Trizivir

Posology Therapy should be prescribed by a physician experienced in the management of HIV infection. The recommended dose of Trizivir in adults (18 years and over) is one tablet twice daily. Trizivir can be taken with or without food.

3 Where discontinuation of therapy with one of the active substances of Trizivir is indicated, or where dose reduction is necessary separate preparations of abacavir, lamivudine and zidovudine are available. 4). Therefore, as dose adjustments of these may be necessary, it is recommended that separate preparations of abacavir, lamivudine and zidovudine be administered to patients with severe renal impairment (creatinine clearance  30 mL/min).

Physicians should refer to the individual summary of product characteristics of these medicinal products. 2). Hepatic impairment Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderate or severe hepatic impairment, therefore the use of Trizivir is not recommended unless judged necessary.

2). Elderly No pharmacokinetic data are currently available in patients over 65 years of age. Special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.

Paediatric population The safety and efficacy of Trizivir in adolescents and children has not been established. No data are available. 4). As dose adjustment of Trizivir is not possible, separate preparations of abacavir, lamivudine and zidovudine should be used.

Physicians should refer to the individual summary of product characteristics of these medicinal products.

8. Patients with end-stage renal disease. 4). 4 Special warnings and precautions for use The special warnings and precautions relevant to abacavir, lamivudine and zidovudine are included in this section. There are no additional precautions or warnings relevant to the combination Trizivir.

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. • Trizivir 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.

g. Kivexa, Ziagen, Triumeq) • Trizivir must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Trizivir after the onset of hypersensitivity may result in a life-threatening reaction.

g. Kivexa, Ziagen, 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 Trizivir 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.

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. 8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.

5 Lactic acidosis Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with zidovudine should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol).

Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. 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 adverse 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.

Lipoatrophy Treatment with zidovudine has been associated with loss […]

The special warnings and precautions relevant to abacavir, lamivudine and zidovudine are included in this section. There are no additional precautions or warnings relevant to the combination Trizivir. 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. • Trizivir 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.

g. Kivexa, Ziagen, Triumeq) • Trizivir must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Trizivir after the onset of hypersensitivity may result in a life-threatening reaction.

g. Kivexa, Ziagen, 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 Trizivir 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.

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. 8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.

5 Lactic acidosis Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with zidovudine should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol).

Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. 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 adverse 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.

Lipoatrophy Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may not be reversible when switching to a zidovudine-free regimen.

Patients should be […]

1. 8. Patients with end-stage renal disease. 4).