October 2005 • www.clinicalneurologynews.com Sleep Disorders 13 Armodafinil Useful Adjunct to CPAP in Apnea

BY BRUCE JANCIN Societies. Based on these findings as well tion of Cephalon’s Provigil (modafinil), the morning in this 12-week, double-blind Denver Bureau as data from two other phase III trials in- which has a markedly shorter half-life than multicenter trial. volving patients with shift work sleep dis- the newer enantiomer. Patients on both doses of armodafinil D ENVER — The investigational drug ar- order or narcolepsy, the drug’s manufac- Jed E. Black, M.D., reported on 392 pa- showed significantly improved daytime modafinil significantly increased daytime turer, Cephalon Inc., has filed a new drug tients with excessive daytime sleepiness as wakefulness, compared with patients on wakefulness in patients with obstructive application seeking approval to market defined by a baseline Epworth Sleepiness placebo, as measured objectively by the sleep apnea who experienced excessive armodafinil (Nuvigil) as a wakefulness- Scale score of 10 or more despite good ad- Maintenance of Wakefulness Test at sleepiness despite regular nighttime con- promoting agent in patients with any of herence to continuous positive airway weeks 4, 8, and 12. tinuous positive airway pressure therapy, three disorders: obstructive sleep ap- pressure (CPAP) therapy for obstructive Moreover, at each assessment, blinded according to the results of two phase III nea/hypopnea syndrome, narcolepsy, or sleep apnea/hypopnea syndrome. Partic- physicians rated the armodafinil-treated clinical trials presented at the annual meet- shift work sleep disorder. ipants were randomized to armodafinil at patients as showing significantly more ing of the Associated Professional Sleep Armodafinil is a single-isomer formula- 150 mg, 250 mg, or placebo once daily in clinical improvement. For example, at the final visit, physicians rated 71% of pa- tients in the 150-mg armodafinil group Slight maternal toxicity, decreased pup weights and an increased incidence Treatment emergent signs and symptoms that occurred during 8 controlled of non-ossified cervical vertebrae were seen at an oral dose of clinical trials and 4 open-label trials were recorded as adverse events by and 74% in the 250-mg group as showing 18 mg/kg/day in a study in which rats were given oral memantine beginning the clinical investigators using terminology of their own choosing. To provide pre-mating and continuing through the postpartum period. Slight maternal an overall estimate of the proportion of individuals having similar types of at least minimal clinical improvement on toxicity and decreased pup weights were also seen at this dose in a study events, the events were grouped into a smaller number of standardized in which rats were treated from day 15 of gestation through the post- categories using WHO terminology, and event frequencies were calculated the Clinical Global Impression of Change partum period. The no-effect dose for these effects was 6 mg/kg, which across all studies. (CGIC) scale compared with 37% of pa- Rx Only is 3 times the MRHD on a mg/m2 basis. All adverse events occurring in at least two patients are included, except Brief Summary of Prescribing Information. There are no adequate and well-controlled studies of memantine in pregnant for those already listed in Table 1, WHO terms too general to be informative, tients taking placebo. From a mean base- women. Memantine should be used during pregnancy only if the potential minor symptoms or events unlikely to be drug-caused, e.g., because they For complete details, please see full Prescribing Information for Namenda. benefit justifies the potential risk to the fetus. are common in the study population. Events are classified by body system line Epworth Sleepiness Scale score of INDICATIONS AND USAGE Nursing Mothers and listed using the following definitions: frequent adverse events - those Namenda (memantine hydrochloride) is indicated for the treatment of It is not known whether memantine is excreted in human breast milk. occurring in at least 1/100 patients; infrequent adverse events 15.5, the armodafinil group (both dosages moderate to severe dementia of the Alzheimer’s type. Because many drugs are excreted in human milk, caution should be - those occurring in 1/100 to 1/1000 patients. These adverse events are combined) improved by a mean of 5.5 exercised when memantine is administered to a nursing mother. not necessarily related to Namenda treatment and in most cases were CONTRAINDICATIONS Pediatric Use observed at a similar frequency in placebo-treated patients in the points, compared with 3.3 points in the Namenda (memantine hydrochloride) is contraindicated in patients with controlled studies. known hypersensitivity to memantine hydrochloride or to any excipients There are no adequate and well-controlled trials documenting the safety Body as a Whole: Frequent: syncope. Infrequent: hypothermia, allergic placebo group. The armodafinil-treated used in the formulation. and efficacy of memantine in any illness occurring in children. reaction. ADVERSE REACTIONS patients rated their global fatigue as im- PRECAUTIONS Cardiovascular System: Frequent: cardiac failure. Infrequent: angina Information for Patients and Caregivers: Caregivers should be instructed The experience described in this section derives from studies in patients with Alzheimer’s disease and vascular dementia. pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial proved by a mean of 1.2 points from a in the recommended administration (twice per day for doses above 5 mg) fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary and dose escalation (minimum interval of one week between dose increases). Adverse Events Leading to Discontinuation: In placebo-controlled trials embolism, pulmonary edema. baseline of 4.9 on the Brief Fatigue In- in which dementia patients received doses of Namenda up to 20 mg/day, Neurological Conditions Central and Peripheral Nervous System: Frequent: transient ischemic Seizures: Namenda has not been systematically evaluated in patients the likelihood of discontinuation because of an adverse event was the ventory; that was twice as great a gain as same in the Namenda group as in the placebo group. No individual attack, cerebrovascular accident, vertigo, ataxia, hypokinesia. Infrequent: with a seizure disorder. In clinical trials of Namenda, seizures occurred in paresthesia, convulsions, extrapyramidal disorder, hypertonia, tremor, 0.2% of patients treated with Namenda and 0.5% of patients treated adverse event was associated with the discontinuation of treatment in 1% in the placebo arm, said Dr. Black of Stan- or more of Namenda-treated patients and at a rate greater than placebo. aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia, with placebo. involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ford (Calif.) University. Genitourinary Conditions Adverse Events Reported in Controlled Trials: The reported adverse ptosis, neuropathy. events in Namenda (memantine hydrochloride) trials reflect experience Conditions that raise urine pH may decrease the urinary elimination of Gastrointestinal System: Infrequent: gastroenteritis, diverticulitis, Armodafinil had no adverse effects on memantine resulting in increased plasma levels of memantine. gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency gastrointestinal hemorrhage, melena, esophageal ulceration. nighttime sleep as assessed by polysom- Special Populations estimates may not apply, as the conditions of use, reporting behavior and Hemic and Lymphatic Disorders: Frequent: anemia. Infrequent: leukopenia. Hepatic Impairment the types of patients treated may differ. Table 1 lists treatment-emergent Metabolic and Nutritional Disorders: Frequent: increased alkaline nography, nor did it affect CPAP use, Namenda undergoes partial hepatic metabolism, with about 48% of signs and symptoms that were reported in at least 2% of patients in phosphatase, decreased weight. Infrequent: dehydration, hyponatremia, administered dose excreted in urine as unchanged drug or as the sum of which continued at an average of 7 hours placebo-controlled dementia trials and for which the rate of occurrence aggravated diabetes mellitus. parent drug and the N-glucuronide conjugate (74%). The pharmacokinetics was greater for patients treated with Namenda than for those treated with of memantine in patients with hepatic impairment have not been Psychiatric Disorders: Frequent: aggressive reaction. Infrequent: delusion, per night throughout the study. placebo. No adverse event occurred at a frequency of at least 5% and investigated, but would be expected to be only modestly affected. personality disorder, emotional lability, nervousness, sleep disorder, libido twice the placebo rate. increased, psychosis, amnesia, apathy, paranoid reaction, thinking abnormal, Results were similar in a separate phase Renal Impairment crying abnormal, appetite increased, paroniria, delirium, depersonalization, No dosage adjustment is needed in patients with mild or moderate renal Table 1: Adverse Events Reported in Controlled Clinical Trials in at Least neurosis, suicide attempt. III trial reported by Max Hirshkowitz, impairment. A dosage reduction is recommended in patients with severe 2% of Patients Receiving Namenda and at a Higher Frequency than renal impairment. Placebo-treated Patients. Respiratory System: Frequent: pneumonia. Infrequent: apnea, asthma, Ph.D. This double-blind study included hemoptysis. Drug-Drug Interactions Body System Placebo Namenda 259 patients with obstructive sleep ap- N-methyl-D-aspartate (NMDA) antagonists: The combined use of Skin and Appendages: Frequent: rash. Infrequent: skin ulceration, pruritus, Adverse Event (N = 922) (N = 940) cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria. Namenda with other NMDA antagonists (amantadine, ketamine, and %% nea/hypopnea syndrome randomized to dextromethorphan) has not been systematically evaluated and such use Special Senses: Frequent: cataract, conjunctivitis. Infrequent: macula should be approached with caution. Body as a Whole lutea degeneration, decreased visual acuity, decreased hearing, tinnitus, 150 mg of armodafinil or placebo for 12 Effects of Namenda on substrates of microsomal enzymes: In vitro studies Fatigue 1 2 blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, Pain 1 3 hemorrhage, eye pain, retinal hemorrhage, xerophthalmia, diplopia, weeks. -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by Cardiovascular System abnormal lacrimation, myopia, retinal detachment. These patients were experiencing ex- memantine. In addition, in vitro studies indicate that at concentrations Hypertension 2 4 Urinary System: Frequent: frequent micturition. Infrequent: dysuria, exceeding those associated with efficacy, memantine does not induce the hematuria, urinary retention. cessive daytime sleepiness despite averag- cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5. Central and Peripheral Nervous System Events Reported Subsequent to the Marketing of Namenda, both US No pharmacokinetic interactions with drugs metabolized by these enzymes and Ex-US ing nearly 7 hours per night of CPAP. are expected. Dizziness 5 7 Although no causal relationship to memantine treatment has been found, Once again, armodafinil resulted in sig- Effects of inhibitors and/or substrates of microsomal enzymes on Namenda: Headache 3 6 the following adverse events have been reported to be temporally Memantine is predominantly renally eliminated, and drugs that are Gastrointestinal System associated with memantine treatment and are not described elsewhere in nificantly improved objective and subjec- substrates and/or inhibitors of the CYP450 system are not expected to Constipation 3 5 labeling: atrioventricular block, bone fracture, carpal tunnel syndrome, alter the metabolism of memantine. Vomiting 2 3 cerebral infarction, chest pain, claudication, colitis, dyskinesia, dysphagia, tive measures of wakefulness. In this tri- Acetylcholinesterase (AChE) inhibitors: Coadministration of Namenda with gastritis, gastroesophageal reflux, grand mal convulsions, intracranial Musculoskeletal System the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of hemorrhage, hepatic failure, hyperlipidemia, hypoglycemia, ileus, al, however, 150 mg/day of armodafinil either compound. In a 24-week controlled clinical study in patients with Back pain 2 3 impotence, malaise, neuroleptic malignant syndrome, acute pancreatitis, also significantly improved the quality of moderate to severe Alzheimer’s disease, the adverse event profile observed Psychiatric Disorders aspiration pneumonia, acute renal failure, prolonged QT interval, with a combination of memantine and donepezil was similar to that of Confusion 5 6 restlessness, Stevens-Johnson syndrome, sudden death, supraventricular long-term episodic memory, although it donepezil alone. Somnolence 2 3 tachycardia, tachycardia, tardive dyskinesia, and thrombocytopenia. Drugs eliminated via renal mechanisms: Because memantine is didn’t affect measures of attention or eliminated in part by tubular secretion, coadministration of drugs that use Hallucination 2 3 ANIMAL TOXICOLOGY the same renal cationic system, including hydrochlorothiazide (HCTZ), Respiratory System Memantine induced neuronal lesions (vacuolation and necrosis) in the speed of memory, according to Dr. triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, Coughing 3 4 multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are Hirshkowitz of the Michael E. DeBakey could potentially result in altered plasma levels of both agents. However, Dyspnea 1 2 coadministration of Namenda and HCTZ/TA did not affect the bioavailability known to occur in rodents administered other NMDA receptor antagonists. Veterans Affairs Medical Center, Houston. of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. Other adverse events occurring with an incidence of at least 2% in Lesions were seen after a single dose of memantine. In a study in which In addition, coadministration of memantine with the antihyperglycemic Namenda-treated patients but at a greater or equal rate on placebo were rats were given daily oral doses of memantine for 14 days, the no-effect Both phase III clinical trials were spon- ® dose for neuronal necrosis was 6 times the maximum recommended drug Glucovance (glyburide and metformin HCl) did not affect agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis, 2 the pharmacokinetics of memantine, metformin and glyburide. insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, human dose on a mg/m basis.The potential for induction of central neuronal sored by Cephalon Inc. ■ Furthermore, memantine did not modify the serum glucose lowering effect depression, upper respiratory tract infection, anxiety, peripheral edema, vacuolation and necrosis by NMDA receptor antagonists in humans of Glucovance®. nausea, anorexia, and arthralgia. is unknown. Drugs that make the urine alkaline: The clearance of memantine was The overall profile of adverse events and the incidence rates for individual DRUG ABUSE AND DEPENDENCE reduced by about 80% under alkaline urine conditions at pH 8. Therefore, adverse events in the subpopulation of patients with moderate to severe Controlled Substance Class: Memantine HCl is not a controlled substance. alterations of urine pH towards the alkaline condition may lead to an Alzheimer’s disease were not different from the profile and incidence Physical and Psychological Dependence: Memantine HCl is a low to 12-Week Improvement on accumulation of the drug with a possible increase in adverse effects. rates described above for the overall dementia population. moderate affinity uncompetitive NMDA antagonist that did not produce Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium Vital Sign Changes: Namenda and placebo groups were compared with any evidence of drug-seeking behavior or withdrawal symptoms upon Epworth Sleepiness Scale bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or respect to (1) mean change from baseline in vital signs (pulse, systolic discontinuation in 2,504 patients who participated in clinical trials at severe infections of the urinary tract). Hence, memantine should be used blood pressure, diastolic blood pressure, and weight) and (2) the incidence therapeutic doses. Post marketing data, outside the U.S., retrospectively with caution under these conditions. of patients meeting criteria for potentially clinically significant changes collected, has provided no evidence of drug abuse or dependence. Carcinogenesis, Mutagenesis and Impairment of Fertility from baseline in these variables. There were no clinically important OVERDOSAGE There was no evidence of carcinogenicity in a 113-week oral study in changes in vital signs in patients treated with Namenda. A comparison of Because strategies for the management of overdose are continually mice at doses up to 40 mg/kg/day (10 times the maximum recommended supine and standing vital sign measures for Namenda and placebo in 5.5 points 2 evolving, it is advisable to contact a poison control center to determine the human dose [MRHD] on a mg/m basis). There was also no evidence of elderly normal subjects indicated that Namenda treatment is not associated latest recommendations for the management of an overdose of any drug. carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks with orthostatic changes. 2 As in any cases of overdose, general supportive measures should be utilized, followed by 20 mg/kg/day (20 and 10 times the MRHD on a mg/m basis, Laboratory Changes: Namenda and placebo groups were compared with and treatment should be symptomatic. Elimination of memantine can be respectively) through 128 weeks. respect to (1) mean change from baseline in various serum chemistry, enhanced by acidification of urine. In a documented case of an Armodafinil (150 or 250 mg) Memantine produced no evidence of genotoxic potential when evaluated hematology, and urinalysis variables and (2) the incidence of patients overdosage with up to 400 mg of memantine, the patient experienced in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro meeting criteria for potentially clinically significant changes from baseline restlessness, psychosis, visual hallucinations, somnolence, stupor and chromosomal aberration test in human lymphocytes, an in vivo cytogenetics in these variables. These analyses revealed no clinically important changes loss of consciousness. The patient recovered without permanent sequelae. assay for chromosome damage in rats, and the in vivo mouse micronucleus in laboratory test parameters associated with Namenda treatment. assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells. ECG Changes: Namenda and placebo groups were compared with 3.3 points No impairment of fertility or reproductive performance was seen in rats respect to (1) mean change from baseline in various ECG parameters and administered up to 18 mg/kg/day (9 times the MRHD on a mg/m2 basis) (2) the incidence of patients meeting criteria for potentially clinically orally from 14 days prior to mating through gestation and lactation in significant changes from baseline in these variables. These analyses Placebo females, or for 60 days prior to mating in males. revealed no clinically important changes in ECG parameters associated with Namenda treatment. Pregnancy Pregnancy Category B: Memantine given orally to pregnant rats and pregnant Other Adverse Events Observed During Clinical Trials Licensed from Merz Pharmaceuticals GmbH rabbits during the period of organogenesis was not teratogenic up to the Namenda has been administered to approximately 1350 patients with Rev. 07/05 Note: Based on data for 392 patients highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, dementia, of whom more than 1200 received the maximum recommended with excessive daytime sleepiness. which are 9 and 30 times, respectively, the maximum recommended dose of 20 mg/day. Patients received Namenda treatment for periods of © 2005 Forest Laboratories, Inc. human dose [MRHD] on a mg/m2 basis). up to 884 days, with 862 patients receiving at least 24 weeks of treatment Source: Dr. Black and 387 patients receiving 48 weeks or more of treatment.