When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Important safety update regarding recommendations for HLA-B*5701 screening and reinitiation of abacavir - 'Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir ..
Ziagen 300 mg film-coated tablets (EU/1/99/112/001)
SPC Changes in Red
Section 3
Added description in brackets ‘(tablets)’
Added statement ‘The tablet can be divided into equal halves.’
Section 4.2
The following paragraphs changed from:
Children less than three months: the data available on the use of Ziagen in this age group are very limited (see section 5.2).
Renal impairment: no dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen should be avoided in patients with end-stage renal disease (see section 5.2).
Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be made in patients with mild hepatic impairment. No data are available in patients with moderate hepatic impairment, therefore the use of abacavir is not recommended unless judged necessary. In patients with mild and moderate hepatic impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see section 5.2). Abacavir is contraindicated in patients with severe hepatic impairment (see section 4.3 and 4.4).
to:
Children less than three months: the experience in children aged less than three months is limited (see section 5.2).
Renal impairment: no dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is not recommended for patients with end-stage renal disease (see section 5.2).
Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be made in patients with mild hepatic impairment. In patients with moderate hepatic impairment, no data are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is used in patients with mild or moderate hepatic impairment, then close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see section 5.2). Abacavir is contraindicated in patients with severe hepatic impairment (see section 4.3 and 4.4).
Section 4.3
Deleted unnecessary detail: ‘Ziagen is contraindicated…’
Changed description ‘adverse events’ to ‘adverse reactions’.
Under the subheading ‘Pancreatitis’ changed description from ‘Ziagen’ to ‘abacavir’
Deleted the following paragraph:
Once daily administration (abacavir 600 mg): the benefit of abacavir as a once daily regimen is mainly based on a study performed in combination with efavirenz and lamivudine, in antiretroviral-naïve adult patients (see section 5.1).
Deleted the following sentence:
‘For patients with severe hepatic impairment, Ziagen is contraindicated (see section 4.3).’
Under the subheading ‘Osteonecrosis’, changed spelling ‘etiology’ to ‘aetiology’
Section 4.4
Added the following paragraph:
Myocardial Infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Ziagen, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Section 4.9
Changed sentence from ‘No unexpected adverse reactions were reported. The effects of higher doses are not known’ to ‘No additional adverse reactions to those reported for normal doses were reported’ Section 6.6 Heading changed to delete ‘and other handling’ Section 10 Changed to 08 June 2009
Section 6.6
Heading changed to delete ‘and other handling’ Section 10 Changed to 08 June 2009
Section 10
Changed to 08 June 2009
The following text has been added:
4.2 Posology and method of administration
………..
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).
5.2 Pharmacokinetic properties
…………………
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Before initiating treatment with abacavir, screening for carriage of HLA-B*5701 should be performed in any HIV-infected patient, irrespective of racial origin.
Abacavir should not be used in patients known to carry HLA-B*5701, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.
·
Analyses of clinical risk factors for hypersensitivity to abacavir have consistently identified the risk for those of black race to be approximately half the risk of other racial groups combined. As this still represents a significant risk (based on the fact that approximately 5% of subjects receiving abacavir develop a hypersensitivity reaction in clinical studies), the same close monitoring should apply to patients of all racial groups.
In addition, two retrospective, case-controlled pharmacogenetic studies have shown that carriage of HLA-B*5701 is associated with a significantly increased risk of clinically suspected hypersensitivity in Caucasians. It is estimated that approximately 50% of patients with the HLA-B*5701 allele develop a suspected hypersensitivity reaction (HSR) during the course of abacavir treatment versus less than 3% of patients who do not have HLA-B*5701 allele in the Caucasian population. This genetic association has not been assessed in prospective controlled clinical studies but such studies are ongoing to better appreciate the association between occurrence of HSR and carriage of HLA-B*5701 allele. However, it is noteworthy that among patients with a suspected hypersensitivity reaction, 50% did not carry HLA-B*5701 in the Caucasian population. Therefore, the clinical diagnosis of suspected hypersensitivity to abacavir must remain the basis for clinical decision-making. It is important to permanently discontinue abacavir and not rechallenge with abacavir if hypersensitivity cannot be ruled out on clinical grounds. Absence of the HLA-B*5701 allele does not justify rechallenge with abacavir due to the potential for a fatal rechallenge reaction. The same recommendation should apply for other races and ethnic groups, although data are more limited in these groups.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Section 4.8:
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).