IY69 A Odimune Tabs Enclo.ai - Cipla

IY69 A 

SCHEDULING STATUS: S4 

PROPRIETARY NAME (AND DOSAGE FORM): 

ODIMUNE (Tablets) 

COMPOSITION: 

Each film-coated tablet contains emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg and efavirenz 600 mg. 

Inactive ingredients include croscarmellose sodium, red oxide of iron, microcrystalline cellulose, hypromellose, corn starch, 

magnesium stearate, sodium lauryl sulphate, hydroxyl propyl cellulose, opadry pink, and opadry brown. 

WARNING: 

THERE HAVE BEEN REPORTS OF LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, IN SOME 

CASES RESULTING IN DEATH, WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH 

OTHER ANTIRETROVIRALS (SEE "WARNINGS"). 

ODIMUNE IS NOT INDICATED FOR THE TREATMENT OF CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV). 

THE SAFETY AND EFFICACY OF ODIMUNE HAVE NOT BEEN ESTABLISHED IN PATIENTS WITH HBV AND HIV 

CO-INFECTION. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B INFECTION HAVE BEEN REPORTED IN 

INDIVIDUALS WHO HAVE DISCONTINUED EMTRICITABINE (200 mg) OR TENOFOVIR. PATIENTS WITH HIV AND HBV 

CO-INFECTION WHO DISCONTINUE ODIMUNE REQUIRE CLOSE MONITORING OF THEIR HEPATIC FUNCTION FOR AT 

LEAST SEVERAL MONTHS; THIS SHOULD INCLUDE BOTH CLINICAL AND LABORATORY FOLLOW-UP. 

APPROPRIATE INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE NECESSARY (SEE "WARNINGS"). 

PHARMACOLOGICAL CLASSIFICATION: 

A 20.2.8 Antimicrobial (chemotherapeutic) agents. Antiviral agents. 

PHARMACOLOGICAL ACTION: 

Mechanism of action: 

Emtricitabine: 

Emtricitabine, a NRTI, is a synthetic nucleoside analogue of cytidine. Cellular enzymes phosphorylate emtricitabine to 

emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate competes with the natural substrate, deoxycytidine 5'-triphosphate, 

and is incorporated into nascent viral DNA leading to chain termination. Thus the activity of HIV-1 reverse transcriptase (RT) is 

inhibited. Emtricitabine 5'-triphosphate weakly inhibits mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ. 

Tenofovir disoproxil fumarate: 

Tenofovir disoproxil fumarate, a NRTI, also known as tenofovir DF, an acyclic nucleoside phosphonate diester analogue of 

adenosine monophosphate, requires initial diester hydrolysis for conversion to tenofovir. Cellular enzymes are responsible for 

subsequent phosphorylations to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT through 

competition with the natural substrate deoxyadenosine 5'-triphosphate. After incorporation into DNA, the DNA chain is terminated. 

Tenofovir diphosphate weakly inhibits mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. 

Efavirenz: 

Efavirenz, a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, diffuses into the cell where it binds 

adjacent to the active site of reverse transcriptase. Thus a conformational change in the enzyme is produced and its function is 

inhibited. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) with respect to template, primer or 

nucleoside triphosphates, with a small component of competitive inhibition. Efavirenz does not inhibit HIV-2 RT and human 

cellular DNA polymerases alpha, beta, gamma and delta. 

Pharmacodynamics: 

Antiviral activity: 

Emtricitabine and tenofovir disoproxil fumarate: 

In combination studies that evaluated the in vitro antiviral activity of emtricitabine and tenofovir collectively, synergistic antiviral 

effects were observed. 


Lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells were used to assess the in vitro 

activity of emtricitabine against laboratory and clinical isolates of HIV. The IC 50 (50 % inhibitory concentration) values for 

emtricitabine were in the range of 0,0013 – 0,64 µM (0,0003 – 0,158 µg/ml). Medicine combination studies of emtricitabine with 

nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse 

transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir) 

demonstrated additive to synergistic effects. The majority of these medicine combinations have not been studied in humans. 

Emtricitabine exhibit antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F and G (IC 50 values ranged from 0,007 – 0,075 µ 

M) and demonstrated strain specific activity against HIV-2 (IC 50 values ranged from 0,007 – 1,5 µM). 


Lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes were used to assess the in vitro 

antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1. The IC 50 values for tenofovir ranged from 0,04 – 8,5 µM. 

Medicine combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, 

stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease 

inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) demonstrated additive to synergistic effects. Tenofovir exhibit 

antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC 50 values ranged from 0,5 – 2,2 µM). The IC 50 values of 

tenofovir against HIV-2 were in the range of 1,6 µM to 4,9 µM. 

Efavirenz: 

The clinical significance of in vitro susceptibility of HIV-1 to efavirenz has not been established. Lymphoblastoid cell lines, 

peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures enriched from PBMCs were used to assess the 

in vitro antiviral activity of efavirenz. The 90 to 95 % inhibitory concentration (IC 90-95 ) of efavirenz for wild type, laboratory adapted 

strains and clinical isolates were in the range of 1,7 to 25 nM. Efavirenz displayed synergistic activity in cell culture in combination 

with the nucleoside analogue reverse transcriptase inhibitors (NRTIs), zidovudine (ZDV) or didanosine (ddI), or the protease 

inhibitor, indinavir (IDV). 

Drug resistance: 


HIV-1 isolates demonstrating reduced susceptibility to the emtricitabine and tenofovir combination have been selected in vitro. 

Following genotypic analysis, the M184V/I and/or K65R amino acid substitutions were identified in the viral RT. 


HIV isolates resistant to emtricitabine have been selected in vitro. Genotypic analysis of these isolates demonstrated that reduced 

emtricitabine susceptibility was associated with a mutation in the HIV RT gene at codon 184. This mutation caused an amino acid 

substitution of methionine by valine or isoleucine (M184V/I). 

HIV isolates resistant to emtricitabine have also been recovered from some patients who received therapy with emtricitabine alone 

or in combination with other antiretroviral medicines. Genotypic analysis of these isolates demonstrated that the resistance was 

caused by M184V/I mutations in the HIV RT gene. 


Isolates of HIV-1 that exhibited reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R 

mutation in reverse transcriptase and demonstrated a reduced susceptibility to tenofovir of between 2- and 4-fold. 

Tenofovir-resistant HIV-1 strains have also been isolated from some patients who received tenofovir in combination with certain 

antiretroviral medicines. Genotypic analysis of the resistant isolates revealed a mutation in the HIV-1 reverse transcriptase gene 

that gave rise to the K65R amino acid substitution. 

Efavirenz: 

Isolates of HIV-1 that demonstrate reduced susceptibility to efavirenz (greater than 380-fold increase in IC 90 ) compared to baseline 

can emerge in vitro. 

Phenotypic changes in evaluable HIV-1 isolates and genotypic changes in plasma virus from selected individuals who received 

therapy with efavirenz in combination with IDV or with ZDV plus lamivudine were monitored. One or more RT mutations at amino 

acid positions 100, 101, 103, 108, 190 and 225 were noted in all 62 patients with a frequency of at least 10 % compared to 

baseline. The most frequently observed mutation (greater or equal to 90 %) was the mutation at RT amino acid position 103 (lysine 

to asparagine). Twenty-six clinical isolates demonstrated a 47-fold mean loss in susceptibility (IC 90 ) to efavirenz. Five clinical 

isolates were assessed for both genotypic and phenotypic changes from baseline. Decreases in susceptibility to efavirenz (range 

from 9- to greater than 312-fold increase in IC 90 ) were seen for these isolates in vitro compared to baseline. All 5 isolates 

possessed at least one of the efavirenz-associated RT mutations. The clinical relevance of phenotypic and genotypic changes 

associated with efavirenz treatment has not been established. 

Cross-resistance: 


It is known that cross-resistance may develop among certain nucleoside reverse transcriptase inhibitors (NRTIs). The M184V/I 

and/or K65R substitutions selected in vitro by the combination of emtricitabine and tenofovir are also seen in some HIV-1 strains 

isolated from individuals failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir 

or didanosine. Cross-resistance among these agents may therefore develop in patients whose virus harbours either or both of 

these amino acid substitutions. 


While emtricitabine-resistant isolates (M184V/I) demonstrated cross-resistance to lamivudine and zalcitabine, these isolates 

retained susceptibility in vitro to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). 

HIV strains isolated from heavily treatment-experienced patients containing the M184V/l amino acid substitution in the context of 

other NRTI substitutions associated with resistance may remain susceptible to tenofovir. HIV-1 isolates harbouring the K65R 

substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, showed reduced susceptibility to inhibition by 

emtricitabine. Viruses containing mutations that made them less susceptible to stavudine and zidovudine (M41L, D67N, K70R, 

L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 viral isolates harbouring the K103N 

substitution that is associated with resistance to NNRTIs was susceptible to emtricitabine. 


HIV-1 isolates from subjects whose HIV-1 expressed an average of 3 zidovudine-associated amino acid substitutions in reverse 

transcriptase (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) demonstrated a reduced susceptibility to tenofovir. HIV-1 with 

multinucleoside resistance with a T69S double insertion mutation in the RT demonstrated reduced susceptibility to tenofovir. 

Efavirenz: 

HIV-1 strains that are cross-resistant to non-nucleoside RT inhibitors emerge rapidly in vitro. Clinical isolates formerly 

characterised as efavirenz-resistant were also phenotypically resistant to nevirapine and delavirdine in vitro in comparison to 

baseline. Clinically derived ZDV-resistant HIV-1 strains isolated and tested in vitro remained susceptible to efavirenz. 

Cross-resistance is unlikely to develop between efavirenz and HIV protease inhibitors due to the different enzyme targets 

involved. 

Pharmacokinetics: 

Adults: 


Subsequent to oral administration of emtricitabine (200 mg), emtricitabine is rapidly absorbed. Peak plasma concentrations are 

reached 1 – 2 hours post-dose. Binding of emtricitabine to human plasma proteins in vitro is less than 4 % and is independent of 

concentration over the range of 0,02 – 200 µg/ml. Median (range) oral bioavailability of emtricitabine under fasting conditions is 92 % 

(83,1 – 106,4 %). At steady state mean (± SD) C max (maximum plasma concentration) of emtricitabine is 1,8 ± 0,72 µg/ml, while mean 

(± SD) AUC at steady state is 10,0 ± 3,12 µg.hr/ml. 

Approximately 86 % of radiolabeled emtricitabine is recovered in the urine and 13 % is recovered as metabolites. Emtricitabine 

metabolites include 3'-sulphoxide diastereomers and their glucuronic acid conjugate. Elimination of emtricitabine is via a combination 

of glomerular filtration and active tubular secretion. Emtricitabine displays a plasma half-life of approximately 10 hours following a 

single oral dose (200 mg). 


Subsequent to oral administration of tenofovir, it takes 1,0 ± 0,4 hours to reach maximum tenofovir serum concentrations. Binding 

of tenofovir to human plasma proteins in vitro is less than 0,7 %. This is not dependent on concentration over the range of 0,01 – 

25 µg/ml. Median (range) oral bioavailability of tenofovir under fasting conditions is 25 % (Not calculated [NC] – 45 %). Tenofovir 

has a mean (± SD) C max of 0,30 ± 0,09 µg/ml and mean (± SD) AUC of 2,29 ± 0,69 µg.hr/ml. 

Following intravenous administration of tenofovir approximately 70 – 80 % of the dose is recovered unchanged in the urine. 

Elimination of tenofovir is through a combination of glomerular filtration and active tubular secretion. Tenofovir has a terminal 

elimination half-life of approximately 17 hours following a single oral dose. 

Effects of food on oral absorption: 

A fixed dose combination tablet of emtricitabine and tenofovir may be taken with or without food. Time to tenofovir C max was 

delayed by approximately 0,75 hours following administration of the combination tablet with a high fat meal or a light meal. 

Compared to administration under fasting conditions, administration with a high fat or light meal resulted in mean increases in 

tenofovir AUC and C max of approximately 35 % and 15 %, respectively. In previous safety and efficacy studies, tenofovir was 

administered under fed conditions. Emtricitabine systemic exposures (AUC and C max) remained unchanged when the combination 

tablet was taken with either a high fat or a light meal. 

Efavirenz: 

Absorption: 

Peak efavirenz plasma concentrations of 1,6 – 9,1 μM are reached by 5 hours following single oral doses of 100 mg to 1600 mg 

given to uninfected volunteers. Although dose-related increases in C max and AUC are seen for doses up to 1600 mg, these 

increases are less than proportional, indicating diminished absorption at higher doses. Steady state plasma concentrations are 

reached in 6 to 7 days. 

Distribution: 

Efavirenz is very highly plasma protein bound (approximately 99,5 – 99,75 %) and predominantly to albumin. Cerebrospinal fluid 

concentrations ranged from 0,26 to 1,19 % (mean 0,69 %) of the corresponding plasma concentrations in HIV-1 infected 

individuals administered 200 to 600 mg efavirenz once daily for at least one month. This is about three times higher than the 

non-protein-bound (free) fraction of efavirenz in plasma. 

Metabolism: 

Efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites. These hydroxylated metabolites 

subsequently undergo glucuronidation. The metabolites are not active against HIV-1. CYP3A4 and CYP2B6 are the major 

isozymes involved in efavirenz metabolism. Efavirenz, through induction of P450 enzymes, induces its own metabolism. 

Elimination: 

Efavirenz has a long terminal half-life of 52 – 76 hours and 40 – 55 hours after single and multiple doses, respectively. Subsequent 

to the administration of a radio-labelled dose, 14 – 34 % of efavirenz is recovered in the urine and 16 – 61 % is recovered in the 

faeces, mainly in the form of metabolites. 

Special populations: 

Gender: 

Emtricitabine and tenofovir pharmacokinetic properties are similar in male and female patients. Pharmacokinetic characteristics 

of efavirenz in patients appear to be similar between men and women. 

Paediatric and geriatric patients: 


Emtricitabine and tenofovir pharmacokinetics have not been evaluated in children < 18 years or in the elderly (> 65 years) (see 

"Special Precautions"). 

Efavirenz: 

Pharmacokinetics of efavirenz have not been studied in subjects aged 65 and over to determine whether they respond differently. 

The pharmacokinetic properties of efavirenz in paediatric patients are similar to those in adults. 

Patients with impaired renal function: 


The pharmacokinetic properties of emtricitabine and tenofovir are altered in patients with impairment of kidney function (see 

"WARNINGS"). The C max and AUC 0-α of emtricitabine and tenofovir are increased in patients with creatinine clearance < 50 

ml/min. The dosing interval for the combination tablet should be modified in patients with creatinine clearance 30 – 49 ml/min. 

Since this is not possible with a fixed dose combination, such a combination should not be administered to patients with creatinine 

clearance < 50 ml/min and in patients with end-stage renal disease requiring dialysis (see "CONTRA-INDICATIONS", 

"WARNINGS" and "DOSAGE AND DIRECTIONS FOR USE"). 

Efavirenz: 

The pharmacokinetic properties of efavirenz have not been studied in patients with renal insufficiency. However, since less than 1 % 

of efavirenz is excreted unchanged in the urine, the impact of impaired renal function on efavirenz elimination should be minimal. 

Patients with hepatic impairment: 


The pharmacokinetic properties of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate have been evaluated in 

non-HIV infected individuals with moderate to severe impairment of liver function. Tenofovir pharmacokinetics were not 

substantially altered in patients with hepatic impairment compared with unimpaired patients. Pharmacokinetic properties of 

emtricitabine or a fixed dose combination of emtricitabine and tenofovir have not been studied in patients with hepatic impairment. 

Since emtricitabine is not metabolised by liver enzymes to a significant extent, the impact of liver impairment should be limited. 

Efavirenz: 

Efavirenz pharmacokinetics have not been adequately studied in patients with impaired hepatic function. 

INDICATIONS: 

ODIMUNE is indicated for the treatment of HIV-1 infection in adults. 

CONTRA-INDICATIONS: 

ODIMUNE is contra-indicated in patients: 

• Who previously demonstrated hypersensitivity to emtricitabine, tenofovir or efavirenz or any of the other components of the 

product. 

• With moderate to severe impairment of renal function (creatine clearance < 50 ml/min) (see "WARNINGS" and "DOSAGE 

AND DIRECTIONS FOR USE"). 

• Who are pregnant or breast feeding (see "PREGNANCY AND LACTATION"). 

• Who are concurrently receiving treatment with astemizole, cisapride, midazolam, triazolam or ergot derivatives, because 

competition for CYP3A4 by the efavirenz in ODIMUNE could result in inhibition of the metabolism of these medicines and 

create the potential for serious and/or life-threatening adverse events (e.g., cardiac dysrhythmias, prolonged sedation or 

respiratory depression). 

• Younger than 18 years of age due to lack of data on safety and efficacy. 

• With severe hepatic impairment. 

• Who are concurrently using voriconazole, since efavirenz significantly decreases voriconazole plasma concentrations, 

while voriconazole significantly increases efavirenz plasma concentrations. Since ODIMUNE is a fixed-dose combination 

product, the dose of efavirenz cannot be altered; therefore voriconazole and ODIMUNE must not be co-administered. 

• Who concomitantly take other medicinal products containing any of the components (efavirenz, emtricitabine or tenofovir) 

or who concomitantly take other cytidine analogues, such as lamivudine, and adefovir dipivoxil. 

WARNINGS: 

ALERT: Find out about medicines that should NOT be taken with ODIMUNE (see "CONTRA-INDICATIONS", 

"INTERACTIONS" and "SIDE-EFFECTS AND SPECIAL PRECAUTIONS"). 

Serious nervous system and psychiatric symptoms have been reported with efavirenz, one of the active ingredients in ODIMUNE. 

Lactic acidosis / Severe hepatomegaly with steatosis: 

Lactic acidosis and severe hepatomegaly with steatosis, which were fatal in some instances, have been reported with the 

administration of nucleoside analogues, such as contained in ODIMUNE, alone or in combination with other antiretrovirals agents. 

Most of these cases have been in women. Possible risk factors include obesity and prolonged nucleoside exposure. Particular 

caution is required when ODIMUNE is administered to any patient with known risk factors for hepatic disease; however, such 

complications have also been reported in patients without known risk factors. Suspend treatment with ODIMUNE in any patient 

who develops clinical or laboratory findings indicative of lactic acidosis or pronounced hepatotoxicity (which may include 

enlargement of the liver and steatosis even in the absence of marked transaminase elevations). 

Patients with HIV and hepatitis B virus co-infection: 

It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) prior to the initiation of therapy 

with antiretroviral agents. ODIMUNE is not indicated for the treatment of chronic HBV infection. The safety and efficacy of 

ODIMUNE have not been confirmed in patients with HBV and HIV co-infection. Severe acute exacerbations of hepatitis B have 

occurred in patients following the discontinuation of emtricitabine (200 mg) and tenofovir disoproxil fumarate. Patients with HBV 

and HIV co-infection who discontinue ODIMUNE require close monitoring of their hepatic function for at least several months; this 

should include both clinical and laboratory follow-up. Appropriate initiation of anti-hepatitis B therapy may be necessary. 

Renal impairment: 

Emtricitabine and tenofovir, two of the active ingredients in ODIMUNE, are principally eliminated by the kidney. Dosing interval 

adjustment of emtricitabine and tenofovir is recommended in all patients with creatinine clearance 30 – 49 ml/min. Since this is not 

possible with a fixed dose combination, ODIMUNE should not be administered to patients with creatinine clearance < 50 ml/min 

or patients requiring haemodialysis (see "DOSAGE AND DIRECTIONS FOR USE"). 

There have been reports of impairment of renal function which included cases of acute renal failure and Fanconi syndrome (renal 

tubular injury with severe hypophosphataemia) in association with the use of tenofovir (see "Side-Effects"). Most of these cases 

developed in patients with underlying systemic or renal disease, or in patients who received nephrotoxic agents. However, some 

of these complications occurred in patients without any identifiable risk factors. 

The use of ODIMUNE should be avoided in patients who are concurrently taking or who have recently taken a nephrotoxic agent. 

Careful monitoring for changes in serum creatinine and phosphorus are necessary in patients at risk for, or with a history of, renal 

dysfunction as well as in patients receiving concomitant nephrotoxic agents. 

INTERACTIONS: 

General interactions: 

No interaction studies have been conducted using ODIMUNE tablets. As ODIMUNE contains efavirenz, emtricitabine and 

tenofovir, any interactions that have been identified with these agents individually may occur with ODIMUNE. Interaction studies 

with these agents have only been performed in adults. 

As a fixed combination, ODIMUNE should not be given concomitantly with other medicinal products containing any of the 

components, efavirenz, emtricitabine or tenofovir, concomitantly with other cytidine analogues, such as lamivudine, and adefovir 

dipivoxil (see "CONTRA-INDICATIONS"). 

ODIMUNE must not be co-administered with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot 

alkaloids, since inhibition of their metabolism may lead to serious, life-threatening events (see "CONTRA-INDICATIONS"). 

The steady state pharmacokinetic properties of emtricitabine and tenofovir remained unchanged when emtricitabine and tenofovir 

disoproxil fumarate were administered together versus each agent given alone. No clinically significant interactions have been 

noted between emtricitabine and tenofovir. 

Co-administration of tenofovir disoproxil fumarate 300 mg once daily for 7 days with emtricitabine, 200 mg once daily for 7 days, 

caused no changes in the C max or AUC of emtricitabine. However, Cmin of emtricitabine increased by 20 % [90 % confidence 

interval (CI) +12 % to +29 %]. The C max, AUC and Cmin of tenofovir were unchanged. 

In vitro and clinical pharmacokinetic drug-drug interaction studies have demonstrated the potential for CYP450 mediated 

interactions involving emtricitabine and tenofovir, two of the active ingredients in ODIMUNE, with other medicinal products is low. 

The kidneys are primarily responsible for the excretion of emtricitabine and tenofovir through a combination of glomerular filtration 

and active tubular secretion. Although no interactions due to competition for renal excretion have been observed, it is possible 

that, when ODIMUNE is co-administered with medicines that are eliminated by active tubular secretion, the concentrations of 

emtricitabine, tenofovir and/or the concomitant medicine may increase. 

Medicines that reduce renal function may increase emtricitabine and/or tenofovir concentrations. 

The efavirenz in ODIMUNE induces CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma 

concentrations when administered concurrently with ODIMUNE. 

No clinically significant drug interactions were demonstrated for tenofovir disoproxil fumarate and efavirenz. Concomitant 

administration of efavirenz 600 mg once daily for 14 days with tenofovir 300 mg once daily did not result in any changes in the 

C max, Cmin or AUC of either efavirenz or tenofovir. 

Abacavir: 

No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active ingredients 

in ODIMUNE, and abacavir. Co-administration of a single dose of abacavir 300 mg with tenofovir 300 mg caused no changes in 

the C max or AUC of tenofovir. However, Cmax of abacavir increased by 12 % (90 % CI -1 % to +26 %), while the AUC remained 

unchanged. 

Adefovir dipivoxil: 


in ODIMUNE, and adefovir dipivoxil. Concomitant administration of a single dose of adefovir dipivoxil 10 mg with tenofovir 300 mg 

did not result in any changes in the C max, Cmin or AUC of tenofovir nor in the Cmax or AUC of adefovir dipivoxil. 

ODIMUNE should, however, not be administered concomitantly with adefovir dipivoxil due to the increased risk of renal toxicity. 

Amprenavir: 

Co-administration of amprenavir/ritonavir and ODIMUNE is not recommended, as efavirenz reduces the C max , C min and AUC of 

amprenavir by 40 %. 

Atazanavir: 

Co-administration of atazanavir 400 mg once daily for 14 days with tenofovir 300 mg once daily resulted in a 14 % increase (90 % 

CI +8 % to +20 %) in tenofovir C max , 24 % increase (+21 % to +28 %) in tenofovir AUC and 22 % increase (+15 % to +30 %) in 

tenofovir C min . Corresponding parameters for atazanavir showed a 21 % decrease (-27 % to -14 %) in C max , 25 % decrease (-30 % 

to -19 %) in AUC and 40 % decrease (-48 % to -32 %) in C min . In HIV-infected patients, addition of tenofovir disoproxil fumarate to 

atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and C min values of atazanavir that were 2,3- and 4-fold higher than the 

respective values observed for atazanavir 400 mg when given alone. 

Co-administration of atazanavir/ritonavir with tenofovir resulted in increased exposure to tenofovir. Higher tenofovir concentrations 

could potentiate tenofovir-associated adverse events, including renal disorders. 

Co-administration of efavirenz with atazanavir in combination with low-dose ritonavir resulted in substantial decreases in 

atazanavir exposure due to CYP3A4 induction, necessitating dosage adjustment of atazanavir. Co-administration of efavirenz and 

atazanavir in combination with ritonavir may lead to increases in efavirenz exposure which may worsen the tolerability profile of 

efavirenz. 

Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination with ODIMUNE. Therefore 

co-administration of atazanavir/ritonavir and ODIMUNE is not recommended. 

Calcium channel blockers: 

When efavirenz is given concomitantly with a calcium channel blocker that is a substrate of the CYP3A4 enzyme, there is a 

potential for reduction in the plasma concentration of the calcium channel blocker. Dose adjustments of diltiazem and other 

calcium channel blockers (such as verapamil, felodipine, nifedipine and nicardipine) when co-administered with ODIMUNE should 

be guided by clinical response. 

Cannabinoid test interaction: 

Efavirenz does not occupy cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected 

volunteers who took efavirenz and are therefore possible with ODIMUNE administration. False positive test results due to 

efavirenz have only been seen with the CEDIA DAU Multi-Level THC assay, which is used for screening, and have not been 

observed with other cannabinoid assays tested – these included tests used for confirmation of positive results. 

Carbamazepine: 

Co-administration of carbamazepine with efavirenz decreased carbamazepine AUC, C max and Cmin with 27 % (90 % CI -20 % to -33 %), 

20 % (-15 % to -24 %), and 35 % (-24 % to -44 %), respectively, due to CYP3A4 induction. Corresponding decreases in efavirenz AUC, 

C max and C min (due to CYP3A4 and CYP2B6 induction) were 36 % (-32 % to -40 %), 21 % (-15 % to -26 %), and 47 % (-41 % to -53 %), 

respectively. No dose recommendation can be made for the use of ODIMUNE with carbamazepine. An alternative anticonvulsant 

should be considered. Carbamazepine plasma levels should be monitored periodically. 

Clarithromycin: 

Co-administration of 400 mg of efavirenz once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted 

in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and C max of clarithromycin decreased with 

39 % and 26 %, respectively, while the AUC and C max of the active clarithromycin hydroxymetabolite were increased with 34 % 

and 49 %, respectively, when used in combination with efavirenz. The clinical significance of these changes in clarithromycin 

plasma levels is not known. Forty-six (46) percent of uninfected volunteers who took efavirenz and clarithromycin developed a 

rash. No dose adjustment of efavirenz is recommended when administered with clarithromycin; however, alternatives to 

clarithromycin should be considered. 

Other antibiotics belonging to the macrolide class, such as erythromycin, have not been studied in combination with ODIMUNE. 

Didanosine: 

Concomitant administration of a single dose of enteric-coated didanosine 400 mg with tenofovir 300 mg did not result in any 

changes in the C max, Cmin or AUC of tenofovir. The same holds true for the combination of buffered didanosine 250 or 400 mg once 

daily for 7 days with tenofovir 300 mg once daily. 

When administered with multiple doses of tenofovir, the C max and AUC of didanosine 400 mg increased significantly. The 

mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with tenofovir 

systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted 

conditions. 

For a detailed summary of the changes in pharmacokinetic parameters for didanosine, please refer to the table below. 

Table 1: Drug interactions: Pharmacokinetic parameters for didanosine in the presence of tenofovir as in ODIMUNE. 

Didanosine dose (mg)/ Tenofovir method of % Difference (90 % CI) vs. didanosine 400 mg 

Method of administration 1 administration 1 N alone, fasted 2 

C max AUC 

Buffered tablets 

400 once daily 3 Fasted 1 hour after 14 ↑28 ↑44 

X 7 days didanosine (↑11 - ↑48) (↑31 - ↑59) 

Enteric-coated tablets 

400 once, fasted With food, 2 hr after 26 ↑48 ↑48 

didanosine (↑25 - ↑76) (↑31 - ↑67) 

400 once, with food Simultaneously with 26 ↑64 ↑60 

didanosine (↑41 - ↑89) (↑44 - ↑79) 

250 once, fasted With food, 2 hr after 28 ↓10 ↔ 

didanosine (↓22 - ↑3) 

250 once, fasted Simultaneously with 28 ↔ ↑14 

didanosine (0 - ↑31) 

250 once, with food Simultaneously with 28 ↓29 ↓11 

didanosine (↓39 - ↓18) (↓23 - ↑2) 

1. Administration with food was with a light meal. 

2. ↑ = increase; ↓ = decrease; ↔ = no difference. 

3. Includes 4 subjects weighing < 60 kg receiving ddI 250 mg. 

Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40 % to 60 % increase in systemic exposure to 

didanosine that may increase the risk for didanosine-related adverse events. Cases of pancreatitis and lactic acidosis, sometimes 

fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been 

associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. 

active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has 

been associated with reports of high rates of virologic failure within several tested combinations. Co-administration of ODIMUNE 

and didanosine is not recommended. 

Famciclovir: 

No clinically significant drug interactions have been observed between emtricitabine, one of the active ingredients in ODIMUNE, 

and famciclovir. Co-administration of a single dose of famciclovir 500 mg with a single dose of emtricitabine 200 mg did not alter 

the C max or AUC of emtricitabine or famciclovir. 

HMG Co-A reductase inhibitors: 

Co-administration of efavirenz with HMG Co-A reductase inhibitors, such as atorvastatin and pravastatin, led to decreases in the 

AUC and C max of the HMG Co-A reductase inhibitors and their active metabolites. Cholesterol levels should be periodically monitored 

when atorvastatin, pravastatin, or simvastatin is co-administered with ODIMUNE. Dosage adjustments of statins may be required. 

Immunosuppressants: 

Co-administration of tacrolimus with emtricitabine or tenofovir disoproxil fumarate did not result in any changes in the AUC, C max 

or C min of tacrolimus, emtricitabine or tenofovir disoproxil fumarate. Although the interaction between efavirenz and tacrolimus has 

not been studied, decreased exposure of tacrolimus may be expected due to CYP3A4 induction. Tacrolimus is not anticipated to 

impact exposure of efavirenz. Dose adjustments of tacrolimus may be required. Close monitoring of tacrolimus concentrations for 

at least two weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ODIMUNE. 

Indinavir: 

No clinically significant drug interactions have been observed between the emtricitabine in ODIMUNE and indinavir. 

Co-administration of a single dose of indinavir 800 mg with a single dose of emtricitabine 200 mg did not alter the C max or AUC of 

emtricitabine or indinavir. 

Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active 

ingredients in ODIMUNE, and indinavir. There was a 14 % increase (90 % CI -3 % to +33 %) in the C max of tenofovir when indinavir 

800 mg three times daily for 7 days was co-administered with tenofovir 300 mg once daily. The C min and AUC of tenofovir remained 

unchanged as did the C min and AUC of indinavir. Indinavir Cmax decreased by 11 % (-30 % to +12 %). 

When indinavir (800 mg every 8 hours) was administered with efavirenz (200 mg every 24 hours), the indinavir AUC and C trough 

were decreased by approximately 31 % and 16 %, respectively, due to enzyme induction. 

Insufficient data are available to make a dosing recommendation for indinavir when dosed with ODIMUNE. While the clinical 

significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic 

interaction should be taken into consideration when choosing a regimen containing both efavirenz, a component of ODIMUNE, 

and indinavir. 

Itraconazole: 

Co-administration of itraconazole and efavirenz resulted in decreased itraconazole AUC, C max and Cmin due to CYP3A4 induction. 

No dose recommendations can be made for the use of ODIMUNE in combination with itraconazole. An alternative antifungal 

treatment should be considered. 

Interaction studies with ODIMUNE and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma 

concentrations of ketoconazole. 

Lamivudine: 

No clinically significant drug interactions have been observed between the tenofovir disoproxil fumarate in ODIMUNE and 

lamivudine. Co-administration of lamivudine 150 mg twice daily for 7 days with tenofovir 300 mg once daily did not result in any 

changes in the C max, Cmin or AUC of tenofovir. While the Cmin and AUC of lamivudine were unchanged, the Cmax decreased by 24 % 

(-34 % to -12 %). 

Due to similarities with emtricitabine, ODIMUNE should not be administered concomitantly with other cytidine analogues, such as 

lamivudine. 

Lopinavir/Ritonavir: 


in ODIMUNE, and lopinavir/ritonavir. Co-administration of a combination of lopinavir 400 mg and ritonavir 100 mg twice daily for 

14 days with tenofovir 300 mg once daily resulted in a 32 % increase (90 % CI +26 % to +38 %) in tenofovir AUC and 29 % 

increase (+23 % to +66 %) in tenofovir C min , while tenofovir C max remained unchanged. There were no changes in C max, Cmin or AUC 

of lopinavir and ritonavir. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal 

disorders. 

When efavirenz 600 mg (administered once daily at bedtime) and ritonavir 500 mg (administered every 12 hours) were studied in 

uninfected volunteers, the combination was not well tolerated. The combination was associated with a higher frequency of adverse 

clinical events (for example dizziness, nausea, paraesthesia, and elevated liver enzymes). Liver enzymes should be monitored 

when efavirenz is used in combination with ritonavir. 

Co-administration of lopinavir/ritonavir with efavirenz resulted in a substantial decrease in lopinavir exposure, necessitating 

dosage adjustment of lopinavir/ritonavir. 

Insufficient data are available to make a dosing recommendation for lopinavir/ritonavir when dosed with ODIMUNE. 

Co-administration of lopinavir/ritonavir and ODIMUNE is not recommended. 

Methadone: 

No clinically significant drug interactions have been identified between the tenofovir disoproxil fumarate in ODIMUNE and 

methadone. Following multiple dosing to HIV-negative individuals receiving chronic methadone maintenance therapy, steady 

state tenofovir pharmacokinetic properties were similar to those observed in previous studies, indicating lack of clinically 

significant drug interactions between methadone and the tenofovir in ODIMUNE. 

Specifically, when methadone 40 – 110 mg once daily for 14 days was given concomitantly with tenofovir 300 mg once daily, 

R-(active), S- and total methadone exposures were similar when dosed alone or with tenofovir. Individual patients were 

maintained on their stable methadone dose. There were no reports of pharmacodynamic alterations, such as opiate toxicity or 

withdrawal signs or symptoms. 

However, concomitant administration of efavirenz with methadone, in HIV-infected IV drug users, resulted in decreased plasma 

concentrations of methadone and signs of opiate withdrawal. Increasing the methadone dose by a mean of 22 % alleviated 

withdrawal symptoms. Patients require monitoring for signs of withdrawal and their methadone dose should be increased as 

required to alleviate withdrawal symptoms. 

Oral contraceptives: 

No clinically significant drug interactions have been observed between the tenofovir disoproxil fumarate in ODIMUNE and oral 

contraceptives. 

Following multiple dosing to HIV-negative subjects taking oral contraceptives, steady state tenofovir pharmacokinetics were 

comparable to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents 

and the tenofovir in ODIMUNE. 

In terms of possible interactions with efavirenz, only the ethinyloestradiol component of oral contraceptives has been studied. After 

multiple dosing with efavirenz, the AUC of a single dose ethinyloestradiol was increased (37 %). The C max of ethinyloestradiol was 

not significantly changed. It is not known whether these effects are clinically significant. A single dose of ethinyloestradiol appeared 

to have no effect on efavirenz C max or AUC. Since the potential interaction between ODIMUNE and oral contraceptive agents has 

not been fully characterised, patients should employ a reliable method of barrier contraception in addition to oral contraceptives. 

Phenytoin, phenobarbital, and other anticonvulsants: 

Efavirenz may potentially reduce or increase the plasma levels of phenytoin, phenobarbital and other anticonvulsants that are 

substrates of CYP450 isoenzymes. When ODIMUNE is administered concomitantly with an anticonvulsant that is a substrate of 

CYP450 isoenzymes, periodic monitoring of anticonvulsant concentrations should be performed. 

ODIMUNE and vigabatrin or gabapentin can be given concurrently without dose adjustment. Clinically significant interactions are 

not expected, because vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are therefore not likely to 

compete for the same metabolic enzymes and elimination pathways as efavirenz. 

Ribavirin: 

No clinically significant drug interactions have been demonstrated between the tenofovir disoproxil fumarate in ODIMUNE and 

ribavirin. Following multiple dosing to HIV-negative individuals receiving single doses of ribavirin, steady state tenofovir 

pharmacokinetics were similar to those seen in previous studies, indicating lack of clinically significant drug interactions between 

ribavirin and the tenofovir in ODIMUNE. 

Rifamycins: 

With concomitant administration in uninfected volunteers, rifampicin reduced efavirenz AUC by 26 % and C max by 20 %. The dose 

of efavirenz must be increased to 800 mg/day when taken in combination with rifampicin. Therefore, when ODIMUNE is 

co-administered with rifampicin, an additional 200 mg/day of efavirenz is recommended. No dose adjustment of rifampicin is 

recommended when given with ODIMUNE. 

Concomitant administration of single doses of rifabutin 300 mg and efavirenz 600 mg resulted in decreases of 38 % (90 % CI -28 % 

to -36 %) in AUC, 32 % (-15 % to -46 %) in C max and 45 % (-31 % to -56 %) in C min of rifabutin. The AUC and C max of efavirenz remained 

unchanged; however, the C min decreased with 12 % (-24 % to -1 %). The daily dose of rifabutin should be increased by 50 % when 

administered with ODIMUNE. Consider doubling the rifabutin dose in regimens where rifabutin is administered 2 to 3 times a week in 

combination with ODIMUNE. 

Ritonavir: 

Efavirenz co-administered with ritonavir 500 mg or 600 mg twice daily is not well tolerated (e.g., dizziness, nausea, paraesthesia and 

elevated liver enzymes may occur). Efavirenz AUC, C max and C min increased with 21 % (+10 % to +34 %), 14 % (+4 % to +26 %), and 

25 % (+7 % to +46 %), respectively. Data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not 

sufficient. Concurrent administration of ritonavir at doses of 600 mg and ODIMUNE is not recommended. When using ODIMUNE in 

a regimen including low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events due to 

a possible pharmacodynamic interaction should be kept in mind. 

Saquinavir: 

When saquinavir (1200 mg given 3 times a day, soft gel capsule formulation) was administered with efavirenz, the saquinavir AUC 

and C max were reduced by 62 % and 50 %, respectively, while the efavirenz AUC, Cmax and Cmin were reduced by 12 %, 13 %, and 

14 %, respectively. Use of ODIMUNE in combination with saquinavir as the sole protease inhibitor is not recommended. 

Data regarding the potential interactions of efavirenz with the combination of saquinavir and ritonavir are not available. Due to 

insufficient data it is not possible to make a dosing recommendation for saquinavir/ritonavir when dosed with ODIMUNE. 

Concomitant administration of saquinavir/ritonavir and ODIMUNE is therefore not recommended. 

Selective serotonin reuptake inhibitors (SSRIs): 

When given in combination with ODIMUNE, sertraline dose increases should be guided by clinical response, since concomitant 

administration of sertraline 50 mg with efavirenz 600 mg resulted in mean decreases in sertraline AUC, C max and Cmin of 39 %, 29 %, 

and 46 %, respectively. 

Co-administration of ODIMUNE and paroxetine does not require dose adjustment. Concomitant administration of efavirenz and 

paroxetine did not cause any changes in the AUC, C max or C min of either paroxetine or efavirenz. 

Co-administration of ODIMUNE and fluoxetine does not require dose adjustment, since fluoxetine shares a similar metabolic profile 

with paroxetine, i.e., strong CYP2D6 inhibitory effect. Therefore, a similar lack of interaction would be expected with fluoxetine. 

Stavudine: 

No clinically significant drug interactions have been observed between the emtricitabine in ODIMUNE and stavudine. 

Co-administration of a single dose of stavudine 40 mg with a single dose of emtricitabine 200 mg did not alter the C max or AUC of 

emtricitabine or stavudine. 

St. John's wort (Hypericum perforatum): 

Patients taking ODIMUNE should not concomitantly use products containing St. John's wort (Hypericum perforatum), since it is 

expected to reduce plasma levels of efavirenz. This effect occurs because of an induction of CYP3A4 and may lead to loss of 

therapeutic effect and development of resistance. 

Voriconazole: 

Co-administration of standard doses of efavirenz and voriconazole is contra-indicated due to significant increases in the AUC and 

C max of efavirenz and significant decreases in the AUC and Cmax of voriconazole. Since ODIMUNE is a fixed-dose combination 

product, the dose of efavirenz cannot be altered; therefore, voriconazole and ODIMUNE must not be co-administered (see 

"CONTRA-INDICATIONS" and "WARNINGS"). 

PREGNANCY AND LACTATION: 

The use of ODIMUNE during pregnancy is not recommended as safety and efficacy have not been established (see 

"CONTRA-INDICATIONS"). 

Barrier contraception should always be employed in combination with other contraceptive methods (e.g., oral or other hormonal 

contraceptives). 

Women of childbearing potential should undergo pregnancy testing prior to initiation of treatment with ODIMUNE (see 


Nursing mothers: HIV-infected mothers should not breast feed their infants. It is not known whether efavirenz, emtricitabine 

or tenofovir are excreted in human milk. Due to the potential for HIV transmission and the potential for serious adverse reactions 

in nursing infants, mothers should be instructed not to breast feed if they are taking ODIMUNE. 

DOSAGE AND DIRECTIONS FOR USE: 

Therapy should be initiated by a physician experienced in the management of HIV infection. 

Adults: 

The recommended dose of ODIMUNE is one tablet taken orally once daily. 

It is recommended that ODIMUNE be swallowed whole with water. 

ODIMUNE should be taken on an empty stomach, since food may increase efavirenz exposure and this may cause an increase 

in the frequency of adverse reactions. In order to improve the tolerability to efavirenz with respect to undesirable effects on the 

nervous system, it is recommended that ODIMUNE be taken at bedtime. 

Children and adolescents: 

ODIMUNE is not recommended for use in children below 18 years of age due to lack of data on safety and efficacy (see 


Elderly: 

Insufficient numbers of elderly patients have been evaluated in clinical trials of the components of ODIMUNE to determine whether 

they respond differently than younger patients. Caution is required when ODIMUNE is prescribed to the elderly, keeping in mind 

the greater frequency of decreased hepatic or renal function in elderly patients. 

Renal impairment: 

ODIMUNE is not recommended for patients with moderate to severe impairment of renal function (creatinine clearance < 50 ml/min). 

Patients with moderate or severe kidney impairment require dose interval adjustments of emtricitabine and tenofovir that cannot be 

achieved with ODIMUNE (see "CONTRA-INDICATIONS" and "WARNINGS"). 

Hepatic impairment: 

The pharmacokinetic properties of ODIMUNE have not been evaluated in patients with hepatic impairment. Patients with mild to 

moderate liver disease (Child-Pugh-Turcotte Grade A or B) may receive the normal recommended dose of ODIMUNE. Patients 

require careful monitoring for adverse reactions, especially nervous system symptoms related to efavirenz. 

If treatment with ODIMUNE is discontinued in patients with HIV and HBV co-infection, these patients should be closely monitored 

for evidence of exacerbation of hepatitis. 

It is important to take ODIMUNE according to a regular dosing schedule to avoid missing doses. Patients should be instructed that, 

if they forget to take ODIMUNE, they should take the missed dose immediately, unless it is less than 12 hours until the next day’s 

dose. In this instance, patients should be instructed to skip the missed dose and to take their next dose at the usual time. 

Where discontinuation of treatment with one of the components of ODIMUNE is indicated or where dose modification is required, 

separate preparations of efavirenz, emtricitabine and tenofovir are available. Please refer to the individual package inserts of 

these medicines. 

If treatment with ODIMUNE is discontinued, it is important to consider the long half-life of efavirenz and long intracellular half-lives 

of tenofovir and emtricitabine. Due to interpatient variability in these parameters and concerns regarding development of 

resistance, HIV treatment guidelines need to be consulted, also taking into consideration the reason for cessation of treatment. 

SIDE-EFFECTS AND SPECIAL PRECAUTIONS: 

Side-Effects: 

EMTRICITABINE: 

Blood and lymphatic system disorders: 

The following side-effects have been reported and frequencies 

are unknown: Neutropenia, anaemia. 

Metabolic and nutrition disorders: 


are unknown: Lactic acidosis, usually accompanied by severe hepatomegaly and steatosis, has been 

associated with nucleoside reverse transcriptase inhibitors. 

Hypertriglyceridaemia and hyperglycaemia. 

Neuropsychiatric system disorders: 

Frequent: Headache, asthenia. 

Less frequent: Depressive disorders, dizziness, sleep disturbances (abnormal dreams, insomnia), neuritis, 

paraesthesia, and peripheral neuropathy. 

Respiratory system disorders: 

Frequent: Increased cough, rhinitis. 

Gastrointestinal system disorders: 

Frequent: Nausea, diarrhoea. 

Less frequent: Abdominal pain, dyspepsia, and vomiting. 

Hepatobiliary system disorders: 


are unknown: Raised liver enzyme concentrations and hyperbilirubinaemia. 

Skin and subcutaneous tissue disorders: 

Less frequent: Rash (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash 

and allergic reactions) and skin discolouration, manifested by hyperpigmentation on the palms 

and/or soles (generally mild). 

Musculoskeletal system disorders: 

Less frequent: Arthralgia, myalgia. 

Renal and urinary system disorders: 

Frequent: Raised creatine kinase. 

TENOFOVIR: 

Blood and lymphatic system disorders: 


are unknown: Neutropenia, haematuria. 

Immune system disorders: 


are unknown: Allergic reactions. 

Metabolism and nutrition disorders: 


are unknown: Lactic acidosis, usually in combination with severe hepatomegaly and steatosis; also 

hypertriglyceridaemia, hyperglycaemia, hypophosphataemia. 


Frequent: Asthenia. 

Less frequent: Anorexia. 


are unknown: Depression, headache, dizziness, insomnia, peripheral neuropathy, and anxiety. 



are unknown: Chest pain, pneumonia, dyspnoea. 


Frequent: Nausea, vomiting, diarrhoea. 

Less frequent: Raised serum amylase concentrations, abdominal pain, and flatulence. 


are unknown: Pancreatitis and dyspepsia. 


Less frequent: Hepatotoxicity, including lactic acidosis. 


are unknown: Raised liver enzymes and hepatitis. 



are unknown: Skin rashes (including pruritus, maculopapular rash, urticaria, vesiculobullous rash and pustular 

rash). 



are unknown: Back pain, myalgia, arthralgia. 

Renal and urinary system disorders: 


are unknown: Raised creatine kinase levels, nephritis, nephrogenic diabetes insipidus, renal impairment, acute 

renal failure, and effects on the renal proximal tubules, including Fanconi syndrome and acute 

tubular necrosis. 

General disorders: 


are unknown: Fever, sweating, and weight loss. 

EFAVIRENZ: 

Metabolic and nutritional disorders: 


are unknown: Weight gain and weight loss. 


Frequent: Dizziness, impaired concentration, somnolence, insomnia, and headache. 

Less frequent: Abnormal dreams, anorexia and hypoaesthesia. 


are unknown: Abnormal coordination, ataxia, convulsions, paraesthesia, neuropathy, tremors, aggravated 

depression, agitation, amnesia, anxiety, apathy, increased appetite, confusion, emotional lability, 

euphoria, hallucinations, impaired coordination, impotence, decreased libido, increased libido, 

neuralgia, peripheral neuropathy, speech disorder and vertigo. 

Disorders of the special senses: 


are unknown: Abnormal vision, tinnitus and taste perversion. 

Cardiovascular system disorders: 


are unknown: Flushing, palpitations and tachycardia. 



are unknown: Asthma, sinusitis, dyspnoea and upper respiratory tract infections. 


Frequent: Nausea, vomiting and diarrhoea. 

Less frequent: Dyspepsia and abdominal pain. 


are unknown: Gastritis, gastroenteritis, gastro-oesophageal reflux, constipation and malabsorption. 



are unknown: Hepatitis, hepatic enzyme increase and hepatic failure. 


Frequent: Rash, pruritus and increased sweating. 


are unknown: Acne, alopecia, eczema, folliculitis, seborrhoea, skin exfoliation, urticaria, erythema multiforme, 

nail disorders, skin discolouration, Stevens-Johnson syndrome. 



are unknown: Arthralgia, myalgia and myopathy. 

General disorders: 

Frequent: Fatigue and pain. 


are unknown: Alcohol intolerance, allergic reactions, asthenia, hot flushes, influenza-like symptoms, malaise, 

pain, syncope and redistribution/accumulation of body fat. 

Laboratory abnormalities: 

Increases in liver enzyme values have occurred, particularly in patients with viral hepatitis. There have been reports of raised 

serum cholesterol and triglyceride concentrations. 

Liver enzymes: Elevations of AST and ALT levels to greater than five times the upper limit of the normal range were observed in 

patients treated with 600 mg of efavirenz. Elevations of GGT levels in patients taking efavirenz may reflect enzyme induction not 

associated with liver toxicity (see "Special Precautions"). 

Lipids: Increases in total cholesterol of 10 to 20 % were noted in some uninfected volunteers taking efavirenz. Increases in 

non-fasting total cholesterol and HDL levels of approximately 20 % and 25 %, respectively, were seen in patients treated with 

efavirenz + ZDV + 3TC and of approximately 40 % and 35 %, in patients treated with efavirenz + IDV. The effects of efavirenz on 

triglyceride and LDL concentrations were not well characterised. Whether these findings are clinically significant are not known 

(see "Special Precautions"). 

Special Precautions: 

Medicine interactions: 

ALERT: Find out about medicines that should NOT be taken with ODIMUNE (see "WARNINGS" and "INTERACTIONS"). 

Since the kidneys are primarily responsible for the elimination of emtricitabine and tenofovir, co-administration of ODIMUNE with 

medicines that reduce renal function or compete for active tubular secretion may cause increases in serum concentrations of 

emtricitabine, tenofovir, and/or other renally eliminated medicines. Examples of such medicines include, but are not limited to, 

adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir. 

ODIMUNE should not be given concurrently with emtricitabine, tenofovir or efavirenz. Due to similarities between emtricitabine 

and lamivudine, ODIMUNE should not be concomitantly administered with other medicines containing lamivudine, including 

lamivudine and zidovudine coformulation, lamivudine for HIV, lamivudine for HBV, abacavir sulphate and lamivudine 

coformulation or abacavir sulphate, lamivudine and zidovudine coformulation. 

Bone effects: 

Tenofovir: 

In a 144-week clinical trial, decreases from baseline in bone mineral density (BMD) were observed at the lumbar spine and hip in 

both treatment arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD 

at the lumbar spine in subjects who took tenofovir + lamivudine + efavirenz compared to subjects who took stavudine + lamivudine 

+ efavirenz. BMD changes at the hip were similar between the two treatment arms. In both groups, the largest part of the decrease 

in BMD occurred in the first 24 to 48 weeks of the study and this reduction was sustained throughout the study (144 weeks). 

Twenty-eight percent of patients who received tenofovir versus 21 % of stavudine-treated patients lost a minimum of 5 % of BMD 

at the spine or 7 % of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients who 

received tenofovir and 6 patients who took stavudine. In addition, there were significant increases in the levels of biochemical 

markers for bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary 

N-telopeptide) in the tenofovir-group relative to the stavudine-group, suggesting increased bone turnover. Serum parathyroid 

hormone levels and 1,25 vitamin D levels were also higher in the group of patients who received tenofovir. With the exception of 

bone-specific alkaline phosphatase, these changes produced values that remained within the normal range. How these 

tenofovir-associated changes in BMD and biochemical markers will affect long-term bone health and future fracture risk is 

unknown. 

HIV infected patients with a history of pathologic bone fracture or who are at risk for osteopenia should undergo bone monitoring. 

Although the effect of calcium and vitamin D supplementation has not been studied, such supplementation may benefit all 

patients. It is necessary to obtain appropriate consultation if bone abnormalities are suspected. 

Fat redistribution: 

There have been reports of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo 

hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" in patients treated with antiretroviral 

agents, such as ODIMUNE. The mechanism and long-term consequences of these events are not known at this time. Whether 

antiretroviral therapy is causally related to these events is not known. 

Immune reconstitution syndrome: 

There have been reports of immune reconstitution syndrome in patients who received combination antiretroviral therapy. During 

the initial phase of treatment with combination antiretroviral agents, an inflammatory response to indolent or residual opportunistic 

infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis] 

may develop in patients whose immune system responds. Such reactions may necessitate further evaluation and treatment. 

Paediatric use: 

The safety and efficacy of ODIMUNE in children have not been established. 

Geriatric use: 

Clinical studies of fixed dose combinations of emtricitabine and tenofovir, as in ODIMUNE, did not include sufficient numbers of 

individuals older than 65 years to establish whether they respond differently from younger subjects. Generally, caution is required 

when doses are selected for elderly patients, bearing in mind the greater frequency of decreased liver, kidney and cardiac 

function, and of concomitant disease or medicinal therapy. 

Skin rash: 

Mild-to-moderate rash, which usually resolves with continued treatment, has been observed with efavirenz use. Treatment with 

appropriate antihistamines and/or corticosteroids may improve tolerability and hasten resolution of symptoms. Treatment with 

ODIMUNE should be discontinued in patients who experience severe rash associated with blistering, desquamation, mucosal 

involvement or fever. Prophylaxis with appropriate antihistamines before start of therapy with ODIMUNE in children may be 

considered. 

Nervous system symptoms: 

There have been reports of nervous system symptoms with efavirenz use (see "Side-Effects"). In addition, psychosis-like 

reactions, including delusions and inappropriate behaviour (including aggressive reactions), have also been reported. These 

reactions occurred predominantly in patients with a history of mental illness or substance abuse. There have been infrequent 

reports of severe acute depression (including suicidal ideation/attempts) in both efavirenz- treated and control-treated patients, 

predominantly in patients with a previous history of depression. Patients should be advised to contact their doctor immediately if 

they experience these symptoms since discontinuation of ODIMUNE may be required. 

Liver enzymes: 

Monitoring of liver enzyme levels is recommended in patients with known or suspected history of hepatitis B or C infection and in 

patients treated with other medicines associated with hepatic toxicity. The benefit of continued therapy with ODIMUNE has to be 

weighed against the unknown risks of significant hepatic toxicity in patients who show persistent elevations of serum 

transaminases to greater than 5 times the upper limit of the normal range (see "Side-Effects"). 

Cholesterol: 

Monitoring of cholesterol and triglyceride levels should be considered in patients treated with ODIMUNE (see "Side-Effects"). 

Opportunistic infections: 

Patients taking ODIMUNE or any other antiretroviral therapy may continue to develop opportunistic infections and other 

complications of HIV infection. They should therefore remain under close clinical observation by medical practitioners with 

experience in the treatment of patients with HIV associated disease. 

Transmission of HIV: 

Patients must be advised that there is no proof that antiretroviral therapies, including ODIMUNE, prevent the risk of transmission 

of HIV to others through sexual contact or blood contamination. Patients must continue to use appropriate precautions. 

Effects on the ability to drive and use machines: 

The efavirenz in ODIMUNE may lead to dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that, 

if they develop these symptoms, they should keep away from potentially hazardous tasks, such as driving or operating machinery. 

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: 

In the event of overdose, the patient must be monitored for evidence of toxicity, and standard supportive treatment given as 

necessary. 


There is limited clinical experience with doses in excess of the therapeutic dose of emtricitabine (200 mg). There were no reports 

of adverse reactions when single emtricitabine doses of 1200 mg were administered to patients in a clinical study. Haemodialysis 

removes approximately 30 % of the emtricitabine dose over a 3-hour dialysis period initiated within

SKEDULERINGSTATUS: S4 

EIENDOMSNAAM (EN DOSEERVORM): 

ODIMUNE (Tablette) 

SAMESTELLING: 

Elke filmbedekte tablet bevat emtrisitabien 200 mg, tenofovir disoproksielfumaraat 300 mg en efavirens 600 mg. 

Onaktiewe bestanddele sluit natriumkroskarmellose, rooi ysteroksied, mikrokristallyne sellulose, hipromellose, mieliestysel, 

magnesiumstearaat, natriumlaurielsulfaat, hidroksielpropielsellulose, opadrie pienk en opadrie bruin in. 

WAARSKUWING: 

GEVALLE VAN MELKSUURASIDOSE EN ERGE HEPATOMEGALIE MET STEATOSE, WAARVAN SOMMIGE 

NOODLOTTIG WAS, IS MET DIE GEBRUIK VAN NUKLEOSIED ANALOË ALLEEN OF IN KOMBINASIE MET ANDER 

ANTIRETROVIRALE MIDDELS GEMELD (SIEN "WAARSKUWINGS"). 

ODIMUNE IS NIE AANGEDUI VIR DIE BEHANDELING VAN CHRONIESE INFEKSIE MET DIE HEPATITIS B VIRUS (HBV) 

NIE. DIE VEILIGHEID EN EFFEKTIWITEIT VAN ODIMUNE IS NIE IN PASIËNTE MET HBV EN MIV GESAMENTLIKE 

INFEKSIE VASGESTEL NIE. ERGE AKUTE OPFLIKKERINGS VAN HEPATITIS B INFEKSIE IS GEMELD IN INDIVIDUE 

WIE BEHANDELING MET EMTRISITABIEN (200 mg) OF TENOFOVIR GESTAAK HET. PASIËNTE MET GESAMENTLIKE 

MIV EN HBV INFEKSIE BENODIG NOUKEURIGE MONITERING VAN HULLE LEWERFUNKSIE VIR TEN MINSTE 

VERSKEIE MAANDE; HIERDIE BEHOORT BEIDE KLINIESE EN LABORATORIUM OPVOLG IN TE SLUIT. TOEPASLIKE 

INISIËRING VAN ANTI-HEPATITIS B TERAPIE MAG NODIG WEES (SIEN "WAARSKUWINGS"). 

FARMAKOLOGIESE KLASSIFIKASIE: 

A 20.2.8 Antimikrobiale (chemoterapeutiese) middels. Antivirale middels. 

FARMAKOLOGIESE WERKING: 

Meganisme van werking: 

Emtrisitabien: 

Emtrisitabien, ‘n NRTI, is ‘n sintetiese nukleosied analoog van sitidien. Sellulêre ensieme fosforileer emtrisitabien tot emtrisitabien 

5'-trifosfaat. Emtrisitabien 5'-trifosfaat kompeteer met die natuurlike substraat, deoksisitidien 5'-trifosfaat en word in nuutvormende 

virale DNA ingebou wat tot ketting terminasie aanleiding gee. Gevolglik word die aktiwiteit van MIV-1 omgekeerde transkriptase 

geïnhibeer. Emtrisitabien 5'-trifosfaat inhibeer soogdier DNA polimerase α, β, ε en mitochondriale DNA polimerase γ swak. 

Tenofovir disoproksielfumaraat: 

Tenofovir disoproksielfumaraat, ‘n NRTI, ook bekend as tenofovir DF, ‘n asikliese nukleosiedfosfonaat diëster analoog van 

adenosienmonofosfaat, benodig aanvanklike diëster hidrolise vir omskakeling na tenofovir. Sellulêre ensieme is verantwoordelik 

vir daaropvolgende fosforilasies om tenofovirdifosfaat te vorm. Tenofovirdifosfaat inhibeer die aktiwiteit van MIV-1 omgekeerde 

transkriptase deur kompetisie met die natuurlike substraat deoksiadenosien 5'-trifosfaat. Na invoeging in DNA word die DNA 

ketting getermineer. Tenofovirdifosfaat inhibeer soogdier DNA polimerase α, β en mitochondriale DNA polimerase γ swak. 

Efavirens: 

Efavirens, ‘n selektiewe nie-nukleosied omgekeerde transkriptase inhibeerder (NNRTI) van MIV-1, diffundeer tot binne die sel 

waar dit naasliggend tot die aktiewe setel van omgekeerde transkriptase bind. Gevolglik vind ‘n strukturele verandering in die 

ensiem plaas en word die funksie daarvan geïnhibeer. Efavirens is ‘n nie-kompeterende inhibeerder van MIV-1 omgekeerde 

transkriptase met verwysing na die primêre, templaat of nukleosied trifosfate, alhoewel daar ook ‘n geringe mate van 

kompeterende inhibisie teenwoordig is. Efavirens inhibeer nie MIV-2 omgekeerde transkriptase of menslike sellulêre DNA 

polimerases alfa, beta, gamma of delta nie. 

Farmakodinamika: 

Antivirale aktiwiteit: 

Emtrisitabien en tenofovir disoproksielfumaraat: 

Kombinasie studies wat die in vitro antivirale aktiwiteit van emtrisitabien en tenofovir gesamentlik geëvalueer het, het sinergistiese 

antivirale effekte getoon. 


Limfoblastoïede sellyne, die MAGI-CCR5 sellyn en perifere bloed mononukleêre selle is gebruik om die in vitro aktiwiteit van 

emtrisitabien teen laboratorium en kliniese isolate van MIV te evalueer. Die IK 50 - (50 % inhibitoriese konsentrasie) waardes vir 

emtrisitabien het tussen 0,0013 – 0,64 µM (0,0003 – 0,158 µg/ml) gevarieer. Additiewe tot sinergistiese effekte is waargeneem in 

studies van kombinasie middels met emtrisitabien en nukleosied omgekeerde transkriptase inhibeerders (abakavir, lamivudien, 

stavudien, salsitabien, sidovudien), nie-nukleosied omgekeerde transkriptase inhibeerders (delavirdien, efavirens, nevirapien) en 

protease inhibeerders (amprenavir, nelfinavir, ritonavir, sakwinavir). Die meerderheid van hierdie middel kombinasies is nie in mense 

bestudeer nie. Emtrisitabien het antivirale aktiwiteit in vitro teen MIV-1 klades A, B, C, D, E, F en G (IK 50-waardes met ‘n reikwydte 

van 0,007 – 0,075 µM) en het stam-spesifieke aktiwiteit teen MIV-2 (IK 50 -waardes met ‘n reikwydte van 0,007 – 1,5 µM) getoon. 


Tenofovir se in vitro antivirale aktiwiteit teen laboratorium en kliniese isolate van MIV-1 was in limfoblastoïede sellyne, primêre 

monosiet/makrofaag selle en perifere bloed limfosiete geëvalueer. Die IK 50 -waardes vir tenofovir het ‘n reikwydte van 0,04 tot 8,5 

µM getoon. Additiewe tot sinergistiese effekte is waargeneem tydens middel kombinasie studies van tenofovir met nukleosied 

omgekeerde transkriptase inhibeerders (abakavir, didanosien, lamivudien, stavudien, salsitabien, sidovudien), nie-nukleosied 

omgekeerde transkriptase inhibeerders (delavirdien, efavirens, nevirapien) en protease inhibeerders (amprenavir, indinavir, 

nelfinavir, ritonavir, sakwinavir). Tenofovir toon in vitro antivirale aktiwiteit teen MIV-1 klades A, B, C, D, E, F, G en O (IK 50 -waardes 

het ‘n reikwydte van 0,5 – 2,2 µM). Die IK 50 -waardes van tenofovir teen MIV-2 het ‘n reikwydte van 1,6 µM tot 4,9 µM. 

Efavirens: 

Die kliniese belang van in vitro vatbaarheid van MIV-1 vir efavirens is nog nie vasgestel nie. Limfoblastoïede sellyne, perifere 

bloed mononukleêre selle (PBMS) en makrofaag/monosiet kulture verryk met PBMS is gebruik om die in vitro antivirale aktiwiteit 

van efavirens te beoordeel. Die 90 tot 95 % inhibitoriese konsentrasie (IK 90-95 ) vir wilde tipe, laboratoriumaangepaste stamme en 

kliniese isolate het tussen 1,7 en 25 nM gewissel. Sinergistiese aktiwiteit is in selkulture getoon wanneer efavirens met die 

nukleosied analoog omgekeerde transkriptase inhibeerders (NRTIs), sidovudien (ZDV) of didanosien (ddI), of die protease 

inhibeerder, indinavir (IDV), gekombineer is. 

Middelweerstand: 


MIV-1 isolate wat verminderde vatbaarheid vir die emtrisitabien en tenofovir kombinasie getoon het, is in vitro geselekteer. Na 

genotipiese analise is die M184V/I en/of K65R aminosuur substitusies in die virale omgekeerde transkriptase geïdentifiseer. 


MIV isolate weerstandig teen emtrisitabien is in vitro geselekteer. Genotipiese analise van hierdie isolate het getoon dat 

verminderde vatbaarheid vir emtrisitabien met ‘n mutasie in die MIV omgekeerde transkriptase geen by kodon 184 geassosieer 

word. Hierdie mutasie het ‘n aminosuur substitusie van metionien met valien of isoleusien (M184V/I) tot gevolg. 

MIV isolate weerstandig teen emtrisitabien is ook geïdentifiseer in sommige pasiënte wie behandeling met emtrisitabien alleen of 

in kombinasie met ander antiretrovirale middels ontvang het. Genotipiese analise van hierdie isolate het getoon dat die weerstand 

deur M184V/I mutasies in die MIV omgekeerde transkriptase geen veroorsaak is. 


Isolate van MIV-1 wat verminderde vatbaarheid vir tenofovir getoon het, is in vitro geselekteer. Hierdie virusse toon ‘n K65R 

mutasie in omgekeerde transkriptase en toon ‘n verminderde vatbaarheid vir tenofovir van tussen 2- tot 4-voudig. 

Tenofovir-weerstandbiedende MIV-1 stamme is ook geïsoleer vanaf sommige pasiënte wie tenofovir in kombinasie met sekere 

antiretrovirale middels ontvang het. Genotipiese analise van die weerstandige isolate het ‘n mutasie in die MIV-1 omgekeerde 

transkriptase geen getoon wat tot die K65R aminosuur substitusie lei. 

Efavirens: 

MIV-1 isolate met verminderde vatbaarheid vir efavirens (> 380-voudige toename in IK 90) in vergelyking met basislyn is in vitro 

geïdentifiseer. 

Fenotipiese veranderinge is in evalueerbare MIV-1 isolate en genotipiese veranderinge is in plasmavirus afkomstig van 

geselekteerde pasiënte wie met efavirens in kombinasie met IDV of met ZDV plus lamivudien behandel is, gemonitor. Een of meer 

RT mutasies is by verskeie aminosuur posisies (100, 101, 103, 108, 190 en 225) in al 62 pasiënte met ‘n frekwensie van ten 

minste 10 % vergeleke met basislyn waargeneem. Die mutasie by RT aminosuur posisie 103 (lisien tot asparagien) is mees 

dikwels (groter of gelyk aan 90 %) waargeneem. Ses-en-twintig kliniese isolate het ‘n 47-voudige gemiddelde verlies in 

vatbaarheid (IK 90 ) vir efavirens getoon. Vyf kliniese isolate is vir beide genotipiese en fenotipiese veranderinge vanaf basislyn 

beoordeel. Verlies in vatbaarheid vir efavirens (reikwydte van 9- tot groter as 312-voudige toename in IK 90 ) in vergelyking met 

basislyn is in vitro in hierdie isolate waargeneem. Al 5 isolate het oor ten minste een van die efavirens-geassosieerde omgekeerde 

transkriptase mutasies beskik. Die kliniese belang van hierdie fenotipiese en genotipiese veranderinge geassosieer met efavirens 

behandeling is nog nie vasgestel nie. 

Kruisweerstandigheid: 


Dit is bekend dat kruisweerstandigheid tussen sekere nukleosied omgekeerde transkriptase inhibeerders (NRTIs) mag ontwikkel. 

Die M184V/I en/of K65R substitusies wat in vitro deur die kombinasie van emtrisitabien en tenofovir geselekteer word, word ook 

gesien in sommige MIV-1 stamme geïsoleer van individue wie behandeling met tenofovir in kombinasie met óf lamivudien óf 

emtrisitabien en óf abakavir óf didanosien gefaal het. Kruisweerstandigheid tussen hierdie middels mag derhalwe ontwikkel in 

pasiënte wie se virus een of beide van hierdie aminosuur substitusies berg. 


Alhoewel emtrisitabien-weerstandbiedende isolate (M184V/I) ook kruisweerstandigheid teen lamivudien en salsitabien getoon 

het, het hierdie isolate in vitro vatbaarheid vir didanosien, stavudien, tenofovir, sidovudien en NNRTIs (delavirdien, efavirens en 

nevirapien) behou. MIV stamme, geïsoleer van pasiënte met baie behandelingsondervinding, wat beskik oor die M184V/l 

aminosuur substitusie in die konteks van ander NRTI substitusies geassosieer met weerstand mag vatbaar vir tenofovir bly. MIV 

isolate met die K65R substitusie, in vivo geselekteer deur abakavir, didanosien, tenofovir en salsitabien, toon verminderde 

vatbaarheid vir inhibisie deur emtrisitabien. Virusse wat mutasies bevat wat hulle minder vatbaar maak vir stavudien en sidovudien 

(M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) of didanosien (L74V) bly sensitief vir emtrisitabien. MIV-1 virale isolate met die 

K103N substitusie wat geassosieer word met weerstand teen NNRTIs was vatbaar vir emtrisitabien. 


MIV-1 isolate van individue wie se MIV-1 ‘n gemiddelde van 3 sidovudien-geassosieerde aminosuur substitusies in omgekeerde 

transkriptase (M41L, D67N, K70R, L210W, T215Y/F of K219Q/E/N) uitgedruk het, het verminderde vatbaarheid vir tenofovir 

getoon. MIV-1 met multinukleosied weerstand met ‘n T69S dubbelinvoeging mutasie in omgekeerde transkriptase toon 

verminderde vatbaarheid vir tenofovir. 

Efavirens: 

MIV-1 stamme met kruisweerstand teen nie-nukleosied omgekeerde transkriptase inhibeerders tree spoedig in vitro na vore. 

Kliniese isolate voorheen as efavirensweerstandig gekarakteriseer, is in vitro ook fenotipies vir nevirapien en delavirdien 

weerstandig in vergelyking met basislyn. ZDV-weerstandige MIV-1 stamme wat klinies verkry is en in vitro geïsoleer en getoets 

is, het vatbaarheid vir efavirens behou. Aangesien verskillende ensiemteikens betrokke is, is dit onwaarskynlik dat 

kruisweerstandigheid tussen efavirens en MIV protease inhibeerders sal ontwikkel. 

Farmakokinetika: 

Volwassenes: 


Na mondelingse toediening van emtrisitabien (200 mg), word emtrisitabien vinnig geabsorbeer. Piek plasmakonsentrasies word 

binne 1 – 2 uur na dosering bereik. Binding van emtrisitabien aan menslike plasmaproteïene in vitro is minder as 4 %. Hierdie is 

nie afhanklik van konsentrasie oor die reikwydte van 0,02 – 200 µg/ml nie. Mediane (reikwydte) orale biobeskikbaarheid van 

emtrisitabien onder vastende toestande is 92 % (83,1 – 106,4 %). By ewewigsvlak is gemiddelde (± SD) C maks (maksimum plasma 

konsentrasie) van emtrisitabien 1,8 ± 0,72 µg/ml, terwyl gemiddelde (± SD) AOK by ewewigsvlak 10,0 ± 3,12 µg.hr/ml is. 

Nagenoeg 86 % van radiogemerkte emtrisitabien word in die uriene herwin en 13 % word as metaboliete herwin. Emtrisitabien 

metaboliete sluit 3'-sulfoksied diastereomere en hulle glukuroonsuur konjugaat in. Eliminasie van emtrisitabien is via ‘n kombinasie 

van glomerulêre filtrasie en aktiewe tubulêre sekresie. Emtrisitabien se plasma halflewe is ongeveer 10 uur na toediening van ‘n 

enkele orale dosis (200 mg). 


Na die orale toediening van tenofovir neem dit 1,0 ± 0,4 uur om maksimum tenofovir serumkonsentrasies te bereik. Binding van 

tenofovir aan menslike plasmaproteïene in vitro is minder as 0,7 %. Dit is nie afhanklik van konsentrasie oor die reikwydte van 

0,01 – 25 µg/ml nie. Mediane (reikwydte) orale biobeskikbaarheid van tenofovir onder vastende toestande is 25 % (Nie bereken 

[NB] – 45 %). Tenofovir het ‘n gemiddelde (± SD) C maks van 0,30 ± 0,09 µg/ml en gemiddelde (± SD) AOK van 2,29 ± 0,69 µg.hr/ml 

Na intraveneuse toediening van tenofovir word ongeveer 70 – 80 % van die dosis onveranderd in die uriene herwin. Eliminasie 

van tenofovir is via ‘n kombinasie van glomerulêre filtrasie en aktiewe tubulêre sekresie. Tenofovir het ‘n terminale eliminasie 

halflewe van ongeveer 17 uur na ‘n enkele orale dosis. 

Effek van voedsel op orale absorpsie: 

Die kombinasie tablet kan met of sonder voedsel geneem word. Die tyd tot tenofovir C maks word met nagenoeg 0,75 uur vertraag 

na toediening van die kombinasie tablet met ‘n hoë-vet maaltyd of ‘n ligte maaltyd. Vergeleke met toediening onder vastende 

toestande het toediening met ‘n hoë-vet of ligte maaltyd tot gemiddelde toenames in tenofovir AOK en C maks van onderskeidelik 

ongeveer 35 % en 15 % gelei. In vorige veiligheids- en effektiwiteitstudies is tenofovir onder gevoede toestande toegedien. 

Emtrisitabien sistemiese blootstellings (AOK en C maks ) het onveranderd gebly wanneer die kombinasie tablet met óf ‘n hoë-vet óf 

ligte maaltyd geneem is. 

Efavirens: 

Absorpsie: 

Piek efavirens plasmakonsentrasies van 1,6 – 9,1 μM word teen 5 uur na toediening van enkel orale dosisse van 100 mg tot 1600 

mg aan ongeïnfekteerde individue bereik. Alhoewel dosisverwante toenames in C maks en AOK gesien word vir dosisse tot 1600 

mg, is hierdie toenames minder as proporsioneel, wat aandui dat absorpsie met hoër dosisse minder is. 

Ewewigsplasmakonsentrasies word binne 6 – 7 dae bereik. 

Verspreiding: 

Efavirens is hoogs aan plasmaproteïene gebonde (ongeveer 99,5 – 99,75 %) –hoofsaaklik aan albumien. Serebrospinale 

vogkonsentrasies wissel vanaf 0,26 tot 1,19 % (gemiddeld 0,69 %) van die ooreenstemmende plasmakonsentrasies in MIV-1 

geïnfekteerde individue wie 200 tot 600 mg efavirens een maal daagliks vir ten minste een maand ontvang het. Hierdie vlakke is 

ongeveer drie maal hoër as die nie-proteïengebonde (vrye) fraksie van efavirens in plasma. 

Metabolisme: 

Efavirens word hoofsaaklik deur die sitochroom P450 sisteem tot gehidroksileerde metaboliete gemetaboliseer. Hierdie 

gehidroksileerde metaboliete ondergaan hierna glukuronidasie. Die metaboliete is nie aktief teen MIV-1 nie. CYP3A4 en CYP2B6 

is die hoof iso-ensieme betrokke by efavirens metabolisme. Efavirens, deur induksie van P450 ensieme, induseer sy eie 

metabolisme. 

Eliminasie: 

Efavirens het ‘n lang terminale halflewe van onderskeidelik 52 – 76 en 40 – 55 uur na enkel- en veelvuldige dosisse. Na toediening 

van ‘n radiogemerkte dosis, word 14 – 34 % van efavirens in die uriene herwin en 16 – 61 % in die feses, hoofsaaklik in die vorm van 

metaboliete. 

Spesiale bevolkings: 

Geslag: 

Emtrisitabien en tenofovir farmakokinetiese eienskappe is soortgelyk in manlike en vroulike pasiënte. Farmakokinetiese 

eienskappe van efavirens in pasiënte blyk om soortgelyk in mans en vrouens te wees. 

Pediatriese en geriatriese pasiënte: 


Emtrisitabien en tenofovir farmakokinetika is nie in kinders < 18 jaar of in bejaardes (> 65 jaar) bestudeer nie (sien "Spesiale 

Voorsorgmaatreëls"). 

Efavirens: 

Farmakokinetika van efavirens is nie bestudeer in individue 65 jaar en ouer om vas te stel of hulle verskillend reageer nie. Die 

farmakokinetiese eienskappe van efavirens in pediatriese pasiënte is soortgelyk aan dié in volwassenes. 

Pasiënte met ingekorte nierfunksie: 


Die farmakokinetiese eienskappe van emtrisitabien en tenofovir is gewysig in pasiënte met ingekorte nierfunksie (sien 

"WAARSKUWINGS"). Die C maks en AOK 0-∞ van emtrisitabien en tenofovir is vermeerder in pasiënte met kreatinienopruiming van 

< 50 ml/min. Die dosisinterval vir die kombinasie moet aangepas word in pasiënte met kreatinienopruiming van 30 – 49 ml/min. 

Aangesien dit nie met ‘n vaste dosis kombinasie moontlik is nie, moet so ‘n kombinasie nie aan pasiënte met kreatinienopruiming 

< 50 ml/min en aan pasiënte met eindstadium niersiekte wat dialise benodig, toegedien word nie (sien "KONTRA-INDIKASIES", 

"WAARSKUWINGS" en "DOSIS EN GEBRUIKSAANWYSINGS"). 

Efavirens: 

Die farmakokinetiese eienskappe van efavirens is nie in pasiënte met nierontoereikendheid bestudeer nie. Aangesien minder as 

1 % van efavirens egter onveranderd in die uriene uitgeskei word, behoort die impak van ingekorte nierfunksie op eliminasie van 

efavirens minimaal te wees. 

Pasiënte met lewerinkorting: 


Die farmakokinetiese eienskappe van tenofovir na ‘n 300 mg dosis tenofovir disoproksielfumaraat is geëvalueer in nie-MIV 

geïnfekteerde individue met matige tot erge inkorting van lewerfunksie. Tenofovir farmakokinetika is nie wesenlik anders in 

pasiënte met lewerinkorting in vergelyking met normale pasiënte nie. Farmakokinetiese eienskappe van die kombinasie tablet of 

emtrisitabien is nie geëvalueer in pasiënte met ingekorte lewerfunksie nie. Aangesien emtrisitabien nie tot ‘n betekenisvolle mate 

deur lewerensieme gemetaboliseer word nie, behoort die impak van lewerinkorting beperk te wees. 

Efavirens: 

Die farmakokinetika van efavirens is nog nie voldoende in pasiënte met lewerinkorting bestudeer nie. 

INDIKASIES: 

ODIMUNE is aangedui vir die behandeling van MIV-1 infeksie in volwassenes. 

KONTRA-INDIKASIES: 

ODIMUNE is teenaangedui in pasiënte: 

• Wie vantevore hipersensitiwiteit vir emtrisitabien, tenofovir, efavirens of enige van die ander komponente van die produk 

getoon het. 

• Met matige tot erge inkorting van nierfunksie (kreatinienopruiming < 50 ml/min) (sien "WAARSKUWINGS" en "DOSIS EN 

GEBRUIKSAANWYSINGS"). 

• Wie swanger is of borsvoed (sien "SWANGERSKAP EN LAKTASIE"). 

• Wie gesamentlik behandeling met astemisool, sisapried, midasolam, triasolam of ergotderivate ontvang, aangesien 

kompetisie vir CYP3A4 deur die efavirens in ODIMUNE tot inhibisie van die metabolisme van hierdie middels mag lei en dit 

mag potensieel ernstige en/of lewensdreigende newe-effekte tot gevolg hê (bv. kardiale disritmieë, verlengde sedasie of 

respiratoriese onderdrukking). 

• Jonger as 18 jaar vanweë gebrek aan data oor veiligheid en effektiwiteit. 

• Met erge lewerinkorting. 

• Wie gesamentlik vorikonasool neem, aangesien efavirens vorikonasool plasmakonsentrasies betekenisvol verminder, 

terwyl vorikonasool efavirens plasmakonsentrasies betekenisvol vermeerder. Aangesien ODIMUNE ‘n vaste dosis 

kombinasie produk is, kan die dosis van efavirens nie verander word nie; dus moet vorikonasool en ODIMUNE nie 

gesamentlik toegedien word nie. 

• Wie gesamentlik enige ander medisinale produkte neem wat enige van die komponente (efavirens, emtrisitabien of 

tenofovir) bevat of wie gesamentlik ander sitidien analoë, soos lamivudien, en adefovir dipivoksiel neem. 

WAARSKUWINGS: 

LET WEL: Vind uit oor middels wat NIE saam met ODIMUNE geneem moet word nie (sien "KONTRA-INDIKASIES", 

"INTERAKSIES" en "NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS"). 

Ernstige senusisteem en psigiatriese simptome is met efavirens, een van die aktiewe bestanddele in ODIMUNE, gemeld. 

Melksuurasidose / Erge hepatomegalie met steatose: 

Melksuurasidose en erge hepatomegalie met steatose, wat in sommige gevalle noodlottig was, is met die toediening van 

nukleosied analoë, soos bevat in ODIMUNE, alleen of in kombinasie met ander antiretrovirale middels gemeld. Meeste van 

hierdie gevalle het in vroue voorgekom. Moontlike risikofaktore sluit obesiteit en verlengde nukleosied blootstelling in. Uiterse 

omsigtigheid is nodig wanneer ODIMUNE toegedien word aan enige pasiënt met bekende risikofaktore vir lewersiekte; tog is 

sodanige komplikasies ook gemeld in pasiënte sonder enige bekende risikofaktore. Staak behandeling met ODIMUNE in enige 

pasiënt wie kliniese of laboratorium bevindings aanduidend van melksuurasidose of uitgesproke hepatotoksisiteit ontwikkel (wat 

vergroting van die lewer en steatose selfs in die afwesigheid van opvallende verhogings in transaminases) mag insluit. 

Pasiënte met hepatitis B en MIV gesamentlike infeksie: 

Dit word aanbeveel dat alle MIV-positiewe pasiënte getoets word vir die teenwoordigheid van hepatitis B virus (HBV) voor die 

aanvang van behandeling met antiretrovirale middels. ODIMUNE is nie aangedui vir die behandeling van chroniese HBV infeksie 

nie. Die veiligheid en effektiwiteit van ODIMUNE is nog nie bevestig in pasiënte met HBV en MIV gesamentlike infeksie nie. Na 

staking van behandeling met emtrisitabien (200 mg) en tenofovir disoproksielfumaraat was daar melding gemaak van erge akute 

opflikkerings van hepatitis B. Pasiënte met HBV en MIV gesamentlike infeksie wie behandeling met ODIMUNE staak, benodig 

noukeurige monitering van hulle lewerfunksie vir ten minste verskeie maande; dit behoort beide kliniese en laboratorium opvolg 

in te sluit. Toepaslike inisiëring van anti-hepatitis B terapie mag nodig wees. 

Renale inkorting: 

Eliminasie van emtrisitabien en tenofovir, twee van die aktiewe substanse in ODIMUNE, is hoofsaaklik via die niere. In alle 

pasiënte met kreatinienopruiming van 30 – 49 ml/min moet die doseringsinterval aangepas word. Aangesien dit nie met ‘n vaste 

dosis kombinasie moontlik is nie, moet ODIMUNE nie aan pasiënte met kreatinienopruiming < 50 ml/min of pasiënte wie 

hemodialise benodig, toegedien word nie (sien "DOSIS EN GEBRUIKSAANWYSINGS"). 

Inkorting van nierfunksie, insluitende gevalle van akute nierversaking en Fanconi se sindroom (renale tubulêre skade met erge 

hipofosfatemie) is in assosiasie met die gebruik van tenofovir gemeld (sien "Newe-Effekte"). Meeste van hierdie gevalle het in 

pasiënte met onderliggende sistemiese of niersiekte ontwikkel, of in pasiënte wie nefrotoksiese middels ontvang het. Sommige 

van hierdie komplikasies het egter ontwikkel in pasiënte sonder enige identifiseerbare risikofaktore. 

Die gebruik van ODIMUNE moet vermy word in pasiënte wie gesamentlik ‘n nefrotoksiese middel neem of onlangs geneem het. 

Versigtige monitering vir veranderinge in serumkreatinien en -fosfor is nodig in pasiënte met ‘n risiko vir, of met ‘n geskiedenis van, 

nierdisfunksie asook in pasiënte wie gepaardgaande nefrotoksiese middels ontvang. 

INTERAKSIES: 

Algemene interaksies: 

Geen interaksiestudies is met ODIMUNE tablette uitgevoer nie. Aangesien ODIMUNE efavirens, emtrisitabien en tenofovir bevat, 

mag enige interaksies wat met hierdie middels individueel geïdentifiseer is, met ODIMUNE voorkom. Interaksiestudies met hierdie 

middels is slegs in volwassenes gedoen. 

As ‘n vaste kombinasie moet ODIMUNE nie saam met ander medisinale produkte wat enige van die bestanddele (efavirens, 

emtrisitabien of tenofovir) bevat, toegedien word nie en ook nie saam met ander sitidien analoë, soos lamivudien, en adefovir 

dipivoksiel nie (sien "KONTRA-INDIKASIES"). 

ODIMUNE moenie saam met terfenadien, astemisool, sisapried, midasolam, triasolam, pimosied, bepridil, of ergotderivate 

toegedien word nie, aangesien inhibisie van hierdie middels se metabolisme erge, lewensdreigende gevolge mag hê (sien 

"KONTRA-INDIKASIES"). 

Die farmakokinetiese eienskappe van emtrisitabien en tenofovir by ewewigsvlak het onveranderd gebly toe emtrisitabien en 

tenofovir disoproksielfumaraat gesamentlik toegedien is versus elke middel afsonderlik gegee. Geen klinies betekenisvolle 

interaksies is tussen emtrisitabien en tenofovir waargeneem nie. 

Gesamentlike toediening van tenofovir disoproksielfumaraat 300 mg een maal per dag vir 7 dae met emtrisitabien 200 mg een 

maal daagliks vir 7 dae het geen veranderinge in die C maks of AOK van emtrisitabien tot gevolg gehad nie. Daarteenoor het die C min 

van emtrisitabien met 20 % [90 % vertrouensinterval (VI) +12 % tot +29 %] vermeerder. Die C maks , AOK en C min van tenofovir was 

onveranderd. 

In vitro en kliniese farmakokinetiese middelinteraksiestudies het gevind dat die potensiaal vir CYP450 bemiddelde interaksies 

tussen emtrisitabien en tenofovir, twee van die aktiewe komponente van ODIMUNE, met ander middels gering is. 

Die niere is primêr verantwoordelik vir die uitskeiding van emtrisitabien en tenofovir deur ‘n kombinasie van glomerulêre filtrasie 

en aktiewe tubulêre sekresie. Alhoewel geen middelinteraksies vanweë kompetisie vir renale uitskeiding waargeneem is nie, is dit 

moontlik dat wanneer ODIMUNE saam met middels toegedien word wat deur aktiewe tubulêre sekresie geëlimineer word, die 

konsentrasies van emtrisitabien, tenofovir en/of die gepaardgaande middel mag toeneem. 

Middels wat nierfunksie belemmer, mag emtrisitabien en/of tenofovir konsentrasies verhoog. 

Die efavirens in ODIMUNE induseer CYP3A4. Ander samestellings wat substrate van CYP3A4 is, mag verlaagde 

plasmakonsentrasies toon wanneer dit saam met ODIMUNE toegedien word. 

Geen klinies beduidende middelinteraksies is vir tenofovir disoproksielfumaraat en efavirens getoon nie. Gesamentlike toediening 

van efavirens 600 mg een maal per dag vir 14 dae met tenofovir 300 mg een maal per dag het nie enige veranderinge in die C maks , 

C min of AOK van óf efavirens óf tenofovir veroorsaak nie. 

Abakavir: 

Geen klinies beduidende middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van 

ODIMUNE, en abakavir waargeneem nie. Gesamentlike toediening van ‘n enkel dosis abakavir 300 mg met tenofovir 300 mg het 

geen veranderinge in die C maks of AOK van tenofovir veroorsaak nie. Die C maks van abakavir het egter met 12 % (90 % VI -1 % tot 

+26 %) toegeneem terwyl die AOK onveranderd gebly het. 

Adefovir dipivoksiel: 

Geen klinies beduidende middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van 

ODIMUNE, en adefovir dipivoksiel waargeneem nie. Gepaardgaande toediening van ‘n enkel dosis van adefovir dipivoksiel 10 mg 

met tenofovir 300 mg het nie tot enige veranderinge in die C maks , C min of AOK van tenofovir of in die C maks of AOK van adefovir 

dipivoksiel gelei nie. 

ODIMUNE moet egter vanweë die verhoogde risiko vir nefrotoksisiteit nie saam met adefovir dipivoksiel toegedien word nie. 

Amprenavir: 

Gepaardgaande toediening van amprenavir/ritonavir en ODIMUNE word nie aanbeveel nie, aangesien efavirens die C maks , C min en 

AOK van amprenavir met 40 % verminder. 

Atasanavir: 

Gesamentlike toediening van atasanavir 400 mg een maal daagliks vir 14 dae met tenofovir 300 mg een maal per dag het tot ‘n 

toename van 14 % (90 % VI +8 % tot +20 %) in tenofovir C maks , van 24 % (+21 % tot +28 %) in tenofovir AOK en van 22 % (+15 

% tot +30 %) in tenofovir C min gelei. Ooreenstemmende parameters vir atasanavir het ‘n afname van 21 % (-27 % tot -14 %) in 

C maks , van 25 % (-30 % tot -19 %) in AOK en van 40 % (-48 % tot -32 %) in C min getoon. In MIV-geïnfekteerde pasiënte het 

toevoeging van tenofovir disoproksielfumaraat tot atasanavir 300 mg plus ritonavir 100 mg tot AOK-en C min -waardes van 

atasanavir gelei wat 2,3- tot 4-voudig hoër was as die onderskeie waardes waargeneem vir atasanavir 400 mg wanneer alleen 

toegedien. 

Gesamentlike toediening van atasanavir/ritonavir met tenofovir het tot verhoogde blootstelling aan tenofovir gelei. Hoër tenofovir 

konsentrasies kan tenofovir-geassosieerde newe-effekte, insluitende renale afwykings, vererger. 

Gesamentlike toediening van efavirens met atasanavir in kombinasie met lae-dosis ritonavir het tot beduidende afnames in 

atasanavir blootstelling gelei vanweë CYP3A4 induksie. Dit het dosisaanpassing van atasanavir genoodsaak. Gesamentlike 

toediening van efavirens en atasanavir in kombinasie met ritonavir mag tot verhoogde efavirens blootstelling lei wat die 

verdraagsaamheidsprofiel van efavirens mag verswak. 

Data om ’n dosisaanbeveling vir atasanavir/ritonavir in kombinasie met ODIMUNE te maak is nie voldoende nie. Derhalwe kan 

gesamentlike toediening van atasanavir/ritonavir en ODIMUNE nie aanbeveel word nie. 

Kalsiumkanaalblokkers: 

Wanneer efavirens saam met ’n kalsiumkanaalblokker wat ’n substraat van die CYP3A4 ensiem is gegee word, is daar ’n 

moontlikheid dat die plasmakonsentrasie van die kalsiumkanaalblokker verminder mag word. Dosisaanpassings van diltiasem en 

ander kalsiumkanaalblokkers (soos verapamil, felodipien, nifedipien en nikardipien) wanneer saam met ODIMUNE toegedien, 

moet deur kliniese respons gelei word. 

Kannabinoïede toetsinteraksie: 

Efavirens bind nie aan kannabinoïede reseptore nie. Vals-positiewe uriene kannabinoïede toetsresultate is verkry in 

ongeïnfekteerde vrywilligers wie efavirens geneem het en is dus moontlik met ODIMUNE toediening. Vals-positiewe 

toetsresultate te wyte aan efavirens is slegs met die CEDIA DAU Multi-Level THC ontleding, wat vir sifting gebruik word, 

waargeneem en nie met ander getoetsde kannabinoïed ontledings nie – dit sluit toetse vir bevestiging van positiewe resultate in. 

Karbamasepien: 

Gesamentlike toediening van karbamasepien met efavirens het die AOK, C maks en C min van karbamasepien met onderskeidelik 27 

% (90 % VI -20 % tot -33 %), 20 % (-15 % tot -24 %), en 35 % (-24 % tot -44 %) laat afneem vanweë CYP3A4 induksie. 

Ooreenstemmende afnames in efavirens AOK, C maks en C min (vanweë CYP3A4 en CYP2B6 induksie) was onderskeidelik 36 % 

(-32 % tot -40 %), 21 % (-15 % tot -26 %), en 47 % (-41 % tot -53 %). Geen dosisaanbeveling kan vir die gebruik van ODIMUNE 

saam met karbamasepien gemaak word nie. ’n Alternatiewe antikonvulsant moet oorweeg word. Karbamasepien vlakke moet 

periodiek gemonitor word. 

Klaritromisien: 

Gesamentlike toediening van 400 mg efavirens een maal daagliks met klaritromisien toegedien as 500 mg elke 12 uur vir sewe 

dae het getoon dat efavirens die farmakokinetika van klaritromisien betekenisvol verander. Die AOK en C maks van klaritromisien het 

met onderskeidelik 39 % en 26 % verminder, terwyl die AOK en C maks van die aktiewe klaritromisien hidroksimetaboliet met 

onderskeidelik 34 % en 49 % vermeerder het tydens gesamentlike toediening met efavirens. Die kliniese belang van hierdie 

veranderinge in klaritromisien plasmavlakke is nie bekend nie. Ses-en-veertig (46) persent van ongeïnfekteerde vrywilligers wie 

efavirens en klaritromisien geneem het, het ’n uitslag ontwikkel. Geen dosisaanpassing word vir efavirens aanbeveel wanneer dit 

saam met klaritromisien gegee word nie; alternatiewe vir klaritromisien moet egter oorweeg word. 

Ander antibiotika wat aan die makrolied klas behoort, soos eritromisien, is nie in kombinasie met ODIMUNE bestudeer nie. 

Didanosien: 

Gepaardgaande toediening van ‘n eenmalige dosis van enteriesbedekte didanosien 400 mg met tenofovir 300 mg het nie enige 

veranderinge in die C maks , C min of AOK van tenofovir veroorsaak nie. Dieselfde is waar vir die kombinasie van gebufferde 

didanosien 250 of 400 mg een maal daagliks vir 7 dae met tenofovir 300 mg een maal per dag. 

Wanneer toegedien saam met veelvuldige dosisse van tenofovir, het die C maks en AOK van didanosien 400 mg betekenisvol 

toegeneem. Die meganisme vir hierdie interaksie is nog nie geïdentifiseer nie. Gesamentlike toediening van didanosien 250 mg 

enteriesbedekte kapsules met tenofovir het sistemiese blootstelling soortgelyk aan dié verkry met die 400 mg enteriesbedekte 

kapsules alleen onder vastende toestande tot gevolg gehad. 

Vir ‘n volledige opsomming van die veranderinge in farmakokinetiese parameters van didanosien, sien asseblief die onderstaande 

tabel. 

Tabel 1: Middelinteraksies: Farmakokinetiese parameters van didanosien in die teenwoordigheid van tenofovir soos bevat in 

ODIMUNE. 

Didanosien dosis (mg) / Tenofovir wyse van % Verskil (90 % VI) vs. didanosien 400 mg alleen, 

Wyse van toediening 1 toediening 1 N vastend 2 

C maks AOK 

Gebufferde tablette 

400 een maal per dag 3 Vastend 1 uur voor 14 ↑28 ↑44 

X 7 dae didanosien (↑11 - ↑48) (↑31 - ↑59) 

Enteriesbedekte kapsules 

400 eenmalig, Met voedsel, 2 uur na 26 ↑48 ↑48 

vastend didanosien (↑25 - ↑76) (↑31 - ↑67) 

400 eenmalig, met Gelyktydig met 26 ↑64 ↑60 

voedsel didanosien (↑41 - ↑89) (↑44 - ↑79) 

250 eenmalig, Met voedsel, 2 uur na 28 ↓10 

vastend didanosien (↓22 - ↑3) ↔ 

250 eenmalig, Gelyktydig met 28 ↔ ↑14 

vastend didanosien (0 - ↑31) 

250 eenmalig, met Gelyktydig met 28 ↓29 ↓11 

voedsel didanosien (↓39 - ↓18) (↓23 - ↑2) 

1. Toediening met voedsel was met ‘n ligte maaltyd. 

2. ↑ = toename; ↓ = afname; ↔ = geen verskil. 

3. Sluit 4 individue in wat < 60 kg geweeg het wat ddI 250 mg ontvang het. 

Gesamentlike toediening van tenofovir disoproksielfumaraat en didanosien lei tot ’n 40 % tot 60 % toename in sistemiese 

blootstelling aan didanosien wat die risiko vir didanosien-verwante newe-effekte mag verhoog. Gevalle van pankreatitis en 

melksuurasidose, soms noodlottig, is gemeld. Gesamentlike toediening van tenofovir disoproksielfumaraat en didanosien teen ’n 

dosis van 400 mg daagliks is met ’n betekenisvolle afname in CD4 seltellings geassosieer, moontlik weens ’n intrasellulêre 

interaksie wat gefosforileerde (d.i. aktiewe) didanosien laat toeneem. ’n Verminderde dosis van 250 mg didanosien toegedien 

saam met tenofovir disoproksielfumaraat is met hoë insidensies van virologiese mislukking binne verskeie getoetsde kombinasies 

geassosieer. Gesamentlike toediening van ODIMUNE en didanosien word nie aanbeveel nie. 

Famsiklovir: 

Geen klinies betekenisvolle middelinteraksies is tussen emtrisitabien, een van die aktiewe komponente van ODIMUNE, en 

famsiklovir waargeneem nie. Gesamentlike toediening van ’n enkel dosis van famsiklovir 500 mg met ’n enkel dosis van 

emtrisitabien 200 mg het nie die C maks of AOK van emtrisitabien of famsiklovir verander nie. 

HMG Ko-A reduktase-inhibeerders: 

Gesamentlike toediening van efavirens met HMG Ko-A reduktase-inhibeerders, soos atorvastatien en pravastatien, lei tot dalings 

in die AOK en C maks van die HMG Ko-A reduktase-inhibeerders en hulle aktiewe metaboliete. Cholesterolvlakke moet periodiek 

gemonitor word wanneer atorvastatien, pravastatien of simvastatien saam met ODIMUNE gegee word. Aanpassings in die dosis 

van die statien mag nodig wees. 

Immuunonderdrukkers: 

Gesamentlike toediening van takrolimus met emtrisitabien of tenofovir disoproksielfumaraat het nie enige veranderinge in die 

AOK, C maks of C min van takrolimus, emtrisitabien of tenofovir disoproksielfumaraat tot gevolg gehad nie. Alhoewel die interaksie 

tussen efavirens en takrolimus nie bestudeer is nie, kan verminderde blootstelling aan takrolimus verwag word vanweë induksie 

van CYP3A4. Dit word nie verwag dat takrolimus blootstelling aan efavirens sal beïnvloed nie. Takrolimus dosisaanpassings mag 

nodig wees. Sorgvuldige monitering van takrolimus konsentrasies word vir ten minste twee weke (totdat stabiele konsentrasies 

bereik word) aanbeveel wanneer behandeling met ODIMUNE begin of gestaak word. 

Indinavir: 

Geen klinies betekenisvolle middelinteraksies is tussen die emtrisitabien in ODIMUNE en indinavir waargeneem nie. 

Gesamentlike toediening van ‘n enkel dosis van indinavir 800 mg met ’n enkel dosis van emtrisitabien 200 mg het nie die C maks of 

AOK van emtrisitabien of indinavir verander nie. 

Soortgelyk is daar geen klinies betekenisvolle middelinteraksies tussen tenofovir disoproksielfumaraat, een van die aktiewe 

komponente van ODIMUNE, en indinavir waargeneem nie. Daar was ’n 14 % toename (90 % VI -3 % tot +33 %) in die C maks van 

tenofovir toe indinavir 800 mg drie keer per dag vir 7 dae saam met tenofovir 300 mg een maal per dag toegedien is. Die C min en AOK 

van tenofovir het onveranderd gebly en so ook die C min en AOK van indinavir. Indinavir C maks het met 11 % (-30 % tot +12 %) afgeneem. 

Wanneer indinavir (800 mg elke 8 uur) saam met efavirens (200 mg elke 24 uur) toegedien is, het indinavir se AOK en C trog met 

onderskeidelik ongeveer 31 % en 16 % vanweë ensieminduksie afgeneem. 

Daar is nie voldoende data om ’n doseringsaanbeveling vir indinavir te maak wanneer dit saam met ODIMUNE gedoseer word 

nie. Alhoewel die kliniese belang van verlaagde indinavir konsentrasies nie vasgestel is nie, moet die omvang van die 

waargeneemde farmakokinetiese interaksie in ag geneem word wanneer ’n behandelingsregimen gekies word wat beide 

efavirens, ’n komponent van ODIMUNE, en indinavir bevat. 

Itrakonasool: 

Gesamentlike toediening van itrakonasool en efavirens het tot verlaagde itrakonasool AOK, C maks en C min gelei vanweë CYP3A4 

induksie. Geen dosisaanbevelings kan vir die gebruik van ODIMUNE in kombinasie met itrakonasool gemaak word nie. ’n 

Alternatiewe antiswammiddel moet oorweeg word. 

Interaksiestudies met ODIMUNE en ketokonasool is nie gedoen nie. Efavirens het die potensiaal om plasmakonsentrasies van 

ketokonasool te verminder. 

Lamivudien: 

Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in ODIMUNE en lamivudien 

waargeneem nie. Gepaardgaande toediening van lamivudien 150 mg twee maal per dag vir 7 dae met tenofovir 300 mg een maal 

per dag het nie enige veranderinge in die C maks , C min of AOK van tenofovir tot gevolg gehad nie. Terwyl die C min en AOK van 

lamivudien onveranderd gebly het, het die C maks met 24 % (90 % VI -34 % tot -12 %) afgeneem. 

Vanweë ooreenkomste met emtrisitabien, moet ODIMUNE egter nie saam met ander sitidien analoë, soos lamivudien, toegedien 

word nie. 

Lopinavir/Ritonavir: 

Geen klinies betekenisvolle middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van 

ODIMUNE, en lopinavir/ritonavir waargeneem nie. Gesamentlike toediening van ‘n kombinasie van lopinavir 400 mg en ritonavir 

100 mg twee maal per dag vir 14 dae met tenofovir 300 mg een maal per dag het gelei tot ‘n toename van 32 % (90 % VI +26 % 

tot + 38%) in tenofovir AOK en van 29 % (+23 % tot +66 %) in tenofovir C min , terwyl tenofovir C maks onveranderd gebly het. Daar 

was geen veranderinge in die C maks , C min of AOK van lopinavir en ritonavir nie. Hoër tenofovir konsentrasies kan 

tenofovir-geassosieerde newe-effekte, veral renale afwykings, vererger. 

Toe efavirens 600 mg (toegedien een maal daagliks met slapenstyd) en ritonavir 500 mg (toegedien elke 12 uur) in 

ongeïnfekteerde vrywilligers bestudeer is, het hulle die kombinasie nie goed verdra nie. Hierdie kombinasie was met ’n hoër 

frekwensie van nadelige kliniese gevolge (byvoorbeeld duiseligheid, naarheid, parestesie en verhoogde lewerensieme) 

geassosieer. Lewerensieme moet gemonitor word wanneer efavirens in kombinasie met ritonavir gebruik word. 

Gepaardgaande toediening van lopinavir/ritonavir met efavirens het ’n beduidende afname in lopinavir blootstelling tot gevolg wat 

‘n dosisaanpassing van lopinavir/ritonavir noodsaak. 

Onvoldoende data is beskikbaar om ’n doseringsaanbeveling vir lopinavir/ritonavir in kombinasie met ODIMUNE te maak. 

Gesamentlike toediening van lopinavir/ritonavir met ODIMUNE word nie aanbeveel nie. 

Metadoon: 

Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in ODIMUNE en metadoon 

geïdentifiseer nie. Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan 

MIV-negatiewe individue wie chroniese metadoon instandhoudingsterapie ontvang het as aan dié vantevore waargeneem. Dit dui 

op ’n gebrek aan klinies betekenisvolle middelinteraksies tussen metadoon en die tenofovir in ODIMUNE. 

Spesifiek, wanneer metadoon 40 – 110 mg een maal per dag vir 14 dae saam met tenofovir 300 mg een maal per dag toegedien 

is, was R-(aktiewe), S- en totale metadoon blootstelling dieselfde hetsy alleen of saam met tenofovir toegedien. Individuele 

pasiënte was instandgehou op hulle stabiele metadoon dosis. Daar was geen melding van farmakodinamiese veranderinge, soos 

opiaattoksisiteit of onttrekkingstekens of –simptome, nie. 

Daarteenoor het gesamentlike toediening van efavirens en metadoon in MIV-geïnfekteerde IV dwelmgebruikers tot verlaagde 

plasmakonsentrasies van metadoon en tekens van opiaatonttrekking gelei. Onttrekkingsimptome is verlig deur die metadoon 

dosis met ‘n gemiddelde van 22 % te verhoog. Pasiënte moet vir onttrekkingstekens gemonitor word en hulle metadoon dosis 

moet verhoog word soos benodig om onttrekkingsimptome te verlig. 

Orale voorbehoedmiddels: 

Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in ODIMUNE en orale 

voorbehoedmiddels waargeneem nie. 

Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan MIV-negatiewe individue wie 

orale voorbehoedmiddels ontvang het as aan dié vantevore waargeneem. Dit dui op ’n gebrek aan klinies betekenisvolle 

middelinteraksies tussen hierdie middels en die tenofovir in ODIMUNE. 

In terme van moontlike interaksies met efavirens, is slegs die etinielestradiol komponent van orale voorbehoedmiddels bestudeer. 

Na veelvuldige dosering met efavirens, was die AOK van etinielestradiol na ’n enkele dosis verhoog (37 %). Die C maks van 

etinielestradiol was nie betekenisvol anders nie. Die kliniese belang van hierdie veranderinge is nie duidelik nie. ‘n Enkele dosis 

etinielestradiol blyk om geen effek op efavirens C maks of AOK te hê nie. Aangesien die potensiële interaksie tussen ODIMUNE en 

orale voorbehoedmiddels nog nie volledig gekarakteriseer is nie, moet pasiënte van ‘n betroubare skansmetode van 

geboortebeperking addisioneel tot orale voorbehoedmiddels gebruik maak. 

Fenitoïen, fenobarbitaal en ander antikonvulsante: 

Efavirens mag potensieel die plasmavlakke van fenitoïen, fenobarbitaal en ander antikonvulsante wat substrate van CYP450 

iso-ensieme is, verminder of vermeerder. Wanneer ODIMUNE gesamentlik met ’n antikonvulsant wat ‘n substraat van CYP450 

iso-ensieme is toegedien word, moet die konsentrasies van die antikonvulsant periodiek gemonitor word. 

ODIMUNE en vigabatrien of gabapentien kan gesamentlik sonder dosisaanpassings gegee word. Klinies betekenisvolle 

interaksies word nie verwag nie, aangesien vigabatrien en gabapentien eksklusief onveranderd in die uriene uitgeskei word en 

derhalwe waarskynlik nie met efavirens vir dieselfde metaboliese ensieme en eliminasie roetes sal kompeteer nie. 

Ribavirien: 

Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in ODIMUNE en ribavirien aangetoon 

nie. Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan MIV-negatiewe individue 

wie enkele dosisse van ribavirien ontvang het as aan dié vantevore waargeneem. Dit dui op ’n gebrek aan klinies betekenisvolle 

middelinteraksies tussen ribavirien en die tenofovir in ODIMUNE. 

Rifamisiene: 

Met gepaardgaande toediening aan ongeïnfekteerde vrywilligers verminder rifampisien efavirens AOK met 26 % en C maks met 20 %. 

Die efavirens dosis moet tot 800 mg/dag vermeerder word wanneer dit in kombinasie met rifampisien gebruik word. Derhalwe word 

‘n bykomende 200 mg efavirens per dag benodig wanneer rifampisien saam met ODIMUNE gedoseer word. Geen dosisaanpassing 

van rifampisien word aanbeveel wanneer dit saam met ODIMUNE gegee word nie. 

Gesamentlike toediening van enkel dosisse van rifabutien 300 mg en efavirens 600 mg lei tot afnames van 38 % (90 % VI -28 % 

tot -36 %) in AOK, 32 % (-15 % tot -46 %) in C maks en 45 % (-31 % tot -56 %) in C min van rifabutien. Die AOK en C maks van efavirens 

het onveranderd gebly; daarteenoor het die C min met 12 % (-24 % tot -1 %) verminder. Die daaglikse dosis van rifabutien moet met 

50 % vermeerder word wanneer dit saam met ODIMUNE gegee word. Skenk oorweging aan verdubbeling van die rifabutien dosis 

in regimens waar rifabutien 2 tot 3 keer per week in kombinasie met ODIMUNE gebruik word. 

Ritonavir: 

Efavirens word nie goed verdra wanneer dit saam met ritonavir 500 mg of 600 mg twee keer per dag gegee word nie (bv. 

duiseligheid, naarheid, parestesie en stygings in lewerensieme mag voorkom). Efavirens se AOK, C maks en C min het onderskeidelik 

met 21 % (+10 % tot +34 %), 14 % (+4 % tot +26 %) en 25 % (+7 % tot +46 %) toegeneem. Data rakende die toleransie vir 

efavirens saam met lae-dosis ritonavir (100 mg een of twee keer daagliks) is nie voldoende nie. Gepaardgaande toediening van 

ritonavir teen dosisse van 600 mg saam met ODIMUNE word nie aanbeveel nie. Wanneer ODIMUNE gebruik word in ‘n regimen 

wat lae-dosis ritonavir insluit, moet die moontlikheid dat die insidensie van efavirens-geassosieerde newe-effekte mag toeneem 

vanweë ‘n moontlike farmakodinamiese interaksie in gedagte gehou word. 

Sakwinavir: 

Wanneer sakwinavir (1200 mg toegedien 3 maal per dag, sagte gel kapsule formule) saam met efavirens toegedien is, was die 

sakwinavir AOK en C maks met onderskeidelik 62 % en 50 % verminder, terwyl efavirens se AOK, C maks en C min met onderskeidelik 

12 %, 13 % en 14 % verminder was. Toediening van ODIMUNE saam met sakwinavir as die enigste protease inhibeerder word 

nie aanbeveel nie. 

Data rakende die potensiële interaksies tussen efavirens en die kombinasie van sakwinavir en ritonavir is nie beskikbaar nie. 

Vanweë gebrekkige data is dit nie moontlik om ‘n dosisaanbeveling vir sakwinavir/ritonavir te maak wanneer dit saam met 

ODIMUNE gedoseer word nie. Gesamentlike gebruik van sakwinavir/ritonavir en ODIMUNE word derhalwe nie aanbeveel nie. 

Selektiewe serotonien heropname-inhibeerders (SSRIs): 

Wanneer sertralien in kombinasie met ODIMUNE voorgeskryf word, moet dosisverhogings van sertralien deur kliniese respons 

gelei word, aangesien gepaardgaande toediening van sertralien 50 mg met efavirens 600 mg tot gemiddelde afnames in sertralien 

se AOK, C maks en C min van onderskeidelik 39 %, 29 % en 46 % gelei het. 

Gepaardgaande toediening van ODIMUNE en paroksetien benodig nie dosisaanpassings nie. Gesamentlike toediening van 

efavirens en paroksetien het nie tot enige veranderinge in die AOK, C maks of C min van óf paroksetien óf efavirens gelei nie. 

Omdat fluoksetien ‘n soortgelyke metaboliese profiel as paroksetien het, dit is sterk CYP2D6 inhibitoriese effek, is 

dosisaanpassings nie nodig wanneer fluoksetien en ODIMUNE gesamentlik gegee word nie. Vanweë die soortgelyke metaboliese 

profiel word ‘n soortgelyke gebrek aan interaksie met fluoksetien verwag. 

Stavudien: 

Geen klinies betekenisvolle middelinteraksies is tussen die emtrisitabien in ODIMUNE en stavudien waargeneem nie. 

Gepaardgaande toediening van ‘n enkele dosis van stavudien 40 mg met ‘n enkele dosis van emtrisitabien 200 mg het nie die 

C maks of AOK van emtrisitabien of stavudien verander nie. 

St. John's wort (Hypericum perforatum): 

Pasiënte wie ODIMUNE neem, moenie daarmee saam produkte gebruik wat St. John's wort (Hypericum perforatum) bevat nie, 

aangesien dit na verwagting plasmavlakke van efavirens sal verminder. Dit geskied as gevolg van induksie van CYP3A4 en mag 

tot verlies van terapeutiese effek en die ontwikkeling van weerstandigheid lei. 

Vorikonasool: 

Gesamentlike toediening van standaard dosisse van efavirens en vorikonasool is teenaangedui vanweë betekenisvolle toenames 

in die AOK en C maks van efavirens en betekenisvolle dalings in die AOK en C maks van vorikonasool. Aangesien ODIMUNE ’n vaste 

dosis kombinasie produk is, kan die dosis van efavirens nie verander word nie; gevolglik moet vorikonasool en ODIMUNE nie 

gesamentlik gegee word nie (sien "KONTRA-INDIKASIES" en "WAARSKUWINGS"). 

SWANGERSKAP EN LAKTASIE: 

Die gebruik van ODIMUNE gedurende swangerskap word nie aanbeveel nie aangesien veiligheid en effektiwiteit nog nie 

vasgestel is nie (sien "KONTRA-INDIKASIES"). 

Skansmetodes van voorbehoeding moet altyd in kombinasie met ander geboortebeperkingsmaatreëls (bv. orale of ander 

hormonale voorbehoeding) gebruik word. 

Vrouens in hulle reproduktiewe jare moet swangerskapstoetse ondergaan voor behandeling met ODIMUNE begin word (sien 

"KONTRA-INDIKASIES"). 

Borsvoedende moeders: MIV-geïnfekteerde moeders moenie hulle babas borsvoed nie. Dit is nie bekend of efavirens, 

emtrisitabien of tenofovir in menslike melk uitgeskei word nie. Vanweë die moontlike oordraging van MIV en die potensiaal vir 

ernstige ongewenste reaksies in suigelinge, moet moeders instruksies ontvang om nie te borsvoed as hulle ODIMUNE 

gebruik nie. 

DOSIS EN GEBRUIKSAANWYSINGS: 

Behandeling moet deur ‘n geneesheer met ondervinding in die behandeling van MIV infeksie geïnisieer word. 

Volwassenes: 

Die aanbevole dosis van ODIMUNE is een tablet oraal toegedien een maal per dag. 

Dit word aanbeveel dat ODIMUNE heel met water gesluk word. 

ODIMUNE moet op ’n leë maag geneem word, aangesien voedsel blootstelling aan efavirens mag vermeerder en dit ‘n toename 

in die frekwensie van newe-effekte tot gevolg mag hê. Om die toleransie vir efavirens in terme van senusisteem newe-effekte te 

verbeter, word dit aanbeveel dat ODIMUNE met slapenstyd geneem word. 

Kinders en adolessente: 

ODIMUNE word nie aanbeveel vir gebruik in kinders onder 18 jaar nie vanweë gebrek aan data rakende veiligheid en effektiwiteit 

(sien "KONTRA-INDIKASIES"). 

Bejaardes: 

Die aantal bejaarde pasiënte wie in kliniese proewe met die komponente van ODIMUNE bestudeer is, was nie voldoende om te 

kon bepaal of hulle anders reageer as jonger pasiënte nie. Omsigtigheid is nodig wanneer ODIMUNE aan bejaardes voorgeskryf 

word en dit moet in gedagte gehou word dat bejaarde pasiënte ‘n hoër frekwensie van inkorting van lewer- en nierfunksie het. 

Nierinkorting: 

ODIMUNE word nie aanbeveel vir pasiënte met matige tot erge inkorting van nierfunksie nie (kreatinienopruiming < 50 ml/min). 

Pasiënte met matige tot erge nierinkorting benodig dosisinterval aanpassings van emtrisitabien en tenofovir wat nie met 

ODIMUNE verkry kan word nie (sien "KONTRA-INDIKASIES" en "WAARSKUWINGS"). 

Lewerinkorting: 

Die farmakokinetiese eienskappe van ODIMUNE is nie in pasiënte met lewerinkorting bestudeer nie. Pasiënte met geringe tot 

matige lewersiekte (Child-Pugh-Turcotte Graad A of B) mag die gewone aanbevole dosis van ODIMUNE ontvang. Pasiënte 

benodig sorgvuldige monitering vir ongewenste reaksies as gevolg van efavirens, veral van die senusisteem. 

Wanneer behandeling met ODIMUNE in pasiënte met MIV en HBV gesamentlike infeksie gestaak word, moet hierdie pasiënte 

sorgvuldig gemonitor word vir bewyse van opflikkering van hepatitis. 

Dit is belangrik om ODIMUNE volgens ‘n gereelde doseringskedule te neem om te voorkom dat dosisse oorgeslaan word. 

Pasiënte moet ingelig word dat, indien hulle vergeet om ODIMUNE te neem, moet hulle die oorgeslane dosis onmiddellik neem, 

tensy dit minder as 12 ure tot die volgende dag se dosis is. In so geval moet pasiënte ingelig word om die oorgeslane dosis weg 

te laat en om hulle volgende dosis op die gewone tyd te neem. 

Waar staking van behandeling met een van die komponente van ODIMUNE aangedui is of waar dosisaanpassing benodig word, 

is afsonderlike preparate van efavirens, emtrisitabien en tenofovir beskikbaar. Verwys asseblief na die individuele voubiljette van 

hierdie middels. 

Wanneer behandeling met ODIMUNE gestaak word, is dit belangrik om die lang halflewe van efavirens en die lang intrasellulêre 

halfleeftye van tenofovir en emtrisitabien in gedagte te hou. As gevolg van interpasiënt variansie in hierdie parameters en kommer 

oor die ontstaan van weerstandigheid, moet MIV behandelingsriglyne geraadpleeg word terwyl die rede vir die staking van 

behandeling ook in ag geneem moet word. 

NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS: 

Newe-Effekte: 

EMTRISITABIEN: 

Hematologiese en limfatiese sisteem afwykings: 

Die volgende newe-effekte is gemeld en die frekwensies 

daarvan is onbekend: Neutropenie, anemie. 

Metaboliese en voedingsafwykings: 


daarvan is onbekend: Melksuurasidose, gewoonlik vergesel van erge hepatomegalie en steatose, is geassosieer met 

die gebruik van nukleosied omgekeerde transkriptase inhibeerders. 

Hiperglisemie en hipertrigliseridemie. 

Neuropsigiatriese sisteem afwykings: 

Dikwels: Hoofpyn, astenie. 

Minder dikwels: Depressiewe steuring, duiseligheid, slaapstoornisse (abnormale drome, slaaploosheid), neuritis, 

parestesie en perifere neuropatie. 

Respiratoriese sisteem afwykings: 

Dikwels: Vermeerderde hoes, rinitis. 

Gastro-intestinale sisteem afwykings: 

Dikwels: Naarheid, diarree. 

Minder dikwels: Abdominale pyn, dispepsie en braking. 

Hepatobiliêre sisteem afwykings: 


daarvan is onbekend: Verhoogde konsentrasies van lewerensieme en hiperbilirubinemie. 

Vel- en subkutane weefselafwykings: 

Minder dikwels: Uitslag (insluitende pruritus, makulopapulêre uitslag, urtikarieë, vesikobulleuse uitslag, pustulêre 

uitslag en allergiese reaksies) en verkleuring van die vel wat manifesteer as hiperpigmentasie op 

die palms en/of voetsole (gewoonlik gering). 

Muskuloskeletale sisteem afwykings: 

Minder dikwels: Artralgie, mialgie. 

Renale en urinêre sisteem afwykings: 

Dikwels: Verhoogde kreatienkinase. 

TENOFOVIR: 

Hematologiese en limfatiese sisteem afwykings: 


daarvan is onbekend: Neutropenie, hematurie. 

Immuunsisteem afwykings: 


daarvan is onbekend: Allergiese reaksies. 

Metabolisme en voedingsafwykings: 


daarvan is onbekend: Melksuurasidose, gewoonlik vergesel van erge hepatomegalie en steatose; ook 

hipertrigliseridemie, hiperglisemie en hipofosfatemie. 


Dikwels: Astenie. 

Minder dikwels: Eetlusverlies. 


daarvan is onbekend: Depressie, hoofpyn, duiseligheid, slaaploosheid, perifere neuropatie en angstigheid. 

Respiratoriese sisteem afwykings: 


daarvan is onbekend: Borskaspyn, pneumonie, dispnee. 


Dikwels: Naarheid, braking, diarree. 

Minder dikwels: Verhoogde serumkonsentrasies van amilase, abdominale pyn en winderigheid. 


daarvan is onbekend: Pankreatitis en dispepsie. 


Minder dikwels: Hepatotoksisiteit, insluitende melksuurasidose. 


daarvan is onbekend: Verhoogde vlakke van lewerensieme en hepatitis. 



daarvan is onbekend: Veluitslae (insluitende pruritus, makulopapulêre uitslag, urtikarieë, vesikobulleuse uitslag en 

pustulêre uitslag). 

Muskuloskeletale sisteem afwykings: 


daarvan is onbekend: Artralgie, rugpyn en mialgie. 

Renale en urinêre sisteem afwykings: 


daarvan is onbekend: Verhoogde vlakke van kreatienkinase, nefritis, nefrogene diabetes insipidus, nierinkorting, akute 

nierversaking en effekte op die renale proksimale tubules, insluitende Fanconi se sindroom en 

akute tubulêre nekrose. 

Algemene afwykings: 


daarvan is onbekend: Koors, sweet en gewigsverlies. 

EFAVIRENS: 

Metaboliese en voedingsafwykings: 


daarvan is onbekend: Gewigstoename en gewigsverlies. 


Dikwels: Duiseligheid, ingekorte konsentrasie, slaperigheid, slaaploosheid en hoofpyn. 

Minder dikwels: Abnormale drome, eetlusverlies en hipestesie. 


daarvan is onbekend: Abnormale koördinasie, ataksie, konvulsies, parestesieë, neuropatie, tremore, verergerende 

depressie, agitasie, geheueverlies, angs, apatie, verhoogde aptyt, verwardheid, emosionele 

labiliteit, euforie, hallusinasies, swak koördinasie, impotensie, verminderde libido, verhoogde 

libido, neuralgie, perifere neuropatie, spraakafwyking en vertigo. 

IY69 A 

Afwykings van die spesiale sintuie: 


daarvan is onbekend: Abnormale visie, tinnitus en smaakstoornisse. 

Kardiovaskulêre sisteem afwykings: 


daarvan is onbekend: Blosing, hartkloppings en tagikardie. 

Respiratories sisteem afwykings: 


daarvan is onbekend: Asma, sinusitis, dispnee en boonste respiratoriese infeksies. 


Dikwels: Naarheid, braking en diarree. 

Minder dikwels: Dispepsie en abdominale pyn. 


daarvan is onbekend: Gastritis, gastro-enteritis, gastro-esofageale refluks, hardlywigheid en wanabsorpsie. 



daarvan is onbekend: Hepatitis, stygings in lewerensieme en lewerversaking. 


Dikwels: Uitslag, pruritus en vermeerderde sweet. 


daarvan is onbekend: Aknee, haarverlies, ekseem, follikulitis, seborree, afskilfering van die vel, urtikarieë, eritema 

multiforme, naelafwykings, velverkleuring, Stevens-Johnson sindroom. 

Muskuloskeletale, been- en bindweefselafwykings: 


daarvan is onbekend: Artralgie, mialgie en miopatie. 

Algemene afwykings: 

Dikwels: Moegheid en pyn. 


daarvan is onbekend: Alkoholintoleransie, allergiese reaksies, astenie, warmgloede, simptome soos dié van griep, 

malaise, pyn, sinkopie en herverspreiding/akkumulasie van liggaamsvet. 

Laboratoriumafwykings: 

Stygings in lewerensiemwaardes het voorgekom, veral in pasiënte met virale hepatitis. Verhoogde serumcholesterol en 

-trigliseried konsentrasies is gemeld. 

Lewerensieme: Stygings in AST en ALT tot meer as vyf keer die boonste grens van normaal is waargeneem in pasiënte wie met 

600 mg efavirens behandel is. Stygings in GGT vlakke in pasiënte wie efavirens neem, mag ‘n weerspieëling van ensieminduksie 

nie geassosieer met lewertoksisiteit nie wees (sien "Spesiale Voorsorgmaatreëls"). 

Lipiede: Stygings in totale cholesterol van 10 tot 20 % was in sommige ongeïnfekteerde vrywilligers wie efavirens geneem het, 

gemerk. Stygings in nie-vastende totale cholesterol en HDL vlakke van onderskeidelik ongeveer 20 % en 25 % was gesien in 

pasiënte wie met efavirens + ZDV + 3TC behandel is en van onderskeidelik ongeveer 40 % en 35 % in pasiënte wie met efavirens 

+ IDV behandel is. Die invloed van efavirens op trigliseried en LDL konsentrasies is nie volledig duidelik nie. Dit is nie bekend of 

hierdie bevindings van kliniese belang is nie (sien "Spesiale Voorsorgmaatreëls"). 

Spesiale Voorsorgmaatreëls: 

Middelinteraksies: 

LET WEL: Vind uit oor middels wat NIE saam met ODIMUNE geneem moet word nie (sien "WAARSKUWINGS" en 

"INTERAKSIES). 

Aangesien die niere primêr vir die eliminasie van emtrisitabien en tenofovir verantwoordelik is, mag gesamentlike toediening van 

ODIMUNE met middels wat nierfunksie verminder of kompeteer vir aktiewe tubulêre sekresie lei tot stygings in 

serumkonsentrasies van emtrisitabien, tenofovir en/of die ander middels wat renaal uitgeskei word. Voorbeelde van sodanige 

middels sluit onder andere adefovir dipivoksiel, sidofovir, asiklovir, valasiklovir, gansiklovir en valgansiklovir in. 

ODIMUNE moenie saam met emtrisitabien, tenofovir of efavirens gegee word nie. Vanweë ooreenkomste tussen emtrisitabien 

en lamivudien, moet ODIMUNE nie saam met ander middels wat lamivudien bevat, gegee word nie. Dit sluit lamivudien en 

sidovudien koformulering, lamivudien vir MIV, lamivudien vir HBV, abakavirsulfaat en lamivudien koformulering of abakavirsulfaat, 

lamivudien en sidovudien koformulering in. 

Effekte op been: 

Tenofovir: 

In ‘n 144-week kliniese studie was afnames vanaf basislyn in beenmineraaldigtheid (BMD) in die lumbale werwels en heup in 

beide behandelingsbene van die studie waargeneem. Teen week 144 was daar ‘n betekenisvolle groter gemiddelde persentasie 

afname vanaf basislyn in BMD in die lumbale werwels van deelnemers wie tenofovir + lamivudien + efavirens geneem het in 

vergelyking met deelnemers wie stavudien + lamivudien + efavirens geneem het. BMD veranderinge in die heup was soortgelyk 

in die twee behandelingsgroepe. In beide groepe het die grootste gedeelte van die afname in BMD in die eerste 24 tot 48 weke 

van die studie plaasgevind en hierdie afname is regdeur die studie (144 weke) gehandhaaf. Agt-en-twintig persent van pasiënte 

wie tenofovir ontvang het teenoor 21 % van stavudien-behandelde pasiënte het ‘n minimum van 5 % van BMD in die werwels of 

7 % van BMD in die heup verloor. Frakture van kliniese belang (uitsluitende vingers en tone) is in 4 pasiënte wie tenofovir ontvang 

het en in 6 pasiënte wie stavudien geneem het, gemeld. Verder was daar betekenisvolle stygings in die vlakke van biochemiese 

merkers vir beenmetabolisme (serumbeenspesifieke alkaliese fosfatase, serumosteokalsien, serum C-telopeptied en urinêre 

N-telopeptied) in die tenofovir-groep vergeleke met die stavudien-groep wat verhoogde omset van been suggereer. 

Serumparatiroïedhormoon vlakke en 1,25 vitamien D vlakke was ook hoër in die groep van pasiënte wie tenofovir ontvang het. 

Met die uitsondering van beenspesifieke alkaliese fosfatase, het hierdie veranderinge waardes tot gevolg gehad wat binne die 

normale reikwydte gebly het. Hoe hierdie tenofovir-geassosieerde veranderinge in BMD en biochemiese merkers langtermyn 

beengesondheid en toekomstige fraktuur risiko gaan beïnvloed is nie bekend nie. MIV geïnfekteerde pasiënte met ‘n geskiedenis 

van patologiese beenfrakture of wie ‘n risiko vir osteopenie het, moet beenmonitering ondergaan. Alhoewel die invloed van 

kalsium- en vitamien D-aanvulling nie bestudeer is nie, mag sulke aanvullings alle pasiënte tot voordeel strek. Dit is noodsaaklik 

om toepaslike konsultasie in te win as beenabnormaliteite vermoed word. 

Herverspreiding van vet: 

Daar is melding gemaak van herverspreiding/akkumulasie van liggaamsvet insluitende sentrale obesiteit, dorsoservikale 

vetvergroting (buffelskof), perifere uittering, uittering van die gesig, borsvergroting en "cushingoïede voorkoms" in pasiënte wie 

met antiretrovirale middels, soos ODIMUNE, behandel is. Die meganisme en langtermyn gevolge van hierdie verskynsels is nie 

tans bekend nie. Dit is ook nie bekend of antiretrovirale terapie oorsaaklik hiermee verband hou nie. 

Immuunheraktivering sindroom: 

Daar is melding gemaak van immuunheraktivering sindroom in pasiënte wie kombinasie antiretrovirale terapie ontvang het. 

Gedurende die aanvanklike fase van behandeling met kombinasie antiretrovirale middels mag ‘n anti-inflammatoriese respons tot 

sluimerende of residuele opportunistiese infeksies [soos Mycobacterium avium infeksie, sitomegalovirus, Pneumocystis jirovecii 

pneumonie (PCP), of tuberkulose] ontwikkel in pasiënte wie se immuunstelsels reageer op behandeling. Sodanige reaksies mag 

verdere evaluasie en behandeling noodsaak. 

Pediatriese gebruik: 

Die veiligheid en effektiwiteit van ODIMUNE in kinders is nog nie vasgestel nie. 

Gebruik in bejaardes: 

Kliniese studies van vaste dosis kombinasies van emtrisitabien en tenofovir, soos in ODIMUNE, het nie ‘n voldoende aantal 

individue ouer as 65 jaar ingesluit om te kon vasstel of hulle anders reageer as jonger persone nie. Omsigtigheid word oor die 

algemeen aanbeveel wanneer dosisse vir bejaarde pasiënte gekies word, inaggenome die groter frekwensie van ingekorte lewer-, 

nier- en kardiale funksie asook gepaardgaande siektetoestande en medisinale behandeling. 

Veluitslag: 

Milde-tot-matige uitslag, wat gewoonlik met volgehoue behandeling opklaar, is met die gebruik van efavirens waargeneem. 

Behandeling met toepaslike antihistamiene en/of kortikosteroïede mag simptome verlig en help om die uitslag vinniger te laat 

opklaar. Behandeling met ODIMUNE moet gestaak word in pasiënte wie ‘n erge uitslag geassosieer met blase, afskilfering, 

slymvliesaantasting o

IY69 A Odimune Tabs Enclo.ai - Cipla

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