Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

The special warnings and precautions relevant to abacavir and lamivudine are included in this section.
There are no additional precautions and warnings relevant to ABACAVIR LAMIVUDINE TARO.

Hypersensitivity reactions (see also section 4.8)

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section 4.8) characterised by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed appropriately.

The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele.
However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this allele.


Therefore, the following should be adhered to:
•    HLA-B*5701 status must always be documented prior to initiating therapy.

•    ABACAVIR LAMIVUDINE TARO should never be initiated in patients with a positive HLA- B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen. (e.g. Ziagen, Trizivir, Triumeq) 
•    ABACAVIR LAMIVUDINE TARO must be stopped without delay, even in the absence of the HLA-B*5701 allele, if anHSR is suspected. Delay in stopping treatment with ABACAVIR LAMIVUDINE TARO after the onset of hypersensitivity may result in a life-threatening reaction.

•    After stopping treatment with ABACAVIR LAMIVUDINE TARO for reasons of a suspected HSR, ABACAVIR LAMIVUDINE TARO or any other medicinal product containing abacavir (e.g. Ziagen, Trizivir, Triumeq) must never be re-initiated.

•    Restarting abacavir containing products following a suspected abacavir HSR can result 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.

•    In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining ABACAVIR LAMIVUDINE TARO tablets 

•       Clinical Description of abacavir HSR
Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up.
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.

Almost all HSR to abacavir include fever and/or rash. Other signs and symptoms that have been observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected adverse reactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms may lead to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis.

The symptoms related to HSR worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of abacavir.
Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.


Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.
Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.



Pancreatitis

Pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.
Risk of virological failure

- Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir disoproxil fumarate as a once daily regimen.
- The risk of virological failure with ABACAVIR LAMIVUDINE TARO might be higher than with other therapeutic options (seesection 5.1).

Liver disease

The safety and efficacy of ABACAVIR LAMIVUDINE TARO has not been established in patients with significant underlying liver disorders. ABACAVIR LAMIVUDINE TARO is not recommended in patients with moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Patients co-infected with chronic hepatitis B or C virus

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV), additional information relating to the use of lamivudine in the treatment of hepatitis B infection can be found in the Summary of Product Characteristics for products containing lamivudine that are indicated for the treatment of HBV.

If ABACAVIR LAMIVUDINE TARO is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see the Summary of Product Characteristics for products containing lamivudine that are indicated for the treatment of HBV).

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues: these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleotide and nucleotide analogues, who presents with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.


Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia (often referred to as PCP). Any inflammatory symptoms should be evaluated, and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease andautoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however,the reported time to onset is more variable and these events can occur many months after initiation of treatment.

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 CART.
Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections

Patients should be advised that ABACAVIR LAMIVUDINE TARO or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection.
Therefore, patients should remain under close clinical observation by physicians experienced in thetreatment of these associated HIV diseases.

Cardiovascular events

Although the available data from clinical and observational studies with abacavir show inconsistent results, several studies suggest an increased risk of cardiovascular events (notably myocardial infarction) in patients treated with abacavir. Therefore, when prescribing Kivexa, action should be taken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

In addition, alternative treatment options to the abacavir containing regimen should be considered when treating patients with a high cardiovascular risk.

Administration in subjects with moderate renal impairment

Patients with a creatinine clearance between 30 and 49 mL/min receiving ABACAVIR LAMIVUDINE TARO may experience a 1.6 - to 3.3 - fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing ABACAVIR LAMIVUDINE TARO to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive ABACAVIR LAMIVUDINE TARO should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with 
ABACAVIR LAMIVUDINE TARO. ABACAVIR LAMIVUDINE TARO should be discontinued and the individual components should be used to construct the treatment regimen.

Drug Interactions

ABACAVIR LAMIVUDINE TARO should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

Excipients
ABACAVIR LAMIVUDINE TARO contains the azo colouring agent sunset yellow, which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

No studies on the effects on ability to drive and use machines have been performed. The clinical status of the patient and the adverse reaction profile of ABACAVIR LAMIVUDINE TARO should be borne in mind when considering the patient’s ability to drive or operate machinery.