(1997; 11 pages)
Amyl nitrite - prescription control proposed
United Kingdom. The Medicines Control Agency has proposed that amyl nitrite should become a prescription-only medicine in view of its misuse as a stimulant. Medical uses of amyl nitrite include the treatment of cyanide or strychnine poisoning.
Reference: The Pharmaceutical Journal Vol. 257, p. 785, 10 August 1996.
Anorectic agents - restricted use
Economic Commission. The Committee on Proprietary Medicinal Products has reviewed the overall risk-benefit of anorectic agents in the treatment of obesity, and in particular the risk of the occurrence of primary pulmonary hypertension. Two categories of anorectic agent were assessed: the serotonergic compounds, dexfenfluramine and fenfluramine; and the “amfetamine-like” compounds, amfepramone, clobenzorex, fenbutrazate, fenproporex, mazindol, mefenorex, cathine (norpseudoephedrine), phendimetrazine, phenmetrazine, phentermine, propylhexedrine.
The Committee has concluded that, although studies confirm the risk of the occurrence of primary pulmonary hypertension, the risk-benefit balance is favourable provided that:
• use is restricted to adjunctive therapy to dietary measures in patients with major obesities with a body mass index of 30 kg/m2 or higher;
• the recommended duration of treatment is 4 to 6 weeks with a maximum duration of 3 months because of the increased risk of primary pulmonary hypertension;
• clear information on the potentially fatal risk of primary pulmonary hypertension related to the intake of anorectic agents is made available both to the physician and the patient.
• treatment is conducted under the supervision of physicians experienced in the treatment of obesity.
The Committee also recommended the inclusion of a boxed warning in the Summary Product Characteristics that clearly sets out the risks associated with these products.
[See also Pharmaceuticals Newsletter No. 8, August 1995, No. 10, October 1996 and Nos. 3&4, March&April 1997]
Reference: Communication from the EMEA dated 4 November 1996, enclosing the Committee for Proprietary Medicinal Products Assessment Report for Anorectic Agents, London, 18 July 1996.
Anthranoids in herbal drugs - restricted indications: amendment
Germany. The Federal Institute for Drugs and Medical Devices announced its revision of the product information of all medicinal products containing anthranoids (hydroxyanthracene derivatives) from the plants Andira, Cassia, Rhamnus, Rheum or Aloe because of experimental data showing evidence of potential genotoxicity and carcinogenicity in a Notification dated 20 June 1996, and listed revised indications for these products.
An amendment to this notification has now been issued stating that the only approved indication for these products is constipation. Therefore the indication for total intestinal evacuation before x-ray examinations and other diagnostic examinations is no longer authorized.
[See also Pharmaceuticals Newsletter Nos. 1&2, January&February 1997]
Reference: Communication from the Federal Institute for Drugs and Medical Devices, Berlin, 20 December 1996, enclosing Notice of Amendment to the Notice of 21 June 1996.
Aristolochia - prescription control proposed
United Kingdom. The Medicines Control Agency has proposed that the plant Aristolochia should be restricted to prescription control because of risk attached to its use without medical supervision and because of its substitution for other plants. One constituent, aristolochic acid, is known to cause kidney damage in humans, while animal studies indicate that it is a carcinogen.
Reference: The Pharmaceutical Journal Vol. 257, p. 174, 10 August 1996.
Ayurvedic medicine - heavy metal contamination
Germany. Ayurvedic medicine is a very old branch of traditional Indian medicine that uses mainly medicinal plants and minerals which are little known in western countries. It is widely used in India, and is increasingly being used in Germany.
However, when importing these products, it should be kept in mind that several cases of chronic lead poisoning have occurred in association with the use of these subtances, with symptoms such as headache, stomach cramps and anaemia. Considerable accumulation of lead in these products has been detected. Every case relating to these products must be reported to the competent authority and the prescribing doctor should be informed of the risk of adulteration of ayurvedic medicines with heavy metals.
Reference: Pharmazeutische Zeitung 141(42): 3846 (1996).
Calcium antagonists (short-acting): nifedipine - not recommended
New Zealand. In the light of recent studies reporting increased mortality in patients with ischaemic heart disease treated with short-acting calcium channel blockers including nifedipine(2,3), the Therapeutics Section of the Ministry of Health has carried out a review of both short-acting and long-acting calcium channel blockers in these patients.
The review concluded that the data possibly linking short-acting dihydropyridine calcium channel blockers to increased cardiovascular mortality cannot be extrapolated to verapamil, diltiazem or long-acting dihydropyridine calcium antagonists.
Monotherapy with short-acting calcium channel blockers is not recommended for patients with angina or clinical evidence of coronary artery disease.
Long-acting calcium antagonists may improve compliance and current evidence suggests that they can safely be used as monotherapy in patients who cannot tolerate alternative medicines and as adjunctive therapy. They can also be employed in the treatment of hypertension in accordance with national or international guidelines.
[See also Pharmaceuticals Newsletter Nos. 3&4, March&April 1997 and No. 3, March 1996]
Reference: Richards M. The safety of short and long-acting calcium antagonists in the treatment of angina and hypertension. Therapeutic Notes No. 22, October 1996, Therapeutics Section, Ministry of Health, Wellington.
Calcium channel blockers (short-acting): nifedipine - reminder concerning use
Germany. Further to the recent studies that report an increased risk of cardiovascular events and mortality in patients with unstable angina and following myocardial infarction treated with the short-acting calcium channel blocker, nifedipine(2,3), the Drug Commission of the German Medical Profession recommends strict compliance with the approved indications for this product, i.e. hypertension and stable angina pectoris.
The Commission points out that nifedipine and other short-acting calcium antagonists (dihydropyridines) are generally contraindicated for unstable angina pectoris, as well as for acute myocardial infarction. For secondary prophylaxis after an acute myocardial infarction, beta-adrenoreceptor antagonists - and not calcium antagonists - are the first choice drugs. Calcium antagonists should generally be avoided in patients with heart failure in addition to a post-infarction condition. The Commission warns that their use contrary to the approved indications can lead to mortality.
Patients should also be informed of the situation because lack of compliance on their part could trigger complications which would then be ascribed to the drug.
[See also Pharmaceuticals Newsletter Nos. 3&4, March&April 1997 and No. 3, March 1996]
1) Notification from the Drug Commission of the German Medical Profession, 23 December 1996.
2) Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose related increase in mortality in patients with coronary heart disease. Circulation 92: 1326-1331 (1995).
3) Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. Journal of the American Medical Association 275: 620-625 (1995).
4) Rehnqvist N, Hjemdahl P, Billing E et al.: Effects on cardiovascular end points and psychological variables of metoprolol and verapamil in patients with stable angina pectoris - The angina prognosis study in Stockholm (APSIS). Journal of the American College of Cardiology 1995, Abstract 313A.
Colloidal silver or silver salts - proposed rule: no longer acceptable in over-the-counter products
United States of America. The Food and Drug Administration has proposed a rule establishing that over-the-counter products containing colloidal silver ingredients or silver salts for internal or external use are no longer acceptable.
The agency is issuing this proposal because colloidal silver ingredients or silver salts are being marketed for numerous serious disease conditions and the agency is not aware of any substantial scientific evidence that supports their use for these diseases, which include human immunodeficiency virus (HIV) and AIDS, cancer, and many infectious diseases.
The dosage form of these colloidal silver products is usually oral, but product labelling also contains directions for topical and, occasionally, intravenous use. Some products have been offered for sale by mail order.
Manufacturers are invited to submit any existing data and information that support the safety and effectiveness of colloidal silver ingredients or silver salts for use other than as an astringent (silver nitrate), a smoking deterrent (silver nitrate or silver acetate) or mild silver protein as an opthalmic anti-infective, all of which have already been reviewed by the agency and found ineffective.
Reference: Federal Register 61(200): 53685-53688 (1996).
Cyclandelate - withdrawn
United States of America. The Food and Drug Administration has announced that the Commissioner of Food and Drugs has taken a final decision to withdraw the marketing approval for the peripheral vasodilator, cyclandelate (CyclospasmolR: Ives Laboratories), indicated for intermittent claudication caused by arteriosclerosis obliterans and as a treatment for cognitive dysfunction in patients suffering from senile dementia of the multi-infarct or Alzheimer’s type.
The decision was taken on the grounds that this product has not been shown to be effective for such uses.
Reference: Federal Register 61(233): 64099-64136 (1996).
Fumaric acid (alkyl esters) - revised data sheet: blood dyscrasias
Germany. The Federal Institute for Drugs and Medical Devices has informed the manufacturer of products containing alkyl esters of fumaric acid and their salts (FumadermR: Fumedica), that it proposes to revise the product information for these products.
The section on “precautions” will be expanded to state that blood picture controls are imperative prior to treatment with fumaric acid and regular blood counts are necessary during treatment every 14 days in the first three months and thereafter every month. The product is to be withdrawn immediately if leukocyte values are below 3000/mm3 or if there are any other changes in the blood picture. Blood counts should then be repeated until they return to normal. In addition, prior to and during treatment liver function tests are necessary at regular intervals (in the first 4 weeks every 14 days and thereafter every four weeks) in order to monitor potentially harmful effects on the liver and kidneys. Therapy is to be discontinued if creatinine levels increase beyond the normal range.
The section on adverse reactions will include flush, heat sensation and diarrhoea, other gastrointestinal symptoms and, in rare cases, nausea, tiredness, drowsiness and headaches, and will state that these symptoms usually subside in the course of treatment. Dose reduction will alleviate complaints in most cases. Frequently observed changes in the blood picture during treatment with FumadermR are leukopenia and lymphopenia, as well as eosinophilia of varying intensity.
[See also Pharmaceuticals Newsletter No. 2, February 1996]
Reference: Communication from the Federal Institute for Drugs and Medical Devices, 9 September 1996.
Homoeopathic medicine - banned
France. The Ministry of Health and Social Affairs has banned the sale of a food supplement containing vitamins, minerals, animal organ extracts and plant extracts (Elementiel CirculationR: Pharal), at a homoeopathic dilution of 4CH. This action was taken after a case of thrombophlebitis was reported in a 21-month old infant and the ensuing investigation concluded that a causal relationship between the product and the reaction was probable. Existing stocks have been seized.
[See also Pharmaceuticals Newsletter No. 3, March 1994]
Reference: Communication from the Ministry of Health and Social Affairs, Paris, 14 February 1997.
Iron-containing dietary supplements - label warning statements & packaging requirements
United States of America. The Food and Drug Administration has decided to require warning statements in the product information of products taken in solid oral dosage form to supplement the dietary intake of iron or to provide iron for therapeutic purposes, and to require unit dose packaging for iron-containing products that contain 30 mg or more of iron per dosage unit. The agency is taking these actions because of the large number of acute iron poisonings, including deaths, in children less than 6 years of age attributable to accidental overdosage of iron-containing products. The FDA is temporarily exempting one form of elemental iron, carbonyl iron, from the packaging requirements of this final rule.
The labelling of such dietary supplement in solid oral form shall bear the following statement prominently and conspicuously:
“WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control centre immediately.”
[See also Pharmaceuticals Newsletter No. 1, January 1995 and Alert No. 53, 3 March 1993]
Reference: Federal Register 62(10): 2218-2250 (1997).
Lamotrigine - restricted use: severe cutaneous reactions
Glaxo Wellcome UK & USA, Germany. The manufacturer of the antiepilepsy agent, lamotrigine (LamictalR) has issued “Dear Doctor” letters in the United Kingdom and the United States of America to alert physicians to reports of severe, potentially life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, in association with its use, especially in children under 16 years of age.
These reactions are described in the prescribing information and are reported to occur in approximately 1 in 1000 adults. Recent information indicates that the incidence of such reactions in children aged 12 years or under is very much higher than that in adults. The estimated incidence of serious reactions in children requiring hospital admission is between 1 in 300 and 1 in 100 patients.
The majority of serious skin reactions occur within 2-8 weeks of starting lamotrigine; however, isolated cases have been reported after prolonged treatment. Although the majority recover on drug withdrawal, some patients experience irreversible scarring and there have been rare cases of death associated with lamotrigine.
All patients (adults and children) who develop rash should, therefore, be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related.
The following risk factors appear to be associated with the development of skin reactions:
• concomitant use of valproic acid which increases the mean half-life of lamotrigine two-fold.
• high initial doses of lamotrigine exceeding the recommended dosage escalation.
Recommended starting doses and dose escalation should therefore not be exceeded.
Moreover, early manifestations of hypersensitivity - such as fever, lymphadenopathy - may occur without evidence of rash. It is therefore recommended that, prior to initiation of treatment with lamotrigine, patients should be instructed to report rash or other signs of hypersensitivity to their physician immediately. If such symptoms develop, the patient should be evaluated immediately and lamotrigine discontinued if an alternative etiology cannot be established.
The UK letter points out that the risk/benefit balance for lamotrigine as an add-on therapy in children aged 12 and under is still favourable and reiterates that initial monotherapy is not recommended.
In the USA, a boxed warning has been added to the product information and doctors are reminded that lamotrigine has not been approved in the USA for use in children under 16 years of age.(1,2)
Germany. The Drug Commission of the German Pharmaceutical Society has published a similar text at the request of Glaxo Wellcome and Destin Arzneimittel in Germany together with a statement to the effect that the benefit/risk ratio of lamotrigine as an adjunctive therapy is still favourable, but that initial monotherapy in children under 12 years of age cannot be recommended until adequate toxicity data have been obtained from controlled studies in these patients.(3)
Note: The Committee on Safety of Medicines in the UK issued a reminder concerning serious skin reactions associated with lamotrigine in October 1996.(4) The Australian Adverse Drug Reactions Advisory Committee reported 8 serious skin reactions associated with lamotrigine received as of December 1996.(5)
1) Dear Doctor letter, Glaxo Wellcome UK, April 1997.
2) Dear Doctor Letter, Glaxo Wellcome Inc., USA, April 1997.
3) Deutsche Apotheker Zeitung 137(15): 1172 (1997).
4) Current Problems in Pharmacovigilance Vol. 22, p.10, October 1996.
5) Australian Adverse Drug Reactions Bulletin, Vol. 16, No. 1, February 1997.
Paracetamol (liquid preparations) - withdrawn
Malaysia. The Drug Control Authority has decided to cancel the registration of all paracetamol 500 mg/5 ml liquid preparations. This decision was taken after the Malaysian Adverse Drug Reactions Advisory Committee received 3 reports of paracetamol toxicity (one fatal) due to overdosage in children associated with the use of paracetamol 500 mg/5 ml instead of the 120mg/5 ml preparation.
Reference: Berita Ubat-Ubatan (Drug Information) 10(3): 11 (1996).
Quinine/methylthioninium chloride combination (injectable) - proposed withdrawal and revision of labelling
Thailand. Further to Alert No. 56 concerning the risk of serious adverse reactions in association with the use of a combination preparation containing quinine dihydrochloride and methylthioninium chloride (methylene blue) as an antimalarial, the Adverse Drug Reactions Committee of the Food and Drug Administration has proposed withdrawal of this product. In addition, a re-evaluation process is under way concerning the labelling of products containing quinine dihydrochloride.
[See DRS Information Exchange Service Alert No. 56 of 28 February 1997]
Reference: Communication from the Food and Drug Administration, Bangkok, dated 26 March 1997.
Valproic acid and panipenem/betamipron or meropenem - interaction
Japan. The Pharmaceutical Affairs Bureau has received reports that concomitant administration of panipenem/betamipron or meropenem resulted in a rapid fall in the level of valproic acid in the plasma and the development of seizures in epileptic patients who had been maintained free of seizures with valproic acid medication.
The reports further state that the subsequent withdrawal of the carbapenems was followed by a rapid increase in valproic acid level and the disappearance of the recurrent epileptic seizures. This interaction has been demonstrated in experiments with monkeys.
The Bureau has decided therefore that the concomitant administration of valproic acid and panipenem/betamipron or meropenem is contraindicated and has revised the relevant data sheets accordingly.
References: Information on Adverse Reactions to Drugs No. 137, May 1996, Pharmaceutical Affairs Bureau, Ministry of Health & Welfare, Tokyo.