ch08.qxd 8/13/2001 ESTROGENS COMPARISON CHART DOSAGE FORMS COMMENTS STEROIDAL AGENTS 0.625 mg Mixture of 50–65% sodium estrone sulfate, 20–35% equilin sulfate, and other estrogenic substances from the urine of pregnant mares Expensive; nausea is rare Tab 0.3, 0.625, 1.25, 2.5 mg 0.625 mg Similar to conjugated estrogens Mixture of 75–85% sodium estrone sulfate and 6.5–15% sodium equilin sulfate obtained from Mexican yams Estradiol, Micronized Estrace Tab 0.5, 1, 1.5, mg Vag Crm 100 mg/g Vag Ring mg mg Moderate cost; some nausea with oral; estradiol is the major estrogen secreted during the reproductive years Estradiol Climara Estraderm Vivelle SR Patch 25, 37.5, 50, 75, 100 µg/day 50 µg/day Estraderm contains alcohol; Climara and Vivelle not contain alcohol and may be less irritating to the skin Estradiol Cypionate Depo-Estradiol Various Inj (in oil) mg/mL — Pain at injection site; variable onset with a duration of 14–28 days (continued ) Page 687 Tab 0.3, 0.625, 0.9, 1.25, 2.5 mg Vag Crm 0.625 mg/g Inj 25 mg Esterified Estrogens Estratab Menest Various 687 Conjugated Estrogens Premarin Various 2:24 PM DRUG EQUIPOTENT PHYSIOLOGIC DOSEa,b ch08.qxd 688 ESTROGENS COMPARISON CHART (continued ) DOSAGE FORMS COMMENTS mg Pain at injection site; variable onset with a duration of 14–21 days Ethinyl Estradiol Estinyl Feminone Tab 0.02, 0.05, 0.5 mg µg Not recommended for estrogen replacement because of its potent hepatic effects (See Estradiol Notes.) Estrone Various Inj 2, mg/mL 0.9 mg No advantage over conjugated/esterified estrogens; estrone is the major estrogen of the postmenopausal years Estropipate Ogen Various Tab 0.625, 1.25, 2.5, mg Vag Crm 1.5 mg/g 0.625 mg Ogen 0.625 mg = 0.75 mg estropipate Ogen 1.25 mg = 1.5 mg estropipate Ogen 2.5 mg = mg estropipate Ogen mg = mg estropipate NONSTEROIDAL AGENTSESTROGENS COMPARISON CHART (continued) Dienestrol Various a Vag Crm 0.01% Potency of estrogens: estradiol > estrone Potency is based on the effects on the liver See monographs or product information for exact dosage regimens for various uses b — Page 688 Inj (in oil) 10, 20, 40 mg/mL 2:24 PM Estradiol Valerate Delestrogen Various 8/13/2001 DRUG EQUIPOTENT PHYSIOLOGIC DOSEa,b ch08.qxd POSTMENOPAUSAL HORMONE REPLACEMENT RISKS AND BENEFITS COMPARISON CHART COMMENTS Cancer, Colon A 46% decrease in colon cancer risk; no effect on rectal cancer In slender women, risk is reduced by up to 75% Cancer, Endometrial Relative risk of 8.2 with unopposed estrogen use; risk increases with higher dosage and duration >5 yr; 34% risk after yr; 20% lifetime probability of needing a hysterectomy with unopposed estrogen therapy Relative risk of with the concurrent addition of a minimum of 10–14 days of progestin No increased risk of estrogen hyperplasia or need for hysterectomy with concurrent progestin therapy Cardiovascular Disease Three meta-analyses and a cohort study suggest a 40–50% reduction in the risk of coronary and fatal heart disease with unopposed estrogens; benefits may be greater in those with heart disease and >15 yr duration of use Decreased lifetime probability of developing coronary artery disease Hormone replacement for ≥1 yr associated with a 52% decreased risk of peripheral arterial disease Unknown protection against stroke Combination with progestin may be protective, but data are insufficient May be related to estrogen’s effects on lipids or direct effect of relaxing blood vessel walls Hypertension Estrogens can reduce BP Hormone replacement is not contraindicated in hypertension Lipids Unopposed oral estrogens reduce LDL and increase HDL by 10–15%; however, estrogens can increase triglyceride levels Progesterone antagonizes beneficial estrogen lipid effects less than medroxyprogesterone Most favorable effects on lipids occur with estrogen alone Nonoral estrogens (eg, patch, vaginal) produce less HDL beneficial effects (continued ) Page 689 Addition of progestin does not reduce risk Regular mammography is recommended Consider limiting duration of treatment to 60 yr No risk found in past users, regardless of duration of use Two meta-analyses show minimal risk with >15 yr of use 8/13/2001 CLINICAL INFORMATION Cancer, Breast 689 RISKS/BENEFITS COMMENTS Mortality unaffected; may require cholecystectomy Osteoporosis Inhibits bone resorption and prevents bone loss; 15–50% increase in bone density if begun within yr of menopause Osteoporosis risk increased in Caucasian and Asian ethnic groups, in sedentary lifestyle, in smokers, with low calcium and vitamin D intake, and excessive alcohol or thyroxine intake Alendronate (Fosamax) orally, intranasal calcitonin (Miacalcin), etidronate (Didronel), and slow-release fluoride also may be effective (See Estradiol Notes.) Fractures One-half as many fractures of spinal and hip bones with >5 yr of use; 28% reduction with 10 yr use; 40% with 15 yr use; and 55% with 20 yr Risk returns near baseline yr or more after cessation of therapy Decreased lifetime probability of osteoporotic fracture Risk increases 4-fold for each SD decrease in bone density at the hip; 66% of femoral neck fractures occur when bone density is below the lowest quartile Bone densitometry can identify women at highest risk Vaginal Bleeding Unpredictable bleeding occurs in 35–40% of women with uteruses yearly Amenorrhea usually occurs after 6–8 months of combination estrogen/ progestin therapy From references 119, 121, 127, 130, 132, 139, and 157–164 Page 690 Estrogen treatment is associated with a 2.1 relative risk (RR) RR of 2.6 with >10 yr of use; RR of 2.4 for users of 1.25 mg or more of conjugated/estrified estrogen 2:24 PM Gallbladder Disease 8/13/2001 CLINICAL INFORMATION ch08.qxd 690 POSTMENOPAUSAL HORMONE REPLACEMENT RISKS AND BENEFITS COMPARISON CHART (continued ) RISKS/BENEFITS ch08.qxd 8/13/2001 2:24 PM Page 691 F EMALE S EX H ORMONES MEDROXYPROGESTERONE ACETATE 691 Depo-Provera, Provera, Various Pharmacology Medroxyprogesterone is a 17␣-acetoxyprogesterone derivative with greater progestational effects and oral efficacy than progesterone Progesterone transforms an estrogen-primed proliferative endometrium into a secretory endometrium Administration and Adult Dosage PO for secondary amenorrhea, or abnormal uterine bleeding, or to induce withdrawal bleeding after postmenopausal estrogen replacement therapy 5–10 mg/day for 5–10 days, depending on the degree of endometrial stimulation desired, beginning on the presumed 16th or 21st day of the cycle for abnormal uterine bleeding In secondary amenorrhea, therapy can be started at any time PO for postmenopausal symptoms and osteoporosis (combined with continuous estrogen) 2.5–5 mg/day.140,141 (See Notes.) PO for relief of vasomotor symptoms 20 mg/day; IM for relief of vasomotor symptoms 150 mg/day.142 (See Notes.) IM for endometrial or renal carcinoma 400 mg– g/week initially for a few weeks, then, if improvement occurs, reduce to maintenance dosage of 400 mg/month (See also Progestin-Only Contraceptives.) Special Populations Geriatric Dosage Same as adult dosage Dosage Forms Tab 2.5, 5, 10 mg; Inj 150, 400 mg/mL Patient Instructions Report immediately if any of the following occur: new severe or persistent headache; blurred vision; calf, chest, or abdominal pain; or any abnormal vaginal bleeding This (oral) drug may be taken with food, milk, or an antacid to minimize stomach upset (Dysfunctional uterine bleeding) expect heavy and severely cramping flow 2–4 days after stopping therapy; expect a normal period after a few days Pharmacokinetics Onset and Duration Withdrawal bleeding (in estrogen-primed endometrium) occurs 3–7 days after the last dose.103,104 Onset of symptomatic relief of hot flashes within 4–7 days; maximum relief after month; duration 8–20 weeks after discontinuation.142 Serum Levels Inhibition of ovulation and tumor response occurs with medroxyprogesterone levels >0.1 ␮g/L (0.25 nmol/L).101,103,104,143 Fate Medroxyprogesterone acetate (MPA) is rapidly absorbed orally with no first-pass metabolism; oral bioavailability is 5.7 ± 3.8%; IM bioavailability is 2.5 ± 1.7%, with a large interpatient variation in serum levels after oral or IM administration.82,143 Higher concentration depot formulation is associated with lower serum concentrations but equivalent bioavailability.144 Peak concentrations occur in 2–7 hr and are 2–10 times higher after oral than after IM depot injection PO 10 mg yields peak levels of 3–4 ␮g/L (7.5–10 nmol/L), declining to 0.3–0.6 ␮g/L (0.8–1.5 nmol/L) by 24 hr; PO 100 mg yields 13 ± ␮g/L (34 ± 18 nmol/L), declining to ␮g/L (5 nmol/L) by 24 hr; PO 500 mg yields 13 ± ␮g/L (34 ± 21 nmol/L) After 150 mg IM of the 150 mg/mL formulation, peak levels of 8.3 ± 3.2 ␮g/L (21 ± nmol/L) occur within a few days, declining to levels of 0.8 ± 0.7 ␮g/L (2 ± 1.8 nmol/L) for 92 ± 44 days After 400 mg IM of the 400 mg/mL formulation, peak serum levels of 6.2 ± 2.3 ␮g/L (16 ± nmol/L) are achieved after 16.3 ± 15.6 days.82,94,103,104,144 The drug is stored in fat; >90% is ch08.qxd 692 8/13/2001 2:24 PM Page 692 H ORMONAL D RUGS protein bound to albumin; 83% of a dose is present in serum as the parent drug and conjugated medroxyprogesterone; it is hydroxylated to 6-␣-hydroxy-MPA and 21-hydroxy-MPA, which have unknown activities From 15% to 20% of a dose is excreted in urine as glucuronide and sulfate conjugates; 45–80% is excreted in feces.94 t¹⁄₂ 50 days, reflecting slow IM absorption from depot Adverse Reactions Frequent breast tenderness, weight gain, and depression occur Adverse lipid effects (increased LDL, decreased HDL) occur with dosages ≥10 mg/day; dosages of 2.5–5 mg/day have negligible effects.121,140,144 (See also Progestin-Only Contraceptives, Postmenopausal Hormone Replacement Risks and Benefits Comparison Chart, and Hormone Excess and Deficiency Symptomatology Comparison Chart.) Contraindications Known or suspected pregnancy or as a diagnostic test for pregnancy Thrombophlebitis, history of deep vein thrombophlebitis, or thromboembolic disorders; known or suspected carcinoma of the breast or endometrium, or other estrogen-dependent tumors; undiagnosed abnormal genital bleeding Although acute liver disease, benign or malignant liver tumors, and history of cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use are listed as contraindications by manufacturers, liver disease is not considered by others to be a contraindication to progestin-only contraceptives.96 Precautions Use with caution in patients with histories of depression, diabetes, gestational diabetes, coronary artery disease, cerebrovascular disease, hyperlipidemia, liver disease, or hypertension Although progestins are not harmful to the fetus during the first months of pregnancy; confirm a negative pregnancy test before reinjecting a woman >2 weeks late for her IM injection.96,105 Progestinonly contraceptives used during breastfeeding pose no risk to the infant,96,103–107 and they usually not decrease breastmilk production if begun after weeks postpartum Drug Interactions Rifampin and cytochrome P450–inducing anticonvulsants can increase progestin metabolism Long-term use of griseofulvin can increase menstrual irregularities.76,96,103,104,108 Parameters to Monitor Complete pretreatment physical examination with special reference to blood pressure, breasts, abdomen, pelvic organs, and Pap smear yearly Notes Continuous administration of low-dose progestin and estrogen combinations in postmenopausal syndrome causes amenorrhea in >50% of women and does not appear to negatively influence blood lipids when compared with cyclic therapy.121,140,141,145 Concurrent administration of estrogen with progestin for amenorrhea might be associated with less breakthrough bleeding than with progestin alone There is no evidence that progestins are effective in preventing habitual abortion or treating threatened abortion MIFEPRISTONE Mifeprex Pharmacology Mifepristone (RU-486) is a synthetic steroid with antiprogestational effects ch08.qxd 8/13/2001 2:24 PM Page 693 F EMALE S EX H ORMONES 693 Adult Dosage PO for pregnancy termination through day 49 of pregnancy 600 mg as a single dose, followed in days by misoprostol 200 mg PO Patients should return on day 14 to assess efficacy of the procedure and bleeding Dosage Forms Tab 200 mg Pharmacokinetics Oral bioavailability is 69% with a 20 mg dose It is 98% bound to albumin and ␣1-acid glycoprotein It is metabolized primarily by CYP3A4 to three major metabolites Most of drug is eliminated in feces, with 9% of the drug and metabolites eliminated in urine Clearance is dose dependent, with 50% eliminated between 12 and 72 hr; the remaining drug is eliminated with a half-life of 18 hr Adverse Reactions Vaginal bleeding and cramping are expected effects of the drug (plus misoprostol) and occur mostly on day Bleeding is generally heavier than a normal menstrual period Other frequent effects are nausea, vomiting, diarrhea, headache, dizziness, and fatigue Drugs that affect CYP3A4 can alter mifepristone metabolism The metabolism of drugs metabolized by CYP3A4 might be affected Contraindications Confirmed or suspected ectopic pregnancy or undiagnosed abdominal mass; IUD in place; chronic adrenal failure; concurrent long-term corticosteroid use; allergy to mifepristone, misoprostol or other prostaglandin; hemorrhagic disorder; anticoagulant therapy; inherited porphyria Notes Pregnancy termination should be conducted only in a setting where a qualified physician can assess the gestational age of the fetus, diagnose ectopic pregnancies, and provide surgical intervention in case of incomplete abortion or severe bleeding (or have made plans to provide such care through others) NORETHINDRONE ACETATE Aygestin Pharmacology Norethindrone acetate is a 19-nortestosterone derivative that shares the actions of progestins It has oral efficacy, greater progestational activity than progesterone, and less androgenic activity than androgens (See also Medroxyprogesterone Acetate, Progesterone.) Administration and Adult Dosage PO for withdrawal bleeding after postmenopausal estrogen replacement therapy or combined for estrogen replacement therapy 2.5–10 mg/day starting on days 15–20 of the cycle and continuing for 5–10 days, or 0.5–1 mg/day continuously combined with estrogen.140,141,145 (See Medroxyprogesterone Acetate Notes.) PO for amenorrhea or abnormal uterine bleeding 2.5–10 mg/day starting on day and ending on day 25 of menses In cases of secondary amenorrhea, therapy can be started at any time.79 PO for endometriosis mg/day for weeks, increasing in 2.5 mg/day increments q weeks until a maintenance dosage of 15 mg/day is reached.80 Special Populations Geriatric Dosage Same as adult dosage Dosage Forms Tab mg Patient Instructions Report immediately if any of the following occur: new severe or persistent headache; blurred vision; calf, chest, or abdominal pain; or any abnormal vaginal bleeding This (oral) drug may be taken with food, milk, or an ch08.qxd 694 8/13/2001 2:24 PM Page 694 H ORMONAL D RUGS antacid to minimize stomach upset (Dysfunctional uterine bleeding) expect heavy and severely cramping flow to days after stopping therapy; expect a normal period after a few days Pharmacokinetics Onset and Duration (Uterine bleeding) after oral administration, acute bleeding should decrease in 1–2 days and stop in 3–4 days (Withdrawal bleeding) onset 3–7 days after last oral dose.81 Fate Norethindrone acetate is rapidly and completely absorbed, with a mean bioavailability of 64 ± 16% because of first-pass metabolism.81–85,94 Norethindrone acetate is rapidly converted to norethindrone in vivo.81,85,87,90 Norethindrone is 36% bound to sex hormone-binding globulin and 61% bound to albumin It is concentrated in body fat and endometrium; breast milk levels are 10% of maternal serum levels Vd is 4.3 ± L/kg; Cl is 0.5 ± 1.5 L/hr/kg Over 50% is eliminated in urine and 20–40% in feces as conjugated glucuronides and sulfates; 65 yr) 13.5 ± 4.2 hr; (children 8–12 yr) 5.4 ± 1.8 hr;39,44 (cirrhosis) 15 hr.46 Adverse Reactions (See Chlorpheniramine.) Contraindications (See Chlorpheniramine.) Precautions (See Chlorpheniramine.) Drug Interactions (See Chlorpheniramine.) Parameters to Monitor (See Chlorpheniramine.) Notes Because of its low degree of efficacy for pruritus, weak suppression of IgE-mediated skin tests, and high sedative potential, diphenhydramine is not the antihistamine of choice for most conditions In the elderly, diphenhydramine is discouraged as a nighttime sleep aid because of its high anticholinergic potential Dimenhydrinate (Dramamine), used for motion sickness, is the 8-chlorotheophyllinate salt of diphenhydramine; 100 mg dimenhydrinate is about equal to 50 mg diphenhydramine FEXOFENADINE Allegra Pharmacology Fexofenadine is a histamine H1-receptor antagonist that is a metabolite of terfenadine It causes little sedation and has little anticholinergic activity (See Antihistamines Comparison Chart.) Adult Dosage PO for allergic rhinitis 180 mg once daily or 60 mg bid; PO for chronic idiopathic urticaria 60 mg bid In renal impairment, reduce initial dosage to 60 mg/day Pediatric Dosage PO (12 yr) same as adult dosage Sedation Anticholinergic +++ +++ 15 (metabolite) ± ± 14 ± ± Page 800 Ebastine Kestine (Investigational— RPR) ADULT DOSAGE 2:46 PM Diphenhydramine HCl Benadryl Various DOSAGE FORMS a 8/13/2001 SIDE EFFECTS HALF-LIFE (HR) (continued ) ch10.qxd ANTIHISTAMINES COMPARISON CHART (continued ) DRUG DOSAGE FORMS ADULT DOSAGE PEDIATRIC DOSAGE a Sedation Anticholinergic PO (pruritus) 25 mg tid-qid; (seasonal allergic rhinitis) titrate up to 150 mg/ day in 1–2 divided doses IM 25–100 mg PO (pruritus) (12 yr) same as adult dosage 35–40 + + Loratadine Claritin Tab 10 mg Syrup mg/mL PO 10 mg/day PO (2–6 yr) mg/day; (>6 yr) 10 mg/day (metabolite: 28) ± ± Phenindamine Tartrate Nolahist Tab 25 mg PO 25 mg q 4–6 hr, to a maximum of 150 mg/day PO (6–11 yr) 12.5 mg q 4–6 hr, to a maximum of 75 mg/day — + ++ 2:46 PM Cap (as pamoate equivalent of HCl salt) 25, 50, 100 mg Susp (as pamoate equivalent of HCl salt) mg/mL Syrup (as HCl) mg/mL Tab (as HCl) 10, 25, 50, 100 mg Inj (as HCl) 25, 50 mg/mL Levocabastine HCl Livostin Page 801 801 Hydroxyzine HCl/ Pamoate Atarax Vistaril Various 8/13/2001 SIDE EFFECTS HALF-LIFE (HR) (continued ) ch10.qxd 802 ANTIHISTAMINES COMPARISON CHART (continued ) DRUG Syrup 1.25, mg/mL Tab 12.5, 25, 50 mg Inj 25, 50 mg/mL Supp 12.5, 25, 50 mg ADULT DOSAGE PO (allergy) 6.25–12.5 mg qid; (motion sickness or sedation) 12.5–25 mg/bid; IM, IV, or PR (PR not recommended