Corticosteroids General Statement.doc

[Guest guest]

Corticosteroids General Statement

Adverse Effects

Adrenocortical

Insufficiency from

AHFS

DI™

When

given in supraphysiologic doses for prolonged periods, glucocorticoids may

cause decreased secretion of endogenous corticosteroids by suppressing

pituitary release of corticotropin (secondary adrenocortical insufficiency).

The degree and duration of adrenocortical insufficiency produced by the drugs

is highly variable among patients and depends on the dose, frequency and time

of administration, and duration of glucocorticoid therapy. This effect may be

minimized by use of alternate-day therapy. (See Alternate-Day Therapy in Dosage

and Administration: Dosage.)

As in

patients with primary adrenocortical insufficiency maintained on

corticosteroids, patients who develop secondary adrenocortical insufficiency

require higher corticosteroid dosage when they are subjected to stress (e.g.,

infection, surgery, trauma). In addition, acute adrenal insufficiency (even

death) may occur if the drugs are withdrawn abruptly or if patients are

transferred from systemic glucocorticoid therapy to beclomethasone dipropionate

oral inhalation therapy. Therefore, the drugs should be withdrawn very

gradually following long-term therapy with pharmacologic dosages. (See

Discontinuance of Therapy in Dosage and Administration: Dosage.) Adrenal

suppression may persist up to 12 months in patients who receive large dosages

for prolonged periods. Until recovery occurs, patients may show signs and

symptoms of adrenal insufficiency when they are subjected to stress and

replacement therapy may be required. Since mineralocorticoid secretion may be

impaired, sodium chloride and/or a mineralocorticoid should also be

administered.

Musculoskeletal

Effects from

AHFS

DI™

Muscle wasting,

muscle pain or weakness, delayed wound healing, and atrophy of the protein

matrix of the bone resulting in osteoporosis, vertebral compression fractures,

aseptic necrosis of femoral or humeral heads, or pathologic fractures of long

bones are manifestations of protein catabolism which may occur during prolonged

therapy with glucocorticoids. These adverse effects may be especially serious

in geriatric or debilitated patients. Before initiating glucocorticoid therapy

in postmenopausal women, the fact that they are especially prone to

osteoporosis should be considered. Glucocorticoids should be withdrawn if

osteoporosis develops, unless their use is life-saving. A high-protein diet may

help to prevent adverse effects associated with protein catabolism.

Osteoporosis

and related fractures are one of the most serious adverse effects of long-term

glucocorticoid therapy. Moderate- to high-dose

glucocorticoid therapy is associated with loss of bone and an increased risk of

fracture. Skeletal wasting ismost

rapid during the initial 6 months of therapy, and trabecular bone is affected

to a greater degree than is cortical bone. The adverse skeletal

effects of glucocorticoids appear to be both dose and duration dependent, with

prednisone dosages of 7.5 mg or more daily for 6 months or longer often

resulting in clinically important bone loss and increased fracture risk. Cumulative dose also

affects the severity of bone loss, although a threshold below which osteopenia

is unlikely has not been elucidated. Alternate-day regimens

have not been shown to be associated with less risk of bone loss than daily

regimens. Bone loss has even been

associated with oral inhalation of glucocorticoids. Most patients receiving

long-term glucocorticoid therapy will develop some degree of bone loss, and

more than 25% will develop osteoporotic fractures. Vertebral fractures have

been reported in 11% of asthmatic patients receiving systemic glucocorticoids

for at least 1 year, and glucocorticoid-treated

patients with rheumatoid arthritis are at increased risk of fractures of the

hip, rib, spine, leg, ankle, and foot.

To

minimize the risk of glucocorticoid-induced bone loss, the smallest possible

effective dosage and duration should be used. Topical and inhaled

preparations should be used whenever possible. Lifestyle modification to

reduce the risk of osteoporosis (e.g., cigarette smoking cessation, limitation

of alcohol consumption, participation in a weight-bearing exercise for 30—60

minutes daily) should be encouraged. Calcium and vitamin D

supplementation, sex hormone replacement therapy, and a weight-bearing exercise

program that maintains muscle mass are suitable first-line therapies aimed at

reducing the risk of adverse bone effects. Thiazide diuretics and

sodium intake restriction may be useful in reducing the hypercalciuria

associated with glucocorticoid therapy. Patients who are unable to

take sex hormone replacement therapy or who have established osteoporosis or

are exhibiting a deterioration in bone mass density despite these interventions

are candidates for biphosphonate or calcitonin therapy.

Alendronate,

a synthetic biphosphonate, is used in conjunction with calcium and vitamin D

supplementation for corticosteroid-induced osteoporosis in patients receiving

glucocorticoids in a daily dosage equivalent to 7.5 mg or more of prednisone

daily and who have low mineral bone density. (See Osteoporosis:

Corticosteroid-induced Osteoporosis under Uses, in Alendronate, 92:00.)

An acute

myopathy has been observed with the use of high doses of glucocorticoids,

particularly in patients with disorders of neuromuscular transmission (e.g.,

myasthenia gravis) or in patients receiving concomitant therapy with

neuromuscular blockingagents (e.g., pancuronium). This acute myopathy is

generalized, may involve ocular and respiratory muscles, and may result in

quadriparesis. Myopathy may be accompanied

by elevated serum creatine kinase [CK, creatine phosphokinase, CPK]

concentrations. Resolution or clinical

improvement of the myopathy may occur weeks to years after discontinuance of

glucocorticoid therapy.

Tendon

rupture, particularly of the Achilles tendon, has occurred in patients

receiving glucocorticoids.

Increased

Susceptibility to Infection from AHFS

DI™

Glucocorticoids,

especially in large doses, increase susceptibility to and mask symptoms of

infection. Infections with any

pathogen, including viral, bacterial, fungal, protozoan, or helminthic

infections in any organ system, may be associated with glucocorticoids alone or

in combination with other immunosuppressive agents. These infections may be

mild, but they can be severe or fatal, and localized infections may

disseminate.

Patients

who become immunosuppressed while receiving glucocorticoids have increased

susceptibility to infections compared with healthy individuals. Some infections such as

varicella (chickenpox) and measles can have a more serious or even fatal

outcome in such patients, particularly in children.

Immunosuppression

is most likely to occur in patients receiving high-dose (e.g., equivalent to 1

mg/kg or more of prednisone daily), systemic glucocorticoid therapy for any

period of time, particularly in

conjunction with glucocorticoid-sparing drugs (e.g., troleandomycin) and/or

concomitant immunosuppressant agents; however, patients

receiving moderate dosages of systemic glucocorticoids for short periods or low

dosages for prolonged periods also may be at risk.

The US

Food and Drug Administration (FDA) states that the possibility of orally

inhaled glucocorticoid therapy causing sufficient immunosuppression to place a

patient at risk of infection also should be considered. However, the risk of such

therapy, including any possible contribution of local pulmonary

immunosuppressant effects of inhaled drug to the development of serious

pulmonary infections (e.g., varicella pneumonia), remains to be more fully

elucidated.

Glucocorticoid-dependent

children should undergo anti-varicella-zoster virus antibody testing. Vaccination should be

considered for those who have absent or inadequate antibody levels. In addition, such children

and any adult who are not likely to have been exposed to varicella or measles

should avoid exposure to these infections while receiving glucocorticoids. If exposure to varicella

or measles occurs in such individuals, administration of varicella zoster

immune globulin (VZIG) or immune globulin, respectively, may be indicated. If varicella develops,

treatment with an antiviral agent (e.g., acyclovir) may be considered, although fatal outcome

(e.g., in those developing hemorrhagic varicella) may not always be avoided

even if such therapy isinitiated aggressively.

The

immunosuppressive effects of glucocorticoids may result in activation of latent

infection or exacerbation of intercurrent infections, including those caused by

Candida, Mycobacterium, Toxoplasma, Strongyloides,

Pneumocystis, Cryptococcus, Nocardia, or Ameba. Glucocorticoids should be

used with great care in patients with known or suspected Strongyloides (threadworm) infection. In such patients,

glucocorticoid-induced immunosuppression may lead to Strongyloides hyperinfection and disseminationwith

widespread larval migration, often accompanied by severe enterocolitis and

potentially fatal gram-negative septicemia.

Some

experts advise that the need to continue at least physiologic replacement

dosages of glucocorticoids in glucocorticoid-dependent patients developing

serious infection should be considered since discontinuance of the drugs before

or after the development of varicella may have contributed to fatal outcome in

some reported cases. Additional insight is

needed regarding the dosages, routes, and types of glucocorticoids as well as

immunologic characteristics likely to place patients at substantial risk of

immunosuppression and serious infection.

The most

common adverse effect of oral inhalation therapy with glucocorticoids is Candida albicans or Aspergillus niger infections of the mouth,

pharynx, and occasionally the larynx. The occurrence of these fungal infections

appears to be dose dependent (e.g., they occur more often at a dosage of

beclomethasone dipropionate of 800 µg/day than at a dosage of 400 µg/day); they

also occur more frequently in women than in men. Some clinicians recommend that

patients rinse their mouths with water and swallow after each oral inhalation

dose to prevent Candida

infection. Usually, Candida or Aspergillus infections are of little

clinical importance, but occasionally they may require antifungal therapy or

discontinuance of the oral inhalation.

Fluid and

Electrolyte Disturbances from AHFS

DI™

Sodium

retention with resultant edema, potassium loss, hypokalemic alkalosis, and

hypertension may occur in patients receiving glucocorticoids. Congestive heart

failure may occur in susceptible patients. These mineralocorticoid effects are

less frequent with synthetic glucocorticoids (except fludrocortisone) than with

hydrocortisone or cortisone, but may occur, especially when synthetic

glucocorticoids are given in high dosage for prolonged periods. Dietary salt restriction

is advisable and potassium supplementation may be necessary in patients

receiving hydrocortisone or cortisone for its anti-inflammatory or

immunosuppressant effects. When glucocorticoids with substantial

mineralocorticoid activity are administered, patients should be instructed to

notify their physicians if edema develops. All glucocorticoids increase calcium

excretion and may cause hypocalcemia.

Ocular Effects from AHFS

DI™

Prolonged

use of glucocorticoids may result in posterior subcapsular and nuclear

cataracts (particularly in children), exophthalmos, or increased intraocular

pressure which may result in glaucoma or may occasionally damage the optic

nerve. Data from acase-control

study indicate that the risk of ocular hypertension or open-angle glaucoma was

increased in patients receiving high dosages of orally inhaled glucocorticoids

(1500 µg or more of flunisolide, 1600 µg of beclomethasone, budesonide, or

triamcinolone) daily for 3 or more months. Patients receiving lower

dosages of orally inhaled or intranasal glucocorticoids were not at increased

risk for these adverse ocular effects. Results from a

population-based study indicate that use of orally inhaled corticosteroids is

associated with development of posterior subcapsular and nuclear cataracts. Establishment of secondary

fungal and viral infections of the eye may also be enhanced in patients

receiving glucocorticoids. Blindness has occurred rarely following

intralesional injection of glucocorticoids around the face and head.

Endocrine Effects from AHFS

DI™

When

glucocorticoids are administered over a prolonged period, they may produce

various endocrine disorders including hypercorticism (cushingoid state) and

amenorrhea or other menstrual difficulties. Corticosteroids may decrease

glucose tolerance, produce hyperglycemia, and aggravate or precipitate diabetes

mellitus especially in patients predisposed to diabetes mellitus. If steroid

therapy is required in patients with diabetes mellitus, changes in insulin or

oral antidiabetic agent dosage or diet may be necessary. Corticosteroids have

also been reported to increase or decrease motility and number of sperm in some

men.

GI Effects from AHFS

DI™

Adverse

GI effects of corticosteroids include nausea, vomiting, anorexia which may

result in weight loss, increased appetite which may result in weight gain,

diarrhea or constipation, abdominal distension, pancreatitis, gastric

irritation, and ulcerative esophagitis. Corticosteroids have been implicated in

the development, reactivation, perforation, hemorrhage, and delayed healing of

peptic ulcers. Although concomitant administration of antacids or other

antiulcer agents (e.g., cimetidine) has been suggested to prevent peptic ulcer

formation in patients receiving high dosages of corticosteroids, routine

concomitant use of these agents does not appear to be warranted since

corticosteroid-induced ulcers occur infrequently (in 2% or less of patients

receiving corticosteroids) and the efficacy of antiulcer therapy in preventing

these ulcers has not been established. However, selective use of preventive

antiulcer therapy may be considered in patients receiving corticosteroids who

are at increased risk of peptic ulcer formation (e.g., those receiving other

ulcerogenic drugs). Gastric irritation may be reduced if oral corticosteroids

are taken immediately before, during, or immediately after meals, or with food

or milk.

Nervous System

Effects from

AHFS

DI™

Adverse

neurologic effects of glucocorticoids have included headache, vertigo,

insomnia, restlessness and increased motor activity, ischemic neuropathy, EEG

abnormalities, and seizures. Glucocorticoids may precipitate mental

disturbances ranging from euphoria, mood swings, depression and anxiety, and

personality changes to frank psychoses. Emotional instability or psychotic

tendencies may be aggravated by the drugs. Increased intracranial pressure with

papilledema (i.e., pseudotumor cerebri) has been reported, generally in

association with withdrawal of glucocorticoid therapy.

Dermatologic Effects

from AHFS

DI™

Various

adverse dermatologic effects are associated with systemic glucocorticoid

administration and include impaired wound healing, skin atrophy and thinning,

acne, increased sweating, hirsutism, facial erythema, striae, petechiae,

ecchymoses, and easy bruising. Dermatologic manifestations of hypersensitivity

to the corticosteroids include hives and/or allergic dermatitis, urticaria, and

angioedema. Burning or tingling of the perineal area may occur after IV

injection of the drugs. Parenteralcorticosteroid therapy has also produced

hypopigmentation or hyperpigmentation, scarring, induration, delayed pain or

soreness, subcutaneous and cutaneous atrophy, and sterile abscesses. Kaposi’s

sarcoma has been reported to occur in patients receiving glucocorticoid

therapy; discontinuance of such therapy may result in remission of the disease.

Other Adverse

Effects from

AHFS

DI™

A steroid

withdrawal syndrome seemingly unrelated to adrenocortical insufficiency and

consisting of anorexia, nausea and vomiting, lethargy, headache, fever, joint

pain, desquamation, myalgia, weight loss, and/or hypotension has been reported

following abrupt withdrawal of glucocorticoids. Symptoms often occurred while

plasma glucocorticoid concentrations were still high but were falling rapidly;

apparently the abrupt change in glucocorticoid concentration rather than a low

concentration per se was responsible for the phenomenon. Bradycardia has

occurred during or after IV administration of large doses of methylprednisolone

sodium succinate but did not appear to be related to the rate or duration of

infusion.

A few

patients have experienced hoarseness, dry mouth, and sore throat during oral

inhalation therapy with glucocorticoids; these adverse effects have also

occurred in patients receiving only the aerosol vehicle and may be minimized by

rinsing the mouth and swallowing after using the aerosol.

Injections

of slightly soluble glucocorticoids may produce atrophy at the site of

injection. (See Dosage and Administration: Administration.) Intra-articularly

administered corticosteroids have caused postinjection flare and Charcot-like

arthropathy.

Arachnoiditis,

meningitis, paraparesis or paraplegia, sensory disturbances, bowel or bladder

dysfunction, headache, and seizures have been reported with intrathecal or epidural

administration of glucocorticoids. Intranasal administration of these drugs has

been associated with allergic reactions and rhinitis. Temporary or permanent

visual impairment, including blindness, has been reported with glucocorticoid

administration by intranasal, ophthalmic, and other routes of administration.

Increasedintraocular pressure, infection, residue or slough at the injection

site, and ocular and periocular inflammation, including allergic reactions,

have been reported with ophthalmic administration of glucocorticoids.

Hypercholesterolemia,

atherosclerosis, thrombosis, thromboembolism, fat embolism, and

thrombophlebitis have also been associated with corticosteroid therapy,

particularly with cortisone. Hypertrophic cardiomyopathy has been reported in

premature infants receiving glucocorticoids (e.g., prednisolone).

Thrombocytopenia has been observed in a few patients following prolonged,

high-dose glucocorticoid therapy. Palpitation, tachycardia, swelling of mouth

and tongue, frequency and urgency of urination,and enuresis have been reported

rarely. Anaphylactic reactions also have been reported rarely with parenteral

glucocorticoid therapy. Glucocorticoids may decrease serum concentrations of

ascorbic acid (vitamin C) and vitamin A; symptoms of vitamin A or C deficiency

may occur rarely.

Transient,

mild, asymptomatic elevations in ALT (SGPT), AST (SGOT), and alkaline

phosphatase concentrations have been reported in patients receiving

glucocorticoids; these effects are not associated with any clinical syndrome

and generally resolve upon discontinuance of glucocorticoid therapy.