1
DRUGDEX DRUG EVALUATIONS
COSYNTROPIN
0.0 OVERVIEW
A. Cosyntropin is a synthetic tetracosapeptide corresponding to the 1st through 24th amino acid residues of naturaladrenocorticotropin hormone and which has all the activity of the natural hormone.
B. DOSING INFORMATION: Cosyntropin may be administered intramuscularly or intravenously at an adult dose of0.25 to 0.75 mg over 2 min/0.25 mg as an adrenal function screening test; the 0.25-mg dose dissolved in sterile salineand injected intramuscularly is most often recommended for this purpose. The same doses may also be administeredas infusions, added to dextrose or saline solutions and administered at a rate of 0.04 mg/hr over 6 hours. Therecommended pediatric (ages 2 yrs or less) dose for this indication is 0.125 mg.
C. PHARMACOKINETICS: Cosyntropin is absorbed only following parenteral administration; it is inactivated whengiven by mouth. When cosyntropin is administered, there is a prompt rise in the plasma hydrocortisone level becauseof stimulated release from the adrenal glands. Following intramuscular injection (with normally functioning adrenals),these elevated hydrocortisone levels peak at 1 hour and decline back to baseline levels at 4 hours. Followingintramuscular injection of the long-acting zinc phosphate or hydroxide preparations (NOT available in the USA), peakadrenally-released plasma hydrocortisone levels occur at 8 hours and remain elevated for greater than 24 hours.
D. CAUTIONS: Cosyntropin is administered only by injection in a health care facility setting; it is generally NOTrecommended for self-injection because of the danger of serious or fatal allergic reactions. Painful local reactionsmay occur if the depot preparation is not injected deep intramuscularly. Periorbital edema, cutaneous rash, anduncomfortable dizziness have been reported. Behavioral deterioration has been reported in infants treated withadrenocorticotropin hormone for myoclonic encephalopathy and infantile spasms. Adverse effects seen duringcorticotropin therapy for infantile spasms include excessive weight gain, diarrhea, increased susceptibility to infectionsdue to immune suppression, worsening of mental state with either dejection or excessive nervousness, acne, menstrualdischarges, electrolyte and calcium abnormalities, hypertension with potential intracranial hemorrhage, transient brainshrinkage noted on CT-scans, and rarely hematuria, melena, or hematemesis.
E. CLINICAL APPLICATIONS:
1. The main use of cosyntropin is as a diagnostic test for adrenocorticotropin hormone insufficiency; it is alsosometimes used to treat ulcerative colitis and Crohn's disease.
1.0 DOSING INFORMATION
1.1 DOSAGE FORMS
A. Information on specific dosage forms can be obtained by entering a brand name or trade name at the "TypeIn Topic" screen or by choosing "ProdIndx."
1.2 STORAGE AND STABILITY
A. PARENTERAL
1. The manufacturer recommends that constituted cosyntropin solutions NOT be retained (Prod InfoCortrosin(R), 1991).
2. When constituted with 0.9 percent sodium chloride for injection, cosyntropin is stable for 24 hours atroom temperature; it is stable for up to 21 days when refrigerated at between 2 and 8 degreescentigrade under a nitrogen atmosphere (see manufacturer's recommendation above, however)(Reynolds, 1990).
3. In solutions with a pH between 5.5 and 7.5, cosyntropin is stable for 12 hours at room temperature.
B. PH
1. A constituted cosyntropin solution has a pH between 5.5 and 7.5.
C. SOLUBILITY
1. Cosyntropin is soluble at 1 part in 70 parts of water (Reynolds, 1990).
1.3 ADULT DOSAGE
1.3.1 NORMAL DOSE
A. PARENTERAL
1. Cosyntropin may be administered intramuscularly or intravenously in an adult dose of 0.25 to0.75 milligram as an ADRENAL FUNCTION SCREENING TEST; the 0.25 milligram dosedissolved in sterile saline and intramuscularly injected is most often recommended for thispurpose (Olin, 1990; Gilman et al, 1990). The same doses may also be administered as infusions,added to dextrose or saline solutions and administered at a rate of 0.04 milligram/hour over 6hours (Olin, 1990).
2. The usual dose of the long-acting cosyntropin depot preparation (NOT available in the USA)for all other indications (mainly ULCERATIVE COLITIS and CROHN'S DISEASE) is an initialadult dose of 1 milligram intramuscularly daily (Reynolds, 1990). This dosage is reduced afteracute effects are controlled to 0.5 milligram every 2 to 3 days, or 1 milligram weekly; all dosesof this preparation are injected deep intramuscularly only.
3. A solution of 0.25 milligram of cosyntropin is equivalent to corticotropin (ACTH) 25 USPunits.
4. A low-dose ACTH test (1 mcg) has been recommended in hypothalamic-pituitary-adrenal axisassessment because results of it closely correlate with those of the insulin tolerance test whileavoiding potential problems of the latter test (Rasmuson et al, 1996).
1.4 PEDIATRIC DOSAGE
1.4.1 NORMAL DOSE
A. PARENTERAL
1. The dose for children 2 years of age or less is generally 0.125 milligram intramuscularly orinjected intravenously over 2 minutes as a DIAGNOSTIC TEST FOR CORTICOTROPININSUFFICIENCY (Olin, 1990).
2. A pediatric dose of 0.25 milligram/1.73 square meters of body surface area has also beenrecommended for the CORTICOTROPIN INSUFFICIENCY TEST (Reynolds, 1990).
3. The recommended dose of the long-acting cosyntropin depot preparation (NOT available inthe USA) for all other indications (usually ULCERATIVE COLITIS and CROHN'S DISEASE) are initial daily pediatric intramuscular doses of 0.25 milligram for children aged 1 month to 2years; 0.25 to 0.5 milligram for children aged 2 to 5 years; and 0.25 to 1 milligram for thoseaged 5 to 12 years. Once the acute effects are controlled, these same doses are given at 2- to8-day intervals as maintenance therapy (Reynolds, 1990).
2.0 PHARMACOKINETICS
2.1 ONSET AND DURATION
2.1.1 ONSET
A. INITIAL RESPONSE:
1. Adrenal insufficiency test, intramuscular: 1 hour (Reynolds, 1990)
a. When cosyntropin is administered, there is a prompt rise in the plasma hydrocortisonelevel because of stimulated release from the adrenal glands. Following intramuscular injection (with normally functioning adrenals), these elevated hydrocortisone levels peakat 1 hour and decline back to baseline levels at 4 hours (Reynolds, 1990).
b. Following intramuscular injection of the long-acting zinc phosphate or hydroxide
preparations (NOT available in the USA), peak adrenally-released hydrocortisone levelsoccur at 8 hours (Reynolds, 1990).
2.1.2 DURATION
A. SINGLE DOSE:
1. Adrenal insufficiency test, intramuscular: Less than 4 hours (Reynolds, 1990)
a. Following intramuscular injection of the long-acting zinc phosphate or hydroxide
preparations (NOT available in the USA), peak adrenally-released hydrocortisone levelsremain elevated for greater than 24 hours (Reynolds, 1990).
2.3 ADME
2.3.1 ABSORPTION
A. BIOAVAILABILITY (F):
1. Parenteral, good (Reynolds, 1990)
a. Cosyntropin is absorbed following parenteral administration only; it is inactivated whengiven by mouth (Reynolds, 1990).
2.3.4 EXCRETION
2.3.4.1 BREAST MILK
A. BREASTFEEDING: Unknown
3.0 CAUTIONS
3.1 CONTRAINDICATIONS
A. Contraindicated in patients having had any type of allergic reaction to either natural adrenocorticotropinhormone or cosyntropin; serious or potentially FATAL allergic reactions have occurred, and 2 deaths havebeen reported in patients who had previous mild allergic reactions to cosyntropin upon later administration oftherapeutic doses (Reynolds, 1990).
3.2 PRECAUTIONS
A. The most worrisome possible side effects are serious or potentially fatal allergic reactions; therefore,patients receiving cosyntropin should be monitored for at least one hour after administration in a controlledsetting (Reynolds, 1990) where medications and resuscitation equipment sufficient to treat such reactions areavailable.
B. Painful local reactions will occur with the long-acting depot cosyntropin preparation (NOT available in theUSA) unless it is administered as a deep intramuscular injection (Burke, 1985).
C. Adverse effects seen during corticotropin therapy for infantile spasms include excessive weight gain,diarrhea, increased susceptibility to infections due to immune suppression, worsening of mental state witheither dejection or excessive nervousness, acne, menstrual discharges, electrolyte and calcium abnormalities,hypertension with potential intracranial hemorrhage, transient brain shrinkage noted on computer-tomographyscans, and rarely hematuria, melena, or hematemesis (Hrachovy & Frost, 1989; Fois et al, 1987; Dreifuss et al,1986; Sorel, 1985).
3.3 ADVERSE REACTIONS
3.3.1 BLOOD
A. HEMATOLOGIC EFFECTS
1. SUBDURAL HEMATOMA and BRAIN ATROPHY occurred in an infant treated with corticotropin for infantile spasms (Watanabe et al, 1981).
3.3.2 CARDIOVASCULAR
A. CARDIOVASCULAR EFFECTS
1. NECROTIZING ANGIITIS, CONGESTIVE HEART FAILURE, and CARDIAC
HYPERTROPHY have been associated with corticotropin administration (Prod Info Acthar(R),1990; Lang et al, 1984; Young et al, 1987).
B. EDEMA
1. FLUID RETENTION is possible with corticotropin (Prod Info Acthar(R), 1990).
C. HYPERTENSION
1. Hypertension was reported in 7% (11/162) of children treated with corticotropin to controlinfantile spasms. The intramuscular dose of corticotropin ranged up to 160 Units/day for 3
weeks, followed by 80 Units/day for 2 weeks, and a gradual withdrawal over the subsequentweek (Riikonen & Donner, 1980).
3.3.3 CENTRAL NERVOUS SYSTEM
A. Uncomfortable DIZZINESS has been reported with administration of the long-acting depotcosyntropin preparation (Clemmensen & Andersen, 1984).
B. BEHAVIORAL DETERIORATION has been reported in infants treated with adrenocorticotropinhormone or cosyntropin for myoclonic encephalopathy and infantile spasms (Rutgers et al, 1988; Sorel,1985).
3.3.4 ENDOCRINE/METABOLIC
A. HYPERNATREMIA
1. Hypernatremia severe enough to warrant discontinuation of cosyntropin therapy was reportedin one child treated for infantile spasms (Dreifuss et al, 1986).
B. ADRENAL HEMORRHAGE
1. Isolated cases of bilateral adrenal hemorrhage have been reported with intravenouscorticotropin infusions in patients with inflammatory bowel disease (Dunlap et al, 1989).
3.3.5 GASTROINTESTINAL
A. ULCER
1. PEPTIC ULCER, PANCREATITIS, ABDOMINAL DISTENSION, and ulcerativeESOPHAGITIS have been associated with corticotropin injection (Prod Info Acthar(R), 1990;
Nakashima & Howard, 1977).
3.3.6 KIDNEY/GENITOURINARY
A. NEPHROTOXICITY
1. Four of 162 children with infantile spasms developed OLIGURIA and HYPERKALEMIAassociated with corticotropin administration (Riikonon & Donner, 1980).
3.3.8 OCULAR
A. OCULAR EFFECTS
1. Corticotropin may cause an increase in intraocular pressure, EXOPHTHALMOS, andGLAUCOMA (Prod Info Acthar(R), 1990).
2. PERIORBITAL EDEMA has been reported with administration of the long-acting depotcosyntropin preparation (Clemmensen & Andersen, 1984).
B. CATARACTS
1. Posterior subcapsular cataracts developed in a 50-year-old female treated with intramuscularinjections of corticotropin 20 Units daily for 2.5 years (Williamson & Dalakos, 1967).
3.3.9 RESPIRATORY
A. PNEUMONIA
1. In a 16-year study of 162 children with infantile spasms treated with corticotropin, infections,including pneumonias, were some of the most common adverse effects noted. Infections weremost frequently observed if the daily dose of corticotropin exceeded 120 Units (Riikonon &
Donner, 1980).
3.3.10 SKIN
A. DERMATOLOGIC EFFECTS
1. PETECHIAE, ECCHYMOSES, FRAGILE SKIN, ACNE, facial ERYTHEMA, increased
PERSPIRATION, and transient pain on injection and INDURATION with intramuscular orsubcutaneous injection of corticotropin have been reported (Prod Info Acthar(R), 1990).
2. A cutaneous RASH was noted in one patient treated with the long-acting depot cosyntropinpreparation when used in combination with chlorpromazine for prophylaxis against cisplatinchemotherapy-induced nausea and vomiting (Colbert et al, 1983).
B. ERYTHEMA MULTIFORME
1. Exudative erythema multiforme developed following a single dose of corticotropin
(Soloshenko & Brailovskii, 1975).
C. SKIN DISCOLORATION
1. Pigmentation of the skin has occasionally been associated with corticotropin administration(Levantine & Almeyda, 1973).
3.3.11 MUSCULOSKELETAL
A. MUSCULOSKELETAL EFFECTS
1. Prolonged administration of corticotropin can cause MUSCLE WEAKNESS, MUSCLEWASTING, VERTEBRAL COMPRESSION FRACTURES, or FRACTURES of the long bones.
These are due to PROTEIN CATABOLISM (Prod Info Acthar(R), 1990; Gilman et al, 1990).
2. Painful local reactions will occur with the long-acting depot cosyntropin preparation (NOTavailable in the USA) unless it is administered as a deep intramuscular injection (Burke, 1985).
B. OSTEONECROSIS
1. ASEPTIC NECROSIS of the femur developed 9 months after a 23-year-old multiple sclerosispatient had been treated with a total of 1070 Units of corticotropin over a 16-day period (Good,1974).
C. OSTEOPOROSIS
1. In a 16-year study of 162 children with infantile spasms treated with corticotropin, 2 childrendeveloped osteoporosis (Riikonon & Donner, 1980).
3.3.12 OTHER
A. HYPERSENSITIVITY
1. ANAPHYLAXIS and hypersensitivity reactions can develop with corticotropin. The risk isincreased with prolonged administration (Prod Info Acthar(R), 1990; Shapiro, 1972).Cosyntropin was successfully administered to a patient with an immediate cutaneous reaction to
porcine corticotropin (Lee et al, 1987).
2. The most worrisome possible side effects of cosyntropin are serious or potentially fatalALLERGIC REACTIONS; therefore, patients receiving cosyntropin should be monitored for at
least one hour after administration in a controlled setting where medications and resuscitation
equipment sufficient to treat such reactions are available (Reynolds, 1990).
B. OVERDOSE See POISINDEX(R) Management "CORTICOSTEROIDS"
C. SUPERINFECTIONS - GASTROINTESTINAL
1. In a 16-year study of 162 children with infantile spasms treated with corticotropin,
INFECTIONS, including those of the gastrointestinal tract, were some of the most commonadverse effects noted. Infections were most frequently observed if the daily dose of corticotropinexceeded 120 Units (Riikonon & Donner, 1980).
3.4 TERATOGENICITY/EFFECTS IN PREGNANCY
A. TERATOGENICITY
1. Natural corticotropin is classified as U.S. Food and Drug Administration's Pregnancy Category C(Prod Info Acthar(R), 1990). Cosyntropin would most likely be similarly classified. See Drug Consult reference: "PREGNANCY RISK CATEGORIES"
3.5 DRUG INTERACTIONS
3.5.1 DRUG-DRUG COMBINATIONS
A. TUBERCULIN
1. Summary: Reactivity to a tuberculin skin test may be depressed or suppressed for as long asfive to six weeks in patients receiving systemic corticosteroids (Prod Info Tubersol(R), 1995).
2. Adverse Effect: decreased reactivity to tuberculin
3. Clinical Management: Clinicians should be alerted to corticosteroid use in patients receivingtuberculin skin tests. Further evaluation of the patient may be warranted if theimmunosuppression caused by corticosteroid use is thought to result in a false-negative test.
4. Severity: minor
5. Onset: delayed
6. Documentation: poor
7. Probable Mechanism: immunosuppression
B. VACCINES
1. Summary: As a general rule, live-attenuated viral or bacterial vaccines should not beadministered to patients who are immunosuppressed as a result of large amounts of corticosteroids (more than 10 mg of prednisone or equivalent for more than two weeks).However, an inadequate response to inactivated vaccines may also occur with immunsuppressiondue to large doses of steroids. Low- to moderate-dose short-term systemic corticosteroid therapy(less than 14 days), topical steroid therapy, long-term alternative-day treatment with low tomoderate doses of short-acting systemic steroids, and intra-articular, bursal, or tendon injectionsof corticosteroids should not be considered contraindications to vaccine administration (CDC,1989). Likewise, doses of steroids given as replacement therapy, such as in Addison's disease, arenot considered immunosuppressive (Grabenstein, 1990). The exact interval between discontinuingimmunosuppressives and regaining the ability to respond to individual vaccines is not known.Estimates vary from three months to one year (Anon, 1991).
2. Adverse Effect: an inadequate immunological response to the vaccine
3. Clinical Management: If possible, delay the administration of vaccines, especially live viral orbacterial types, in persons immunosuppressed with large doses of corticosteroids. However, the
clinical judgment of the responsible physician should prevail.
4. Severity: moderate
5. Onset: delayed
6. Documentation: fair
7. Probable Mechanism: suppression of the immune system
3.5.4 INTRAVENOUS ADMIXTURES
3.5.4.1 COMPATIBILITIES - SOLUTIONS
A. DEXTROSE SOLUTIONS
1. Dextrose solutions (recommended for the dilution of cosyntropin; conditions not
specified) (Trissel, 1990)
B. SODIUM CHLORIDE
1. Sodium chloride 0.9% (may be used for the reconstitution of cosyntropin to a
concentration of 25 IU/mL; reconstituted solution is stable for 24 hours at roomtemperature or 3 weeks under refrigeration; may be used to further dilute cosyntropin,final concentration not stated, and solution is stable for 12 hours at room temperatureprovided that pH of the solution is between 5.5 and 7.5) (Kirschenbaum & Latiolais,1976)
3.5.4.3 INCOMPATIBILITIES - SOLUTIONS
A. BLOOD
1. Blood (may inactivate cosyntropin) (Trissel, 1990)
2. For More Information:
See Drug Consult reference: "BLOOD IV COMPATIBILITIES"
B. PLASMA
1. Plasma (may inactivate cosyntropin) (Trissel, 1990)
4.0 CLINICAL APPLICATIONS
4.1 MONITORING PARAMETERS
4.1.1 THERAPEUTIC
A. PHYSICAL EXAMINATION
1. The most worrisome possible side effects are serious or potentially fatal allergic reactions;therefore, patients receiving cosyntropin should be monitored for at least one hour after
administration in a controlled setting where medications and resuscitation equipment sufficient to
treat such reactions are available (Reynolds, 1990).
2. The clinical disappearance of spasms and normalization (flattening) of the
electroencephalogram should be monitored; a temporary worsening of the behavioral state (either
dejected or hyperirritable) does NOT indicate the need to discontinue therapy (Sorel, 1985).
4.1.2 TOXIC
A. PHYSICAL EXAMINATION
1. The most worrisome possible side effects are serious or potentially fatal allergic reactions;therefore, patients receiving cosyntropin should be monitored for at least one hour after
administration in a controlled setting where medications and resuscitation equipment sufficient to
treat such reactions are available (Reynolds, 1990).
4.2 PATIENT INSTRUCTIONS
A. HOW TO TAKE THIS MEDICATION
1. Cosyntropin is administered only by injection in a health care facility setting; it is generally NOTrecommended for self-injection because of the danger of serious or fatal allergic reactions (Reynolds,1990).
B. POSSIBLE SIDE EFFECTS FROM THIS MEDICATION
1. The most worrisome possible side effects are serious or potentially fatal allergic reactions; therefore,patients receiving cosyntropin should be monitored for at least one hour after administration in acontrolled setting (Reynolds, 1990) where medications and resuscitation equipment sufficient to treat
such reactions are available.
2. Periorbital edema, cutaneous rash, and uncomfortable dizziness have been reported with
administration of the long-acting depot cosyntropin preparation (Clemmensen & Andersen, 1984;Colbert et al, 1983).
C. STORAGE INSTRUCTIONS FOR THIS MEDICATION
1. When constituted with 0.9 percent sodium chloride for injection, cosyntropin is stable for 24 hours atroom temperature; it is stable for up to 21 days when refrigerated at between 2 and 8 degreescentigrade under a nitrogen atmosphere (Reynolds, 1990). Constituted solutions of pH 5.5 to 7.5 arestable for 12 hours at room temperature.
2. However, the manufacturer recommends that constituted solutions not be retained (Prod InfoCortrosyn(R), 1991).
4.3 PLACE IN THERAPY
A. While cosyntropin may be used for any indication for which natural adrenocorticotropin hormone (ACTH)is utilized (refer to corticotropin drug evaluation for more information), it is usually restricted to use as adiagnostic testing agent for the investigation of corticotropin insufficiency, and sometimes for the treatment ofulcerative colitis or Crohn's disease (Reynolds, 1990).
B. In much of the literature, it is unclear whether natural ACTH or cosyntropin was administered for a largevariety of indications including diagnosis of corticotropin insufficiency, acute gout, Guillain-Barre' syndrome,control of infantile spasms (West's syndrome) and childhood seizures, Bell's palsy, multiple sclerosis, rheumaticdiseases, vitiligo, myasthenia gravis, herpes zoster, asthma and status asthmaticus, ulcerative colitis, diagnosis ofSheehan's syndrome, adjunct to smoking cessation, schizophrenia, hay fever, myoclonic encephalopathy, acuteinflammatory polyneuropathy, and prevention of peripheral neuropathy, nausea, and vomiting during cisplatinchemotherapy.
4.4 MECHANISM OF ACTION/PHARMACOLOGY
A. MECHANISM OF ACTION
1. Cosyntropin is a synthetic tetracosapeptide corresponding to the 1st through 24th amino acid residuesof natural adrenocorticotropin hormone and which has all the activity of the natural hormone tostimulate release of corticoid hormones by the adrenal gland (Reynolds, 1990; Gilman et al, 1990; ProdInfo Cortrosyn(R), 1991).