Neostigmine Methylsulfate

Class: Parasympathomimetic (Cholinergic) Agents
Note: This monograph also contains information on Neostigmine Bromide
VA Class: AU300
CAS Number: 59-99-4
Brands: Prostigmin

Introduction

Reversible anticholinesterase agent.^{a b c}

Uses for Neostigmine Methylsulfate

Myasthenia Gravis

Symptomatic management of myasthenia gravis to improve muscle strength.^{a b c}

Not effective in patients resistant to anticholinesterase drugs.^a

Differential diagnosis of myasthenia gravis.^a However, edrophonium is preferred except in lengthy procedures involving tests of limb strength.^a

Surgery

Postoperative reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., tubocurarine, metocurine, gallamine [all no longer commercially available in the US], pancuronium).^{a b}

Not effective and should not be used for reversal of depolarizing neuromuscular agents (e.g., succinylcholine, decamethonium).^a

Postoperative Distention and Urinary Retention

Prevention and treatment of postoperative distention and urinary retention after excluding mechanical obstruction;^{a b} bethanechol chloride usually preferred.^a

Aminoglycoside Toxicity

Has been used to antagonize the neuromuscular blocking effects of aminoglycoside antibiotics† (e.g., kanamycin) with variable results; some clinicians found neostigmine ineffective.^a (See Specific Drugs under Interactions.)

Acceleration of Barium Transit through Small Intestine

Has been used to accelerate barium transport through the small bowel†; other agents may be more effective.^a

Neostigmine Methylsulfate Dosage and Administration

General

Diagnosis of Myasthenia Gravis

• 
  

  Discontinue all anticholinesterase drugs for at least 8 hours before administering neostigmine methylsulfate.^a

  
  


• 
  

  Administer atropine sulfate IM 30 minutes before or IV concurrently with IM neostigmine methylsulfate to prevent adverse muscarinic effects.^a

  
  


• 
  

  Determine placebo response by measuring muscle strength in cranial musculature before and after atropine sulfate administration.^a

  
  


• 
  

  Other myopathies may show slight improvement in muscle strength; however, only myasthenia gravis responds with marked improvement.^a

  
  

Treatment of Myasthenia Gravis

• 
  

  Dosage, route, and frequency of administration depend on the requirements and clinical response of the patient.^a Carefully individualize dosage according to individual requirements and response and minimize adverse effects by precise dosage adjustment.^a

  
  


• 
  

  Use parenteral form if oral therapy is impractical^b or in acute myasthenic crisis if difficulty in breathing and swallowing is present.^c Transfer to the oral formulation as soon as tolerated.^c

  
  


• 
  

  Dosage requirements may vary from day to day, according to remissions and exacerbations of the disease and the physical and emotional stress suffered by the patient.^a

  
  


• 
  

  Treat mild exacerbations by increasing dosage under medical supervision as long as increase produces symptomatic improvement.^a

  
  


• 
  

  Complete restoration of muscle strength is rare; do not attempt to relieve all symptoms by increasing dosage above maximum response level.^a

  
  


• 
  

  Once stabilized on neostigmine, may teach patients how to recognize adverse muscarinic effects and self-modify dosage or take atropine, if necessary.^a

  
  


• 
  

  Individual muscle groups respond differently to the same dose; may produce weakness in one while increasing strength in another.^a Measure vital capacity whenever increasing dosage to ensure good respiratory function.^a Have adequate facilities for CPR, cardiac monitoring, endotracheal intubation, and respiratory assistance available during dosage adjustment.^a

  
  


• 
  

  Patients may become refractory after prolonged treatment; decreasing dosage or withdrawing drug for several days under medical supervision may restore responsiveness.^a

  
  


• 
  

  If the patient is placed on a ventilator or corticosteroid therapy is begun, reduce dosage or eliminate neostigmine, if possible.^a

  
  

Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects

• 
  

  Always have atropine and medications to treat shock readily available in case of hypersensitivity reaction.^b

  
  


• 
  

  Give IV atropine sulfate or glycopyrrolate immediately prior to or concurrently with neostigmine (in separate syringes) when reversing the actions of nondepolarizing neuromuscular blocking agents to minimize neostigmine's adverse muscarinic effects.^{103 a b} If bradycardic, give IV antimuscarinics before neostigmine to increase pulse rate to about 80 bpm.^{a b}

  
  


• 
  

  Optimum time for neostigmine administration is during hyperventilation when blood CO₂ concentration is low.^b

  
  


• 
  

  Patient must be well ventilated; maintain patent airway until complete recovery of normal respiration is assured.^{a b} Observe closely for recurrent respiratory depression.^a

  
  

Parenteral Administration

• 
  

  Prior or simultaneous administration of atropine may be advisable when administering large parenteral doses of neostigmine methylsulfate.^{a b}

  
  

Administration

Administer neostigmine bromide orally; administer neostigmine methylsulfate IV, IM, or sub-Q.^{a b c}

Oral Administration

Administer orally, adjusting frequency and timing of administration according to individual response.^a

Parenteral Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer neostigmine methylsulfate IV, IM, or sub-Q.^{a b}

Surgery: Give by slow IV injection.^a

Dosage

Available as neostigmine bromide and neostigmine methylsulfate; dosage expressed in terms of the salts.^{a b c}

Pediatric Patients

Myasthenia Gravis

Diagnosis

IM

Children: 0.025–0.04 mg/kg.^{103 a} Give 0.011 mg/kg atropine sulfate sub-Q or IM 30 minutes before neostigmine or IV immediately before the IM neostigmine test dose.^{103 a} (See Pediatric Use under Cautions.)

Treatment

Oral

2 mg/kg daily divided into doses administered every 3–4 hours as needed.¹⁰³ (See Pediatric Use under Cautions.)

Adjust dosage so the patient takes larger doses at times of greatest fatigue (e.g., 30 minutes before meals if difficulty eating).^{a c}

Oral dosage changes may take several days to show results.^a When a further increase in dosage produces no corresponding increase in muscle strength, reduce dosage to the previous level.^a

Oral dosage requirements are approximately 30 times parenteral dosage requirements.^a Generally 15 mg oral neostigmine bromide is equivalent to 0.5 mg parenteral neostigmine methylsulfate.^c

IM, IV, or Sub-Q

0.01–0.04 mg/kg every 2–4 hours.^{103 104} In neonates, myasthenia gravis tends to be self-limiting; gradually reduce daily dosage until drug can be withdrawn.^a (See Pediatric Use under Cautions.)

Surgery

Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects

IV

Infants: 0.025–0.1 mg/kg (with atropine sulfate or glycopyrrolate).¹⁰³ (See Pediatric Use under Cautions.)

Children: 0.025–0.08 mg/kg (with atropine sulfate or glycopyrrolate).¹⁰³

Adults

Myasthenia Gravis

Diagnosis

IM

0.022 mg/kg.^{103 a} Give 0.011 mg/kg atropine sulfate IM 30 minutes before the test or IV atropine sulfate immediately before the IM neostigmine test dose.^a

If cholinergic reaction occurs, discontinue test and give 0.4–0.6 mg or more IV atropine sulfate.^a

If test is inconclusive, retest another day using 0.031 mg/kg neostigmine methylsulfate IM preceded by 0.016 mg/kg IM atropine sulfate.^a

Treatment

Oral

Initially, 15 mg 3 times daily.^a Increase gradually at intervals ≥24 hours.^a

Usual maintenance dosage: 15–375 mg daily (average 150 mg daily);^{a c} some patients may require 30–40 mg every 2–4 hours.^a

Adjust dosage so the patient takes larger doses at times of greatest fatigue (e.g., 30 minutes before meals if difficulty eating).^{a c}

Oral dosage changes may take several days to show results.^a When a further increase in dosage produces no corresponding increase in muscle strength, reduce dosage to the previous level.^a

Oral dosage requirements are approximately 30 times parenteral dosage requirements.^a Generally 15 mg oral neostigmine bromide is equivalent to 0.5 mg parenteral neostigmine methylsulfate.^c

IV, IM, or Sub-Q

Initially, 0.5–2.5 mg as needed.^a

Give 0.6–1.2 mg IV atropine sulfate concurrently with (but in a separate syringe) large parenteral neostigmine doses to counteract adverse muscarinic effects; observe patient closely for cholinergic reactions.^{a b}

Surgery

Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects

IV

0.5–2.5 mg.^a Give concurrently with (but in a separate syringe) or immediately after 0.6–1.2 mg IV atropine sulfate^{a b} or 0.2–0.6 mg glycopyrrolate.^a Repeat as required; total neostigmine methylsulfate dose usually ≤5 mg.^b

For cardiac or severely ill patients, titrate dosage with a peripheral nerve stimulator.^{a b}

Full recovery usually occurs within 3–5 minutes but may be delayed in patients with extreme debilitation, hypokalemia, or carcinomatosis, or with concurrent use of certain broad spectrum antibiotics (e.g., aminoglycosides) or anesthetic agents (e.g., ether).^a

Postoperative Distention and Urinary Retention

Prevention

IM or Sub-Q

0.25 mg as soon as possible after surgery; repeat every 4–6 hours for 2–3 days.^{a b}

Treatment

IM or Sub-Q

0.5 mg; exclude mechanical obstruction before giving neostigmine.^{a b}

If no response within 1 hour of first dose in patients with urinary retention, catheterize patient; repeat 0.5-mg doses every 3 hours for at least 5 doses after bladder is emptied.^{a b}

Prescribing Limits

Adults

Surgery

Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects

IV

Usually do not exceed total dose of 5 mg.^{a b}

Special Populations

No special population dosage recommendations at this time.^{a b c}

Cautions for Neostigmine Methylsulfate

Contraindications

• 
  

  Known hypersensitivity to neostigmine.^{a b c}

  
  


• 
  

  Mechanical obstruction of the intestinal or urinary tract.^{a b c}

  
  


• 
  

  Peritonitis.^{a b c}

  
  


• 
  

  Neostigmine bromide should not be used in patients with known hypersensitivity to bromides.^{a c}

  
  

Warnings/Precautions

Warnings

Cholinergic Crisis

Overdosage may result in cholinergic crisis (e.g., excessive salivation and sweating, miosis, nausea, vomiting, diarrhea, bradycardia or tachycardia, hypotension, confusion, seizures, coma, severe muscle weakness, paralysis); may result in death.^{a b c} If overdosage occurs, withdraw all anticholinesterase drugs, maintain adequate respiration, and give IV atropine.^{a b c}

Myasthenic crisis due to increased disease severity also causes extreme muscle weakness; symptomatic differentiation from cholinergic crisis may be difficult.^{a b c} Time to onset of symptoms approximately 1 hour after dose suggests neostigmine overdosage; onset 3 hours after dose suggests underdosage or resistance.^a May require use of edrophonium chloride for the differential diagnosis.^{a b c}

If severe cholinergic reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., atropine sulfate).^{a b c}

Concomitant Diseases

Use with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias, or peptic ulcer.^{b c}

Avoid large oral doses in patients with megacolon or decreased GI motility because of risk of accumulation and toxicity when GI motility is restored.^a Also avoid large oral doses in conditions that might cause increased absorption from the intestinal tract.^c

Do not use in patients with peritonitis or doubtful bowel viability.^a

Ileorectal Anastomoses

Neostigmine-induced peristalsis may disrupt recently completed ileorectal anastomoses if given postoperatively.^a Halothane anesthesia may decrease risk; however, manufacturer states neostigmine should not be administered in the presence of high concentrations of halothane or cyclopropane.^{a b}

Sensitivity Reactions

Bromide Sensitivity

Use caution in patients with known bromide sensitivity; acneiform rash may develop.^a Usually disappears when neostigmine bromide is discontinued.^a

Specific Populations

Pregnancy

Category C.^{b c}

Risk of uterine irritability and induction of premature labor if anticholinesterase agents are given IV near term.^{b c}

Lactation

Not known whether neostigmine is distributed into milk.^{b c} Discontinue nursing or the drug.^{b c}

Pediatric Use

Manufacturers state that safety and efficacy have not been established in pediatric patients, but the drug has been used in this population (e.g., neonatal myasthenia gravis).^{103 104 b c}

Common Adverse Effects

Salivation, muscle fasciculation, intestinal cramps, diarrhea.^{a b c}

Interactions for Neostigmine Methylsulfate

Specific Drugs

Drug	Interaction	Comments
Aminoglycosides (e.g., kanamycin, neomycin, streptomycin )	Possible accentuation of neuromuscular blockadea b c	Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c
Anesthetics, local and general	Interferes with neuromuscular transmissiona b c	Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c Do not administer neostigmine in presence of high halothane or cyclopropane concentrationsa b
Antiarrhythmic agents	Interferes with neuromuscular transmissiona b c	Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c
Anticholinergic drugs	Possible reduced intestinal motilityc	Use caution if co-administered with oral neostigminec
Atropine	Antagonizes muscarinic effects of neostigminea	Interaction used to therapeutic advantage to counteract muscarinic symptoms of neostigmine toxicity; however, atropine also may mask manifestations of neostigmine overdose and prevent early detection of cholinergic crisisa b c
Dexpanthenol	Converted to pantothenic acid in vivo; possible additive effects due to increased acetylcholine productiona
Neuromuscular blocking agents, depolarizing (e.g., decamethonium [no longer commercially available in the US], succinylcholine)	Possible enhanced and/or prolonged neuromuscular blockadea b c	Do not use for reversal of depolarizing neuromuscular blockadea
Neuromuscular blocking agents, nondepolarizing (e.g., gallamine, metocurine, tubocurarine [all no longer commercially available in the US], pancuronium)	Antagonism of nondepolarizing muscle relaxant effectsa	Interaction used to therapeutic advantage to reverse muscle relaxation induced by neuromuscular blocking agents after surgerya

Neostigmine Methylsulfate Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed (1–2%) from GI tract following oral administration.^{a c}

Peak plasma concentrations occur 1–2 hours after oral ingestion with considerable interindividual variations or about 30 minutes after IM injection.^{a b c}

Onset

Effects on peristaltic activity begin 2–4 hours after oral administration or 10–30 minutes after parenteral injection.^{a b}

Maximal effects within 20–30 minutes after parenteral administration.^a

Duration

2.5–4 hours after IM injection.^{a b}

Distribution

Extent

Not expected to cross the placenta in therapeutic doses; may cross the placenta with large oral doses.^a Not known whether distributed into human milk.^a

Plasma Protein Binding

15–25% to serum albumin.^{a b c}

Elimination

Metabolism

Metabolized via hydrolysis by cholinesterases and by microsomal enzymes in the liver.^{a b c}

Elimination Route

Excreted in urine as unchanged drug (50%) and metabolites (30%).^{a b}

Half-life

Oral: 42–60 minutes (mean: 52 minutes).^c

IV: 47–60 minutes (mean: 53 minutes).^b

IM: 51–90 minutes.^b

Stability

Storage

Oral

Tablets

Tight containers at <40°C; preferably 15–30°C.^a

Parenteral

Injection

15–30°C.^b Protect from light; store in carton until use.^b Do not freeze.^a

Compatibility

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

Drug Compatibility

Y-Site Compatibility (Neostigmine Methylsulfate)HID

Compatible

Heparin sodium

Hydrocortisone sodium succinate

Potassium chloride

Vitamin B complex with C

Compatibility in Syringe (Neostigmine Methylsulfate)HID

Compatible

Glycopyrrolate

Heparin sodium

Ondansetron HCl

Pentobarbital sodium

Thiopental sodium

ActionsActions

• 
  

  Reversibly inhibits acetylcholinesterase and prolongs and exaggerates the effects of acetylcholine.^{a b c} Has direct cholinomimetic effect on skeletal muscle.^{a b c}

  
  


• 
  

  Produces generalized cholinergic responses including miosis, bradycardia, increased tonus of intestinal musculature, constriction of bronchi and ureters, and stimulation of secretion by salivary and sweat glands.^a

  
  


• 
  

  At sufficiently high dosage, directly blocks action at autonomic ganglia, causes CNS stimulation followed by CNS depression and, ultimately, depolarization blockade.^{a c}

  
  

Advice to Patients

• 
  

  Patients with myasthenia gravis: Importance of carefully following prescribed dosage instructions.^a Importance of keeping a daily record of condition to assist clinician in determining optimal therapeutic regimen.^c

  
  


• 
  

  Importance of informing clinician of any allergy to bromide or anticholinesterase drugs.^{a c}

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{a b c}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{a b c}

  
  


• 
  

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

  
  

Preparations

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

Neostigmine Bromide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder
Oral	Tablets	15 mg	Prostigmin (scored)	Valeant

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

Neostigmine Methylsulfate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder*
Parenteral	Injection	0.5 mg/mL*	Neostigmine Methylsulfate Injection	Abraxis, American Regent, Baxter, Teva
		1 mg/mL*	Neostigmine Methylsulfate Injection	Abraxis, American Regent, Baxter, Teva

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 February 2008. 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.

100. Miller LS, Staas WE Jr, Herbison GJ. Abdominal problems in patients with spinal cord lesions. Arch Phys Med Rehabil. 1975; 56:405-8. [PubMed 1164181]

101. Glick ME, Meshkinpour H, Haldeman S et al. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology. 1984; 86:287-94. [PubMed 6690355]

102. Miller LS. Neostigmine for severe constipation with spinal cord lesions. Ann Intern Med. 1984; 101:279.

103. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby; 2002:772

104. Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2470

a. AHFS drug information 2007. McEvoy GK, ed. Neostigmine bromide, neostigmine methylsulfate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1245-7.

b. American Regent Laboratories, Inc. Neostigmine methylsulfate injection, USP prescribing information. Shirley, NY; 2002 Sept.

c. ICN Pharmaceuticals, Inc. Prostigmin (neostigmine bromide) tablets prescribing information. Costa Mesa, CA; 1998 Nov.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1203-4.

More Neostigmine Methylsulfate resources

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

Compare Neostigmine Methylsulfate with other medications

• Myasthenia Gravis

Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension

Pronunciation: FEN-il-EF-rin/DEX-klor-fen-IR-a-meen/DEX-troe-meth-OR-fan
Generic Name: Phenylephrine/Dexchlorpheniramine/Dextromethorphan
Brand Name: Donatussin DM

Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension is used for:

Relieving symptoms of sinus congestion, runny nose, sneezing, itchy nose or throat, itchy or watery eyes, and cough due to colds, upper respiratory infections, and allergies. It may also be used for other conditions as determined by your doctor.

Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension is a decongestant, antihistamine, and cough suppressant combination. The decongestant works by constricting blood vessels and reducing swelling in the nasal passages. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing. The cough suppressant works in the brain to help decrease the cough reflex to reduce a dry cough.

Do NOT use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension if:

• you are allergic to any ingredient in Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or severe heart problems


• you are unable to urinate or are having an asthma attack


• you take droxidopa, sodium oxybate (GHB), or you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension:

Some medical conditions may interact with Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of adrenal gland problems (eg, adrenal gland tumor), heart problems (eg, fast, slow, or irregular heartbeat; heart disease), high or low blood pressure, diabetes, blood vessel problems, stroke, glaucoma or increased pressure in the eye, or thyroid problems


• if you have a history of asthma, chronic cough, lung or breathing problems (eg, chronic bronchitis, emphysema, sleep apnea), or chronic obstructive pulmonary disease (COPD), or if your cough occurs with large amounts of mucus


• if you have a history of stomach or bowel pulcers; a blockage of your stomach, bladder, or intestines; kidney problems; or trouble urinating; or if you have an enlarged prostate or other prostate problems

• Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased


• Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, linezolid, MAOIs (eg, phenelzine), selective serotonin reuptake inhibitors (SSRIs) (eg, citalopram, fluoxetine), sodium oxybate (GHB), or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension's side effects


• Bromocriptine or hydantoins (eg, phenytoin) because the risk of their side effects may be increased by Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension:

• Take Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension.

Important safety information:

• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Do not take diet or appetite control medicines while you are taking Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension without checking with your doctor.


• Before you start any new medicine, check the label to see if it has a decongestant, antihistamine, or cough suppressant in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Do not use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension for a cough with a lot of mucus. Do not use it for a long-term cough (eg, caused by asthma, emphysema, smoking). However, you may use it for these conditions if your doctor tells you to.


• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• If your symptoms do not get better within 5 to 7 days or if they get worse, check with your doctor.


• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension may interfere with skin allergy tests. If you are scheduled for a skin test, talk to your doctor. You may need to stop taking Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension for a few days before the tests.


• Tell your doctor or dentist that you take Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension before you receive any medical or dental care, emergency care, or surgery.


• Some of these products contain phenylalanine. If you must have a diet that is low in phenylalanine, ask your pharmacist if it is in your product.


• Use Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension with caution in the ELDERLY; they may be more sensitive to its effects, especially confusion, dizziness, drowsiness, dry mouth, nervouseness, sleeplessness, and trouble urinating.


• Caution is advised when using Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension in CHILDREN; they may be more sensitive to its effects, especially excitability.


• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension should be used with extreme caution in CHILDREN younger than 6 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension while you are pregnant. Some ingredients of Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension are found in breast milk. Do not breast-feed while taking Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension.

Possible side effects of Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); confusion; difficulty urinating or inability to urinate; fast or irregular heartbeat; fever, chills, or persistent sore throat; hallucinations; loss of coordination; mental or mood changes (eg, depression); seizures; severe dizziness, drowsiness, lightheadedness, or headache; severe dryness of mouth, nose, and throat; severe or persistent trouble sleeping; shortness of breath; tremor; unusual bruising or bleeding; unusual tiredness or weakness; vision problems (eg, double vision, severe or persistent blurred vision).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; flushing; hallucinations; mental or mood changes; muscle spasms; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; trouble breathing; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension:

Store Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Do not freeze. Store away from heat and light. Keep Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Phenylephrine/Dexchlorpheniramine/Dextromethorphan Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Phenylephrine/Dexchlorpheniramine/Dextromethorphan resources

• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Use in Pregnancy & Breastfeeding
• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Drug Interactions
• Phenylephrine/Dexchlorpheniramine/Dextromethorphan Support Group
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• Cough and Nasal Congestion

Calcough Children's Soothing Syrup

1. Name Of The Medicinal Product

Glycerin and Blackcurrant Soothing Cough Syrup or Glycerin and Blackcurrant Linctus or Benylin Dry Coughs Blackcurrant or CalCough Children's Soothing Syrup or Benylin Children's Blackcurrant Flavour Cough Syrup

2. Qualitative And Quantitative Composition

Active Ingredient Glycerin Ph. Eur. Liquid sugar (Equivalent to sucrose B.P.

Quantity per 5ml 0.75ml 1.93ml 1.7g)

3. Pharmaceutical Form

Liquid

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of irritating, tickling dry coughs and sore throats.

4.2 Posology And Method Of Administration

Adults, elderly and children over 5 years: 10ml

Children 1 - 5 years: 5ml

The dose may be repeated three or four times a day.

Children under one year: Not to be given to children under 1 year.

For oral administration.

4.3 Contraindications

Hypersensitivity or intolerance to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Diabetics should take note of the carbohydrate content of this product.

Do not give to children under one year.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant interactions known.

4.6 Pregnancy And Lactation

The safety of this medicine during pregnancy and lactation has not been established, but is not considered to constitute a hazard during these periods.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

No adverse effects would be anticipated.

4.9 Overdose

Overdosage would not be expected to cause any problems and treatment would be merely symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycerin and sucrose have demulcent properties and will soothe irritated sore throats and possibly block sensory cough receptors within the respiratory tract.

5.2 Pharmacokinetic Properties

Glycerin is readily absorbed from the gastrointestinal tract and undergoes extensive metabolism principally in the liver. It may be used in the synthesis of lipids, and is metabolised to glucose or glycogen or oxidised to carbon dioxide and water. It may also be excreted in the urine unchanged.

Sucrose is hydrolysed in the small intestine by the enzyme sucrase to glucose and fructose which are then absorbed.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid monohydrate gran

Sodium benzoate

Anthocyanin

Blackcurrant Flavour 1740.7107 IFF

Blackcurrant Juice 1740.1436 IFF

Liquid Glucose BPC 1963

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

125ml, 150ml or 200ml white flint glass, or amber glass bottle with an aluminium roll-on pilfer-proof cap with a flowed in liner, or a triseal (LDPE/EPE/LDPE) liner.

Alternative caps: A wadless polypropylene tamper evident cap, or a child resistant polypropylene cap with a LDPE liner.

A double ended measuring spoon of 2.5ml and 5.0ml capacity may optionally be provided with the product.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

Trading as: BCM

8. Marketing Authorisation Number(S)

PL 00014/0307

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: Date of Last Renewal:

14 March 1984 25 July 2000

10. Date Of Revision Of The Text

April 2010

Gemcitabine Hydrochloride

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2′-Deoxy-2′,2′-difluoro-cytidine monohydrochloride
Molecular Formula: C₉H₁₁F₂N₃O₄•ClH
CAS Number: 122111-03-9
Brands: Gemzar

Introduction

Antimetabolite antineoplastic agent; a synthetic pyrimidine nucleoside.^{1 2 4}

Uses for Gemcitabine Hydrochloride

Breast Cancer

Used in combination with paclitaxel as first-line therapy for metastatic breast cancer in patients who did not respond to previous anthracycline-containing chemotherapy or in whom such chemotherapy was contraindicated.^a

Non-small Cell Lung Cancer

Used for initial treatment in patients with inoperable, locally advanced (stage IIIA or IIIB) or metastatic (stage IV) non-small cell lung cancer in combination with cisplatin.^{1 5 27 28 54 58 68}

Used as monotherapy† for advanced non-small cell lung cancer^{36 37 38 49 50 51 54} in patients with relapsed or refractory advanced non-small cell lung cancer who previously were treated with platinum-containing chemotherapy regimens⁴¹ or in those who have not received prior chemotherapy.^{36 37 38 50 51}

Use of chemotherapy generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond.⁵² Individualize decision to use chemotherapy according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.^{52 54 55}

Pancreatic Cancer

Used as first-line therapy^{1 10 57} for the palliative treatment of locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas.^{1 5}

Also used as second-line therapy in patients previously treated with fluorouracil.^{1 11}

Bladder Cancer

Used alone^{22 23 24} or in combination therapy⁵ (i.e., cisplatin)^{59 59 60} for the treatment of advanced or metastatic bladder cancer†.

Objective responses to gemcitabine have been observed in patients with metastatic bladder cancer that did not respond to previous treatment with cisplatin-based regimens, including some patients with hepatic metastases.^{24 25}

Ovarian Cancer

Currently being investigated for use in the treatment of advanced epithelial ovarian cancer†.^{5 62 63 64 65 66}

Gemcitabine Hydrochloride Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Perform CBC, including differential and platelets, prior to each dose of gemcitabine.¹ Modify or temporarily withhold dosage if myelosuppression is detected, according to the degree of hematologic toxicity.¹ When used in combination with other antineoplastic agents, dosage modification of the concomitant agent also may be required for hematologic and/or nonhematologic toxicity.

  
  

Administration

IV Administration

Administer by IV infusion.^{1 11 57}

The drug is for IV use only.^a

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vials containing 200 mg or 1 g of gemcitabine by adding 5 or 25 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide a solution containing 38 mg/mL (accounts for the displacement volume of lyophilized powder).^{1 3 21} Shake to dissolve.¹

Total volume upon reconstitution for vials labeled as containing 200 mg or 1 g is about 5.26 or 26.3 mL, respectively.^{1 3}

Smaller volumes should not be used for reconstitution; concentrations >38 mg/mL may exceed the solubility of the drug and result in incomplete dissolution.^{1 3}

Discard any unused portion after preparation of the appropriate dose.¹

Dilution

Reconstituted solutions can be infused IV without further dilution or as solutions that have been further diluted in 0.9% sodium chloride injection to concentrations as low as 0.1 mg/mL.¹

Rate of Administration

Infuse over a period of 30 minutes.¹

Prolonged IV infusion (>60 minutes) is associated with a prolonged half-life and increased toxicity, including clinically important myelosuppression.^{1 15} (See Elimination under Pharmacokinetics.) Infusion time should not exceed 60 minutes.¹

Dosage

Available as gemcitabine hydrochloride; dosage expressed in terms of gemcitabine.¹

Individualize dosage based on body surface area and patient tolerance and response.¹

Adults

Breast Cancer

IV

1250 mg/m² given on days 1 and 8 of a 21-day cycle; administer in combination with paclitaxel 175 mg/m², given on day 1, as a 3-hour infusion before administration of gemcitabine.^a

Patients should have an absolute granulocyte count of ≥1500/mm³ and platelet count of ≥100,000/mm³ prior to each cycle.^a Adjust dosage according to granulocyte and platelet counts obtained on day 8 of therapy (see Table 1).^a

Table 1. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Paclitaxel in Breast Cancer

Absolute Granulocyte Count (per mm3)		Platelets (per mm3)	Gemcitabine Dosage in Next Cycle (expressed as % of full dose)
≥1200	and	>75,000	100%
1000–1199	or	50,000–75,000	75%
700–999	and	≥50,000	50%
<700	or	<50,000	Withhold dose

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, acccording to clinician’s judgment.^a

Non-small Cell Lung Cancer

Combination Therapy with Cisplatin

Optimum dosage regimen has not been established.¹

IV

1000 mg/m² administered on days 1, 8, and 15 of each 28-day cycle (4-week schedule) or 1250 mg/m² administered on days 1 and 8 of each 21-day cycle (3-week schedule).^{1 27 28} Administer cisplatin 100 mg/m² on day 1 following completion of the gemcitabine infusion.¹

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.^a

See Table 2 for gemcitabine dosage modification for hematologic toxicity.

Table 2. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Cisplatin in Non-small Cell Lung Cancer

Absolute Granulocyte Count (per mm3)		Platelets (per mm3)	Gemcitabine Dose Modification (expressed as % of full dose)
≥1000	and	≥100,000	100%1
500–999	or	50,000–99,000	75%1 3
<500	or	<50,000	Withhold dose until counts exceed these levels

Monotherapy

IV

1000 or 1250 mg/m² once weekly for 3 weeks followed by 1 week of rest.^{36 37 38 41 42 44 50 51}

Pancreatic Cancer

Initial Dosing Cycle

IV

1 g/m² once weekly;^{1 11 57} repeat at weekly intervals as tolerated for up to 7 weeks, followed by a week of rest from treatment.¹ If necessary, reduce or withhold dosage according to the degree of hematologic toxicity. (See Table 3 for dosage modification for hematologic toxicity.)¹

Table 3. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Cisplatin in Non-small Cell Lung Cancer

Absolute granulocyte count (per mm3)		Platelets (per mm3)	Gemcitabine Dose Modification (expressed as % of full dose)
≥1000	and	≥100,000	100%1
500–999	or	50,000–99,000	75%1 3
<500	or	<50,000	Withhold dose until counts exceed these levels

Subsequent Dosing Cycles

IV

1 g/m² once weekly for 3 consecutive weeks, followed by a week of rest from treatment.¹

Dosage may be increased to 1.25 g/m² weekly for 3 consecutive weeks, followed by a week of rest, in patients who successfully complete the initial 7-week or subsequent 3-week cycle of therapy at the full weekly dosage, provided nadirs of the absolute granulocyte and platelet counts are >1500 and 100,000/mm³, respectively, and WHO nonhematologic toxicity > grade 1 is not present.^{1 11} Dosage can be further increased to 1.5 g/m² weekly given in 3-week cycles if previous 3-week course is tolerated (i.e., hematologic parameters are met and no evidence of WHO nonhematologic toxicity >1).¹

If necessary, reduce or withhold dosage according to the degree of hematologic toxicity.¹ (See Table 3.)

In clinical trials, patients received an average of 3 cycles of therapy.³

Prescribing Limits

Do not administer more frequently than once weekly, since risk of toxicity is increased with such dosing.^{1 16} Infusion time should not exceed 60 minutes.¹ (See Rate of Administration under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.¹

Renal Impairment

No specific recommendations for dosage adjustment; use with caution.¹

Geriatric Patients

Decreased clearance.¹ No dosage adjustments in patients >65 years of age except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).¹

Female Patients

Decreased clearance.¹ No dosage adjustments except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).¹

Cautions for Gemcitabine Hydrochloride

Contraindications

• 
  

  Known hypersensitivity to gemcitabine or any ingredient in the formulation.^a

  
  

Warnings/Precautions

Warnings

IV Administration

IV infusion over >60 minutes and administration more frequent than once weekly may be associated with increased toxicity (e.g., myelosuppression).¹ (See Rate of Administration under Dosage and Administration.)

Hematologic Effects

Myelosuppression, including leukopenia, anemia, and thrombocytopenia, (usually dose-limiting) may require blood transfusions.^a Perform a CBC, including differential and platelets, prior to each dose; modify dosage accordingly.¹

Pulmonary Effects

Severe adverse pulmonary effects, sometimes fatal (e.g., pulmonary edema, interstitial pneumonitis, pulmonary fibrosis, ARDS), have been reported.^{1 70 71} Onset of pulmonary symptoms has occurred up to 2 weeks following administration of the last dose; rarely, respiratory failure and death have occurred despite discontinuance of therapy.¹

Dyspnea, occasionally accompanied by bronchospasm, has been reported.¹ Possible dose-limiting pulmonary toxicity (e.g., esophagitis, pulmonary fibrosis, and pneumonitis) in patients receiving concurrent thoracic radiation therapy for non-small cell lung cancer.⁷²

Discontinue therapy immediately and institute appropriate supportive care (e.g., diuretics, corticosteroids) promptly in patients who develop severe adverse pulmonary effects.^{1 70 71}

Renal Effects

Risk of hemolytic-uremic syndrome and/or renal failure; rarely fatal or requires dialysis despite discontinuance of therapy.¹ Discontinue therapy immediately and consider a diagnosis of hemolytic-uremic syndrome in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, reticulocytosis, and/or severe thrombocytopenia with or without evidence of renal failure (e.g., elevation of S_cr or BUN).^{1 70}

Hepatic Effects

Severe hepatotoxicity, including hepatic failure and death, has been reported rarely.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;^a embryotoxic and fetotoxic in animals.^a If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.^a

Sensitivity Reactions

Anaphylactoid reactions reported rarely.^a

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under close supervision of qualified clinician experienced in cancer chemotherapy.^a Adverse effects generally are reversible and do not require discontinuance of therapy; however, dosage adjustments may be required.^a

Assess renal and hepatic function prior to and periodically during therapy.^a

Specific Populations

Pregnancy

Category D.^a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether gemcitabine is distributed into human milk.^a Discontinue nursing because of potential risk to nursing infants.^a

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 3}

Geriatric Use

Decreased clearance and increased half life.^{1 a} Possible increased incidence of severe (grade 3/4) thrombocytopenia.^a

Hepatic Impairment

Use with caution; assess hepatic function prior to and periodically during therapy.^a

Renal Impairment

Use with caution; assess renal function prior to and periodically during therapy.^a

Women

Decreased clearance.¹ Women tolerate the drug more poorly than men, are less likely to progress to subsequent cycles, and are more likely to experience hematologic toxicity (i.e., neutropenia, thrombocytopenia).^{1 3}

Common Adverse Effects

Myelosuppression, transient elevations of serum AST and ALT, proteinuria, hematuria, nausea, vomiting, pain, fever, fatigue, rash, dyspnea, diarrhea, edema, flu-like symptoms, infection, alopecia, stomatitis, somnolence, paresthesias, and injection site reactions.^a

Gemcitabine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained up to 30 minutes after discontinuance of the infusion.^a

Distribution

Extent

Volume of distribution increases with length of infusion.^a Not extensively distributed into tissues following IV infusion over <70 minutes (volume of distribution 50 L/m²).^a Following long infusion times, volume of distribution is 370 L/m², indicating slow equilibration into tissues.^a

Plasma Protein Binding

Negligible.^a

Special Populations

Volume of distribution is affected by gender.^a

Elimination

Metabolism

Converted intracellularly to active metabolites (gemcitabine diphosphate and gemcitabine triphosphate).^{1 2 4 19 58}

Elimination Route

Excreted principally in urine as unchanged drug (<10%) and as inactive metabolite.^a

Half-life

Increases with age.^a

42, 48, 61, and 79 minutes for men 29, 45, 65, and 79 years of age, respectively.^a

49, 57, 73, and 94 minutes for women 29, 45, 65, and 79 years of age, respectively.^a

32–94 minutes following short infusions; 245–638 minutes following long infusions.^a

Special Populations

Clearance is reduced and half-life increased in women and geriatric patients.¹

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C); do not refrigerate since crystallization may occur.^a

Solutions are stable for 24 hours at 20–25°C.¹

Compatibility

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

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Amifostine
Amikacin sulfate
Aminophylline
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Aztreonam
Bleomycin sulfate
Bumetanide
Buprenorphine HCl
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Cefazolin sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Chlorpromazine HCl
Cimetidine HCl
Ciprofloxacin
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dactinomycin
Daunorubicin HCl
Dexamethasone sodium phosphate
Dexrazoxane
Diphenhydramine HCl
Dobutamine HCl
Docetaxel
Dopamine HCl
Doxorubicin HCl
Doxycycline hyclate
Droperidol
Enalaprilat
Etoposide
Etoposide phosphate
Famotidine
Floxuridine
Fluconazole
Fludarabine phosphate
Fluorouracil
Gentamicin sulfate
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Hydroxyzine HCl
Idarubicin HCl
Ifosfamide
Leucovorin calcium
Linezolid
Lorazepam
Mannitol
Meperidine HCl
Mesna
Metoclopramide HCl
Metronidazole
Mitoxantrone HCl
Morphine sulfate
Nalbuphine HCl
Ofloxacin
Ondansetron HCl
Oxaliplatin
Paclitaxel
Potassium chloride
Promethazine HCl
Ranitidine HCl
Sodium bicarbonate
Streptozocin
Teniposide
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Topotecan HCl
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Acyclovir sodium
Amphotericin B
Cefotaxime sodium
Furosemide
Ganciclovir sodium
Imipenem–cilastatin sodium
Irinotecan HCI
Lansoprazole
Methotrexate sodium
Methylprednisolone sodium succinate
Mitomycin
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Prochlorperazine edisylate

ActionsActions

• 
  

  Cell-cycle specific, acting principally in the S phase of the cell cycle; the drug also may cause cellular arrest at the G₁—S border.¹

  
  


• 
  

  Combined actions of diphosphate and triphosphate metabolites lead to inhibition of DNA synthesis.^{1 2 4 19 20 58}

  
  


• 
  

  Gemcitabine diphosphate interferes with subsequent de novo nucleotide production^{1 2 4 58} by inhibiting ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis.^{1 2 4 58}

  
  


• 
  

  Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA.^{1 2 4 58} Following incorporation of gemcitabine triphosphate into the DNA chain, a single additional nucleotide, a normal base pair, is added and DNA synthesis is terminated, resulting in apoptosis (programmed cell death).^{1 2 4 58}

  
  


• 
  

  DNA polymerase ε is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand,^{1 2 3 4 58} which results in a prolonged intracellular half-life of gemcitabine compared with other nucleoside analogs such as cytarabine and is thought to contribute to gemcitabine’s expanded spectrum of antineoplastic activity relative to such agents.^{4 58}

  
  

Advice to Patients

• 
  

  Risk of myelosuppresion.^a

  
  


• 
  

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

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.^a

  
  


• 
  

  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.

Gemcitabine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	200 mg (of gemcitabine)	Gemzar (with mannitol)	Lilly
		1 g (of gemcitabine)	Gemzar (with mannitol)	Lilly

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gemzar 1GM Solution (LILLY): 1/$850.02 or 3/$2395.88

Gemzar 200MG Solution (LILLY): 1/$170.43 or 3/$503.19

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 2007. 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

1. Eli Lilly and Company. Gemzar (gemcitabine) prescribing information. Indianapolis, IN: 2003 Jan 6.

2. Eli Lilly and Company. Treatment IND of Gemzar (gemcitabine) for patients with pancreatic cancer. Protocol No. B9E-MC-JHEW (c). Indianapolis, IN: Eli Lilly and Company; 1995 Feb 2.

3. Eli Lilly and Company, Indianapolis, IN: Personal communication.

4. Eli Lilly and Company. Gemzar (gemcitabine hydrochloride) product information. Indianapolis, IN: 1995 Apr 27.

5. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

6. Pancreatic cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jul 3.

7. Brennan MF, Kinsella TJ, Casper ES. Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:849-82.

8. Weiss GR, Burris HA III, Eckardt JR et al. New anticancer agents. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:132-67.

9. Vaughn DJ, Treat J. Cancers of the large bowel and hepatobiliary tract. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:495-10.

10. Carmichael J, Fink U, Russell RC et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996; 73:101-5. [PubMed 8554969]

11. Rothenberg ML, Moore MJ, Cripps MC et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996; 7:347-53. [PubMed 8805925]

12. Moore M, Andersen J, Burris H et al. A randomized trial of gemcitabine (GEM) versus 5FU as first-line therapy in advanced pancreatic cancer. Proc Annu Meet Soc Clin Oncol. 1995; 14:A473.

13. Andersen JS, Burris HA, Casper E et al. Development of a new system for assessing clinical benefit for patients with advanced pancreatic cancer. Proc Annu Meet Am Soc Clin Oncol. 1994; 13:A1600.

14. Lawrence TS, Chang EY, Hahn TM et al. Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys. 1996; 34:867-72. [PubMed 8598364]

15. Pollera CF, Ceribelli A, Crecco M et al. Prolonged infusion of gemcitabine: a preliminary report of a Phase I study. Ann Oncol. 1992; 3(Suppl 5):52.

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70. Food and Drug Administrati