PHARMACY & FORMULARY Symptom Management Resources INSOMNIA • Algorithm for Hemodialysis Patients • Supplemental Summary • Hypnotic Monographs TABLE OF CONTENTS Insomnia Treatment Algorithm in Hemodialysis Patients . . . Insomnia Treatment Algorithm for Hemodialysis Patients: Supplemental Evidence for Treatment Options . . . . . . . . . . . . . . . . . . . . . .1 . . . . . . 2 Medications for Insomnia Trazodone (Deseryl®) . . . . . . . . . . . Zolpidem (Sublinox ) Oral Disintegrating Tablet . ® . . . . . . . . . . . . . . . . . . . . . . 3 . . . . .4 Zopiclone (Imovane®) . . . . . . . . . . . . . . . . . . . . . . . . . 5 Lorazepam (Ativan ) . . . . . . . . . . . . . . . . . . . . . . . . . 6 . . . . . . . . . . . . . . . ® Oxazepam (Serax ) . ® Temazepam (Restoril ) ® . . . . . . . . . . . . . . . . . . . . . . . . . . 7 . . . . . . 8 Insomnia Treatment Algorithm for Hemodialysis Patients Assessment • Sleep symptoms (latency, total sleep time, early and/or frequent waking, daytime impact) • Duration of symptoms • Dialysis impact on insomnia (napping on dialysis, getting up too early for AM dialysis) • Sleep hygiene assessment • Detailed medication history • Social habits – caffeine, alcohol, nicotine, other recreational drug use* Consider Etiology • • • • • • • • • • • • • Dialysis schedule related Medication related Sleep apnea Restless leg syndrome, periodic limb movement disorder Pruritus Pain Depression, anxiety Psychosocial problems Nocturia (if applicable) Heart failure COPD GERD Thyroid abnormality Medication and Causes of Insomnia* • • • • • Recreational Drugs Alcohol Amphetamines and methamphetamines Caffeine Nicotine Drug withdrawal Cardiovascular agents • Beta blockers Diuretics (if late in the day) Endocrine agents Corticosteroids Thyroid hormone Stimulants Dextroamphetamine Methylphenidate Neurologic and psychotropic agent Bupropion Lamotrigine Levodopa Phenytoin SNRI, e.g. venlafaxine SSRI, e.g. fluoxetine Miscellaneous agents Donepezil Interferon Stimulant laxatives Oral contraceptives Pseudoephedrine Salbutamol/salmeterol Theophylline *Contact pharmacist if in doubt Treatment • • Medication Options Treat/eliminate underlying cause(s) Implement good sleep hygiene measures, relaxation techniques and cognitive behavior therapy • • Minimize use after 3-4 weeks Avoid OTC sleep aids (e.g. diphenhydramine), short-acting benzodiazepine (e.g. triazolam), long-acting benzodiazepine (e.g. flurazepam or diazepam), chloral hydate, tricyclic antidepressant or antipsychotic • Usual sedative dose (give HS PRN) • Zopiclone 3.75-15 mg • Trazodone 25-100 mg (if no orthostatic hypotension) • Benzodiazepines: • Temazepam 15-30 mg • Lorazepam 0.5-2 mg • Oxazepam 10-30 mg • Zolpidem 10 mg SL (10 mg dose not recommended in elderly) • Melatonin 3 mg (note: there is NO standardization or regulation on health products in Canada; a reputable source is recommended) Reassess in 2-4 weeks Implement Good Sleep Hygiene Measures (Reassess in 2-4 weeks) Click here for link. • Wake up at the same time every morning • Do not go to bed until you feel sleepy • Do not “try” to fall asleep • Avoid napping during the day • Improve your sleep environment • Avoid caffeine in the evening • Start a regular exercise and activity program • Save your bedroom for sleep (and sex) only • Leave your day’s dilemmas at the door • Incorporate relaxation techniques INADEQUATE RELIEF • Purple: Covered by BCPRA Blue: Covered by Pharmacare Green: Special authority Black: No coverage SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 1. Insomnia Treatment Algorithm for Hemodialysis Patients Supplemental Summary Chronic insomnia in hemodialysis patients are common and likely multifactorial. It is prudent to identify and minimize contributing factors, if feasible. Chloral hydrate – contraindicated in patients with severe renal impairment; risk of overdose due to its low therapeutic index. There are increasing evidence supporting the effectiveness of both non-pharmacologic and pharmacologic therapies for insomnia; however, the literature is lacking in patients with chronic kidney disease (CKD) and therefore treatment recommendations are extrapolated from the general population. In addition, most studies assess shortterm treatment of insomnia and not the chronic issue faced by CKD patients. L-tryptophan – data on the efficacy and safety of this medication is lacking. Also, combination with other serotonergic medications, e.g. SSRIs, SNRIs, may lead to serotonin syndrome. In terms of non-pharmacological therapies, good sleep hygiene is strongly encouraged. Compliance with sleep hygiene is usually poor; hence, it is important for patients to understand that successful treatment is only possible if they are willing to change ingrained bad habits. Cognitive behavioral therapy, relaxation techniques, or structured exercise programs should also be considered either before or concurrently with pharmacological treatment. Only 2 hypnotic studies were conducted in hemodialysis patients. One randomized, doubleblind, placebo-controlled, crossover study1 compared zaleplon 10 mg PO HS (or 5 mg if age >65 years) vs. placebo x 15 days in 10 hemodialysis patients with insomnia. Zaleplon was found to improve subjective sleep quality and a reduced sleep latency from 35 to 17.6 minutes (p<0.01). Medication is mostly indicated for transient insomnia and should be reassessed after 2 to 4 weeks with the goal of minimizing its use. MEDICATIONS TO AVOID Antihistamines (over-the-counter), e.g. diphenhydramine – due to their adverse effects (anticholingeric, dizziness), residual daytime sedation, and high risk of tolerance. Antipsychotics (sedating), e.g. quetiapine, olanzapine, methotrimeprazine – due to their risk of tardive dyskinesia and anticholinergic or orthostatic hypotensive adverse effects (for traditional antipsychotics). Benzodiazepines– long-acting, e.g. flurazepam, chlordiazepoxide or diazepam – due to their residual effects (sedation, impaired cognitive and psychomotor function). Benzodiazepines– short-acting, e.g. triazolam – due to the risk of antegrade amnesia, rebound insomnia or daytime anxiety. SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A Tricyclic antidepressants, e.g. amitriptyline – due to their adverse effects (anticholinergic, cardiovascular). EVIDENCE The other randomized, double-blind, placebo controlled, crossover study2 involved melatonin 3 mg vs. placebo PO HS x 6 weeks in 20 patients. Patients reported reduced sleep latency from 44.5 to 15.5 minutes (p=0.002) and improved sleep efficiency from 67.3% to 73.1% (p=0.01) after melatonin treatment. STUDY REFERENCES 1. Sabbatini M, Crispo A, Pisani A, et al. Zaleplon improves sleep quality in maintenance hemodialysis patients. Nephron Clin Pract 2003;94:c99-103. 2. Koch BC, Nagtegaal JE, Hagen EC, et al. The effects of melatonin on sleep-wake rhythm of daytime haemodialysis patients: a randomized, placebo-controlled, crossover study (EMSCAP). Br J Clin Pharmacol 2009;67(1):68-75. GENERAL REFERENCES Gusbeth-Tatomir P, Boisteanu D, Seica A, et al. Sleep disorders: a systematic review of an emerging major clinical issue in renal patients. Int Urol Nephrol 2007;39:1217-26. Novak M, Shapiro CM, Mendelsson D, et al. Diagnosis and management of insomnia in dialysis patients. Sem Dial 2006;19:25-31. U P D AT E D N OV E M B E R 2 0 1 2 2. Hypnotics NON-BENZODIAZEPINES Trazodone (Deseryl®) Mechanism of Action Blocks reuptake of serotonin; also blocks histamine H1 and alpha-1 adrenergic receptors. Pharmacokinetics Onset: 1-3 hours Peak level 0.5-2 hours Half-life 4-7.5 hours Adverse Effects Orthostatic hypotension; headache; hangover; priapism in male (rare). Dosing Guidelines (Normal Renal Function) 12.5-25 mg PO HS PRN; may titrate by 12.5-25 mg PO weekly to a maximum of 200 mg PO HS PRN. Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage Yes Cost (30-day supply) without dispensing fee 50 mg PO HS $2.40 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 3. Hypnotics NON-BENZODIAZEPINES Zolpidem (Sublinox®) Oral Disintegrating Tablet Mechanism of Action Selective binding at 1 or more receptor subtype of GABA receptor. Pharmacokinetics Onset: 30 minutes Peak level 80 minutes Half-life ~2.5 hours Duration 6-8 hours Food delays absorption Hepatic metabolism mainly via CYP3A4 (~60%) Adverse Effects Drowsiness, dizziness, diarrhea; complex sleep-related behavior (e.g. sleep driving). Dosing Guidelines (Normal Renal Function) 10 mg SL HS PRN Note: 10 mg dose is not recommended in the elderly (SL tablets are not to be cut). Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage No Cost (30-day supply) without dispensing fee 10-mg PO HS $99.90 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 4. Hypnotics NON-BENZODIAZEPINES Zopiclone (Imovane®) *This drug needs a special authority request to be covered under Pharmacare Mechanism of Action Selective binding at 1 or more receptor subtype of GABA receptor. Pharmacokinetics Onset: 30 minutes Peak level 1-1.5 hours Half-life 5 hours Extensive hepatic metabolism via CYP3A4 and CYP2C8. Adverse Effects Drug mouth, bitter taste, possibly lower incidence of tolerance and withdrawal, complex sleep-related behavior (e.g. sleep driving). Dosing Guidelines (Normal Renal Function) 3.75-7.5 mg PO HS PRN; titrate weekly to a maximum of 15 mg PO HS PRN. Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage Special Authority is needed for the treatment of insomnia with: 1. Diagnosis of HIV/AIDS or 2. Person with identified psychiatric diagnosis or 3. Person intolerant to, or failed on, at least three specified benzodiazepines or 4. Person intolerant to, or failed on, at least two identified benzodiazepines and one other specified hypnotic agent or 5. Person with a history of drug or alcohol addiction or 6. Fragile, elderly patient Cost (30-day supply) without dispensing fee 7.5 mg PO HS $15.00 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 5. Hypnotics BENZODIAZEPINES Lorazepam (Ativan®) Mechanism of Action Binds to benzodiazepine receptors on the postsynaptic GABA; enhanced inhibitory effect of GABA on neuronal excitability by increased neuronal membrane permeability to chloride ions. Pharmacokinetics Onset: intermediate (30-60 minutes) Peak level 1-4 hours Half-life ~15 (8-24) hours. Adverse Effects Increased risk of falls/fractures, accidents, especially elderly; dependence, decreased cognition with long-term use, dizziness, incoordination; complex sleeprelated behavior (e.g. sleep driving). Dosing Guidelines (Normal Renal Function) 0.5-1 mg PO HS PRN Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage Yes Cost (30-day supply) without dispensing fee 1 mg PO HS $1.50 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 6. Hypnotics BENZODIAZEPINES Oxazepam (Serax®) Mechanism of Action Binds to benzodiazepine receptors on the postsynaptic GABA; enhanced inhibitory effect of GABA on neuronal excitability by increased neuronal membrane permeability to chloride ions. Pharmacokinetics Onset: intermediate to slow Peak level 1-4 hours Half-life ~8 (3-25) hours. Adverse Effects Increased risk of falls/fractures, accidents, especially elderly, dependence, decreased cognition with long-term use, dizziness, incoordination; complex sleep related behavior (e.g. sleep driving). Dosing Guidelines (Normal Renal Function) 10-30 mg PO HS PRN Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage Yes Cost (30-day supply) without dispensing fee 15 mg PO HS $1.80 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 7. Hypnotics BENZODIAZEPINES Temazepam (Restoril®) Mechanism of Action Binds to benzodiazepine receptors on the postsynaptic GABA; enhanced inhibitory effect of GABA on neuronal excitability by increased neuronal membrane permeability to chloride ions. Pharmacokinetics Onset: intermediate to slow Peak level 2-3 hours Half-life ~11 (3-25) hours. Adverse Effects Increased risk of falls/fractures, accidents, especially elderly, dependence, decreased cognition with long-term use, dizziness, incoordination; complex sleeprelated behavior (e.g. sleep driving). Dosing Guidelines (Normal Renal Function) 15-30 mg PO HS PRN Renal Dosing Guidelines GFR (mL/min) >50 (mL/min) 10 to 50 (mL/min) <10 (mL/min) 100% 100% 100% Supplemental Dose After IHD PD None None Pharmacare Coverage Yes Cost (30-day supply) without dispensing fee 15 mg PO HS $2.10 Return to Table of Contents SY M P TO M M A N A G E M E N T R E S O U R C E S : I N S O M N I A U P D AT E D N OV E M B E R 2 0 1 2 8.