Download CH91 Page 1-5 - Pharmacotherapy

91-1
SECTION 9
WOMEN’S HEALTH (GYNECOLOGIC DISORDERS)
medication, thus allowing them to make informed and educated decisions for themselves and their children.1 The PLLR
removes pregnancy letter categories—A, B, C, D, and X. The
PLLR also requires the label to be updated when information
becomes outdated. Prescription drugs and biologic products
submitted after June 30, 2015 will use the new format immediately while labeling for prescription drugs approved on or
before June 30, 2001, will be phased in gradually.
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PREGNANCY AND LACTATION
Pregnant at This Age?. . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II
Lisa R. Garavaglia, PharmD, BCPS
CASE SUMMARY
• Refer to the FDA’s website for a comparison of the “old versus
new” labeling using PLLR.
Paroxetine:
• Paroxetine is not recommended during pregnancy, especially
during the first trimester. Its use during the first trimester
of pregnancy has been associated with twice the rate of congenital malformations (ventricular septal defects, VSD; atrial
septal defects, ASD) compared with that seen in the general
neonatal population.2,3
A 44-year-old woman reports experiencing two to three episodes of
nausea per day with vomiting occasionally in the evenings. Her gastrointestinal symptoms began about 2 weeks ago and have remained
consistent, preventing her from going to work. Around the same
time her GI symptoms began, she started having frequent, painful
urination and was diagnosed with a urinary tract infection. She is on
day 5 of 7-day antibiotic treatment with nitrofurantoin. She states
that she feels “run down” all the time and needs to start feeling
better soon, or she will lose her job. She took a pregnancy test, and
it is positive. She is extremely concerned about her “blood thinner”
medication, remembering that she could not take it with her previous three pregnancies. She has a history of depression, hypothyroidism, and hypertension, and has a mechanical prosthetic heart valve.
• Based upon the above information, GlaxoSmithKline changed
the prescribing information for paroxetine in 2005 to reflect a
change in FDA Pregnancy Category from C to D.
• Second- and third-trimester exposure may result in perinatal
jitteriness, irritability, urinary retention, bowel obstruction,
seizures (after 20th week), and persistent pulmonary hypertension of the newborn (PPHN). The majority of infants have
signs that are mild and transient (most disappear by 2 weeks).4
Neonatal adaptation syndrome occurs in 10–30% of patients;
this is self-limiting and resembles opioid withdrawal.2 Studies
have failed to show long-term negative neurobehavioral effects
such as deficits in cognition, learning, or behavior.
QUESTIONS
Problem Identification
1.Create a list of the patient’s potential drug therapy problems
(now that she is pregnant). Be sure to include the information
that indicates the severity of this patient’s problems.
Warfarin:5
Refer to Table 91-1 in this Instructor’s Guide for FDA Pregnancy
Category (Risk Factor) definitions.
• Effective on June 30, 2015, the pregnancy and lactation labeling rule (PLLR) is a new format to assist healthcare providers
in assessing benefit versus risk and in subsequent counseling
of pregnant women and nursing mothers who need to take
• Pregnancy risk factor X (avoid specifically in weeks 6–12)
• “Warfarin syndrome”: nasal hypoplasia, microphthalmia,
hypoplasia of the extremities, intrauterine growth retardation
(IUGR), heart disease, scoliosis, and deafness (5.6%)
• Increased rate of miscarriage and stillbirth by week 20 (32%)
• Mental retardation (IQ <80)
• CNS malformations (agenesis of the corpus callosum, Dandy–
Walker malformations, and optic malformation)
TABLE 91-1 US Food and Drug Administration Pregnancy Category Definitions1
Category A: Controlled studies showed no risk to humans. Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.
Category B: No evidence of risk in humans. Animal studies have revealed no evidence of harm to the fetus. However, there are no adequate and well-controlled studies
in pregnant women or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to
the fetus.
Category C: Risks cannot be ruled out in humans. Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant
women or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Category D: Clear evidence of risk in humans. Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However,
the benefits of therapy may outweigh the potential risk.
Category X: Drugs contraindicated in human pregnancy. Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive
evidence of fetal abnormalities. The use of the product is contraindicated in women who are pregnant or may become pregnant.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
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Lisinopril:
Hypothyroidism:
SECTION 9
• Pregnancy risk factor C (first trimester); pregnancy risk
factor D (second and third trimesters)5
• Continue on supplemental therapy with levothyroxine
• First-trimester risks: congenital malformations (cardiovascular
and CNS)5
• Goal TSH is trimester-specific: 1st: 0.1–2.5 mU/L, 2nd:
0.2–3 mU/L, 3rd: 0.3–3 mU/L.10
• Second- and third-trimester risks: crosses the placenta and
interferes with fetal hemodynamics of kidney, which may result
in oligohydramnios, neonatal anuria, and renal failure5,6
Women’s Health (Gynecologic Disorders)
Levothyroxine:
• Pregnancy risk factor A; safe in pregnancy7
Nitrofurantion:
• Pregnancy risk factor B
• Contraindicated in patients at term or during labor due to
hemolytic anemia of newborn8
Desired Outcome
2.What are the goals of therapy for this patient’s preexisting disease states/conditions (hypertension, depression, mechanical
heart valve requiring anticoagulation, and hypothyroidism)
during her pregnancy?
Hypertension:
• Minimize the risk of maternal cardiovascular or cerebrovascular events and protect the fetus from growth retardation.
• Treat complicated mild hypertension (44 years old,
BP 160/90 mm Hg, mechanical valve, but no end organ damage) with antihypertensives.6
• Goal of therapy in women without end-organ damage is systolic pressure 120–160 mm Hg and diastolic pressure between
80–105 mm Hg.6
Depression:
• Relieve symptoms of the mother’s depression and minimize
exposure of antidepressant medications to the fetus.
• Determine the risk/benefit of treating the patient’s disease
based on her preferences and her depression history (number
and severity of depressive episodes, suicidal ideation/suicide
attempts, and psychiatric admissions) and counsel the patient
based on the benefit-risk ratio.2
• If the decision is made to continue the current antidepressant,
but the patient’s symptoms are NOT relieved, it is appropriate
to discuss switching to another agent. However, the change
should be done with caution and close monitoring.
Mechanical heart valve:
• All pregnant patients with mechanical prosthetic valves must
receive continuous therapeutic anticoagulation with frequent
monitoring; antithrombotic therapy is essential because of the
risk of valve thrombosis and death or systemic embolism is
high in the absence of proper anticoagulation.8,9 Therapeutic
goals depend on agent chosen:
✓Warfarin (contraindicated in weeks 6–12): goal INR 2.5–3.5
(obtained weekly until stable).8
✓Low-molecular weight heparin (LMWH): goal anti-Xa level
0.8–1.2 (drawn 4–6 hours postdose; obtained at least every
2 weeks or with large weight changes).8,9
✓ Unfractionated heparin (UFH): goal activated partial thromboplastin time (aPTT) 66–90 seconds (obtained 6 hours
after third dose, every few days until stable, then weekly).8
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
• Patient may require increased dose during pregnancy
Therapeutic Alternatives
3.a. What are the benefits and risks of treating this patient’s
depression and hypertension and in providing anticoagulation for thromboembolism prophylaxis in light of the
patient’s mechanical heart valve?
Depression:
• Adequate treatment of depression throughout pregnancy may
help minimize overall risks of harm to both the mother and
the baby. Specifically, if depression is not adequately treated
during pregnancy, the mother may be at increased risk for
experiencing the following: inability to take care of herself,
suicidal ideation/suicide attempts, insomnia, and risk-taking
behavior which could subsequently increase her risk of acquiring a sexually transmitted infection that could potentially also
be passed on to the baby.2,4 In addition, untreated depression
in the mother has been linked with an increased incidence of
low-birth weight, decreased fetal growth, and postnatal complications (eg, crying) in infants, as well as increased hospitalization of the mother.2–4 Untreated depression is the strongest
predictor of postpartum depression which is considered a true
medical emergency.
• On the other hand, the benefits of discontinuing antidepressant
medication in the mother during pregnancy include protecting the fetus from malformations, cardiac defects, persistent
pulmonary hypertension, spontaneous abortion, and neonatal
adaptation syndrome.2,3
Hypertension:
• Control of blood pressure during pregnancy is essential in
order to prevent maternal complications such as the development of superimposed preeclampsia defined as systolic blood
pressure ≥140 mm Hg or diastolic ≥90 mm Hg and proteinuria
or signs of end organ failure (which could lead to eclampsia,
possible seizures, and maternal death) as well as placental
abruption.6
• Conversely, many antihypertensive agents (especially
angiotensin-converting enzyme inhibitors and angiotensin II
receptor antagonists) are not safe for the fetus and can cause
both congenital and renal malformations. Treatment with
some antihypertensive agents can also result in decreased
placental perfusion, preterm birth, and fetal growth restriction.
Anticoagulation for pregnant patients with mechanical
heart valves:
• In order to reduce the risk of valvular thrombosis and potential thromboembolism, chronic anticoagulation is required for
all patients with mechanical heart valves. The risk of valvular
thrombosis and death or systemic embolism is quite high for
such patients in the absence of proper anticoagulation with
antithrombotic therapy.8
• Even in the absence of a mechanical heart valve, the risk of
venous thromboembolism is five to six times higher in pregnancy versus the risk in nonpregnant patients.11 Further, the
prevalence of thromboembolism is higher in women with
inherited thrombosis risk factors and generally, those >35 years
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• In the absence of anticoagulation, there exists an increased risk
of bleeding in pregnancy, which can lead to threatened abortion, signify placental abruption, or be the result of placenta
previa.
• Considering the risk to the fetus, UFH or LMWH are considered to be the safest agents, because they do not cross the
placenta.8
✓Second and third trimester: Warfarin (adjusted to INR goal)
plus aspirin 75–100 mg daily until 36 weeks is the safest
option for the mother. If the mother chooses to avoid the
fetal risk associated with warfarin therapy, therapeutic SC
LMWH twice per day should be provided as stated above.
✓At time for delivery (~36 weeks): Dose-adjusted continuous
infusion of UFH (maintaining the aPTT at 2.0–2.5 times
control) should be initiated 24 hours before planned induction of labor or cesarean delivery and LMWH or warfarin
discontinued.
✓Cessation of low-dose aspirin is suggested in the week prior
to planned delivery.
• Warfarin is contraindicated in pregnancy particularly during
weeks 6–12 and near term. The risks of warfarin use to the fetus
include CNS malformations, stillbirth, “warfarin syndrome”
(described previously), embryopathy from week 6–10, and
microhemorrhages, leading to fetopathy.5
Optimal Plan
• Direct thrombin inhibitors (eg, dabigatran) and direct factor
Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) should not
be considered alternatives to therapy with warfarin or heparin
in patients with prosthetic valves (during or outside of pregnancy). Dabigatran specifically is contraindicated in patients
with mechanical heart valves.
Labetalol:
3.b.What pharmacotherapeutic alternatives may be used to
manage the patient’s depression, hypertension, and anticoagulation for her heart valve?
Depression4:
• Sertraline 50 mg daily (Pregnancy Category C; most commonly reported SSRI with the least reported birth defects)
• Citalopram 20 mg daily (Pregnancy Category C). Recent Bayesian analysis reports that some birth defects occur 2–3.5 time
more frequently in infants of women treated with paroxetine
or fluoxetine early in pregnancy.
Hypertension6:
• Any of the following: labetalol 100 mg BID (max 2400 mg/
day), nifedipine XL 30 mg/day (max 120 mg/day), or methyldopa 250 mg BID (max 3 g/day)
• Adjunctive agents: hydrochlorothiazide 12.5 mg/day (max
50 mg/day) or hydralazine 50 mg/day (max 300 mg/day)
• Anticoagulation for mechanical heart valve: The 2014 AHA/
ACC valvular heart disease guideline, the 2012 ACCP Consensus Conference on Antithrombotic Therapy, and the 2011
European Society of Cardiology (ESC) guidelines on the management of cardiovascular disease during pregnancy included
recommendations concerning anticoagulation in women with
mechanical prosthetic valves who become pregnant. The following recommendations are from the 2014 AHA/ACC guidelines and include:9
✓First trimester: For patients with baseline warfarin dose
≤5 mg/day, continue warfarin with close INR monitoring
throughout the first trimester. Alternative for patients who
wish to avoid the risk of low-dose warfarin during the first
trimester is dose-adjusted SC LMWH from 6 to 12 weeks to
achieve target anti-Xa levels of 0.8–1.2 unit/mL at 4–6 hours
post-dose. For patients whose baseline warfarin dose is
4.a. The physician decided to prescribe labetalol for the patient’s
hypertension and enoxaparin for anticoagulation. What
dose, schedule, and duration are the best for this patient for
each of these medications?
• The usual recommended dose for labetalol is 100 mg BID
(max 2400 mg/day).
• Based on the overall low rate of adverse effects and good
efficacy, labetalol is a good option for first-line treatment of
chronic hypertension in pregnancy. For those patients with
Stage 1 hypertension (systolic blood pressure 140–159 mm
Hg or diastolic blood pressure 90–99 mm Hg) tapering off the
drug is an option in the first trimester with close monitoring
of blood pressure throughout the remainder of the pregnancy.
In this case, because of the patient’s age (40), she is considered
to have complicated, rather than uncomplicated, hypertension,
which will necessitate the use of antihypertensive medication
throughout her pregnancy with close monitoring.6
Enoxaparin:
• The recommended dose of enoxaparin for prevention of
thromboembolism is 1 mg/kg actual body weight/dose, given
subcutaneously every 12 hours or 80 mg Q 12 H for our
patient. It is extremely important to adjust the dose based on
anti-Xa levels in this population.
• A switch to UFH at 36 weeks is recommended in the event that
a patient may receive epidural or spinal medication or may
require a C-section.8,9
4.b. The patient has been asymptomatic for more than a year and
has agreed to discontinue her antidepressant. What are your
recommendations for stopping the medication?
• Taper paroxetine slowly such as 25% reduction in dose every
1–2 weeks to avoid withdrawal symptoms.2
• Consider possible fetal echocardiography.3
• Recommend psychotherapy.
• Recommend against herbal therapies (eg, St. John’s wort and
others) due to the lack of FDA regulation and the fact that no
studies have specifically examined their use in pregnancy.
• Monitor mother bimonthly for signs and symptoms of severe
depression after tapering the drug, especially those that could
result in harm to the baby (ie, suicidal ideation, insomnia, risktaking behaviors, inability to care for herself).2,3
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Pregnancy and Lactation
• Options for anticoagulation during pregnancy include vitamin K antagonists (eg, warfarin), LMWH, or UFH. Although
LMWH or UFH can be substituted for vitamin K antagonists,
doubt has been raised about their effectiveness for the prevention of valvular thrombosis and systemic embolism in pregnant
patients with mechanical heart valves.9 Most recent consensus
is that UFH throughout pregnancy is a poor anticoagulant with
a high incidence of thromboembolic events.9
>5 mg/day, switch to dose-adjusted SC LMWH throughout
the first trimester as described above. During the first trimester, whether patients receive warfarin or heparin anticoagulation, add low-dose aspirin (75–100 mg/day).
CHAPTER 91
of age have an increased incidence of thromboembolism
occurrence.
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Outcome Evaluation
SECTION 9
5.What clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcomes for the patient’s hypertension and anticoagulation
therapy and to detect or prevent medication-related adverse
effects?
Hypertension:6,7
Women’s Health (Gynecologic Disorders)
• Check baseline laboratory tests: urinalysis, urine culture, and
serum creatinine, glucose, and electrolytes (to rule out renal
disease and diabetes mellitus).
• Obtain an electrocardiogram and ophthalmologic evaluation
in women with long-standing hypertension.
• Have patient monitor blood pressure at home during the day.
(Goal systolic blood pressure should be between 120 and
160 mm Hg and goal diastolic pressure should be between
80 and 105 mm Hg.)
• Monitor fundal growth: Perform ultrasound at 16–20 weeks;
repeat at 28 weeks and then every 3 weeks until delivery. If
evidence of fetal growth restriction is found, fetoplacental
assessment to include umbilical artery Doppler velocimetry is
recommended.
• For women with proteinuria on a urine dipstick, check a
quantitative test for urine protein (watch for symptoms of
preeclampsia).
Anticoagulation:
• Monitor anti-Xa levels (goal is 0.8–1.2 unit/mL 4–6 hours
postdose). Monitor bimonthly for the first few months and
then monthly throughout pregnancy (adjust dose by 10 mg/kg
if levels are high or low, respectively)9
• Monitor for signs of bleeding (bruising, nose bleeds, etc.)
• Monitor for signs or symptoms of clotting (shortness of breath,
chest pain, etc.)
Patient Education
and headache. If you experience any of these potential side
effects, contact your physician.
• This medication has the potential to interact with many other
medications and herbal or natural products. Avoid dong quai,
yohimbe, ginseng, and natural licorice. You should consult
your physician before taking any other medications to ensure
that they are safe to take during your pregnancy and that they
will not interact with this medication.
Enoxaparin9:
• This medication is administered subcutaneously (or directly
underneath the skin) and into the belly. Using the thumb and
forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a
45–90° angle. It is recommended not to rub the injection site
after administration, as bruising will occur. Rotate injection
sites.
• Administer an 80-mg syringe every 12 hours (one syringe for
each dose).
• Because of how this drug works in the blood, there is high possibility of bruising.
• Report any signs of bleeding (eg, blood in your stool or urine,
nose bleeds, bleeding gums) to your physician immediately. In
addition, report any heart palpitations, chest pain, and/or right
arm weakness or pain to your physician immediately. Signs of
clotting such as shortness of breath or pain in your calf with
redness and swelling should be reported to your physician
as well.
• Store this medication at room temperature.
■■ FOLLOW-UP QUESTIONS
1.Based on the American College of Obstetricians and Gynecologists (ACOG) guidelines, what would you recommend to the
patient?
• All antidepressants are excreted into the breast milk.
6.What information should be provided to the patient to
enhance adherence to the medication, ensure successful therapy, and minimize adverse effects?
• The American Academy of Pediatrics and LactMed (National
Institutes of Health) consider SSRIs–SNRIs compatible with
breastfeeding. The numerous nutritional and immunologic
advantages of breastfeeding far outweigh the risk.2
Paroxetine:
• If she does restart paroxetine:
• This medication is used to treat your depressive symptoms and
could be continued throughout your pregnancy as discussed
and advised by your physician. If the decision is made to stop
the drug, your physician will advise you how to taper this
medication off over a few weeks. You may be able to restart this
medication after you deliver your baby.
• Take 20 mg tablet once daily with or without food. If a dose
is missed, take the dose as soon as you remember that day to
avoid any 24-hour period without drug.
• Side effects: Drowsiness, vivid dreams, constipation, and
decreased libido.
Labatelol6:
✓Recommend starting at lowest effective dose (10 mg/day).
✓Advise the patient that breastfeeding should be immediately
stopped if the nursing infant develops abnormal symptoms,
such as irritability, poor feeding, or disturbed sleep, which
may be due to exposure to the medication.2
2.What is the Pregnancy and Lactation Labeling Rule?
• December 2014, the FDA published the Content and Format of
Labeling for Human Prescription Drug and Biological Products:
Requirements for Pregnancy and Lactation Labeling (PLLR).1
✓The PLLR removes pregnancy letter categories A, B, C, D,
and X.
• This medication is safe to use during pregnancy and will help
to control your blood pressure throughout your pregnancy.
Take one 100 mg tablet by mouth twice daily. You can take this
medication with or without food/drink.
✓ The PLLR requires changes to the content and format for the
information presented in the drug labeling to assist healthcare providers in assessing the benefit versus the risk and
in subsequent counseling of pregnant women and nursing
mothers who need to take the medication.
• Side effects: Frequently occurring side effects which may occur
include dizziness, postural hypotension (ie, your blood pressure may drop suddenly when you stand up), fatigue, nausea,
✓Prescriptions drugs and biologic products submitted after
June 30, 2015, will use the new format immediately while
labeling for prescription drugs approved on or before
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
91-5
• New labeling:
✓Pregnancy (including labor and delivery): includes information from pregnancy exposure registries, risk summary,
clinical considerations, and data.
✓Lactation (including nursing mothers): provides information about using drug while breastfeeding (eg, amount of
drug in breast milk, potential effects on the breastfed infant).
REFERENCES
1.U.S. Food and Drug Administration. Pregnancy and lactation
labeling (drug) final rule. Available at: http://www.fda.gov/Drugs
/DevelopmentApprovalProcess/DevelopmentResources/Labeling
/ucm093307.htm. Accessed April 16, 2016.
2.Koren G, Nordeng H. Antidepressant use during pregnancy: the
benefit-risk ratio. Am J Obstet Gynecol 2012;207:157–163.
3. Pearlstein T. Depression during Pregnancy. Best Pract Res Clin Obstet
Gynaecol 2015;29:754–764.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Pregnancy and Lactation
✓Females and Males of Reproductive Potential (new): information about need for pregnancy testing, contraception
recommendations, and information on fertility as relates to
the drug.
4. Yonkers KA, Wisner K, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists.
Gen Hosp Psychiatry 2009;31:403–413.
5.Buhimschi C, Weiner C. Medications in pregnancy and lactation
Part 1. Teratology. Obstet Gynecol 2009;113:166–188.
6. American College of Obstetricians and Gynecologists. Hypertension in
pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol
2013;122:1122–1131.
7.Buhimschi C, Weiner C. Medications in pregnancy and lactation
Part 2. Drugs with minimal or unknown human teratogenic effect.
Obstet Gynecol 2009;113:417–432.
8.Bates SM, Greer IA, Middeldrop S, et al. VTE, thrombophilia,
antithrombotic therapy, and pregnancy: antithrombotic therapy
and prevention of thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012;141(2 Suppl):e691S–e736S. doi:10.1378/chest.11-2300.
9. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guidelines
for the management of patients with valvular heart disease: executive
summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol 2014;63:2438–2488.
10. Kaplan MM. Management of thyroxine during pregnancy. Endocr
Pract 1996;2:281–286.
11. Marik PE, Plante LH. Venous thromboembolic disease and pregnancy.
N Eng J Med 2008;359:2025–2033.
CHAPTER 91
June 30, 2001, will be phased in gradually. Over-the-counter
will not be affected by the rule.