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New Drugs III – Alendronate (Fosamax®), Dorzolamide (Trusopt®), Acarbose (Prandase®), Olanzapine (Zyprexa®)

Therapeutics Letter, issue 20, July - August 1997

Alendronate (Fosamax®)
Dorzolamide (Trusopt®)
Acarbose (Prandase®)
Olanzapine (Zyprexa®)

Alendronate (Fosamax®)

Alendronate is a bisphosphonate bone resorption inhibitor in the same class as etidronate and clodronate.

  • Indication: Treatment of osteoporosis or Paget's disease of the bone.
  • Mechanism of action: Alendronate inhibits osteoclastic bone resorption.
  • Pharmacokinetics: Oral bio-availability is very low (0.7%) and is substantially diminished by food or fluids. A proportion of absorbed drug becomes incorporated into bone. Inactivated primarily by renal elimination.
  • Evidence of effectiveness: Two trials compare the effectiveness of alendronate to placebo in postmenopausal women. In one methodologically weak trial (1) 994 women, with extremely low bone mineral density (BMD) of the lumbar spine (>2.5 SD below the mean) were randomized to placebo or alendronate and followed for 3 years. In those with no previous fracture (79% of total), alendronate reduced the incidence of new vertebral fractures detected by xray from 2% to 1%, absolute risk reduction (ARR) = 1%, number needed to treat (NNT) =100 for 3 years. In the other trial (2) 2027 women with pre-existing pathologic fractures were randomized to placebo or alendronate. Alendronate reduced the incidence of symptomatic (painful) fractures from 18.2% to 13.6%, ARR = 4.6%, NNT = 22 for 3 years. In Paget's disease one randomized trial (3) in 89 patients, compared 6 months of alendronate, 40 mg/day, with etidronate, 400 mg/day. Decrease in alkaline phosphatase, the primary measure of effect, was greater with alendronate, 79%, than etidronate, 44%.
  • Major adverse effects: The placebo-controlled trials (1),(2) reported no increased evidence of adverse events including upper gastrointestinal problems with alendronate. Adverse events from post-marketing data (4) reveal a major concern with severe esophageal injury (51 reports) most often occurring during the first month of therapy.
  • Dose and cost: Osteoporosis: 10 mg daily ($1.75/day). Take on an empty stomach with >200 ml of water in AM; remain upright for > 30 minutes after ingestion to prevent esophageal injury. Paget's disease of bone, 40 mg daily ($4.66/day) for 6 months.
  • Conclusions: In women with extremely low BMD, 100 need treatment for 3 years to prevent 1 fracture detected on x-ray. In women with a previous pathologic fracture, 22 need treatment for 3 years to prevent one symptomatic fracture.

Dorzolamide (Trusopt®)

Dorzolamide is a carbonic anhydrase inhibitor for topical ocular administration.

  • Indication: Chronic treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
  • Mechanism of action: Dorzolamide is a sulfonamide which inhibits carbonic anhydrase II in the ciliary processes of the eye resulting in decreased aqueous humor secretion.
  • Pharmacokinetics: Dorzolamide acts locally and is absorbed systemically. The systemic effect accumulates over time, but there is no evidence in trials to date that this leads to significant metabolic acidosis. Inactivated primarily by renal elimination.
  • Evidence of efficacy: Dorzolamide 2% TID has been shown in double-masked placebo controlled trials to lower intraocular pressure by 3-5 mm Hg (5). When compared with timolol 0.5% BID, in a large multicentre trial (n = 184), the mean per cent reduction in intraocular pressure was greater for timolol, 29%, than for dorzolamide, 24% (6). Dorzolamide efficacy is similar to pilocarpine when used as adjunctive therapy to timolol (7).
  • Major adverse effects: Bitter taste occurs frequently (25%) but is usually transient. Local irritation (incidence 10%), stinging, itching, and conjunctivitis occur more frequently than with timolol (6) and may necessitate stopping therapy.
  • Dose and cost: Dorzolamide 2% TID ($0.90/day) as compared to timolol 0.5% BID ($0.34/day) and pilocarpine 2% TID ($0.06/day).
  • Conclusions: Dorzolamide provides a clear therapeutic advantage over oral carbonic anhydrase. It should be reserved for patients in whom topical beta blockers or pilocarpine are not tolerated or ineffective. More safety and effectiveness evidence is needed.

Acarbose (Prandase®)

Arcarbose is a new antidiabetic drug that acts by a unique mechanism of action. It inhibits hydrolysis of complex starches to glucose in the small intestine.

  • Indication: As adjunctive therapy to diet in the treatment of patients with non-insulin dependent diabetes mellitus (NIDDM).
  • Mechanism of action: Acarbose lowers postprandial glucose concentrations by competitive inhibition of pancreatic alpha-amylase and intestinal membrane-bound alpha-glucoside hydrolases.
  • Pharmacokinetics: Acts locally in the gastrointestinal tract and less than 2% is absorbed in active form. Inactivated by metabolism by intestinal bacteria or eliminated unchanged in feces.
  • Evidence of efficacy: Over 50 published controlled trials of the effects of acarbose dating back to 1979, have examined the effects of acarbose. In a Canadian multicenter randomized controlled trial (8) (354 NIDDM patients), for example, acarbose decreased HbA1C levels by 0.9% as compared to placebo over a 1 year period in 3 groups of patients already treated with diet, sulfonylureas or metformin. Acarbose has more effect on post-prandial than fasting glucose and does not lead to increase in insulin concentrations or weight gain.
  • Major adverse effects: Mainly gastrointestinal side effects. In the Canadian trial for example: flatulence, absolute risk increase (ARI) =34%, diarrhea, ARI = 23%, and abdominal cramps and discomfort, ARI = 16%. Also noted: a low incidence of reversible elevations of serum transaminases and bilirubin.
  • Dose and cost: Acarbose 25-100 mg TID taken with the first bite of meals ($0.34 - $0.94/day). Metformin 0.5-2.5 g/day ($0.14 - $0.69/day). Glyburide 2.5 mg daily to 10 mg BID ($0.04 - $0.29/day).
  • Conclusions: Acarbose can be used as an adjunct to diet and other oral agents to achieve glucose control in patients with NIDDM. Its main disadvantages are cost and the high incidence of gastrointestinal side effects.

Olanzapine (Zyprexa®)

Olanzapine is an atypical antipsychotic drug that structurally resembles and binds to some of the same receptors as clozapine (Clozaril®).

  • Indication: Treatment of schizophrenia and other psychotic disorders.
  • Mechanism of action: The drug binds to multiple receptors: serotonergic, dopaminergic, histaminergic H1, alpha1-adrenergic, and muscarinic. The role these actions play in its efficacy and toxicity is unknown.
  • Pharmacokinetics: Oral bioavailability is good. Inactivated primarily by liver metabolism. Elimination half-life of about 30 hours.
  • Evidence of effectiveness: There are two published randomized controlled six-week trials. One (N=335) compared three doses of olanzapine, 7 ± 1 mg/day, 12 ± 2 mg/day and 16 ± 2 mg/day, to placebo and haloperidol, 16±4 mg/day (9). The other (10) (N=1,996) compared a titrated dose of olanzapine (13.2 mg/day) with a titrated dose of haloperidol (11.8 mg/day). The first study showed modest efficacy for the highest dose of olanzapine (48% with >40 % improvement in Brief Psychiatric Rating Scale) which was similar to that with haloperidol (47%). In the second study the response to olanzapine was better than to haloperidol, however, the efficacy of both drugs was less than the first. The poor response to haloperidol in the second study was likely because 77% of the patients entered were intolerant or unresponsive to their last course of antipsychotic therapy. Olanzapine (mean modal dose 17 mg/day) has also been compared to risperidone (mean modal dose 7 mg/day) in an unpublished 8-week interim analysis of a 28-week double-blind trial. The response rates at 8 weeks (> 40% improvement) were similar for olanzapine, 29% and risperidone, 26%.
  • Major adverse effects: In the RCTs with haloperidol the incidence of extrapyramidal side effects (dystonia, akathesia, tremor,and hypertonia) was less for olanzapine than that with haloperidol, however, the incidence of other side effects (constipation, dry mouth, weight gain and elevated ALT values) were greater for olanzapine. In the RCT with risperidone the incidence of any extrapyramidal event at 8 weeks was greater with risperidone (27%) than with olanzapine (17%). Neutropenia has been documented with olanzapine in at least 3 cases in Vancouver (11).
  • Dose and cost: Single daily doses of 10 to 20 mg. ($6.75 - $13.50/day) as compared to haloperidol (Haldol®) 5-20 mg daily ($0.16-0.52/day), risperidone (Risperdal®), 1-4 mg BID ($2.09-8.35/day), and clozapine (Clozaril®), 100 mg BID to 200 mg TID ($7.58-22.74/day).
  • Conclusion: Olanzapine is effective in the symptomatic management of schizophrenia and has fewer extrapyramidal side effects in short-term trials. Long-term effectiveness and safety remain to be established. In the meantime it should be reserved for patients who are refractory to or demonstrate significant intolerance to standard antipsychotic therapy.
Note: see Therapeutics Letter 15 for definition and calculation of ARR, ARI and NNT.

References:

  1. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443.
  2. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541.
  3. Weinstein SE, Altman R, Conte JM, et al. Comparative study of alendronate versis etidronate for the treatment of Paget's disease of bone. J Clin Endocrin Metab 1996;81:961-967.
  4. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;334:1016-21.
  5. Wilkerson M, Cyrlin M, Lippa EA, et al. Four week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch Ophthal 1993;111:1343-1350.
  6. Heijl A, Strahlman E, Sverrisson T, et al. A comparison of dorzolamide and timolol in patients with pseudoexfoliation and glaucoma or ocular hypertension. Ophthalmology 1997;104:137-142.
  7. Strahlman ER, Vogel R, Tipping R, et al. The use of dorzolamide nad pilocarpine as adjunctive therapy to timolol in patients with elevated intraocular pressure. Ophthalmology 1996;103:1283-1293.
  8. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med 1994;121:928-935.
  9. Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol. Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996;14: 111-123.
  10. Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: Results of an international collaborative trial. Am J Psychiatry 1997;154: 457-465.
  11. Shalansky K. Olanzapine: Atypical antipsychotic. Drug and Therapeutics Newsletter 1997;4: 2-3.
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