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.
4.2 Posology and method of administration
Added subheading ‘Posology’.
4.3 Contraindications
Added the following contraindication:
Kivexa should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.
4.5 Interaction with other medicinal products and other forms of interaction
Added warning that the co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure and the co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.
Interaction data was updated in line with the tabular format described in the HIV guideline
4.6 Fertility, pregnancy and lactation
Updated statements regarding use in pregnancy, lactation and added statement regarding fertility.
Added ‘fertility’ to the heading
5.1 Pharmacodynamic properties
Updated in line with the Annex B template of the guideline on the clinical development of medicinal products for the treatment of HIV infection, as requested by the CHMP: Restructured with data obtained from literature review and reports previously submitted by the MAH, in line with the HIV guideline EMEA/CPMP/EWP/633/02. The revision concerned the data on in vitro antiviral activity against HIV-1, including non-B subtypes, and HIV-2 for the individual drug components abacavir and lamivudine and/or in combination; data on the impact of selection for additional resistance mutations upon the susceptibility to abacavir or lamivudine in-vitro and in vivo and for therapy-naive versus experienced patients. Furthermore the clinical experience data was organised under separate headings for treatment naïve patients and treatment-experienced patients. In addition the results of treatment-naïve studies CNA30021, EPZ104057 (HEAT), CNA109586 (ASSERT) are now presented in the proposed tabulated format. The tables for CNA30021, EPZ104057 (HEAT) and CNA109586 (ASSERT) have been updated with additional sub-group analyses for baseline ribonucleic acid (RNA) for each of the studies and also for baseline CD4 categories for the CNA30021 study. Data from studies CAL30001 and ESS30008 has been revised to expand on the statistical test results of the analyses. Two tables were introduced from CAL30001 and CNA30021 studies on the Proportion of Patients with <50 cps/mL at Week 48 by Genotypic
4.1 Therapeutic indications
Added reference to sections 4.4 and 5.1 of the SPC
4.4 Special warnings and precautions for use
Added a new sub-heading ‘Risk of virological failure’, under which the following statement was added to the existing statement regarding Triple nucleoside therapy: - The risk of virological failure with Kivexa might be higher than with other therapeutic options (see section 5.1). 5.1 Pharmacodynamic properties Updated the Clinical Experience with data from the HEAT and ASSERT studies regarding virological response in the treatment of therapy-naïve patients.
- The risk of virological failure with Kivexa might be higher than with other therapeutic options (see section 5.1).
Updated the Clinical Experience with data from the HEAT and ASSERT studies regarding virological response in the treatment of therapy-naïve patients.
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
Section 4.1 -Therapeutic indications, Section 4.4 - Special warnings and precautions for use, Section 4.8 - Undesirable effects
Amended text Highlighted in Red
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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).
Pharmacotherapeutic group: 'nucleoside reverse transcriptase inhibitors (NTRIs).Antivirals for treatment of HIV infections, combinations. ATC code: J05AR02.
Changes to Sections 4.1 and 4.4
* 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.
Section 5.1 Pharmacodynamic Properties
...
In vivo resistance (Therapy experienced patients): The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy and confer high-level resistance to lamivudine.
Section 5.2 Pharmacokenetic properties
Intracellular pharmacokinetics
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours.
Section 4.4
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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).