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WHO Pharmaceuticals Newsletter 1997, No. 01&02
(1997; 10 pages)
Table of Contents
View the documentRegulatory actions
View the documentDrug surveillance
View the documentNew developments
View the documentNew approvals
View the documentMedical devices
View the documentGeneral information
View the documentVeterinary medicine

Regulatory actions

Adrenal cortex extract - alert concerning serious adverse reactions

USA. The Food and Drug Administration has issued an alert concerning 30 ml vials of Hallmark Labs injectable “adrenal cortex extract” distributed by Phyne Pharmaceuticals, because this product can cause serious and life-threatening injuries.

Since April 1996, the FDA and the Centers for Disease Control and Prevention and many state agencies have received some 54 reports of abscesses forming at the sites of injection of these products. Adrenal cortex extract - usually derived from the adrenal glands of cattle, sheep or swine - is not approved for use by the FDA for any indication.

The adrenal cortex extract of concern may have been prepared under conditions that could have led to its contamination. These products could also be improperly labelled - containing indications for use that might expose immunocompromised patients to particular risk.

The FDA has taken regulatory steps to identify the parties responsible for the manufacture and distribution of these potentially contaminated products, and to ensure that they are promptly removed from the market. Physicians or consumers who have adrenal cortex extract products bearing “Hallmark Labs” on the label were instructed to immediately stop using the product and to contact the FDA. Patients experiencing swelling, tenderness, other signs of infection at the site of injection or other adverse reactions were urged to contact their physician immediately.

References: HHS News P96-13 dated 30 August 1996.

Alendronic acid - recommendations on use: oesophageal reactions

UK. Alendronic acid (FosamaxR: Merck & Co.) is a biphosphonate used for the treatment of osteoporosis in postmenopausal women. Between September 1995 and March 1996, the Committee on Safety of Medicines has received 116 spontaneous reports of 197 adverse reactions. Of these, 10 reports involved the oesophagus. Approximately 9,000 patients have been treated with alendronic acid in the UK.

Worldwide, some 445,000 patients have received alendronic acid and 211 oesophageal reactions have been reported, of which 36 were serious. Pre-marketing studies suggested that oesophageal reactions occurred in approximately 1.5% of patients. However, more severe reactions have occurred after marketing, and in about half the reported cases where relevant data had been recorded, alendronic acid had not been taken in accordance with the prescribing information.

In order to minimize the risk of oesophageal reactions, the following recommendations should be observed:

• Alendronic acid should be taken with a full glass of plain water immediately after getting up in the morning.

• Patients should not lie down for at least 30 minutes after taking the tablets and until after their first food of the day.

• Patients should be specifically instructed not to take the tablets at bedtime or before getting up in the morning.

Alendronic acid should not be prescribed for patients with abnormalities of the oesophagus (e.g. stricture or achalasia) or with other factors that delay oesophageal emptying. It should be used with caution in patients with upper gastrointestinal problems (e.g. dysphagia, oesophageal disease, gastritis, duodenitis and peptic ulceration).

The frequency of upper gastrointestinal adverse reactions appears to be greater when alendronic acid is used in conjunction with nonsteroidal anti-inflammatory drugs including acetylsalicylic acid (aspirin).

[See also Pharmaceuticals Newsletter Nos. 5/6, May/June 1996]

Reference: Current Problems in Pharmacovigilance Vol. 22, July 1996.

Amphotericin B (intravenous) - revised product information: anaphylaxis

UK. The Committee on Safety of Medicines recommends that a test dose of amphotericin B be administered before commencing the first infusion, to avoid the risk of anaphylaxis. A small amount of amphotericin B (e.g. 1 mg) should be infused over about 10 minutes and the patient carefully observed for about 30 minutes.

Prophylactic antipyretics or hydrocortisone should only be used in patients who have previously experienced acute adverse reactions, and in whom continued treatment with amphotericin B is essential.

The product information has been updated to reflect these recommendations.

Reference: Current Problems in Pharmacovigilance Vol. 22, July 1996.

Anthranoids in herbal drugs - revised data sheet: restricted indications

Germany. The Federal Institute for Drugs and Medical Devices has revised 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.

The permitted indications will be limited as follows:

a) For medicinal products containing drugs, drug preparations or isolated ingredients of the above-mentioned plant genera:

- Short-term treatment of constipation.

b) For fixed combinations of senna leaf with peppermint oil and caraway oil or fixed combinations of aloe with celandine.

- Short-term use in cases of constipation, especially if it is accompanied by intestinal spasms.

c) For medicinal products containing drugs, drug preparations or isolated ingredients of the above-mentioned plant genera which are intended for single administration:

- Total intestinal evacuation before x-ray examinations and other diagnostic examinations.

In addition, the new product information includes several contraindications.

[See also Pharmaceuticals Newsletter No. 2, February 1995]

Reference: Communication from the Federal Institute for Drugs and Medical Devices, Berlin, 18 September 1996, enclosing notification of 21 June 1996.

Blood and blood components - procedures for potentially contaminated products

USA. The Food and Drug Administration has issued a final rule establishing written procedures for appropriate action by centres that have collected blood and blood components that are potentially contaminated by human immunodeficiency virus (HIV).

This can happen when a person donates blood early in infection, during the period when the antibody to HIV is not detectable by a screening test, but HIV is present in the donor’s blood (a so-called “window” period). If the donor attempts to donate blood at a later date, the test for HIV may, at that time, be repeatedly reactive.

The centre should perform more specific testing using a licensed test and notify consignees to quarantine previously collected whole blood, blood components, source plasma or source leukocytes in order that they may take appropriate action including notification of transfusion recipients.

Blood establishments are required to prepare and follow written standard operating procedures defining steps to be taken when “lookback” circumstances arise. They must also maintain the necessary records to carry out these procedures, and notify consignees within 72 hours of repeatedly reactive test results. Blood establishments that provide transfusion services must also notify physicians of prior donation recipients, or the recipients themselves, of the need for HIV testing and counselling.

The full text of this final rule is available on request.

[See also Pharmaceuticals Newsletter No. 7, July 1993]

Reference: Federal Register 61(175): 47413-47423 (1996).

Chlormezanone - withdrawn because of cutaneous toxicity: update

France, Japan, Germany, Portugal. In October 1996, the manufacturers voluntarily withdrew chlormezanone-containing preparations in France, and one manufacturer, Sanofi, subsequently decided to withdraw the drug worldwide. This action followed an analysis carried out by the Pharmacovigilance Unit of the French Agency for Medicines of reports of adverse effects associated with the muscle relaxant, chlormezanone, used alone or in combination, which identifed a risk of severe cutaneous reactions including life-threatening toxic epidermal necrolysis, borderline bullous major forms, Stevens-Johnson syndrome, erythema multiforme, fixed drug eruption, borderline bullous minor form and genital bullae [See Alert No. 53, 18 October 1996].

Since this action was taken, licence holders of TrancopalR and of chlormezanone in Japan have voluntarily recalled chlormezanone products.

In Germany, where measures were being implemented to restrict the use of chlormezanone, licence holders of TrancopalR and other chlormezanone preparations have withdrawn their products from the market.

In Portugal, the Board of Management of the National Institute of Pharmacy and Medicines has revoked the marketing authorization of brand names containing chlormezanone. In all cases the licence holder is Sanofi Winthrop.


1) Pharmacovigilance, Agence du Medicament dated 14 October 1996.

2) Roujeau J-C, Kelly JP, Naldi L et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. New England Journal of Medicine 333(24): 1600-1607 (1995).

3) Communication from Ministry of Health & Welfare, Tokyo, Japan, 29 October 1996.

4) Deutsche Apotheker Zeitung 136(42): 3590 (1996)

5) Notification from the Board of Management, Instituto Nacional da Farmacia e do Medicamento (INFARMED), Lisbon, 11 November 1996.

Herbal medicines adulterated with diclofenac - banned

Singapore. The Ministry of Health has banned four Chinese herbal medicines which were found to be adulterated with the nonsteroidal anti-inflammatory drug, diclofenac.

The four products are:

1) Ba Bao Fen Shi Huo Luo Dan (Mei Hua brand), claimed to be a good treatment for rheumatism.

2) She Xiang Zhui Feng Tou Gu Wan (Mei Hua brand). The claimed functions of this medicine include anti-rheumatism, dissipation of stasis in the tendons and nervous channels, activating blood circulation, discharging bruise, anti-inflammatory and analgesic action, and strengthening bones.

3) 101 Wei Yao Ling (Mei Hua brand). It is claimed to act as an antacid, anticholinergic and is used to protect gastric mucous membrane, to treat stomach pain, hyperacidity, gastric and duodenal ulcers and chronic gastritis, etc.

4) Zhen Zhu Tou Tong Ling (Fen Yien brand), claimed to be of value in the treatment of migraine, headache, trigeminal neuralgia and severe headache.

Reference: Communication from the Institute of Science and Forensic Medicine, Singapore, dated 18 July 1996.

Ketorolac - extension of suspension

Germany. The Federal Institute for Drugs and Medical Devices has informed manufacturers of pharmaceutical products containing the nonsteroidal anti-inflammatory agent, ketorolac trometamol (ToratexR), that the suspension of marketing authorizations for these products has been extended until 30 November 1998.

The product was initially suspended in June 1993 because of a high incidence of serious adverse effects, including renal failure.

[See also Pharmaceuticals Newsletter Nos. 11/12, November/December 1994 and No.2, February 1995]

Reference: Deutsche Apotheker Zeitung 136(30): 2516 (1996).

Quinidine/verapamil - restricted use

Germany. The Pharmaceuticals Commission in agreement with the Federal Institute for Drugs and Medical Devices has issued information on measures taken to minimize risks associated with a fixed combination product containing the antiarrhythmics quinidine and verapamil (CordichinR: Knoll).

The indications are restricted to:

- cardioversion in vestibular flutter and fibrillation when electrocardioversion is contraindicated.

- recurrent chronic vestibular flutter after successful conversion with CordichinR in patients in whom restoration of the sinus rhythm has led to an improvement of severe symptoms.

For both indications, treatment should be interrupted if one of the following symptoms is observed: symptomatic hypotension, bradycardia, torsade de pointes, tachycardia, ventricular tachycardia, QTc interval greater than 0.550, increase in QTc-value to more than 30% over the output value.

In the framework of the revision of indications for this product, the Federal Institute for Drugs and Medical Devices has requested clinical studies to verify the benefit/risk ratio of CordichinR. These should be completed by 1999, and the newly modified indications will be valid until that time.

[See also Pharmaceuticals Newsletter Nos. 5/6, May/June 1995]

Reference: Deutsche Apotheker Zeitung 136(29): 2438-2439 (1996).

Tamoxifen - revised package insert: warnings

South Africa. The Medicines Control Council has revised the package insert of pharmaceutical products containing tamoxifen to include the following warnings:

“Endometrial changes. An increased incidence of endometrial changes, including hyperplasia, polyps and cancer, has been reported in association with tamoxifen treatment. Any patients receiving or having previously received tamoxifen, who report vaginal bleeding, should be promptly investigated.

“Side effects and special precautions. Tamoxifen was genotoxic in some in vitro and in vivo genotoxicity tests in rodents. Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.”

Reference: Communication from the Medicines Control Council, Pretoria dated 22 June 1996.

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