Vasopressin

Class: Pituitary
VA Class: HS702
CAS Number: 11000-17-2
Brands: Pitressin

Introduction

Exogenous antidiuretic hormone (ADH); maintains serum osmolality in normal range and acts as a vasopressor.^{b 150 152 157}

Uses for Vasopressin

Diabetes Insipidus

Prevention or control of polydypsia, polyuria, and dehydration in diabetes insipidus caused by a deficiency of endogenous posterior pituitary ADH (neurohypophyseal diabetes insipidus), but desmopressin usually considered drug of choice.^b

May be used in the initial or emergency treatment of the disease, but, because of its short duration of action, its use is impractical for chronic therapy.¹⁵⁴

Intranasal aqueous vasopressin may be effective for daily maintenance therapy and the degree of absorption is usually adequate to control mild diabetes insipidus; other drugs are preferred (e.g., chlorpropamide).¹⁵⁴

Polyuria

May correct fluid imbalance associated with transient polyuria due to ADH deficiency accompanying neurosurgery or head injury.¹⁵⁴

Not effective in controlling polyuria caused by renal disease, nephrogenic diabetes insipidus, hypokalemia or hypercalcemia, or polyuria secondary to the administration of demeclocycline or lithium carbonate.^b

CPR

Used for its vasopressor effects; may give 1 dose to replace first or second dose of epinephrine in ACLS during CPR.^{150 152 153 157}

Comparably effective to epinephrine in patients with cardiac arrest^{150 152 153 157 160 161 163 166} (presented with VF or pulseless electrical activity); however, conflicting evidence exists whether vasopressin is more effective than epinephrine in patients with asystolic cardiac arrest.^{150 152 153 157 164 165}

May enhance the probability of return of spontaneous circulation (ROSC), survival to hospital admission, as well as hospital discharge.^{150 152 153 157 160 161 162 164 165}

Combination of vasopressin and epinephrine (if refractory) has been reported to be more effective than repeated epinephrine alone for refractory cardiac arrest;^{152 153 157 159 166} however, optimal timing of vasopressin administration in relation to epinephrine use during cardiac arrest not fully established (i.e., replacement of first versus second epinephrine dose).¹⁵⁸

Abdominal Distention

To stimulate peristalsis in the prevention or relief of intestinal paresis, postoperative abdominal distention, and distention complicating pneumonias or toxemias.^b

Abdominal Radiographic Procedures

To dispel interfering gas shadows and/or to concentrate the contrast media prior to abdominal radiographic procedures including IV urography, cholecystography, and kidney biopsy.¹⁵⁴

Diagnostic Uses

Although vasopressin injection has been used as a provocative test for pituitary release of growth hormone and corticotropin†, arginine hydrochloride and insulin generally are considered the most reliable diagnostic indicators of growth hormone reserve.^b

GI Hemorrhage

Administered IV† or intra-arterially† into the superior mesenteric artery as an adjunct in the treatment of acute and life-threatening, massive GI hemorrhage† caused by ruptured esophageal varices (e.g., in alcoholic cirrhotics), peptic ulcer disease, esophagogastritis, esophageal laceration, acute gastritis, colitis associated with Behcet’s disease, colonic diverticulosis, small intestinal typhoid infection, Mallory-Weiss syndrome, or intestinal perforation.^b

Infused into the mesenteric artery† prior to and during portosystemic shunt surgery for esophageal varices†.¹⁵⁴

May provide effective control of bleeding, but there is no evidence that the drug substantially improves overall survival.^b

Should not preclude use of other measures (e.g., blood transfusions, esophageal tamponade, paracentesis, ice water gavage, sclerotherapy, emergency surgery) when indicated.¹⁵⁴

Vasodilatory Shock

May consider for hemodynamic support as a continuous infusion† in vasodilatory shock† such as septic shock and sepsis syndrome, if conventional adrenergic vasopressor drugs are ineffective.^{150 151 157}

Vasopressin Dosage and Administration

General

• 
  

  May administer 1–2 glasses of water with vasopressin to reduce occurrence of adverse effects (e.g., skin blanching, abdominal cramps, nausea) and improve therapeutic response.^{154 155}

  
  

Administration

Administer IM or sub-Q.^b

May administer topically to nasal mucosa for antidiuresis; do not inhale.^b

May administer IV† (e.g., for ACLS during CPR, GI hemorrhage), by intraosseous injection† (e.g., for ACLS during CPR) or intra-arterially (e.g., for GI hemorrhage).^{b 157} Although vasopressin may be administered via an endotracheal tube† for ACLS during CPR, a specific dose is not established and IV† or intraosseous† administration is preferred because of more predictable drug delivery and pharmacologic effect.¹⁵⁷

IM or Sub-Q Administration

Usually, administer IM or sub-Q at 3- to 4-hour intervals as needed.¹⁵⁴

Intranasally

May be applied topically to the nasal mucosa as a spray, drops, or via a saturated pledget; the drug should not be inhaled.¹⁵⁴

IV or Intra-arterial Administration

May administer by IV injection† for ACLS during CPR.^{b 157}

May administer by continuous IV† or intra-arterial† infusion (e.g., for GI hemorrhage†).¹⁵⁴

GI hemorrhage, particularly alcoholic cirrhotics: Preferably, administer initially by continuous IV infusion, since intra-arterial infusion is not more effective but is technically more difficult; patients who fail to respond adequately to initial IV infusion therapy may respond to intra-arterial infusion therapy.^b

GI hemorrhage: Perform intra-arterial† or IV† administration only under the supervision of a clinician familiar with the pharmacologic effects of vasopressin and with all acceptable treatment modalities for GI bleeding.¹⁵⁴

GI hemorrhage: Intra-arterial† infusion requires specialized techniques, including angiographic placement of the catheter; limit to clinicians familiar with this method of administration and the management of potential complications.^b

Dilution

GI hemorrhage, intra-arterial or continuous IV infusion: Generally dilute with 0.9% sodium chloride or 5% dextrose injection to a concentration of 0.1–1 unit/mL.^b

Rate of Administration

GI hemorrhage: Adjust rate to response and tolerance.^b

GI hemorrhage, IV infusion: Into a peripheral vein via controlled-infusion device; usually, 0.2–0.9 units/minute.^b

GI hemorrhage, intra-arterial infusion: Usually, into the superior mesenteric artery via controlled-infusion device; usually, 0.1–0.5 units/minute.^b

GI hemorrhage, intra-arterial infusion: Also into the splenic or celiac axis usually, 0.1–0.5 units/minute.^b

Diverticular hemorrhage, intra-arterial infusion: Into the inferior mesenteric artery.^b

Intraosseous Administration

For ACLS during CPR in adults, may administer by intraosseous injection†; onset of action and systemic concentrations are comparable to those achieved with central venous administration.¹⁵⁷

Dosage

Potency of vasopressin (arginine and lysine) is standardized according to pressor activity in rats and is expressed in USP posterior pituitary (pressor) units.^b

Antidiuretic activity of commercially available preparations may be variable.¹⁵⁴

Antidiuretic dosages are variable and must be adjusted according to response; to avoid adverse effects, it is desirable to give doses that are just sufficient to elicit the desired response.^{154 155}

Adults: 10 units elicit full physiologic response; 5 units adequate in many cases.¹⁵⁴

Pediatric Patients

Diabetes Insipidus

Neurohypophyseal

IM or Sub-Q

2.5–10 units 2–4 times daily.^b

Intranasal

Individualize dosage and dosing interval according to response.^b

Abdominal Distention and Abdominal Radiographic Procedures

IM

Give doses proportionately reduced from adult dose.¹⁵⁵

Diagnostic Uses

Provocative Testing for Growth Hormone and Corticotropin Release

IM

0.3 units/kg; then obtain blood specimens and assay for hormones.^b

Adults

Diabetes Insipidus

Neurohypophyseal

IM or Subcutaneous

5–10 units 2–4 times daily as needed;¹⁵⁵ range 5–60 units daily.¹⁵⁴

Intranasal

Individualize dosage and dosing interval according to response.^b

CPR (Cardiac Arrest)

VF, Pulseless VT, Pulseless Electrical Activity, and Asystole in ACLS

IV

40 units, given as a single dose, may replace first or second dose of epinephrine.^{152 157}

Intraosseous†

40 units, given as a single dose, may replace first or second dose of epinephrine.¹⁵⁷

Abdominal Distention and Abdominal Radiographic Procedures

Abdominal Distention

IM

Usually, 5 units; may give subsequent doses every 3–4 hours, increasing to 10 units if necessary.^{154 155}

Dosage applies to prevention and relief of postoperative distention and other causes.¹⁵⁵

Abdominal Radiographic Procedures

Sub-Q

5–15 units given 2 hours and repeated 30 minutes prior to abdominal radiographs and kidney biopsy (before films are exposed)¹⁵⁵ ; usually give an enema prior to the first dose.¹⁵⁵

Diagnostic Uses

Provocative Testing for Growth Hormone and Corticotropin Release

IM

10 units; then obtain blood specimens and assay for hormones.

GI Hemorrhage

Esophageal Varices and GI Bleeding

IV Infusion

Dosage is empiric and must be individualized according to response and tolerance.^b

Because many of the adverse effects are dose related, the lowest possible effective dosage should be used.^b

Usually initiate at 0.2–0.4 units/minute and progressively increase to 0.9 units/minute if necessary.^b Additional benefit at higher rates unlikely.^b

After 24 hours, the infusion rate should be tapered according to patient response, but administration of vasopressin has been continued for 3 days to 2 weeks.¹⁵⁴

Intra-arterial Infusion

Dosage is empiric and must be individualized according to the response and tolerance.^b

Because many of the adverse effects are dose related, the lowest possible effective dosage should be used.^b

Usually, 0.1–0.5 units/minute; after 20–30 minutes, the vasoconstrictive and clotting responses to intra-arterial vasopressin can be assessed by angiography.^b

Response also can be monitored with portal pressures or hepatic wedge pressures.^b

After 24 hours, the infusion rate should be tapered according to patient response, but administration of vasopressin has been continued for 3 days to 2 weeks.¹⁵⁴

Vasodilatory Shock

IV Infusion

Optimum dosage and duration remain to be established; usually, 0.02–0.1 units/minute.¹⁵¹

Special Populations

Hepatic Impairment

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

Renal Impairment

No specific dosage recommendations for patients with renal impairment.

Geriatric Patients

No specific dosage recommendations compared to younger adults.

Cautions for Vasopressin

Contraindications

• 
  

  Chronic nephritis accompanied by nitrogen retention, until reasonable nitrogen concentrations are attained.^b

  
  


• 
  

  History of anaphylaxis or other hypersensitivity to vasopressin of any component in the formulation.^b

  
  

Warnings/Precautions

Warnings

Diseases in Which Rapid Addition to Extracellular Fluids May Be Hazardous

Use cautiously in patients with seizure disorders, migraine, asthma, heart failure, vascular disease (especially of the coronary arteries), angina pectoris, coronary thrombosis, renal disease, goiter with cardiac complications, arteriosclerosis, or any other disease in which rapid addition to extracellular fluids may be hazardous.^b

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions characterized by urticaria, angioedema, bronchoconstriction, fever, rash, wheezing, dyspnea, circulatory collapse, cardiac arrest, and anaphylaxis.¹⁵⁴

Appropriate agents for the treatment of hypersensitivity reactions should be readily available.¹⁵⁴

Major Toxicities

Water Intoxication

May produce water intoxication.^b

Observe closely for signs of possible development (see Monitoring under Cautions) to prevent ensuing seizures, coma, and death.^b

Water intoxication may be treated with water restriction and temporary withdrawal of vasopressin until polyuria occurs.^b

Severe water intoxication may require osmotic diuresis (e.g., with mannitol, hypertonic dextrose, or urea alone or with furosemide).¹⁵⁵

Little danger with small antidiuretic doses of vasopressin to control diabetes insipidus when fluid intake is not excessive.¹⁵⁴

Hypertonic saline solutions are not indicated unless immediate correction of hyponatremia is required.¹⁵⁴

Cardiac Effects

In large doses, may produce increased blood pressure, bradycardia, minor arrhythmias, premature atrial contraction, heart block, peripheral vascular constriction or collapse, coronary insufficiency, decreased cardiac output, myocardial ischemia, and myocardial infarction.¹⁵⁴

Extreme caution, if at all, in patients with vascular disease (especially of the coronary arteries), since even small doses can precipitate angina; AMI risk with large doses.¹⁵⁴

Coronary vasodilators (e.g., amyl nitrite, nitroglycerin) may be used to treat angina if it occurs.¹⁵⁴

An ECG should be used to monitor the hormone’s cardiac effects during IV or intra-arterial therapy.^{154 155}

General Precautions

Polyuria

Caution in preoperative and postoperative polyuric patients, since vasopressin requirements may be considerably less than normal.^b

Monitoring

Monitor fluid intake and output closely, especially in comatose or semicomatose patients.^b

Monitor electrolyte balance periodically.^b

Perform ECGs periodically during therapy.¹⁵⁴

Observe for early signs of water intoxication (e.g., drowsiness, listlessness, headache, confusion, anuria, weight gain) in order to prevent ensuing seizures, coma, and death).^b

Risks of Intra-arterial Administration

Risk of coronary thrombosis, mesenteric infarction, venous thrombosis, infarction and necrosis of the small bowel, and peripheral emboli resulting from intra-arterial catheterization and infusion into the superior mesenteric artery.^b

Specific Populations

Pregnancy

Category C.^{155 a}

Although doses sufficient for an antidiuretic effect are not likely to produce tonic uterine contractions that could be deleterious to the fetus or threaten the continuation of the pregnancy, use in pregnant women only when clearly needed.^b

When administered in ACLS, may decrease blood flow to the uterus; however, the woman must be resuscitated for survival of the fetus.¹⁵⁷

Lactation

Caution if used in nursing women.¹⁵⁵

Pediatric Use

Children are particularly sensitive to vasopressin’s effects (e.g., volume/hydration disturbances); exercise caution.¹⁵⁴

Safety and efficacy as vasopressor therapy for pediatric advanced life support (PALS) not established;¹⁵⁰ insufficient evidence to make a recommendation for or against routine use during cardiac arrest in pediatric patients.¹⁵⁷

Geriatric Use

Geriatric patients are particularly sensitive to vasopressin’s effects; exercise caution.¹⁵⁴

Common Adverse Effects

Adverse effects associated with low doses are infrequent and mild, but increase in frequency and severity with high doses.¹⁵⁴

Common adverse effects include circumoral pallor, sweating, tremor, pounding in the head, abdominal cramps, passage of gas, vertigo, nausea, vomiting, and eructation.¹⁵⁴ In addition, diarrhea, intestinal hyperactivity, and uterine cramps may occur.¹⁵⁴

Patients can be advised that some of these effects (e.g., blanching of the skin, abdominal cramps, nausea) may be minimized by taking 1 or 2 glasses of water at the time of vasopressin administration.¹⁵⁴

Interactions for Vasopressin

Specific Drugs

Drug	Interaction	Comments
Alcohol	May block the antidiuretic activity of vasopressin in varying degrees155 a
Antidepressants, tricyclic	May potentiate the antidiuretic response to vasopressin155 a
Carbamazepine	May potentiate the antidiuretic response to vasopressin155 a
Chlorpropamide	May potentiate the antidiuretic response to vasopressin155 a
Clofibrate	May potentiate the antidiuretic response to vasopressin155 a
Demeclocycline	May block the antidiuretic activity of vasopressin in varying degrees155 a
Epinephrine	May block the antidiuretic activity of vasopressin in varying degrees155 a
Fludrocortisone	May potentiate the antidiuretic response to vasopressin155 a
Heparin	May block the antidiuretic activity of vasopressin in varying degrees155 a
Lithium	May block the antidiuretic activity of vasopressin in varying degrees155 a
Norepinephrine	May block the antidiuretic activity of vasopressin in varying degrees155 a
Drugs blocking antidiuretic effect	May block the antidiuretic activity of vasopressin in varying degrees155
Drugs potentiating antidiuretic effect	May potentiate the antidiuretic response to vasopressin155 a
Ganglionic blocking agents	Ganglionic blocking agents may produce a marked increase in sensitivity to the hormone’s pressor effects155
Phenformin	May potentiate the antidiuretic response to vasopressin155 a
Urea	May potentiate the antidiuretic response to vasopressin155 a

Vasopressin Pharmacokinetics

Absorption

Destroyed by trypsin which is found in the GI tract and, therefore, must be administered parenterally or intranasally.^b

Absorption of vasopressin through the nasal mucosa is relatively poor.¹⁵⁴

Duration

Sub-Q or IM, antidiuretic activity: Variable but effects are usually maintained for 2–8 hours.^b

Plasma Concentrations

Urine isotonicity is maintained when plasma concentrations of vasopressin are approximately 1 microunit/mL, while plasma concentrations of 4.5–6 microunits/mL produce maximum concentration of urine.^b

Distribution

Extent

Distributed throughout the extracellular fluid.^b

Plasma Protein Binding

No evidence of plasma protein binding.^b

Elimination

Metabolism

The majority of a dose is rapidly destroyed in the liver and kidneys.¹⁵⁴

Elimination Route

Sub-Q: Approximately 5% of a dose is excreted in urine unchanged after 4 hours.¹⁵⁴

IV: 5–15% of the total dosage appears in urine.¹⁵⁴

Half-life

About 10–20 minutes.^{154 155}

Special Populations

Oxytocinase, a circulating enzyme produced early in pregnancy, is capable of cleaving the polypeptide; otherwise, plasma inactivation of vasopressin is negligible.¹⁵⁴

Stability

Storage

Parenteral

Injection

Store between 15–25°C (59° and 77°F); do not freeze.¹⁵⁵

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

Admixture CompatibilityHID

Compatible
Verapamil HCl156

Evaluated by pushing vasopressin through a Y-site over 5 seconds

Y-Site Compatibility HID

Compatible
Amiodarone HCl
Argatroban
Diltiazem HCl
Dobutamine HCl
Dopamine HCl
Drotrecogin alfa (activated)
Epinephrine HCl
Heparin sodium
Lidocaine HCl
Milrinone lactate
Nitroglycerin
Norepinephrine bitartrate
Pantoprazole sodium
Phenylephrine HCl
Procainamide HCl

ActionsActions

• 
  

  Exogenous vasopressin elicits all the pharmacologic responses usually produced by endogenous vasopressin (antidiuretic hormone);^b primary physiologic role of vasopressin is to maintain serum osmolality within a normal range.¹⁵⁴

  
  


• 
  

  Produces relatively concentrated urine by increasing reabsorption of water by the renal tubules. Its action in regulating body fluid balance is mediated by renal vasopressin V₂ receptors, which are coupled to adenyl cyclase and the generation of cyclic AMP.¹⁵¹ At the tubular level, vasopressin stimulates adenyl cyclase activity, leading to increases in cyclic adenosine monophosphate (AMP).^b Cyclic AMP increases water permeability at the luminal surface of the distal convoluted tubule and collecting duct, resulting in increased urine osmolality and decreased urinary flow rate.¹⁵⁴

  
  


• 
  

  Conserves up to 90% of the water that might otherwise be excreted in the urine. Vasopressin also increases reabsorption of urea by the collecting ducts.^b

  
  


• 
  

  Increases coronary blood flow and the availability of oxygen to the myocardium.^{152 153} A preferred approach in patients with asystolic cardiac arrest would be to administer vasopressin rather than epinephrine initially, reserving epinephrine for patients who do not experience ROSC with the initial vasopressin doses.^{152 153}

  
  


• 
  

  In doses greater than those required for antidiuretic effects, vasopressin directly stimulates contraction of smooth muscle V₁ receptors.^b

  
  


• 
  

  The vasoconstrictive action of vasopressin is mediated by vascular V₁ receptors;^{150 151} the vascular receptors are coupled to phospholipase C, resulting in release of calcium from sarcoplasmic reticulum in smooth muscle cells, leading to vasoconstriction.¹⁵¹

  
  


• 
  

  Causes vasoconstriction, particularly of capillaries and of small arterioles, resulting in decreased blood flow to the splanchnic, coronary, GI, pancreatic, skin, and muscular systems.¹⁵⁴

  
  


• 
  

  When administered into the celiac or superior mesenteric arteries, vasopressin constricts gastroduodenal, left gastric, superior mesenteric, and splenic arteries; however, hepatic arteries are not constricted and, instead, hepatic blood flow often increases.^b

  
  


• 
  

  In the intestinal tract, increases peristaltic activity, particularly of the large bowel; also causes an increase in GI sphincter pressure and a decrease in gastric secretion but has no effect on gastric acid concentration. Contraction of smooth muscle of the gallbladder and of the urinary bladder also occurs.^{154 a}

  
  


• 
  

  Oxytocic properties of vasopressin are minimal, but in large doses the drug may stimulate uterine contraction.^b The hormone also possesses slight milk ejecting properties but its role during lactation is negligible.¹⁵⁴

  
  


• 
  

  In addition to its peripheral effects, vasopressin causes release of corticotropin, growth hormone, and follicle-stimulating hormone.¹⁵⁴

  
  

Advice to Patients

• 
  

  Importance of alerting patients that ceratin adverse effects (e.g., blanching of skin, abdominal cramps, nausea) may be reduced by taking 1 or 2 glasses of water at the time of administration. These side effects are usually not serious and probably will disappear within a few minutes.¹⁵⁵

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹⁵⁴

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁵⁴

  
  


• 
  

  Importance of informing patients of other important precautionary information.^a (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Vasopressin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	20 units/mL*	Pitressin	Monarch
			Vasopressin Injection

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

150. The American Heart Association in Collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2000; 102(Suppl I) I-87,I-130-1, I-143, I-145-8, I-150, I-307, I-309, I-319.

151. Rozenfeld V, Cheng WM. The role of vasopressin in the treatment of vasodilation in shock states. Ann Pharmacother. 2000; 34:250-3. [IDIS 439877] [PubMed 10676834]

152. Wenzel V, Krismer AC, Arntz H et al for the European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004; 350:105-13. [IDIS 509448] [PubMed 14711909]

153. Mcintyre KM. Vasopressin in asystolic cardiac arrest. N Engl J Med. 2004; 350:179-81. [PubMed 14711918]

154. AHFS Drug Information 2003. McEvoy, GK, ed. Vasopressin. Bethesda, MD: American Society of Health-System Pharmacists; 2003: 3050-2.

155. Monarch. Pitressin (vasopressin injection, USP) prescribing information. Bristol, TN: 1998 Jul.

156. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:1358.

157. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

158. Miano TA, Crouch MA. Evolving role of vasopressin in the treatment of cardiac arrest. Pharmacotherapy. 2006; 26:828-39. [PubMed 16716136]

159. Guyette FX, Guimond GE, Hostler D et al. Vasopressin administered with epinephrine is associated with a return of a pulse in out-of-hospital cardiac arrest. Resuscitation. 2004; 63:277-82. [PubMed 15582762]

160. Lindner KH, Dirks B, Strohmenger HU et al. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet. 1997; 349:535-7. [PubMed 9048792]

161. Lindner KH, Prengel AW, Brinkmann A et al. Vasopressin administration in refractory cardiac arrest. Ann Intern Med. 1996; 124:1061-4. [PubMed 8633820]

162. Mann K, Berg RA, Nadkarni V. Beneficial effects of vasopressin in prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002; 52:149-56. [PubMed 11841882]

163. Morris DC, Dereczyk BE, Grzybowski M et al. Vasopressin can increase coronary perfusion pressure during human cardiopulmonary resuscitation. Acad Emerg Med. 1997; 4:878-83. [PubMed 9305429]

164. Stiell IG, Hebert PC, Wells GA et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001; 358:105-9. [PubMed 11463411]

165. Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis. Arch Intern Med. 2005; 165:17-24. [PubMed 15642869]

166. Wenzel V, Lindner KH. Vasopressin combined with epinephrine during cardiac resuscitation: a solution for the future? Crit Care. 2006; 10:125.

a. Monarch Pharmaceuticals. Pitressin (vasopressin injection, USP) prescribing information. Bristol, TN: 1998 Jul.

b. AHFS drug information 2004. McEvoy GK, ed. Vasopressin. Bethesda, MD: American Society of Health-System Pharmacists; 2004:3070-3.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1610-1.

More Vasopressin resources

• Vasopressin Side Effects (in more detail)
• Vasopressin Use in Pregnancy & Breastfeeding
• Vasopressin Drug Interactions
• Vasopressin Support Group
• 0 Reviews for Vasopressin - Add your own review/rating

• Vasopressin Prescribing Information (FDA)


• vasopressin Concise Consumer Information (Cerner Multum)


• vasopressin Injection Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Vasopressin with other medications

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• Diabetes Insipidus
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• Gastrointestinal Hemorrhage
• Postoperative Gas Pains
• Ventricular Fibrillation
• Ventricular Tachycardia

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Ingredient matches for Isolong

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International Drug Name Search

Numorphan

oxymorphone hydrochloride

Dosage Form: Suppositories and Injection, USP CII

Numorphan Description

Numorphan (oxymorphone hydrochloride, USP), a semi-synthetic opioid substitute for morphine, is a potent analgesic.

Oxymorphone hydrochloride is a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pKa1 and pKa2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98.

Numorphan Injection is available in two concentrations, 1 mg/mL, 1 mL ampul and 1.5 mg/mL, 10 mL vial of oxymorphone hydrochloride. In addition, each 1 mg/mL ampul contains 8.0 mg/mL sodium chloride. Each 1.5 mg/mL vial contains 8.0 mg/mL sodium chloride, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben. pH for both the ampul and vial is adjusted with hydrochloric acid.

The Numorphan Rectal Suppository is available in a concentration of 5 mg of oxymorphone hydrochloride in a base consisting of polyethylene glycol 1000 and polyethylene glycol 3350.

Numorphan - Clinical Pharmacology

Numorphan is a potent opioid analgesic. Administered parenterally, 1 mg of Numorphan is approximately equivalent in analgesic activity to 10 mg of morphine sulfate.

Many of the effects described below are common to the class of opioid analgesics, including Numorphan.

Central Nervous System (CNS)

Opioid analgesics exert their principal pharmacologic effects on the CNS and the gastrointestinal tract. The principal actions of therapeutic value are analgesia and sedation. The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects.

Opioids produce respiratory depression by direct action on brain stem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Opioids depress the cough reflex by direct action on the cough center in the medulla. Opioids cause miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic. Marked mydriasis may be seen with worsening hypoxia.

Gastrointestinal Tract and Other Smooth Muscle

Opioids decrease gastric, biliary, and pancreatic secretions. These drugs cause a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased while tone is increased to the point of spasm. The end result is constipation. Opioids can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Opioids increase smooth muscle tone in the urinary tract and can induce spasms. Urinary urgency and difficulty with urination may result. These effects, in conjunction with the central effect of these drugs on release of vasopressin, may produce oliguria.

Pharmacokinetics

The onset of action of parenterally administered Numorphan is rapid; initial effects are usually perceived within 5 to 10 minutes. Its duration of action is approximately 3 to 6 hours.

Distribution

After an IV dose, the steady state volume of distribution was 3.08 ± 1.14 L/kg in healthy male and female subjects.

Metabolism

Oxymorphone undergoes extensive hepatic metabolism in humans. After a 10 mg oral dose, 49% was excreted over a five-day period in the urine. Of this, 82% was excreted in the first 24 hours after administration. The recovered drug-related products contained the oxymorphone (1.9%), the conjugate of oxymorphone (44.1%), the 6β-carbinol produced by 6-keto reduction of oxymorphone (0.3%), and the conjugates of 6β-carbinol (2.6%) and 6α-carbinol (0.1%).

Elimination

In healthy subjects, the mean terminal half-life of oxymorphone was 1.3 ± 0.7 hours. The mean systemic clearance was 2.0 ± 0.5 L/min.

Indications and Usage for Numorphan

Numorphan Suppository is indicated for the relief of moderate to severe pain.

Numorphan Injection is indicated for the relief of moderate to severe pain. It is also indicated for preoperative medication, for support of anesthesia, for obstetrical analgesia, and for relief of anxiety in patients with dyspnea associated with pulmonary edema secondary to acute left ventricular dysfunction.

Contraindications

Numorphan should not be administered to patients who are hypersensitive to oxymorphone hydrochloride or to any of the other ingredients in Numorphan, or hypersensitive to morphine analogs.

Numorphan should not be administered to individuals during an acute asthmatic attack or to patients with severe respiratory depression, upper airway obstruction, or any patient who has or is suspected of having a paralytic ileus. Numorphan should not be used in the treatment of pulmonary edema secondary to a chemical respiratory irritant. Opioid analgesics cause pooling of blood in the extremities by decreasing peripheral vascular resistance. This effect results in decreases in venous return, cardiac work, and pulmonary venous pressure, and blood is shifted from the central to peripheral circulation which would not be beneficial in the treatment of pulmonary edema secondary to a chemical respiratory irritant.

Warnings

Interactions with Other Central Nervous System Depressants

Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics or other CNS depressants (including alcohol) concomitantly with Numorphan may exhibit an additive CNS depression (see PRECAUTIONS; Drug Interactions).

Respiratory Depression

Numorphan should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma.

Head Injury and Increased Intracranial Pressure

The possible respiratory depressant effects of potent analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated in the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, potent analgesics can produce effects which may obscure the clinical course of patients with head injuries. Therefore, Numorphan should be used in these circumstances only when essential, and then should be administered with extreme caution.

Acute Abdominal Conditions

The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Drug Dependence

Numorphan, as with other opioid drugs, can produce tolerance, psychological dependence, and physical dependence and has the potential for being abused (see DRUG ABUSE AND DEPENDENCE).

Pregnancy

Safe use in pregnancy has not been established (relative to possible adverse effects on fetal development). As with other analgesics, the use of Numorphan in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child (see PRECAUTIONS).

Precautions

General

Special Risk Patients

Numorphan should be used with caution in elderly and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal or hepatic disease. Caution should also be exercised in patients with hypothyroidism, acute alcoholism, delirium tremens, convulsive disorders, Addison’s disease, gallbladder disease or gallstones, prostatic hypertrophy or urethral stricture, recent gastrointestinal or genitourinary tract surgery, inflammatory bowel disease, diarrhea secondary to poisoning until the toxin is eliminated, diarrhea secondary to pseudomembranous colitis, cardiac arrhythmias, increased ocular pressure, and toxic psychosis. Debilitated and elderly patients and those with severe liver disease should receive smaller doses of Numorphan.

Hypotensive Effect

Opioid analgesics may cause severe hypotension in patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or coadministration of drugs such as phenothiazines or general anesthetics. Administer with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure. Orthostatic hypotension may occur in ambulatory patients.

Information for Patients

Patients should be cautioned regarding the following:

Drowsiness, dizziness, or lightheadedness related to the use of this medication may impair mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car, operating machinery, etc.

This medication, like other opioid analgesics, will add to the effect of alcohol and other CNS depressants [such as antihistamines, sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, and monoamine oxidase (MAO) inhibitors]. Alcohol should not be consumed while taking Numorphan.

Withdrawal side effects may be precipitated by suddenly stopping this drug after prolonged use (regular use for several weeks or more). The medication should be gradually reduced before completely discontinuing use.

Elderly patients are more sensitive to opioid analgesics, especially the respiratory depressant effects and opioid induced urinary retention. Lower doses or longer dosing intervals may be required.

Orthostatic hypotension may occur with the use of this medication, especially in ambulatory patients. Patients should get up slowly from a lying or sitting position.

Numorphan (oxymorphone hydrochloride, USP) may be habit forming and has the potential for being abused. Tolerance, psychological and physical dependence can occur.

Safe use in pregnancy has not been established. Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence, and neonatal withdrawal may occur.

Laboratory Tests

Opioids may increase biliary tract pressure with resultant increases in plasma amylase or lipase.

Drug Interactions

The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced (see WARNINGS).

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia.

In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have not been performed in animals to evaluate the carcinogenic potential of Numorphan. Studies to evaluate the mutagenic potential of Numorphan have not been conducted. There have been no studies to evaluate the effect of Numorphan on fertility.

Usage in Pregnancy

Teratogenic Effects: Pregnancy Category C: Numorphan was reported to produce malformations in offspring of hamsters that received 1,500 times the recommended human dose on Day 8 of gestation. There have been no adequate and well-controlled studies of reproductive toxicity in other laboratory animals or in pregnant women. It is not known whether Numorphan can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. As with other opioid analgesics, the use of Numorphan in pregnancy or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child.

Non-teratogenic Effects

Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence. Neonatal withdrawal may occur. Symptoms usually appear during the first days of life and may include convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, yawning, and increased respiratory rate.

Labor and Delivery

Numorphan should be used with caution during labor. Sinusoidal fetal heart rate patterns may occur with the use of opioid analgesics.

Opioid analgesics in therapeutic doses may prolong labor. Generally, the effect of opioids on the pregnant uterus appears to depend on the time of administration; administration of the drugs during the latent phase of the first stage of labor, or before cervical dilation of 4-5 cm has occurred, may hamper the progress of labor.

Opioid analgesics, including Numorphan, may cause respiratory depression in the newborn. The effect of Numorphan, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

It is not known whether Numorphan is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when Numorphan is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Numorphan in pediatric patients below the age of 18 years have not been established.

Adverse Reactions

As with all potent opioid analgesics, possible side effects when using Numorphan include:

Central Nervous System

Drowsiness, sedation, lightheadedness, unusual tiredness or weakness, headache, dysphoria, euphoria, miosis, diplopia, blurred vision, nervousness, restlessness, confusion, mental clouding, trouble sleeping, paradoxical CNS stimulation, hallucinations, mental depression.

Gastrointestinal System

Nausea, vomiting, dry mouth, constipation, biliary tract spasm, cramps or pain, loss of appetite, paralytic ileus or toxic megacolon in patients with inflammatory bowel disease.

Cardiovascular System

Hypotension, orthostatic hypotension particularly in ambulatory patients, tachycardia, bradycardia, palpitations, flushing.

Respiratory System

Respiratory depression, atelectasis, allergic bronchospastic reaction, allergic laryngeal edema, allergic laryngospasm.

Genitourinary System

Ureteral spasm, urinary hesitancy or retention, antidiuretic effect.

Dermatologic

Itching, sweating, injection site reaction, allergic reaction (such as skin rash, hives, and/or itching, swelling of the face).

Drug Abuse and Dependence

Numorphan is a Schedule II opioid and is subject to the Federal Controlled Substances Act.

Numorphan, as with other opioid drugs, can produce tolerance, psychological dependence, and physical dependence and has the potential for being abused. The addiction potential of the drug appears to be about the same as for morphine.

Withdrawal symptoms may occur when opioids are abruptly discontinued after prolonged use. Withdrawal symptoms may be characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep, and mydriasis during the first 24 hours. These symptoms often increase in severity and over the next 72 hours may be accompanied by increasing irritability, anxiety, weakness, twitching, and spasms of muscles; kicking movements; severe backaches; abdominal and leg pains; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, anorexia, vomiting, intestinal spasm, diarrhea, coryza, and repetitive sneezing; increase in body temperature, blood pressure, respiratory rate and heart rate. Because of excessive loss of fluids through sweating, vomiting and diarrhea, there is usually marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse can occur. Without treatment most observable symptoms disappear in 5-14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2-6 months characterized by decreasing insomnia, irritability, and muscular aches. In addition, the patient may have miosis and a slight lowering of blood pressure, pulse rate, and body temperature; respiratory centers exhibit a decreased response to the stimulatory effects of carbon dioxide.

The dose of Numorphan should be gradually reduced before discontinuation in those patients who require treatment for physical dependence.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS; Usage in Pregnancy).

Overdosage

Signs and Symptoms

Serious overdosage with Numorphan is characterized by respiratory depression, (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Treatment

Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride (NARCAN®) is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxymorphone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route and simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxymorphone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration.

Naloxone hydrochloride should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In addition, it should be considered that the use of an opioid antagonist in patients physically dependent on opioids may precipitate an acute withdrawal syndrome that cannot be readily suppressed while the action of the antagonist persists. If respiratory depression is associated with muscular rigidity, administration of a neuromuscular blocking agent may be necessary to facilitate assisted or controlled ventilation. Muscular rigidity may also respond to opioid antagonist therapy.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

Numorphan Dosage and Administration

Smaller doses of Numorphan than those recommended below should be used for debilitated and elderly patients and those with severe liver disease.

Usual Adult Dosage of Numorphan Injection

Subcutaneous or intramuscular administration: initially 1 mg to 1.5 mg, repeated every 4 to 6 hours as needed. Intravenous: 0.5 mg initially. In non debilitated patients the dose can be cautiously increased until satisfactory pain relief is obtained. For analgesia during labor 0.5 mg to 1 mg intramuscularly is recommended.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Usual Adult Dosage of Numorphan Rectal Suppositories

One suppository, 5 mg, every 4 to 6 hours. In non debilitated patients the dose can be cautiously increased until satisfactory pain relief is obtained.

How is Numorphan Supplied

For Injection

DEA Order Form Required

1 mg/mL 1 mL ampuls

(paraben/sodium dithionite-free) (box of 10)        NDC 63481-444-10

1.5 mg/mL 10 mL multiple dose vials

(sodium dithionite-free) (box of 1)        NDC 63481-445-01

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]

Protect from light.

For Rectal Suppositories

DEA Order Form Required

5 mg Wrapped in gold foil (box of 6)        NDC 63481-761-06

Store under refrigeration 2° - 8°C (36°- 46°F).

Manufactured for:

Endo Pharmaceuticals Inc.

Chadds Ford, Pennsylvania 19317

Numorphan® is a Registered Trademark of Endo Pharmaceuticals Inc.

NARCAN® is a Registered Trademark of Endo Pharmaceuticals Inc.

Copyright © Endo Pharmaceuticals Inc. 2004

Printed in U.S.A.

542789/April, 2004

Numorphan  oxymorphone hydrochloride  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63481-444 Route of Administration PARENTERAL DEA Schedule CII

INGREDIENTS Name (Active Moiety) Type Strength oxymorphone hydrochloride (oxymorphone) Active 1 MILLIGRAM  In 1 MILLILITER sodium chloride Inactive 8.0 MILLIGRAM  In 1 MILLILITER hydrochloric acid Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63481-444-10 10 AMPULE In 1 BOX contains a AMPULE 1 1 mL (MILLILITER) In 1 AMPULE This package is contained within the BOX (63481-444-10)

Numorphan  oxymorphone hydrochloride  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63481-445 Route of Administration PARENTERAL DEA Schedule CII

INGREDIENTS Name (Active Moiety) Type Strength oxymorphone hydrochloride (oxymorphone) Active 1.5 MILLIGRAM  In 1 MILLILITER sodium chloride Inactive 8 MILLIGRAM  In 1 MILLILITER methylparaben Inactive 1.8 MILLIGRAM  In 1 MILLILITER propylparaben Inactive 0.2 MILLIGRAM  In 1 MILLILITER hydrochloric acid Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63481-445-01 1 VIAL In 1 BOX contains a VIAL, MULTI-DOSE 1 10 mL (MILLILITER) In 1 VIAL, MULTI-DOSE This package is contained within the BOX (63481-445-01)

Numorphan  oxymorphone hydrochloride  suppository

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63481-761 Route of Administration RECTAL DEA Schedule CII

INGREDIENTS Name (Active Moiety) Type Strength oxymorphone hydrochloride (oxymorphone) Active 5 MILLIGRAM  In 1 SUPPOSITORY polyethylene glycol 1000 Inactive   polyethylene glycol 3350 Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63481-761-06 6 SUPPOSITORY In 1 BOX None

Revised: 05/2006Endo Pharmaceuticals Inc.

More Numorphan resources

• Numorphan Side Effects (in more detail)
• Numorphan Use in Pregnancy & Breastfeeding
• Numorphan Drug Interactions
• Numorphan Support Group
• 0 Reviews for Numorphan - Add your own review/rating

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• Labor Pain
• Pain

Schnitzler Syndrome Medications

Definition of Schnitzler Syndrome:

Schnitzler syndrome is a rare disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of a specific protein in the blood (monoclonal IgM gammopathy).

Drugs associated with Schnitzler Syndrome

The following drugs and medications are in some way related to, or used in the treatment of Schnitzler Syndrome. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Drug List:

Kineret

Nplate

Generic Name: Romiplostim
Class: Hematopoietic Agents
VA Class: BL400
CAS Number: 267639-76-9

REMS:

FDA approved a REMS for romiplostim to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of romiplostim and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biosynthetic (recombinant DNA-derived) Fc-peptide fusion protein; thrombopoietin-receptor agonist.^{1 3}

Uses for Nplate

Idiopathic Thrombocytopenic Purpura

Treatment of chronic idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) in patients who have had an inadequate response to corticosteroids, immunoglobulins, or splenectomy and in whom the degree of thrombocytopenia and clinical status increase bleeding risk.^{1 3}

Do not use to normalize platelet counts since excessive increases in platelet count may increase the risk of thromboembolic complications.¹

Not indicated for the treatment of thrombocytopenia associated with myelodysplastic syndrome or thrombocytopenia associated with any condition other than chronic ITP.¹

Nplate Dosage and Administration

General

• 
  

  Monitor CBC, including platelet count and peripheral blood smear, weekly until achieve a stable platelet count (≥50,000/mm³ for ≥4 weeks without dosage adjustment); monitor at least monthly thereafter.¹

  
  


• 
  

  After romiplostim discontinuance, monitor CBC, including platelet count, weekly for at least 2 weeks; potential for worsening thrombocytopenia following discontinuance.¹

  
  


• 
  

  May be used with other drugs to treat ITP such as corticosteroids, danazol, azathioprine, immune globulin IV (IGIV), and Rh_o(D) immune globulin.¹ If the platelet count increases to ≥50,000/mm³, medical therapies for ITP may be reduced or discontinued.¹

  
  

Restricted Distribution Program

• 
  

  FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for romiplostim.⁹ Goals are to promote informed risk-benefit decisions before initiating the drug; to ensure its appropriate use while patients are receiving therapy; and to establish the overall long-term safety and safe use of romiplostim by periodically monitoring all patients for various adverse effects.⁹ The REMS program consists of a medication guide, a communication plan, and elements to ensure safe use.⁹

  
  


• 
  

  Romiplostim is prescribed and distributed under a restricted distribution program, the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) program.^{1 4 5} Only prescribers and patients registered with the program are able to prescribe, administer, and receive romiplostim.^{1 5} Clinicians may contact 877-675-2831 (877-Nplate1) or visit for additional information and to enroll in Amgen’s Nplate NEXUS program for romiplostim.¹

  
  

Administration

Reconstitution

Romiplostim lyophilized powder is supplied in single-use vials containing 375 mcg (to deliver 250 mcg) or 625 mcg (to deliver 500 mcg) of the drug.¹ Reconstitute lyophilized romiplostim using only sterile water for injection without preservatives; do not use bacteriostatic water for injection.¹ (See Storage under Stability.) Reconstitute the powder by adding 0.72 or 1.2 mL of preservative-free sterile water for injection to a vial labeled as containing 250 or 500 mcg, respectively, of romiplostim.¹

Gently swirl and invert the vial to facilitate dissolution, which generally takes <2 minutes; do not shake or vigorously agitate the vial.¹

Reconstitution of the lyophilized drug as directed provides a clear and colorless solution containing 250 or 500 mcg per 0.5 or 1 mL, respectively, for sub-Q administration.¹

Sub-Q Administration

Administer by sub-Q injection.¹

A clinician should administer romiplostim;^{1 5} the patient should not self-administer the drug.²

Injection volumes of the drug may be very small; administer romiplostim using a syringe calibrated in increments of 0.01 mL.¹ Exercise extra care to ensure the accuracy of the administered dose because of the potential for serious adverse effects following administration of excessive doses.^{1 5}

Dosage

Adults

Idiopathic Thrombocytopenic Purpura

Sub-Q

Initially, 1 mcg/kg weekly based on actual body weight.¹

Adjust dosage at weekly intervals in increments of 1 mcg/kg (up to a maximum dosage of 10 mcg/kg weekly) until a platelet count of ≥50,000/mm³ is achieved.¹

Reduce dosage by 1 mcg/kg weekly if platelet count is >200,000/mm³ for 2 consecutive weeks.¹ Do not administer if platelet count is >400,000/mm³; assess the platelet count weekly and resume romiplostim at a dosage reduced by 1 mcg/kg weekly once the platelet count is <200,000/mm³.¹ Discontinue romiplostim if, after 4 weeks of therapy at the maximum recommended dosage of 10 mcg/kg weekly, the platelet count has not increased to a level sufficient to avoid clinically important bleeding.¹

Monitor CBC, including platelet count and peripheral blood smear, weekly until a stable platelet count (≥50,000/mm³ for ≥4 weeks without dosage adjustment) has been achieved; monitor CBC, including platelet count and peripheral blood smear, at least monthly thereafter.¹ Because of the potential for worsening thrombocytopenia following discontinuance of romiplostim, monitor CBC, including platelet count, weekly for at least 2 weeks after drug discontinuance.¹

Prescribing Limits

Adults

Idiopathic Thrombocytopenic Purpura

Sub-Q

Maximum 10 mcg/kg weekly.¹

Special Populations

No special population dosage recommendations at this time.¹

Cautions for Nplate

Contraindications

• 
  

  Manufacturer states none known.¹

  
  

Warnings/Precautions

General Precautions

Bone Marrow Reticulin Deposition and Bone Marrow Fibrosis

Thrombopoietin (TPO)-receptor agonists (e.g., romiplostim) increase the risk of development or progression of reticulin fiber deposition within the bone marrow, thereby increasing the risk for bone marrow fibrosis or myelofibrosis.¹ Risk of development of bone marrow fibrosis with cytopenias not excluded in clinical studies of romiplostim.¹

Evaluate a peripheral blood smear prior to starting romiplostim therapy and monthly thereafter once a stable dosage has been achieved.¹ Examination of the peripheral blood smear should include establishment of a baseline level of cellular morphologic abnormalities and monthly evaluations to detect new or worsening morphologic abnormalities (e.g., teardrop or nucleated erythrocytes, immature leukocytes). ¹ Perform CBC monthly to evaluate new or worsening cytopenias.¹ If a new or worsening morphologic abnormality or cytopenia develops, discontinue romiplostim and consider a bone marrow biopsy, with additional staining for fibrosis.¹

Thrombocytopenia Following Romiplostim Discontinuance

Risk of thrombocytopenia, which may be more severe than prior to therapy, after discontinuance of romiplostim.¹ May result in increased risk of bleeding, especially if romiplostim is discontinued while the patient is receiving concomitant antiplatelet or anticoagulation therapy.¹

Following discontinuance of romiplostim, perform CBC including platelet count weekly for at least 2 weeks.¹ Consider additional ITP therapy for worsening thrombocytopenia.¹

Thrombosis/Thromboembolism

Risk of thrombosis or a thromboembolic complication as a result of excessive increase in platelet count secondary to excessive dosages of romiplostim.¹ To minimize the risk, do not use romiplostim to normalize platelet counts; use drug only to maintain a platelet count of ≥50,000/mm³ according to the dosage adjustment guidelines.¹ (See Dosage under Dosage and Administration.)

Malignancy

Romiplostim stimulates the TPO receptor present on the surface of hematopoietic cells; may increase the risk for a hematologic malignancy, especially in patients with myelodysplastic syndrome (MDS). ¹ Do not use romiplostim to treat or correct thrombocytopenia related to an underlying hematologic cause (e.g., myelodysplasia) or resulting from chemotherapy; use romiplostim only for thrombocytopenia associated with chronic ITP.¹

Laboratory Monitoring

Obtain CBC, including platelet count and peripheral blood smear, prior to starting therapy and weekly during the dosage adjustment phase, then monthly once a stable dosage has been achieved.¹ Baseline peripheral blood smears should establish the presence and extent of red blood cell and leukocyte abnormalities.¹ After romiplostim is discontinued, evaluate CBC with platelet count weekly for at least 2 weeks to monitor for worsening thrombocytopenia.¹

Lack or Loss of Response

In cases of lack of response (i.e., hyporesponsiveness) or failure to maintain a platelet response, consider performing an evaluation of possible causative factors (e.g., presence of neutralizing antibodies, evidence of bone marrow fibrosis).¹ Blood samples for detection of antibody formation can be sent to Amgen to determine if antibodies to either romiplostim or TPO are present.¹

Discontinue romiplostim if the platelet count does not increase sufficiently after 4 weeks of treatment at the highest recommended dosage of 10 mcg/kg weekly.¹

Immunogenicity

Binding antibodies to romiplostim and TPO reported, including anti-romiplostim neutralizing antibodies.⁸ No clinical impact on safety or efficacy observed in patients who tested positive for antibodies.⁸

Specific Populations

Pregnancy

Category C.¹ Pregnancy registry at 1-887-Nplate1 (1-887-675-2831).¹

Lactation

Not known whether romiplostim is distributed into human milk; however, human immunoglobulin G antibody (IgG) is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy in geriatric patients ≥65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Not studied in hepatic impairment.¹ Use with caution.¹

Renal Impairment

Not studied in patients with renal impairment.¹ Use with caution.¹

Common Adverse Effects

Arthralgia,¹ dizziness,¹ insomnia,¹ myalgia,¹ extremity pain,¹ abdominal pain.¹

In the extension study: headache, nasopharyngitis, confusion, fatigue.⁶

Interactions for Nplate

No formal drug interaction studies to date.¹

Nplate Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations attained approximately 7–50 hours (median: 14 hours) following sub-Q administration of romiplostim doses of 3–15 mcg/kg.¹

Distribution

Extent

Not known whether romiplostim is distributed into milk.¹

Elimination

Elimination Route

Elimination of the drug is partly dependent on the TPO receptor on platelets.¹ High platelet counts are associated with low serum romiplostim concentrations.¹

Half-life

Approximately 1–34 days (median: 3.5 days).¹

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.¹ Store vials in carton to protect from light until used.¹

Protect reconstituted solutions from light and store at 25°C or refrigerated at 2–8°C for up to 24 hours prior to administration.¹ Do not administer more than one dose from each single-use vial; discard any unused portions of the solution.¹

Actions

• 
  

  Biosynthetic (recombinant DNA-derived) Fc-peptide fusion protein; thrombopoietin receptor agonist.^{1 3} Produced by recombinant DNA technology in Escherichia coli.¹

  
  


• 
  

  Contains 2 identical single-chain subunits, each consisting of human IgG₁ Fc domain covalently linked at the C-terminus to a peptide containing 2 thrombopoietin receptor-binding domains.¹

  
  


• 
  

  Has no amino acid sequence homology to endogenous thrombopoietin.^{1 3}

  
  


• 
  

  Binds to the thrombopoietin receptor (also known as cMp1) and activates intracellular transcriptional pathways leading to increased platelet production.^{1 3}

  
  

Advice to Patients

• 
  

  Importance of understanding that romiplostim treatment can only be administered by a clinician enrolled in the Nplate NEXUS program; all patients receiving romiplostim must be enrolled in the NEXUS program.¹ (See Restricted Distribution Program under Dosage and Administration.)

  
  


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  Under the REMS program approved by FDA, medication guide must be provided prior to each dose of romiplostim.⁹ Importance of carefully reading medication guide before initiating therapy and prior to receiving each dose.^{1 2 9}

  
  


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  Importance of understanding that the goal of therapy is to achieve and maintain a platelet count of ≥50,000/mm³ to reduce the risk of bleeding, not to normalize platelet counts.¹

  
  


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  Risk of worsening thrombocytopenia with possible bleeding following discontinuance of romiplostim, compared with such risks prior to starting therapy; increased risk if patient is receiving concomitant anticoagulant or antiplatelet drugs.¹

  
  


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  Risk of reticulin fiber formation in bone marrow with possible progression to bone marrow fibrosis.¹

  
  


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  Risk of thrombosis or thromboembolism.¹

  
  


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  Risk of progression of underlying MDS or hematologic malignancy.¹

  
  


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  Risk of adverse events associated with long-term administration not fully known.¹

  
  


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  Importance of avoiding situations or drug therapies that may increase risk of bleeding.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of romiplostim is restricted.^{1 4 5} (See Restricted Distribution Program under Dosage and Administration.)

Romiplostim

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for subcutaneous use	375 mcg (to deliver 250 mcg)	Nplate	Amgen
		625 mcg (to deliver 500 mcg)	Nplate	Amgen

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Amgen. Nplate (romiplostim) for injection prescribing information. Thousand Oaks, CA; 2008 Aug.

2. Amgen. Nplate (romiplostim) for injection medication guide. Thousand Oaks, CA; 2008 Aug.

3. Kuter DJ, Bussel JB, Lyons RM et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008: 371:395-403.

4. Pazdur R. Letter regarding approval of biologics license application for romiplostim (BL 125268/0). Rockville, MD: US Food and Drug Administration; 2008 Aug 22.

5. Amgen. Nexus healthcare professional brochure: Understanding and supporting Nplate (romiplostim) and patients. Available at: . Accessed 2008 Oct 3.

6. Bussel JB, Kuter DJ, Pullarkat V et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009; 113:2161-71. [PubMed 18981291]

7. Kuter DJ, Phil D, Mufti G et al. Evaluation of bone marrow reticulin formation in romiplostim-treated adult patients with chronic immune thrombocytopenic purpura (ITP). Blood. 2008; 112: Abstract 3416.

8. Jawa V, Hokom M, Hu J et al. Low immunogenicity to romiplostim in clinical studies with ITP subjects. Blood. 2008; 112: Abstract 3425.

9. Amgen. BLA 125268 Nplate (romiplostim): risk evaluation and mitigation strategy (REMS). Thousand Oaks, CA; 2010 Mar 23. Available from FDA website (). Accessed 2011 Feb 8.

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