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 muscarinicor serotonin receptors. This pattern of activity differs from that seen withatypical antipsychotics.
The oral formulation has a bioavailability of 48%, but is not extensivelymetabolised. Most of the drug is excreted unchanged, with an elimination half-lifeof 12 hours. Clearance is reduced in patients with renal impairment.
A meta-analysis of trials which compared amisulpride with conventional antipsychoticdrugs found that it had greater efficacy in patients with acute schizophrenia.1 Amisulpridehas been compared with haloperidol in patients with chronic schizophrenia.After one year, a study of 60 in-patients found no significant difference inoverall efficacy, but there was a trend suggesting amisulpride may be morebeneficial for negative symptoms.2 Anotherlarger study (488 patients) also found that amisulpride had a greater effectthan haloperidol on negative symptoms.3
Like the atypical antipsychotics, amisulpride causes fewer extrapyramidaladverse effects than conventional drugs. Its extrapyramidal effects are doserelated. Common adverse effects include insomnia, anxiety, agitation and weightgain. The release of prolactin may result in problems such as galactorrhoeaand amenorrhoea. There is a potential for amisulpride to cause torsade de pointesas it prolongs the QT interval. Amisulpride is therefore contraindicated incombination with other drugs which cause QT prolongation. Caution is also advisedif 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 studyfound 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 randomizedcontrolled trials. Am J Psychiatry 2002;159:188-90.
2. Speller JC, Barnes TR, Curson DA, Pantelis C, AlbertsJL. One year, low-dose neuroleptic study of in-patients with chronic schizophreniacharacterised by persistent negative symptoms. Br J Psychiatry 1997;171:564-8.
3. Colonna L, Saleem P, Dondey-Nouvel L, Rein W. Long-termsafety 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, FleurotO, Rein W. Amisulpride vs. risperidone in the treatment of acute exacerbationsof 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 sleepinessduring the day. A multiple sleep latency test can help to confirm the diagnosis.1 Treatmentof daytime sleepiness may require the use of psychostimulants. Modafinilnow offers an alternative to dexamphetamine and methylphenidate.
The mechanism of action of modafinil is unclear. It does not bind with receptorsfor noradrenaline, dopamine or serotonin.
Patients take a single dose in the mornings. This is rapidly absorbed withthe peak plasma concentration being achieved within four hours. Modafinil iseliminated mainly by metabolism, with most of the metabolites being excretedin the urine. Cytochrome P450 3A4 may be involved in the metabolism so thereis 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 modafinilwith placebo.2,3 Severaltests such as the Epworth sleepiness scale1 wereused 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 adverseeffects. Common adverse reactions while taking modafinil included headache,nausea and nervousness. Like other stimulants, modafinil has some euphoriceffects so there is the possibility that it could be abused.
While the 400 mg dose is well tolerated it has no significant advantage overthe 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 improvementsmay be of questionable clinical relevance. For example, patients can stay awakefor five minutes if they are taking a placebo and for eight minutes if theyare taking modafinil. Continuous treatment may result in reduced plasma concentrationsof modafinil when it induces it own metabolism. As the double-blind clinicaltrials only lasted for nine weeks it is not known if modafinil is effectivein long-term treatment of narcolepsy. It has no role in patients complainingof a general tiredness or lack of energy.
References
1. Southcott AM. Sleepstudies. Aust Prescr 1998;21:40-3.
2. US Modafinil in Narcolepsy Multicenter Study Group.Randomized trial of modafinil for the treatment of pathological somnolencein 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 somnolenceof 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 combinationwith interferon alfa-2b.1 This interferon has to be given by injection threetimes a week. To reduce the frequency of injections interferon alfa-2b hasbeen conjugated with polyethylene glycol to produce peginterferon which hasa reduced renal clearance.
Peginterferon is injected once a week. The site of the subcutaneous injectionshould be varied with each dose. Plasma concentrations reach a maximum 15-44hours after the injection and are sustained for 48-72 hours. The eliminationhalf-life of interferon alfa-2b is about seven hours and renal clearance accountsfor 80% of the total clearance. Conjugation with polyethylene glycol reducesrenal clearance to 30% of the total and increases the elimination half-lifeto 40 hours.
The efficacy of peginterferon has been assessed in 1219 previously untreatedpatients with chronic hepatitis C confirmed by liver biopsy. Patients wererandomised to receive interferon alfa-2b three times a week or a weekly injectionof one of three different doses of peginterferon. They were treated for 48weeks. Six months after completing treatment, 12% of the patients taking interferonalfa-2b had undetectable concentrations of hepatitis C RNA and normal concentrationsof alanine aminotransferase (see 'HepatitisC: diagnosis and monitoring' Aust Prescr 1999;22:91-4). This responsewas significantly less than the 18-25% of the patients who responded to peginterferon.
Although all the doses of peginterferon were efficacious, the recommendeddose is 0.5 microgram/kg. The dose may be doubled for patients infected withgenotype 1 virus. (This genotype is associated with a poor response to interferon.)If the virus is still present after six months of treatment, peginterferonshould be stopped.
Peginterferon causes more injection site reactions than interferon alfa-2b,but overall the pattern of adverse reactions is similar. Common complaintsare flu-like symptoms in the first few weeks of treatment, headache, tiredness,myalgia and fevers. As granulocytopenia occurs in 4-7% of cases, patients withfever require investigation. Thrombocytopenia can also occur. Patients shouldhave their eyes examined before treatment as the interferons can cause ophthalmologicalproblems such as retinal haemorrhages. Interferon alfa-2b may also exacerbatepsoriasis. Some patients develop depression during treatment, so a previoushistory of a serious psychiatric condition is a contraindication to treatment.While peginterferon is used to treat chronic hepatitis, it is not recommendedfor patients with severe hepatic dysfunction.
Although more patients respond to peginterferon than interferon alfa-2b theresponse rate is much lower than the 43% seen with the combination of interferonalfa-2b and ribavirin.1 Anothertrial therefore studied the effectiveness of peginterferon in combination withribavirin.
This open trial randomised 1530 previously untreated patients to take eitherinterferon alfa-2b and ribavirin or one of two regimens of peginterferon alfa-2band ribavirin. The patients were treated for 48 weeks then followed up foranother 24 weeks. Viral RNA was undetectable in 47% of the patients given interferonalfa-2b or the lower dose regimen of peginterferon alfa-2b. In patients whohad taken a higher dose (1.5 microgram/kg/week) of peginterferon the responsewas 54% - a statistically significant advantage. This regimen was also advantageousfor patients with the genotype 1 virus. A sustained virological response wasfound in 42% compared with 33% of the patients given interferon alfa-2b. Thehigher dose, however, resulted in more frequent adverse reactions includingneutropenia.2
Although the high dose regimen produces a bigger response in patients withgenotype 1 virus it has no significant advantage over lower doses or interferonalfa-2b for patients infected with other genotypes. Identifying the best regimenwill require further research to clarify the most effective dose of ribavirin.Despite these issues, the combination of peginterferon alfa-2b and ribavirinmay become the treatment of choice for chronic hepatitis C, if it is foundto be cost-effective.
References
1. International Hepatitis Interventional Therapy Group.Randomised trial of interferon a2b plus ribavirin for 48weeks or for 24 weeks versus interferon a2b plus placebofor 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet1998;352:1426-32.
2. International Hepatitis Interventional Therapy Group.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plusribavirin 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 onthe reuptake of serotonin or dopamine. This gives it a relatively selectivemechanism of action on neurotransmission. The resulting increased concentrationof noradrenaline in synapses may help some patients with depression.
Although short-term studies show that reboxetine improves depression morethan a placebo, the difference is not always statistically significant. Aneight-week study of 347 elderly patients found that reboxetine had similarefficacy to imipramine.1 Anothereight-week study of 168 patients showed no significant differences in the overallefficacy between reboxetine and fluoxetine.2
A multicentre study investigated what happened to 283 patients during longer-termtreatment. Patients who had responded to six weeks’ treatment with reboxetine,were randomised to continue therapy or switch to a placebo. After 46 weeks56% 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 asteady state is reached within five days. If there has been no response tothe starting dose, it can be increased after three weeks. A lower startingdose is recommended in the elderly. Lower doses are also appropriate for patientswith renal or hepatic impairment as the drug is eliminated in the urine andby metabolism.
The metabolism of reboxetine involves cytochrome P450 (CYP3A4). Inhibitorsof this enzyme, for example ketoconazole, will increase plasma concentrationsof reboxetine.
In the comparison with imipramine, adverse events occurred in 68% of the patientstaking reboxetine and 71% of those taking impramine.1 Comparisonof reboxetine and fluoxetine shows that adverse events occur in approximately67% of patients taking either drug.2 Theadverse effects of reboxetine include dry mouth, constipation, insomnia, dizzinessand 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 withglaucoma, prostatic hypertrophy/difficult micturition, cardiovascular diseaseor a history of seizures.
As depression often requires months of treatment, it would be reasonable towait until more long-term safety data are available before prescribing reboxetine.A comparative study with venlafaxine, which inhibits the reuptake of serotoninas well as noradrenaline, would be informative.
References
1. Katona C, Bercoff E, Chiu E, Tack P, Versiani M, WoelkH. Reboxetine versus imipramine in the treatment of elderly patients with depressivedisorders: 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-CastiglioniR. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-termtreatment 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
The T-score (
) is explained in 'New drugs: transparency', Vol 32 No 3, Aust Prescr 2009;32:80-1.
