TRIZIVIR® 300 mg/150 mg/300 mg film-coated tablets
Each film-coated tablet contains 300 mg of abacavir (as sulfate), 150 mg lamivudine and 300 mg zidovudine.
For the full list of excipients see section 6.1.
Film-coated tablet (tablet).
Blue-green capsule-shaped film-coated tablets engraved with “GX LL1” on one side.
Trizivir is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults (see sections 4.4 and 5.1). This fixed combination replaces the three components (abacavir, lamivudine and zidovudine) used separately in similar doses. It is recommended that treatment is started with abacavir, lamivudine, and zidovudine separately for the first 6-8 weeks (see section 4.4). The choice of this fixed combination should be based not only on potential adherence criteria, but mainly on expected efficacy and risk related to the three nucleoside analogues.
The demonstration of the benefit of Trizivir is mainly based on results of studies performed in treatment naive patients or moderately antiretroviral experienced patients with non-advanced disease. In patients with high viral load (> 100,000 copies/ml) choice of therapy needs special consideration (see section 5.1).
Overall, the virologic suppression with this triple nucleoside regimen could be inferior to that obtained with other multitherapies notably including boosted Protease inhibitors or non nucleoside reverse transcriptase inhibitors, therefore the use of Trizivir should only be considered under special circumstances (e.g. co-infection with tuberculosis).
Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin(see section 4.4). . Abacavir should not be used in patients known to carry the HLA-B*5701 allele.
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.
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.
Special populations
Renal impairment
Whilst no dose adjustment of abacavir is necessary in patients with renal dysfunction, lamivudine and zidovudine concentrations are increased in patients with renal impairment due to decreased clearance. 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 reduced renal function (creatinine clearance ≤ 50 ml/min). Physicians should refer to the individual summary of product characteristics of these medicinal products. Trizivir should not be administered to patients with end-stage renal disease (see sections 4.3 and 5.2).
Hepatic impairment
Trizivir is contraindicated in patients with hepatic impairment (see sections 4.3 and 5.2).
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.
Dose adjustments in patients with haematological adverse reactions
Dose adjustment of zidovudine may be necessary if the haemoglobin level falls below 9 g/dl or 5.59 mmol/l or the neutrophil count falls below 1.0 x 109/l (see sections 4.3 and 4.4). 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.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8
Patients with end-stage renal disease.
Patients with hepatic impairment.
Due to the active substance zidovudine, Trizivir is contraindicated in patients with abnormally low neutrophil counts (< 0.75 x 109/l), or abnormally low haemoglobin levels (< 7.5 g/dl or 4.65 mmol/l) (see section 4.4).
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.
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Hypersensitivity Reactions (see also section 4.8 ):
Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) 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. (e.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.
• After stopping treatment with Trizivir for reasons of a suspected HSR, Trizivir or any other medicinal product containing abacavir (e.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. 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.
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Lactic acidosis
Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. 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 nucleoside analogues 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 nucleoside analogues 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.
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Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These adverse reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy
CART has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these adverse reactions are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8 ).
Haematological adverse reactions
Anaemia, neutropenia and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine doses (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should therefore be carefully monitored (see section 4.3) in patients receiving Trizivir. These haematological effects are not usually observed before four to six week's therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.
In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months. Additionally, dose adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with Trizivir, or in patients with pre-existing bone marrow compromise e.g. haemoglobin < 9 g/dl (5.59 mmol/l) or neutrophil count < 1.0 x 109/l (see section 4.2). As dose adjustment of Trizivir is not possible separate preparations of zidovudine, abacavir and lamivudine should be used. Physicians should refer to the individual prescribing information for these medicinal products.
Pancreatitis
Cases of pancreatitis have occurred rarely in patients treated with abacavir, lamivudine and zidovudine. However, it is not clear whether these cases were due to treatment with these medicinal products or to the underlying HIV disease. Treatment with Trizivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
Liver disease
If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SmPC.
The safety and efficacy of Trizivir has not been established in patients with significant underlying liver disorders. Trizivir is contraindicated in patients with hepatic impairment (see section 4.3).
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 Trizivir is discontinued in patients co-infected with hepatitis B virus, 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 Zeffix SmPC).
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 hepatitis B or C virus
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).
Children and adolescents
Because insufficient data are available, the use of Trizivir in children or adolescents is not recommended. In this patient population, hypersensitivity reactions are particularly difficult to identify.
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 mycobacterium infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.
Osteonecrosis
Although the aetiology 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.
Opportunistic infections
Patients should be advised that Trizivir 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 the treatment of these associated HIV diseases.
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 Trizivir, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Transmission
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Drug Interactions:
To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with NNRTIs or PIs (see section 5.1).
Trizivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.
The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).
The combination of lamivudine with cladribine is not-recommended (see section 4.5).
Trizivir contains abacavir, lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to Trizivir. Clinical studies have shown that there are no clinically significant interactions between abacavir, lamivudine and zidovudine.
Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase; co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Zidovudine is primarily metabolised by UGT enzymes; co-administration of inducers or inhibitors of UGT enzymes could alter zidovudine exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.
Abacavir, lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P450 enzymes.
Interaction studies have only been performed in adults. The list below should not be considered exhaustive but is representative of the classes studied.
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Drugs by Therapeutic Area
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Interaction
Geometric mean change (%)
(Possible mechanism)
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Recommendation concerning co-administration
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ANTIRETROVIRAL MEDICINAL PRODUCTS
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Didanosine/Abacavir
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Interaction not studied.
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No dosage adjustment necessary.
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Didanosine/Lamivudine
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Interaction not studied.
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Didanosine/Zidovudine
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Interaction not studied.
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Stavudine/Abacavir
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Interaction not studied.
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Combination not recommended.
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Stavudine/Lamivudine
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Interaction not studied.
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Stavudine/Zidovudine
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In vitro antagonism of anti-HIV activity between stavudine and zidovudine could result in decreased efficacy of both drugs.
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ANTI-INFECTIVE PRODUCTS
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Atovaquone/Abacavir
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Interaction not studied.
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As only limited data available the clinical significance is unknown.
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Atovaquone/Lamivudine
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Interaction not studied.
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Atovaquone/Zidovudine
(750 mg twice daily with food/200 mg thrice daily)
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Zidovudine AUC ↑33%
Atovaquone AUC ↔
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Clarithromycin/Abacavir
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Interaction not studied.
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Separate administration of Trizivir and clarithromycin by at least 2 hours
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Clarithromycin/Lamivudine
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Interaction not studied.
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Clarithromycin/Zidovudine
(500 mg twice daily/100 mg every 4 hours)
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Zidovudine AUC ↓12%
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Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Abacavir
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Interaction not studied.
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No Trizivir dosage adjustment necessary, unless patient has renal impairment (See Section 4.2).
When concomitant administration with co-trimoxazole is warranted, patients should be monitored clinically. High doses of trimethoprim/ sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided.
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Trimethoprim/sulfamethoxazole
(Co-trimoxazole)/Lamivudine
(160mg/800mg once daily for 5 days/300mg single dose)
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Lamivudine: AUC ↑40%
Trimethoprim: AUC ↔
Sulfamethoxazole: AUC ↔
(organic cation transporter inhibition)
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Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Zidovudine
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Interaction not studied.
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ANTIFUNGALS
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Fluconazole/Abacavir
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Interaction not studied.
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As only limited data are available the clinical significance is not known. Monitor for signs of zidovudine toxicity (see section 4.8).
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Fluconazole/Lamivudine
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Interaction not studied.
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Fluconazole/Zidovudine
(400 mg once daily/200 mg thrice daily)
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Zidovudine AUC ↑74%
(UGT inhibition)
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ANTIMYCOBACTERIALS
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Rifampicin/Abacavir
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Interaction not studied.
Potential to slightly decrease abacavir plasma concentrations through UGT induction.
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Insufficient data to recommend dosage adjustment.
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Rifampicin/Lamivudine
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Interaction not studied.
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Insufficient data to recommend dosage adjustment.
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Rifampicin/Zidovudine
(600mg once daily/200 mg thrice daily)
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Zidovudine AUC ↓48%
(UGT induction)
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ANTICONVULSANTS
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Phenobarbital/Abacavir
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Interaction not studied.
Potential to slightly decrease abacavir plasma concentrations through UGT induction.
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Insufficient data to recommend dosage adjustment.
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Phenobarbital/Lamivudine
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Interaction not studied.
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Phenobarbital/Zidovudine
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Interaction not studied.
Potential to slightly decrease zidovudine plasma concentrations through UGT indu |
