Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685
Pharmacotherapeutic group: A 20.2.8 Antiviral agents
Antiviral for systemic use, antivirals for treatment of HIV infections, combinations
ATC code: J05AR06
RIZENE is a fixed dose combination film-coated tablet containing efavirenz, emtricitabine and tenofovir disoproxil fumarate disoproxil fumarate.
Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) of HIV-1 but is not an inhibitor of HIV-2 RT and human cellular DNA polymerases α, β, γ, δ. Efavirenz activity is mediated predominantly by non-competitive inhibition of HIV-1 RT.
Emtricitabine is a synthetic nucleoside cytidine analogue and a nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated intracellularly to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into the emerging viral DNA, an event that results in DNA chain termination. Emtricitabine has a low affinity for mammalian DNA polymerases α, β, and ε and mitochondrial DNA polymerase γ.
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphate diester analogue of adenosine monophosphate and is a nucleotide reverse transcriptase inhibitor (NRTI). Initial diester hydrolysis is required for conversion of tenofovir disoproxil fumarate to tenofovir and subsequently to tenofovir diphosphate through phosphorylations by cellular enzymes. Tenofovir is converted intracellularly in stages to the diphosphate. The tenofovir diphosphate competitively inhibits HIV-1 RT and incorporation into viral DNA. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and after the incorporation into DNA, by DNA chain termination. Tenofovir diphosphate has a low affinity for mammalian DNA polymerases α and β and mitochondrial DNA polymerase γ.
Co-formulation of efavirenz and tenofovir or emtricitabine and tenofovir or emtricitabine and efavirenz exhibits additive to synergistic antiviral effects in cell cultures.
Efavirenz demonstrates additive antiviral activity against HIV-1 when combined with nonnucleoside reverse transcriptase inhibitors (NNRTIs) (delaviridine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and the fusion inhibitor enfuvirtide. Efavirenz is not active against HIV-2.
In medicine combinations of emtricitabine with NRTIs, NNRTIs and PIs, additive to synergistic effects have been observed.
In medicine combinations of tenofovir with NRTIs, NNRTIs and PIs, additive to synergistic effects have been observed.
Resistance to efavirenz and the emergence of cross-resistant strains to other NNRTIs has been observed.
Resistance to emtricitabine may occur and the emergence of cross-resistance to other NRTIs may occur.
Resistance to tenofovir may be observed in some strains of HIV, and cross-resistance to other reverse transcriptase inhibitors may occur.
Cross-resistance among the medicines tenofovir, lamivudine, emtricitabine, abacavir, didanosine, may occur in patients whose virus harbours either M184V/I and/or K65R amino acid substitutions. These amino acid substitutions have been observed in cell culture but are also observed in some HIV-1 isolates from subjects failing treatment by the combination of tenofovir with emtricitabine or lamivudine, and either abacavir or didanosine.
Following oral administration, efavirenz is absorbed and peak plasma concentrations are achieved in about 3 to 5 hours. Steady state plasma concentrations following multiple doses are observed after about 6 to 10 days. Efavirenz is highly bound to human plasma proteins especially albumin. Efavirenz is predominantly metabolised by hepatic CYP450 isoenzymes CYP3A4 and CYP2B6. CYP450 enzymes are induced by efavirenz, thereby efavirenz induces its own metabolism. The terminal half-life following multiple doses of efavirenz is 40 to 55 hours while the terminal half-life after a single dose is 52 to 72 hours. 14 to 34% of a dose is excreted via urinary excretion and 16 to 61% is excreted as unchanged efavirenz via faecal excretion mechanisms.
Following oral administration, emtricitabine is absorbed through the gastrointestinal tract. Peak plasma concentrations are achieved within 1 to 2 hours while the plasma elimination half-life is 10 hours. The mean absolute bioavailability of emtricitabine is 93%. Emtricitabine is bound minimally to plasma proteins with binding reported to be less than 4%. It is excreted primarily unchanged in the urine and to a lesser extent in the faeces so it is metabolised to a restricted extent. Haemodialysis is partially capable of removing emtricitabine.
Following single oral dosing, tenofovir disoproxil fumarate 300 mg is absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved after 1 to 2 hours. Oral bioavailability is approximately 25% in fasted patients. Tenofovir has a plasma elimination half-life of approximately 17 hours after a single oral dose. Distribution of tenofovir is wide spread predominantly into the kidneys and liver and also into other body tissues. Plasma protein binding is minimal at 1% and to serum proteins at 7%. Excretion of tenofovir is predominantly via urinary excretion by both active tubular secretion and glomerular filtration. Haemodialysis is capable of removing tenofovir.
RIZENE has not been evaluated in the presence of food.
Efavirenz administered with a high fat meal can result in AUC increases up to 28% and Cmax increases up to 79%.
Emtricitabine and tenofovir disoproxil fumarate combined administrations with a light meal or a high fat meal can exhibit tenofovir disoproxil fumarate AUC increases of up to 35% and tenofovir disoproxil fumarate Cmax increases of up to 15%, without any effects on emtricitabine exposure.
Oral bioavailability of tenofovir disoproxil fumarate can be improved from the average 25% when it is taken with a high fat meal.
RIZENE has not been studied in patients less than 18 years old and is therefore not recommended for use in this population group. RIZENE has not been fully evaluated for use in elderly patients (older than 65 years of age).
Efavirenz has not been studied in patients with renal impairment. However less than 1% of efavirenz is excreted unchanged into the urine. Therefore, the impact of renal impairment on the elimination of efavirenz should be minimal. The pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate are affected in patients with renal insufficiency. When creatinine clearance is less than 50 ml/min, the AUC0-∞ and Cmax of emtricitabine and tenofovir disoproxil fumarate is increased for both active ingredients (see sections 4.2, 4.3 and 4.4).
The impact of efavirenz on hepatic impairment has not been studied.
There is no evidence of pharmacokinetic changes in patients with hepatic impairment when compared to healthy patients with normal liver function. Emtricitabine is not significantly metabolised by liver enzymes and therefore the impact of liver impairment should be limited.
Studies of tenofovir in non-HIV infected patients with moderate to severe hepatic impairment did not demonstrate substantial pharmacokinetic changes.
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