(Aust Prescr 2002;25:120-3)
Some of the views expressed in the following notes on newly approved products should be regarded as tentative, as there may have been limited published data and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. As a result of fuller experience, initial comments may need to be modified. The Committee is prepared to do this. Before new drugs are prescribed, the Committee believes it is important that full information is obtained either from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Solian (Sanofi-Synthelabo)
100 mg, 200 mg and 400 mg film-coated tablets
Approved indication: schizophrenia
Australian Medicines Handbook section 18.2
Amisulpride is a benzamide antipsychotic which antagonises dopamine receptors.
It binds to the D2 and D3 dopamine receptors, but has little affinity for muscarinic
or serotonin receptors. This pattern of activity differs from that seen with
atypical antipsychotics.
The oral formulation has a bioavailability of 48%, but is not extensively
metabolised. Most of the drug is excreted unchanged, with an elimination half-life
of 12 hours. Clearance is reduced in patients with renal impairment.
A meta-analysis of trials which compared amisulpride with conventional antipsychotic
drugs found that it had greater efficacy in patients with acute schizophrenia.1 Amisulpride
has been compared with haloperidol in patients with chronic schizophrenia.
After one year, a study of 60 in-patients found no significant difference in
overall efficacy, but there was a trend suggesting amisulpride may be more
beneficial for negative symptoms.2 Another
larger study (488 patients) also found that amisulpride had a greater effect
than haloperidol on negative symptoms.3
Like the atypical antipsychotics, amisulpride causes fewer extrapyramidal
adverse effects than conventional drugs. Its extrapyramidal effects are dose
related. Common adverse effects include insomnia, anxiety, agitation and weight
gain. The release of prolactin may result in problems such as galactorrhoea
and amenorrhoea. There is a potential for amisulpride to cause torsade de pointes
as it prolongs the QT interval. Amisulpride is therefore contraindicated in
combination with other drugs which cause QT prolongation. Caution is also advised
if the patient is taking diuretics or other drugs which may cause hypokalaemia.
While amisulpride has effects which are similar to those of the atypical antipsychotics,
there is little information about the relative benefits. One eight-week study
found amisulpride and risperidone had similar efficacy in acute schizophrenia.4
References
1. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride,
an unusual ‘atypical’ antipsychotic: a meta-analysis of randomized
controlled trials. Am J Psychiatry 2002;159:188-90.
2. Speller JC, Barnes TR, Curson DA, Pantelis C, Alberts
JL. One year, low-dose neuroleptic study of in-patients with chronic schizophrenia
characterised by persistent negative symptoms. Br J Psychiatry 1997;171:564-8.
3. Colonna L, Saleem P, Dondey-Nouvel L, Rein W. Long-term
safety and efficacy of amisulpride in subchronic or chronic schizophrenia.
Int Clin Pychopharmacol 2000;15:13-22.
4. Peuskens J, Bech P, Möller HJ, Bale R, Fleurot
O, Rein W. Amisulpride vs. risperidone in the treatment of acute exacerbations
of schizophrenia. Psychiatry Res 1999;88:107-17.
Modavigil (CSL)
100 mg tablets
Approved indication: narcolepsy
Australian Medicines Handbook section 16.8.3
In addition to disturbing sleep, narcolepsy is associated with excessive sleepiness
during the day. A multiple sleep latency test can help to confirm the diagnosis.1 Treatment
of daytime sleepiness may require the use of psychostimulants. Modafinil
now offers an alternative to dexamphetamine and methylphenidate.
The mechanism of action of modafinil is unclear. It does not bind with receptors for noradrenaline, dopamine or serotonin.
Patients take a single dose in the mornings. This is rapidly absorbed with
the peak plasma concentration being achieved within four hours. Modafinil is
eliminated mainly by metabolism, with most of the metabolites being excreted
in the urine. Cytochrome P450 3A4 may be involved in the metabolism so there
is a potential for interactions with inducers and inhibitors of this enzyme.
Modafinil may also induce its own metabolism.
Two clinical trials compared different doses (200 mg and 400 mg) of modafinil
with placebo.2,3 Several
tests such as the Epworth sleepiness scale1 were
used to assess the outcomes. Both doses of modafinil improved the patients’ symptoms,
but not all of the changes were significantly greater than placebo.3
During these trials approximately 5% of patients withdrew because of adverse
effects. Common adverse reactions while taking modafinil included headache,
nausea and nervousness. Like other stimulants, modafinil has some euphoric
effects so there is the possibility that it could be abused.
While the 400 mg dose is well tolerated it has no significant advantage over
the 200 mg dose. Approximately 60% of patients will improve with 200 mg daily
(38% of patients will improve with a placebo). Some of the significant improvements
may be of questionable clinical relevance. For example, patients can stay awake
for five minutes if they are taking a placebo and for eight minutes if they
are taking modafinil. Continuous treatment may result in reduced plasma concentrations
of modafinil when it induces it own metabolism. As the double-blind clinical
trials only lasted for nine weeks it is not known if modafinil is effective
in long-term treatment of narcolepsy. It has no role in patients complaining
of a general tiredness or lack of energy.
References
1. Southcott AM. Sleep
studies. Aust Prescr 1998;21:40-3.
2. US Modafinil in Narcolepsy Multicenter Study Group.
Randomized trial of modafinil for the treatment of pathological somnolence
in narcolepsy. Ann Neurol 1998;43:88-97.
3. US Modafinil in Narcolepsy Multicenter Study Group.
Randomized trial of modafinil as a treatment for the excessive daytime somnolence
of narcolepsy. Neurology 2000;54:1166-75.
Peg-Intron (Schering-Plough)
vials containing 50, 80, 100, 120 and 150 microgram as powder for injection
Approved indication: chronic hepatitis C
Australian Medicines Handbook section 14.2.2
The treatment of choice for chronic hepatitis C is ribavirin in combination
with interferon alfa-2b.1 This interferon has to be given by injection three
times a week. To reduce the frequency of injections interferon alfa-2b has
been conjugated with polyethylene glycol to produce peginterferon which has
a reduced renal clearance.
Peginterferon is injected once a week. The site of the subcutaneous injection
should be varied with each dose. Plasma concentrations reach a maximum 15-44
hours after the injection and are sustained for 48-72 hours. The elimination
half-life of interferon alfa-2b is about seven hours and renal clearance accounts
for 80% of the total clearance. Conjugation with polyethylene glycol reduces
renal clearance to 30% of the total and increases the elimination half-life
to 40 hours.
The efficacy of peginterferon has been assessed in 1219 previously untreated
patients with chronic hepatitis C confirmed by liver biopsy. Patients were
randomised to receive interferon alfa-2b three times a week or a weekly injection
of one of three different doses of peginterferon. They were treated for 48
weeks. Six months after completing treatment, 12% of the patients taking interferon
alfa-2b had undetectable concentrations of hepatitis C RNA and normal concentrations
of alanine aminotransferase (see â↚¬ËœHepatitis
C: diagnosis and monitoringâ↚¬â†žÂ¢ Aust Prescr 1999;22:91-4). This response
was significantly less than the 18-25% of the patients who responded to peginterferon.
Although all the doses of peginterferon were efficacious, the recommended
dose is 0.5 microgram/kg. The dose may be doubled for patients infected with
genotype 1 virus. (This genotype is associated with a poor response to interferon.)
If the virus is still present after six months of treatment, peginterferon
should be stopped.
Peginterferon causes more injection site reactions than interferon alfa-2b,
but overall the pattern of adverse reactions is similar. Common complaints
are flu-like symptoms in the first few weeks of treatment, headache, tiredness,
myalgia and fevers. As granulocytopenia occurs in 4-7% of cases, patients with
fever require investigation. Thrombocytopenia can also occur. Patients should
have their eyes examined before treatment as the interferons can cause ophthalmological
problems such as retinal haemorrhages. Interferon alfa-2b may also exacerbate
psoriasis. Some patients develop depression during treatment, so a previous
history of a serious psychiatric condition is a contraindication to treatment.
While peginterferon is used to treat chronic hepatitis, it is not recommended
for patients with severe hepatic dysfunction.
Although more patients respond to peginterferon than interferon alfa-2b the
response rate is much lower than the 43% seen with the combination of interferon
alfa-2b and ribavirin.1 Another
trial therefore studied the effectiveness of peginterferon in combination with
ribavirin.
This open trial randomised 1530 previously untreated patients to take either
interferon alfa-2b and ribavirin or one of two regimens of peginterferon alfa-2b
and ribavirin. The patients were treated for 48 weeks then followed up for
another 24 weeks. Viral RNA was undetectable in 47% of the patients given interferon
alfa-2b or the lower dose regimen of peginterferon alfa-2b. In patients who
had taken a higher dose (1.5 microgram/kg/week) of peginterferon the response
was 54% - a statistically significant advantage. This regimen was also advantageous
for patients with the genotype 1 virus. A sustained virological response was
found in 42% compared with 33% of the patients given interferon alfa-2b. The
higher dose, however, resulted in more frequent adverse reactions including
neutropenia.2
Although the high dose regimen produces a bigger response in patients with
genotype 1 virus it has no significant advantage over lower doses or interferon
alfa-2b for patients infected with other genotypes. Identifying the best regimen
will require further research to clarify the most effective dose of ribavirin.
Despite these issues, the combination of peginterferon alfa-2b and ribavirin
may become the treatment of choice for chronic hepatitis C, if it is found
to be cost-effective.
References
1. International Hepatitis Interventional Therapy Group.
Randomised trial of interferon a2b plus ribavirin for 48
weeks or for 24 weeks versus interferon a2b plus placebo
for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet
1998;352:1426-32.
2. International Hepatitis Interventional Therapy Group.
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus
ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
Lancet 2001;358:958-65.
Edronax (Pharmacia)
4 mg tablets
Approved indication: major depression
Australian Medicines Handbook section 18.1
Reboxetine inhibits the reuptake of noradrenaline, but has little effect on
the reuptake of serotonin or dopamine. This gives it a relatively selective
mechanism of action on neurotransmission. The resulting increased concentration
of noradrenaline in synapses may help some patients with depression.
Although short-term studies show that reboxetine improves depression more
than a placebo, the difference is not always statistically significant. An
eight-week study of 347 elderly patients found that reboxetine had similar
efficacy to imipramine.1 Another
eight-week study of 168 patients showed no significant differences in the overall
efficacy between reboxetine and fluoxetine.2
A multicentre study investigated what happened to 283 patients during longer-term
treatment. Patients who had responded to six weeks’ treatment with reboxetine,
were randomised to continue therapy or switch to a placebo. After 46 weeks
56% of the patients switched to placebo had relapsed compared with only 22%
of those who continued reboxetine.3
Doses of reboxetine are rapidly absorbed. The half-life is 13 hours and a
steady state is reached within five days. If there has been no response to
the starting dose, it can be increased after three weeks. A lower starting
dose is recommended in the elderly. Lower doses are also appropriate for patients
with renal or hepatic impairment as the drug is eliminated in the urine and
by metabolism.
The metabolism of reboxetine involves cytochrome P450 (CYP3A4). Inhibitors
of this enzyme, for example ketoconazole, will increase plasma concentrations
of reboxetine.
In the comparison with imipramine, adverse events occurred in 68% of the patients
taking reboxetine and 71% of those taking impramine.1 Comparison
of reboxetine and fluoxetine shows that adverse events occur in approximately
67% of patients taking either drug.2 The
adverse effects of reboxetine include dry mouth, constipation, insomnia, dizziness
and tachycardia. ECG changes appear in 15% of elderly patients taking reboxetine.
Hypotension can occur, but is less likely than in patients taking imipramine.1
Prescribers should be cautious about prescribing reboxetine to patients with
glaucoma, prostatic hypertrophy/difficult micturition, cardiovascular disease
or a history of seizures.
As depression often requires months of treatment, it would be reasonable to
wait until more long-term safety data are available before prescribing reboxetine.
A comparative study with venlafaxine, which inhibits the reuptake of serotonin
as well as noradrenaline, would be informative.
References
1. Katona C, Bercoff E, Chiu E, Tack P, Versiani M, Woelk
H. Reboxetine versus imipramine in the treatment of elderly patients with depressive
disorders: a double-blind randomised trial. J Affect Dis 1999;55:203-13.
2. Massana J, Möller H-J, Burrows GD, Montenegro RM.
Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder.
Int Clin Psychopharmacol 1999;14:73-80.
3. Versiani M, Mehilane L, Gaszner P, Arnoud-Castiglioni
R. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term
treatment of major depressive disorder. J Clin Psychiatry 1999;60:400-6.
NEW STRENGTHS
Azamun (Douglas)
25 mg tablets
Apoven (Douglas)
500 microgram/mL solution for inhalation
Chem mart Ipratropium (Faulding Healthcare)
500 microgram/mL solution for inhalation
GenRx Ipratropium (Faulding Healthcare)
500 microgram/mL solution for inhalation
Healthsense Ipratropium (Faulding Healthcare)
Terry White Chemists Ipratropium (Faulding Healthcare)
500 microgram/mL solution for inhalationNEW COMBINATIONS
Accuretic (Pfizer)
tablets containing 10 mg quinapril/12.5 mg hydrochlorothiazide and 20 mg quinapril/12.5 mg hydrochlorothiazide
