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Sexual & Reproductive Health ii. Therapeutic (a) Enoxaparin 1 mg/kg subcutaneously every 12 hours (b) Dalteparin 200 units/kg subcutaneously daily or 100 units/kg subcutaneously every 12 hours (c) Tinzaparin 175 units/kg subcutaneously daily (d) Heparin 10,000 units sub...

Sexual & Reproductive Health ii. Therapeutic (a) Enoxaparin 1 mg/kg subcutaneously every 12 hours (b) Dalteparin 200 units/kg subcutaneously daily or 100 units/kg subcutaneously every 12 hours (c) Tinzaparin 175 units/kg subcutaneously daily (d) Heparin 10,000 units subcutaneously every 12 hours with target activated partial thromboplastin time (aPTT) range (1.5–2.5) 6 hours after injection or adjusted-dose unfractionated heparin subcutaneously every 12 hours, with mid-interval aPTT target of 2 times the control e. May consider switching LMWH to heparin at 36 weeks of gestation to permit induction of anesthesia during labor and delivery because of the lower risk of an epidural or spinal hematoma with regional anesthesia and a greater ease of heparin reversal by protamine sulfate. f. Prophylaxis with LMWH or UFH should be discontinued 12 hours before cesarean section or vaginal delivery. Therapeutic doses should be discontinued 24 hours before cesarean section or vaginal delivery. g. Consider timing of catheter placement for anesthesia as well. h. Continue anticoagulation for 6 weeks postpartum. i. For women experiencing heparin-induced thrombocytopenia, consider fondaparinux; limited data and crosses placenta. G. Gestational Diabetes Mellitus (GDM) 1. Diagnostic approaches (Table 11) Table 11. GDM Diagnostic Approaches Approach Criteria Two-step approach ACOG, NIH 50-g oral glucose test Plasma measured 1 hr after If ≥ 130 mg/dL or 140 mg/dL, give 100-g, 3-hr glucose test Obtain A1C at initial prenatal visit; IADPSG, ADA if elevated, patient has overt diabetes; no further testing 75-g oral glucose test Plasma measured at fasting, 1 and 2 hr One-step approach Organizations Comments Given at 24–28 weeks’ gestation; may be earlier in those with risk factors Given at 24–28 weeks’ gestation; should be fasting for at least 8 hours ADA = American Diabetes Association; GDM = gestational diabetes mellitus; IADPSG = International Association of the Diabetes and Pregnancy Study Groups; NIH = National Institutes of Health. 2. Diagnostic criteria a. Two-step approach: 100-g 3-hour oral glucose test (OGTT) used after initial screening; if greater than or equal to values at two or more points, consider GDM (Table 12). Table 12. 3-Hr Oral Glucose Test Reference Range Time Fasting 1 hr 2 hr 3 hr Plasma Glucose Concentration (mg/dL) Carpenter-Coustan 95 180 155 140 Plasma Glucose Concentration (mg/dL) National Diabetes Data Group 105 190 165 145 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-578 Sexual & Reproductive Health b. One-step approach: Based on 75-g 2-hour oral glucose test (Table 13) Table 13. Glucose Reference Range for 2-Hr Oral Glucose Test Time Fasting 1 hr 2 hr Plasma Glucose 92 mg/dL ≥ 180 mg/dL ≥ 153 mg/dL 3. Insulin (first line): None of the currently available human insulin preparations have been shown to cross the placenta. No specific insulin regimen has been recommended over another for treatment of GDM in pregnancy. 4. Sulfonylureas (glyburide) in patients unable to use insulin injections; however, evidence shows they may be inferior to insulin and metformin because of increased risk of hypoglycemia and macrosomia in the infant. In addition, they have been shown to cross the placenta (Diabetes Care 2021;44:S20010). ACOG recommends against use as first-line therapy stating that glyburide does not yield similar outcomes as insulin (Obstet Gynecol 2018;131:e49-64). 5. Metformin may have advantage over glyburide; studies are ongoing, (not first line), associated with some risk of premature birth and also may cross the placenta; may emerge as possible treatment, according to ACOG (Diabetes Care 2021;44:S200-10; Obstet Gynecol 2018;131:e49-64). 6. Insulin is considered the preferred treatment when pharmacologic treatment of GDM is indicated. In women who decline insulin or who the obstetrician believes that are unable to safely administer insulin, metformin is a reasonable alternative. Previous meta-analyses have noted increased risks of macrosomia and hypoglycemia with glyburide compared with insulin. Observational studies have reported higher rates of preeclampsia, hyperbilirubinemia, and stillbirth with the use of glyburide as compared with insulin (BMJ 2015;350:h102. Am J Obstet Gynecol 2005;193:118-24). H. Pregnancy-Induced Hypertension: Hypertension occurring after 20 weeks’ gestation 1. Gestational hypertension: 140/90 mm Hg or more, occurring at least 4 hours apart on two different occasions in women with previously normal blood pressure without proteinuria or pathologic edema 2. Preeclampsia: Hypertension plus proteinuria (300 mg/dL or more every 24 hours, or protein/creatinine ratio of 3.0 mg/dL or more, or dipstick reading of 2+), any other severe features of preeclampsia such as systolic blood pressure higher than 160 mm Hg or diastolic blood pressure higher than 110 mm Hg at least 4 hours apart and on two occasions (unless antihypertensive treatment was started before this time), thrombocytopenia (platelet count less than 100,000/mm3), impaired liver function (increased levels of liver function enzymes to twice normal or severe right upper quadrant pain or epigastric pain refractory to medication and not accounted for by other diagnoses), new development of renal insufficiency (serum creatinine greater than 1.1 mg/dL or a doubling of the serum creatinine without evidence of other renal disease), pulmonary edema, new development of headache that does not respond to therapy and has no known cause, or visual changes (ACOG Chronic Hypertension in Pregnancy. Obstet Gynecol 2019;133:e26-e50; ACOG Gestational Hypertension and Preeclampsia. Obstet Gynecol 2019;133:e1-e25). 3. Eclampsia: Includes the features of preeclampsia with the addition of tonic-clonic seizures 4. Chronic hypertension: Preexisting hypertension before 20 weeks’ gestation 5. Chronic hypertension with superimposed preeclampsia: New-onset proteinuria after 20 weeks, sudden 2- to 3-fold increase in proteinuria, sudden increase in blood pressure, increased aspartate transaminase–alanine transaminase, thrombocytopenia ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-579 AL GRAWANY Sexual & Reproductive Health 6. Prevention: Women at high risk of preeclampsia development may take aspirin 81–162 mg beginning in late first trimester; a study showed lower incidence of preeclampsia development in women who were administered 150 mg of aspirin from 11 to 14 weeks of gestation to 36 weeks. For women at high risk of preeclampisa, low-dose aspirin should be initiated between 12–28 weeks gestation (optimally before 16 weeks) and continued daily until delivery. 7. Risk of preeclampsia and aspirin use a. Recommend low-dose aspirin if the patient has one or more of these high-risk factors (history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal disease, or autoimmune disease) b. Consider low-dose aspirin if the patient has more than one of these moderate-risk factors: nulliparity, BMI greater than 30 kg/m2, family history of preeclampsia in mother or sister, sociodemographic characteristics (Black/African American, low socioeconomic status), older than 35 years, personal history of adverse pregnancy outcomes, more than a 10-year pregnancy interval. c. Do not recommend low-dose aspirin in previous uncomplicated full-term delivery (Obstet Gynecol 2019;133:e1-e25; N Engl J Med 2017;377:613-22). 8. Treatment a. Delivery if at term b. If not at term, get bed rest and monitor blood pressure. c. Severe preeclamptic, parenteral magnesium sulfate to prevent seizures d. Labetalol (oral), nifedipine (oral, extended release) are first-line therapies. e. Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period: Labetalol (intravenous), hydralazine (intravenous), nifedipine (oral, immediate release; concern for serious adverse effects when used simultaneously with magnesium) f. Medications to avoid: Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists I. Preterm Labor 1. Definitions a. Term labor: Weeks 37–40 b. Preterm labor: Uterine contractions with cervical changes before week 37 2. Nonpharmacologic treatment a. Inhibition of labor not usually tried before week 20. b. Bed rest, hydration, and sedation 3. Prophylaxis at 16–36 weeks for patients with a history of preterm labor: 17-hydroxyprogesterone caproate 250 mg intramuscularly every week 4. Tocolytic drugs (inhibit uterine contractions), especially if cervix dilated less than 4 cm and membranes intact; short term use only a. β-Agonists i. Terbutaline: Often subcutaneously ii. Adverse effects: Hypotension, tachycardia, hypokalemia, tremor, nervousness, angina, headache, hypoglycemia in patients with diabetes mellitus iii. FDA warning for use beyond 48 hours because of severe adverse effects in the mother such as elevated heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and myocardial ischemia. Warning also against use of oral terbutaline for preterm labor because of lack of efficacy. b. Magnesium sulfate i. Inhibits uterine activity by antagonism of calcium. ii. Anticonvulsant in eclampsia. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-580 Sexual & Reproductive Health iii. Serum magnesium concentrations 5–8 mEq/L. Monitor closely for signs of toxicity because the therapeutic range is close to the range that may cause respiratory or cardiac depression. Toxicity may be reversed with calcium gluconate (intravenously). iv. May be drug of choice in patients with diabetes. c. Prostaglandin synthetase inhibitors (NSAIDs) i. Prostaglandins are in amniotic fluid during labor and delivery but not during pregnancy. ii. Indomethacin: Oral or rectal iii. Adverse effects: Premature closure of ductus arteriosus, necrotizing enterocolitis, intracranial hemorrhage, renal dysfunction iv. Limit use to 72 hours. d. Calcium channel blockers i. Calcium necessary for muscle contraction; limit use to 48 hours, should be used with caution in combination with magnesium sulfate due to a risk of reduced heart rate, contractility, and left ventricular systolic pressure. ii. Nifedipine: Typically used; use caution when administered near administration of magnesium, may result in hypotension. iii. Verapamil: Large doses needed that mother usually cannot tolerate. J. Induction of Labor 1. Induction indicated when: a. Severe maternal infection b. Uterine bleeding c. Preeclampsia or eclampsia d. Diabetes mellitus e. Macrosomia f. Maternal renal insufficiency g. Premature rupture of membranes after week 36 h. Evidence of placental insufficiency i. Postdatism (more than 42 weeks) 2. Inducing agents a. Oxytocin i. Drug of choice for labor induction ii. Intravenous administration iii. Adverse effects: Uterine rupture, uteroplacental hypoperfusion, fetal distress from hypoxia b. Ergot alkaloids i. Not used to induce labor at term or late in pregnancy. ii. Violent, sustained uterine contractions iii. Decrease postpartum or postabortion bleeding iv. Oral and parenteral c. Prostaglandins: Used primarily for cervical ripening i. Dinoprostone also known as PGE2 (prostaglandin E2) (a) Vaginal gel or insert, sometimes compounded suppositories (b) Applied to cervix (c) Adverse effects: Headache, nausea, vomiting, diarrhea, abdominal pain, and uterine hyperstimulation ii. Misoprostol (off-label use), also known as PGE1 (prostaglandin E1) (a) Available orally and vaginally (b) Adverse effects: Headache, nausea, vomiting, diarrhea, abdominal pain, and uterine hyperstimulation ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-581 Sexual & Reproductive Health K. Medication Abortion 1. Can be used to terminate a pregnancy up to 70 days (10 weeks) gestation; calculated from the first day of the last menstrual period 2. Contraindications a. Presence of IUD b. Long-term corticosteroid use c. Use of anticoagulant therapy d. Blood coagulation disorder e. Ectopic pregnancy 3. Medication regimen a. Combination of mifepristone and misoprostol b. Mifepristone i. Progesterone antagonist that competitively inhibits progesterone at receptor sites ii. Dose: 200 mg tablet orally for 1 dose c. Misoprostol i. Prostaglandin analogue that causes cervical softening, dilation, and uterine contractions ii. Dose: 800 mcg (4 tablets) bucally (place 2 tablets inside each cheek for 30 minutes, then swish with water and swallow) iii. Taken 24–48 hours after mifepristone iv. Regimens without FDA approval include use of misoprostol alone Patient Case 5. S.E. is a 28-year-old woman who would like to get pregnant soon. Her medical history includes hypertension and allergies. Her medications include lisinopril, nasal saline spray, and folic acid. Which option is best to treat her hypertension while she is pregnant or trying to conceive? A. Continue lisinopril and add hydrochlorothiazide. B. Discontinue lisinopril and all other medications. C. Discontinue lisinopril and start labetalol. D. Continue lisinopril and add atenolol. VI. OVERVIEW OF CONTRACEPTION A. Epidemiology 1. About 45% of pregnancies are unintended in the United States, with about 42% of those resulting in abortions (according to 2011 data, N Engl J Med 2016;374:843-52). 2. Among female contraceptive users in 2016, 28% were using female permanent contraception, 21% were using pills and 13% were using an intrauterine device (IUD) (www.guttmacher.org/fact-sheet/ contraceptive-method-use-united-states). B. Physiology Review: Menstrual Cycle 1. Follicular phase: GnRH stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH); FSH stimulates estradiol secretion and stimulates follicles to develop; one in particular will become the dominant follicle (in the first half of cycle); later in follicular phase, LH causes an increase in androgen values. 2. Ovulation: Typically occurs midcycle; mature follicle ruptures; a surge in LH occurs just before ovulation. 3. Luteal phase: Progesterone is the more dominant hormone in the second half of cycle. 4. Menses: Hormones have decreased, and withdrawal bleeding occurs if a woman does not become pregnant. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-582 Sexual & Reproductive Health C. Factors in Selecting Contraception 1. Effectiveness a. Theoretical: Method failure if patient uses method perfectly (e.g., combined oral contraceptive [pills] [COCs] have 99% theoretical effectiveness in preventing pregnancy) b. Actual: Combines method failure plus patient failure (e.g., COCs have 93% actual effectiveness when average patient use is considered). Sometimes referred to as “typical use” rates. 2. Importance of not being pregnant 3. Likelihood and ability to adhere 4. Frequency of intercourse: Frequent versus infrequent 5. Age may affect adherence or adverse effect risks. 6. Cost and ability to pay 7. Adverse effects 8. Perceptions, misperceptions, risk-benefit 9. Concomitant drug use 10. Health status and habits 11. Patient preference 12. Cultural preferences 13. Religious influences D. Methods of Birth Control 1. Abstinence 2. Male or female sterilization 3. Natural family planning 4. Spermicides 5. Barrier methods a. Diaphragm or cervical cap b. Condom c. Female condom d. Sponge 6. Hormonal contraception a. Combined contraceptives—contain both an estrogen and a progestin i. Combined oral contraceptive (COC) pills ii. Transdermal patch iii. Vaginal ring b. Progestin-only—does not contain any estrogen i. Progestin-only pill (POP or minipill) ii. Progestin-only injectable iii. Implanted rod 7. Intrauterine device (IUD) a. Copper b. Progestin-containing 8. Lactic acid, citric acid, and potassium bitartrate vaginal gel (PHEXXI) 9. Emergency contraception ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-583 Sexual & Reproductive Health VII. C  OMBINED HORMONAL CONTRACEPTIVES A. Indications 1. FDA label approved a. Prevent pregnancy b. Acne (Estrostep Fe, Ortho Tri-Cyclen, YAZ, Beyaz) c. Premenstrual dysphoric disorder (YAZ, Beyaz) 2. Off-label use a. Hirsutism b. Cycle control c. Headaches d. Premenstrual syndrome e. Iron-deficiency anemia f. Relief of menstrual cramps B. Components 1. Estrogen a. Type of estrogens available in products in the United States i. Ethinyl estradiol (in almost all products), estradiol valerate (Natazia), estetrol (Nexstellis) ii. Mestranol (not used often) b. Pharmacologic actions of estrogen in contraceptives i. Feeds back to the pituitary, inhibiting FSH and ovulation. ii. Increases aldosterone concentrations, results in increased sodium and water retention. iii. Increases sex hormone–binding globulin, which is produced in the liver and binds free androgens; this may result in clearing up hormone-mediated acne and unwanted facial hair or hirsutism in women. c. Adverse effects attributed to estrogen i. Nausea, vomiting ii. Bloating, edema iii. Irritability iv. Cyclic weight gain v. Cyclic headache vi. Hypertension vii. Breast fullness, tenderness 2. Progestin a. Types of progestins available in products in the United States i. Norethindrone ii. Norethindrone acetate iii. Ethynodiol diacetate iv. Norgestrel v. Levonorgestrel vi. Desogestrel vii. Norgestimate viii. Etonogestrel ix. Drospirenone x. Dienogest xi. Segesterone acetate ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-584 Sexual & Reproductive Health b. Pharmacologic actions of progestins in contraceptives i. Feeds back to pituitary and helps inhibit ovulation (not a main action). ii. Causes endometrial atrophy (thinning of uterus lining). iii. Thickens cervical mucus (inhibits sperm from traveling). c. Adverse effects caused by progestin i. Headaches ii. Increased appetite iii. Increased weight gain iv. Depression, fatigue v. Changes in libido vi. Androgenic adverse effects (a) Hair loss, hirsutism (b) Acne, oily skin C. Contraindications for Combined Hormonal Contraceptives 1. The Centers for Disease Control and Prevention (CDC) medical eligibility criteria are separated into four categories: a. Category 1: A condition for which there is no restriction on the use of contraceptive method b. Category 2: A condition in which the advantages of using the method generally outweigh the theoretical or proven risks c. Category 3: A condition in which the theoretical or proven risks usually outweigh the advantages of using the method d.  Category 4: A condition that represents an unacceptable health risk if the contraceptive method is used 2. Examples of category 4 contraindications for combined hormonal contraceptives a. Less than 21 days postpartum for women with no risk factors for DVT (regardless of breastfeeding status), b. Smoker (15 cigarettes or more per day) and/or 35 and older, though conservatively, any smoking can be a risk factor c. Blood pressure greater than 160/100 mm Hg d. Vascular disease e. Current DVT or pulmonary embolism or history of DVT or pulmonary embolism f. Complicated diabetes showing nephropathy, neuropathy, or retinopathy g. Major surgery with prolonged immobilization h. Known thrombogenic mutations i. Current or history of ischemic heart disease j. Stroke (history of cerebrovascular accident) k. Migraine headache with aura l. Current breast cancer m. Systemic lupus erythematosus with positive or unknown antiphospholipid antibodies n. Active cancer (metastatic, receiving therapy, or within 6 months after clinical remission). D. Adverse Effects (see Estrogen and Progestin sections earlier for specific hormone-causing adverse effects) 1. Discontinuation of hormonal contraceptives was due to: a. Bleeding irregularities: 32% b. Nausea: 19% c. Weight gain: 14% d. Mood swings: 14% e. Breast tenderness: 11% f. Headache: 11% ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-585 Sexual & Reproductive Health 2. Management of adverse effects a. Breakthrough bleeding i. Consider new product after trying the product for 3 months, assess adherence. ii. If early in the cycle, there is probably not enough estrogen; select a regimen with higher estrogen activity. iii. If late in the cycle, there is probably not enough progestin; select a regimen with higher progestin activity. iv. In general, if breakthrough bleeding occurs, it is best to select a regimen with higher estrogen and progestin activities. b. Nausea i. More likely to be related to estrogen component. ii. Suggest the patient take the pill at night before bed or with food. iii. If possible, try the product for 3 months; nausea may subside. c. Acne i. More likely to be related to the androgenic properties of progestin. ii. Select a product with lower androgenic activity. iii. Alternatively, select a product with higher estrogen activity. 3. Serious adverse effects (ACHES) a. A: Abdominal pain; could signal liver problems or gallbladder. b.  C: Chest pain, shortness of breath, coughing up blood; could signal myocardial infarction or blood clot in lung. c. H: Headaches (severe); could signal stroke, blood clot. d.  E: Eye problems (blurred vision, flashing lights, blindness); could signal optic neuritis, stroke, clots. e. S: Severe leg pain with or without swelling; could signal DVT. Patient Case 6. A 22-year-old woman started taking levonorgestrel 0.1 mg/ethinyl estradiol 20 mcg tablet daily 4 months ago for contraception. She has breakthrough bleeding at the start of her active pills that lasts a few days before resolving. As a pharmacist working under a collaborative practice agreement, which oral contraceptive on her formulary is best to prescribe? Oral Contraceptive Characteristics of Progestin Component Estrogen Progestin Androgen Property Property Property Levonorgestrel 0.1 mg/ethinyl estradiol 20 mcg Low Low Low Desogestrel 0.15 mg/ethinyl estradiol 30 mcg Intermediate High Low Norethindrone 0.5 mg/ethinyl estradiol 35 mcg Low Low Low Norethindrone acetate 1.5 mg/ethinyl estradiol 30 mcg Low High High A. Continue levonorgestrel 0.1 mg/ethinyl estradiol 20 mcg for another 3 months. B. Change to desogestrel 0.15 mg/ethinyl estradiol 30 mcg. C. Change to norethindrone acetate 1.5 mg/ethinyl estradiol 30 mcg. D. Change to norethindrone 0.5 mg/ethinyl estradiol 35 mcg. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-586 Sexual & Reproductive Health E. Common Drug Interactions (list not all-inclusive) Table 14. Common Drug Interactions with Hormonal Contraception Increase Effect of HC Decrease Effect of HC Acetaminophen Ascorbic acid Atazanavir Atorvastatin Ginseng Indinavir Red clover (may increase or decrease effect of combined HCs) Rosuvastatin Tranexamic acid Voriconazole Amprenavir Aprepitant Barbiturates Bexarotene Bosentan Carbamazepine Darunavir Efavirenz Felbamate Griseofulvin Lopinavir Modafinil Mycophenolate mofetil Nelfinavir Nevirapine Oxcarbazepine Phenobarbital Phenytoin/fosphenytoin Pioglitazone Primidone Red clover (may increase or decrease effect of combined HCs) Rifamycins Ritonavir Rufinamide Saquinavir St. John’s wort Tipranavir Drugs that Are Increased or Decreased by HC Acetaminophen Antidepressants, tricyclic Aspirin Benzodiazepines β-Blockers Caffeine Clofibric acid Corticosteroids Cyclosporine Fosamprenavir Lamotrigine Levothyroxine Morphine Paclitaxel Salicylic acid Selegiline Tacrine Tacrolimus Theophyllines Tizanidine Valproic acid HC = hormonal contraceptives. 1. Simplified list of drug-drug interactions according to the U.S. Medical Eligibility Criteria for Contraceptive Use 2016 (www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf) a. Nucleoside reverse transcriptase inhibitors, maraviroc, HIV integrase strand transfer inhibitors (category 1: before treating any patients, recommend to check specific product information) b. Nonnucleoside reverse transcriptase inhibitors (category 1 or 2: before treating any patients, recommend to check specific product information) c. Ritonavir-boosted protease inhibitors (category 2; exception: ritonavir-boosted lopinavir) d. Protease inhibitors without ritonavir (category 1: indinavir; category 2: – nelfinavir and atazanavir; category 3: fosamprenavir) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-587 Sexual & Reproductive Health e. Antiepileptics (category 3) f. Rifampin or rifabutin (category 3) g. St. John’s wort (category 2) h.  Broad-spectrum antibiotics, antifungals, antiparasitics (category 1); U.S. Medical Eligibility Criteria for Contraceptive Use 2016 suggest that no alternative form of contraception is necessary with broad-spectrum antibiotics, but other antibiotics may require an alternative form of contraception (see text that follows) i.  Reported antibiotic cases in the literature: Tetracycline, minocycline, erythromycin, penicillins, and cephalosporins; pharmacokinetic studies have not shown decreased hormonal contraceptive concentrations with tetracycline, doxycycline, ampicillin, metronidazole, quinolones, or fluconazole. i. Proposed mechanisms of drug interactions (a) Interference of absorption: Ethinyl estradiol is conjugated in the liver, excreted in bile, hydrolyzed by intestinal bacteria, and reabsorbed as an active drug; non–liver enzymeinducing antibiotics temporarily decrease colonic bacteria and inhibit enterohepatic circulation of ethinyl estradiol. Gut flora have recovered 3 weeks after the introduction of antibiotics. (b) Liver enzyme induction (rifampin and griseofulvin): The metabolism of progesterone and estrogen is accelerated. ii. Use a backup method (BUM) for the length of antibiotic therapy plus 7 days after discontinuing antibiotic. F. Types of Hormonal Contraceptives 1. Oral a. COC regimens i. Monophasic: Same amount of hormone in pill every day except in placebo pills ii. Biphasic: Amount of hormone may change halfway through cycle. iii. Triphasic: Amount of hormone changes every week. (a) Traditional: Progestin usually changes and estrogen stays the same. (b) Estrophasic: Estrogen changes. iv. Quadriphasic: Estrogen changes and progestin changes; four varying amounts throughout monthly pack b. Dosing i. High-dose estrogen: Higher than 35 mcg (up to 50 mcg) ii. Low-dose estrogen: Less than 35 mcg (generally 20–35 mcg) iii. Very low-dose estrogen: Less than 10 mcg c. Effectiveness: When taken every day at the same time, 99.7% (perfect use), typical use (about 93%) (Contraceptive Technology, 21st ed. New York: Ardent Media, 2018) d. Adherence: 68% continue after 1 year e. Start methods i. Same-day start: Start taking an active pill the first day of menses. ii. Sunday start: Start taking an active pill the first Sunday after menses begins (use a BUM for at least 7 days, most conservative for 1 month). iii. Quick start: Start taking an active pill at the physician’s office or first day of prescription, regardless of menstrual cycle day. Use a BUM for at least 7 days. Most conservative; use a BUM for 1 month. Menses will not begin until all the active pills have been taken. iv. When changing pills from brand to brand, start the new pack of pills after finishing the placebo pills from the old pack. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-588 Sexual & Reproductive Health f. Counseling i. Proper use: Take 1 tablet once daily at the same time every day. ii. Adverse effects (a) See previous text. (b) Adverse effects usually subside after 3 months; general recommendation is to stay on a brand for at least 3 months if adverse effects are not excessively bothersome. iii. Missed doses: Missed COC pill means more than 24 hours between doses. (a) General recommendations for missed combined oral contraceptives (MMWR Recomm Rep 2016;65:1-66) (1) Missed 1 pill (24 hours or more, but less than 48 hours): Take missed dose as soon as possible, continue taking the remaining doses at the usual time even if it means taking 2 tablets in one day, no BUM needed; generally EC is not necessary but may be considered (except ulipristal) if the patient missed doses earlier in the cycle or in the last week of the previous pack. (2) Missed 2 or more pills: If two or more doses are missed, more than 48 hours since scheduled administration time, may recommend the following: (A) Take most recent doses as soon as possible. (B) Continue taking remaining doses at the usual time even if it means taking 2 tablets in one day. (C) Use a BUM or avoid intercourse until 7 active tablets have been taken for 7 consecutive days. (D) Use EC (except for ulipristal) if unprotected intercourse occurred in the previous 5 days. (b) Package inserts can be consulted for recommendations based on specific products. g. Unique formulations (other AB-rated products may be available that are not listed here) i. Natazia (estradiol valerate/dienogest), four-phase oral contraceptive containing estradiol valerate/dienogest; only 2 tablets of placebo ii. Azurette, Bekyree, Kariva, Mircette, Pimtrea, Simliya, Viorele, Volnea (ethinyl estradiol/ desogestrel): 2 days of placebo and 5 days of estrogen only (10 mcg), instead of 7 days of placebo iii. Femcon Fe, Wymzya FE, (ethinyl estradiol 35 mcg/norethindrone 0.4 mg): Chewable tablets with iron tablets instead of placebo iv. Lo Loestrin Fe (ethinyl estradiol 10 mcg/norethindrone acetate 1 mg): Lowest oral estrogen COC tablet v. Generess Fe, Layolis Fe, Kaitlib Fe (ethinyl estradiol 25 mcg/norethindrone 0.8 mg): 24 chewable active tablets and 4 tablets of ferrous fumarate 75 mg vi. Drospirenone progestin-containing contraceptives (a) Drospirenone: Analog of spironolactone, similar to spironolactone 25 mg (b) Exercise caution with drugs that increase potassium such as high doses of NSAIDs, heparin, ACE inhibitors, and potassium-sparing diuretics. (c) No diuretic effect, has antimineralocorticoid effects, decreases bloating effect of ethinyl estradiol. (d) Antiandrogenic: Best for acne, hirsutism, or male pattern balding in women (e) Possible increased risk of DVT, FDA safety communication, April 2012 (f) Products (other AB-rated products may be available) (1) Yasmin (ethinyl estradiol 30 mcg/drospirenone 3 mg) (2) Yaz (ethinyl estradiol 20 mcg/drospirenone 3 mg): 4 days of placebo, approved use for premenstrual dysphoric disorder, acne. (3) Safyral (ethinyl estradiol 30 mcg/drospirenone 3 mg and 0.451 mg of levomefolate calcium) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-589