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Regulatory and Safety Matters Etanercept: serious haematological reactions European Union -The European Agency for the Evaluation of Medicinal Products (EMEA) has received information of 10 cases of serious blood dyscrasias, some with fatal outcome, in rheumatoid arthritis patients treated with etanercept (Enbrel®). Etanercept is indicated for active rheumatoid arthritis in adults and active polyarticular-course juvenile chronic arthritis in patients with an inadequate response to methotrexate. Since first marketing, an estimated 80 000 patients have been treated worldwide. A review has been made of adverse reaction reports and the prescribing and patient information has been modified through a rapid procedure. The following information has been brought to the urgent attention of prescribers: • Cases of pancytopenia and aplastic anaemia, some with fatal outcome, have been reported rarely (less than 1 in 1000 patients); • Caution should be exercised in patients with a previous history of blood dyscrasias. • All patients should be informed of the signs and symptoms suggestive of blood dyscrasias or infections, i.e. persistent fever, sore throat, bruising, bleeding, paleness. They should seek immediate medical advice. • If blood dyscrasias are confirmed, etanercept should be discontinued. Reference: EMEA Public Statement on etanercept (Enbrel®) - Serious haematological reactions and demyelination disorders. EMEA/H/300871. http:// www.emea.eu.int
lnfliximab is a new treatment for patients with rheumatoid arthritis and Crohn disease not responding to established therapies. lnfliximab was first approved in 1999 for the treatment of Crohn disease and in February 200 for rheumatoid arthritis. The manufacturer has since received a number of reports of the onset or reaction of potentially lifethreatening tuberculosis infections in treated patients. In many cases these reports have originated in countries with a high incidence of TB and also in patients who have been previously treated with immunosuppressants and/or corticosteroids. In a sign"ificant number of cases, the onset of active tuberculosis occurred after three or less infusions of infliximab. However, clinical experience is still limited and long-term effects cannot be ruled out. Prescribers and patients should be informed of the risk and be especially vigilant for signs of infection throughout treatment. Patients should be evaluated for active and latent tuberculosis before initiation of treatment. If active tuberculosis is suspected, infliximab should be withheld and the risk/benefit for the patient considered. The product remains useful for the treatment of Crohn disease and rheumatoid arthritis in patients who have not responded to alternative therapies. Reference: 1. Committee on Safety of Medicines Press Release. 20 December 2000. http://www.open.gov.uk/mca
2. EMEA Public Statement on inf/iximab -reports of tuberculosis infections. EMEA/CPMP/4445/00. http:// www.emea.eu.int
Phenylpropanolamine withdrawn from drug products United States of America- Steps have been taken by the Food and Drug Administration to remove phenylpropanolamine from all products because of the risk of haemorrhagic stroke. Manufacturers have been requested to discontinue marketing products containing phenylpropanolamine, which is used as a decongestant in many over-the-counter and prescription cough and cold medications and in weight loss products.
lnfliximab: safety restrictions European Union -The European Agency for the Evaluation of Medicinal Products (EMEA) has issued a public statement regarding tuberculosis or other opportunistic infections following infliximab (Remicade®) therapy.
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The decision was taken following a review of the Haemorrhagic Stroke Project during a meeting of the Nonprescription Drugs Advisory Committee The FDA believes that although the risk of haemorrhagic stroke is very low, the conditions for which these products are used do not warrant the increased risk. Reference: FDA Talk Paper, T00-58, November 2000
Reference: Health Canada Advisory. Press Release, 2000-108, 6 November 2000.
Phenylpropanolamine: strengthening of patient information United Kingdom -The Committee on Safety of Medicines (CSM) has considered new evidence from the Haemorrhagic Stroke Project. During its meeting on 8 November 2000, it concluded that the evidence of a link between haemorrhagic stroke and phenylpropanolamine (PPA) was weak and associated with uses not licensed in the United Kingdom. Furthermore, over-the-counter cold and influenza remedies on the market in the UK have a lower maximum daily dose (1 00 mg) than similar products in the United States (1). However, the debate over safety of phenylpropanolamine may not apply to UK products. In Europe, a different isomer known as norpseudoephedrine is used (2). This consideration of the isomer may explain why many of the adverse drug reactions reported in Europe describe an alteration of mental status whereas those in North America are more often compatible with hypertension. The CSM has since endorsed this advice and recommended that manufacturers should improve existing product information with more prominent warni11gs (1 ). Patients who are concerned about taking products containing PPA should consult their pharmacist, who may suggest alternative remedies. PPA-containing products should not be used by certain groups of patients, such as those with high blood pressure or heart disease. References 1. Committee on Safety of Medicines Press release. 18 December 2000. http://www.open.gov.uk/mca 2. Pharmaceutical Journal, 265: 709 (2000).
Labelling revision for phenylpropanolamine Japan -The Ministry of Health and Welfare has instructed domestic manufacturers and wholesalers of drugs containing phenylpropanolamine (PPA), a drug linked to haemorrhagic stroke in the United States, to revise the precautions statement of the package insert. This will now list hypertension and a history of cerebral haemorrhage as contraindications while drawing attention to the risk of haemorrhagic stroke. This action follows a large-scale epidemiological survey conducted in the United States between 1994 and 1999 showing that women who use PPA as an appetite suppressant have a higher incidence of haemorrhagic stroke. The reason is not clear, but is believed to relate to the large doses used. Reference: Pharma Japan, 1724, 4 December 2000.
Phenylpropanolamine advisory to consumers Canada - Health Canada has issued an advisory concerning phenylpropanolamine (PPA) concerning a reported association with haemorrhagic stroke. PPA is widely used as a nasal decongestant in prescription and non-prescription cough and cold, sinus and combination allergy products. Although the risk of haemorrhagic stroke is low, it is difficult to predict who is at risk. A public recommendation has been made for consumers not to use any products containing PPA until a full assessment has been completed. Many of the reports of a suspected link between PPA and haemorrhagic stroke from the Unitea States have been in young women using PPA as an appetite suppressant. However, PPA has not been approved for such use or for weight loss in Canada.
Levacetylmethadol and cardiac disorders European Union -The European Agency for the Evaluation of Medicinal Products (EMEA) has received information on 10 case reports of lifethreatening cardiac disorders including ventricular rhythm disorders such as torsades de pointes in patients treated with levacetylmethadol (Orlaam®).
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Levacetylmethadol is indicated for the substitution maintenance treatment of opiate addiction in adults previously treated with methadone. Reports include 5 cases of cardiac arrest, 3 cases of cardiac arrhythmia and 2 cases of syncope. The QT inteNal was prolonged in 7 of the patients and 4 of these had an episode of torsades de pointes. Three patients required a pacemaker insertion. Lifethreatening cases occurred in young patients, a population at low risk of developing these cardiac disorders given the relatively low exposure of the product. As an interim and precautionary measure while a full comparative risk/benefit assessment is made, the following warning has been brought to the attention of prescribers. • Prescribers are advised not to start any new patients on levacetylmethadol therapy; and • Patients currently taking levacetylmethadol should contact their doctor for advice regarding their treatment. They must not stop taking levacetylmethadol suddenly without seeking medical advice. Attention is drawn to the special warnings and precautions already included in the product information for levacetylmethadol. Reference: EMEA Public Statement on levacetylmethadol. 19 December 2000. http://www.emea.eu.int
The Food and Drug Administration has requested manufacturers to replace bovine-derived materials obtained from countries where bovine spongiform encephalopathy (BSE) has been reported with materials from BSE-free countries. The Public Health SeNice recommends that all persons continue to be vaccinated according to current schedules. Reference: Morbidity and Mortality Weekly Report, 49(50): 1137-1138 (2000). http://www.cdc.gov/mmwr
Products containing human albumin Portugal - An evaluation carried out by the Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) has concluded that the risk of transmission of variant Creutzfeldt-Jakob disease (vCJD) through blood or human plasma products is highly unlikely. However, in view of the scarcity of information available on the risk of transmission of vCJD through blood or human plasma products, the Institute Nacional da Farmacia e do Medicamento (INFARMED) notes that there is no evidence that transmission is impossible. Therefore INFARMED has decided that every medicinal product containing human albumin as an excipient should obtain authorization from INFARMED, batch by batch, before distribution. Reference: Deliberation of the Institute Nacional do Farmacia e do Medicamento (IN FARMED), 25 August 2000.
Bovine-derived materials and vaccines: US recommendations United States of America -The Center for Biologics Evaluation and Research (CBER) convened a meeting in July 2000 of the Transmissible Spongiform Encephalopathy Advisory Committee and the Vaccines and Related Biological Products Advisory Committee to discuss the status of vaccines which have been manufactured with bovinederived materials. No evidence exists that cases of variant Creutzfeldt-Jakob disease (vCJD) are related to the use of vaccines, and no cases of vCJD have been reported in the United States. The Committees concluded that the risk of vCJD posed by vaccines in the United States was theoretical and remote. This conclusion was based on the inherent low risk of the bovine materials involved and /or the dilutions of materials during manufacture. The Committees concluded that the benefits of vaccination outweigh any remote risk of vCJD.
Stavudine and didanosine: pregnancy advisory The manufacturer of stavudine (Zerit®) and didanosine (Videx®) has warned health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed these HIV drugs with other antiretrovirals. Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs may be damaged. Severe lactic acidosis is an infrequent, but documented complication of nucleoside analogues. Pancreatitis is also a complication of stavudine and didanosine.
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This new warning follows three reported cases of fatal lactic acidosis that occurred in pregnant women taking a combination of drugs to treat HIV. Several nonfatal cases of pancreatitis with or without lactic acidosis or hepatic failure have occurred in pregnant women receiving stavudine plus didanosine. It is unclear whether pregnancy potentiates these adverse effects. The manufacturer recommends that the combination of the two drugs should be prescribed to pregnant women only when the potential benefit clearly outweighs the potential risk. For example, when other treatment options have been exhausted. The Food and Drug Administration has strengthened the black box warning to include this new prescribing information. Patients receiving the combination should be closely monitored since this syndrome may develop abruptly and in the absence of abnormal laboratory values. Health care professionals should maintain a high index of suspicion in monitoring these patients and are encouraged to report any adverse effects. Reference: FDA Talk Paper, T01-02 (2001).
Prescribers should be aware that although methysergide drug holidays are generally recommended to prevent fibrotic changes, these changes can still occur and may affect cardiac valves. Reference: Australian Adverse Drug Reactions Bulletin, 19(4): 15 (2000).
Greater control for cisapride United Arab Emirates- After studying reports of rare but serious ventricular arrhythmias caused by the gastrointestinal motility drug cisapride, the UAE Ministry of Health has made cisapride a Registered Prescription (RP) drug. An RP drug can only be prescribed using a special duplicate and numbered prescription with details recorded and forwarded to the Ministry of Health. This allows complete follow up of all users. Severe penalties are in place for any pharmacist who supplies an RP drug without the correct prescription. The UAE decision recognizes that cisapride remains a unique drug and that some patients may not be able to use alternatives. These control measures are meant to ensure that only specialists will prescribe the drug. Reference: Drug Control Department, UAE Ministry of Health. Drug Information Bulletin, November 2000.
Methysergide and cardiac valvulopathy Australia - Methysergide is an ergot alkaloid used in the prophylaxis of migraine. Its most serious known adverse effect is retroperitoneal fibrosis. It has also been reported to be associated with fibrotic changes to other organs including heart valves. The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two recent reports describing cardiac valvulopathy. The prescribing information for methysergide states that continuous administration of the drug should not exceed 6 months and then should be withdrawn for 3-4 weeks before recommencement. Of particular interest in the two ADRAC reports was that the cardiac abnormalities occurred despite interrupted treatment according to directions. The valve damage reported appears to be similar to that with cases of carcinoid syndrome, use with ergotamine and, more recently, fenfluramine. Many of these reports describe the presence of a white surface plaque on the valves. These observed similarities suggest that a common factor may be causing the damage and may be related to the action of excess serotonin. 228
New combination drug for HIV United States of America -The Food and Drug Administration (FDA) has approved Trizivir® alone or in combination with other antiretroviral agents, for the treatment of HIV infection in adults and adolescents. Trizivir® is a combination of three synthetic nucleoside analogues previously approved by the FDA: abacavir, lamivudine, and zidovudine. Benefits relate to the requirement for only one tablet twice daily which is expected to improve adherence to treatment. In clinical studies of abacavir, about 5% of patients developed hypersensitivity reactions that can be serious or fatal. These include fever, skin rash, fatigue, gastrointestinal symptoms, pharyngitis, dyspnoea and cough. Rechallenge is contraindicated. Other possible effects include lactic acidosis, liver reactions, anaemia, neutropenia, nausea, fatigue and myopathy. Reference: Journal of the American Medical Association, 285 (2001).
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Tacrolimus for atopic dermatitis United States of America- The Food and Drug Administration has approved a new treatment for eczema, tacrolimus ointment 0.1% and 0.03% for adults and 0.03% for children 2 years and under. It is indicated for patients with moderate to severe eczema who are intolerant of standard therapies. Common side effects associated with tacrolimus are temporary stinging or burning sensation on application. The adverse effects of ultraviolet light on the skin may be accentuated. It is therefore important for patients to avoid sunlight, UVA or UVB light. Reference; FDA Talk Paper, T00-67 (2000).
The FDA has been concerned about reported cases of intestinal damage resulting from reduced blood flow to the intestine (ischaemic colitis) and severely obstructed or ruptured bowels (complications of severe constipation). Post-marketing reports of serious adverse events, included 5 reports of death. As of 10 November 2000, the FDA has received and reviewed a total of 70 cases of serious post-marketing adverse events, including cases of ischaemic colitis and severe constipation. Of the 70 cases, 34 resulted in hospitalization without surgery, 10 resulted in surgical procedures, and 3 resulted in death. The FDA has received two additional reports of death that the agency did not classify as being cases of ischaemic colitis or severe complications of constipation. References:
Letrozole approved for advanced breast cancer United States of America -The Food and Drug Administration has approved letrozole (Femara®) as a first-line treatment for postmenopausal women with hormone receptor positive or hormone receptor unknown, advanced or metastatic breast cancer. Letrozole, an aromatase inhibitor, was previously approved for cancer which had not responded to anti-estrogen drugs. In a randomized, double-blind, multinational trial of over 900 postmenopausal women, letrozole was shown to be more effective tl;lan tamoxifen by providing patients with a median of 3.6 more months before tumours worsened. The incidence of adverse effects in the study was similar for the two drugs with the most frequently reported adverse effects including bone pain, hot flushes, back pain nausea, arthralgia and dyspnoea. Reference: FDA Talk Paper, T01-03 (2001).
1. FDA Talk PaperT00-65 dated 28 November 2000. http://www.fda.gov/bbs/topics/ANSWERS/ANS01058.html 2. WHO Drug Information, 14(3): 166 (2000).
Basiliximab: hypersensitivity reactions The manufacturer of basiliximab (Simulect®), has informed health care providers of 17 cases of severe acute hypersensitivity reactions, including anaphylaxis, occurring in patients following the administration of basiliximab. The onset of reactions occurred within 24 hours following initial exposure and/or following re-exposure. Labelling recommends that medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, are available for immediate use and that the second dose of basiliximab is withheld if a hypersensitivity reaction occurs. The labelling for basiliximab has been revised to reflect this new information. Healthcare professionals are urged to report all serious adverse events suspected to be associated with the use of basiliximab to the manufacturer or the relevant authority. Reference: Letter to Health Care Providers, Novartis, 6 October 2000. http://www.fda.gov/medwatch/safety/2000/ simule.htm
Alosetron withdrawn United States of America- The manufacturer of alosetron (Lotronex®), has informed the Food and Drug Administration (FDA) that it has voluntarily withdrawn this product from the market (1 ). Alosetron is a prescription medication approved to treat irritable bowel syndrome in women (2). The FDA is advising patients taking alosetron to contact their healthcare providers to discuss treatment alternatives.
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Budipine: cardiac reactions Germany- The manufacturer of the antiParkinson agent, budipine (Parkinsan®), has revised the contraindications in the product information to include patients with cardiomyopathy, myocarditis and AV block II and Ill as well as patients with a history of ventricular arrhythmia, especially tachycardia (torsades de pointes). This action was taken by the Federal Institute for Drugs and Medical Devices which found that the incidence of cardiac adverse reactions was not adequately reflected in the product information. In addition, doctors are advised that an electrocardiogram should be performed before the start of therapy, and again one to three weeks afterwards and on increase of the dosage. With regard to risk factors for electrolyte imbalance, laboratory tests ~hould ~e performed. If symptoms such as palpitations, diZZiness or syncope appear, budipine should be withdrawn and the patient examined for aTprolongation. References: Deutsche Apotheker Zeitung 140(41 ): 4662 (2000).
Benzathine penicillin: fatal mega-unit injections Zim~abwe
-The Medicines Control Authority has rece1ved 3 reports of death associated with benzathine penicillin injections from 3 different manufacturers.
Prior to these reports -from 1993 to 1999 -the Authority has received only one report of an ady~rse. reaction associated with benzathine penicillin 1n]ect1on where a patient had fainted for about 30 seconds after administration of the injection, but recovered. No concomitant medicines were taken. It was also reported that the patient had suffered a previous adverse reaction following a penicillin injection. It is not clear whether these cases represent a higher incidence of hypersensitivity than would normally be expected with this drug. Reference: Drug Information Bulletin Vol. 4 No. 2 June 2000. , ,
Disulfiram: hepatic reactions Capecitabine: revised data sheet The m_an~facturer of the antineoplastic drug, capec1tabme (Xeloda®), has informed prescribers of !mportant safety-related changes to the labelling to mclude contraindications in patients with severe renal impairment. In addition, for patients with moderate renal impairment, the starting dose of capecitabine should be reduced. Updated data indicate that patients with moderate or sev~re renal impairment had a high rate of grade 3-4 senous adverse events. The increased incidence of undesirable effects did not impact negatively on the overall benefit for these patients when treated with capecitabine since the tumour response rate was maintained. Patients with mild renal im~airment, although experiencing slightly more senous adverse events and withdrawals than normal, maintained their overall benefiVrisk ratio. Reference: "Dear Doctor" letter dated 28 November 2000. http://www.fda.gov/medwatch/safety
- Disulfiram is prescribed as an adjunct the treatment of chronic alcoholism inhibiting the enzyme, aldehyde dehydrogenase. The combination of alcohol and disulfiram leads to an accumulation of acetaldehyde which induces classic symptoms such as flushing of the face, tachycardia, dyspnoea, nausea and vomiting. 1n
~weden
Disulfiram may also cause severe liver injuries. In the Swedish Drug Reference List (FASS), liver damage is labelled as "a rare adverse reaction (<1/ 1 000), usually with similar symptoms as for acute hepatitis and/or icterus as well as increased levels of SGOT an_d SGPT and bilirubin". This effect may be an allergic as well as toxic reaction. In the Swedish adverse drug reactions register, SWEDIS, 149 case reports associated with disulfiram have been received since 1971. Of these reports there are 157 adverse reactions in total of which 63 cite liver and biliary system disorders.' Out of these 63 reports, seven have been classified as serious. The duration of treatment varied from five weeks to three months before onset of the reaction.
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In three of these cases, the patients also took other drugs: sertraline, paroxetine and venlafaxine. These drugs may also be implicated in the reaction. In three cases of severe liver damage with fatal outcome, disulfiram was suspected to have caused the reaction. If signs of liver damage should appear, it is recommended that disulfiram be discontinued and liver tests performed. Reference: Information from the Medicines Product Agency, Volume 11, Number 5, 2000.
Interstitial nephritis may be caused by infection, autoimmunity and glomerular disease as well as hypersensitivity to medicines, particularly antibacterials and nonsteroidal anti-inflammatory agents. The medicines most commonly implicated are methicillin, penicillin, sulphonamides, cotrimoxazole, cefalosporins, rifampicin, fenoprofen, mefenamic acid, allopurinol, phenytoin and thiazides. There are no known reports of death as a result of this adverse reaction. In four of the published cases, renal function deteriorated again when omeprazole was reintroduced. Patients taking omeprazole, or any of the medicines listed above, who present with symptoms and signs of hypersensitivity should be withdrawn pending nephrology assessment. Reference: Prescriber Update No. 2, October 2000. http:// www.medsafe.govt.nz
Isoniazid and rifampicin: severe skin reactions Zimbabwe- The Medicines Control Authority has recently received four adverse reaction reports of "burn-like lesions on the whole body and mucosal ulcerations" associated with isoniazid and rifampicin. None of the four patients were taking concomitant medicines. All patients recovered. It was noted from records at the WHO Collaborating Centre for International Drug Monitoring that since 1993 the Authority had received seven reports of skin reactions (rash, pruritus) associated with rifampicin and isoniazid. Five of the seven reports indicated that the patients were also taking ethambutol and pyrazinamide. Reference: Drug Information Bulletin, Vol. 4, No. 2, June 2000.
Ozagrel sodium: kidney function disorder Japan - Ozagrel sodium, a thromboxane synthesis enzyme inhibitor is indicated for the improvement of postoperative cerebrovascular contraction and accompanying cerebral ischaemia and for improvement of motility disturbance due to acute cerebral thrombosis. In April 1994 and April 1996, abnormal kidney function, increase of BUN, and increase of creatinine were added to the labelling. However, 14 serious cases of acute renal failure have since been reported to the Ministry of Health and Welfare. Manufacturers have accordingly been directed to include "abnormal renal function" in the product labelling. Reference: Ministry of Health and Welfare (MHW) Pharmaceuticals and Medical Devices Safety Information, No. 162, Tokyo 27 September 2000.
Omeprazole-i nduced interstitial nephritis New Zealand - Acute renal impairment caused by interstitial nephritis is a rare complication of treatment with omeprazole. The New Zealand Centre for Adverse Reaction Monitoring (CARM) has received 7 reports of acute renal failure due to interstitial nephritis associated with omeprazole. While omeprazole use was being monitored, two reports of interstitial nephritis were received from a total cohort of 22 050 patients. There were several other reports of renal failure. Recognition of interstitial nephritis may be difficult because the symptoms of renal impairment are non-specific and diagnosis of renal dysfunction can only be made by carrying out biochemical tests. In general, the presenting features described for interstitial nephritis are fever, rash and eosinophilia but these features are not always seen.
Drug information to the public Japan -The Health Policy Bureau of the new Ministry of Health, Labour and Welfare plans to create a council responsible for the provision of easy-to-understand information to the general public on indications, adverse reactions, and prices of drugs on the Japanese market.
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The council will be created in response to the price system reforms decided at the end of 1999. The policy calls for systems making it possible to supply comparable drug information to the general public. The council will have about 15 members, including representatives of drug manufacturers and wholesalers. It will evaluate the use of new technologies, especially those used by drug companies, to disseminate information effectively. The council will also deal with a discrepancy in existing laws. At present, the Pharmaceutical Affairs Law controls the supply of information through the Internet as advertisements, while information to medical institutions remains uncontrolled because such information is not considered to be an advertisement. Reference: Pharma Japan 1731, 29 January 2001.
• An NNew Caledonia/20/99 (H1 N1 )-like virus. • A B/Sichuan/379/99-like virus (B/Johannesburg/5/ 99 and BNictoria/504/2000 are B/Sichuan/379/99like viruses). WHO strongly recommends the use of vaccine as an effective preventive measure against this potentially fatal disease. About 50 - 80% of vaccine recipients will be protected against the disease when there is a good match between the vaccine and strains of circulating influenza virus. However, in those cases where the vaccine does not fully protect against influenza, severity of illness and frequency of complications are reduced. Most populations have been previously exposed to influenza A(H3N2), influenza A(H1 N1) and B viruses and are known to have some degree of residual immunity. One dose of influenza vaccine should therefore be sufficient for all ages except young children. Previously unimmunized children should receive two doses of vaccine at an interval of at least four weeks. The specific vaccine viruses used in each country should be approved by the national control authorities who are responsible for making recommendations on their use. Reference: Weekly Epidemiological Record, 76: 58 (2001).
Northern hemisphere influenza vaccine composition World Health Organization -The composition for the northern hemisphere influenza season (20012002) has been decided and communicated to vaccine manufacturers. It is recommended that the influenza vaccine should contain the following three components: • An NMoscow/1 0/99 (H3N2)-Iike virus (NPanama/ 2007/99 is this kind of virus).
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