Lisdexamfetamine Dimesylate

Class: Amphetamines
VA Class: CN801
Chemical Name: (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethly] hexanamide dimethanesulfonate
Molecular Formula: C₁₅H₂₅N₃O (CH₄O₃S)₂
CAS Number: 608137-32-2
Brands: Vyvanse

• Abuse Potential


• 
  

  Amphetamines have a high potential for abuse.¹

  
  


• 
  

  Administration of amphetamines for prolonged periods of time may lead to drug dependence.¹

  
  


• 
  

  Particular attention should be paid to the possibility of individuals obtaining amphetamines for nontherapeutic use or distribution to others, and the drugs should be prescribed or dispensed sparingly.¹

  
  


• 
  

  The possibility that family members may abuse the patient’s medication should be considered.⁵

  
  

• Sudden Death and Serious Cardiovascular Events


• 
  

  Possible sudden death and serious cardiovascular events, particularly in individuals who abuse amphetamines.^{1 6 9} (See Sudden Death and Serious Cardiovascular Events under Cautions.)

  
  

Introduction

Prodrug of dextroamphetamine; noncatechol, sympathomimetic amine with CNS-stimulating activity.^{1 8 28}

Uses for Lisdexamfetamine Dimesylate

Attention Deficit Hyperactivity Disorder

Used as an adjunct to psychological, educational, social, and other remedial measures in the treatment of attention deficit hyperactivity disorder (ADHD) (hyperkinetic disorder, hyperkinetic syndrome of childhood, minimal brain dysfunction).^{1 3 6 7 8 28}

Safety and efficacy established in children 6–12 years of age who met criteria for ADHD (combined type or predominantly hyperactive-impulsive type) and also in adults who met criteria for ADHD.^{1 2 3 4 29 30}

Almost all studies comparing behavioral therapy versus stimulants alone have shown a much stronger therapeutic effect from stimulants than from behavioral therapy, and stimulants (e.g., amphetamines, methylphenidate) remain the drugs of choice for the management of ADHD.^{5 6 7 10 11 12 13 14 15 16 17 18 19 20}

Drug therapy is not indicated in all patients with ADHD, and such therapy should be considered only after a complete evaluation including medical history has been performed.^{1 6 17 18}

Use should depend on age, adequate diagnosis (based on medical, special psychological, educational, and social resources), and the clinician’s assessment of the severity, duration, and frequency of symptoms and should not depend solely on one or more behavioral characteristics.^{1 5 6 17}

Lisdexamfetamine Dimesylate Dosage and Administration

Administration

Oral Administration

Administer once daily in the morning without regard to meals.¹ Because of potential for insomnia, avoid administering in the afternoon.^{1 28 30}

Capsule may be swallowed whole or may be opened and the entire contents dissolved in water immediately prior to administration; resulting solution should not be stored for use at a later time.^{1 28}

Do not subdivide capsule contents; do not administer a dose less than the entire contents of one capsule.¹

Dosage

Available as lisdexamfetamine dimesylate; dosage expressed in terms of the salt.¹

Adjust dosage according to individual response and tolerance; the smallest dose required to produce the desired response should always be used.^{1 6 30}

When possible, therapy should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued treatment.^{1 6}

Pediatric Patients

Attention Deficit Hyperactivity Disorder

Oral

Children 6–12 years of age: Initially, 30 mg once daily (as initial treatment for ADHD or in patients being switched to lisdexamfetamine from other drugs); dosage may be adjusted in 10- or 20-mg increments at weekly intervals; maximum 70 mg daily.^{1 28 30}

If the initial 30-mg daily dosage is not tolerated, dosage may be decreased to 20 mg daily.²⁷

Adults

Attention Deficit Hyperactivity Disorder

Oral

Initially, 30 mg once daily (as initial treatment for ADHD or in patients being switched to lisdexamfetamine from other drugs); dosage may be adjusted in 10- or 20-mg increments at weekly intervals; maximum 70 mg daily.^{1 28}

If the initial 30-mg daily dosage is not tolerated, dosage may be decreased to 20 mg daily.²⁷

Prescribing Limits

Pediatric Patients

Attention Deficit Hyperactivity Disorder

Oral

Children 6–12 years of age: Maximum 70 mg daily.¹

Long-term use (i.e., >4 weeks) has not been studied systematically.¹ If used for long-term therapy, periodically reevaluate the usefulness of the drug.¹

Adults

Attention Deficit Hyperactivity Disorder

Oral

Maximum 70 mg daily.¹

Long-term use (i.e., >4 weeks) has not been studied systematically.¹ If used for long-term therapy, periodically reevaluate the usefulness of the drug.¹

Special Populations

No special population dosage recommendations at this time.¹

Cautions for Lisdexamfetamine Dimesylate

Contraindications

• 
  

  Contraindicated in patients with advanced arteriosclerosis,^{1 5 28} symptomatic cardiovascular disease,^{1 5 28} moderate to severe hypertension,^{1 5 28} hyperthyroidism,^{1 5 28} known hypersensitivity or idiosyncrasy to sympathomimetic amines,^{1 5} glaucoma,^{1 5 28} or a history of drug abuse;^{1 5 28} within 14 days of MAO inhibitor therapy;^{1 5 28} and in agitated patients.^{1 28}

  
  


• 
  

  Although amphetamines generally should not be used in patients with a history of drug abuse,^{1 5} some experts state that this is not an absolute contraindication, provided the patient can be monitored more carefully than would otherwise be indicated.⁵

  
  

Warnings/Precautions

Warnings

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of stimulants; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.^{1 9}

Epidemiologic data suggest a possible association between use of stimulants and sudden unexplained death in healthy children and adolescents.^{31 32 33} FDA unable to conclude that these data affect evaluation of overall risk and benefit of stimulants used to treat ADHD in children and adolescents.³¹ FDA is conducting an ongoing safety review of amphetamines and other stimulants to evaluate possible link between use of these agents and sudden death in children.^{31 32 33} Pediatric patients with ADHD and their parents should avoid discontinuing the child’s use of such stimulants before consulting a clinician.³¹

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).^{1 5 6}

In general, avoid use of CNS stimulants in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.^{1 6 8 9} (See Contraindications under Cautions.)

Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.^{1 28}

Other Warnings and Precautions

Least amount of lisdexamfetamine feasible should be prescribed or dispensed at one time in order to minimize possible overdosage.¹

Effects on BP and Heart Rate

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur.^{1 28} Modest increases not expected to have short-term sequelae; however, monitor all patients for larger changes in BP and heart rate.¹

Caution advised in patients with underlying medical conditions that might be affected by increases in BP or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).¹

Exacerbation or Precipitation of Psychotic Symptoms

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.^{1 5}

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.^{1 6} If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.^{1 6}

Precipitation of Manic Symptoms

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder; use with caution in these patients.¹ Prior to initiating therapy, carefully screen patients with ADHD and comorbid depressive symptoms to identify risk for bipolar disorder; screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, or depression).¹

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.¹ If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.¹

Aggression

Aggressive behavior and hostility (frequently observed in children and adolescents with ADHD) reported in patients receiving drug therapy for ADHD.¹ No systematic evidence that stimulants cause these adverse effects; however, monitor patients beginning treatment for ADHD for onset or worsening of aggressive behavior or hostility.^{1 6}

Growth Suppression

Long-term (i.e., >12 months) administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.^{1 6} Dose-related weight loss reported in children during 4 weeks of therapy with lisdexamfetamine.¹

Manufacturer recommends monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.^{1 6 28} However, AAP states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.⁷

Seizures

Possible lowering of seizure threshold in patients with history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without history of seizures and with no prior evidence of EEG abnormalities.^{1 28} If seizures occur, discontinue therapy.¹

Visual Effects

Visual disturbances (e.g., difficulty with accommodation, blurred vision) reported with stimulants.^{1 28}

Tics

Amphetamines reported to exacerbate motor and phonic tics and Tourette’s syndrome.¹ However, a history of tics or their development during therapy is not an absolute contraindication to continued use.^{1 5 7} Nevertheless, evaluate for presence of tics and Tourette’s syndrome in children and their families prior to initiating stimulant therapy.¹

Other CNS Effects

Amphetamines may impair the ability to engage in potentially hazardous activities (e.g., operating machinery or vehicles).¹

Specific Populations

Pregnancy

Category C.^{1 25}

Risk of prematurity, low birth weight, and withdrawal symptoms (e.g., dysphoria, lassitude, agitation) in infants born to dependent women.^{1 25}

Lactation

Distributed into milk; discontinue nursing or the drug.^{1 25}

Pediatric Use

Safety and efficacy of lisdexamfetamine not established in children 3–5 years of age.¹ Amphetamines not recommended for ADHD in children <3 years of age.^{1 5 6} Not studied to date in adolescents.¹

Aggressive behavior, hostility, and psychotic (e.g., hallucinations, delusional thinking) or manic symptoms reported in children and adolescents receiving stimulants for management of ADHD.¹ (See Warnings under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.¹ Epidemiologic data also suggest a possible association between use of stimulants and sudden death in healthy children and adolescents.^{31 32 33} (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Long-term administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.¹ (See Growth Suppression under Cautions.)

Geriatric Use

Lisdexamfetamine has not been studied in this population.¹

Hepatic Impairment

Not specifically studied in hepatic impairment.²⁷

Renal Impairment

Not specifically studied in renal impairment.²⁷

Common Adverse Effects

Children 6–12 years of age: Decreased appetite,^{1 6 28 29 30} insomnia,^{1 6 28 29 30} upper abdominal pain,^{1 28 30} irritability,^{1 6 28 30} vomiting, ^{1 28} weight loss,^{1 6 28 30} nausea,^{1 28} dry mouth,^{1 28} dizziness,^{1 28 30} affect lability,¹ rash,¹ tic,¹ pyrexia,¹ somnolence.¹

Adults: Decreased appetite,¹ insomnia,¹ dry mouth,¹ diarrhea,¹ nausea,¹ anxiety,¹ anorexia,¹ jitteriness,¹ increased BP,¹ agitation,¹ restlessness,¹ hyperhidrosis,¹ increased heart rate,¹ tremor,¹ dyspnea.¹

Interactions for Lisdexamfetamine Dimesylate

Active metabolite (dextroamphetamine) inhibits MAO.¹

Lisdexamfetamine is not metabolized by CYP isoenzymes.¹ In vitro studies suggest only minor inhibition of CYP isoenzymes 1A2, 2D6, and 3A4 by amphetamine and/or its metabolites.¹

Specific Drugs, Tests, and Foods

Drug, Test, or Food	Interaction	Comments
Acidifying agents, urinary (ammonium chloride, sodium acid phosphate, cranberry juice)	Increased urinary excretion and decreased serum concentrations and efficacy of amphetamines1 8
Adrenergic blockers	Potential inhibition of adrenergic blockade1
Alkalinizing agents (carbonic anhydrase inhibitors, sodium bicarbonate)	Decreased urinary excretion of amphetamines8
Antidepressants, tricyclic (desipramine, protriptyline)	Enhanced activity of tricyclic antidepressants; desipramine or protriptyline cause striking and sustained increases in the concentration of dextroamphetamine in the brain; cardiovascular effects can be potentiated1
Antihistamines	Amphetamines may counteract the sedative effects of antihistamines1
Antihypertensives	Amphetamines may antagonize the hypotensive effects of antihypertensives1
Chlorpromazine	Chlorpromazine inhibits the central stimulant effects of amphetamines by blocking dopamine and norepinephrine receptors1	Can be used to treat amphetamine poisoning1
Ethosuximide	Intestinal absorption of ethosuximide may be delayed1
Haloperidol	Haloperidol inhibits the central stimulant effects of amphetamines by blocking dopamine receptors1
Lithium carbonate	Lithium may inhibit the anorectic and stimulatory effects of amphetamine1
MAO inhibitors	MAO inhibitors slow the metabolism of amphetamines, increasing their effect on the release of norepinephrine and other monoamines leading to headaches and other signs of hypertensive crisis1 Toxic neurologic effects, hypertensive crisis, and malignant hyperpyrexia can occur, sometimes with fatal results1	Amphetamines contraindicated in patients currently or recently (within 14 days) receiving MAO inhibitor1
Meperidine	Amphetamines potentiate the analgesic effect of meperidine1
Methenamine	Acidifying agents used with methenamine increase urinary excretion and decrease efficacy of amphetamines1
Norepinephrine	Amphetamines enhance the adrenergic effects of norepinephrine1
Phenobarbital	Amphetamines may delay absorption of phenobarbital; concomitant use may produce a synergistic anticonvulsant action1
Phenytoin	Amphetamines may delay absorption of phenytoin; concomitant use may produce a synergistic anticonvulsant action1
Propoxyphene	In propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur1
Sympathomimetic agents	Enhanced activity of sympathomimetic agents1	Use with caution1
Test, plasma corticosteroids	Elevated plasma corticosteroid concentrations; this increase is greatest in the evening1
Test, urinary steroids	Possible interference with urinary steroid determinations1
Veratrum alkaloids	Amphetamines inhibit the hypotensive effect of veratrum1

Lisdexamfetamine Dimesylate Pharmacokinetics

Absorption

Bioavailability

Lisdexamfetamine (a prodrug of dextroamphetamine) is rapidly absorbed from the GI tract.^{1 28} Peak plasma concentrations of lisdexamfetamine occur in approximately 1 hour; concentrations are low and transient; nonquantifiable by 8 hours after administration.¹ Peak plasma concentrations of dextroamphetamine occur in approximately 3.5–3.7 hours.^{1 3 30}

Onset

Occurs within 2 hours after oral administration.³

Duration

Approximately 10–12 hours.^{1 8 27}

Food

Food (high-fat meal) delays time to peak plasma concentration of dextroamphetamine by about 1 hour but does not affect magnitude of peak plasma concentration or AUC of dextroamphetamine.¹

Distribution

Extent

Amphetamines readily cross the blood-brain barrier and are distributed into most body tissues.²⁶

Amphetamines are distributed into milk in concentrations 3–7 times maternal blood concentrations.^{21 25}

Elimination

Metabolism

Lisdexamfetamine (a prodrug of dextroamphetamine) is converted to l-lysine and dextroamphetamine by first-pass intestinal and/or hepatic metabolism.¹

Lisdexamfetamine is not metabolized by CYP isoenzymes.¹

Elimination Route

Excreted principally in urine.¹ Approximately 96% of a 70-mg radiolabeled oral dose of lisdexamfetamine was recovered in urine; parent drug accounted for about 2% of the recovered radioactivity.¹

Changes in urinary pH may alter excretion of amphetamines.¹ (See Specific Drugs, Tests, and Foods under Interactions.)

Half-life

Lisdexamfetamine: <1 hour;^{1 8} dextroamphetamine: 9.4–13 hours.^{3 8 30}

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Amphetamines are sympathomimetic amines with CNS stimulant activity.^{1 23}

  
  


• 
  

  Lisdexamfetamine is a prodrug of dextroamphetamine; dextroamphetamine may block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneural space.^{1 23 28 30}

  
  


• 
  

  Pharmacologic actions of amphetamines are qualitatively similar to those of ephedrine and include CNS and respiratory stimulation and sympathomimetic activity including pressor response, bronchodilation, and contraction of the urinary bladder sphincter.^{23 24}

  
  


• 
  

  Theories of dysfunction in ADHD focus on the prefrontal cortex, which controls many executive functions (e.g., planning, impulse control).⁵ Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function.⁵

  
  


• 
  

  Produces an anorexigenic effect, leading to loss of weight.^{1 5 23} No primary effect on appetite has been demonstrated in humans and it has been postulated that anorexigenic effects are secondary to increased sympathetic activity resulting from release of norepinephrine and dopamine.²²

  
  

Advice to Patients

• 
  

  Provide patient or caregiver with a copy of the manufacturer’s patient information (medication guide); discuss and answer questions about its contents as needed.¹ Instruct patient or caregiver to read and understand contents of medication guide before initiating therapy and each time the prescription is refilled.¹

  
  


• 
  

  Advise parents with concerns about long-term effects (e.g., effects on weight) and the need for continued therapy that drug holidays can be considered in consultation with the patient’s clinician.^{5 6 7} However, the benefits versus risks of such interruptions in therapy have not been established.⁷

  
  


• 
  

  Question about possible substance abuse, including in other family members (since they may abuse the patient’s medication supply).¹

  
  


• 
  

  Advise to take drug in the morning to minimize insomnia.¹

  
  


• 
  

  Advise that appetite suppression may occur.^{1 5} Giving the morning dose with a meal and providing a high-caloric drink or snack late in the evening when the stimulant effects have subsided may be helpful.⁵

  
  


• 
  

  Advise to inform clinician immediately if adverse cardiovascular (e.g., chest pain, shortness of breath, fainting) or psychiatric effects (e.g., hallucinations, delusional thinking, mania) occur.¹

  
  


• 
  

  Instruct about the potential for amphetamines to impair patient’s ability to perform potentially hazardous activities, such as driving or operating heavy machinery.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses/conditions (e.g., cardiac/cardiovascular disease, thyroid disease, glaucoma, suicidal ideation or behaviors, mental/psychiatric disorder, seizures).¹

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.¹

Lisdexamfetamine Dimesylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	20 mg	Vyvanse (C-II)	Shire
		30 mg	Vyvanse (C-II)	Shire
		40 mg	Vyvanse (C-II)	Shire
		50 mg	Vyvanse (C-II)	Shire
		60 mg	Vyvanse (C-II)	Shire
		70 mg	Vyvanse (C-II)	Shire

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.

Vyvanse 20MG Capsules (SHIRE US INC.): 20/$125.99 or 30/$177.98

Vyvanse 30MG Capsules (SHIRE US INC.): 20/$126.99 or 30/$189.97

Vyvanse 40MG Capsules (SHIRE US INC.): 20/$113.99 or 30/$170.97

Vyvanse 50MG Capsules (SHIRE US INC.): 20/$118.57 or 30/$171.45

Vyvanse 70MG Capsules (SHIRE US INC.): 20/$117.29 or 30/$171.45

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 June 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Shire US Inc. Vyvanse (lisdexamfetamine dimesylate) capsules prescribing information. Wayne, PA; 2008 Apr.

2. Biederman J, Krishnan S, Zhang Y et al. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007; 29:450-63. [PubMed 17577466]

3. Shire US Inc., Wayne, PA: Personal communication.

4. Biederman J, Boellner SW, Childress A et al. Improvements in symptoms of attention-deficit/hyperactivity disorder in school-aged children with lisdexamfetamine (NRP-104) and mixed amphetamine salts, extended-release versus placebo. Poster presented at 159th annual meeting of the American Psychiatric Association. Toronto, Canada: 2006 May 24.

5. American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents and adults. Washington, DC; 2001. From the AACAP website. Accessed 2007 Aug 15.

6. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with attention deficit hyperactivity disorder. Washington, DC; 2007. From the AACAP website. Accessed 2007 Aug 15.

7. American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder. Clinical treatment guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001; 108:1033-44. [IDIS 470916] [PubMed 11581465]

8. Anon. Lisdexamfetamine dimesylate (Vyvanse) for ADHD. Med Lett Drugs Ther. 2007; 49:58-9.

9. US Food and Drug Administration. Adderall and Adderall XR (amphetamine): sudden death in children. Rockville, MD; 2005 Feb 9. Alert for Healthcare Professionals.

10. National Institutes of Health Office of Medical Applications of Research. NIH Consensus statement: diagnosis and treatment of attention deficit hyperactivity disorder. 1998; 16(Nov 16-18): in press. From NIH web site [1998 Nov 19]).

11. Swanson JM, Sergeant JA, Taylor E et al. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 1998; 351:429-33. [IDIS 403568] [PubMed 9482319]

12. Goldman LS, Genel M, Bexman RJ et al for the Council on Scientific Affairs et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA. 1998; 279:1100-7. [IDIS 402940] [PubMed 9546570]

13. Shaffer D. Attention deficit hyperactivity disorder in adults. Am J Psychiatry. 1994; 151:633-8. [PubMed 7909410]

14. Spencer T, Biederman J, Wilens TE et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry. 1998; 59(Suupl 7):59-68. [IDIS 409837] [PubMed 9680054]

15. Popper CW. Antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 1997; 58(Suppl 14):14-29. [IDIS 398614] [PubMed 9418743]

16. Smith BH, Pelham WE, Gnagy E et al. Equivalent effects of stimulant treatment for attention-deficit hyperactivity disorder during childhood and adolescence. J Am Acad Child Adolesc Psychiatry. 1998; 37:314-21. [IDIS 402147] [PubMed 9519637]

17. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999; 56:1073-86. [IDIS 440533] [PubMed 10591283]

18. Taylor E. Development of clinical services for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999; 56:10979.

19. The MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder. Arch Intern Med. 1999; 56:1088-96.

20. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children’s Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. J Am Acad Child Adolesc Psychiatry. 2000; 39:908-19. [IDIS 449214] [PubMed 10892234]

21. Drugs used in obesity. In: Drug evaluations subscription. Chicago, IL: American Medical Association; III/PSY-6:1-16, Winter 1992.

22. Littner M, Johnson SF, McCall WV et al for the American Academy of Sleep Medicine Standards of Practice Committee. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001; 24:451-66. [PubMed 11403530]

23. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Lazo JS, Parker KL, eds.Goodman and Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2005:237-95.

24. GlaxoSmithKline. Dexedrine (dextroamphetamine sulfate) extended-release capsules and tablets prescribing information. Research Triangle Park, NC; 2007 Mar.

25. Amphetamine. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:74-80.

26. Weiner N. Norepinephrine, epinephrine, and the sympathomimetic amines. In: Gilman AG, Goodman LS, Rall TW et al, eds.Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: Macmillan; 1985:145-80.

27. Shire Pharmaceuticals, Wayne, PA: Personal communication.

28. Hussar DA. New drugs: aliskiren hemifumarate, lisdexamfetamine dimesylate, and lapatinib. J Am Pharm Assoc. 2007; 47:425-6, 428-30.

29. Biederman J, Boellner SW, Childress A et al. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry. 2007; 62:970-6. [PubMed 17631866]

30. Blick SK, Keating GM. Lisdexamfetamine. Pediatr Drugs. 2007; 9:129-35.

31. Food and Drug Administration. FDA Alert: Information for healthcare professionals: Communication about an ongoing safety review of stimulant medications [dexmethylphenidate (marketed as Focalin, Focalin XR), dextroamphetamine (marketed as Dexedrine, Dexedrine Spansules, Dextrostat, and generics), lisdexamfetamine (marketed as Vyvanse), methamphetamine (marketed as Desoxyn), methylphenidate (marketed as Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, and Ritalin-SR), mixed salts amphetamine (marketed as Adderall and Adderall XR), and pemoline (marketed as Cylert and generics)] used in children with attention-deficit/hyperactivity disorder (ADHD). Rockville, MD; 2009 Jun 23. From the FDA website.

32. Gould MS, Walsh BT, Munfakh JL et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009; 166:992-1001. [PubMed 19528194]

33. Vitiello B, Towbin K. Stimulant treatment of ADHD and risk of sudden death in children. Am J Psychiatry. 2009; 166:955-7. [PubMed 19528196]

34. US Food and Drug Administration. AHRQ and FDA to collaborate in largest study ever of possible heart risks with ADHD medications. FDA News September 17, 2007. From FDA web site.

More Lisdexamfetamine Dimesylate resources

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

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Dosage Form: kit - tablet, capsules
Prevpac®

(lansoprazole 30 mg capsules, amoxicillin 500 mg capsules, USP, and clarithromycin 500 mg tablets, USP)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prevpac and other antibacterial drugs, Prevpac should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

THESE PRODUCTS ARE INTENDED ONLY FOR USE AS DESCRIBED. The individual products contained in this package should not be used alone or in combination for other purposes. The information described in this labeling concerns only the use of these products as indicated in this daily administration pack. For information on use of the individual components when dispensed as individual medications outside this combined use for treating Helicobacter pylori (H. pylori), please see the package inserts for each individual product.

Prevpac Description

Prevpac consists of a daily administration card containing two PREVACID 30 mg capsules, four amoxicillin 500-mg capsules, USP, and two clarithromycin 500 mg tablets, USP, for oral administration.

PREVACID® (lansoprazole) Delayed-Release Capsules

The active ingredient in PREVACID delayed release capsules is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular weight of 369.37. PREVACID has the following structure:

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

Each delayed-release capsule contains enteric-coated granules consisting of 30 mg of lansoprazole (active ingredient) and the following inactive ingredients: sugar sphere, sucrose, methacrylic acid copolymer, low substituted hydroxypropyl cellulose, starch, magnesium carbonate, talc, polyethylene glycol, titanium dioxide, polysorbate 80, hydroxypropyl cellulose, colloidal silicon dioxide, D&C Red No. 28, FD&C Blue No. 1, and FD&C Red No. 40.

Amoxicillin Capsules, USP

Amoxicillin is a semi synthetic antibiotic, an analogue of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S, 5R, 6R)-6-[(R)-(-)-2-amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. Its empirical formula is C16H19N3O5S • 3H2O with a molecular weight of 419.45. Amoxicillin has the following structure:

Amoxicillin capsules are intended for oral administration. Each yellow opaque capsule contains amoxicillin trihydrate equivalent to 500 mg of amoxicillin.

Inactive ingredients: Capsule shells - yellow ferric oxide, titanium dioxide, gelatin, black ferric oxide; Capsule contents – cellulose microcrystalline and magnesium stearate. Meets USP Dissolution Test 2.

BIAXIN® Filmtab® (clarithromycin tablets, USP)

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. Clarithromycin has the following structure:

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. Each yellow oval film-coated immediate-release tablet contains 500 mg of clarithromycin and the following inactive ingredients: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.

Prevpac - Clinical Pharmacology

Pharmacokinetics

Pharmacokinetics when all three of the Prevpac components (PREVACID capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of PREVACID and amoxicillin or PREVACID and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of PREVACID, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.

PREVACID

PREVACID capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

Absorption

The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is consistent over the concentration range of 0.05 to 5.0 mcg/mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of PREVACID, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Amoxicillin

Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. It diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound.

Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.

Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

Clarithromycin

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered every 8 to 12 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is up to 1 mcg/mL, and its elimination half-life is about 7 to 9 hours. The steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with a 500 mg tablet administered every 12 hours.

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Special Populations

Geriatric Use

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.

Renal Impairment

In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function.

Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment.

Gender

In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results (see PRECAUTIONS, PREVACID, Use in Women).

Race

The pooled pharmacokinetic parameters of PREVACID from twelve U.S. Phase I studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of PREVACID in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

Pharmacodynamics

Microbiology

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter pylori

Pretreatment Resistance

Clarithromycin pretreatment resistance rates (≥2.0 mcg/mL) were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (≤0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and 2 of 100 patients (2.0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori.

Table 1: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes*

Clarithromycin Pretreatment Results		Clarithromycin Post-treatment Results
		H. pylori negative - eradicated	H. pylori positive – not eradicated Post-treatment susceptibility results
			S†	I†	R†	No MIC
* Includes only patients with pretreatment clarithromycin susceptibility test results † Susceptible (S) MIC ≤0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1.0 mcg/mL, Resistant (R) MIC ≥2 mcg/mL
Triple Therapy 14-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399, M93-131, M95-392)
Susceptible†	112	105				7
Intermediate†	3	3
Resistant†	17	6			7	4
Triple Therapy 10-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399)
Susceptible†	42	40	1		1
Intermediate†
Resistant†	4	1			3

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done if possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily per amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.1 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 107 – 1 × 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

* These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods. † There were not enough organisms with MICs greater than 0.25 mcg/mL to determine a resistance breakpoint.
Clarithromycin MIC (mcg/mL)*	Interpretation
≤0.25	Susceptible (S)
0.5-1.0	Intermediate (I)
≥2.0	Resistant (R)
Amoxicillin MIC (mcg/mL)*,†	Interpretation
≤0.25	Susceptible (S)

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Microorganisms	Antimicrobial Agent	MIC (mcg/mL)*
* These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.
H. pylori ATCC 43504	Clarithromycin	0.015-0.12
H. pylori ATCC 43504	Amoxicillin	0.015-0.12

Antisecretory activity

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 2.

Table 2: Mean Antisecretory Effects After Single and Multiple Daily PREVACID Dosing

		PREVACID
Parameter	Baseline Value	15 mg		30 mg
		Day 1	Day 5	Day 1	Day 5
NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%.
* (p<0.05) versus baseline only. † (p<0.05) versus baseline and lansoprazole 15 mg.
Mean 24 Hour pH	2.1	2.7*	4.0*	3.6†	4.9†
Mean Nighttime Hour pH	1.9	2.4	3.0*	2.6	3.8†
% Time Gastric pH>3	18	33*	59*	51†	72†
% Time Gastric pH>4	12	22*	49*	41†	66†

After the initial dose in this study, increased gastric pH was seen within 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within 1 to 2 hours post-dosing with 15 mg of lansoprazole.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given daily, twice daily and three times daily.

Table 3: Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing

PREVACID
Parameter	30 mg daily	15 mg twice daily	30 mg twice daily	30 mgthree time daily
* (p<0.05) versus PREVACID 30 mg daily † (p<0.05) versus PREVACID 30 mg daily, 15 mg twice daily and 30 mg twice daily
% Time Gastric pH>5	43	47	59*	77†
% Time Gastric pH>6	20	23	28	45†

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.

Clinical Studies

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of Prevpac as triple 14-day therapy for the eradication of H. pylori. The triple therapy regimen (PREVACID 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) produced statistically significantly higher eradication rates than PREVACID plus amoxicillin, PREVACID plus clarithromycin, and amoxicillin plus clarithromycin dual therapies.

H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations. The combination of PREVACID plus amoxicillin and clarithromycin as triple therapy was effective in eradicating H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of PREVACID triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.

Table 4 H. pylori Eradication Rates – Triple Therapy

(PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)
Study	Duration	Triple Therapy Evaluable Analysis*	Triple Therapy Intent-to-Treat Analysis†
* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy. † Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. ‡ (p<0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy § (p<0.05) versus clarithromycin/amoxicillin dual therapy ¶ The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.
M93-131	14 days	92‡ [80.0-97.7] (N=48)	86‡ [73.3-93.5] (N=55)
M95-392	14 days	86§ [75.7-93.6] (N=66)	83§ [72.0-90.8] (N=70)
M95-399¶	14 days	85 [77.0-91.0] (N=113)	82 [73.9-88.1] (N=126)
	10 days	84 [76.0-89.8] (N=123)	81 [73.9-87.6] (N=135)

Indications and Usage for Prevpac

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

The components in Prevpac (PREVACID, amoxicillin, and clarithromycin) are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see CLINICAL STUDIES and DOSAGE AND ADMINISTRATION).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prevpac and other antibacterial drugs, Prevpac should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Please refer to the full prescribing information for amoxicillin and clarithromycin.

Contraindications

Prevpac is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID.

A history of allergic reaction to any of the penicillins is a contraindication.

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.

Concomitant administration of Prevpac and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see Drug Interactions). There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.

For information about contraindications of other drugs that may be used in combination with amoxicillin or clarithromycin, refer to the CONTRAINDICATIONS section of their package inserts.

Warnings

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. ALTHOUGH ANAPHYLAXIS IS MORE FREQUENT FOLLOWING PARENTERAL THERAPY, IT HAS OCCURRED IN PATIENTS ON ORAL PENICILLINS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AMOXICILLIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS - Pregnancy).

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see PRECAUTIONS).

For information about warnings of other drugs that may be used in combination with amoxicillin or clarithromycin, refer to the WARNINGS section of their package inserts.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin and/or amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

Symptomatic response to therapy with Prevpac does not preclude the presence of gastric malignancy.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, Prevpac should be discontinued and appropriate therapy instituted.

Prescribing Prevpac in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

For information about precautions of other drugs that may be used in combination with Prevpac, refer to the PRECAUTIONS section of their package inserts.

Information for Patients

Each dose of Prevpac contains four pills: one pink and black capsule (PREVACID), two opaque, yellow capsules (amoxicillin) and one yellow tablet (clarithromycin). Each dose should be taken twice per day before eating. Patients should be instructed to swallow each pill whole.

Prevpac may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.

Patients should be counseled that antibacterial drugs including Prevpac should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Prevpac is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Prevpac or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

Amoxicillin

As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy.

Drug Interactions

No drug interaction studies have been conducted specifically with Prevpac. The following drug interactions are for the individual drug components: PREVACID (lansoprazole), amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician's assessment of among other things, the cumulative or net effect of the drug components of Prevpac.

PREVACID

PREVACID causes long-lasting inhibition of gastric acid secretion. PREVACID substantially decreases the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, PREVACID, or other proton pump inhibitors, should not be co-administered with atazanavir.

It is theoretically possible that PREVACID may also interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that PREVACID does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Theophylline

When PREVACID was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when PREVACID is started or stopped to ensure clinically effective blood levels.

Tacrolimus

Concomitant administration of lansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Warfarin

In a study of healthy subjects, neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including PREVACID, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Sucralfate

In a single-dose crossover study examining PREVACID 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with PREVACID and there was no evidence of a change in the efficacy of PREVACID.

Amoxicillin

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.

Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.

Clarithromycin

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.

Concomitant administration of single doses of clarithr