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New drugs
(Aust Prescr 1999;22:20-3)
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.
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 already available in Australia.1 Candesartan adds to the choices for treating mild to moderate hypertension.
The tablets contain a prodrug which is rapidly converted to active candesartan during absorption. Peak serum concentrations are reached within 4 hours. Food increases the rate of absorption, but does not affect the bioavailability which is approximately 14%. Most of a dose is excreted in the urine, so a lower starting dose is recommended for the elderly and patients with severe renal impairment. The terminal half-life is approximately 9 hours. Although the effect on blood pressure peaks a few hours after a dose, its duration permits once daily dosing.
Candesartan reduces blood pressure more than placebo. The maximum effect on blood pressure is reached within one month. This effect is comparable to the effects of hydrochlorothiazide, amlodipine or enalapril. A dose of 16 mg candesartan may 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 of candesartan in heart failure was halted because of concerns about increased mortality. While the significance of this observation is unclear, the drug is not recommended for patients with heart failure. It should not be used in patients with renal artery stenosis and should be used with caution in patients who are salt or volume depleted.
R E F E R E N C E
1. Johnson CI. Angiotensin receptor antagonists for the treatment of hypertension. Aust Prescr 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 with Alzheimer's disease. This abnormality has led to trials of anticholinesterases such as tacrine (see `Tacrine in the treatment of Alzheimer's disease' Aust Prescr 1996;19:14-7). Donepezil is also an inhibitor of acetylcholinesterase, but has less peripheral activity than tacrine.
Clinical trials of donepezil have studied patients with mild to moderately severe Alzheimer's disease. Rating scales and subjective assessments have been used to evaluate its effects. The drug has been more efficacious than placebo in studies of 12-24 weeks' duration. While these responses may have statistical significance, their clinical significance is unclear.
Donepezil is given once a day. It takes 3 weeks to reach a steady state as the half-life is approximately 70 hours. While some donepezil is excreted unchanged in the urine, it is also metabolised. As the metabolic pathways include cytochrome P450 2D6 and 3A4, there is a potential for drug interactions, but donepezil is said to have no significant interaction with theophylline, cimetidine, warfarin or digoxin.
The increase in cholinergic activity contributes to some of the adverse effects of donepezil. The most common adverse effects are nausea, vomiting and diarrhoea. The clinical trials on which marketing approval is based were only of up to 6 months' duration, so long-term safety data are limited.
There appear to have been no trials comparing donepezil and tacrine. Donepezil is better tolerated with only 5-13% of patients stopping treatment because of adverse effects. (Approximately 17% of the patients who received tacrine in clinical trials had to stop treatment.) Patients taking donepezil do not require the frequent monitoring of liver function which is required when starting tacrine. While donepezil may have some advantages over tacrine, both drugs only have modest therapeutic effects. Neither drug halts the progression of the 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 commonly causes irritation. While podophyllotoxin has a mainly destructive action, imiquimod is thought to modify the immune response.
The cream is applied to the warts for 3 nights each week and is left on for 6-10 hours. This appears to induce the production of interferon alpha and other cytokines. Imiquimod has no antiviral action.
A double-blind placebo-controlled trial randomised 51 non-immunosuppressed patients 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 of the other patients, the warts reduced in size. In the placebo group, the response was significantly less and no patient had a complete response.1 Other studies have shown similar benefits, but the recurrence rate after treatment is not significantly different from placebo. Efficacy has not been demonstrated in immunocompromised patients.
Most of the adverse effects of imiquimod are local skin reactions. The majority of patients will develop erythema. Erosion, itching and burning can also occur. Only 4 of the 327 patients in the clinical trials discontinued the drug because of skin reactions. Very little imiquimod is absorbed through the skin. As the potential systemic absorption is increased, imiquimod should not be applied to 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 effectiveness needs to be compared with that of podophyllotoxin and other treatments such as liquid nitrogen or laser therapy. As the maximum duration of treatment allowed is 16 weeks, there is a need for information about the use of imiquimod for warts which recur.
R E F E R E N C E
1. Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol 1998;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 in Japan 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 channels which leads to arterial dilatation. The haemodynamic effects include reductions in end diastolic pressure and systemic resistance.
Patients with chronic stable angina can take nicorandil twice a day. The drug is rapidly absorbed with a bioavailability of 75%. Most of the drug is rapidly eliminated from plasma, but the plasma concentration is not closely linked to the effect of nicorandil. Most of the drug is metabolised and the metabolites are mainly excreted in the urine.
The most common adverse effect of nicorandil is headache. This caused up to 10% of patients to stop treatment in some clinical studies. However, the headache tends 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 of angina. Although the studies have been relatively short, the tolerance seen with 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 a role in patients with angina who do not respond to conventional treatment. Although there are no reported interactions with beta blockers or calcium channel blockers, 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 cell surface markers. For example, non-Hodgkin's B-cell lymphomas have specific surface antigens. Rituximab is a genetically engineered monoclonal antibody against the CD20 antigen on the B lymphocytes.
Rituximab is thought to act by binding to the CD20 antigen. This leads to the lysis of the B lymphocytes. There is a marked decline in the number of B cells in the peripheral blood soon after the first dose.
Although the prognosis for patients with non-Hodgkin's lymphoma is worse than for those with Hodgkin's disease, it has improved with chemotherapy. Unfortunately, some patients will be refractory to treatment and others will relapse. Some of these patients may benefit from rituximab.
The main study of rituximab involved 166 patients given 4 doses at weekly intervals. This resulted in a complete response in 10 patients and a partial response in 70 patients. The median time for patients to respond was 50 days and the highest response rate was seen in patients who had previously had an autologous bone marrow transplant.
Rituximab is diluted and then infused slowly. Its pharmacokinetics probably resemble those of immunoglobulins. After the fourth infusion of a course, the half-life is 190 hours and rituximab will be detectable for 3-6 months after treatment.
Some adverse effects are the predictable result of infusing an antibody containing human protein e.g. hypersensitivity reactions. The majority of patients develop fevers and chills during the first infusion. Patients may complain of nausea, itching, weakness and headache. Hypotension and bronchospasm can develop. If these adverse effects occur, the infusion should be slowed or stopped and supportive care given e.g. intravenous saline. The incidence of infusion-related events declines from 80% during the first infusion to 40% with subsequent infusions.
As the CD20 antigen is found on normal as well as malignant lymphocytes, a fall in lymphocytes is to be expected. It is unclear if this significantly alters the risk of infection. The lymphocytes begin to recover 6 months after treatment and usually return to normal during the next 6 months. Although the CD20 antigen is not found on stem cells or plasma cells, severe haematological abnormalities can occur. These include neutropenia, anaemia and thrombocytopenia.
The studies of rituximab have been uncontrolled, but its efficacy is probably similar to that of cladribine or fludarabine. While rituximab increases the therapeutic options for patients with relapsed or refractory low grade non-Hodgkin's lymphomas, 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 hypovolaemia e.g. due to bleeding. The infusion can also be used when haemodilution or extra-corporeal circulation 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 being treated 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 systemic effects.
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 action in the ileum. As budesonide undergoes extensive first-pass metabolism to less potent metabolites, systemic effects may be reduced.
To induce remission in patients with Crohn's disease in the ileum or ascending colon, a dose of 9 mg is given each morning. The total duration of therapy should 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 Of the 88 patients given budesonide, 29 had adverse effects due to treatment compared with 48 of the 88 people given prednisolone. Although budesonide caused significantly fewer 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 conditions such as diabetes mellitus, hypertension or glaucoma. The response of the hypothalamic-pituitary axis to stress may be reduced.
As budesonide is likely to be more expensive than prednisolone, prescribers will have to judge whether the lower efficacy is offset by the reduction in adverse 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
