|The Therapeutics Initiative presents critically appraised summary evidence primarily from controlled drug trials. Such evidence applies to patients similar to those involved in the trails, and may not be generalizable to every patient. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare/PharmaNet databases without identifying individual physicians, pharmacies or patients. The Therapeutics Initiative is funded by the BC Ministry of Health through a 5-year grant to the University of BC. The Therapeutics Initiative provides evidence based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.|
Click here to download a printable version of this Therapeutics Letter in Adobe Acrobat PDF format (100 KB).
Approved indication: “Symptomatic relief of depressive illness.” 1
Mechanism of action:
As with all antidepressants the mechanism of therapeutic benefit is unknown. It is an inhibitor of a number of receptors including adrenergic, serotonergic, histaminic and muscarinic. It is classified as an atypical antidepressant and is unrelated to tricyclics, selective serotonin reuptake inhibitors or monoamine oxidase inhibitors.
Pharmacokinetics: Mirtazapine is inactivated by liver metabolism. Mean half-life is 26 hours for men and 37 hours for women; half-life is prolonged in the elderly and in the presence of liver and renal disease.1
Evidence of efficacy: The effectiveness of mirtazapine for use longer than 6 weeks has not been systematically evaluated in controlled clinical trials. The one longer-term study only followed a subset of treatment responders, invalidating randomization and thus interpretation.2 Two randomized controlled trials (RCT) claim an advantage for mirtazapine 3, 4 and one does not. 5 Twelve randomized controlled trials 5-18 and three meta-analyses 19-21 evaluated mirtazapine compared to other antidepressants, including amitriptyline, clomipramine, doxepin, trazodone, paroxetine, citalopram and fluoxetine. The main efficacy measure was symptomatic improvement as indicated by a ≥ 50% reduction from baseline in the Hamilton Depression Rating Scale (HAM-D) or by a score of ≤ 7, signifying remission of depression. Between 20-40% of patients in these 5-6 week trials were lost to follow-up, weakening the validity of study results, and no consistent advantage or disadvantage was observed for mirtazapine. Doses of mirtazapine and comparators varied considerably between trials.
Adverse effects: The common and serious adverse effects (from the product monograph) expressed as absolute risk increase over placebo are as follows: somnolence 36%, increased appetite 15%, dry mouth 10%, weight gain 10%, elevated cholesterol 8%, constipation 6%, dizziness 4%, liver enzyme elevations (ALT >3 times normal) 2%, neutropenia 1.5%, mania/hypomania 0.2%, agranulocytosis 0.07%, and seizure 0.03%. 1
and cost: Approved dose is 15-45 mg/day
($0.69 -$ 2.06/day).
The three least expensive antidepressants in B.C. are: amitriptyline (Elavil®, generic) 75-300 mg/day ($0.04 – $0.16/day), imipramine (Tofranil®, generic) 75-300 mg/day ($0.05 – $0.17/day) and trimipramine (Surmontil®, generic) 75-300 mg/day ($0.55 – $1.11/day).
The three most expensive antidepressants in B.C. are: sertraline (Zoloft®) 50-200 mg/day ($1.31 – $2.80/day), venlafaxine (Effexor®) 75-300 mg/day ($1.64 – $3.50/day) and paroxetine (Paxil®) 20-50 mg/day ($1.76 – $3.64/day).
Conclusion: Mirtazapine has no proven efficacy or safety advantage over other antidepressant therapies. It has a prominent sedative effect and patients should be warned that it may cause mental or motor impairment. Longer-term trials with adequate follow-up are needed.
Approved indication: “Treatment of diagnosed postmenopausal osteoporosis in females greater than 5 years postmenopause with low bone mass relative to healthy premenopausal females.” 22
Mechanism of action: Salmon-calcitonin inhibits bone resorption by reducing the activity of osteoclasts; it has 40-50 times more affinity for cell surface receptor binding sites than mammalian calcitonins. The mechanism of the acute analgesic effect of salmon-calcitonin is unknown. 23
Pharmacokinetics: The bioavailability of salmon-calcitonin nasal spray is 3-50% relative to intramuscular administration. The drug is rapidly absorbed by the nasal mucosa. The elimination half-life is about 45 minutes. 22
of efficacy: Two RCTs have assessed the efficacy of salmon
calcitonin nasal spray on the rates of vertebral collapse (radiographically-detected)
and non-vertebral fractures in postmenopausal women with bone mineral density (BMD)
levels 2 standard deviations or more below mean values of 30 year old women. 24,
25 The first RCT, a 2-year dose-response study, had a sample size too
small to detect differences in fracture rates.
The PROOF study was a 5-year study that randomized participants with at least one vertebral collapse at baseline to receive 100, 200 or 400 IU of salmon-calcitonin, or placebo. The primary endpoint was the incidence of new vertebral collapse compared to placebo. In 817 patients with vertebral fractures at baseline and follow-up radiographs, 21.3% taking 200 or 400 IU salmon calcitonin vs. 29.6% taking placebo experienced ≥ 1 new collapse (RR 0.72 [0.54-0.96], ARR 8.3%, NNT = 12 for 3 years). There was no effect of the drug on non-vertebral or symptomatic fractures. Fifty-nine percent of the 1255 participants withdrew from the study prematurely.
Adverse effects: Rhinitis (nasal congestion, nasal discharge, or sneezing) occurred in 22% of participants receiving salmon-calcitonin vs. 15% of placebo participants in the PROOF study (ARI 7%).
Dose and cost: The recommended dose is 200 IU (one spray) daily ($1.48/day). Nostrils are to be alternated. It should be taken in conjunction with at least 1000 mg elemental calcium per day and 400 IU vitamin D per day. Other drugs for the same indication are: etidronate (Didrocal®) one tablet daily ($0.43/day), alendronate (Fosamax®) 10 mg daily ($1.84/day), risedronate (Actonel®) 5 mg daily ($1.93/day), raloxifene (Evista®) 60 mg daily ($1.69/day).Conclusion: Salmon-calcitonin nasal spray reduces radiographically-detected new vertebral collapse in patients with at least one vertebral collapse and low BMD (ARR 8.3%), but has no effect on non-vertebral fractures. Long term compliance is poor, even in a trial setting.
Approved indications for both: “acute sinusitis, community-acquired pneumonia (CAP) and acute exacerbation of chronic bronchitis (AECB). 26, 27 Additional indications for gatifloxacin are uncomplicated and complicated UTI, pyelonephritis and uncomplicated gonorrhoea.” 26
Mechanism of action: similar to other fluroquinolone antibiotics.
Pharmacokinetics: Both are well absorbed with half-lives of 12 hours. Gatifloxacin is eliminated by the kidney and moxifloxacin is metabolized by the liver. 26, 27
of effectiveness: Gatifloxacin has been compared with other
antibiotics in 9 double blind RCTs. Eight of these trials show clinical efficacy
ranging from 88 to 98%, which was not different from levofloxacin, ofloxacin,
clarithromycin and erythromycin in the treatment of acute sinusitis, CAP, AECB,
UTI and gonorrhoea. 28-35 In one trial, gatifloxacin was
significantly more effective than cefuroxime axetil (ARR 12%) in the treatment
of AECB. 36
Moxifloxacin has been compared with other antibiotics in 10 double blind RCTS. These trials show clinical efficacy for the treatment of acute sinusitis, CAP and AECB ranging from 88 to 97%, which was similar to levofloxacin, cefuroxime axetil, clarithromycin, amoxicillin, or azithromycin (87 to 95%). 37-48
Adverse effects: Gatifloxacin and moxifloxacin have tolerability profiles similar to other fluroquinolones. Adverse effects include: gastrointestinal upset [nausea, diarrhoea, vomiting and abdominal pain], headache, and dizziness. Adverse effects reported since marketing are ventricular tachycardia, renal failure, peripheral neuropathy, myositis, and tendonitis. 26, 27
Dose and cost: Gatifloxacin (Tequin®), 400mg once daily ($5.36/day), Moxifloxacin (Avelox®), 400mg once daily ($5.36/day), ciprofloxacin (Cipro®) 250 to 500 mg BID ($4.76 – 5.40/day) ofloxacin* (Floxin®, generic) 400 mg BID ($3.81/day) levofloxacin* (Levaquin®), 250 to 500 mg daily ($4.85 – 5.52/day). *See Therapeutics Letter #26.Conclusion: Gatifloxacin and moxifloxacin have no proven clinical advantages over other fluroquinolones, macrolides or amoxicillin. Based on cost they are not first choice drugs for their approved indications.
ARR=Absolute Risk Reduction
NNT=Number Needed to Treat to prevent one event
ARI=Absolute Risk Increase
|This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to March, 2002. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 50 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians.|
Khan MC. A randomized, double-blind placebo-controlled 5-weeks’
study of Org 3770 (mirtazapine) in major depression. Human
Psychopharmacology 1995; 10(SUPPL. 2): S119-S124
Claghorn JL, Lesem MD. A double-blind placebo-controlled study of Org
3770 in depressed outpatients. J Affect Disord 1995; 34:165-171
Vartiainen H, Leinonen E. Double-blind study of mirtazapine and
placebo in hospitalized patients with major depression. Eur
Neuropsychopharmacol 1994; 4:145-150
Smith WT, Glaudin V, Panagides J, Gilvary E. Mirtazapine vs.
amitriptyline vs. placebo in the treatment of major depressive disorder. Psycopharmacol
Bull 1990; 26:191-196
Bremner JD, Smith WT. Org 3770 VS amitriptyline in the continuation
treatment of depression: A placebo controlled trial. Eur J Psychiatr 1996;
Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo
controlled trial in depressed elderly patients. Human Psychopharmacology
Bruijn JA, Moleman P, Mulder PGH et al. A double blind, fixed
blood-level study comparing mirtazapine with imipramine in depressed
in-patients. Psychopharmacology (Berl) 1996; 127:231-237
Hoyberg OJ, Maragakis B, Mullin J et al. A double-blind multicentre comparison of
mirtazapine and amitriptyline in elderly depressed patients. Acta Psychiatr
Scand 1996; 93:184-190
Lodge A, Bennie E et al. A multicentre, double-blind, amitriptyline-controlled
study of mirtazapine in patients with major depression. Journal of
Psychopharmacol 1996; 10:235-240
Richou H, Ruimy P, Charbaut J et al. A multicentre, double-blind, clomipramine-controlled
efficacy and safety study of Org 3770. Human Psychopharmacology 1995;
Zivkov M, De Jongh GD. Org 3770 versus amitriptyline: a 6-week randomized double-blind
multicentre trial in hospitalized depressed patients. Human
Psychopharmacology 1995; 10:173-180
Marttila M, Jaaskelainen J, Jarvi R et al. A double-blind study comparing the efficacy
and tolerability of mirtazapine and doxepin in patients with major depression.
Eur Neuropsychopharmacol 1995; 5:441-446
O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major
depression. J Clin Psychiatry 2000; 61:656-663
Leinone E, Skarstein J, Behnke K et al. Efficacy and tolerability of mirtazapine versus
citalopram: a double-blind, randomized study in patients with major depressive
disorder. Nordic Antidepressant Study Group. Int Clin Psychopharmacol 1999;
DP, van Moffaert M, Timmerman L, Kremer CM.
Mirtazapine: efficacy and tolerability in comparison with fluoxetine
in patients with moderate to severe depressive disorder. J Clin Psychiatry
Moffaert M, de Wilde J, Vereecken A et al. Mirtazapine is more effective than
trazodone: a double-blind controlled study in hospitalized patients with major
depression. Int Clin Psychopharmacol 1995; 10:3-9
Stahl S, Zivkov M, Reimitz PE et al. Meta-analysis of randomized double-blind
placebo-controlled efficacy and safety studies of mirtazapine versus
amitriptyline in major depression. Acta Psychiatr Scand Suppl 1997;
J, Barkin RL. A Meta-analysis of eight randomized double-blind controlled
trials of mirtazapine for the treatment of patients with major depression and
symptoms of anxiety. J Clin Psychiatry 1998; 59:123-127
Roes KCB, Pols AG. Efficacy of Org 3770 (mirtazepine) vs amitriptyline in
patients with major depressive disorder: A meta-analysis. Human
Psychopharmacology 1995; 10(SUPPL. 2): S135-S145.
Novartis Pharmaceuticals. Synthetic calcitonin (Salmon) nasal spray (Miacalcin
NS). Bone Metabolism Regulator. Product
Monograph. Ottawa, 2000.
GP, Paspati I, Karachalios T, et al. Pain relief from nasal salmon calcitonin
in osteoporotic vertebral crush fractures: A double-blind, placebo-controlled
clinical study. Acta Orthop Scand Suppl 1997; 275:112-114.
K, Hansen, MA, Jensen, SB, Christiansen, C. Effect of salmon-calcitonin given
intranasally on bone mass and fracture rates in established osteoporosis: a
dose-response study. BMJ 1992; 305:556-561.
CH 3rd, Silverman S, Andriano KA. A randomized trial of nasal spray salmon
calcitonin in postmenopausal women with established osteoporosis: the prevent
recurrence of osteoporotic fractures study. Am
J Med 2000; 109:267-276.
Gatifloxacin. (Tequin®) Fluoroquinolone antibiotic. Product
Moxifloxacin hydrochloride (Avelox®). Fluroquinolone antibiotic.
Fogarty C, McAdoo M, Paster RZ et al.
Gatifloxacin vs clarithromycin in the management of acute sinusitis. J
Respir Dis 1999; 20(11 Suppl):S17-21.
Sullivan JG, McEl
Ramirez JA, Nguyen T-H, Tellier G et al. Treating community-acquired
pneumonia with once-daily gatifloxacin vs twice-daily clarithromycin. J Respir
Dis 1999; 20(11 Suppl):S40-48.
Fogarty C, Dowell M, Ellison WT et al. A comparison gatifloxacin and
ceftriaxone/clarithromycin in the treatment of community acquired pneumonia
requiring hospitalization. J Respir Dis 1999; 20(11 Suppl):S60-69.
Saito A, Koike T, Takeichi K et al. A double
blind comparative study of gatifloxacin
and levofloxacin in pneumonia. Japanese
Journal of Chemotherapy 1999; 47:712-33.
Gotfried MH, DeAbate CA, Fogarty C et al. Comparison of 5-day,
short-course gatifloxacin therapy with 7-day gatifloxacin therapy and 10-day
clarithromycin therapy for acute exacerbation of chronic bronchitis. Clin Ther.
Y, Ban Y, Kumamoto Y et al. Comparative study on gatifloxacin
and levofloxacin in complicated urinary tract infections. Japanese Journal of
Chemotherapy 1999; 47:662-679.
Stoner BP, Douglas JM. Jr., Martin DH et al.
Single-dose gatifloxacin compared with ofloxacin for the treatment of
uncomplicated gonorrhea: a randomized, double-blind, multicenter trial. Sex
Transm Dis 2001; 28:136-142.
CA, McIvor RA, McElvaine P et al. Once-daily gatifloxacin vs twice-daily
cefuroxime axetil in the treatment of acute exacerbations of chronic bronchitis.
J Respir Dis 1999; 20(11 Suppl):S23-29.
R, Gehanno P, Nikolaidis P et al. A comparison of the safety and efficacy of
moxifloxacin (BAY 12-8039) and cefuroxime axetil in the treatment of acute
bacterial sinusitis in adults. The Sinusitis Study Group. Respir Med 2000;
Burke T. Villanueva C, Mariano H. Jr. et al. Comparison
of moxifloxacin and cefuroxime axetil in the treatment of acute maxillary
sinusitis. Clin Ther 1999; 21:1664 – 1677.
D. Bruya T. Kureishi A. et al. Short-course
versus 7-day levofloxacin therapy for treatment of acute exacerbations of
chronic bronchitis. Today's Therapeutic Trends 2001; 19:117-136
Moxifloxacin HCl compared with azithromycin for acute exacerbation of chronic
bronchitis. Journal Pharm Technol
S., DeAbate A, Haverstock, et al. Short course of moxifloxacin therapy for
treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis
Study group. Respir Med 2000; 94:18-27.
CA. Mathew CP. Warner JH. et al. The
safety and efficacy of short course (5-day) moxifloxacin vs. azithromycin in the
treatment of patients with acute exacerbation of chronic bronchitis. Respir Med
Kubin R, Ballin I et al. Five-day moxifloxacin therapy compared with 7-day
clarithromycin therapy for the treatment of acute exacerbation of chronic
bronchitis. J Antimicrob Chemother 1999; 44 :501-513.
Jr. Larsen LS. Fogarty CM. et al. Safety
and efficacy of sequential (IV to PO) moxifloxacin
for the treatment of community-acquired pneumonia in hospitalized patients.
Today's Therapeutic Trends 2001;19: 251-270.
Petitpretz P. Arvis P. Marel M. et al. Oral moxifloxacin
vs high-dosage amoxicillin in the treatment of mild-to-moderate,
community-acquired, suspected pneumococcal pneumonia in adults. Chest. 2001;
G. Meyer HP. Winter J. Verhoef L. The efficacy and safety of two oral moxifloxacin regimens compared to oral clarithromycin in the treatment of
community-acquired pneumonia. Respir Med. 2001; 95:
Pearl J, Williams J et al. Efficacy and safety of ten-day moxifloxacin 400 mg
once daily in the treatment of patients with community acquired pneumonia.
Community Acquired Pneumonia Study Group. Respir Med. 2000; 94:97-105.
C, Grossman C. Williams J et al. Efficacy and safety of moxifloxacin vs
clarithromycin for community acquired-pneumonia. Infect Med 1999; 16:748-763.
Please send feedback!
Back to Therapeutics Letter.
Back to the Therapeutics Initiative Home Page.
©Therapeutics Initiative. Last updated: May 31, 2002.