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.
Agenerase (Glaxo Wellcome)
150 mg capsules, and 240 mL bottles containing 15 mg/mL oral solution
Approved indication: HIV-1
Australian Medicines Handbook Section 5.3.5
Amprenavir is the fifth protease inhibitor to be approvedfor use in Australia. It can be used to treat HIV infection in combinationwith other antiretroviral drugs, such as zidovudine and lamivudine. By inhibitingthe protease in HIV-1, amprenavir results in the production of non-infectiousvirions.
Patients take amprenavir twice a day. As the dose is 20 mg/kg the patientsneed to take several capsules. The oral solution is less bioavailable thanthe capsules, so the doses are not equivalent. Although absorption is affectedby food, amprenavir can be taken with or without food. The volume of distributionis large, but amprenavir does not greatly penetrate the blood brain barrier.Concentrations in cerebrospinal fluid are less than 1% of the plasma concentration.
Amprenavir is eliminated by hepatic metabolism and has a half-life of 7-11hours. The metabolism of amprenavir involves cytochrome CYP3A4. It thereforehas many potential interactions including those with other drugs used to treatHIV. Patients taking amprenavir should not be given drugs such as midazolam,triazolam, ergot derivatives and rifampicin.
Clinical trials show that adding amprenavir to a combination of zidovudineand lamivudine in previously untreated patients is more efficacious than thecombination alone. Almost 60% of patients will have concentrations of viralRNA less than 400 copies/mL after 16 weeks of treatment. An open label extensionof this study resulted in 43% of the patients being at or below the targetconcentration after 48 weeks.1
In patients who have previously had treatment, but not with a protease inhibitor,30% will have less than 400 copies/mL after 48 weeks. If amprenavir is givento patients who have already been treated with a protease inhibitor, 34% willhave less than 200 copies/mL after 24 weeks of taking the dual protease inhibitorregimen. The response rate is reduced if the patients have previously takena non-nucleoside reverse transcriptase inhibitor.
Adverse effects are common and include nausea, vomiting and diarrhoea. Somepatients will develop rashes. These usually resolve spontaneously, but theStevens-Johnstone syndrome has been reported. Other uncommon adverse effectsinclude lipodystrophy, hyperlipidaemia and diabetes mellitus.
The capsule formulation contains vitamin E, so patients are advised not totake supplements of vitamin E. The oral solution is not suitable for youngchildren and pregnant women because it contains the potentially toxic propyleneglycol. This formulation is also contraindicated in patients with hepatic orrenal impairment.
In patients who have not previously had a protease inhibitor as part of theirtreatment, indinavir may be better tolerated and have greater efficacy thanamprenavir. However, it is only approved for patients who have previously beentreated with a protease inhibitor. HIV can become resistant to protease inhibitors,however the profile of resistance to amprenavir differs from that of otherprotease inhibitors. It may therefore have a role in 'salvage therapy' whenresistance to other protease inhibitors has developed
Reference
1. GoodgameJC, Pottage JC, Jablonowski H, Hardy WD, Stein A, Fischl M, et al. Amprenavirin combination with lamivudine and zidovudine versus lamivudine and zidovudinealone in HIV-1-infected antiretroviral-naive adults. Antivir Ther 2000;5:215-25.
AZEP (Sigma)
0.1% nasal spray
Approved indication: allergic rhinitis
Australian Medicines Handbook Section 9.4.3
When seasonal or perennial rhinitis is severe enough torequire drug treatment, a topical antihistamine is an alternative to topicalnasal corticosteroids. Azelastine is an H1-receptor antagonist which has beenapproved for use in patients over five years old.
Patients spray a dose of azelastine into each nostril twice a day. Within 15minutes this starts to relieve nasal symptoms induced by histamine or allergens.The effect of a dose can last for up to 12 hours. Part of each dose is absorbed.This is then extensively metabolised with most of the metabolites being excretedin the faeces. The major metabolite, desmethylazelastine, is also an H1-receptorantagonist. It has a half-life of 56 hours so there is a potential for accumulationwith twice-daily doses.
In studies of seasonal allergic rhinitis, azelastine was as effective as oralterfenadine at reducing symptoms such as rhinorrhoea, nasal irritation andsneezing. Similar results were observed in patients with perennial allergicrhinitis.
Most of the adverse effects occur in the nose. They include stinging, itching,sneezing and epistaxis. Some patients will develop an altered taste sensationand possibly nausea.
While azelastine may have a more rapid effect, it is not more effective thannasal corticosteroids. In a placebo-controlled trial budesonide had a significantlygreater effect on the symptoms of perennial allergic rhinitis.1 Ashort study (two weeks) found that beclomethasone produced a greater improvementin the overall symptoms of seasonal allergic rhinitis.2
References
1. Stern MA, Wade AG, RidoutSM, Cambell LM. Nasal budesonide offers superior symptom relief in perennialallergic rhinitis in comparison to nasal azelastine. Ann Allergy Asthma Immunol1998;81:354-8.
2. Newson-Smith G, Powell M,Baehre M, Garnham SP, MacMahon MT.
A placebo controlled study comparing the efficacy of intranasal azelastineand beclomethasone in the treatment of seasonal allergic rhinitis. Eur ArchOtorhinolaryngol 1997;254:236-41.
Prohance (Bracco)
279.3 mg/mL in 5, 10, 15 and 20 mL vials and 5, 10, 15 and 17 mL syringes
Approved indication: magnetic resonance imaging
Gadoteridol adds to the choice of contrast agents for usein magnetic resonance imaging. It is a non-ionic complex of gadolinium witha low molecular weight. Gadoteridol does not cross the blood-brain barrier,but if the barrier is damaged gadoteridol will penetrate into lesions suchas tumours. It also highlights areas of increased vascularity so it has beenused to improve the delimitation of lesions elsewhere in the body.
Apart from its paramagnetic effects, gaditeridol has no pharmacological activityin the body. After intravenous injection, most of the dose is excreted unchangedin the urine within 24 hours. There is little information about the effectof renal impairment on the clearance of gadoteridol. Severe renal impairmentis a contraindication.
Adverse reactions are uncommon, but prescribers need to be equipped to dealwith anaphylactoid reactions. The more frequent adverse effects of gadoteridolinclude nausea, altered taste, headache and pain at the injection site.
Gadoteridol has been available in Europe and the USA for several years. Itdoes not appear to have any significant advantages over similar products.
Somatuline LA (Ipsen)
glass vials containing 40 mg as powder (only 30 mg is available for the patientdue to losses of the active ingredient during sterilisation, resuspension andadministration)
Approved indication: acromegaly
Australian Medicines Handbook Section 10.6.4
Somatostatin is a peptide which inhibits the secretion ofgrowth hormone. Synthetic analogues of somatostatin, such as octreotide andlanreotide, can therefore be used in the treatment of acromegaly which resultsfrom an excessive concentration of growth hormone.
Lanreotide is indicated for patients whose concentrations of growth hormoneremain high despite surgery and/or radiotherapy. It is also indicated for patientswho are refractory to treatment with a dopamine agonist.
A modified-release formulation allows lanreotide to be initially given every14 days. After reconstitution it is injected intramuscularly. There is a rapidrelease, followed by a prolonged release from the microparticles in the formulation.The half-life of this formulation is approximately five days. Although theproduct is injected its bioavailability is 57%.
A European study involving 125 patients compared injections of 30 mg lanreotideevery 10-14 days with monthly injections of 20 mg of modified-release octreotide.The growth hormone concentration was reduced significantly more by octreotidethan by lanreotide and more patients reached the target concentrations.1
The most frequent adverse effects of lanreotide are reactions at the injectionsite and gastrointestinal upsets. As lanreotide may reduce gall bladder motility,patients should have an ultrasound scan before treatment and every six monthsduring treatment.
Although more than half the patients treated with lanreotide will respond satisfactorily,some need injections more frequently than every 14 days. Lanreotide may beless effective than octreotide.
Reference
1. Chanson P, Boerlin V,Ajzenberg C, Bachelot Y, Benito P, Bringer J, et al. Comparison of octreotideacetate LAR and lanreotide SR in patients with acromegaly. Clin Endocrinol2000;53:577-86.
Zyvox (Pharmacia)
600 mg film-coated tablets
granules for oral suspension (20 mg/mL)
infusion bags containing 600 mg/300 mL
Approved indication: specified infections
Australian Medicines Handbook Section 5.1
The oxazolidinones are a new class of antibiotic. They arelikely to have a role in the treatment of infections caused by resistant organisms.
Linezolid is the first drug of the class to be approved in Australia. Its inhibitionof bacterial protein synthesis makes it bacteriostatic against staphylococciand enterococci, and bactericidal against most streptococci. Linezolid canbe used to treat methicillin-resistant staphylococci and vancomycin-resistantenterococci. It is not active against Haemophilus influenzae, Pseudomonas aeruginoia, Neisseria or Enterobacteriaceae. Legionella and Moraxellacatarrhalis are only intermediately susceptible to linezolid.
When taken by mouth, linezolid is almost completely absorbed. It has a half-lifeof 5-7 hours and is mainly eliminated by metabolism. As linezolid weakly inhibitsmonoamine oxidase there is a potential for interactions with tyramine and sympathomimeticdrugs such as pseudoephedrine.
Adverse effects are common; 70% of the patients in one study had an adverseevent.1 The most frequentproblems are headache, nausea, diarrhoea and candidiasis. Liver function iscommonly disturbed and some patients develop myelosuppression. The haemoglobinand platelet count should be checked in any patient who takes linezolid formore than two weeks. Patients are also at risk of pseudomembranous colitis.
Some of the trials investigating the efficacy of linezolid have not been published.One published study was a double-blind comparison with vancomycin for the treatmentof 396 patients with nosocomial pneumonia. Approximately 18% of the inpatientsgiven linezolid died compared with 25% of the vancomycin group. None of thedeaths in the linezolid group were due to a lack of response. The cure ratewas 53% for linezolid and 52% for vancomycin.1
Although linezolid has been studied in soft tissue infections and community-acquiredpneumonia, as well as in nosocomial pneumonia, it is not approved for generaluse in these conditions. As linezolid is unlikely to have cross-resistancewith other antibiotics, because of its different mechanism of action, it shouldbe reserved for organisms which are resistant to other antibiotics. As linezolidhas oral formulations it may have a practical advantage over quinupristin/dalfopristin(see 'Newdrugs' Aust Prescr 2000;23:65), which is approved for the intravenous treatmentof resistant organisms, but the two drugs have not been compared in clinicaltrials.
Reference
1. Rubinstein E, Cammarata SK,Oliphant TH, Wunderink RG. Linezolid (PNU-100766) versus vancomycin in thetreatment of hospitalized patients with nosocomial pneumonia: a randomized,double-blind, multicenter study. Clin Infect Dis 2001;32:402-12.
Mobic (Boehringer Ingelheim)
7.5 mg and 15 mg tablets
Approved indication: osteoarthritis
Australian Medicines Handbook Section 15.1
The new cyclo-oxygenase inhibitors are being promoted asdrugs which inhibit the COX-2 enzyme more than the COX-1 enzyme. Although meloxicamis in a different class of non-steroidal anti-inflammatory drugs, it also inhibitsCOX-2 more than COX-1 (see'COX-2 inhibitors' Aust Prescr 2000;23:30-2).
Patients take meloxicam once a day. It is absorbed slowly and has a half-lifeof 15-20 hours. Most of the dose is metabolised and this involves cytochromeP450 2C9 and 3A4. Although CYP2C9 predominates, caution is needed if an inhibitorof CYP3A4 is prescribed concurrently with meloxicam. It is contraindicatedin patients taking drugs, such as sulfamethoxazole, which inhibit CYP2C9.
In clinical trials meloxicam has been as effective as sustained-release diclofenacin relieving the symptoms of osteoarthritis. For short-term treatment, meloxicamwas as effective as piroxicam.
If taken for more than six months, meloxicam is associated with gastrointestinaladverse effects in more than 20% of patients. Common problems include diarrhoea,dyspepsia and nausea. Although the overall incidence may be less than for similardrugs, there is no clear reduction in serious adverse effects such as bleedingor perforation of peptic ulcers.
Daivonex (Aust Prescr 2001;24:158)
There was a typographical error in the New Formulations section of New drugs, regarding calcipotriol scalp solution (CSL). The brand name is Daivonex, not Diavonex.
The T-score (
) is explained in 'New drugs: transparency', Vol 30 No 1, Aust Prescr 2007;30:26-7.
