 1.5/30 21 Day oral tablets, 2009; Prod Info MICROGESTIN(R) 1/20 oral tablets, 2007; Prod Info MICROGESTIN(R) 1.5/30 oral tablets, 2007; Prod Info Tri-Legest(R) 21 oral tablets, 2012).
    b) CASE REPORT: Headache was reported following a single acute ingestion of 160 mg of estradiol valerate in a 19-year-old woman (Punnonen & Salmi, 1983).
    C) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) In a literature review of the risk of stroke in patients taking low-dose oral contraceptives (less than 50 mcg ethinyl estradiol), the pooled odds ratios (ORs) from the 16 case-control studies found an increased risk of thrombotic stroke (OR, 2.74; 95% CI 2.24 to 3.35) but not hemorrhagic stroke (OR 1.3; 95% confidence interval (CI), 0.99 to 1.71). The pooled odds ratio from the 4 cohort studies showed no increased risk of stroke associated with oral contraceptive use (OR, 0.95; 95% CI, 0.51 to 1.78) (Chan et al, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Acute (single) overdose of oral contraceptives is only occasionally (less than 10%) associated with nausea or vomiting (Mofenson et al, 1984).
    b) CASE REPORT: Nausea was reported following a single acute ingestion of 160 mg of estradiol valerate in a 19-year-old woman (Punnonen & Salmi, 1983).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal cramps have been reported with the use of ethinyl estradiol/norethindrone acetate oral contraceptive therapy (Prod Info Junel(R) 1/20 oral tablets, 2011; Prod Info Junel(R) 1.5/30 oral tablets, 2011; Prod Info LOESTRIN(R) 1/20 21 Day oral tablets, 2009; Prod Info LOESTRIN(R) 1.5/30 21 Day oral tablets, 2009; Prod Info MICROGESTIN(R) 1/20 oral tablets, 2007; Prod Info MICROGESTIN(R) 1.5/30 oral tablets, 2007; Prod Info Tri-Legest(R) 21 oral tablets, 2012).
    C) CHOLECYSTITIS
    1) WITH THERAPEUTIC USE
    a) GALLBLADDER DISEASE: The use of oral contraceptives has been associated with gallbladder disease (Anon, 1976).
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute pancreatitis was associated with the use of an estrogen-containing contraceptive in a 23-year-old woman (Parker, 1983).
    E) ULCER OF ESOPHAGUS
    1) WITH POISONING/EXPOSURE
    a) Esophageal ulcers have been seen in patients where oral contraceptives have become stuck in the esophagus and dissolved there. This occurred after ingesting the tablets without water, then lying down (Oren & Fich, 1991).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) BENIGN NEOPLASM OF LIVER
    1) WITH THERAPEUTIC USE
    a) HEPATIC ADENOMAS: Benign hepatic adenomas have been associated with the use of oral contraceptives (Baum, 1973; Stauffer, 1975; Antoniades, 1975; Ameriks, 1975; Sherlock, 1975).
    1) Malignant transformation was reported in one case (Davis, 1975).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSMENORRHEA
    1) WITH THERAPEUTIC USE
    a) Dysmenorrhea has been reported with oral contraceptive use (Prod Info COMBIPATCH(R) transdermal system, 2006).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) WITHDRAWAL BLEEDING
    1) WITH THERAPEUTIC USE
    a) Withdrawal bleeding following chronic exposure has been reported, but vaginal bleeding has not been described after acute ingestions (Prod Info Estrostep, 2001).
    B) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a prospective observational study by the Western Australian Poisons Information Centre (WAPIC) of 41 female toddlers (mean age, 34 months (33.5 +/- 10.2 months; range, 14 to 57 months)) with unintentional acute exposure to oral contraceptive pills containing ethinylestradiol, no major effects or cases of vaginal bleeding were reported. The median number of active pills ingested was 4 with the mean dose of ethinylestradiol (the only estrogen present in oral contraceptives available in Australia) being 288.1 +/- 357 mcg (range, 30 to 2310 mcg; median 150 mcg). Follow-up calls were made 3 to 11 days after exposure. The authors concluded that a single dose of 150 mcg of ethinylestradiol would not induce endometrial proliferation. However, based on the small sample size, a larger study is suggested. It was also thought that the number of pills ingested by the children in this study may have been an overestimation (Lynch et al, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Oral contraceptives and ethinyl estradiol are classified as FDA pregnancy category X. Oral contraceptives are contraindicated during pregnancy and there is no need for their use during pregnancy. Oral contraceptives are excreted into breast milk and may decrease the quantity and quality of breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) DROSPIRENONE/ETHINYL ESTRADIOL/LEVOMEFOLATE: An increased risk of birth defects has not been demonstrated in infants following maternal use of combination oral contraceptives before pregnancy. There is no evidence of teratogenicity, particularly limb reduction or cardiovascular defects, when women inadvertently used the combination contraceptive early in pregnancy (Prod Info SAFYRAL(TM) oral tablets, 2010; Prod Info BEYAZ(R) oral tablets, 2010).
    2) ESTRADIOL VALERATE/DIENOGEST: An increased risk of birth defects has not been demonstrated in infants following maternal use of estradiol valerate/dienogest before pregnancy. There is no evidence of teratogenicity, particularly limb reduction or cardiovascular defects, when women inadvertently used the combination contraceptive early in pregnancy (Prod Info NATAZIA(R) oral tablets, 2012).
    3) ETHINYL ESTRADIOL/LEVONORGESTREL: An increased risk of birth defects has not been demonstrated in infants following maternal use of ethinyl estradiol/levonorgestrel before pregnancy. There is no evidence of teratogenicity, particularly limb reduction or cardiovascular defects, when women inadvertently used the combination contraceptive early in pregnancy (Prod Info SEASONALE(R) oral tablets, 2009).
    4) ETHINYL ESTRADIOL/NORGESTIMATE: An increased risk of birth defects has not been demonstrated in infants following maternal use of ethinyl estradiol/norgestimate before pregnancy. There is no evidence of teratogenicity, particularly limb reduction or cardiovascular defects, when women inadvertently used combination contraceptives early in pregnancy (Prod Info ORTHO TRI-CYCLEN(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Oral contraceptives, including ethinyl estradiol-containing contraceptives, are FDA pregnancy category X. Oral contraceptives are contraindicated during pregnancy as there is no need for their use during pregnancy (Prod Info SAFYRAL(TM) oral tablets, 2010; Prod Info BEYAZ(R) oral tablets, 2010; Prod Info SEASONALE(R) oral tablets, 2009).
    B) HEART MALFORMATION
    1) CASE REPORT: There is a single case of an infant with transposition of the great vessels born to a 24-year-old woman who ingested 120 to 150 combined oral contraceptive pills early in the first trimester of pregnancy. However, no cause and effect relationship could be determined (Redline & Abramowsky, 1981).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Small quantities of oral contraceptive steroids and metabolites are present in breast milk of women using oral contraceptives. Estrogen-containing oral contraceptives may also reduce breast milk production (Prod Info ORTHO TRI-CYCLEN(R) oral tablets, 2015; Prod Info NATAZIA(R) oral tablets, 2012; Prod Info SAFYRAL(TM) oral tablets, 2010; Prod Info BEYAZ(R) oral tablets, 2010; Prod Info SEASONALE(R) oral tablets, 2009). An alternate form of contraception should be used during breastfeeding until the child is completely weaned from breast milk (Prod Info ORTHO TRI-CYCLEN(R) oral tablets, 2015)
    2) DROSPIRENONE/ETHINYL ESTRADIOL/LEVOMEFOLATE: When oral drospirenone 3 mg/ethinyl estradiol 0.03 mg tablets were administered to postpartum women, approximately 0.02% of the drospirenone dose was excreted into the breast milk within 24 hours which would result in a maximum daily drospirenone dose of approximately 0.003 mg in a nursing infant (Prod Info SAFYRAL(TM) oral tablets, 2010; Prod Info BEYAZ(R) oral tablets, 2010).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) There is an increased risk of cervical cancer or intraepithelial neoplasia according to some studies. However, causality of combination oral contraceptives is controversial due to other competing factors, including differing sexual behaviors.
    B) Although past studies have shown a possible association between increased rates of breast cancer and combination oral contraceptive use, recent studies do not confirm this association.
    C) There is an increased risk of hepatocellular carcinoma with long-term (longer than 8 years) combination contraceptive use; however, attributable risk of hepatic cancers is less than one case per million combination oral contraceptive users.
    D) ESTRADIOL VALERATE/DIENOGEST
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of estradiol valerate/dienogest.
    3.21.3) HUMAN STUDIES
    A) CERVICAL CANCER
    1) There is an increased risk of cervical cancer or intraepithelial neoplasia according to some studies. However, causality of combination oral contraceptives is controversial due to other competing factors, including differing sexual behaviors (Prod Info Natazia oral tablets, 2010)
    B) HEPATOCELLULAR CARCINOMA
    1) There is an increased risk of hepatocellular carcinoma with long-term (longer than 8 years) combination contraceptive use; however, attributable risk of hepatic cancers is less than one case per million combination oral contraceptive users (Prod Info Natazia oral tablets, 2010).
    C) LACK OF EFFECT
    1) BREAST CANCER
    a) Although past studies have shown a possible association between increased rates of breast cancer and combination oral contraceptive use, recent studies do not confirm this association (Prod Info Natazia oral tablets, 2010).
    3.21.4) ANIMAL STUDIES
    A) STROMAL UTERINE POLYPS
    1) ESTRADIOL VALERATE/DIENOGEST
    a) MICE: There was a significantly higher incidence of stromal polyps of the uterus when female mice were given oral dienogest doses of 100 mg/kg/day (10.6 times the human dose of 3 mg based on dienogest AUC) in a 24-month carcinogenicity study in which male mice were given oral dienogest doses of 5, 15, and 50 mg/kg/day and female mice were given oral doses of 10, 30, and 100 mg/kg/day (1.1, 3.5, and 10.6 times the human dose) (Prod Info Natazia oral tablets, 2010).
    B) LACK OF EFFECT
    1) ESTRADIOL VALERATE/DIENOGEST
    a) RATS: There was no evidence of drug-related neoplasms when rats were given oral dienogest doses of 1, 3, and 10 mg/kg/day (0.2, 1.4 and 6.1 times the human dose of 3 mg based on dienogest AUC) in a 104-week carcinogenicity study (Prod Info Natazia oral tablets, 2010).

Genotoxicity

    A) ESTRADIOL VALERATE/DIENOGEST
    1) Dienogest was NOT mutagenic in the following tests: in vitro reverse mutation tests in bacteria, chromosome aberration tests in human lymphocytes, mouse lymphoma cells, and Chinese hamster lung cells, and tests of unscheduled DNA synthesis (UDS) in rat and human liver cells. Results of an in vivo mouse micronucleus test, a rat liver initiation-promotion model, and an in vitro/in vivo UDS test in female rats were also negative with dienogest (Prod Info Natazia oral tablets, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Concentrations of the hormones in oral contraceptives are not clinically useful.
    B) No routine laboratory studies are needed in most patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with pure oral contraceptive overdoses do not need admission. Children with exposure to iron-containing products should follow the iron guidelines for admission.
    B) If a multiple ingestion is suspected or the oral contraceptive contains iron gastric decontamination may be considered.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with inadvertent ingestions can be managed at home. If oral contraceptives containing iron are ingested, asymptomatic patients ingesting less than 40 mg/kg elemental iron can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients for any additional questions.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) The following patients should be sent to a healthcare facility for evaluation: Patients with self-harm ingestions; patients ingesting iron-containing oral contraceptives at a dose of more than 40 mg/kg elemental iron or who have symptoms (nausea, vomiting, or other gastrointestinal complaints).

Monitoring

    A) Concentrations of the hormones in oral contraceptives are not clinically useful.
    B) No routine laboratory studies are needed in most patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) There is no need for GI decontamination.
    6.5.2) PREVENTION OF ABSORPTION
    A) There is no need for GI decontamination.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Acute overdose of oral contraceptives generally requires no treatment.
    2) Monitor patient for toxic symptoms and treat symptomatically.
    a) CASE SERIES/LACK OF EFFECT: In a prospective observational study by the Western Australian Poisons Information Centre of 41 female toddlers (mean age: 34 months (33.5 +/- 10.2 months; range: 14-57 months)) with unintentional acute exposure to oral contraceptive pills containing ethinylestradiol, no major effects or cases of vaginal bleeding were reported. The median number of active pills ingested was 4 with the mean dose of ethinylestradiol being 288.1 +/- 357 mcg (range: 30-2310 mcg; median 150 mcg). In nine cases (male or female) the child purportedly ingested the entire month's supply or more. Only 4 children developed symptoms including lethargy, vomiting, and retching. The authors concluded that a single dose of 150 mcg of ethinylestradiol would not induce endometrial proliferation. Further studies with a larger sample size are suggested (Lynch et al, 2009).
    B) MONITORING OF PATIENT
    1) Concentrations of the hormones in oral contraceptives are not clinically useful.
    2) No routine laboratory studies are needed in most patients.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis and hemoperfusion are not of value.

Range Of Toxicity

Summary

    A) TOXICITY: A human toxic dose has not been established. Significant toxicity has not been reported after overdose. THERAPEUTIC DOSE: Oral contraceptives are available in various brands, doses, and formulations.

Therapeutic Dose

    7.2.1) ADULT
    A) Oral contraceptives are available in various brands, doses, and formulations.
    7.2.2) PEDIATRIC
    A) POSTMENARCHAL ADOLESCENTS: Oral contraceptives are available in various brands, doses, and formulations.
    B) PREMENARCHAL GIRLS AND ADOLESCENTS: Oral contraceptives are not indicated for use in premenarchal girls and adolescents.

Minimum Lethal Exposure

    A) A human toxic dose has not been established.

Maximum Tolerated Exposure

    A) ADULT
    1) A 19-year-old woman developed a slight increase in serum phospholipid and triglyceride concentrations soon after an ingestion of 160 mg of estradiol valerate (Punnonen & Salmi, 1983).
    B) PEDIATRIC
    1) Children who ingested up to thirty (30) 2-mg Ortho Novum(R) tablets, were lavaged and developed no untoward effects (Picchioni, 1965).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Following a single oral dose of 160 mg of estradiol valerate, the serum estradiol concentration was 3 nanomoles/L at 15 hours after ingestion (Punnonen & Salmi, 1983).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) It is well known that the primary mission of oral contraceptives, which have been marketed since 1960, regardless of which derivative, is modification of the female reproductive cycle.
    B) Oral contraceptives produce mucus that is less acceptable to spermatozoa, alter the endometrium, and suppress the folicle-stimulating hormone luteinizing hormone sequence from the anterior pituitary, resulting in the suppression of ovulation.

Physicochemical

Physical Characteristics

    A) ETHINYL ESTRADIOL is a white, odorless crystalline powder that is insoluble in water and soluble in alcohol, chloroform, ether, vegetable oils and in solutions of fixed alkali hydroxides.
    B) ETHYNODIOL DIACETATE is an odorless, white crystalline powder that is insoluble in water and soluble in alcohol, chloroform, ether; sparingly soluble in fixed oils.
    C) LEVONORGESTREL is an odorless, white powder that is soluble in chloroform; slightly soluble in alcohol; and practically insoluble in water.
    D) MESTRANOL is an odorless, white crystalline powder that is soluble in chloroform, dehydrated alcohol, and dioxane; slightly soluble in methanol; and insoluble in water.
    E) NORETHINDRONE is an odorless, white crystalline powder that is soluble in chloroform and dioxane; sparingly soluble in alcohol; slightly soluble in ether; and practically insoluble in water.
    F) NORETHINDRONE ACETATE is an odorless, white crystalline powder that is soluble in chloroform, dioxane, ether, and alcohol and practically insoluble in water.
    G) NORETHYNODREL is an odorless, white crystalline powder that is soluble in acetone and chloroform; sparingly soluble in alcohol; and very slightly soluble in hexane and in water.
    H) NORGESTREL is an odorless, white crystalline powder that is soluble in chloroform, sparingly soluble in alcohol, and insoluble in water.

Molecular Weight

    A) DROSPIRENONE: 366.5 (Prod Info BEYAZ(R) oral tablets, 2010)
    B) ESTRADIOL VALERATE: 356.5 (Prod Info DELESTROGEN(R) solution for IM injection, 2004)
    C) ETHINYL ESTRADIOL: 296.4 (Prod Info BEYAZ(R) oral tablets, 2010)
    D) ETHYNODIOL DIACETATE: 384.51
    E) LEVONORGESTREL: 312.45
    F) MESTRANOL: 310.44
    G) NORETHINDRONE: 298.42
    H) NORETHINDRONE ACETATE: 340.46
    I) NORETHYNODREL: 298.42
    J) NORGESTREL: 312.45

References

General Bibliography

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    2) Anon: Serious adverse effects of oral contraceptives and estrogen. Med Letter Drugs Ther 1976; 18:21-23.
    3) Antoniades K: JAMA 1975; 234:628.
    4) Baum JK: Lancet 1973; 2:926.
    5) Chan WS, Ray J, Wai EK, et al: Risk of stroke in women exposed to low-dose oral contraceptives. Arch Intern Med 2004; 164:741-747.
    6) Davis M: Br Med J 1975; 4:496.
    7) Grant WM: Toxicology of the Eye, 3rd ed, Charles C. Thomas, Springfield, IL, 1986.
    8) Jick SS, Vasilakis C, & Jick H: Pregnancies and terminations after 1995 warning about third-generation oral contraceptives. Lancet 1998; 351:1404-1405.
    9) Lynch AM, McKay B, & Murray L: Assessment of short-term outcomes following unintentional ingestions of "oral contraceptive pills" by toddlers. Clin Toxicol (Phila) 2009; 47(2):174-177.
    10) Mann JI: Br Med J 1975; 2:241.
    11) Miale JB & Kent JW: The effects of oral contraceptives on the results of laboratory tests. Am J Obstet Gynecol 1974; 120:264-272.
    12) Mofenson HC, Greensher J, & Caraccio TR: Ingestions considered nontoxic. Clin Lab Med 1984; 4:587-602.
    13) Oren R & Fich A: Oral contraceptive-induced esophageal ulcer: two cases and literature review. Dig Dis Sci 1991; 36:1489-1490.
    14) Parker WA: Estrogen-induced pancreatitis. Clin Pharm 1983; 2:75-79.
    15) Picchioni AL: Acute overdose of oral contraceptives. Am J Hosp Pharm 1965; 22:486.
    16) Product Information: BEYAZ(R) oral tablets, drospirenone ethinyl estradiol levomefolate calcium oral tablets. Bayer HealthCare Pharmaceuticals, Inc, Wayne, NJ, 2010.
    17) Product Information: COMBIPATCH(R) transdermal system, estradiol / norethindrone acetate transdermal system. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2006.
    18) Product Information: DELESTROGEN(R) solution for IM injection, estradiol valerate solution for IM injection. Monarch Pharmaceuticals,Inc, Bristol, TN, 2004.
    19) Product Information: Estrostep, norethindrone acetate and ethinyl estradiol. Parke-Davis, Morris Plains, NJ, 2001.
    20) Product Information: Junel(R) 1.5/30 oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2011.
    21) Product Information: Junel(R) 1/20 oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2011.
    22) Product Information: LOESTRIN(R) 1.5/30 21 Day oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Duramed Pharmaceuticals, Inc (per DailyMed), Pomona, NY, 2009.
    23) Product Information: LOESTRIN(R) 1/20 21 Day oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Duramed Pharmaceuticals, Inc (per DailyMed), Pomona, NY, 2009.
    24) Product Information: MICROGESTIN(R) 1.5/30 oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Watson Pharma (per DailyMed), Corona, CA, 2007.
    25) Product Information: MICROGESTIN(R) 1/20 oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Watson Pharma (per DailyMed), Corona, CA, 2007.
    26) Product Information: NATAZIA(R) oral tablets, estradiol valerate estradiol valerate dienogest oral tablets. Bayer HealthCare Pharmaceuticals Inc. (per manufacturer), Wayne, NJ, 2012.
    27) Product Information: Natazia oral tablets, estradiol valerate estradiol valerate dienogest oral tablets. Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, 2010.
    28) Product Information: ORTHO TRI-CYCLEN(R) oral tablets, norgestimate ethinyl estradiol oral tablets. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2015.
    29) Product Information: SAFYRAL(TM) oral tablets, drospirenone/ethinyl estrodiol/levomefolate calcium oral tablets. Bayer HealthCare Parmaceuticals, Inc., Wayne, NJ, 2010.
    30) Product Information: SEASONALE(R) oral tablets, levonorgestrel / ethinyl estradiol oral tablets. Duramed Pharmaceuticals, Inc, Pomona, NY, 2009.
    31) Product Information: Tri-Legest(R) 21 oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2012.
    32) Product Information: femhrt(R) oral tablets, norethindrone acetate ethinyl estradiol oral tablets. Warner Chilcott (US), LLC (per DailyMed), Rockaway, NJ, 2011.
    33) Punnonen R & Salmi T: Effects of a massive single oral dose of oestradiol valerate in a young woman. Ann Clin Res 1983; 15:134-136.
    34) Redline RW & Abramowsky CR: Transposition of the great vessels in an infant exposed to massive doses of oral contraceptives. Am J Obstet Gynecol 1981; 141:468-469.
    35) Sanchez-Ojanguren J, Escudero D, & Zapata A: Occlusion of the right common carotid artery due to oral estrogen overdose. Rev Neurol 1998; 27(158):604-606.
    36) Sherlock S: Gut 1975; 16:753.
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    38) USP: Drug Information for the Health Care Professional, USPDI 11th ed, United States Pharmacopeial Convention, Inc, Rockville, MD, 1988.
    39) de Bruijn SFTM, Stam J, & Vandenbroucke JP: Increased risk of cerebral venous sinus thrombosis with third-generation oral contraceptives. Lancet 1998; 351:1404.
    40) de Bruijn SFTM, Stam J, Koopman MMW, et al: Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions.. BMJ 1998a; 316:589-592.