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CUSHING SYNDROME
A Tale of Two Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II
Andrew Y. Hwang, PharmD
John G. Gums, PharmD, FCCP
CASE SUMMARY
A 31-year-old woman presents with complaints of fatigue, weakness, edema, a 50-lb weight gain over the past 2 years, and depression with insomnia. The patient has cushingoid features on physical
examination, and laboratory evaluation reveals hyperglycemia and
dyslipidemia. Initial urinary and plasma testing reveals hypercortisolism. A magnetic resonance imaging scan performed after referral
to an endocrinologist indicates the presence of an enlarged pituitary
gland, but a discrete tumor cannot be localized. Specific laboratory
testing for plasma and urinary steroids confirms the diagnosis of
Cushing disease. Transsphenoidal surgery to remove a clearly circumscribed pituitary microadenoma is the treatment of choice if
the tumor can be localized. In this patient’s case, the tumor cannot
be localized, and subtotal resection of the anterior pituitary would
normally be the recommended treatment. However, this patient
wishes to have children in the future, which makes pituitary irradiation with adjunctive drug therapy a feasible option. Drugs used
with radiation therapy to lower circulating cortisol levels include
mitotane, ketoconazole, metyrapone, and others. With any of these
options, normalization of cortisol levels may take some time. Furthermore, the manifestations of Cushing disease may persist for an
extended period following normalization. Treatments for cardiovascular, bone, and psychological complications were instituted.
QUESTIONS
Problem Identification
1.a. Create a list of this patient’s drug therapy problems.
• Cushing disease (pituitary mass) requiring drug or other
treatment.
• Possible exacerbation of hypercortisolism secondary to intermittent intranasal corticosteroid use.
• Hirsutism probably caused by Cushing disease, but it could
also be caused by levonorgestrel.
• Elevated blood pressure probably caused by Cushing disease,
but it could also be caused by levonorgestrel.
• Elevated plasma glucose probably caused by Cushing disease.
• Elevated total cholesterol and triglycerides probably caused by
Cushing disease.
• Metabolic syndrome (as evidenced from the above three
problems).
• Weakness and fatigue probably caused by Cushing disease, but
they could also be caused by levonorgestrel.
• Edema probably caused by Cushing disease.
• Depression probably caused by Cushing disease, but it could
also be caused by levonorgestrel.
• Signs: Truncal obesity, rounding face (moon facies), hirsutism,
thin skin, purple striae (more common in men, but also found
in women), elevated blood pressure, (+) JVD, 2+ pedal pitting
edema bilaterally.
• Symptoms: Fatigue, weakness, sadness/depression with insomnia, weight gain, edema, easy bruising, blurred vision, occasional back pain.
• Laboratory values: Elevated plasma glucose, total cholesterol,
and triglycerides; mild hypokalemia; elevated urinary free
cortisol (UFC), salivary cortisol, and positive response on
overnight dexamethasone suppression test (DST). However,
the overnight DST test may not be reliable, given concomitant
use of levonorgestrel which can cause false-positive results in
this test.
• Lack of menstrual irregularities is inconsistent with the diagnosis, but the patient is receiving exogenous estrogen/progestin
(Lessina).
1.c. What information (presentation, history, laboratory values,
imaging) can be used to identify the most likely etiology of
Cushing syndrome?
• Exogenous administration of glucocorticoids is the most common cause of Cushing syndrome and the use of mometasone
may be causing or exacerbating underlying hypercortisolism.
Given that disease severity correlates with exogenous glucocorticoid potency, dose, frequency, and route, the administration
of an intermittent intranasal corticosteroid at approved doses
is unlikely to be the sole cause of Cushing syndrome in this
patient.
• The presence of edema, (+) JVD, and borderline hypokalemia suggest mineralocorticoid excess and volume expansion.
Mineralocorticoid excess (and resulting volume expansion)
can occur when high concentrations of cortisol or its metabolites overwhelm 11β-hydroxysteroid dehydrogenase type II
enzymes, allowing cortisol to activate mineralocorticoid receptors to a greater extent. These findings are most consistent with
ectopic corticotropin syndrome or Cushing disease with very
high cortisol production.1
• Following establishment of hypercortisolism, subsequent measurement of a high plasma adrenocorticotropic hormone
(ACTH) concentration suggests ACTH-dependent Cushing
syndrome. Corticotropin-releasing hormone (CRH) stimulation test results confirmed this finding.
• MRI revealed enlarged pituitary gland, suggesting Cushing
disease, which is consistent with the above findings.
Desired Outcome
2.What are the goals of pharmacotherapy in this case?
• Elimination of hypercortisolism.
• Prevention of associated disorders (depression, diabetes, cardiovascular disease, and electrolyte disturbances).
• Reduction of morbidity and mortality from untreated disease.
• Cure of disease by removal of the tumor is a surgical goal.
Therapeutic Alternatives
3.a. What nondrug therapies might be useful for this patient?
• Transsphenoidal surgery (80–90% cured).
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Cushing Syndrome
Steven M. Smith, PharmD, MPH, BCPS
1.b. What information (signs, symptoms, and laboratory values)
indicates the presence or severity of Cushing syndrome?
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• Headaches (possibly caused by pituitary mass), which may
require treatment.
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• Pituitary irradiation (45–85% cured).
SECTION 8
• Total bilateral adrenalectomy (100% cured, but risk for development of Nelson syndrome exists2) which requires lifelong
mineralocorticoid and glucocorticoid replacement.
3.b.What feasible pharmacotherapeutic alternatives are available for the treatment of Cushing disease?
Endocrinologic Disorders
• Medical therapy is generally reserved for specific circumstances such as in patients waiting for radiotherapy to be
effective, when surgery is ineffective, after chemotherapy,
or when there are severe consequences of hypercortisolism.
Pharmacotherapy can be divided into four categories based
on site of action of the agent: (1) steroidogenesis inhibitors,
(2) adrenolytic agents, (3) neuromodulators of ACTH release,
and (4) glucocorticoid-receptor blocking agents. Therapy with
these drugs is continued indefinitely as long as the patient has
hypercortisolism. These agents are not curative, and their beneficial effects are usually reversed on discontinuation.
• Steroidogenic inhibition involves inhibiting adrenal synthesis of
cortisol to decrease circulating cortisol levels.3 Steroidogenic
inhibitors are recommended to lower cortisol secretion under
specific conditions: (1) second-line treatment after transsphenoidal surgery in patients with Cushing disease, with or
without radiation therapy; (2) primary treatment in patients
with ectopic ACTH secretion; (3) adjunctive treatment in adrenocortical carcinoma.3 When these agents are used as monotherapy in Cushing disease, breakthrough hypercortisolism
may occur secondary to corticotropin oversecretion.2
✓Ketoconazole (Nizoral) lowers cortisol in Cushing disease,
resulting in normal corticosteroid values in 84% of patients,
with an additional 11% of patients reporting improvement.
Through its antiandrogenic activity, ketoconazole can also
lower plasma testosterone values, which may be useful in
this patient who has hirsutism. Sustained ketoconazole treatment also can have beneficial effects on serum cholesterol
levels, which may be useful for this patient with dyslipidemia. Ketoconazole can cause reversible elevation of hepatic
transaminases, and recent concerns over severe hepatotoxicity have led to strict limitations on the use of ketoconazole
for treatment of fungal infections (which require lower
doses than does Cushing syndrome) by the US Food and
Drug Administration and the European Medicines Agency.
Other adverse effects include gynecomastia and GI upset.
Numerous cytochrome P450 (CYP) interactions are also
possible. The usual oral daily dose is 400–1600 mg, divided
into multiple doses. The dose should be titrated to maintain
UFC within the upper limits of normal.
✓Metyrapone (Metopirone) has a rapid onset of action compared to ketoconazole and may initially cause an increase in
plasma ACTH concentrations because of a sudden drop in
cortisol. It lowers serum cortisol in about 80% of patients but
normalizes it in only about 25%. Adverse effects include GI
complaints (nausea, vomiting, and abdominal discomfort),
central nervous system effects (somnolence, vertigo, headache, and dizziness), and allergic rash. The usual oral daily
dose is 1000–2000 mg, divided into every 6 hour dosing.
Metyrapone is no longer marketed, but can be obtained for
compassionate use through the manufacturer.
✓Etomidate (Amidate) is an imidazole derivative structurally
similar to ketoconazole with a quick onset of action. Available only as a parenteral formulation, its use is limited to
patients with acute hypercortisolemia requiring emergency
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treatment or in patients preparing for surgery. Excessive
sedation is a concern when using etomidate, and close monitoring in a hospital setting is recommended. Dosing may
vary, and it is often administered as an intravenous bolus
followed by an infusion.
• Adrenolytic agent.
✓Mitotane (ortho, para, dichloro-diphenyldichloroethane;
o,p′-DDD, Lysodren) decreases cortisol secretion rate,
plasma cortisol concentrations, UFC, and plasma concentrations of the 17-substituted steroids. This agent is cytotoxic
and degenerates the zona fasciculata and reticularis resulting
in adrenal cortex atrophy. Mitotane produces a measurable
tumor reduction in 50% of patients; 75% of patients have
>30% reduction in urinary steroids. Because mitotane can
severely reduce steroid production, the patient should be
hospitalized before initiating therapy. If necessary, steroid
replacement therapy can be given. Approximately 80% of
mitotane-treated patients develop GI side effects such as
nausea, vomiting, anorexia, or diarrhea. Lethargy, somnolence, and other central nervous system adverse reactions
occur in approximately 40% of patients. The usual dose is
1–4 g/day, given in divided doses 3 or 4 times daily. The
maximal dose is 12 g/day; however, most patients are unable
to tolerate doses above 8 g/day. Doses can be titrated down
over time, as UFC allows, and mitotane can be discontinued
1 year after irradiation if UFC has normalized. Approximately one-third of patients will have sustained cortisol suppression following discontinuation of mitotane; however, it
can be re-initiated if hypercortisolemia recurs.
• Neuromodulators of ACTH release decrease ACTH secretion in
patients with Cushing disease as a means of decreasing cortisol
concentrations. These agents, also known as pituitary-directed
therapy, are recommended in patients with Cushing disease
who are not surgical candidates or who have persistent disease
following transsphenoidal surgery.3
✓Cabergoline is a dopamine D2 receptor agonist that can initially reduce ACTH secretion in about half of patients with
Cushing disease. Long-term remission (2–3 years) has been
seen in 30–40% of patients; however, hypercortisolism can
recur in about 29% of initial responders.3,4 Adverse effects
include nausea, orthostasis, headache, nasal congestion,
constipation, and psychiatric symptoms (nightmares, vivid
dreams, and psychosis). The usual dose is 0.5–7 mg once
weekly.
✓Pasireotide (Signifor), a somatostatin analogue, causes rapid
and sustained suppression of UFC concentrations. It is
particularly effective at normalizing UFC concentrations
in patients whose baseline UFC is <5 times the upper limit
of normal. The usual dose range is 600 or 900 mcg injected
subcutaneously twice daily. Pasireotide has also been shown
to improve blood pressure, weight, LDL cholesterol, and
quality of life, but commonly causes hyperglycemia. Other
adverse effects include GI symptoms (nausea, diarrhea, and
cholelithiasis), increased hepatic transaminases, sinus bradycardia, and QT prolongation.
• Glucocorticoid receptor-blocking agent.
✓Mifepristone (Mifeprex and Korlym) blocks cortisol action at
the receptor site, and is therefore useful in all etiologies of
hypercortisolism. It is highly effective in reversing the manifestations of hypercortisolism such as hyperglycemia, hypertension, and weight gain. Mifepristone is recommended for
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4.a. What drug, dosage form, dose, schedule, and duration of
therapy are best for treating this patient’s Cushing disease?
• The optimal plan would be to perform transsphenoidal microadenomectomy if a clearly circumscribed microadenoma can
be identified and resected. Otherwise, patients should undergo
85–90% resection of the anterior pituitary. Such radical resection often results in panhypopituitarism, disrupting normal sex
hormone, thyroid hormone, and growth hormone regulation.
Thus, patients wishing to have children should receive pituitary
irradiation instead. This procedure has a lower incidence of
generalized hypopituitary dysfunction. If the latter therapy
fails, bilateral total adrenalectomy should be performed.
• This patient has an enlarged pituitary gland, but no focal inhomogeneity that would suggest an isolated adenoma. She does
not wish to have surgery and desires to have children. Therefore, irradiation and adjunctive therapy are the best options at
this time. Given her desire to have children, special attention
will have to be paid to the pregnancy risks associated with her
pharmacotherapeutic regimen.
✓ During the 3–60 months required to achieve maximum benefit from irradiation, the hypercortisolism can be controlled
with pharmacotherapy, either as single agent or combination
therapy. Irradiation and adjunctive mitotane therapy results
in a remission rate of 80% in the first year, which increases
further in later years. Mitotane can be discontinued after
1 year if the UFC has normalized and can be re-initiated if
hypercortisolism recurs. By 3 years, 80–90% of patients will
have achieved biochemical remission and will no longer
require mitotane. Four to six weeks of therapy with mitotane
is usually required before a benefit is seen.
✓Ketoconazole is a faster alternative to treat the symptoms of
hypercortisolism during the time it takes for the radiation to
take effect. Unfortunately, it does not promote remission as
mitotane does.
✓Therefore, the best treatment option is probably to treat this
patient with irradiation and adjunctive drug therapy until
the effects of the irradiation are observed. The choice of
adjunctive agent depends on how quickly this patient wishes
to try to have another child. Mitotane is a pregnancy category D drug with potential teratogenic activity. Since drug
plasma concentrations may persist for months, pregnancy
should be avoided years after discontinuing the medication.3
Ketoconazole is a pregnancy category C drug. Therefore,
the risks and benefits must be evaluated before the patient
contemplates pregnancy or if she becomes pregnant. However, there are case reports of successful use of ketoconazole
during pregnancy. Thus, if she wishes to become pregnant in
the next 1–2 years, ketoconazole may be the preferred agent.
Additionally, ketoconazole has anti-androgenic effects and
sustained therapy may improve serum cholesterol levels,
✓The neuromodulatory agents, cabergoline and pasireotide,
could also be used as adjunctive therapy. Cabergoline is
a pregnancy category B drug and may be a safe option if
the patient wishes to become pregnant during treatment.
However, this agent may not be as effective, with only about
30–40% of patients achieving a sustained response. Pasireotide is a pregnancy category C drug, and thus, the risks
and benefits should be evaluated prior to initiating therapy.
Given that the patient’s baseline UFC concentrations are
below 5 times the upper limit of normal, pasireotide may be
effective in correcting this patient’s hypercortisolism. However, the patient also presents with hyperglycemia, which
makes this agent a less attractive option.
✓ Mifepristone is pregnancy category X and should be avoided.
4.b.What adjunctive pharmacotherapy may be required if the
therapy identified above is successful?
• Many agents, particularly steroidogenesis inhibitors and adrenolytic agents, can induce adrenal insufficiency by blocking the
production of glucocorticoids and/or degenerating the adrenal
cortex.
• Frequent monitoring of 24-hour UFC or serum cortisol concentration should be sufficient to detect treatment-induced
adrenal insufficiency.
• Steroid replacement (ie, prednisone or others) should be given
as needed to stabilize patients awaiting surgery or those awaiting a response from alternative therapies.
Outcome Evaluation
5.What clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent adverse events?
• Monitor for adrenal insufficiency by checking daily serum
cortisol concentration (target value >5 mcg/dL) while an inpatient. Checking frequent 24-hour UFC concentration (target
value >20 mcg) as an outpatient is essential with all types of
adrenal blocking medications.
• Monitor liver function tests (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) at baseline,
at 1–2 weeks, biweekly for 2 months, then bimonthly for the
next 4 months during ketoconazole therapy. Additionally, total
bilirubin, prothrombin time, and INR testing should be monitored routinely during treatment. Discontinue ketoconazole
if the alanine aminotransferase or aspartate aminotransferase
rises to >3 times the upper limit of normal or if the patient
develops clinical signs of hepatotoxicity.
• To monitor for successful treatment with radiation (which
may take from 3 to 60 months), the patient should be without symptoms and have a plasma cortisol of 5–25 mcg/dL or
24-hour UFC of 20–100 mcg while not on concomitant drug
therapy for Cushing disease. Perform re-testing based on
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Cushing Syndrome
Optimal Plan
which could be advantageous for this patient. However, if
she wishes to wait, mitotane has a better chance of inducing
remission within 1–2 years, after which she may try without
any drug interference. The initial mitotane dose is 1 g PO
daily, which is increased by 0.5–1 g/day every 1–4 weeks if a
response is not seen. The initial ketoconazole dose is 200 mg
PO once daily, increased at 4- to 7-day intervals until UFC
concentrations become normal. Metyrapone is an effective
agent, but should be avoided in this patient due to the risk of
androgenic side effects and mineralocorticoid excess.
CHAPTER 88
the treatment of endogenous Cushing syndrome, including
Cushing disease, in patients with type 2 diabetes or glucose
intolerance, and who are not eligible for, or have had poor
response, to surgery.3 Mifepristone use leads to higher cortisol and ACTH levels; therefore, treatment must be guided
by clinical signs rather than laboratory testing. Common
adverse effects include fatigue, nausea, headache, arthralgia,
peripheral edema, endometrial thickening, and decreased
serum potassium. The usual oral dose is 600–1200 mg/day.
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SECTION 8
patient symptoms and response. It is reasonable to recheck
these tests during the course of therapy, at the end of therapy,
and again within the first 3–6 months after completion of
therapy. The final check is performed to monitor for any signs
of relapse.
Patient Education
Endocrinologic Disorders
6.What information should be provided to the patient to
enhance adherence, to ensure successful therapy, and to minimize adverse events?
Ketoconazole (Nizoral):
• This drug is often used to treat fungal infections, but it is also
useful in treating the symptoms caused by Cushing disease.
• You will take one 200 mg tablet by mouth daily and increase
the dose only if instructed to do so by your physician.
• If you miss a dose, take it as soon as you remember; however, if
it is almost time for the next dose, just take the next dose at the
regularly scheduled time and skip the missed dose.
• Take this tablet with food to decrease stomach upset and to
increase the amount that gets into your system.
• Some possible side effects include nausea, vomiting, and
abdominal pain, which can be minimized by taking it with
food.
• If you are allergic to this drug, you may develop a rash or
another reaction. If this occurs, do not take any more of the
drug until you speak with your physician. If the reaction
becomes severe or if you have trouble breathing, get someone
to take you to the emergency room.
• This medicine can also cause liver damage, but your physician
will monitor your liver enzymes to help prevent this uncommon side effect. Avoiding alcohol may also reduce your risk
of developing liver damage. In rare cases, serious liver damage
may occur even with close laboratory monitoring and avoidance of alcohol. Contact your physician if you develop loss of
appetite, nausea and/or vomiting, yellowing of your skin or
eyes, very dark urine, or pale stools after taking this drug.
• There is not enough information available to clearly establish
whether ketoconazole is safe or dangerous during pregnancy.
It is important to discuss the continued use of this medicine
with your doctor before you try to become pregnant or if you
become pregnant.
Mitotane (Lysodren):
• This medicine is used to reduce the amount of corticosteroid
hormones produced by the adrenal glands in patients with
Cushing disease.
• Take two 500 mg tablets by mouth daily. Your physician will
be increasing this dose every week if you do not respond to
the initial doses.
• Take the very first dose at bedtime with a light snack.
• If you miss a dose, take it as soon as you remember; however, if
it is almost time for the next dose, skip the missed dose and just
take the next dose at the regularly scheduled time.
• The most common side effects of mitotane include nausea,
vomiting, diarrhea, and loss of appetite, which may be reduced
by taking each dose with food.
• Patients commonly become drowsy, fatigued, and/or dizzy
when taking this medication, especially in the beginning of
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
therapy. Therefore, avoid drinking alcoholic beverages or taking other drugs that may make you drowsy while taking this
medication. Use caution when driving or operating machinery
until you know how this medicine affects you.
• Some patients also get a rash while taking mitotane; inform
your physician if this occurs.
• This medication is unsafe during pregnancy and may cause
harm to the unborn baby. It is important to contact your
physician right away if you become pregnant while taking this
medication. Birth control should be used to prevent pregnancy
during treatment and after stopping this drug. Discuss with
your physician to see how long you need to use birth control
after you stop taking mitotane.
■■ FOLLOW-UP QUESTIONS
1.What advantages does measuring late-night salivary cortisol
have over measuring late-night serum cortisol concentrations?
• Salivary cortisol has equal sensitivity, specificity, and diagnostic accuracy to midnight serum cortisol. In addition, it can be
performed on an outpatient basis. This avoids hospitalization,
thus minimizing the risk of false positives (due to the stress
response) and cost.
2.What changes, if any, should be made to the treatment of allergic rhinitis?
• Mometasone, an intranasal corticosteroid, should be discontinued to reduce the risk of exacerbating hypercortisolism.
• The patient may be switched to any of the second-generation
(“non-sedating”) H1 antihistamines such as fexofenadine, cetirizine, or loratadine. These agents are appropriate for patients
with predominantly early-phase reactions such as sneezing,
itching, rhinorrhea, and ocular symptoms.
• If nasal symptoms predominate, a systemic decongestant
(eg, pseudoephedrine) would be appropriate. She should not
exceed 180 mg as a total daily dose of pseudoephedrine since
higher doses are associated with an increased risk of elevated
blood pressure (which she already has).
3.What pharmacologic therapy would you recommend to reduce
her risk of fracture?
• Bone mineral density returns to normal very slowly following
remission of Cushing syndrome. Thus, treatment to speed the
process is indicated. Bisphosphonates, specifically alendronate
and risedronate, carry an FDA-approved indication for treatment of glucocorticoid-induced osteoporosis. Usual doses for
this indication are alendronate 5–10 mg daily or risedronate
5 mg daily. Teriparatide is also FDA-approved for the treatment
of glucocorticoid-induced osteoporosis, but is often not used as
first-line given its cost and route of administration. The usual
dose of teriparatide is 20 mcg subcutaneously once daily.
4.What medication changes would you suggest at this time?
• The calcium-sparing effects of thiazide diuretics are potentially beneficial in patients with concomitant osteoporosis or
osteopenia. However, the potassium wasting from the thiazide
appears to be exacerbating the preexisting hypokalemia associated with mineralocorticoid excess from Cushing syndrome.
This degree of hypokalemia would account for her symptoms at her follow-up visit. Discontinuation of the thiazide
can be considered, although aggressive potassium supplementation might be sufficient to maintain normokalemia.
88-5
REFERENCES
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Cushing Syndrome
1. Newell-Price J, Bertagna X, Grossman AB, Nierman LK. Cushing’s
syndrome. Lancet 2006;367:1605–1617.
2. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol
2015;7:281–293.
3. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s
Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin
Endorcrinol Metab 2015;100:2807–2831.
4. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet 2015;386(9996):913–927.
CHAPTER 88
The choice of a replacement antihypertensive is not clear-cut.
Agents antagonizing the renin-angiotensin-aldosterone system
(eg, angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, and aldosterone antagonists) are good
choices in theory, as they cause dose-dependent elevations in
serum potassium. Calcium channel blockers are also an acceptable alternative. β-Blockers are less attractive, as they have the
potential to worsen blood glucose, cholesterol, and mood. If
ketoconazole is selected for the treatment of Cushing disease
in this patient, its numerous potential CYP interactions, most
notably CYP3A4, must be considered when selecting pharmacotherapy for the patient’s comorbid conditions.