Abacavir hypersensitivity cases following an interruption of therapy

16 September 2000. Related: Treatment alerts.

Following the updated warning on abacavir from the US FDA the European Medicines Evaluation Agency (EMEA) has also issued a warning to European patients and physicians.

The warnings concern the potentially fatal hypersensitivity reaction to abacavir which occurs in approximately 5% of those taking this drug. It was known previously that restarting abacavir after experiencing symptoms of hypersensitivity could trigger and acute reaction which was potentially fatal. It was also known that hypersensitivity may be difficult to detect as many of the symptoms may mimic other common illnesses. This new warning, however, comes after reports of severe or fatal reactions occurring after abacavir was restarted in patients who had NO previous symptoms of hypersensitivity.

This means that there is the potential for anyone who was previously tolerating abacavir but who interrupted treatment for any reason to develop a life threatening reaction if they restart this drug. In some patients who developed hypersensitivity the reason for stopping abacavir was simply running out of the drug. In others abacavir was stopped during the treatment of other medical conditions.

The following public statement contains essential information for anyone prescribing or taking Ziagen (abacavir) 1.

The European Agency’s for the Evaluation of Medicinal Products (EMEA) scientific committee, the Committee for Proprietary Medicinal Products (CPMP), has recently been made aware of new information related to serious hypersensitivity reactions associated with Ziagen (abacavir).

Hypersensitivity reactions (HSR) are a known concern with this product. These potentially serious reactions are usually characterised by the appearance of symptoms indicating multi-organ system involvement. Nearly all the patients with HSR experience fever or rash but symptoms may mimic other common gastrointestinal or respiratory diseases. These reactions usually occur within the first 6 weeks of treatment, but can occur at any time, and were the subject of an urgent safety restriction in January of this year (please see EMEA public statement EMEA/1952/00 dated 24th January 2000 for further information.)

Hypersensitivity reactions with rapid onset may occur when treatment with Ziagen is restarted in patients who were not previously diagnosed as having a hypersensitivity reaction. These patients typically had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction.

The EMEA wishes to draw attention to the following updated information on the management of hypersensitivity reactions to Ziagen:

Managing Hypersensitivity Reactions

• To avoid a delay in diagnosis and minimise the risk of a life threatening hypersensitivity reaction, Ziagen must be discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicines.) If re-introduction is judged necessary it must be done in a hospital setting.
• If a decision is made to re-start Ziagen in patients who had stopped for any other reasons (such as occurrence of only one of the key symptoms of hypersensitivity or no preceding symptoms of hypersensitivity prior to stopping Ziagen), this must be done in a setting where medical assistance is readily available.

Informing Patients

• Patients must be made aware of the possibility of a hypersensitivity reaction to Ziagen and the need to contact their doctor immediately for advice should they develop signs or symptoms possibly linked to a hypersensitivity reaction.
• Patients who have stopped Ziagen due to symptoms which indicated or which were possibly due to a hypersensitivity reaction, should not restart Ziagen (or any other abacavir containing medicinal product) since restarting results in a return of symptoms within hours. The reoccurrence is usually more severe and may be life- threatening or fatal.
• Patients who have stopped Ziagen for any reason, and particularly if due to possible adverse reactions or illness must be advised to contact their doctor before re-starting.
• Patients should be reminded to read the package leaflet and to keep the alert card included in the pack with them at all times.

As an urgent measure, the prescribing and patient information and the labelling have been modified through a rapid procedure at the request of the marketing authorisation holder. The EMEA thought it necessary to provide this new information to the public. Relevant changes to the product information are indicated below. For the complete scientific evaluation of Ziagen and the complete revised product information see the European Public Assessment Report, also available on the EMEA website.

For further information contact:

Mr Noel Wathion, Head of Sector Pharmacovigilance and Regulatory Affairs, Unit of Evaluation of Medicines for Human Use

1 Ziagen 300 mg film-coated tablets and 20 mg/ml oral solution contain abacavir, a nucleoside reverse transcriptase inhibitor, and were authorised in the EU on the 8th July 1999 for the antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus infected adults. Ziagen is marketed in Austria, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden and United Kingdom.

EMEA 2000 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged

Provisional Changes Introduced to Information to Prescribers

Ziagen 300 mg film-coated tablets as relevant example

4.4 Information for prescribers

Special warnings and special precautions for use

Hypersensitivity Reaction (see also 4.8 Undesirable effects)

In clinical studies approximately 4% of subjects receiving abacavir develop a hypersensitivity reaction; some of these cases were life threatening and resulted in a fatal outcome despite taking precautions.

Description

Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome.

Other signs and symptoms may include respiratory symptoms such as dyspnoea, sore throat, or cough, gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).

The symptoms related to this hypersensitivillv reaction worsen with continued therapy and can be life threatening. These symptoms usually resolve upon discontinuation of Ziagen.

Management

Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with Ziagen, with consultation every two weeks.

Patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue Ziagen immediately.

Ziagen, or any other abacavir containing medicinal product, MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen must be discontinued ifhypersensitivitj, cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). If reintroduction is judged necessary, it must be done in a hospital setting.

Special care is needed for those patients simultaneously starting treatment with Ziagen and other medicinal products known to induce skin toxicity (such as non nucleoside reverse transcriptase inhibitors). This is because it could be difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions

Management after an interruption of Ziagen therapy

If therapy with Ziagen has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction prior to stopping.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after re-starting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy, and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to re-start Ziagen this must be done in a setting where medical assistance is readily available.

Essential patient information

• Prescribers must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction.
• Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life threatening reaction or death.
• Patients developing signs or symptoms possibly linked with a hypersensitivity reaction MUST CONTACT their doctor IMMEDIATELY.
• In order to avoid restarting Ziagen, patients who have experienced a hypersensitivity reaction should be asked to return the remaining Ziagen tablets or oral solution to the pharmacy.
• Patients who have stopped Ziagen for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting.
• Patients should be advised of the importance of taking Ziagen regularly.
• Each patient should be reminded to read the Package Leaflet included in the Ziagen pack. They should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.

Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis have been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

Pancreatitis has been reported, but a causal relationship to Ziagen treatment is uncertain.

Insufficient data are available to recommend the use of Ziagen in children. In this population, hypersensitivity reactions are particularly difficult to identify.

Data to support the use of Ziagen in patients with moderate hepatic impairment are not currently available, therefore, administration of Ziagen should be avoided in these patients.

Ziagen should not be administered to patients with end-stage renal disease (see 5.2 Pharmacokinetic properties).

Patients receiving Ziagen or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Patients should be advised that current antiretroviral therapy, including Ziagen, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

4.8 Undesirable effects

Hypersensitivity (see also 4.4 Special warnings and special precautions for use):

In clinical studies, approximately 4% of subjects receiving abacavir developed a hypersensitivity reaction; some of these were life threatening and resulted in fatal outcome despite taking precautions. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever.

The signs and symptoms of this hypersensitivity reaction are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of hypersensitivity has resulted in Ziagen being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Close medical supervision is necessary during the first two months, with consultations every two weeks.

Risk factors that may predict the occurrence or severity of hypersensitivity to abacavir have not been identified. However, it is likely that intermittent therapy may increase the risk of developing sensitisation and therefore occurrence of clinically significant hypersensitivity reactions.

Consequently, patients should be advised of the importance of taking Ziagen regularly.

Restarting Ziagen following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction was usually more severe than on initial presentation, and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen must be discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). If reintroduction is judged necessary it must be done in a hospital setting.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after re-starting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to restart Ziagen this must be done in a setting where medical assistance is readily available.

Each patient must be warned about this hypersensitivity reaction to abacavir.

For many of the other adverse events reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV disease or as a result of the disease process.

The following adverse reactions may be related to Ziagen. The majority of these have not been treatment limiting. Care however must be taken to eliminate the possibility of a hypersensitivity reaction if any of these symptoms occur.

Gastrointestinal: nausea, vomiting, diarrhoea Other: headache, fever, lethargy, fatigue, anorexia

Pancreatitis has been reported, but a causal relationship to Ziagen treatment is uncertain.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4 Special warnings and special precautions for use).

In controlled clinical studies laboratoty abnormalities related to Ziagen treatment were uncommon, with no differences in incidence observed between Ziagen treated patients and the control arms.

The full document, including INFORMATION TO PATIENTS and the ALERT CARD TEXT is available online

Comment

Despite these new warnings it is still unclear what might constitute an interruption in treatment while on abacavir. It probably isn’t missing one dose, but is it 2, 3 or more? Once that interruption has occurred, for whatever reason, treating physicians recommend admission to hospital for 2-3 days to monitor if abacavir is restarted.

Abacavir is contained in the Glaxo Wellcome drug Ziagen™ and as one of the three drugs contained in Trizivir™. These warnings apply equally to both Ziagen and Trizivir.

Unfortunately, although Trizivir would seem attractive for those who might experience adherence problems, this population may also be the most likely to interrupt and restart inadvertently.

Shockingly Glaxo Wellcome in response to press concerns over the safety of abacavir acknowledged the safety issues but in a misplaced attempt to play down fears incorrectly stated that ‘the problems were well known.’

A spokesman for Glaxo Welcome commented that ‘This has been so well documented that it is very well known, especially within the HIV community,’ This is in stark contrast to the EMEA public statement which clearly states that these additional warnings were the result of new information.