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.
Azopt (Alcon)
10 mg/mL in 5 mL dispensers
Approved indication: raised intraocular pressure
Australian Medicines Handbook Section 11.2.7
Conditions such as open-angle glaucoma cause increases in intraocular pressurewhich can result in blindness. The intraocular pressure can be reduced by drugswhich decrease the production, or increase the outflow, of aqueous humour.Carbonic anhydrase inhibitors reduce the production of aqueous humour and canbe given topically. Dorzolamide was the first topical member of the class tobe approved in Australia.
Brinzolamide is structurally similar to dorzolamide. It has a high affinityfor carbonic anhydrase-II, the predominant form of the enzyme in the eye. Afterbrinzolamide is instilled into the eye, some drug is absorbed into the circulation.It is mainly distributed to the red blood cells. As the half-life of brinzolamidein whole blood is 111 days, it takes 6-9 months for the drug concentrationsto reach a steady state. These concentrations are not great enough to interferewith the normal functions of carbonic anhydrase in the body.
During short-term clinical trials a twice-daily dose of brinzolamide 1% hasreduced intraocular pressure by approximately 3-5 mmHg. In an 18-month studythe mean reductions in intraocular pressure were 2.7-3.9 mmHg with brinzolamideand 4.7-5.6 mmHg with timolol 0.5% (a topical beta blocker).1 Anotherstudy compared brinzolamide 1% with dorzolamide 2%, and timolol 0.5% for threemonths. All three drugs had similar effects on intraocular pressure and therewere no significant differences in the efficacy of the two carbonic anhydraseinhibitors.2 Adding brinzolamide to treatmentwith timolol can produce further reductions in intraocular pressure.
Most of the adverse effects of brinzolamide are related to the instillationof the drops. Patients may develop blurring of vision, and sore or painfuleyes. They may also complain of a bitter taste.
Although brinzolamide has been used as monotherapy, the carbonic anhydraseinhibitors are second-line drugs. A three-times daily dose was used in someclinical trials, but 76% of patients will respond adequately to a twice-dailydose of brinzolamide.2 This may give the drugan advantage over dorzolamide which is instilled three times a day. Anotheradvantage is that brinzolamide instillation causes significantly less discomfort.2
References
1. Brinzolamide Long-Term Therapy Study Group. The long-termsafety and efficacy of brinzolamide 1.0% (Azopt) in patients with primary open-angleglaucoma or ocular hypertension. Am J Ophthalmol 2000;129: 136-43.
2. Brinzolamide Primary Therapy Study Group. Clinical efficacyand safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitorfor primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 1998;126:400-8.
Implanon (Organon)
68 mg implants
Approved indication: contraception
Australian Medicines Handbook Section 17.1.4
The approval of etonogestrel implants adds to the choice of progestogen-onlymethods of contraception. Etonogestrel is a metabolite of desogestrel whichis used in some combined contraceptive pills.
The implant is 40 mm long and has a diameter of 2 mm. It is loaded insidea stainless steel applicator. After anaesthetising the area, the implant isinserted under the skin of the inner side of the upper arm. The inserting isdone in the first five days of the menstrual cycle if the woman is not usingthe contraceptive pill. Women changing from a progestogen-only pill can havethe implant at any stage of the cycle.
While etonogestrel does affect the cervical mucus, its main contraceptiveeffect is the inhibition of ovulation. Inhibitory concentrations of etonogestrelare reached within one day of insertion. One implant will release these concentrationsof etonogestrel for at least two years. It should be removed after three years.The effect of etonogestrel quickly wears off after the implant is removed.This may be useful when managing adverse effects.
In clinical trials no pregnancies have occurred. The main problems have beenthe adverse effects associated with progestogens. The menstrual pattern islikely to change, some women will have irregular bleeding, others will haveamenorrhoea. These changes often prompt women to ask for the implant to beremoved. Other adverse effects include breast pain, acne and weight gain.
Prescribers who intend to offer etonogestrel as a contraceptive option shouldensure they are instructed in how to insert and remove the implant.
Remicade (Schering-Plough)
vials containing 100 mg as lyophilised powder
Approved indication: Crohn's disease
Crohn's disease causes chronic inflammation in the gastrointestinal tract.With time it tends to respond less well to treatment and many patients willdevelop complications such as a fistula. The cause of the disease is unknown,but an immune mechanism may be involved. Patients with Crohn's disease produceincreased amounts of tumour necrosis factor alpha (TNF-alpha). This factormay be responsible for inducing the mucosal inflammation.
Animal studies found that inflammation can be reduced by antibodies to TNF-alpha.Infliximab is a monoclonal antibody which neutralises TNF-alpha in humans.It was studied in a randomised controlled trial of 108 patients with moderateto severe Crohn's disease. Four weeks after a single infusion, 65% of the patientsgiven infliximab had a clinical response compared with only 17% of the patientsgiven a placebo. The disease went into remission in 33% of the infliximab groupbut only 4% of the placebo group.1
Another study investigated 94 patients with abdominal or perianal fistulas.These patients were given an infusion of infliximab or a placebo. This infusionwas repeated two weeks and six weeks later. The number of draining fistulasdecreased by half in 62% of the infliximab group compared with 26% of the placebogroup. In 46% of the infliximab group the fistulas healed, while only 13% ofthe placebo group had an absence of any draining fistulas.2
Infliximab is a human form of a mouse monoclonal antibody produced using recombinanttechniques. Approximately 16% of patients will have a reaction to its infusion.They may develop urticaria, fevers and chills. Some patients experience fallsor rises in blood pressure so it is important that they are observed duringand after the two hour infusion. Patients who develop antichimeric antibodiesare more likely to have infusion reactions. These antibodies could also alterthe pharmacokinetics of infliximab. The half-life of infliximab is normallyabout 10 days and it takes up to six months for serum concentrations to becomeundetectable.
Approximately 5% of patients withdrew from clinical trials of infliximab becauseof adverse events. Apart from infusion reactions adverse effects include headache,nausea, vomiting and abdominal pain. The patients given infliximab developedmore infections than patients given a placebo. Although infliximab does notcause a generalised suppression of the immune system, caution is needed particularlyif the patient has been taking immunosuppressive drugs for their Crohn's disease.It is unclear if infliximab increases the risks of developing lymphoproliferativedisorders. Some patients will develop autoantibodies and cases of a lupus-likesyndrome have been reported.
More information is needed on the long-term effectiveness of infliximab. Inthe short-term study the proportion of patients with a clinical response after12 weeks had declined and the number of patients in remission was not significantlydifferent from placebo.1 If symptoms recur thetreatment can be repeated within 14 weeks. Readministration after this periodis currently not recommended because of the risk of delayed hypersensitivityreactions.
Recombinant products tend to be expensive. Infliximab is therefore reservedfor patients who have not responded to conventional therapies for moderateto severe Crohn's disease.
References
1. Crohn's disease cA2 Study Group. A short-term study ofchimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn's disease.N Engl J Med 1997;337:1029-35.
2. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L,van Hogezand RA, et al. Infliximab for the treatment of fistulas in patientswith Crohn's disease. N Engl J Med 1999;340:1398-405.
Tamiflu (Roche)
75 mg capsules
Approved indication: influenza
Australian Medicines Handbook Section 5.3.2
Oseltamivir is the second neuraminidase inhibitor to receive Australian approvalfor the treatment of influenza. Unlike its predecessor, zanamivir, oseltamiviris taken by mouth.
After absorption oseltamivir is converted to its active form, oseltamivircarboxylate. The plasma concentrations of this metabolite reach a peak withinthree hours and then decline with a half-life of 6-10 hours. Oseltamivir carboxylateis excreted in the urine, so the dose should be reduced if renal function isimpaired.
In a clinical trial, twice-daily doses of 75 mg or 150 mg were compared witha placebo. The 629 adults involved in the trial had presented within 36 hoursof developing a febrile respiratory illness. Laboratory testing confirmed thepresence of influenza virus (mostly influenza A) in 374 cases. In these casesoseltamivir reduced the duration of illness by more than 30%.1
Patients given oseltamivir are more likely to experience gastrointestinalupsets than those given a placebo. In clinical trials 12% of patients sufferedvomiting and a further 11% complained of nausea. There is potential for theinfluenza virus to develop resistance.
Although patients treated with oseltamivir recover significantly faster thanthose given a placebo, the difference is only about one day. Treating 1000patients reduces illness by 254 hours. However, patients given 75 mg twicea day were able to resume their normal activities 2-3 days sooner than thosegiven a placebo. Giving a higher dose does not make patients recover more quickly.1 Asfew elderly or debilitated people were included in the clinical trials, thebest strategy for those at risk is still immunisation to prevent influenza.Little information is available about the efficacy of oseltamivir in influenzaB.
Reference
1. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, BettisR, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivirin treating acute influenza. JAMA 2000;283:1016-24.
Pariet (Janssen-Cilag)
10 mg and 20 mg enteric-coated tablets
Approved indications: peptic ulcer, gastro-oesophageal reflux disease
Australian Medicines Handbook Section 12.1.4
Rabeprazole is the fourth proton pump inhibitor to be approved in Australia.The other members of the class are omeprazole, lansoprazole and pantoprazole.These drugs are potent inhibitors of acid secretion.1
The suppression of acid secretion begins within an hour of taking rabeprazoleand lasts for up to 48 hours. This duration of action is much greater thanthe one hour half-life. The drug is metabolised by the cytochrome P450 system(CYP3A4 and CYP2C19) with most of the metabolites appearing in the urine.
Rabeprazole has been compared with omeprazole for each of its approved indications.Although many patients with duodenal ulcer will require treatment for Helicobacterpylori, the proton pump inhibitors can also be effective. After four weeksof treatment rabeprazole and omeprazole had healed more than 90% of the patients.Similar results were found after treating patients with gastric ulcers forsix weeks, and patients with erosive or ulcerative gastro-oesophageal refluxdisease for eight weeks. If patients with gastro-oesophageal reflux take rabeprazoleor omeprazole for a year only about 5% will have a relapse.
Like other proton pump inhibitors rabeprazole is well tolerated. The commonestcomplaints in clinical trials included diarrhoea, headache and nausea. Therehave been reports of erythema and bullous skin reactions.
The product information states that rabeprazole does not have clinically significantinteractions with other drugs metabolised by cytochrome P450. Rabeprazole does,however, interact with digoxin and ketoconazole.
Although rabeprazole may reduce the pain of peptic ulcer more than omeprazole,it has no clear advantage. The cost of rabeprazole may determine if it is widelyprescribed.
Reference
1. Yeomans ND. Drugs that inhibit acid secretion. AustPrescr 2000;23:57-9.
Metalyse (Boehringer Ingelheim)
vials containing 8000 IU and 10 000 IU
Approved indication: thrombolysis
Australian Medicines Handbook Section 7.3
For more than a decade, patients with acute myocardial infarctions have beentreated with infusions of thrombolytic drugs such streptokinase. The aim oftreatment is to restore the blood flow through the coronary artery relatedto the infarct. Research has aimed at developing drugs which restore more bloodflow and do not require a prolonged infusion.
Alteplase is a genetically engineered plasminogen activator. (The activationof plasminogen produces plasmin which breaks down the fibrin in the thrombosis.)Tenecteplase has a similar structure to alteplase and is also produced by geneticengineering. The differences in structure give tenecteplase better fibrin specificityand a longer half-life than alteplase.
Tenecteplase can be given by a single bolus injection. This will improve theblood flow through the infarct-related artery in most patients within 90 minutes.The elimination is biphasic with a terminal half-life of approximately twohours. Clearance is by hepatic metabolism.
A large study involving nearly 17 000 patients has compared a bolus of tenecteplasewith a 90 minute infusion of alteplase. All the patients were meant to be treatedwithin six hours of developing the symptoms of acute myocardial infarction.They were also given aspirin and heparin. After 30 days a similar proportionof each treatment group had died. The mortality rate for tenecteplase was 6.18%and it was 6.15% for alteplase.1
Fibrinolytic drugs increase the risk of stroke. In the comparative trial 1.78%of the patients given tenecteplase had a stroke compared with 1.66% of thealteplase group. While the frequency of intracranial bleeding was the samefor both drugs, tenecteplase caused significantly fewer non-cerebral haemorrhages.Only 4.3% of the tenecteplase group needed a blood transfusion compared with5.5% of the alteplase group.1
Despite the reduced need for transfusion, haemorrhage is still a common complication.More than 26% of the tenecteplase group had a bleeding complication. Tenecteplaseis contraindicated in patients with an increased risk of bleeding. This includespatients with severe hypertension, peptic ulcers within the last three months,those who are taking warfarin and those who have had recent surgery or trauma,including cardiac resuscitation.
Although most patients in the clinical trial were treated soon after theirinfarction, tenecteplase has been approved for use up to 12 hours later. Thismatches the indication for alteplase. While tenecteplase seems to have a fewadvantages over alteplase, its relative cost-effectiveness will determine ifit becomes the preferred treatment option.
Reference
1. ASSENT-2 investigators. Single-bolus tenecteplase comparedwith front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blindrandomised trial. Lancet 1999;354:716-22.
NEW DELIVERY SYSTEMS
Mirena (Schering)
intrauterine device containing 52 mg levonorgestrel
Approved indications: contraception, menorrhagia, hormone replacement therapy
Australian Medicines Handbook Section 17.1.2
This product is a T-shaped intrauterine device with a cylinder of levonorgestrelaround the long arm. The levonorgestrel is covered by a membrane which controlsthe release of the drug. At first the release rate is 20 microgram per day.The device contains enough levonorgestrel to last for five years.
The actions of levonorgestrel in the uterine cavity have a contraceptive effect(see `Progestogen-onlymethods of contraception' Aust Prescr 1999;22:6-8). Contraceptive protectionis immediate because the product also acts as an intrauterine contraceptivedevice. The contraception is highly effective with a pregnancy rate of 0.16per 100 women years, however 37% of these pregnancies are ectopic.
If there are no organic causes, the device can be used to treat menorrhagia.For some women it is preferable to hysterectomy.1 Thedevice's ability to prevent endometrial hyperplasia also enables it to be usedto provide the progestogenic component in regimens of continuous hormone replacementtherapy.
Some of the levonorgestrel is absorbed into the circulation and may inhibitovulation. While there are other general effects such as acne, breast tendernessand weight changes, most adverse reactions affect the urogenital system. Themenstrual pattern changes with spotting being a particular problem in the firstfew months after insertion. Increased bleeding or pain may be symptoms thatthe device is being expelled. The expulsion rate over five years is 2-6 per100. Without the device in place, fertility soon returns. Conception occurswithin a year in 80% of the women who have the device removed in order to becomepregnant.
Pelvic infection may occur less frequently than with other intrauterine devices,but pelvic inflammatory disease is still a contraindication. The device shouldbe removed if a pelvic infection does not rapidly respond to antibiotics.
While a levonorgestrel-releasing device may have some advantages it is notsuitable for all women. It should not be the first choice for contraceptionin young nulliparous women. The device may also be unsuitable for postmenopausalwomen if atrophic changes have narrowed the cervical canal.
Reference
1. Lahteenmaki P, Haukkamaa M, Puolakka J, Riikonen U, SainioS, Suvisaari J, et al. Open randomised study of use of levonorgestrel releasingintrauterine system as alternative to hysterectomy. Br Med J 1998;316:1122-6.
NEW FORMULATIONS
Dysport (Ipsen)
500 IPSEN Units lyophilised powder
(Dysport is not therapeutically equivalent to the other botulinum toxin preparation currently available on the Australian market.)
Strepfen (Boots Healthcare)
8.75 mg lozenges
OxyNorm (Mundipharma)
5 mg capsules
NEW STRENGTHS
Lipobay (Bayer)
400 microgram tablets
Climara 25 (Schering)
1.97 mg transdermal patches
Climara 75 (Schering)
5.69 mg transdermal patches
NEW PROPRIETARY BRANDS
Alphapril (Alphapharm)
5 mg, 10 mg and 20 mg tablets
Lisodur (Alphapharm)
5 mg, 10 mg and 20 mg tablets
Allermax (Schering-Plough)
50 microgram per actuation aqueous nasal spray
Climen 28 (Schering)
packs containing 16 oestradiol valerate 2 mg tablets and 12 oestradiol valerate 2mg/cyproterone acetate 1 mg tablets
Epaq Inhaler (Arrow)
100 microgram per dose
The T-score (
) is explained in 'New drugs: transparency', Vol 30 No 1, Aust Prescr 2007;30:26-7.
