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.
Atacand (Astra)
4 mg, 8 mg and 16 mg tablets
Approved indication: hypertension
AMH Section 6.4.5
Two AT1 receptor antagonists (losartan and irbesartan) are alreadyavailable in Australia.1 Candesartan adds to the choices for treatingmild to moderate hypertension.
The tablets contain a prodrug which is rapidly converted to active candesartanduring absorption. Peak serum concentrations are reached within 4 hours. Foodincreases the rate of absorption, but does not affect the bioavailability whichis approximately 14%. Most of a dose is excreted in the urine, so a lower startingdose is recommended for the elderly and patients with severe renal impairment.The terminal half-life is approximately 9 hours. Although the effect on bloodpressure peaks a few hours after a dose, its duration permits once daily dosing.
Candesartan reduces blood pressure more than placebo. The maximum effect onblood pressure is reached within one month. This effect is comparable to theeffects of hydrochlorothiazide, amlodipine or enalapril. A dose of 16 mg candesartanmay cause a greater reduction in diastolic blood pressure than 50 mg losartan.In common with other AT1 receptor antagonists, few patients (2.4%)had to withdraw from clinical trials because of adverse effects. A study ofcandesartan in heart failure was halted because of concerns about increasedmortality. While the significance of this observation is unclear, the drugis not recommended for patients with heart failure. It should not be used inpatients with renal artery stenosis and should be used with caution in patientswho are salt or volume depleted.
Reference
1. Johnson CI. Angiotensin receptor antagonists for the treatment of hypertension. AustPrescr 1998;21:95-7.
Aricept (Pfizer)
5 mg and 10 mg tablets
Approved indication: Alzheimer's disease
AMH Section 16.5
The concentration of acetylcholine is reduced in the brains of patients withAlzheimer's disease. This abnormality has led to trials of anticholinesterasessuch as tacrine (see `Tacrinein the treatment of Alzheimer's disease' Aust Prescr 1996;19:14-7). Donepezilis also an inhibitor of acetylcholinesterase, but has less peripheral activitythan tacrine.
Clinical trials of donepezil have studied patients with mild to moderatelysevere Alzheimer's disease. Rating scales and subjective assessments have beenused to evaluate its effects. The drug has been more efficacious than placeboin studies of 12-24 weeks' duration. While these responses may have statisticalsignificance, their clinical significance is unclear.
Donepezil is given once a day. It takes 3 weeks to reach a steady state asthe half-life is approximately 70 hours. While some donepezil is excreted unchangedin the urine, it is also metabolised. As the metabolic pathways include cytochromeP450 2D6 and 3A4, there is a potential for drug interactions, but donepezilis said to have no significant interaction with theophylline, cimetidine, warfarinor digoxin.
The increase in cholinergic activity contributes to some of the adverse effectsof donepezil. The most common adverse effects are nausea, vomiting and diarrhoea.The clinical trials on which marketing approval is based were only of up to6 months' duration, so long-term safety data are limited.
There appear to have been no trials comparing donepezil and tacrine. Donepezilis better tolerated with only 5-13% of patients stopping treatment becauseof adverse effects. (Approximately 17% of the patients who received tacrinein clinical trials had to stop treatment.) Patients taking donepezil do notrequire the frequent monitoring of liver function which is required when startingtacrine. While donepezil may have some advantages over tacrine, both drugsonly have modest therapeutic effects. Neither drug halts the progression ofthe disease, nor are they approved for use by severely affected patients.
Aldara (3M Pharmaceuticals)
5% cream in single-use sachets
Approved indication: genital and perianal warts
AMH Section 8.5
Podophyllotoxin has been the drug of choice for anogenital warts, but it commonlycauses irritation. While podophyllotoxin has a mainly destructive action, imiquimodis thought to modify the immune response.
The cream is applied to the warts for 3 nights each week and is left on for6-10 hours. This appears to induce the production of interferon alpha and othercytokines. Imiquimod has no antiviral action.
A double-blind placebo-controlled trial randomised 51 non-immunosuppressedpatients to receive imiquimod and 57 to receive placebo for up to 8 weeks.The warts of 19 patients in the treatment group disappeared and, in most ofthe other patients, the warts reduced in size. In the placebo group, the responsewas significantly less and no patient had a complete response.1 Otherstudies have shown similar benefits, but the recurrence rate after treatmentis not significantly different from placebo. Efficacy has not been demonstratedin immunocompromised patients.
Most of the adverse effects of imiquimod are local skin reactions. The majorityof patients will develop erythema. Erosion, itching and burning can also occur.Only 4 of the 327 patients in the clinical trials discontinued the drug becauseof skin reactions. Very little imiquimod is absorbed through the skin. As thepotential systemic absorption is increased, imiquimod should not be appliedto urethral, vaginal or rectal warts. Imiquimod is not teratogenic in animals,but the manufacturer does not recommend its use during pregnancy.
Although the efficacy of imiquimod is greater than placebo, its effectivenessneeds to be compared with that of podophyllotoxin and other treatments suchas liquid nitrogen or laser therapy. As the maximum duration of treatment allowedis 16 weeks, there is a need for information about the use of imiquimod forwarts which recur.
Reference
1. Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM. Treatmentof genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol1998;38:230-9.
Ikorel (Rhone Poulenc Rorer)
10 mg and 20 mg tablets
Approved indication: angina pectoris
AMH Section 6.2
Nicorandil is a new type of vasodilator. However, it has been marketed inJapan for over a decade. The drug is a nitrate derivative, so it relaxes vascular,particularly venous, smooth muscle. It also opens the muscle's potassium channelswhich leads to arterial dilatation. The haemodynamic effects include reductionsin end diastolic pressure and systemic resistance.
Patients with chronic stable angina can take nicorandil twice a day. The drugis rapidly absorbed with a bioavailability of 75%. Most of the drug is rapidlyeliminated from plasma, but the plasma concentration is not closely linkedto the effect of nicorandil. Most of the drug is metabolised and the metabolitesare mainly excreted in the urine.
The most common adverse effect of nicorandil is headache. This caused up to10% of patients to stop treatment in some clinical studies. However, the headachetends to improve as treatment continues. Other adverse effects include nausea,vomiting, dizziness and flushing.
Nicorandil is probably as effective as other drugs used in the treatment ofangina. Although the studies have been relatively short, the tolerance seenwith nitrates does not appear to be a problem. Until more experience is obtained,nicorandil is unlikely to be used as a first-line treatment. It may have arole in patients with angina who do not respond to conventional treatment.Although there are no reported interactions with beta blockers or calcium channelblockers, there are few data on the use of nicorandil in a combined regimen.
Mabthera (Roche Products)
10 mg/mL in 10 mL and 50 mL vials
Approved indication: lymphoma
AMH Section 14
The idea of treating tumours with antibodies to the cancer cells is appealing.Some lymphomas may be suitable for such immunotherapy because of their cellsurface markers. For example, non-Hodgkin's B-cell lymphomas have specificsurface antigens. Rituximab is a genetically engineered monoclonal antibodyagainst the CD20 antigen on the B lymphocytes.
Rituximab is thought to act by binding to the CD20 antigen. This leads tothe lysis of the B lymphocytes. There is a marked decline in the number ofB cells in the peripheral blood soon after the first dose.
Although the prognosis for patients with non-Hodgkin's lymphoma is worse thanfor those with Hodgkin's disease, it has improved with chemotherapy. Unfortunately,some patients will be refractory to treatment and others will relapse. Someof these patients may benefit from rituximab.
The main study of rituximab involved 166 patients given 4 doses at weeklyintervals. This resulted in a complete response in 10 patients and a partialresponse in 70 patients. The median time for patients to respond was 50 daysand the highest response rate was seen in patients who had previously had anautologous bone marrow transplant.
Rituximab is diluted and then infused slowly. Its pharmacokinetics probablyresemble those of immunoglobulins. After the fourth infusion of a course, thehalf-life is 190 hours and rituximab will be detectable for 3-6 months aftertreatment.
Some adverse effects are the predictable result of infusing an antibody containinghuman protein e.g. hypersensitivity reactions. The majority of patients developfevers and chills during the first infusion. Patients may complain of nausea,itching, weakness and headache. Hypotension and bronchospasm can develop. Ifthese adverse effects occur, the infusion should be slowed or stopped and supportivecare given e.g. intravenous saline. The incidence of infusion-related eventsdeclines from 80% during the first infusion to 40% with subsequent infusions.
As the CD20 antigen is found on normal as well as malignant lymphocytes, afall in lymphocytes is to be expected. It is unclear if this significantlyalters the risk of infection. The lymphocytes begin to recover 6 months aftertreatment and usually return to normal during the next 6 months. Although theCD20 antigen is not found on stem cells or plasma cells, severe haematologicalabnormalities can occur. These include neutropenia, anaemia and thrombocytopenia.
The studies of rituximab have been uncontrolled, but its efficacy is probablysimilar to that of cladribine or fludarabine. While rituximab increases thetherapeutic options for patients with relapsed or refractory low grade non-Hodgkin'slymphomas, its precise role in treatment needs clarification.
Gelofusine (B. Braun)
4% solution in 500 mL and 1000 mL containers
Approved indication: plasma volume substitute
This product has been available overseas for many years. A similar product(polygeline 3.5%) is already available in Australia.
An infusion of succinylated gelatin retains fluid in the intravascular space.The effect lasts for 3-4 hours. This can be useful in the treatment of hypovolaemiae.g. due to bleeding. The infusion can also be used when haemodilution or extra-corporealcirculation is needed.
Colloidal plasma volume substitutes can cause anaphylaxis in susceptible patients.A fall in blood pressure may cause clinical confusion if the patient was beingtreated for hypotension.
NEW FORMULATIONS
Entocort (Astra)
3 mg controlled release capsules
Approved indication: Crohn's disease
AMH Section 12.6
Corticosteroids are often used to control episodes of inflammatory bowel disease.This treatment is effective, but has many potential adverse reactions. Therefore,there is a need for a drug which will induce remission, but cause few systemiceffects.
Budesonide is a corticosteroid which has been used in the treatment of asthma.This new formulation was devised to release the drug close to its site of actionin the ileum. As budesonide undergoes extensive first-pass metabolism to lesspotent metabolites, systemic effects may be reduced.
To induce remission in patients with Crohn's disease in the ileum or ascendingcolon, a dose of 9 mg is given each morning. The total duration of therapyshould not exceed 12 weeks, including 2-4 weeks for tapering off the dose.Budesonide is not approved for maintenance treatment.
A randomised double-blind trial has compared budesonide with prednisolone.1 Ofthe 88 patients given budesonide, 29 had adverse effects due to treatment comparedwith 48 of the 88 people given prednisolone. Although budesonide caused significantlyfewer adverse effects, it induced remission in fewer (39) patients than prednisolone(48).
The adverse effects associated with budesonide resemble those of other steroids.Caution is required when prescribing budesonide for patients with conditionssuch as diabetes mellitus, hypertension or glaucoma. The response of the hypothalamic-pituitaryaxis to stress may be reduced.
As budesonide is likely to be more expensive than prednisolone, prescriberswill have to judge whether the lower efficacy is offset by the reduction inadverse effects.
Diavonex (CSL)
50 microgram/g cream in 30 g and 100 g packs
Quilonum SR (SmithKline Beecham)
450 mg slow-release tablets
Airomir (3M Pharmaceuticals)
100 microgram/actuation
Efexor XR (Wyeth)
75 mg and 150 mg modified-release capsules
The T-score (
) is explained in 'New drugs: transparency', Vol 30 No 1, Aust Prescr 2007;30:26-7.
