New Article Directory Alaska: April 2012

Sunday, 29 April 2012

Phenobarbital

Class: Barbiturates
VA Class: CN301
CAS Number: 50-06-6
Brands: Luminal

Introduction

Barbiturate;^a ^b ^c ^d anxiolytic, sedative, hypnotic, and anticonvulsant.^a ^b ^f

Uses for Phenobarbital

Insomnia and Anxiety

Relief of anxiety, tension, and apprehension.^c ^d However, barbiturates used infrequently for routine sedation, since there are few clinical situations in which oral barbiturates provide a safety or efficacy advantage over nonbarbiturate sedatives/hypnotics.^f

Short-term treatment of insomnia.^c ^d However, generally not used orally as a hypnotic because several hours are required to achieve maximal effects^a and barbiturates have decreased effectiveness for sleep induction and maintenance after 2 weeks.^d

Drug Withdrawal

Withdrawal of barbiturate or nonbarbiturate hypnotics in patients who are physically dependent on these drugs.^a

Surgery

Preoperatively, to produce sedation and relieve anxiety.^a ^c

Seizure Disorders

Management of tonic-clonic seizures and partial seizures; used alone (particularly in infants and young children) or, more commonly, in combination with phenytoin or other anticonvulsants.^b

Prevention of febrile seizures in infants and young children.^b

Second-line agent in the termination of status epilepticus; may be useful to prevent seizure recurrence after seizures are initially terminated with other anticonvulsants (e.g., diazepam, phenytoin) or for termination of status epilepticus that does not respond to initial therapy with other anticonvulsants.^b ^c Usefulness of parenteral phenobarbital in terminating acute seizure episodes is limited by its slow onset of action.^a ^b ^d

Prophylactic management of epilepsy.^c ^d

Hyperbilirubinemia in Neonates

Prevention and treatment of hyperbilirubinemia in neonates†.^a

Cholestasis

Has been used to reduce bilirubin concentrations in patients with congenital nonhemolytic unconjugated hyperbilirubinemia† or chronic intrahepatic cholestasis†.^a

Has been used in the management of hyperlipemia associated with intrahepatic and extrahepatic cholestasis†.^a

Phenobarbital Dosage and Administration

General

Adjust dosage carefully and slowly according to individual requirements and response.^a ^b

Following chronic administration, withdraw phenobarbital slowly to avoid the possibility of precipitating withdrawal symptoms if the patient is physically dependent on the drug.^a ^d

To prevent rebound in rapid eye movement (REM) sleep, withdrawal of a single therapeutic dose over 5 or 6 days (e.g., reducing dosage from 3 to 2 doses daily for 1 week) has been recommended when barbiturates are discontinued following prolonged use.^a

Seizures

2–3 weeks of therapy may be required to achieve full anticonvulsant effects.^b

When transferring a patient to another anticonvulsant drug, reduce phenobarbital dosage gradually over 1 week while, at the same time, instituting therapy with a low dose of the replacement drug.^b

Withdraw phenobarbital or reduce dosage slowly to avoid precipitating seizures or status epilepticus.^b

Insomnia

Do not administer for periods >2 weeks.^a

Administration

Administer orally or by IM or slow IV injection.^a ^b ^c ^d Sub-Q injection not recommended.^a ^d

Oral Administration

Frequently administered in 2 or 3 divided doses;^a however, there is no advantage in dividing the daily dosage (because of the long half-life).^a ^b

IV Administration

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

Reserve IV administration for emergency treatment of acute seizure states; however, usefulness in these conditions is limited.^a ^b (See Seizure Disorders under Uses.)

Patient should be hospitalized and under close supervision.^a

To minimize the risk of irritation and thrombosis, do not use small veins (e.g., those on the dorsum of the hands or wrist).^d

Avoid intra-arterial injection.^b (See Intra-arterial Injection under Cautions.)

Rate of Administration

≤60 mg/minute.^a ^b ^d

IM Administration

Maximum volume of single injections is 5 mL; administer deeply into a large muscle to avoid tissue irritation.^d

Dosage

Available as phenobarbital sodium; dosage expressed in terms of the salt.^d

Pediatric Patients

Anxiety

Oral

6 mg/kg daily or 180 mg/m² daily, in 3 equally divided doses.^a ^c

Surgery

Oral

1–3 mg/kg preoperatively.^a ^d

IM

16–100 mg administered 60–90 minutes before surgery;^a alternatively, 1–3 mg/kg preoperatively.^a ^d

Drug Withdrawal

Oral

Infants: 3–10 mg/kg daily.^a After symptoms are relieved, decrease dosage gradually and withdraw drug completely over a 2-week period.^a

Seizure Disorders

Oral

15–50 mg 2 or 3 times daily.^c Alternatively, 3–5 mg/kg or 125 mg/m² daily.^b

IV or IM

4–6 mg/kg daily for 7–10 days to reach therapeutic blood concentrations; alternatively, 10–15 mg/kg daily.^d

Prevention of Febrile Seizures

Oral

3–4 mg/kg daily.^b

Status Epilepticus

IV or IM

15–20 mg/kg IV over 10–15 minutes.^d Alternatively 100–400 mg IM or IV; allow up to 30 minutes for maximum anticonvulsant effect before administering additional doses (to prevent overdosage).^b

Hyperbilirubinemia in Neonates†

Oral

7 mg/kg per day from the first to fifth day of life.^a

IM, then Oral

5 mg/kg IM on the first day of life, followed by 5 mg/kg orally on the second to seventh day.^a

Cholestasis†

Oral

Children <12 years of age: Dosages of 3–12 mg/kg daily in 2 or 3 divided doses have been used.^a

Adults

Insomnia and Anxiety

Anxiety

Oral

30–120 mg daily.^c

Insomnia

Oral

100–320 mg.^c

100–320 mg.^c ^d

Drug Withdrawal

Oral

30-mg dose for each 100- to 200-mg dose of the barbiturate or nonbarbiturate hypnotic that the patient has been taking daily, administered in 3 or 4 divided doses.^a If the patient shows signs of withdrawal on the first day, a loading dose of 100–200 mg of phenobarbital sodium may be administered IM in addition to the oral dose.^a

After stabilization on phenobarbital sodium, decrease the total daily dose of phenobarbital sodium by 30 mg per day.^a After withdrawal symptoms are relieved, gradually decrease dosage and withdraw completely over a 2-week period.^a

Surgery

IM

100–200 mg given 60–90 minutes before surgery.^a ^d

Seizure Disorders

Oral

100–300 mg daily,^b ^c usually at bedtime.^b

Status Epilepticus

IV or IM

20–320 mg; repeat in 6 hours, if necessary.^d Alternatively, 200–600 mg; allow up to 30 minutes for maximum anticonvulsant effect before administering additional doses (to prevent overdosage).^b

Some clinicians administer phenobarbital sodium IV until seizures stop or a total dose of 20 mg/kg has been given.^a ^b Discontinue IV injections as soon as the desired effect is obtained.^b

Cholestasis†

Oral

Dosages of 90–180 mg daily in 2 or 3 divided doses have been used.^a

Special Populations

Hepatic Impairment

Dosage reduction recommended in patients with hepatic impairment;^c ^d ^e avoid use in patients with marked hepatic impairment.^c ^d

Renal Impairment

Dosage reduction recommended.^d ^e

Geriatric Patients

Dosage reduction recommended.^d ^e ^f

Cautions for Phenobarbital

Contraindications

Known hypersensitivity to any barbiturates.^c ^d

Respiratory disease in which dyspnea or obstruction is evident.^c ^d

Marked impairment of hepatic function.^c ^d

History of manifest or latent porphyria^c ^d (due to potential for exacerbation of acute intermittent porphyria or porphyria variegata).^f

Previous addiction to sedative and/or hypnotic drugs.^c ^d

Warnings/Precautions

Warnings

Pain Reaction

Potential for paradoxical excitement and/or euphoria, restlessness, or delirium in patients with severe pain.^f Barbiturates could mask important symptoms in patients with acute or chronic pain.^d ^f Use with caution in such patients.^d ^f Should not be used to relieve pain or to produce sedation or sleep in the presence of uncontrolled pain.^c ^f

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence.^c ^d (See Contraindications under Cautions.)

WIthdrawal Effects

Abrupt cessation after prolonged use in dependent individuals may result in withdrawal symptoms (e.g., delirium, convulsions) and potentially be fatal.^c ^d Drug must be withdrawn gradually in patients receiving excessive dosages over extended periods of time.^d

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.^c ^d

Concurrent use of other CNS depressants may potentiate CNS depression.^c ^d (See Specific Drugs under Interactions.)

Respiratory and Cardiovascular Effects

Possible respiratory depression, apnea, laryngospasm, hypertension, or vasodilation and hypotension, particularly if phenobarbital is administered IV too rapidly.^d ^f Administer slowly; personnel and equipment should be readily available for administration of artificial respiration.^d ^f

Sensitivity Reactions

Dermatologic Effects and Hypersensitivity Reactions

Exfolative dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), sometimes fatal, reported rarely.^b ^c ^d Because skin eruptions can precede potentially fatal reactions, discontinue phenobarbital whenever dermatologic reactions occur.^d ^f

Hypersensitivity reactions (e.g., localized swelling, particularly of the eyelids, cheeks, or lips; erythematous dermatitis) may occur, particularly in patients with a history of asthma, urticaria, or angioedema.^c

General Precautions

Intra-arterial Injection

Inadvertent intra-arterial administration can cause spasm and severe pain along the affected artery, resulting in local reactions varying in severity from transient pain to gangrene.^d

Discontinue injection if the patient complains of pain or if signs of inadvertent intra-arterial injection (e.g., patches of discolored skin, a white hand with cyanosed skin, delayed onset of action) occur.^b ^d Appropriate therapy for such inadvertent injection has not been fully established; consult manufacturers’ labeling for current recommendations.^b ^d

Suicide

Use with caution, if at all, in depressed patients; potential for suicidal tendencies.^c ^d ^f Prescribe drug in the smallest feasible quantity.^c

Concomitant Diseases

Use parenterally with extreme caution in debilitated patients or patients with severe hepatic impairment, pulmonary or cardiac disease, status asthmaticus, uremia, or shock.^d ^f

Specific Populations

Pregnancy

Tablets: Category B.^c Injection: Category D.^d

Barbiturates have caused postpartum hemorrhage and hemorrhagic disease in neonates; readily reversible with vitamin K therapy.^f ⁱ

Possible withdrawal symptoms in neonates born to women who received barbiturates throughout the last trimester of pregnancy.^f Premature neonates are particularly susceptible to the depressant effects of barbiturates.^f

Lactation

Distributed into milk; use with caution.^c ^d

Pediatric Use

May produce paradoxical excitement and hyperactivity or exacerbate existing hyperactivity; if severe, substitute another barbiturate or therapeutic agent.^b

Possible behavioral (e.g., hyperactivity, fussiness, lethargy, disturbed sleep, irritability, disobedience, stubbornness, depressive symptoms) or cognitive effects (e.g., deficits on neuropsychiatric tests, impaired short-term memory and memory concentration tasks) associated with anticonvulsant use.^d ⁱ If such changes occur and alternative causes are not readily evident, consider the possibility that anticonvulsant therapy may be responsible and the need for dosage reduction or substitution of alternative anticonvulsant(s).ⁱ

Phenobarbital sodium injection contains benzyl alcohol.^d Manufacturer does not recommend use in neonates;^d AAP states that the presence of small amounts of this preservative in a commercially available injection should not proscribe its use when indicated in neonates.^h

Geriatric Use

Possible increased sensitivity to barbiturates.^d Geriatric patients may frequently react to barbiturates with excitement, confusion, or depression.^c ^f

Hepatic Impairment

Use with caution; should not be used in patients with marked hepatic impairment.^c ^d (See Contraindications under Cautions.)

Renal Impairment

Use with extreme caution in patients with nephritis.^b ^d Use parenterally with extreme caution in patients with uremia.^d ^f

Common Adverse Effects

Residual sedation, drowsiness, lethargy, vertigo, nausea, vomiting, headache.^c ^d ^f

Interactions for Phenobarbital

Metabolized by hepatic microsomal enzymes.^d Induces hepatic microsomal enzymes.^c ^d

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral (e.g., warfarin)	Possible decreased plasma warfarin concentrations^c ^d	Monitor PT; adjust anticoagulant dosage as necessary, especially with initiation or discontinuance of phenobarbital^c ^f
Antidepressants, tricyclics	Antidepressant may precipitate seizures, resulting in decreased seizure controlⁱ Potentiation of respiratory depression following toxic doses of tricyclic antidepressantsⁱ	Monitor epileptic patients for decreased seizure control following initiation of antidepressant therapy; adjust phenobarbital dosage, if necessaryⁱ
CNS depressants (e.g., sedatives, hynotics, antihistamines, tranquilizers, alcohol)	Possible additive depressant effects^c ^d
Contraceptives, oral	Possible enhanced metabolism of estrogenic and progestinic components; potential for decreased oral contraceptive effectiveness and increased risk of pregnancy with phenobarbital pretreatment or concurrent therapy^d	Consider alternate methods of contraception^d
Corticosteroids	Possible increased corticosteroid metabolism^d	Dosage adjustment of corticosteriod may be required;^d closely monitor asthmatics receiving corticosteroids when phenobarbital is initiatedⁱ
Doxycycline	Possible decreased half-life of doxycycline; effect may persist up to 2 weeks after discontinuance of phenobarbital^d	If possible, avoid concomitant administration;^f if administered concomitantly, monitor clinical response to doxycycline^d
Griseofulvin	Possible decreased griseofulvin absorption, resulting in decreased blood concentrations^d	Avoid concomitant administration;^d if concomitant therapy is necessary, administration of griseofulvin in 3 divided daily doses may improve absorption.^f Monitor blood griseofulvin concentrations and increase dosage, if necessary^f
MAO inhibitors	Possible prolongation of phenobarbital effects^d	Dosage adjustment of phenobarbital may be required^f
Phenytoin	Increased, decreased, or no change in plasma phenytoin concentrations reported^d ⁱ	Monitor plasma concentrations of phentoin and phenobarbital; adjust dosages as necessary^d ⁱ
Valproic acid	Possible increased plasma phenobarbital concentrations^d	Monitor plasma phenobarbital concentrations and adjust dosage as needed^d

Phenobarbital Pharmacokinetics

Absorption

Bioavailability

Slowly absorbed from GI tract following oral administration,^b with peak plasma concentrations usually attained within 8–12 hours and peak brain concentrations in 10–15 hours.^b

Following IV administration, ≥15 minutes may be required to reach peak brain concentrations.^d

Onset

Following oral administration, onset occurs within 30 minutes.^c

Following IV administration, onset occurs within 5 minutes, with maximum CNS depression occurring ≥15 minutes after administration.^b ^d Onset is slower following IM administration.^b ^d

Duration

About 5–6 hours^c or 4–6 hours^d following oral or parenteral administration, respectively.

Plasma Concentrations

Plasma concentrations of 10–25 mcg/mL associated with anticonvulsant activity in most patients.^d Concentrations >50 mcg/mL may produce coma; concentrations >80 mcg/mL are potentially lethal.^b

Distribution

Extent

Rapidly distributed to all tissues and fluids, with high concentrations in the brain, liver, and kidneys.^d

Crosses the placenta and is distributed into milk.^d

Plasma Protein Binding

20–45%.^b

Elimination

Metabolism

Metabolized primarily by hepatic microsomal enzymes.^d

Elimination Route

Excreted prinicipally in urine (25–50% as unchanged drug).^d

Half-life

Adults: 53–118 hours.^d

Children and neonates: 60–180 hours.^d

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C.^c Protect from moisture.^c

Elixir

Tight containers at 20–25°C.^e

Parenteral

Injection

15–30°C.^d

Compatibility

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

Parenteral

Solution Compatibility^HID

Compatible
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose–Ringer’s injection combinations
Dextrose–Ringer’s injection, lactated, combinations
Dextrose–saline combinations
Dextrose 2.5, 5, or 10% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Invert sugar 5 and 10% in sodium chloride 0.9%
Invert sugar 5 and 10% in water
Ionosol products
Ringer’s injection
Ringer’s injection, lactated
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M
Incompatible
Alcohol 5%, dextrose 5%

Drug Compatibility

Admixture CompatibilityHID
Compatible
Amikacin sulfate
Aminophylline
Calcium chloride
Calcium gluconate
Colistimethate sodium
Dimenhydrinate
Meropenem
Polymyxin B sulfate
Thiopental sodium
Verapamil HCl
Incompatible
Chlorpromazine HCl
Ephedrine sulfate
Hydralazine HCl
Hydrocortisone sodium succinate
Hydroxyzine HCl
Meperidine HCl
Morphine sulfate
Norepinephrine bitartrate
Pentazocine lactate
Procaine HCl
Prochlorperazine mesylate
Promethazine HCl
Streptomycin sulfate
Vancomycin HCl

Y-site CompatibilityHID
Compatible
Doxapram HCl
Enalaprilat
Fentanyl citrate
Fosphenytoin sodium
Levofloxacin
Linezolid
Meropenem
Methadone HCl
Morphine sulfate
Propofol
Sufentanil citrate
Incompatible
Amphotericin B cholesteryl sulfate complex
Lansoprazole
Variable
Hydromorphone HCl

ActionsActions

CNS effects appear to be related, at least partially, to the drug’s ability to enhance activity of GABA, the principal inhibitory neurotransmitter in the CNS,¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ by altering inhibitory synaptic transmissions that are mediated by GABA_A receptors.¹⁰⁵ ¹⁰⁶ ¹⁰⁸

Capable of producing all levels of CNS depression—from mild sedation to hypnosis to deep coma to death.^c ^d

Anticonvulsant effects of barbiturates are multiple and rather nonselective.ⁱ Principal mechanism of action appears to be reduction of monosynaptic and polysynaptic transmission resulting in decreased excitability of the entire nerve cell; barbiturates also increase the threshold for electrical stimulation of the motor cortex.ⁱ

Barbiturates lower serum bilirubin concentrations in neonates and patients with congenital nonhemolytic unconjugated hyperbilirubinemia, presumably by induction of glucuronyl transferase, the enzyme that conjugates bilirubin.^f

Advice to Patients

Potential for phenobarbital to impair mental alertness or physical coordination; do not drive or operate machinery until effects on individual are known.^c ^d

Importance of taking exactly as prescribed; do not exceed the recommended dosage.^c ^d

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.^c ^d Importance of avoiding alcohol while taking the drug.^c ^d

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^c ^d

Importance of advising patients of other important precautionary information.^c ^d (See Cautions.)

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drugs.

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

Phenobarbital
Routes	Dosage Forms	Strengths
Oral	Elixir	20 mg/5 mL C-IV*
	Tablets	15 mg*
		16 mg C-IV*
		30 mg C-IV*
		32 mg C-IV*
		60 mg C-IV*
		65 mg C-IV*
		100 mg C-IV*

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

Phenobarbital Sodium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	30 mg/mL*	Phenobarbital Sodium Injection ( C-IV; with alcohol 10% and propylene glycol 75%)	Wyeth
		60 mg/mL*	Phenobarbital Sodium Injection ( C-IV; with alcohol 10% and propylene glycol 75%)	Wyeth
		65 mg/mL*	Phenobarbital Sodium Injection ( C-IV; with alcohol 10% benzyl alcohol 1.5% and propylene glycol 67.8%)	Baxter
		130 mg/mL*	Luminal Sodium ( C-IV; with alcohol 10% and propylene glycol 67.8%)	Sanofi-Aventis
			Phenobarbital Sodium Injection ( C-IV; with alcohol 10% and propylene glycol 75%)	Wyeth
			Phenobarbital Sodium Injection ( C-IV; with alcohol 10% benzyl alcohol 1.5% and propylene glycol 67.8%)	Baxter

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.

PHENobarbital 16.2MG Tablets (QUALITEST): 100/$12.99 or 300/$16.98

PHENobarbital 20MG/5ML Elixir (QUALITEST): 473/$26.96 or 1419/$79.29

PHENobarbital 32.4MG Tablets (QUALITEST): 100/$11.99 or 200/$14.98

PHENobarbital 64.8MG Tablets (QUALITEST): 100/$12.99 or 200/$15.98

PHENobarbital 97.2MG Tablets (QUALITEST): 100/$12.99 or 200/$19.96

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 April 2010. 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. Jones-Pharma. Brevital sodium (methohexital sodium) for injection prescribing information (dated 2001 Mar 28). In: Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:1815-17.

103. Abbott. Pentothal thiopental sodium for injection prescribing information. North Chicago, IL; 1993 Nov.

104. Carmichael FJ, Haas DA. General Anesthetics. In: Kalant H and Roschlau WHE, eds. Principles of Medical Pharmacology. 6th edition. New York: Oxford University Press; 1998:278-92.

105. Evers AS, Crowder CM. General Anesthetics. In: Hardman JG, Gilman AG, Limbird LE, eds Goodman and Gilman’s The pharmacological basis of therapeutics. 10th ed. McGraw-Hill; 2001: 337-44.

106. Donnelly AJ, Shafer AL. Perioperative care. In: Young LL, Koda-Kimble MA, eds. Applied Therapeutics: The clinical use of drugs. 6th ed. Vancouver WA: Applied Therapeutics, Inc.; 1995:8-1-8-24.

107. Tanelian DL, Kosek P, Mody I et al. The role of the GABA_A receptor/chloride channel complex in anesthesia. Anesthesiology. 1993; 78:757-76. [IDIS 316350] [PubMed 8385426]

108. Hales TG, Olsen RW. Basic pharmacology of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED, eds. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:295-306.

a. AHFS Drug Information 2004. McEvoy GK, ed. Phenobarbital . Bethesda, MD: American Society of Health-System Pharmacists; 2004:2370-1.

b. AHFS Drug Information 2004. McEvoy GK, ed. Phenobarbital. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2108-9.

c. West-ward Pharmaceutical Corp. Phenobarbital tablets prescribing information. Eatontown, NJ; 2001 Jan.

d. Elkins-Sinn, Inc. Phenobarbital Sodium injection prescribing information. Cherry Hill, NJ; 2002 Apr.

e. Pharmaceutical Associates, Inc. Phenobarb elixir prescribing information. Greenville, NC; 2000 Apr.

f. AHFS Drug Information 2004. McEvoy GK, ed. Barbiturate general statement . Bethesda, MD: American Society of Health-System Pharmacists; 2004:2363-6.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1331-5.

h. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356 8.

i. AHFS Drug Information 2004. McEvoy GK, ed. Anticonvulsants general statement . Bethesda, MD: American Society of Health-System Pharmacists; 2004:2102-7.

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Hyperbilirubinemia
Insomnia
Sedation
Seizures

estramustine

Generic Name: estramustine (ES tra MUS teen)

Brand Names: Emcyt

What is estramustine?

Estramustine is a cancer medication that interferes with the growth of cancer cells and slows their growth and spread in the body.

Estramustine is used to treat metastatic or progressive prostate cancer.

Estramustine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about estramustine?

You should not use this medication if you are allergic to estramustine, or if you have a blood clot, swelling of a vein caused by a blood clot, or if you have ever had an allergic reaction to estradiol or nitrogen mustard.

Before taking estramustine, tell your doctor if you have a history of stroke or heart attack, diabetes, heart disease, high blood pressure, migraine headaches, seizures, liver or kidney disease, or Paget's disease.

Take estramustine on an empty stomach, at least 1 hour before or 2 hours after a meal. Do not take this medication with milk, milk products, or calcium-rich foods such as ice cream, yogurt, broccoli, and others. Also avoid using antacids or vitamin/mineral supplements that contain calcium. Calcium can make it harder for your body to absorb estramustine, which could make it less effective.

If a man fathers a child while taking estramustine, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Ask your doctor how long you should continue using condoms after you stop taking estramustine.

What should I discuss with my healthcare provider before taking estramustine?

You should not use this medication if you are allergic to estramustine, or if you have:

a blood clot;

swelling of a vein caused by a blood clot; or

if you have ever had an allergic reaction to estradiol or nitrogen mustard.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely take estramustine:

a history of blood clot, stroke, or heart attack;

diabetes;

high blood pressure (hypertension);

heart disease or coronary artery disease (atherosclerosis);

congestive heart failure;

migraine headaches;

epilepsy or other seizure disorder;

liver disease;

kidney disease; or

a metabolic bone disease (such as Paget's disease).

How should I take estramustine?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Take estramustine on an empty stomach, at least 1 hour before or 2 hours after a meal. Take this medication with water, not with milk or other dairy products.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your blood pressure may also need to be checked. Do not miss any scheduled appointments.

This medication can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you are using estramustine.

Store estramustine capsules in the refrigerator and do not allow it to freeze.

See also: Estramustine dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include swelling, shortness of breath, chest pain, or sudden numbness in any part of your body.

What should I avoid while taking estramustine?

Do not take this medication with milk, milk products, or calcium-rich foods such as ice cream, yogurt, broccoli, and others. Also avoid using antacids or vitamin/mineral supplements that contain calcium. Calcium can make it harder for your body to absorb estramustine, which could make it less effective.

Estramustine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using estramustine and call your doctor at once if you have a serious side effect such as:

chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

sudden numbness or weakness, especially on one side of the body;

sudden headache, confusion, problems with vision, speech, or balance;

chest pain, sudden cough, wheezing, rapid breathing, fast heart rate;

pain or swelling in one or both legs;

feeling short of breath, even with mild exertion;

swelling, rapid weight gain; or

easy bruising.

Less serious side effects may include:

nausea, loss of appetite, diarrhea, upset stomach;

feeling weak or tired;

breast swelling or tenderness; or

impotence.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Estramustine Dosing Information

Usual Adult Dose for Prostate Cancer:

Initial Dose: 14 mg per kg daily, given in 3 or 4 divided doses.

Patients should be treated for thirty to ninety days before the physician determines the possible benefits of continued therapy. Therapy should be continued as long as the favorable response lasts. Some patients have been maintained on therapy for more than three years at doses ranging from 10 to 16 mg per kg of body weight per day.

Patients should be instructed to take estramustine capsules at least 1 hour before or 2 hours after meals. Estramustine capsules should be swallowed with water. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with estramustine.

What other drugs will affect estramustine?

There may be other drugs that can interact with estramustine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More estramustine resources

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

estramustine Advanced Consumer (Micromedex) - Includes Dosage Information

Estramustine MedFacts Consumer Leaflet (Wolters Kluwer)

Emcyt Prescribing Information (FDA)

Emcyt Monograph (AHFS DI)

Compare estramustine with other medications

Prostate Cancer

Where can I get more information?

Your doctor or pharmacist can provide more information about estramustine.

See also: estramustine side effects (in more detail)

Saturday, 28 April 2012

History, Nephrolithiasis Medications

There are currently no drugs listed for "History, Nephrolithiasis".

Definition of History, Nephrolithiasis:

The presence of calculi in the kidney or collecting system.

The calculi are usually small (2-12mm) solid, crystalline, concretions that develop in the kidney and eventually pass through the genitourinary tract. Stones may be composed of calcium, phosphate or uric acid.

Drug List:

Friday, 27 April 2012

Mengivac A+C (Sanofi Pasteur MSD Limited)

1. Name Of The Medicinal Product

Mengivac A+C^®

Meningococcal Polysaccharide Vaccine BP

2. Qualitative And Quantitative Composition

Each 0.5 millilitre dose of vaccine contains:

Active Ingredients:

Neisseria meningitidis serogroup A polysaccharide……………50 micrograms

Neisseria meningitidis serogroup C polysaccharide……………50 micrograms

3. Pharmaceutical Form

Lyophilised powder for injection following reconstitution with isotonic buffered diluent.

4. Clinical Particulars

4.1 Therapeutic Indications

Active immunisation against meningococcal meningitis caused by N.meningitidis serogroups A and C.

a. Travel: Vaccination should be offered to travellers visiting parts of the world where the risk of contracting meningococcal meningitis is high. These regions include countries within the African meningitis belt (countries whose borders are between The Equator and latitude 15° North), parts of the Middle East and parts of the Indian Sub-Continent.

b. Contacts of cases: Family members and close contacts of disease cases of group A and group C meningococcal meningitis should be immunised. The vaccine does not protect against group B disease.

c. Local outbreaks: To help control local outbreaks of meningococcal group A and group C disease, vaccination may be recommended by appropriate Public Health Authorities.

Post vaccination immunity lasts at least 3 years.

4.2 Posology And Method Of Administration

Administer by deep subcutaneous or intramuscular injection.

Adults, elderly and children over 18 months of age: a single dose of 0.5 millilitre of reconstituted vaccine.

Children under 18 months of age: Mengivac A+C^® should not generally be given to children under 18 months except during epidemics (see Section 4.4).

4.3 Contraindications

Hypersensitivity to the vaccine or any component of the vaccine.

Vaccination should be delayed in the presence of acute infectious illness.

4.4 Special Warnings And Precautions For Use

As with any vaccine, appropriate medical treatment, including epinephrine (adrenaline) should be readily available for immediate use in case of anaphylactic reaction following injection.

Mengivac A+C^® confers protection against meningitis caused by meningococci of serogroups A and C. Immunisation does not protect against meningococci of other serogroups or against meningitis caused by other organisms.

Mengivac A+C^® should not generally be given to children under 18 months except during epidemics. Clinical data has confirmed the efficacy of the A component over 3 months of age. The response to the C component is only transitory but can be of limited value during a severe epidemic.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No studies have been performed in pregnant animals. There is insufficient data in humans to recommend the use of the vaccine in pregnancy and lactation unless the benefit outweighs the risk, e.g. in the event of an epidemic.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The adverse reactions reported during clinical trials and post-marketing surveillance studies were generally mild and transient.

Local reactions at the injection site: Transient local pain sometimes associated with oedema or erythema are reported. More severe local reactions are uncommon.

Systemic adverse events: Allergic-type reactions (urticaria, erythematous rash), fever, headache, myalgia or arthralgia and gastro-intestinal disorders are very rarely observed. Exceptionally, more severe hypersensitivity reactions such as anaphylaxis were reported. Very rare cases of neurological reactions (paraesthesia, meningism, convulsions or blurred vision) were observed. No causal relationship with the vaccine could be established.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mengivac A+C^® contains purified polysaccharides from Neisseria meningitidis serogroups A and C, and confers protection against meningococcal meningitis caused by N. meningitidis serogroup A and serogroup C.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

No further information.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months when stored between +2ºC and +8ºC.

6.4 Special Precautions For Storage

Store between +2ºC and +8ºC. Do not freeze diluent.

6.5 Nature And Contents Of Container

Lyophilised vaccine	single or multidose (ten dose) type 1 glass vial with a siliconised rubber stopper and aluminium overcap.
Diluent	single dose prefilled syringe (type 1 glass) or multidose type 1 glass vial.

6.6 Special Precautions For Disposal And Other Handling

After reconstitution, use within one hour. Shake well immediately before use.

7. Marketing Authorisation Holder

Aventis Pasteur MSD Limited

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire

SL6 1QP

8. Marketing Authorisation Number(S)

PL 6745/0048 - Lyophilised vaccine

PL 6745/0029 - Diluent

9. Date Of First Authorisation/Renewal Of The Authorisation

7 February 1994

10. Date Of Revision Of The Text

March 2000

11. LEGAL CATEGORY

POM

^® Registered trademark

4006241/MGV/RA271/0300/A

Wednesday, 25 April 2012

Polaramine

Generic Name: dexchlorpheniramine (dex klor fen IR a meen)

Brand Names: Polaramine

What is Polaramine (dexchlorpheniramine)?

Dexchlorpheniramine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in your body.

Dexchlorpheniramine is used to treat sneezing; runny nose; itching, watery eyes; hives; rashes; itching; and other symptoms of allergies and the common cold.

Dexchlorpheniramine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Polaramine (dexchlorpheniramine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Dexchlorpheniramine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking dexchlorpheniramine. Do not crush, chew, or break any timed-release forms of dexchlorpheniramine. Swallow them whole. They are specially formulated to release slowly into your body.

Who should not take Polaramine (dexchlorpheniramine)?

Do not take dexchlorpheniramine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A very dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

glaucoma or increased pressure in the eye;

a stomach ulcer;

an enlarged prostate, bladder problems, or difficulty urinating;

an overactive thyroid (hyperthyroidism);

hypertension or any type of heart problems; or

asthma.

You may not be able to take dexchlorpheniramine, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

Dexchlorpheniramine is in the FDA pregnancy category B. This means that it is not likely to harm an unborn baby. Do not take dexchlorpheniramine without first talking to your doctor if you are pregnant. Infants are especially sensitive to the effects of antihistamines, and serious side effects could occur in a nursing baby. Dexchlorpheniramine is not recommended if you are breast-feeding a baby. Do not take dexchlorpheniramine without first talking to your doctor if you are nursing a baby. If you are over 60 years of age, you may be more likely to experience side effects from dexchlorpheniramine. You may require a lower dose of this medication.

How should I take Polaramine (dexchlorpheniramine)?

Take dexchlorpheniramine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Dexchlorpheniramine can be taken with or without food.

Do not crush, chew, or break any timed-release forms of dexchlorpheniramine. Swallow them whole. They are specially formulated to release slowly into your body.

To ensure that you get a correct dose, measure the syrup form of dexchlorpheniramine with a special dose-measuring spoon or cup, not with a regular tablespoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Never take more of this medication than is prescribed for you. The regular-release tablets and the syrup are usually taken every 4 to 6 hours as needed (four to six times a day). The timed-release tablets and capsules are usually taken every 8 to 10 hours as needed (two or three times a day).

Store dexchlorpheniramine at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take a double dose of this medication unless otherwise directed by your doctor.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a dexchlorpheniramine overdose include extreme sleepiness, confusion, weakness, ringing in the ears, blurred vision, large pupils, dry mouth, flushing, fever, shaking, insomnia, hallucinations, and possibly seizures.

What should I avoid while taking Polaramine (dexchlorpheniramine)?

Polaramine (dexchlorpheniramine) side effects

Stop taking dexchlorpheniramine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take dexchlorpheniramine and talk to your doctor if you experience

sleepiness, fatigue, or dizziness;

headache;

dry mouth; or

difficulty urinating or an enlarged prostate.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Polaramine (dexchlorpheniramine)?

Talk to your pharmacist before taking other over-the-counter cough, cold, allergy, or insomnia medications. These products may contain medicines similar to dexchlorpheniramine, which could lead to an antihistamine overdose.

Before taking this medication, tell your doctor if you are taking any of the following medicines:

anxiety or sleep medicines such as alprazolam (Xanax), diazepam (Valium), chlordiazepoxide (Librium), temazepam (Restoril), or triazolam (Halcion);

medications for depression such as amitriptyline (Elavil), doxepin (Sinequan), nortriptyline (Pamelor), fluoxetine (Prozac), sertraline (Zoloft), or paroxetine (Paxil); or

any other medications that make you feel drowsy, sleepy, or relaxed.

Drugs other than those listed here may also interact with dexchlorpheniramine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Polaramine resources

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

Dexchlorpheniramine Prescribing Information (FDA)

Dexchlorpheniramine Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Polaramine with other medications

Allergic Reactions
Hay Fever

Where can I get more information?

Your pharmacist has more information about dexchlorpheniramine written for health professionals that you may read.

See also: Polaramine side effects (in more detail)

Tuesday, 24 April 2012

Pentagastrin Injection BP (Cambridge Laboratories)

1. Name Of The Medicinal Product

Pentagastrin Injection BP

2. Qualitative And Quantitative Composition

Pentagastrin BP 0.025% w/v

3. Pharmaceutical Form

Solution for Injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Pentagastrin Injection BP is used for the diagnostic testing of gastric secretion.

4.2 Posology And Method Of Administration

For administration either subcutaneously or by continuous intravenous infusion.

Adults (including the elderly) and Children

The following procedure is adopted for testing gastric secretion with Pentagastrin Injection BP:

The patient receives no medication (eg. antacids, etc.) that might affect the results of the test for 24 hours and no food for 12 hours before the test. On the morning of the test a radio-opaque tube (Leven no. 7 or Ryles`s 12 – 16Fr.) is passed into the patients by the way of the nose. Radiological observation is used to ensure that the tube is correctly positioned in the lower part of the body of the stomach.

The tube is securely fastened to the patient`s nose and forehead with adhesive tape to ensure that it is not displaced. The patient lies on his left side.

The gastric juices are then collected by applying continuous suction (at 30-50 mm Hg below atmospheric pressure) to this tube, supplemented by manual suction. The patient takes occasional deep breaths to improve collection. The basal secretion is obtained by collecting samples at 15 minute intervals over an hour.

Pentagastrin Injection BP is then given, either at a dose of:

(a) 6 micrograms/kg bodyweight subcutaneously, or

(b) 0.6 micrograms/kg/hour as a continuous intravenous infusion. A tuberculin syringe is used to give a dose correct to 0.01 ml.

If dilution is required normal saline may be used.

Specimens of the gastric juices are again collected over periods of 10 or 15 minutes. The volume of the sample is measured and it is immediately filtered through gauze into a bottle. The acidity of each sample is determined by titration.

4.3 Contraindications

When the patient has previously shown a severe idiosyncratic response to the drug, Pentagastrin Injection BP should not be administered.

4.4 Special Warnings And Precautions For Use

As pentagastrin stimulates gastric acid secretion it should be used with caution in patients with acute or bleeding peptic ulcer disease, though there is no clinical evidence to contraindicate use.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Pregnancy: Pentagastrin Injection BP should not be administered during pregnancy.

Lactation: no special precautions are required.

4.7 Effects On Ability To Drive And Use Machines

No precautions are required.

4.8 Undesirable Effects

At the recommended dosage the incidence of side effects is extremely small, although very occasionally an individual may respond with hypotension and associated dizziness and faintness. Other unwanted effects reported are mild abdominal discomfort, abdominal cramps, nausea, vomiting, flushing, sweating, headaches, drowsiness or exhaustion, heaviness or weakness of the legs, allergic reactions, bradycardia, tachycardia, anxiety and panic attacks. These effects disappear once administration of `Pentagastrin Injection BP` has ceased.

4.9 Overdose

The form of presentation makes it unlikely that overdosage will occur, and no such occurrence has been reported. As maximal secretory response is produced by the normal dosage, increased dosage would be expected to have no sequel other than an accentuation of the known side effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pentagastrin is a synthetic pentapeptide containing the carboxyl terminal tetrapeptide responsible for the actions of natural gastrins. The most prominent action of pentagastrin is to stimulate the secretion of gastric acid, pepsin and intrinsic factor. Additonally, it stimulates pancreatic secretion, inhibits absorption of water and electrolytes from the ileum, contracts the smooth muscle of the lower oesophageal sphincter and stomach (but delays gastric emptying time), relaxes the sphincter of Oddi and increases blood flow in the gastric mucosa.

5.2 Pharmacokinetic Properties

Pentagastrin stimulates gastric acid secretion approximately ten minutes after subcutaneous injection, with peak response occurring in most cases twenty to thirty minutes after administration. Duration of activity is usually between sixty and eighty minutes.

Pentagastrin is rapidly absorbed after administration. Pentagastrin has a short half-live (10 minutes or less) in the circulation. It is metabolised primarily in the liver and excretion is mainly by the kidneys.

5.3 Preclinical Safety Data

Pentagastrin is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride Ph.Eur

Water for Injections Ph.Eur

Ammonium bicarbonate BP

N. Ammonia solution } pH Adjustment

N. Hydrochloric acid }

Final Excipient Composition in Solution

Sodium chloride

Water

Ammonium chloride

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store in a refrigerator. Do not freeze. Keep container in the outer carton.

6.5 Nature And Contents Of Container

2 ml glass ampoules in boxes of 5.

6.6 Special Precautions For Disposal And Other Handling

If dilution is required Sodium Chloride Injection BP may be used. This solution should be prepared immediately before it is required for use.

Administrative Data

7. Marketing Authorisation Holder

Cambridge Laboratories Limited

Deltic House

Kingfisher Way

Silverlink Business Park

Wallsend

Tyne & Wear

NE28 9NX

8. Marketing Authorisation Number(S)

PL 12070/0020

9. Date Of First Authorisation/Renewal Of The Authorisation

First authorisation 9/2/73

Renewed 15/10/95

10. Date Of Revision Of The Text

March 2005

Sunday, 22 April 2012

Zetia

Generic Name: Ezetimibe
Class: Cholesterol Absorption Inhibitors
VA Class: CV350
Chemical Name: [3R - [3α(S*),4β]] - 1 - (4 - fluorophenyl) - 3 - [3 - (4 - fluorophenyl) - 3 - hydroxypropyl] - 4 - (4 - hydroxyphenyl) - 2 - azetidinone
Molecular Formula: C₂₄H₂₁F₂NO₃
CAS Number: 163222-33-1

Introduction

Antilipemic agent;¹ cholesterol absorption inhibitor.² ⁴ ⁵ ⁸

Uses for Zetia

Primary Hypercholesterolemia and Mixed Dyslipidemia

Use alone or in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia.¹ ¹² Effects on cardiovascular morbidity and mortality not established.¹

Use in fixed combination with simvastatin (i.e., Vytorin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia.¹²

Use in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia.¹ Effects on cardiovascular morbidity and mortality not established.¹ Use with a fibric acid derivative other than fenofibrate not studied and currently not recommended.¹ (See Specific Drugs under Interactions.)

Produces negligible increases in HDL-cholesterol concentrations.¹ ²

Drug therapy is not a substitute for but an adjunct to nondrug therapies and measures (e.g., dietary management, weight control, physical activity, management of potentially contributory disease), which should be continued when drug therapy is initiated.⁹ ¹⁰ ¹¹

Homozygous Familial Hypercholesterolemia

Use in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available.¹ ¹²

Effects in patients currently undergoing LDL apheresis compared with those in patients not undergoing the procedure not established.⁴ Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) not established.⁴

Homozygous Familial Sitosterolemia (Phytosterolemia)

Adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia.¹ ⁶ ⁸

Reductions in sitosterol and campesterol concentrations were consistent between patients receiving ezetimibe with or without bile acid sequestrants.¹

Effect of reducing plasma concentrations of sitosterol and campesterol on cardiovascular morbidity and mortality not established.¹

Zetia Dosage and Administration

General

Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug.¹

Monitoring during Antilipemic Therapy

Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

Administration

Oral Administration

Administer orally without regard to meals.¹

Combination therapy with a statin or fenofibrate: May administer ezetimibe at same time as the statin or fenofibrate, in accordance with recommended dosing schedule for these drugs.¹

Combination therapy with a bile acid sequestrant: Administer ≥2 hours before or ≥4 hours after bile acid sequestrant.¹

Ezetimibe/simvastatin fixed-combination preparation: Administer orally in the evening without regard to meals.¹²

Dosage

Pediatric Patients

Dyslipidemias

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Homozygous Familial Hypercholesterolemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Homozygous Familial Sitosterolemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Adults

Dyslipidemias

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

10 mg once daily.¹

Ezetimibe/simvastatin fixed combination (Vytorin): Initially, ezetimibe 10 mg/simvastatin 20 mg once daily in the evening.¹² In patients requiring less aggressive LDL-cholesterol lowering, consider dosage of ezetimibe 10 mg/simvastatin 10 mg once daily.¹² In patients requiring LDL-cholesterol reductions ≥55%, may initiate therapy with ezetimibe 10 mg/simvastatin 40 mg once daily.¹² Determine serum cholesterol concentrations ≥2 weeks after initiation of therapy and adjust dosage as needed.¹² Usual maintenance dosage range is ezetimibe 10 mg and simvastatin 10–80 mg once daily.¹²

Homozygous Familial Hypercholesterolemia

Oral

10 mg once daily.¹

Ezetimibe/simvastatin fixed combination (Vytorin): Ezetimibe 10 mg/simvastatin 40 mg or ezetimibe 10 mg/simvastatin 80 mg once daily in the evening.¹² Use as adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.¹²

Homozygous Familial Sitosterolemia

Oral

10 mg once daily.¹

Special Populations

Hepatic Impairment

Ezetimibe

No dosage adjustment needed in patients with mild hepatic impairment.¹ Do not use in patients with moderate or severe hepatic impairment.¹

Ezetimibe/Simvastatin Fixed Combination

No dosage adjustment needed in patients with mild hepatic impairment.¹² Do not use in patients with moderate or severe hepatic impairment.¹²

Renal Impairment

Ezetimibe

No dosage adjustment needed in patients with renal impairment.¹

Ezetimibe/Simvastatin Fixed Combination

No dosage adjustment needed in patients with mild to moderate renal impairment.¹² Do not use in patients with severe renal impairment unless patient has already tolerated treatment with a simvastatin dosage ≥5 mg daily; in such patients, exercise caution and monitor closely.¹²

Geriatric Patients

Ezetimibe

No dosage adjustment needed in geriatric patients (≥65 years of age).¹

Ezetimibe/Simvastatin Fixed Combination

No dosage adjustment needed in geriatric patients (≥65 years of age).¹²

Cautions for Zetia

Contraindications

Known hypersensitivity to ezetimibe or any ingredient in the formulation.¹

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, angioedema, rash, and urticaria reported.¹ ¹²

Major Toxicities

Hepatic Effects

Transient elevations in serum aminotransferase (transaminase) concentrations (i.e., AST, ALT)³ ⁴ >3 times the ULN reported.¹ ¹² Elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹ Hepatitis reported during postmarketing surveillance; however, causal relationship not established.¹ ¹²

When used with a statin, perform liver function tests at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin.¹

Musculoskeletal Effects

Marked (>10 times ULN) elevations of CK (CPK) reported.¹ Elevations in CK concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹

Myalgia, myopathy (i.e., unexplained muscle pain, tenderness, or weakness and CK concentration >10 times ULN), and/or rhabdomyolysis reported during postmarketing experience.¹ ¹² Most cases of rhabdomyolysis occurred in patients receiving statin therapy prior to initiating ezetimibe; however, rhabdomyolysis also reported very rarely following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).¹ ¹²

Immediately discontinue ezetimibe and any concomitant statin or fibric acid derivative (e.g., gemfibrozil, fenofibrate) if myopathy is diagnosed or suspected.¹ ¹²

General Precautions

Combination Therapy with Statins or Fenofibrate

When used in combination or fixed combination with a statin or fenofibrate, consult prescribing information of specific statin or fenofibrate for detailed information on usual cautions, precautions, and contraindications of these drugs.¹ ¹²

Risk of Cancer

Fixed combination of ezetimibe and simvastatin (Vytorin) reported in one trial (Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] study) to be possibly associated with an increased risk of cancer.¹⁵ ¹⁷ Preliminary results of this study in approximately 1900 patients revealed a higher incidence of cancer and fatal cancer in patients receiving fixed-combination preparation (11.1 and 4.1%, respectively) compared with those receiving placebo (7.5 and 2.5%, respectively).¹⁵ ¹⁷ However, interim data from 2 ongoing randomized trials evaluating >20,000 patients with chronic kidney disease or acute coronary syndrome showed no increased risk of cancer following use of fixed-combination preparation.¹⁶ ¹⁷ FDA will review final study report of the SEAS trial to assess additional safety data and provide insight into the risk of cancer.¹⁷

Specific Populations

Pregnancy

Category C.¹

Fixed combination of ezetimibe and simvastatin (Vytorin): Category X (due to simvastatin component).¹²

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use in nursing women not recommended unless potential benefits justify possible risks to infant.¹

Pediatric Use

Safety and efficacy not established in children <10 years of age; use not recommended in these children.¹

Safety and efficacy of ezetimibe/simvastatin fixed-combination preparation not established in pediatric patients.¹²

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹ ¹²

Hepatic Impairment

Safety of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently not known; use not recommended in such patients.¹

Common Adverse Effects

Ezetimibe monotherapy: Back pain,¹ ² arthralgia,¹ ² diarrhea,¹ ³ sinusitis,¹ abdominal pain,¹ ³ coughing,¹ pharyngitis,¹ ⁴ viral infection,¹ fatigue.¹

Ezetimibe in combination with a statin: Upper respiratory tract infection,¹ ² ⁴ ¹² headache,¹ ² ⁴ ¹² back pain,¹ influenza,¹² myalgia,¹² abdominal pain,¹ sinusitis,¹ arthralgia,¹ diarrhea,¹ pharyngitis,¹ pain in extremity,¹² chest pain,¹ ⁴ dizziness.¹

Adverse effects associated with combination therapy generally similar to those reported with monotherapy.¹ However, elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹

Interactions for Zetia

Does not inhibit or induce CYP1A2, 2D6, 2C8, 2C9, or 3A4.¹ Pharmacokinetic interactions with drugs metabolized by these isoenzymes (e.g., caffeine, dextromethorphan, tolbutamide, IV midazolam) unlikely.¹

No formal drug interaction studies performed with fixed-combination preparation.¹² When using this preparation, consider the drug interactions associated with simvastatin.¹²

Specific Drugs

Drug	Interaction	Comments
Antacids	Decreased ezetimibe peak plasma concentrations but no effect on AUC¹
Bile acid sequestrants	Decreased ezetimibe AUC¹	Administer ezetimibe ≥2 hours before or ≥4 hours after bile acid sequestrant¹
Caffeine	Pharmacokinetic interaction unlikely¹
Cimetidine	Pharmacokinetic interaction unlikely¹
Cyclosporine	Increased ezetimibe and cyclosporine concentrations; possible greater ezetimibe exposure in patients with severe renal impairment ¹ ¹² Increased risk of myopathy/rhabdomyolysis when used concomitantly with fixed-combination preparation of ezetimibe and simvastatin (particularly at higher dosages)¹²	Use concomitantly with caution;¹ monitor cyclosporine concentrations with concomitant use¹ Do not administer fixed-combination preparation unless patient has already tolerated simvastatin dosage ≥5 mg daily.¹² If used concomitantly, dosage of fixed-combination preparation should not exceed ezetimibe 10 mg/simvastatin 10 mg once daily¹²
Dextromethorphan	Pharmacokinetic interaction unlikely¹
Digoxin	Pharmacokinetic and pharmacologic interaction unlikely¹
Fat-soluble vitamins	Pharmacokinetic interaction with vitamins A, D, and E unlikely¹ ⁸
Fibric acid derivatives (fenofibrate, gemfibrozil)	Increased plasma concentrations of ezetimibe¹ Ezetimibe associated with increased cholesterol excretion in gall bladder bile;¹ fibric acid derivatives may increase cholesterol excretion in bile, leading to cholelithiasis¹ Cholecystectomy reported¹ Very rare postmarketing reports of myopathy/rhabdomyolysis with concomitant use¹	Concomitant use with a fibric acid derivative other than fenofibrate currently not recommended¹ (see Musculoskeletal Effects under Cautions) If concomitant use with gemfibrozil cannot be avoided, manufacturer states that dosage of fixed-combination preparation should not exceed ezetimibe 10 mg/simvastatin 10 mg once daily¹² If cholelithiasis is suspected during concomitant use with fenofibrate, perform gallbladder studies and consider alternative antilipemic therapy¹
Glipizide	Pharmacokinetic interaction unlikely¹
HMG-CoA reductase inhibitors (statins) (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)	Pharmacokinetic interaction unlikely¹ ³ ⁵ Rare postmarketing reports of myopathy/rhabdomyolysis with concomitant use¹	Monitor liver function according to recommendations for statin with concomitant use¹ Discontinue ezetimibe and any concomitant statin if myopathy diagnosed or suspected¹ (see Musculoskeletal Effects under Cautions)
Midazolam (IV)	Pharmacokinetic interaction unlikely¹
Oral contraceptives	Pharmacokinetic interaction unlikely¹
Tolbutamide	Pharmacokinetic interaction unlikely¹
Warfarin	Pharmacokinetic and pharmacologic interaction unlikely based on one study¹ ⁸ ¹² Increased INR with combined ezetimibe-warfarin therapy reported during post-marketing experience; most patients also on other drugs¹ ¹²	Monitor INR appropriately if ezetimibe is initiated in a patient receiving warfarin¹

Zetia Pharmacokinetics

Absorption

Bioavailability

Approximately 93% of dose is absorbed systemically following oral administration.¹

Bioavailability is variable.¹ Absolute bioavailability cannot be determined because ezetimibe is virtually insoluble in aqueous media suitable for injection.¹ Ezetimibe/simvastatin fixed-combination preparation is bioequivalent to corresponding dosages of the individual components.¹²

Peak plasma concentrations attained within 4–12 hours following oral administration.¹

Onset

Maximal or near-maximal reductions in serum lipoprotein and apolipoprotein concentrations achieved within 2 weeks.¹ ² ⁸

Duration

Reductions in serum lipoprotein and apolipoprotein concentrations maintained during continued therapy.¹ ² ⁸

Food

Food (high-fat or nonfat meals) does not affect extent of absorption.¹ High-fat meals associated with increased peak plasma concentrations.¹

Special Populations

Increased plasma concentrations in geriatric individuals (≥65 years of age), in patients with hepatic impairment, and in patients with severe renal impairment.¹ (See Special Populations under Dosage and Administration.)

No differences in pharmacokinetic parameters between blacks and Caucasians.¹ Studies in Asian individuals indicated similar pharmacokinetics as observed in Caucasian individuals.¹

Distribution

Plasma Protein Binding

>90%.¹

Elimination

Metabolism

Rapidly metabolized principally in small intestine and liver to ezetimibe glucuronide (active).¹ Ezetimibe and ezetimibe glucuronide constitute approximately 10–20% and 80–90%, respectively, of total drug in plasma.¹

Possible enterohepatic recycling.¹

Elimination Route

Excreted in feces (78%) and urine (11%) within 10 days after dosing.¹ Major component in feces is ezetimibe (69% of administered dose); major component in urine is ezetimibe glucuronide (9% of administered dose).¹

Half-life

Approximately 22 hours for both ezetimibe and ezetimibe glucuronide.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

Ezetimibe/simvastatin fixed-combination preparation: Well-closed containers at 20–25°C.¹² When subdividing contents of a large-quantity container, repackage into tightly closed, light-resistant containers; entire contents must be repackaged immediately upon opening.¹²

ActionsActions

Localizes at brush border of small intestine and inhibits absorption of cholesterol,³ ⁴ ⁸ resulting in decreased delivery of intestinal cholesterol to liver.¹ Intestinal absorption of cholesterol reduced by approximately 54% in a limited number of patients with hypercholesterolemia.¹ ⁶

Has been shown to reduce concentrations of noncholesterol sterols,⁸ including sitosterol and campesterol.¹ ⁶

Does not appear to inhibit hepatic cholesterol synthesis or increase bile acid excretion.¹ Does not appear to inhibit absorption of triglycerides, fatty acids, bile acids, progesterone, or ethyl estradiol.¹ No clinically relevant effects on plasma concentrations of fat-soluble vitamins A, D, and E;⁸ does not appear to impair adrenocortical steroid production.¹

Cholesterol-lowering effects of ezetimibe and statins or of ezetimibe and fenofibrate are additive.¹

Advice to Patients

Importance of adherence to prescribed directions for use, particularly when used concomitantly with other antilipemic agents.¹ ¹²

Importance of adherence to National Cholesterol Education Program (NCEP)’s dietary recommendations.⁸

Risk of myopathy; importance of promptly informing clinicians of unexplained muscle pain, weakness, or tenderness.¹ ¹²

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹ ¹²

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹ ¹²

Importance of informing patients of other important precautionary information.¹ ¹² (See Cautions.)

Preparations

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

Ezetimibe
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	10 mg	Zetia	Merck/Schering-Plough

Ezetimibe Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	10 mg with Simvastatin 10 mg	Vytorin	Merck/Schering-Plough
		10 mg with Simvastatin 20 mg	Vytorin	Merck/Schering-Plough
		10 mg with Simvastatin 40 mg	Vytorin	Merck/Schering-Plough
		10 mg with Simvastatin 80 mg	Vytorin	Merck/Schering-Plough

Comparative Pricing

Vytorin 10-10MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$132.53 or 90/$377.15

Vytorin 10-20MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$129.98 or 90/$369.54

Vytorin 10-40MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$128.7 or 90/$378.47

Vytorin 10-80MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$129.98 or 90/$369.54

Zetia 10MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$128.37 or 90/$367.18

Disclaimer

References

1. Merck/Schering-Plough Pharmaceuticals. Zetia (ezetimibe) tablets prescribing information. North Wales, PA; 2006 May.

2. Dujovne CA, Ettinger MP, McNeer JF et al for the Ezetimibe Study Group. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002; 90:1092-7. [IDIS 490188] [PubMed 12423709]

3. Gagne C, Bays HE, Weiss SR et al for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002; 90:1084-91. [IDIS 490187] [PubMed 12423708]

4. Gagne C, Gaudet D, and Bruckert E for the Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002; 105:2469-75. [IDIS 482036] [PubMed 12034651]

5. Kosoglou T, Meyer I, Veltri EP et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol. 2002; 54:309-19. [IDIS 489553] [PubMed 12236852]

6. Sudhop T, Lutjohann D, Kodal A et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002; 106:1943-8. [IDIS 490884] [PubMed 12370217]

7. Ezzet F, Krishna G, Wexler DB et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 2001; 23:871-85. [IDIS 467647] [PubMed 11440287]

8. Merck/Schering-Plough, PA: Personal communication.

9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-23.

10. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, MD: National Institutes of Health. (NIH publication No. 01-3670.)

11. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site.

12. Merck/Schering-Plough. Vytorin (ezetimibe and simvastatin) tablets prescribing information. North Wales, PA; Nov 05.

13. Ballantyne CM, Houri J, Notarbartolo A et al for the Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003; 107:2409-15. [PubMed 12719279]

14. Food and Drug Administration. Vytorin (ezetimibe and simvastatin) tablets [Undated: Merck/Schering-Plough Pharmaceuticals]. Rockville, MD; FDA Action Date October 24, 2006. From Drugs@FDA website.

15. Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-56. [PubMed 18765433]

16. Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008; 359:1357-66. [PubMed 18765432]

17. Food and Drug Administration. Early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia): FDA investigates a report from the SEAS trial. Rockville, MD; 2008 Aug 21. Available from FDA website. Accessed 2008 Oct 9.

18. Food and Drug Administration. Follow-up to the January 25, 2008 early communication about an ongoing data review for ezetimibe/simvastatin (marketed as Vytorin), ezetimibe (marketed as Zetia), and simvastatin (marketed as Zocor). Rockville, MD; 2009 Jan 8. Available from FDA website. Accessed 2009 Sep 10.

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Zetia Prescribing Information (FDA)

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