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 IOWA MEDICAID P & T COMMITTEE THERAPEUTIC CLASS REVIEW NOVEMBER 13, 2008 STIMULANTS AND RELATED AGENTS SYNOPSIS Attention Deficit Hyperactivity Disorder, otherwise known as ADHD, is one of the most prevalent childhood psychiatric disorders. This disorder affects approximately 3‐7% of children34 and about 4% of adults36; prevalence is higher in boys than girls. Signs and symptoms of ADHD typically commence between the ages of infancy to 7 years of age.34 Currently, ADHD is viewed as a chronic disorder, since about three‐quarters of those with an ADHD diagnosis as a child still meet criteria during adolescence and one‐half still meet criteria during adulthood.36 The criteria for a definitive ADHD diagnosis are detailed in the American Psychiatric Association’s Diagnostic and Statistical Manual (APA DSM‐IV). There are several symptoms that are associated with ADHD, including inattentiveness, distractibility, impulsivity, and hyperactivity. Per the DSM‐IV, to meet criteria for ADHD diagnosis, one must have at least 6 inattention symptoms and six hyperactivity symptoms present greater than 6 months, must have these symptoms prior to the age of 7, the symptoms must occur in at least two different settings (eg. school, home), impairment due to symptoms must be seen, and other mental disorders must be ruled out.37 Management of ADHD includes non pharmacologic and pharmacologic treatment. Non pharmacologic management includes education on the disorder, as well as individual and family psychotherapy. Pharmacologic management includes treatment that available in several drug classes. Stimulants are considered first line treatment for ADHD. Other agents to treat ADHD include certain antidepressants; however, although there are currently no antidepressants with FDA approval, they are still considered Iowa Medicaid P&T Committee Stimulants and Related Agents‐2 second line. Atomoxetine, certain antihypertensives, and arousal agents including modafinil armodafinil are other available treatment options. 36 Stimulants are also used to treat another psychiatric disorder called Narcolepsy. Narcolepsy is defined as excessive daytime sleepiness, even when there is a sufficient amount of sleep time from the night. There are also four other symptoms that may or may not occur, including cataplexy, sleep paralysis, hypnagogic hallucinations, and automatic behavior. In addition to stimulants, arousal medications, including Provigil® and Nuvigil®, and Xyrem® are all approved for use for the treatment of Narcolepsy.35 This therapeutic class consists of drugs which treat Attention‐deficit Hyperactivity Disorder: the methylphenidates (MPHs), the amphetamines (AMPs), the non‐stimulant atomoxetine (Strattera®), and drugs which are used to treat symptoms of Narcolepsy and to improve wakefulness: modafinil (Provigil®) and its R‐enantiomer, armodafinil (Nuvigil®), sodium oxybate (Xyrem®), AMPs and MPHs. The drugs in the amphetamine group include: amphetamine salt combos (Adderall®, Adderall XR®), dextroamphetamine (Dexedrine®, Dextrostat®), lisdexamfetamine (Vyvanse®), methamphetamine (Desoxyn®), and the methylphenidates: dexmethylphenidate (Focalin®, Focalin XR®), methylphenidate (Daytrana patch®, Ritalin®), methylphenidate ER capsules (Metadate CD, Ritalin LA®), and methylphenidate ER tablets (Concerta®, Metadate ER®, Ritalin SR®). FDA APPROVED INDICATIONS 1‐14, 32‐33 All medications in this therapeutic class have an FDA approved indication to treat Attention Deficit Hyperactivity Disorder (ADHD), except for Provigil®, Nuvigil® and Xyrem®. Although Provigil® (in a form called Sparlon) has more than 2 double blind placebo controlled studies supporting both the safety and efficacy to treat ADHD, the FDA submitted a non‐approval letter to Cephalon because of the development of skin rashes and Stevens Johnson syndrome and Cephalon abandoned FDA approval. As a result, Nuvigil® also has a warning about this adverse effect. When amphetamines, methylphenidates or Strattera® are being used to treat ADHD, it is essential for them to be used in combination with educational and psychosocial interventions. The effectiveness of these medications for treatment of ADHD has been demonstrated only in short clinical trials, and their efficacy has not been assessed in long‐term treatment. Long‐ acting methylphenidates and amphetamines with durations of action of 8‐12 hours may be prescribed initially or substituted once the immediate release methylphenidate or amphetamines have been titrated. The established length of time supporting the effectiveness in clinical trials varies upon product; however, if being used for longer periods of time than supported by studies, it is advised that there be intermittent evaluations to determine effectiveness. Strattera® is currently the only medication in this therapeutic class that is indicated as maintenance treatment. Desoxyn® (methamphetamine) is indicated for exogenous obesity. The following table includes medications that have unique indications. Iowa Medicaid P&T Committee Stimulants and Related Agents‐3 Drug Narcolepsy Improve wakefulness associated with Narcolepsy, Shift work, or Obstructive Sleep Apnea/Hypopnea Syndrome amphetamine salt combo (Adderall®) X dextroamphetamine (Dexedrine®) (Dextrostat®) X methamphetamine (Desoxyn®) X methylphenidate (Ritalin®) X methylphenidate ER tabs (Metadate ER®) (Ritalin‐SR®) X armodafinil (Nuvigil®) X modafinil (Provigil®) X sodium oxybate (Xyrem®) X1 Exogenous Obesity 1
Cataplexy and Improve Wakefulness Associated with Narcolepsy only DOSAGE FORMS, DOSE, MANUFACTURER 1‐14,32‐33 The dosing of Desoxyn® for use with its indication is a 5mg tablet taken one‐half hour before meals; however, this dosing should only be used for a few weeks because of its addictive potential. Daytrana® is a transdermal preparation of methylphenidate (MPH) which must be applied to the hip area each morning. It is recommended that it be removed after 9 hours. If there is evidence of a hypersensitivity reaction (not just mild erythema) to the patch, then any attempts to give oral MPH thereafter will be marked with a skin reaction at the site of previous eruption. As a result, it is not recommended to re‐try patient with oral MPH after this adverse reaction. Xyrem® solution is available through the Xyrem Success Program. Drug Iowa Medicaid P&T Committee Dosage Forms Dose Manufacturer Stimulants and Related Agents‐4 Drug amphetamine salt combo (Adderall®) amphetamine salt combo XR (Adderall XR®) dextroamphetamine (Dexedrine®) Dosage Forms Tablets: 5mg, 7.5mg, 10mg, 12.5.mg, 15mg, 20mg, 30mg Capsules: 5mg, 10mg, 15mg, 20mg, 25mg, 30mg Spansules: 5mg, 10mg, 15mg Tablets: 5mg Dose Manufacturer 5‐60mg daily Various generic manufacturers (Shire Richwood) 10‐30mg daily in AM Shire 5‐60mg /day in divided doses Various generic manufacturers (GlaxoSmithKline) dextroamphetamine (Dextrostat®) Tablets: 5mg, 10mg 5‐60mg/day in divided dose Various generic manufacturers (Shire Richwood) lisdexamfetamine (Vyvanse®) Capsules: 20mg, 30mg, 40mg, 50mg, 60mg, 70mg 30‐70mg QD Shire methamphetamine (Desoxyn®) Tablets: 5mg 5‐25mg QD Various generic manufacturers (Abbott) dexmethylphenidate (Focalin®) dexmethylphenidate (Focalin XR®) Capsules: 10mg, 18mg, 25mg, 40mg, 60mg, 80mg, 100mg Tablets: 2.5mg, 5mg, 10mg Capsule: 5mg, 10mg, 15mg, 20mg 1.2mg/kg divided once or twice daily. Max: 100mg daily 2.5mg BID Max: 10mg BID 5‐10mg QD Max: 20mg QD methylphenidate (Daytrana®) Transdermal System: 10mg, 15mg, 20mg, 30mg One patch daily methylphenidate (Ritalin®) Tablets: 5mg, 10mg, 20mg 20‐60mg in divided doses of BID‐TID Various generic manufacturers (Novartis) methylphenidate ER (Metadate CD®) Capsules: 10mg, 20mg, 30mg, 40mg, 50, 60mg 20‐60mg QAM before breakfast UCB methylphenidate ER (Ritalin LA®) Capsules: 10mg, 20mg, 30mg, 40mg 20‐60mg QAM Novartis atomoxetine (Strattera®) Iowa Medicaid P&T Committee Max: 30mg Eli Lilly and Comp. Teva (Novartis ) Novartis Shire Stimulants and Related Agents‐5 Drug Dosage Forms Dose Manufacturer methylphenidate ER (Concerta®) Tablets: 18mg, 27mg, 26mg, 54mg 18‐72mg QAM, not to exceed 2mg/kg/day McNeil methylphenidate ER (Metadate ER®) Tablets: 10mg, 20mg 10‐60mg in divided TID dosing UCB methylphenidate ER tablets (Ritalin‐SR®) Tablets: 20mg 20‐60mg in divided TID dosing Novartis armodafinil (Nuvigil®) Tablets: 50mg, 150mg, 250mg 150mg or 250mg in am; but no consistent data supporting additional benefit of higher dose Cephalon modafinil (Provigil®) Tablets: 100mg, 200mg 200mg QAM or 1 hr prior to shift work Cephalon Oral Solution: 500mg/ml Starting dose: 4.5 g/night, given as 2.25g at HS and 2.5‐4 hrs later. ↑to a max of 9 g/night in increments of 1.5 g/night (0.75g/dose) Jazz sodium oxybate (Xyrem®) PHARMACOLOGY 1‐14, 32‐33 Methylphenidates and amphetamines are sympathomimetic amines. Dextoamphetamine is the d‐ enantiomer of amphetamine. Methylphenidate is a racemic mixture containing both d‐ and l‐enantiomers; however, the d‐enantiomer is more active pharmacologically. Because Focalin® and Focalin XR® are d‐
enantiomers only, they are dosed at half the dosage of other racemic MPH products and at about the same dosing as amphetamine (AMP) products. The exact mechanism of action (MOA) of MPHs and AMPs in ADHD is unknown; however, it is believed that these drugs block the reuptake of norepinepherine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space in the CNS. It has been demonstrated that Strattera® is a presynaptic norepinepherine reuptake inhibitor and therefore, can increase CNS norepinepherine levels. Provigil ® and Nuvigil ® are not typical stimulants in terms of dopamine and norepinepherine release. They may increase dopamine release from striatal neurons16, but they are also known to affect hypocretin, histamine, epinephrine, gamma‐aminobutyric acid, and glutamate receptors17. The MOA of Xyrem® in cataplexy is unknown. It is the sodium salt of the well‐known drug of abuse, gamma‐hydroxybutyrate (GHB), Iowa Medicaid P&T Committee Stimulants and Related Agents‐6 a CNS depressant. PHARMACOKINETICS 1‐14,32‐33
Since the 1940s until the last ten years, the only stimulants that were available were short acting single pulse wax matrix MPHs and AMPs. Then pharmacokinetic studies showed sustained levels of stimulants led to good clinical outcomes, and drug companies began developing new formulations of MPHs and AMPS. Although individual drugs in both groups have different TMax, the most important clinical differences are in their duration of action. Clinically these drugs can be divided into the short‐acting formulations of about 3‐4 hours, intermediate formulation of 5‐6 hours, and the longer‐acting formulations of 6‐12 hours (See table below). Despite its name, Ritalin SR® and Metadate‐ER® are considered short‐acting formulations. Some of the new formulations are a combination of immediate and delayed release “beads” in various proportions (e.g., Ritalin LA®, is in a SODAS® (Spheroidal Oral Drug Absorption System technology which leads to a bi‐modal concentration –time profile with two distinct peaks). Adderall XR® delivers 4 different salts of amphetamine with 50% of each immediate and delayed “beads”. Ritalin LA® and Focalin XR® have a similar mix of MPH. Metadate CD® has 30% immediate and 70% delayed “beads”. Concerta®, an OROS (osmotic released) MPH has 22% immediate and 78% delayed MPH. Vyvanse® is a pro‐drug of dextroamphetamine which releases dextroamphetamine from its lysine attachment in the gastrointestinal tract when it undergoes hydrolysis. It is not bioequivalent to other dextroamphetamine products. Theoretically, it has less abuse‐potential than other AMP formulations because it is a pro‐drug. Strattera® has a peak concentration of 1 hour without food, and it has a half‐life of 5 hours for individuals that are extensive metabolizers of CYP2D6. Its pharmacodynamic action is longer than its half‐life and can be given once daily with most individuals, but it may require bid dosing in some. Provigil® is a racemic mixture of 90% of l‐enantiomer and 10% of the d‐enantiomer. With a half‐life of 15 hours, Nuvigil® is the longer‐lived enantiomer of Provigil®. The concentration time profiles of 50mg of Nuvigil® and 100 mg Provigil ® are virtually identical. Xyrem® has a half‐life of between 0.5 and 1 hour, and its pharmacokinetics is non‐linear. It must be given BID after an evening meal while the patient is in bed because it has a short half‐life, its absorption is changed by food intake, and because it is a CNS depressant. Because some children cannot swallow pills, whether a drug can be opened and added to a spoonful of food to be swallowed is an important consideration, and the drugs that have this option can be viewed in table below. In addition, because of their convenience and the fact that the medication may not have to be given in school, longer acting formulations have largely replaced the short acting ones. Iowa Medicaid P&T Committee Stimulants and Related Agents‐7 Drug Duration of Action‐ Short or Long Other amphetamine salt combo (Adderall®) Short amphetamine salt combo ER (Adderall® XR) Long Caps can be opened Short Short Contains FD&C Yellow #5 dexedrine spansule (Dexedrine® SR) Long after a 2 hr delay lisdexamfetamine (Vyvanse®) Long methamphetamine (Desoxyn®) N/A atomoxetine (Strattera®) Intermediate dexmethylphenidate (Focalin®) Short Long Caps can be opened Short methylphenidate transdermal (Daytrana®) Long methylphenidate ER caps (Metadate CD®) Long Caps can be opened methylphenidate ER caps (Ritalin LA®) Long Caps can be opened methylphenidate ER tabs (Concerta®) Long‐8‐12 hours methylphenidate ER tabs (Ritalin‐SR®) Short methylphenidate ER tabs (Metadate ER®) Short dextroamphetamine tab (Dexedrine®) dextroamphetamine (Dextrostat®) dexmethylphenidate ER (Focalin® XR) methylphenidate (Ritalin®) Iowa Medicaid P&T Committee Stimulants and Related Agents‐8 CLINICAL TRIALS For children with ADHD, the National Institute for Health and Clinical Excellence (NICE) in England (2006) has reviewed the relative efficacy of MPH, AMPs and Strattera® in an exhaustive report and concluded that in terms of clinical efficacy, one cannot distinguish between these drugs. Therefore, it ranks them in terms of cost: in the English health system, AMPs are first choice followed by MPHs and then atomoxetine (Strattera®) 21. A critique of this document by Schlander (2008) has pointed out that several excellent studies that showed the clinical inferiority of Strattera to methylphenidate and Concerta® had been omitted from the NICE analysis22, 23, 24. In head‐to head studies, Strattera® has also been shown to be less potent than Adderall XR both in terms of time course and therapeutic efficacy25 in boys and girls 6‐12 years of age26. Five head‐to‐head studies of Strattera® and various stimulants were reviewed by Gibson et al 2006, and they concluded that stimulants remain first choice, with Strattera an alternative treatment27. A similar conclusion is reached by Treatment Guidelines from The Medical Letter (2006)28 and the Texas Algorithm (http://www.dshs.state.tx.us/mhprograms/adhdpage.shtm. Strattera® has a niche as first treatment in children and families who have a substance abuse history and who may abuse stimulants. For adults with ADHD, a meta‐analysis of 26 RCTs showed the superiority of short acting stimulants, predominantly MPH29. However, many of the early studies used low dose MPH and improved efficacy of MPH in adult ADHD has been associated only with doses of MPH up to 1.3mg/kg/day30. Narcolepsy is a rare disorder of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Medication is directed at specific symptoms. AMPs and MPHs are often used for the symptoms of excessive daytime sleepiness, but have no effect on cataplexy. Antidepressants may be used to treat cataplexy, sleep paralysis and hypnagogic hallucinations31, but review by the Cochrane Database of their use in cataplexy finds them poorly substantiated (Cochrane Database Syst Rev. 2005;(3):CD003724). In the Practice Parameters of the American Academy of Sleep Medicine, AMPs, MPHs, Xyrem®, Provigil®, and Nuvigil® are listed as effective treatments for excessive sleepiness31. Xyrem® additionally is listed as an effective treatment of cataplexy. There are no head‐to‐head studies of medication treatments for narcolepsy or for the other indications of these drugs. CONTRAINDICATIONS 1‐14, 32‐33 All medications in this therapeutic category share a common contraindication of hypersensitivity to the main active ingredient or any component of the compound. This is the only contraindication that Provigil® and Nuvigil® carry. However, there are two additional contraindications common to the whole class, excluding Provigil®, Nuvigil® and Xyrem®. These include glaucoma (narrow angle glaucoma for atomoxetine) and concomitant treatment with MAOIs or use of drugs within this class within 14 days following administration of MAOIs. Iowa Medicaid P&T Committee Stimulants and Related Agents‐9 The AMPs possesses common contraindications. One is a known hypersensitivity or idiosyncrasy to the sympathomimetic amines. In addition, other contraindications common to the AMP include agitation, those with a history of substance abuse, advanced atherosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, and hyperthyroidism. Both AMPs and MPHs are contraindicated in children with pre‐existing cardiac abnormalities and with adults with these conditions, as well as with cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease or other serious cardiac problems. It is recommended that Strattera® either not be used or careful consideration given to individuals with similar difficulties. Both AMPs and MPHs carry a contraindication if the patient has tics or has a family history of Tourette’s syndrome. However, in the last 10 years, there have been a series of clinical studies whose outcomes contradict this recommendation18, and it is commonplace nowadays to use these stimulants in individuals with ADHD and tics. Individuals should be monitored for tics, and since serious tics occasionally result, the stimulants can be discontinued. Xyrem® is contraindicated in patients being treated with sedative or hypnotic agents and those with the inborn error of metabolism: succinic semialdehyde dehydrogenase deficiency. SPECIAL POPULATIONS 1‐14,32‐33 The ages vary within the pediatric population where safety and efficacy has been established. The chart below includes the ages at which both safety and efficacy has been established in the pediatric population. All medications in this therapeutic category are pregnancy category C. Dexmethylphenidate and methylphenidate have not truly been studied with renal insufficiency; however, methylphenidate is metabolized so that at least 80% shows in the urine as ritalinic acid, which is an inactive drug. It is thought that since there is a small percentage of the drug left unchanged in the urine that there would be little effect for those with renal insufficiency. Xyrem® has not been studied with renal or hepatic impairment; however, there is no effect expected because of the route of metabolism. Lastly, there is not enough information to support whether doses of Nuvigil® needed to be adjusted in those with renal impairment. Drug Pediatrics Pregnancy Category Dosage change with Renal Insufficiency Dosage change with Hepatic Insufficiency amphetamine Salt Combo (Adderall®) ≥ 3 yrs C Not studied Not studied amphetamine Salt Combo ER (Adderall® XR) ≥6 yrs C Not studied Not studied dextroamphetamine (Dexedrine®) ≥ 3 yrs C Not studied Not studied Iowa Medicaid P&T Committee Stimulants and Related Agents‐10 Drug Pediatrics Pregnancy Category Dosage change with Renal Insufficiency Dosage change with Hepatic Insufficiency lisdexamfetamine (Vyvanse®) 6‐12 yrs C Not studied Not studied methamphetamine (Desoxyn®) ≥ 12 yrs C Not studied Not studied atomoxetine (Strattera®) ≥ 6 yrs C Not required Moderate to Severe: Yes dexmethylphenidate (Focalin®) ≥ 6 yrs C Not required Not studied dexmethylphenidate (Focalin® XR) ≥ 6 yrs C Not required Not studied methylphenidate ≥ 6 yrs C Not studied Not studied armodafinil (Nuvigil®) ≥ 17 yrs C Further studies required Severe; ↓ dose modafinil (Provigil®) ≥ 16 yrs C Not studied Severe: reduce dose by ½ sodium Oxybate (Xyrem®) >16 yrs B Not studied Not studied ADVERSE DRUG REACTIONS 1‐15, 32‐33 MPHs and AMPS are Schedule 2 controlled substances and have a warning for potential of abuse and dependence. Therefore, Strattera® which is not a controlled substance would be an appropriate option for those with ADHD along with a history of substance abuse or in children with a family history of substance abuse. Strattera® does have a black box warning indicating of increased risk of suicidal ideation in children or adolescents; however, clinical trials performed did not result in any suicides. Those started on this therapy, as with any therapy in this class, should be monitored closely. Any changes in behaviors should be discussed The amphetamine products carry cardiovascular side effects, including tachycardia, palpitations, and blood pressure elevations. As a result, blood pressure should be monitored in those even with mild hypertension. Iowa Medicaid P&T Committee Stimulants and Related Agents‐11 Additional adverse reactions with the amphetamine group include overstimulation, restlessness, dry mouth, unpleasant taste, and suppression of growth in children with long‐term use. The methylphenidate products carry common adverse reactions, including nervousness and insomnia as the two most frequent. Cardiovascular effects, including palpitations, tachycardia, and increase/decrease in pulse are common to this group as well. Once again, blood pressure should be monitored in those even with mild hypertension. Other miscellaneous side effects that occur with the methylphenidate products include Tourette syndrome (rare), hypersensitivity reaction and weight loss during prolonged therapy. Provigil® and Nuvigil® are Schedule 4 controlled substances, and they have specific warnings for serious rash, including Stevens‐Johnson syndrome. In clinical trials of Provigil®, the incidence of rash leading to discontinuation in children less than 17 years was 0.8%, including 1 case of possible Stevens‐ Johnson syndrome. The possible onset of psychiatric adverse reactions is noted for both drugs. Xyrem® is a Schedule 3 controlled substance and its active ingredient, GHB is in the Schedule 1 class (the most restrictive). Xyrem®, as a CNS depressant, has a specific warning about being ingested only while in bed and not engaging in dangerous activities for at least 6 hours after ingestion. It is noted that Xyrem® can impair respiratory drive, especially in individuals who are already impaired. Confusion, neuropsychiatric adverse events such as hallucinations, sleepwalking and depression are noted as is urinary and rectal incontinence. Consideration in adding Xyrem’s sodium intake to individuals with heart failure, hypertension and compromised renal function is also noted. The following table summarizes the most common treatment‐emergent adverse reactions that were reported. Not all drugs are listed, as not all drugs had trials performed and information supplied in the prescribing information. These are all taken from the pediatric population, except for Provigil®, Nuvigil® and Xyrem®. Side Effects Abd Pain N/V Loss of App. Diarrhea amphetamine salt combo ER (Adderall® XR) 14% 5%/7% 22% 2% 2% 17% 9% 4% lisdexamfetamine (Vyvanse®) 12% 6%/9% 39% ‐ 5% 19% 3% 9% 12% atomoxetine (Strattera®) 18% 10%/11% 16% ‐ 5% ‐ ‐ 3% 19% dexmethylphenidate (Focalin®) 15% 9% 6% ‐ ‐ ‐ ‐ ‐ ‐ dexmethylphenidate (Focalin® XR) 8% ‐ 30% ‐ ‐ ‐ ‐ ‐ 25% Iowa Medicaid P&T Committee Dizziness Insomnia Emot. Weight H/A Lability Loss Stimulants and Related Agents‐12 Abd Pain N/V Loss of App. Diarrhea ‐ 12%/10% 25% ‐ ‐ 13% 6% 9% ‐ 7% ‐ 9% ‐ ‐ 5% ‐ ‐ 12% ‐ ‐ 2% ‐ ‐ 2% ‐ ‐ ‐ 7% ‐/3% 2% 2% 2% 5% ‐ ‐ 9% armodafinil (Nuvigil®) 2% 8% 1% 4% 5% 5% 17% modafinil (Provigil®) ‐ 11%/‐ 4% 6% 5% 5% 1% ‐ 34% sodium oxybate (Xyrem®) 21%/8% 17% 22% Side Effects methylphenidate transdermal system (Daytrana®) methylphenidate ER caps (Metadate CD®) methylphenidate ER capsules (Ritalin® LA) methylphenidate ER tablets (Concerta®) Dizziness Insomnia Emot. Weight H/A Lability Loss (Abd.Pain‐ Abdominal Pain,N/V‐Nausea/Vomiting, Loss of App‐ Loss of Appetite, Emot. Lability‐Emotional Lability, H/A‐Headache) DRUG‐DRUG INTERACTIONS 1‐14,32‐33 Amphetamines: Drugs are metabolized by CYP2D6 and may be increased by potent CYP2D6 inhibitors. They may also be modest inhibitors of CYP2D6. They are proserotonergic and may be additive with other proserotonergic agents. Amphetamines may delay the absorption of a variety of drugs including ethosuximide, phenytoin and phenobarbital, and its own absorption may be inhibited or facilitated by alkalinizing and acidifying agents. As a sympathomimetic agent, it can be additive with other sympathomimetic agents and with MAOIs, and may cause a hypertensive reaction. Drug/Class Iowa Medicaid P&T Committee Major Metabolic Route Clinical Recommendations Stimulants and Related Agents‐13 Drug/Class Major Metabolic Route Clinical Recommendations Potent CYP2D6 inhibitors (e.g. Fluoxetine, Paroxetine) CYP2D6 May ↑ levels of amphetamines MAO Inhibitors (including Zyvox®) SSRIs, lithium and others MAOIs slow amphetamine metabolism and may ↑ release of MAOs, additive with agents that affect brain monoamine concentration Additive to proserotonergic agents ↑ hypertension reaction may occur so avoid combination ↑ risk of serotonin syndrome; monitor agents Strattera®: Strattera® is metabolized by CYP2D6 principally and by CYP2C19 as a minor pathway19. Drug/Class Major Metabolic Route Clinical Recommendations MAO Inhibitors (including Zyvox®) Additive with other agents that affect brain monoamine concentration Avoid combination since hypertension reaction can occur CYP2D6 Inhibitors (Ex. Paroxetine, Fluoxetine, Quinidine) CYP2D6 Atomoxetine CMax 3‐4 fold ↑, but atomoxetine wide therapeutic index, monitor albuterol Additive Use with caution due to ↑ effects on BP and heart rate Methylphenidates: MPH is metabolized by carboxylesterase CES1A120 and small amount by CYP2D6. These drugs may be inhibitors of CYP2D6 and therefore may increase the concentration of tricyclic antidepressants that are substrates of CYP2D6 (e.g., imipramine). MPH is proserotonergic and may be additive with other pro‐
serotonergic agents, and like other catacholamines, may be additive with MAOIs. Drug/Class Major Metabolic Route Clinical Recommendations MAO Inhibitors (including Zyvox®) Additive with other agents that affect brain monoamine ↑ hypertension reaction may occur so avoid combination Iowa Medicaid P&T Committee Stimulants and Related Agents‐14 Drug/Class Major Metabolic Route Clinical Recommendations concentration pro‐serotonergic agents (e.g., SSRIs, lithium) Additive proserotonergic ↑ risk of serotonin syndrome and ↑ SSRI levels; monitor pressor agents (e.g., dopamine) Additive affects Caution when combined albuterol May be additive effects on blood pressure and heart rate Caution when combined Provigil® and Nuvigil®: Provigil® and Nuvigil® are principally metabolized by deamination, with a minor pathway of CYP3A4 and ABCB1. As a result, they may be vulnerable to potent CYP3A4 inhibitor and inducers. They are also moderate CYP3A4 inducers and can reduce the concentration of drugs with narrow therapeutic indices (e.g., cyclosporine, ethinyl estradiol). They are CYP2C19 inhibitors and likely can increase levels of omeprazole32, although no clinical studies are available for the racemic mixture. Drug/Class Major Metabolic Route Clinical Recommendations Provigil® and Nuvigil ® induce CYP3A4 Provigil® and Nuvigil® induce CYP3A4 Effectiveness is ↓so alternative method of contraception is suggested up to 1 month after discontinuation potent Inducers of CYP3A4 (Exs. Carbamazepine, Phenobarbital, Rifampin) CYP3A4 Provigil® and Nuvigil® levels ↓, monitor potent Inhibitors of CYP3A4 (Ex. Ketoconazole) CYP3A4 Provigil® and Nuvigil® levels ↑, monitor cyclosporine oral contraceptives/estrogens Adjust Cyclosporine dose since levels can ↑ by 50% Xyrem® This drug is metabolized via the Krebs cycle. As a CNS depressant, Xyrem® has warnings about co‐
administration with alcohol, sedatives, and other CNS depressants. Iowa Medicaid P&T Committee Stimulants and Related Agents‐15 SUMMARY
Meta‐analyses have shown that AMPs and MPHs, both Schedule 2 substances, are equally effective treatments for ADHD. Different formulations of them can be organized by their duration of action into short, intermediate and longer‐acting agents. Strattera®, a non‐stimulant non Schedule 2 agent has a niche to treat individuals with ADHD who might abuse Schedule 2 agents or who live in families that might do so. Desoxyn® has an additional indication for treatment of exogenous obesity but has high addiction potential Provigil®, Nuvigil ® and Xyrem® are effective treatments for some symptoms of narcolepsy and the first two, for improving wakefulness in other conditions and Obstructive Sleep Apnea (OSA). Although Xyrem® is unique in its indication for the treatment of cataplexy in narcolepsy, it has a high potential for abuse (and is a Schedule 3 drug) since its active ingredient is a drug of abuse, gamma‐hydroxybutyrate (GHB). Special precautions for its use at night in bed after eating must be undertaken because of it short half‐life and possible CNS depression. There are no head‐to‐head trials of medications to treat narcolepsy, OSA, or to improve wakefulness. REFERENCES 1.
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Provigil [package insert]. Frazer, PA: Cephalon Inc; 2007. Iowa Medicaid P&T Committee Stimulants and Related Agents‐16 14.
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