Sustiva

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ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 50 mg hard capsules 
SUSTIVA 100 mg hard capsules 
SUSTIVA 200 mg hard capsules 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

SUSTIVA 50 mg hard capsules 
Each hard capsule contains 50 mg of efavirenz. 

Excipient with known effect 
Each hard capsule contains 28.5 mg of lactose (as monohydrate). 

SUSTIVA 100 mg hard capsules 
Each hard capsule contains 100 mg of efavirenz. 

Excipient with known effect 
Each hard capsule contains 57.0 mg of lactose (as monohydrate). 

SUSTIVA 200 mg hard capsules 
Each hard capsule contains 200 mg of efavirenz. 

Excipient with known effect 
Each hard capsule contains 114.0 mg of lactose (as monohydrate). 

For the full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM 

Hard capsule 

SUSTIVA 50 mg hard capsules 
Dark yellow and white, printed with "SUSTIVA" on the dark yellow cap and "50 mg" on the white 
body.

SUSTIVA 100 mg hard capsules 
White, printed with "SUSTIVA" on the body and "100 mg" on the cap. 

SUSTIVA 200 mg hard capsules 
Dark yellow, printed with "SUSTIVA" on the body and "200 mg" on the cap. 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

SUSTIVA is indicated in antiviral combination treatment of human immunodeficiency virus-1 (HIV-
1) infected adults, adolescents and children 3 months of age and older and weighing at least 3.5 kg. 

SUSTIVA has not been adequately studied in patients with advanced HIV disease, namely in patients 
with CD4 counts < 50 cells/mm3, or after failure of protease inhibitor (PI) containing regimens. 
Although cross-resistance of efavirenz with PIs has not been documented, there are at present 
insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of 
regimens containing SUSTIVA. 



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For a summary of clinical and pharmacodynamic information, see section 5.1. 

4.2 Posology and method of administration 

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

Posology 

Efavirenz must be given in combination with other antiretroviral medicines (see section 4.5). 

In order to improve the tolerability of nervous system adverse reactions, bedtime dosing is 
recommended (see section 4.8). 

Adults 

The recommended dose of efavirenz in combination with nucleoside analogue reverse transcriptase 
inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily. 

Dose adjustment 

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose must be 
increased to 400 mg every 12 hours and the efavirenz dose must be reduced by 50%, i.e., to 300 mg 
once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be 
restored (see section 4.5). 

If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the 
dose of efavirenz to 800 mg/day may be considered (see section 4.5). 

Children and adolescents (3 months to 17 years) 

The recommended dose of efavirenz in combination with a PI and/or NRTIs for patients between 3 
months and 17 years of age is described in Table 1. Efavirenz intact hard capsules must only be 
administered to children who are able to reliably swallow hard capsules.  

Table 1: Paediatric dose to be administered once daily* 

Body Weight efavirenz Number of Capsules or 
Tablets and Strength to 

Administer 
kg Dose (mg) 

3.5 to < 5 100 one 100 mg capsule

5 to < 7.5 150 one 100 mg capsule + one 
50 mg capsule 

7.5 to < 15 200 one 200 mg capsule 
15 to < 20 250 one 200 mg capsule + one 

50 mg capsule
20 to < 25 300 three 100 mg capsules

25 to < 32.5 350 three 100 mg capsules + 
one 50 mg capsule

32.5 to < 40 400 two 200 mg capsules
≥ 40 600 one 600 mg tablet OR 

three 200 mg capsules

*For information on the bioavailability of the capsule contents mixed with food vehicles, see 
section 5.2. 



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Special populations 

Renal impairment 

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, 
less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal 
impairment on efavirenz elimination should be minimal (see section 4.4). 

Hepatic impairment 

Patients with mild liver disease may be treated with their normally recommended dose of efavirenz. 
Patients should be monitored carefully for dose-related adverse reactions, especially nervous system 
symptoms (see sections 4.3 and 4.4). 

Paediatric population 

The safety and efficacy of efavirenz in children below the age of 3 months or weighing less than 
3.5 kg have not been established. No data are available. 

Method of administration 

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz 
concentrations observed following administration of efavirenz with food may lead to an increase in 
frequency of adverse reactions (see sections 4.4. and 5.2). 

Patients who cannot swallow  

Capsule sprinkle: for patients at least 3 months old and weighing at least 3.5 kg who cannot swallow 
capsules, the capsule contents can be administered with a small amount of food using the capsule 
sprinkle method of administration (see section 6.6 for instructions). No additional food should be 
consumed for up to 2 hours after administration of efavirenz.. 

4.3 Contraindications 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

Patients with severe hepatic impairment (Child Pugh Class C) (see section 5.2). 

Co-administraion with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or 
ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) 
because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the 
potential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias, 
prolonged sedation or respiratory depression] (see section 4.5). 

Co-administration with elbasvir (EBR) and grazoprevir (GZR) due to the potential for significant 
decreases in plasma concentrations of EBR and GZR (see section 4.5). 

Herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of decreased 
plasma concentrations and reduced clinical effects of efavirenz (see section 4.5). 

Patients with: 

- a family history of sudden death or of congenital prolongation of the QTc interval on 

electrocardiograms, or with any other clinical condition known to prolong the QTc interval. 

- a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with 

congestive cardiac failure accompanied by reduced left ventricle ejection fraction. 

- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia. 



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Patients taking drugs that are known to prolong the QTc interval (proarrythmic).  

These drugs include: 

- antiarrhythmics of classes IA and III, 

- neuroleptics, antidepressive agents, 

- certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, 

imidazole and triazole antifungal agents, 

- certain non-sedating antihistamines (terfenadine, astemizole), 

- cisapride, 

- flecainide, 

- certain antimalarials,  

- methadone. 

4.4 Special warnings and precautions for use 

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing 
regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice 
of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration 
the potential for viral cross-resistance (see section 5.1). 

Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, 
and tenofovir disoproxil is not recommended unless needed for dose adjustment (for example, with 
rifampicin). 

Coadministration of sofosbuvir/velpatasvir with efavirenz is not recommended (see section 4.5). 
Concomitant administration of velpatasvir/sofosbuvir/ voxilaprevir with efavirenz is not recommended 
(see section 4.5). 
Coadministration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma 
concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Coadministration 
of glecaprevir/pibrentasvir with efavirenz is not recommended (see section 4.5). 

Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5). 

When prescribing medicinal products concomitantly with efavirenz, physicians should refer to the 
corresponding Summary of Product Characteristics. 

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines.  

If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected 
intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral 
medicinal products. The antiretroviral medicinal products should be restarted at the same time upon 
resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of 
antiretroviral agents is not advisable because of the increased potential for selection of resistant virus. 

Rash

Mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves with 
continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and 
hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration 
has been reported in less than 1% of patients treated with efavirenz. The incidence of erythema 
multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz must be discontinued in 



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patients developing severe rash associated with blistering, desquamation, mucosal involvement or 
fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting 
therapy with other antiretroviral agents to avoid development of resistant virus (see section 4.8). 

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class 
is limited (see section 4.8). Efavirenz is not recommended for patients who have had a life-threatening 
cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI. 

Psychiatric symptoms 

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a 
prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse 
reactions. In particular, severe depression was more common in those with a history of depression. 
There have also been post-marketing reports of severe depression, death by suicide, delusions, 
psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptoms 
such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately 
to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to 
determine whether the risks of continued therapy outweigh the benefits (see section 4.8). 

Nervous system symptoms 

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and 
abnormal dreaming are frequently reported adverse reactions in patients receiving efavirenz 600 mg 
daily in clinical studies (see section 4.8). Nervous system symptoms usually begin during the first one 
or two days of therapy and generally resolve after the first 2 - 4 weeks. Patients should be informed 
that if they do occur, these common symptoms are likely to improve with continued therapy and are 
not predictive of subsequent onset of any of the less frequent psychiatric symptoms. 

Seizures 

Convulsions have been observed in adult and paediatric patients receiving efavirenz, generally in the 
presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant 
medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and 
phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, 
carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with 
efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures. 

Hepatic events 

A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic 
disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be 
considered for patients without pre-existing hepatic dysfunction or other risk factors. 

QTc Prolongation 

QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1).  

Consider alternatives to efavirenz for coadministration with a drug with a known risk of Torsade de 
Pointes or when to be administered to patients at higher risk of Torsade de Pointes.  

Effect of food 

The administration of efavirenz with food may increase efavirenz exposure (see section 5.2) and may 
lead to an increase in the frequency of adverse reactions (see section 4.8). It is recommended that 
efavirenz be taken on an empty stomach, preferably at bedtime. 

Immune Reactivation Syndrome 



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

Weight and metabolic parameters 

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

Osteonecrosis 

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement. 

Special populations 

Liver disease 

Efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2) and 
not recommended in patients with moderate hepatic impairment because of insufficient data to 
determine whether dose adjustment is necessary. Because of the extensive cytochrome P450-mediated 
metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution 
must be exercised in administering efavirenz to patients with mild hepatic impairment. Patients should 
be monitored carefully for dose-related adverse reactions, especially nervous system symptoms. 
Laboratory tests should be performed to evaluate their liver disease at periodic intervals (see 
section 4.2). 

The safety and efficacy of efavirenz has not been established in patients with significant underlying 
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral 
therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. Patients with 
pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver 
function abnormalities during combination antiretroviral therapy and should be monitored according to 
standard practice. If there is evidence of worsening liver disease or persistent elevations of serum 
transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued 
therapy with efavirenz needs to be weighed against the potential risks of significant liver toxicity. In 
such patients, interruption or discontinuation of treatment must be considered (see section 4.8). 

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver 
enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please 
refer also to the relevant product information for these medicinal products. 

Renal insufficiency 



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The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, 
less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal 
impairment on efavirenz elimination should be minimal (see section 4.2). There is no experience in 
patients with severe renal failure and close safety monitoring is recommended in this population. 

Elderly patients 

Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether 
they respond differently than younger patients. 

Paediatric population

Efavirenz has not been evaluated in children below 3 months of age or who weigh less than 3.5 kg. 
Therefore, efavirenz should not be given to children less than 3 months of age. 

Rash was reported in 59 of 182 children (32%) treated with efavirenz  and was severe in six patients. 
Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may 
be considered. 

Lactose 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.  

4.5 Interaction with other medicinal products and other forms of interaction 

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of 
these enzymes may have decreased plasma concentrations when co-administered with efavirenz. In 
vitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initially 
increase the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates with 
narrow therapeutic index (see section 4.3). Efavirenz may be an inducer of CYP2C19 and CYP2C9; 
however, inhibition has also been observed in vitro and the net effect of co-administration with 
substrates of these enzymes is not clear (see section 5.2). 

Efavirenz exposure may be increased when given with medicinal products (for example, ritonavir) or 
food (for example, grapefruit juice), which inhibit CYP3A4 or CYP2B6 activity. Compounds or 
herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these 
enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John’s 
wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not 
recommended (see section 4.4). 

QT Prolonging Drugs 

Efavirenz is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval 
and Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant 
agents, certain antibiotics including some agents of the following classes: macrolides,  
fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics 
(terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3). 

Paediatric population

Interaction studies have only been performed in adults. 

Contraindications of concomitant use 

Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, 
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, 



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ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-
threatening events (see section 4.3). 

Elbasvir/grazoprevir 

Concomitant administration of efavirenz with elbasvir/grazoprevir is contraindicated because it may 
lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in 
elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. (see section 4.3). 

St. John’s wort (Hypericum perforatum) 

Co-administration of efavirenz and St. John’s wort or herbal preparations containing St. John’s wort is 
contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John’s wort due 
to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort. If a patient is 
already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible efavirenz levels. 
Efavirenz levels may increase on stopping St. John’s wort and the dose of efavirenz may need 
adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of 
treatment. (see section 4.3). 

Other interactions 

Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease 
inhibitors and other non-antiretroviral medicinal products are listed in Table 2 below (increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or 
“q12h”). If available, 90% or 95% confidence intervals are shown in parentheses. Studies were 
conducted in healthy subjects unless otherwise noted.  

Table 2: Interactions between efavirenz and other medicinal products in adults 

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

ANTI-INFECTIVES
HIV antivirals 
Protease inhibitors (PI) 
Atazanavir/ ritonavir/Efavirenz 
(400 mg once daily/100 mg once 
daily/600 mg once daily, all 
administered with food) 

Atazanavir (pm): 
AUC: ↔* (↓9 to ↑10) 
Cmax: ↑17%* (↑8 to ↑27)
Cmin: ↓42%* (↓31 to ↓51)

Co-administration of efavirenz 
with atazanavir/ritonavir is not 
recommended. If the co-
administration of atazanavir 
with an NNRTI is required, an 
increase in the dose of both 
atazanavir and ritonavir to 
400 mg and 200 mg, 
respectively, in combination 
with efavirenz could be 
considered with close clinical 
monitoring.

Atazanavir/ritonavir/Efavirenz 
(400 mg once daily/200 mg once 
daily/600 mg once daily, all 
administered with food) 

Atazanavir (pm): 
AUC: ↔*/** (↓10 to ↑26) 
Cmax: ↔*/** (↓5 to ↑26) 
Cmin: ↑ 12%*/** (↓16 to ↑49) 
(CYP3A4 induction). 
* When compared to atazanavir 
300 mg/ritonavir 100 mg once daily in 
the evening without efavirenz. This 
decrease in atazanavir Cmin might 
negatively impact the efficacy of 
atazanavir. 
** based on historical comparison 



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Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Darunavir/ritonavir/Efavirenz 
(300 mg twice daily*/100 mg 
twice daily/600 mg once daily) 

*lower than recommended doses; 
similar findings are expected with 
recommended doses. 

Darunavir: 
AUC: ↓ 13% 
Cmin: ↓ 31% 
Cmax: ↓ 15% 
(CYP3A4 induction) 
Efavirenz: 
AUC: ↑ 21% 
Cmin: ↑ 17% 
Cmax: ↑ 15% 
(CYP3A4 inhibition) 

Efavirenz in combination with 
darunavir/ritonavir 800/100 mg 
once daily may result in 
suboptimal darunavir Cmin. If 
efavirenz is to be used in 
combination with 
darunavir/ritonavir, the 
darunavir/ritonavir 600/100 mg 
twice daily regimen should be 
used. This combination should 
be used with caution.See also 
ritonavir row below.

Fosamprenavir/ritonavir/Efavirenz 
(700 mg twice daily/100 mg twice 
daily/600 mg once daily) 

No clinically significant 
pharmacokinetic interaction 

No dose adjustment is necessary 
for any of these medicinal 
products. See also ritonavir row 
below.

Fosamprenavir/Nelfinavir/ 
Efavirenz 

Interaction not studied. No dose adjustment is necessary 
for any of these medicinal 
products.

Fosamprenavir/Saquinavir/ 
Efavirenz 

Interaction not studied. Not recommended as the 
exposure to both PIs is expected 
to be significantly decreased.

Indinavir/Efavirenz 
(800 mg q8h/200 mg once daily) 

Indinavir: 
AUC : ↓ 31% (↓ 8 to ↓ 47) 
Cmin : ↓ 40%
A similar reduction in indinavir 
exposures was observed when indinavir 
1000 mg q8h was given with efavirenz 
600 mg daily. 
(CYP3A4 induction) 
Efavirenz: 
No clinically significant 
pharmacokinetic interaction 

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 and indinavir. 

No dose adjustment is necessary 
for efavirenz when given with 
indinavir or indinavir/ritonavir. 

See also ritonavir row below. 

Indinavir/ritonavir/Efavirenz 
(800 mg twice daily/100 mg twice 
daily/600 mg once daily) 

Indinavir: 
AUC: ↓ 25% (↓ 16 to ↓ 32)b

Cmax: ↓ 17% (↓ 6 to ↓ 26)b

Cmin: ↓ 50% (↓ 40 to ↓ 59)
b

Efavirenz: 
No clinically significant 
pharmacokinetic interaction 
The geometric mean Cmin for indinavir 
(0.33 mg/l) when given with ritonavir 
and efavirenz was higher than the mean 
historical Cmin (0.15 mg/l) when 
indinavir was given alone at 800 mg 
q8h. In HIV-1 infected patients (n = 6), 
the pharmacokinetics of indinavir and 
efavirenz were generally comparable to 
these uninfected volunteer data.



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Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Lopinavir/ritonavir soft capsules or 
oral solution/Efavirenz 

Lopinavir/ritonavir tablets/ 
Efavirenz 
(400/100 mg twice daily/600 mg 
once daily) 
(500/125 mg twice daily/600 mg 
once daily) 

Substantial decrease in lopinavir 
exposure.  

Lopinavir concentrations: ↓ 30-40% 

Lopinavir concentrations: similar to 
lopinavir/ritonavir 400/100 mg twice 
daily without efavirenz 

With efavirenz, an increase of 
the lopinavir/ritonavir soft 
capsule or oral solution doses 
by 33% should be considered 
(4 capsules/~6.5 ml twice daily 
instead of 3 capsules/5 ml twice 
daily). Caution is warranted 
since this dose adjustment 
might be insufficient in some 
patients. The dose of 
lopinavir/ritonavir tablets 
should be increased to 
500/125 mg twice daily when 
co-administered with efavirenz 
600 mg once daily. 
See also ritonavir row below.

Nelfinavir/Efavirenz 
(750 mg q8h/600 mg once daily) 

Nelfinavir: 
AUC: ↑ 20% (↑ 8 to ↑ 34) 
Cmax: ↑ 21% (↑ 10 to ↑ 33)
The combination was generally well 
tolerated.

No dose adjustment is necessary 
for either medicinal product. 

Ritonavir/Efavirenz 
(500 mg twice daily/600 mg once 
daily) 

Ritonavir: 
Morning AUC: ↑ 18% (↑ 6 to ↑ 33)
Evening AUC: ↔ 
Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)
Evening Cmax: ↔ 
Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) 

b

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) 
b

Efavirenz: 
AUC: ↑ 21% (↑ 10 to ↑ 34)  
Cmax: ↑ 14% (↑ 4 to ↑ 26)
Cmin: ↑ 25% (↑ 7 to ↑ 46) 

b

(inhibition of CYP-mediated oxidative 
metabolism) 
When efavirenz was given with 
ritonavir 500 mg or 600 mg twice 
daily, the combination was not well 
tolerated (for example, dizziness, 
nausea, paraesthesia and elevated liver 
enzymes occurred). Sufficient data on 
the tolerability of efavirenz with low-
dose ritonavir (100 mg, once or twice 
daily) are not available. 

When using efavirenz with low-
dose ritonavir, the possibility of 
an increase in the incidence of 
efavirenz-associated adverse 
events should be considered, 
due to possible 
pharmacodynamic interaction. 

Saquinavir/ritonavir/Efavirenz Interaction not studied. No data are available to make a 
dose recommendation. See also 
ritonavir row above. Use of 
efavirenz in combination with 
saquinavir as the sole protease 
inhibitor is not recommended.

CCR5 antagonist
Maraviroc/Efavirenz 
(100 mg twice daily/600 mg once 
daily) 

Maraviroc: 
AUC12: ↓ 45% (↓ 38 to ↓ 51)

Cmax: ↓ 51% (↓ 37 to ↓ 62)
Efavirenz concentrations not measured, 
no effect is expected.

Refer to the Summary of 
Product Characteristics for the 
medicinal product containing 
maraviroc. 

Integrase strand transfer inhibitor



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Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Raltegravir/Efavirenz 
(400 mg single dose/ -) 

Raltegravir: 
AUC: ↓ 36% 
C12: ↓ 21% 
Cmax: ↓ 36% 
(UGT1A1 induction)

No dose adjustment is necessary 
for raltegravir. 

NRTIs and NNRTIs
NRTIs/Efavirenz Specific interaction studies have not 

been performed with efavirenz and 
NRTIs other than lamivudine, 
zidovudine, and tenofovir disoproxil. 
Clinically significant interactions are 
not expected since the NRTIs are 
metabolised via a different route than 
efavirenz and would be unlikely to 
compete for the same metabolic 
enzymes and elimination pathways.

No dose adjustment is necessary 
for either medicinal product. 

NNRTIs/Efavirenz Interaction not studied.  Since use of two NNRTIs 
proved not beneficial in terms 
of efficacy and safety, co-
administration of efavirenz and 
another NNRTI is not 
recommended.

Hepatitis C antivirals 
Boceprevir/Efavirenz 
(800 mg 3 times daily/600 mg 
once daily) 

Boceprevir: 
AUC: ↔ 19%* 
Cmax: ↔ 8% 
Cmin: ↓ 44% 
Efavirenz: 
AUC: ↔ 20% 
Cmax: ↔ 11% 
(CYP3A induction - effect on 
boceprevir) 
*0-8 hours 
No effect (↔) equals a decrease in 
mean ratio estimate of ≤20% or 
increase in mean ratio estimate of 
≤25%

Plasma trough concentrations of 
boceprevir were decreased 
when administered with 
efavirenz. The clinical outcome 
of this observed reduction of 
boceprevir trough 
concentrations has not been 
directly assessed. 

Telaprevir/Efavirenz 
(1,125 mg q8h/600 mg once daily) 

Telaprevir (relative to 750 mg q8h): 
AUC: ↓ 18% (↓ 8 to ↓ 27) 
Cmax: ↓ 14% (↓ 3 to ↓ 24) 
Cmin: ↓ 25% (↓ 14 to ↓ 34)% 
Efavirenz: 
AUC: ↓ 18% (↓ 10 to ↓ 26) 
Cmax: ↓ 24% (↓ 15 to ↓ 32) 
Cmin: ↓ 10% (↑ 1 to ↓ 19)% 
(CYP3A induction by efavirenz)

If efavirenz and telaprevir are 
co-administered, telaprevir 
1,125 mg every 8 hours should 
be used. 



13

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Simeprevir/Efavirenz 
(150 mg once daily /600 mg once 
daily) 

Simeprevir:  
AUC: ↓71% (↓67 to ↓74)  
Cmax: ↓51% (↓46 to ↓56) 
Cmin: ↓91% (↓88 to ↓92) 
Efavirenz: 
AUC: ↔  
Cmax: ↔ 
Cmin: ↔ 
No effect (↔) equals a decrease in 
mean ratio estimate of ≤20% or 
increase in mean ratio estimate of 
≤25% 
(CYP3A4 enzyme induction)

Concomitant administration of 
simeprevir with efavirenz 
resulted in significantly 
decreased plasma 
concentrations of simeprevir 
due to CYP3A induction by 
efavirenz, which may result in 
loss of therapeutic effect of 
simeprevir. Co-administration 
of simeprevir with efavirenz is 
not recommended. 

Sofosbuvir/ velpatasvir ↔sofosbuvir 

↓velpatasvir 

↔efavirenz

Concomitant administration 
of sofosbuvir/velpatasvir 
with efavirenz resulted in a 
reduction (approximately 
50%) in the systemic 
exposure of velpatasvir. The 
mechanism of the effect on 
velpatasvir is induction of 
CYP3A and CYP2B6 by 
efavirenz. Coadministration 
of sofosbuvir/velpatasvir 
with efavirenz is not 
recommended.  Refer to the 
prescribing information for 
sofosbuvir/velpatasvir for 
more information.

Velpatasvir/ sofosbuvir/ 
voxilaprevir

↓velpatasvir 

↓voxilaprevir

Concomitant administration 
of velpatasvir/sofosbuvir/ 
voxilaprevir with efavirenz is 
not recommended, as it may 
decrease concentrations of 
velpatasvir and voxilaprevir. 
Refer to the prescribing 
information for 
velpatasvir/sofosbuvir/ 
voxilaprevir for more 
information.



14

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Protease inhibitor : 

Elbasvir/ grazoprevir 

↓elbasvir 

↓grazoprevir

↔efavirenz

Concomitant administration 
of efavirenz with 
elbasvir/grazoprevir is 
contraindicated because it 
may lead to loss of virologic 
response to 
elbasvir/grazoprevir. This 
loss is due to significant 
decreases in elbasvir and 
grazoprevir plasma 
concentrations caused by 
CYP3A4 induction. Refer to 
the prescribing information 
for elbasvir/grazoprevir for 
more information.

Glecaprevir/pibrentasvir ↓glecaprevir 

↓ pibrentasvir 

Concomitant administration 
of glecaprevir/pibrentasvir 
with efavirenz may 
significantly decrease plasma 
concentrations of glecaprevir 
and pibrentasvir, leading to 
reduced therapeutic effect. 
Coadministration of 
glecaprevir/pibrentasvir with 
efavirenz is not 
recommended. Refer to the 
prescribing information for 
glecaprevir/pibrentasvir for 
more information.

Antibiotics
Azithromycin/Efavirenz 
(600 mg single dose/400 mg once 
daily)

No clinically significant 
pharmacokinetic interaction. 

No dose adjustment is necessary 
for either medicinal product. 

Clarithromycin/Efavirenz 
(500 mg q12h/400 mg once daily)

Clarithromycin: 
AUC: ↓ 39% (↓ 30 to ↓ 46) 
Cmax: ↓ 26% (↓ 15 to ↓ 35) 
Clarithromycin 14-hydroxymetabolite: 
AUC: ↑ 34% (↑ 18 to ↑ 53) 
Cmax: ↑ 49% (↑ 32 to ↑ 69) 
Efavirenz: 
AUC: ↔ 
Cmax: ↑ 11% (↑ 3 to ↑ 19) 
(CYP3A4 induction) 
Rash developed in 46% of uninfected 
volunteers receiving efavirenz and 
clarithromycin.

The clinical significance of 
these changes in clarithromycin 
plasma levels is not known. 
Alternatives to clarithromycin 
(e.g. azithromycin) may be 
considered. No dose adjustment 
is necessary for efavirenz.  

Other macrolide antibiotics 
(e.g.,erythromycin)/Efavirenz

Interaction not studied. No data are available to make a 
dose recommendation.



15

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Antimycobacterials
Rifabutin/Efavirenz 
(300 mg once daily/600 mg once 
daily) 

Rifabutin: 
AUC: ↓ 38% (↓ 28 to ↓ 47) 
Cmax: ↓ 32% (↓ 15 to ↓ 46) 
Cmin: ↓ 45% (↓ 31 to ↓ 56)  
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 12% (↓ 24 to ↑ 1) 
(CYP3A4 induction) 

The daily dose of rifabutin 
should be increased by 50% 
when administered with 
efavirenz. Consider doubling 
the rifabutin dose in regimens 
where rifabutin is given 2 or 
3 times a week in combination 
with efavirenz. The clinical 
effect of this dose adjustment 
has not been adequately 
evaluated. Individual 
tolerability and virological 
response should be considered 
when making the dose 
adjustment (see section 5.2).

Rifampicin/Efavirenz 
(600 mg once daily/600 mg once 
daily) 

Efavirenz: 
AUC: ↓ 26% (↓ 15 to ↓ 36)

Cmax: ↓ 20% (↓ 11 to ↓ 28) 
Cmin: ↓ 32% (↓ 15 to ↓ 46) 
(CYP3A4 and CYP2B6 induction) 

When taken with rifampicin in 
patients weighing 50 kg or 
greater, increasing efavirenz 
daily dose to 800 mg may 
provide exposure similar to a 
daily dose of 600 mg when 
taken without rifampicin. The 
clinical effect of this dose 
adjustment has not been 
adequately evaluated. 
Individual tolerability and 
virological response should be 
considered when making the 
dose adjustment (see section 
5.2). No dose adjustment is 
necessary for rifampicin, 
including 600 mg

Antifungals
Itraconazole/Efavirenz 
(200 mg q12h/600 mg once daily)

Itraconazole:  
AUC: ↓ 39% (↓ 21 to ↓ 53)

Cmax: ↓ 37% (↓ 20 to ↓ 51) 
Cmin: ↓ 44% (↓ 27 to ↓ 58) 
(decrease in itraconazole 
concentrations: CYP3A4 induction) 
Hydroxyitraconazole: 
AUC: ↓ 37% (↓ 14 to ↓ 55) 

Cmax: ↓ 35% (↓ 12 to ↓ 52) 
Cmin: ↓ 43% (↓ 18 to ↓ 60) 
Efavirenz:  
No clinically significant 
pharmacokinetic change. 

Since no dose recommendation 
for itraconazole can be made, 
alternative antifungal treatment 
should be considered. 



16

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Posaconazole/Efavirenz 
--/400 mg once daily 

Posaconazole: 
AUC: ↓ 50%  
Cmax: ↓ 45% 
(UDP-G induction) 

Concomitant use of 
posaconazole and efavirenz 
should be avoided unless the 
benefit to the patient outweighs 
the risk. 

Voriconazole/Efavirenz 
(200 mg twice daily/400 mg once 
daily) 

Voriconazole/Efavirenz 
(400 mg twice daily/300 mg once 
daily) 

Voriconazole: 
AUC: ↓ 77%

Cmax: ↓ 61% 
Efavirenz: 
AUC: ↑ 44% 
Cmax: ↑ 38% 
Voriconazole: 
AUC: ↓ 7% (↓ 23 to ↑ 13) * 
Cmax: ↑ 23% (↓ 1 to ↑ 53) * 
Efavirenz: 
AUC: ↑ 17% (↑ 6 to ↑ 29) ** 
Cmax: ↔** 
*compared to 200 mg twice daily alone 
** compared to 600 mg once daily 
alone 
(competitive inhibition of oxidative 
metabolism)

When efavirenz is co-
administered with voriconazole, 
the voriconazole maintenance 
dose must be increased to 
400 mg twice daily and the 
efavirenz dose must be reduced 
by 50%, i.e., to 300 mg once 
daily. When treatment with 
voriconazole is stopped, the 
initial dose of efavirenz should 
be restored.  

Fluconazole/Efavirenz 
(200 mg once daily/400 mg once 
daily)

No clinically significant 
pharmacokinetic interaction  

No dose adjustment is necessary 
for either medicinal product. 

Ketoconazole and other imidazole 
antifungals

Interaction not studied No data are available to make a 
dose recommendation.

Antimalarials 
Artemether/lumefantrine/ 
Efavirenz 
(20/120 mg tablet, 6 doses of 4 
tablets each over 3 days/600mg 
once daily) 

Artemether: 
AUC: ↓ 51%  
Cmax: ↓ 21%  
Dihydroartemisinin: 
AUC: ↓ 46% 
Cmax: ↓ 38%  
Lumefantrine: 
AUC: ↓ 21%  
Cmax: ↔ 
Efavirenz: 
AUC: ↓ 17% 
Cmax: ↔ 
(CYP3A4 induction)

Since decreased concentrations 
of artemether, 
dihydroartemisinin, or 
lumefantrine may result in a 
decrease of antimalarial 
efficacy, caution is 
recommended when efavirenz 
and artemether/lumefantrine 
tablets are coadministered. 

Atovaquone and proguanil 
hydrochloride/Efavirenz 
(250/100 mg single dose/600 mg 
once daily) 

Atovaquone: 
AUC: ↓ 75% (↓ 62 to ↓ 84) 
Cmax: ↓ 44% (↓ 20 to ↓ 61) 
Proguanil: 
AUC: ↓ 43% (↓ 7 to ↓ 65) 
Cmax: ↔ 

Concomitant administration of 
atovaquone/proguanil with 
efavirenz should be avoided. 



17

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

ACID REDUCING AGENTS
Aluminium hydroxide-magnesium 
hydroxide-simethicone 
antacid/Efavirenz 
(30 ml single dose/400 mg single 
dose) 
Famotidine/Efavirenz 
(40 mg single dose/400 mg single 
dose)

Neither aluminium/magnesium 
hydroxide antacids nor famotidine 
altered the absorption of efavirenz.  

Co-administration of efavirenz 
with medicinal products that 
alter gastric pH would not be 
expected to affect efavirenz 
absorption. 

ANTIANXIETY AGENTS
Lorazepam/Efavirenz 
(2 mg single dose/600 mg once 
daily)

Lorazepam:  
AUC: ↑ 7% (↑ 1 to ↑ 14) 
Cmax: ↑ 16% (↑ 2 to ↑ 32) 
These changes are not considered 
clinically significant.

No dose adjustment is necessary 
for either medicinal product. 

ANTICOAGULANTS
Warfarin/Efavirenz 
Acenocoumarol/Efavirenz 

Interaction not studied. Plasma 
concentrations and effects of warfarin 
or acenocoumarol are potentially 
increased or decreased by efavirenz.

Dose adjustment of warfarin or 
acenocoumarol may be 
required. 

ANTICONVULSANTS
Carbamazepine/Efavirenz 
(400 mg once daily/600 mg once 
daily)

Carbamazepine: 
AUC: ↓ 27% (↓ 20 to ↓ 33) 
Cmax: ↓ 20% (↓ 15 to ↓ 24) 
Cmin: ↓ 35% (↓ 24 to ↓ 44) 
Efavirenz: 
AUC: ↓ 36% (↓ 32 to ↓ 40)

Cmax: ↓ 21% (↓ 15 to ↓ 26)
Cmin: ↓ 47% (↓ 41 to ↓ 53)
(decrease in carbamazepine 
concentrations: CYP3A4 induction; 
decrease in efavirenz concentrations: 
CYP3A4 and CYP2B6 induction)  
The steady-state AUC, Cmax and Cmin
of the active carbamazepine epoxide 
metabolite remained unchanged. Co-
administration of higher doses of either 
efavirenz or carbamazepine has not 
been studied.

No dose recommendation can 
be made. An alternative 
anticonvulsant should be 
considered. Carbamazepine 
plasma levels should be 
monitored periodically. 

Phenytoin, Phenobarbital, and 
other anticonvulsants that are 
substrates of CYP450 isoenzymes 

Interaction not studied. There is a 
potential for reduction or increase in 
the plasma concentrations of 
phenytoin, phenobarbital and other 
anticonvulsants that are substrates of 
CYP450 isoenzymes when co-
administered with efavirenz.

When efavirenz is co-
administered with an 
anticonvulsant that is a substrate 
of CYP450 isoenzymes, 
periodic monitoring of 
anticonvulsant levels should be 
conducted.

Valproic acid/Efavirenz 
(250 mg twice daily/600 mg once 
daily) 

No clinically significant effect on 
efavirenz pharmacokinetics. Limited 
data suggest there is no clinically 
significant effect on valproic acid 
pharmacokinetics.

No dose adjustment is necessary 
for efavirenz. Patients should be 
monitored for seizure control. 



18

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Vigabatrin/Efavirenz 
Gabapentin/Efavirenz 

Interaction not studied. Clinically 
significant interactions are not expected 
since vigabatrin and gabapentin are 
exclusively eliminated unchanged in 
the urine and are unlikely to compete 
for the same metabolic enzymes and 
elimination pathways as efavirenz.

No dose adjustment is necessary 
for any of these medicinal 
products. 

ANTIDEPRESSANTS 
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz 
(50 mg once daily/600 mg once 
daily) 

Sertraline: 
AUC: ↓ 39% (↓ 27 to ↓ 50)  
Cmax: ↓ 29% (↓ 15 to ↓ 40) 
Cmin: ↓ 46% (↓ 31 to ↓ 58) 
Efavirenz:  
AUC: ↔ 
Cmax: ↑ 11% (↑ 6 to ↑ 16) 
Cmin: ↔  
(CYP3A4 induction)

Sertraline dose increases should 
be guided by clinical response. 
No dose adjustment is necessary 
for efavirenz. 

Paroxetine/Efavirenz 
(20 mg once daily/600 mg once 
daily)

No clinically significant 
pharmacokinetic interaction 

No dose adjustment is necessary 
for either medicinal product. 

Fluoxetine/Efavirenz Interaction not studied. Since 
fluoxetine shares a similar metabolic 
profile with paroxetine, i.e. a strong 
CYP2D6 inhibitory effect, a similar 
lack of interaction would be expected 
for fluoxetine.

No dose adjustment is necessary 
for either medicinal product. 

NOREPINEPHRINE AND DOPAMINE REUPTAKE INHIBITOR 
Bupropion/Efavirenz 
[150 mg single dose (sustained 
release)/600 mg once daily] 

Bupropion: 
AUC: ↓ 55% (↓ 48 to ↓ 62)  
Cmax: ↓ 34% (↓ 21 to ↓ 47)  
Hydroxybupropion:  
AUC: ↔ 
Cmax: ↑ 50% (↑ 20 to ↑ 80)
(CYP2B6 induction)

Increases in bupropion dosage 
should be guided by clinical 
response, but the maximum 
recommended dose of 
bupropion should not be 
exceeded.  No dose adjustment 
is necessary for efavirenz. 

ANTIHISTAMINES
Cetirizine/Efavirenz 
(10 mg single dose/600 mg once 
daily)

Cetirizine: 
AUC: ↔ 
Cmax: ↓ 24% (↓ 18 to ↓ 30)
These changes are not considered 
clinically significant. 
Efavirenz:  
No clinically significant 
pharmacokinetic interaction

No dose adjustment is necessary 
for either medicinal product. 



19

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

CARDIOVASCULAR AGENTS 
Calcium Channel Blockers 
Diltiazem/Efavirenz 
(240 mg once daily/600 mg once 
daily) 

Diltiazem: 
AUC: ↓ 69% (↓ 55 to ↓ 79)  
Cmax: ↓ 60% (↓ 50 to ↓ 68)  
Cmin: ↓ 63% (↓ 44 to ↓ 75) 
Desacetyl diltiazem: 
AUC: ↓ 75% (↓ 59 to ↓ 84)  
Cmax: ↓ 64% (↓ 57 to ↓ 69) 
Cmin: ↓ 62% (↓ 44 to ↓ 75) 
N-monodesmethyl diltiazem: 
AUC: ↓ 37% (↓ 17 to ↓ 52) 
Cmax: ↓ 28% (↓ 7 to ↓ 44) 
Cmin: ↓ 37% (↓ 17 to ↓ 52) 
Efavirenz: 
AUC: ↑ 11% (↑ 5 to ↑ 18)

Cmax: ↑ 16% (↑ 6 to ↑ 26) 
Cmin: ↑ 13% (↑ 1 to ↑ 26)
(CYP3A4 induction) 
The increase in efavirenz 
pharmacokinetic parameters is not 
considered clinically significant.

Dose adjustments of diltiazem 
should be guided by clinical 
response (refer to the Summary 
of Product Characteristics for 
diltiazem). No dose adjustment 
is necessary for efavirenz. 

Verapamil, Felodipine, Nifedipine 
and Nicardipine 

Interaction not studied. When efavirenz 
is co-administered with a calcium 
channel blocker that is a substrate of 
the CYP3A4 enzyme, there is a 
potential for reduction in the plasma 
concentrations of the calcium channel 
blocker.

Dose adjustments of calcium 
channel blockers should be 
guided by clinical response 
(refer to the Summary of 
Product Characteristics for the 
calcium channel blocker). 

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors
Atorvastatin/Efavirenz 
(10 mg once daily/600 mg once 
daily) 

Atorvastatin: 
AUC: ↓ 43% (↓ 34 to ↓ 50)

Cmax: ↓ 12% (↓ 1 to ↓ 26) 
2-hydroxy atorvastatin: 
AUC: ↓ 35% (↓ 13 to ↓ 40)

Cmax: ↓ 13% (↓ 0 to ↓ 23)
4-hydroxy atorvastatin: 
AUC: ↓ 4% (↓ 0 to ↓ 31) 
Cmax: ↓ 47% (↓ 9 to ↓ 51)
Total active HMG Co-A reductase  
inhibitors:  
AUC: ↓ 34% (↓ 21 to ↓ 41)
Cmax: ↓ 20% (↓ 2 to ↓ 26) 

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of atorvastatin may 
be required (refer to the 
Summary of Product 
Characteristics for atorvastatin). 
No dose adjustment is necessary 
for efavirenz. 

Pravastatin/Efavirenz 
(40 mg once daily/600 mg once 
daily) 

Pravastatin: 
AUC: ↓ 40% (↓ 26 to ↓ 57) 
Cmax: ↓ 18% (↓ 59 to ↑ 12) 

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of pravastatin may 
be required (refer to the 
Summary of Product 
Characteristics for pravastatin). 
No dose adjustment is necessary 
for efavirenz.



20

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Simvastatin/Efavirenz 
(40 mg once daily/600 mg once 
daily) 

Simvastatin: 
AUC: ↓ 69% (↓ 62 to ↓ 73) 
Cmax: ↓ 76% (↓ 63 to ↓ 79) 
Simvastatin acid: 
AUC: ↓ 58% (↓ 39 to ↓ 68)
Cmax: ↓ 51% (↓ 32 to ↓ 58) 
Total active HMG Co-A reductase 
inhibitors: 
AUC: ↓ 60% (↓ 52 to ↓ 68) 
Cmax: ↓ 62% (↓ 55 to ↓ 78) 
 (CYP3A4 induction) 
Co-administration of efavirenz with 
atorvastatin, pravastatin, or 
simvastatin did not affect efavirenz 
AUC or Cmax values.

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of simvastatin may 
be required (refer to the 
Summary of Product 
Characteristics for simvastatin). 
No dose adjustment is necessary 
for efavirenz. 

Rosuvastatin/Efavirenz Interaction not studied. Rosuvastatin is 
largely excreted unchanged via the 
faeces, therefore interaction with 
efavirenz is not expected.

No dose adjustment is necessary 
for either medicinal product. 

HORMONAL CONTRACEPTIVES
Oral: 
Ethinyloestradiol + Norgestimate/ 
Efavirenz 
(0.035 mg + 0.25 mg once 
daily/600 mg once daily) 

Ethinyloestradiol: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 8% (↑ 14 to ↓ 25) 
Norelgestromin (active metabolite): 
AUC: ↓ 64% (↓ 62 to ↓ 67) 
Cmax: ↓ 46% (↓ 39 to ↓ 52) 
Cmin: ↓ 82% (↓ 79 to ↓ 85) 
Levonorgestrel (active metabolite): 
AUC: ↓ 83% (↓ 79 to ↓ 87) 
Cmax: ↓ 80% (↓ 77 to ↓ 83) 
Cmin: ↓ 86% (↓ 80 to ↓ 90) 
(induction of metabolism) 
Efavirenz: no clinically significant 
interaction. 
The clinical significance of these 
effects is not known.

A reliable method of barrier 
contraception must be used in 
addition to hormonal 
contraceptives (see section 4.6). 

Injection: 
Depomedroxyprogesterone acetate 
(DMPA)/Efavirenz 
(150 mg IM single dose DMPA) 

In a 3-month drug interaction study, no 
significant differences in MPA 
pharmacokinetic parameters were 
found between subjects receiving 
efavirenz-containing antiretroviral 
therapy and subjects receiving no 
antiretroviral therapy. Similar results 
were found by other investigators, 
although the MPA plasma levels were 
more variable in the second study. In 
both studies, plasma progesterone 
levels for subjects receiving efavirenz 
and DMPA remained low consistent 
with suppression of ovulation.

Because of the limited 
information available, a reliable 
method of barrier contraception 
must be used in addition to 
hormonal contraceptives (see 
section 4.6). 

Implant: Etonogestrel/Efavirenz Decreased exposure of etonogestrel 
may be expected (CYP3A4 induction). 
There have been occasional 
postmarketing reports of contraceptive 
failure with etonogestrel in efavirenz-
exposed patients.

A reliable method of barrier 
contraception must be used in 
addition to hormonal 
contraceptives (see section 4.6).



21

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

IMMUNOSUPPRESSANTS
Immunosuppressants metabolized 
by CYP3A4 (eg, cyclosporine, 
tacrolimus, sirolimus)/Efavirenz 

Interaction not studied. Decreased 
exposure of the immunosuppressant 
may be expected (CYP3A4 induction). 
These immunosuppressants are not 
anticipated to affect exposure of 
efavirenz. 

Dose adjustments of the 
immunosuppressant may be 
required. Close monitoring of 
immunosuppressant 
concentrations for at least 2 
weeks (until stable 
concentrations are reached) is 
recommended when starting or 
stopping treatment with 
efavirenz.

OPIOIDS
Methadone/Efavirenz 
(stable maintenance, 35-100 mg 
once daily/600 mg once daily) 

Methadone: 
AUC: ↓ 52% (↓ 33 to ↓ 66)
Cmax: ↓ 45% (↓ 25 to ↓ 59) 
(CYP3A4 induction) 
In a study of HIV infected intravenous 
drug users, co-administration of 
efavirenz with methadone resulted in 
decreased plasma levels of methadone 
and signs of opiate withdrawal. The 
methadone dose was increased by a 
mean of 22% to alleviate withdrawal 
symptoms. 

Concomitant administration 
with efavirenz should be 
avoided due to the risk for QTc 
prolongation (see section 4.3). 

Buprenorphine/naloxone/Efavirenz Buprenorphine: 
AUC: ↓ 50%
Norbuprenorphine: 
AUC: ↓ 71% 
Efavirenz: 
No clinically significant 
pharmacokinetic interaction 

Despite the decrease in 
buprenorphine exposure, no 
patients exhibited withdrawal 
symptoms. Dose adjustment of 
buprenorphine or efavirenz may 
not be necessary when co-
administered. 

a 90% confidence intervals unless otherwise noted. 
b 95% confidence intervals. 

Other interactions: efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid 
test results have been reported with some screening assays in uninfected and HIV-infected subjects 
receiving efavirenz. Confirmatory testing by a more specific method such as gas chromatography/mass 
spectrometry is recommended in such cases. 

4.6 Fertility, pregnancy and lactation 

Women of childbearing potential 

See below and section 5.3. Efavirenz should not be used during pregnancy, unless the patient’s clinical 
condition requires such treatment. Women of childbearing potential should undergo pregnancy testing 
before initiation of efavirenz.  

Contraception in males and females 

Barrier contraception should always be used in combination with other methods of contraception (for 
example, oral or other hormonal contraceptives, see section 4.5). Because of the long half-life of 
efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is 
recommended.  

Pregnancy 



22

There have been seven retrospective reports of findings consistent with neural tube defects, including 
meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-
containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective 
and 1 retrospective) including events consistent with neural tube defects have been reported with the 
fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate. 
A causal relationship of these events to the use of efavirenz has not been established, and the 
denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development 
(at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz 
during the first trimester of pregnancy. 

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 
pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births. 
One child was reported to have a neural tube defect, and the frequency and pattern of other birth 
defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as 
those in HIV negative controls. The incidence of neural tube defects in the general population ranges 
from 0.5-1 case per 1,000 live births. 

Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3). 

Breast-feeding 

Efavirenz has been shown to be excreted in human milk.  There is insufficient information on the 
effects of efavirenz in newborns/infants. Risk to the infant can not be excluded. Breast-feeding should 
be discontinued during treatment with SUSTIVA. It is recommended that HIV infected women do not 
breast-feed their infants under any circumstances in order to avoid transmission of HIV. 

Fertility 

The effect of efavirenz on male and female fertility in rats has only been evaluated at doses that 
achieved systemic drug exposures equivalent to or below those achieved in humans given 
recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of male 
or female rats (doses up to 100 mg/kg/bid), and did not affect sperm or offspring of treated male rats 
(doses up to 200 mg/bid). The reproductive performance of offspring born to female rats given 
efavirenz was not affected.  

4.7 Effects on ability to drive and use machines 

Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be 
instructed that if they experience these symptoms they should avoid potentially hazardous tasks such 
as driving or operating machinery. 

4.8 Undesirable effects 

Summary of the safety profile 

Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 
600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most 
frequently reported adverse reactions of at least moderate severity reported in at least 5% of patients 
were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most 
notable adverse reactions associated with efavirenz are rash and nervous system symptoms. Nervous 
system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 
weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric 
adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and 
seizures have been reported in patients treated with efavirenz. The administration of efavirenz with 
food may increase efavirenz exposure and may lead to an increase in the frequency of adverse 
reactions (see section 4.4). 



23

The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006) 
in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration 
180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine + 
lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not 
associated with any new safety concerns. 

Tabulated list of adverse reactions 

Adverse reactions of moderate or greater severity with at least possible relationship to treatment 
regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended 
dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions 
observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens. 
Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to 
< 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); or very rare (< 1/10,000). 

Immune system disorders 
uncommon hypersensitivity 

Metabolism and nutrition disorders 
common hypertriglyceridaemia* 

uncommon hypercholesterolaemia* 

Psychiatric disorders
common abnormal dreams, anxiety, depression, 

insomnia* 

uncommon affect lability, aggression, confusional state, 
euphoric mood, hallucination, mania, 
paranoia, psychosis†, suicide attempt, suicide 
ideation, catatonia* 

rare delusion ‡, neurosis ‡, completed suicide‡,*
Nervous system disorders 
common  cerebellar coordination and balance 

disturbances†, disturbance in attention 
(3.6%), dizziness (8.5%), headache (5.7%), 
somnolence (2.0%)* 

uncommon agitation, amnesia, ataxia, coordination 
abnormal, convulsions, thinking abnormal,* 
tremor†

Eye disorders
uncommon vision blurred 

Ear and labyrinth disorders
uncommon tinnitus†, vertigo 

Vascular disorders
uncommon flushing†

Gastrointestinal disorders
common abdominal pain, diarrhoea, nausea, vomiting 

uncommon pancreatitis 



24

Hepatobiliary disorders
common aspartate aminotransferase (AST) 

increased*, alanine aminotransferase (ALT) 
increased*, gamma-glutamyltransferase 
(GGT) increased* 

uncommon hepatitis acute 

rare  hepatic failure‡,* 

Skin and subcutaneous tissue disorders
very common rash (11.6%)* 

common pruritus 

uncommon erythema multiforme, Stevens-Johnson 
syndrome* 

rare photoallergic dermatitis†

Reproductive system and breast disorders
uncommon gynaecomastia 

General disorders and administration site conditions
common Fatigue 

*,†,‡ See section Description of selected adverse reactions for more details. 

Description of selected adverse reactions 

Information regarding post-marketing surveillance 

†These adverse reactions were identified through post-marketing surveillance; however, the 
frequencies were determined using data from 16 clinical trials (n=3,969).  

‡These adverse reactions were identified through post-marketing surveillance but not reported as drug-
related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare" was 
defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) on the 
basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of 
patients treated with efavirenz in these clinical trials (n=3,969). 

Rash 

In clinical studies, 26% of patients treated with 600 mg of efavirenz experienced skin rash compared 
with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of 
patients treated with efavirenz. Severe rash occurred in less than 1% of patients treated with efavirenz, 
and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-
Johnson syndrome was approximately 0.1%. 

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two 
weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with 
efavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because of 
rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is 
restarted. 



25

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class 
is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy, 
primarily based on retrospective cohort data from published literature, range from 13 to 18%, 
comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.) 

Psychiatric symptoms 

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In 
controlled trials, the frequency of specific serious psychiatric events were: 

Efavirenz regimen 
(n=1,008)

Control regimen 
(n=635)

- severe depression 1.6% 0.6%
- suicidal ideation 0.6% 0.3%
- non-fatal suicide attempts 0.4% 0%
- aggressive behaviour 0.4% 0.3%
- paranoid reactions 0.4% 0.3%
- manic reactions 0.1% 0%

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric 
adverse reactions with frequencies ranging from 0.3% for manic reactions to 2.0% for both severe 
depression and suicidal ideation. There have also been post-marketing reports of death by suicide, 
delusions, psychosis-like behaviour and catatonia. 

Nervous system symptoms 

In clinical controlled trials, frequently reported adverse reactions included, but were not limited to 
dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system 
symptoms of moderate-to-severe intensity were experienced by 19% (severe 2%) of patients compared 
to 9% (severe 1%) of patients receiving control regimens. In clinical studies 2% of patients treated 
with efavirenz discontinued therapy due to such symptoms. 

Nervous system symptoms usually begin during the first one or two days of therapy and generally 
resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system 
symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous 
system symptoms may occur more frequently when efavirenz is taken concomitantly with meals 
possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to 
improve the tolerability of these symptoms and can be recommended during the first weeks of therapy 
and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or 
splitting the daily dose has not been shown to provide benefit. 

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset 
nervous system symptoms among efavirenz-treated patients were generally similar to those in the 
control arm. 

Hepatic failure 

A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing 
hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing 
in some cases to transplantation or death.

Immune Reactivation Syndrome 

In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 



26

also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). 

Osteonecrosis 

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). 
The frequency of this is unknown (see section 4.4). 

Laboratory test abnormalities 

Liver enzymes: elevations of AST and ALT to greater than five times the upper limit of the normal 
range (ULN) were seen in 3% of 1,008 patients treated with 600 mg of efavirenz (5-8% after long-
term treatment in study 006). Similar elevations were seen in patients treated with control regimens 
(5% after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 
4% of all patients treated with 600 mg of efavirenz and 1.5-2% of patients treated with control 
regimens (7% of efavirenz-treated patients and 3% of control-treated patients after long-term 
treatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction. 
In the long-term study (006), 1% of patients in each treatment arm discontinued because of liver or 
biliary system disorders. 

Amylase: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels 
greater than 1.5 times the upper limit of normal were seen in 10% of patients treated with efavirenz 
and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases 
in serum amylase is unknown. 

Metabolic parameters 

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 

Paediatric population 

Undesirable effects in children were generally similar to those of adult patients. Rash was reported 
more frequently in children (59 of 182 (32%) treated with efavirenz) and was more often of higher 
grade than in adults (severe rash was reported in 6 of 182 (3.3%) of children). Prophylaxis with 
appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.. 

Other special populations 

Liver enzymes in hepatitis B or C co-infected patients: in the long-term data set from study 006, 
137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 
84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for 
hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected 
patients in study 006, elevations in AST to greater than five times ULN developed in 13% of 
efavirenz-treated patients and in 7% of controls, and elevations in ALT to greater than five times ULN 
developed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with 
efavirenz and 2% in the control arm discontinued because of liverdisorders (see section 4.4).

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 



27

4.9 Overdose 

Some patients accidentally taking 600 mg twice daily have reported increased nervous system 
symptoms. One patient experienced involuntary muscle contractions. 

Treatment of overdose with efavirenz should consist of general supportive measures, including 
monitoring of vital signs and observation of the patient’s clinical status. Administration of activated 
charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for 
overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove 
significant quantities of it from blood. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase 
inhibitors. ATC code: J05AG03 

Mechanism of action 

Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse 
transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or 
δ). 

Cardiac Electrophysiology 

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo 
controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects 
enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 
genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax 
observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz 
concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the 
mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in 
subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days 
(see section 4.5).

Antiviral activity 

The free concentration of efavirenz required for 90 to 95% inhibition of wild type or zidovudine-
resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell 
lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures. 

Resistance 

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 
48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to 
that observed against wild type viral strains. The single substitutions which led to the highest 
resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100 
(L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold 
resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing 
K103N in addition to other amino acid substitutions in RT. 

K103N was the most frequently observed RT substitution in viral isolates from patients who 
experienced a significant rebound in viral load during clinical studies of efavirenz in combination with 
indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving 
efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 



28

225 were also observed, but at lower frequencies, and often only in combination with K103N. The 
pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of 
the other antiviral medicines used in combination with efavirenz. 

Cross resistance 

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the 
K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine-
resistant clinical isolates examined were cross-resistant to efavirenz and contained the K103N 
substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant 
to efavirenz. 

Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed 
evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen 
isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and 
delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-to-
isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates 
tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and 
delavirdine. 

The potential for cross resistance between efavirenz and PIs is low because of the different enzyme 
targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of the 
different binding sites on the target and mechanism of action. 

Clinical efficacy 

Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely 
with CD4 counts < 50 cells/mm3, or in PI or NNRTI experienced patients. Clinical experience in 
controlled studies with combinations including didanosine or zalcitabine is limited. 

Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in 
combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of 
quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and NRTI-
experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced patients 
over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 
1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used without 
efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of NRTIs 
given every 12 hours were used in each of these studies. 

Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or 
efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to 
be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count 
was 341 cells/mm3 and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for 
study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 3. 
In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who 
terminated the study early for any reason, or who had a missing HIV-RNA measurement that was 
either preceded or followed by a measurement above the limit of assay quantification were considered 
to have HIV-RNA above 50 or above 400 copies/ml at the missing time points. 



29

Table 3: Efficacy results for study 006 

Responder rates (NC = Fa) 
Plasma HIV-RNA 

Mean change 
from 

baseline-CD4 
cell count

< 400 copies/ml  
(95% C.I.b)

< 50 copies/ml  
(95% C.I.b)

cells/mm3 

(S.E.M.c)
Treatment 
Regimend

n 48 weeks 48 weeks 48 weeks 

EFV + 
ZDV + 3TC

202 67% 
(60%, 73%)

62% 
(55%, 69%)

187 
(11.8)

EFV + IDV 206 54% 
(47%, 61%)

48% 
(41%, 55%)

177 
(11.3)

IDV + 
ZDV + 3TC

206 45% 
(38%, 52%)

40% 
(34%, 47%)

153 
(12.3)

a NC = F, noncompleter = failure. 
b C.I., confidence interval. 
c S.E.M., standard error of the mean. 
d EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir. 

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with 
EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), 
suggest durability of response in terms of proportions of patients with HIV RNA < 400 copies/ml, 
HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell count.  

Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled 
196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 
327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed 
to change their patient’s NRTI regimen upon entry into the study. Responder rates were highest in 
patients who switched NRTIs.  

Table 4: Efficacy results for studies ACTG 364 and 020 

Responder rates (NC = Fa) 
Plasma HIV-RNA 

Mean change from 
baseline-CD4 cell 

count
Study Number/ 
Treatment Regimensb

n % (95% C.I.c) % (95% C.I.) cells/mm3 (S.E.M.d) 

Study ACTG 364 
48 weeks

< 500 copies/ml < 50 copies/ml 

EFV + NFV + NRTIs 65 70 (59, 82) --- --- 107 (17.9)
EFV + NRTIs 65 58 (46, 70) --- --- 114 (21.0)
NFV + NRTIs 66 30 (19, 42) --- --- 94 (13.6)

Study 020 
24 weeks

< 400 copies/ml < 50 copies/ml 

EFV + IDV + NRTIs 157 60 (52, 68) 49 (41, 58) 104 (9.1)
IDV + NRTIs 170 51 (43, 59) 38 (30, 45) 77 (9.9)

a 
NC = F, noncompleter = failure. 

b EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor; 
NFV, nelfinavir. 

c C.I., confidence interval for proportion of patients in response. 
d S.E.M., standard error of the mean. 
---, not performed. 

Paediatric population 



30

 Study AI266922 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive 
and -experienced paediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 
years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10
copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The 
median time on study therapy was 132 weeks; 27% of patients discontinued before Week 48. Using an 
ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at 
Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in 
CD4+ count at 48 weeks was 215 cells/mm3 and the median increase in CD4+ percentage was 6%. 

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in paediatric patients 
who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 
9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 
4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm

3, and median CD4+ percentage was 
18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 
48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and 
<50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase 
from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in 
CD4+ percentage was 13%. 

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviral-naive and 
NRTI-experienced paediatric patients. One hundred two patients 3 months to 16 years of age (median 
5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior 

antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median 

CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on 
study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, 
the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 
were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count 

at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.

5.2 Pharmacokinetic properties 

Absorption 

Peak efavirenz plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following single oral 
doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in Cmax and 
AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting 
diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours) did not 
change following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days. 

In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 
200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady 
state Cmax was 12.9 ± 3.7 μM (29%) [mean ± S.D. (% C.V.)], steady state Cmin was 
5.6 ± 3.2 μM (57%), and AUC was 184 ± 73 μM·h (40%). 

Effect of food 

The bioavailability of a single 600 mg dose of efavirenz hard capsules in uninfected volunteers was 
increased 22% and 17%, respectively, when given with a meal of high fat or normal composition, 
relative to the bioavailability of a 600 mg dose given under fasted conditions (see section 4.4).

Bioavailability of hard capsule contents mixed with food vehicles 



31

In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg hard 
capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly, yogurt or infant 
formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under 
fasted conditions. 

Distribution 

Efavirenz is highly bound (approximately 99.5 - 99.75%) to human plasma proteins, predominantly 
albumin. In HIV-1 infected patients (n = 9) who received efavirenz 200 to 600 mg once daily for at 
least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the 
corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-
protein-bound (free) fraction of efavirenz in plasma. 

Biotransformation 

Studies in humans and in vitro studies using human liver microsomes have demonstrated that 
efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with 
subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially 
inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major 
isozymes responsible for efavirenz metabolism and that it inhibited P450 isozymes 2C9, 2C19, and 
3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at 
concentrations well above those achieved clinically. 

Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant 
of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, 
the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be 
excluded. 

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own 
metabolism, which may be clinically relevant in some patients. In uninfected volunteers, multiple 
doses of 200 - 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation 
(22 - 42% lower) and a shorter terminal half-life compared with single dose administration (see 
below). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 
substrate) are reduced in the presence of efavirenz (see section 4.5, table 2). 
Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been 
contradictory reports of both increased and decreased exposures to substrates of these enzymes when 
coadministered with efavirenz in vivo. The net effect of coadministration is not clear. 

Elimination 

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and 40 -
 55 hours after multiple doses. Approximately 14 - 34% of a radiolabelled dose of efavirenz was 
recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz. 

Hepatic impairment 

In a single-dose study, half life was doubled in the single patient with severe hepatic impairment 
(Child Pugh Class C), indicating a potential for a much greater degree of accumulation. A multiple-
dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic 
impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine 
whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz 
pharmacokinetics. 

Gender, race, elderly 



32

Although limited data suggest that females as well as Asian and Pacific Island patients may have 
higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic 
studies have not been performed in the elderly. 

Paediatric population 

The pharmacokinetic parameters for efavirenz at steady state in paediatric patients were predicted by a 
population pharmacokinetic model and are summarized in Table 5 by weight ranges that correspond to 
the recommended doses. 

Table 5: Predicted steady-state pharmacokinetics of efavirenz (capsules/capsule sprinkles) in 
HIV-infected paediatric patients 

Body Weight Dose Mean AUC(0-24) 
µM·h

Mean Cmax 
µg/mL

Mean Cmin 
µg/mL

3.5-5 kg 100 mg 220.52 5.81 2.43
5-7.5 kg 150 mg 262.62 7.07 2.71
7.5-10 kg 200 mg 284.28 7.75 2.87
10-15 kg 200 mg 238.14 6.54 2.32
15-20 kg 250 mg 233.98 6.47 2.3
20-25 kg 300 mg 257.56 7.04 2.55

25-32.5 kg 350 mg 262.37 7.12 2.68
32.5-40 kg 400 mg 259.79 6.96 2.69

>40 kg 600 mg 254.78 6.57 2.82

5.3 Preclinical safety data 

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays. 

Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of 20 foetuses/ 
newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma efavirenz 
concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with 
secondary enlargement of the tongue were observed in one foetus, microophthalmia was observed in 
another foetus, and cleft palate was observed in a third foetus. No malformations were observed in 
foetuses from efavirenz-treated rats and rabbits. 

Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for ≥ 1 year at a dose 
resulting in mean AUC values approximately 2-fold greater than those in humans given the 
recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has 
been observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenz 
for ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the 
recommended dose (see sections 4.4 and 4.8). 

Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female 
mice, but not in male mice. The mechanism of tumour formation and the potential relevance for 
humans are not known. 

Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic 
potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the 
potential carcinogenic risk to humans. 

6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients 

SUSTIVA 50 mg hard capsules 



33

Capsule core: Sodium laurilsulfate, Lactose monohydrate, Magnesium stearate, Sodium starch 
glycolate 

Capsule shell: Gelatine, Sodium laurilsulfate, Yellow iron oxide (E172), Titanium dioxide (E171), 
Silicon dioxide (E551) 

Printing ink: Cochineal carminic acid (E120), Indigo carmine (E132), Titanium dioxide (E171) 

SUSTIVA 100 mg hard capsules 
Capsule core: Sodium laurilsulfate, Lactose monohydrate, Magnesium stearate, Sodium starch 
glycolate 

Capsule shell: Gelatine, Sodium laurilsulfate, Titanium dioxide (E171), Silicon dioxide (E551) 

Printing ink: Cochineal carminic acid (E120), Indigo carmine (E132), Titanium dioxide (E171) 

SUSTIVA 200 mg hard capsules 
Capsule core: Sodium laurilsulfate, Lactose monohydrate, Magnesium stearate, Sodium starch 
glycolate 

Capsule shell: Gelatine, Sodium laurilsulfate, Yellow iron oxide (E172), Silicon dioxide (E551) 

Printing ink: Cochineal carminic acid (E120), Indigo carmine (E132), Titanium dioxide (E171) 

6.2 Incompatibilities 

Not applicable.

6.3 Shelf life 

SUSTIVA 50 mg hard capsules 
SUSTIVA 100 mg hard capsules 
3 years. 

SUSTIVA 200 mg hard capsules 
For bottles: 3 years. 
For blisters: 2 years. 

6.4 Special precautions for storage 

This medicinal product does not require any special storage conditions. 

6.5 Nature and content of container 

SUSTIVA 50 mg hard capsules 
HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 30 hard 
capsules. 

SUSTIVA 100 mg hard capsules 
HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 30 hard 
capsules. 

SUSTIVA 200 mg hard capsules 
HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 90 hard 
capsules. 
Packs of 42 x 1 hard capsules in aluminium/PVC perforated unit dose blisters. 
Not all pack sizes may be marketed. 



34

6.6 Special precautions for disposal and other handling 

No special requirements for disposal. 

Use in the paediatric population 

For patients at least 3 months old and weighing at least 3.5 kg who cannot swallow capsules, the 
capsule contents can be administered with a small amount (1-2 teaspoons) of food using the capsule 
sprinkle method of administration. Patients and caregivers must be instructed to open the capsule 
carefully to avoid spillage or dispersion of the capsule contents into the air. It is recommended to hold 
the capsule with the cap facing up and to pull the cap away from the body of the capsule, and to mix 
the capsule contents with food in a small container. The mixture should be administered as soon as 
possible, but no more than 30 minutes after mixing. After administration of the efavirenz-food 
mixture, an additional small amount (approximately 2 teaspoons) of food must be added to the empty 
mixing container, stirred to disperse any remaining residue of the medicinal product, and administered 
to the patient. No additional food should be consumed for up to 2 hours after administration of 
efavirenz.  

7. MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/001-004 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

Date of first authorisation: 28 May 1999 
Date of latest renewal: 23 April 2014 

10. DATE OF REVISION OF THE TEXT 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



35

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 600 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Each film-coated tablet contains 600 mg of efavirenz. 

Excipient with known effect 
Each film-coated tablet contains 249.6 mg of lactose (as monohydrate). 

For the full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM 

Film-coated tablet 

Dark yellow, capsule-shaped, printed with “SUSTIVA” on both sides.

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

SUSTIVA is indicated in antiviral combination treatment of human immunodeficiency virus-1 (HIV-
1) infected adults, adolescents and children 3 months of age and older and weighing at least 3.5 kg. 

SUSTIVA has not been adequately studied in patients with advanced HIV disease, namely in patients 
with CD4 counts < 50 cells/mm3, or after failure of protease inhibitor (PI) containing regimens. 
Although cross-resistance of efavirenz with PIs has not been documented, there are at present 
insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of 
regimens containing SUSTIVA. 

For a summary of clinical and pharmacodynamic information, see section 5.1. 

4.2 Posology and method of administration 

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

Posology 

Efavirenz must be given in combination with other antiretroviral medicines (see section 4.5). 

In order to improve the tolerability of nervous system adverse reactions, bedtime dosing is 
recommended (see section 4.8). 

Adults and adolescents over 40 kg

The recommended dose of efavirenz in combination with nucleoside analogue reverse transcriptase 
inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily. 

Efavirenz film-coated tablets are not suitable for children weighing less than 40 kg. Efavirenz hard 
capsules are available for these patients. 



36

Dose adjustment 

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose must be 
increased to 400 mg every 12 hours and the efavirenz dose must be reduced by 50%, i.e., to 300 mg 
once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be 
restored (see section 4.5). 

If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the 
dose of efavirenz to 800 mg/day may be considered (see section 4.5). 

Special populations 

Renal impairment 

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, 
less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal 
impairment on efavirenz elimination should be minimal (see section 4.4). 

Hepatic impairment 

Patients with mild liver disease may be treated with their normally recommended dose of efavirenz. 
Patients should be monitored carefully for dose-related adverse reactions, especially nervous system 
symptoms (see sections 4.3 and 4.4). 

Paediatric population 

The safety and efficacy of efavirenz in children below the age of 3 months or weighing less than 
3.5 kg have not been established. No data are available. 

Method of administration 

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz 
concentrations observed following administration of efavirenz with food may lead to an increase in 
frequency of adverse reactions (see sections 4.4. and 5.2). 

4.3 Contraindications 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

Patients with severe hepatic impairment (Child Pugh Class C) (see section 5.2). 

Co-administraion with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or 
ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) 
because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the 
potential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias, 
prolonged sedation or respiratory depression] (see section 4.5). 

Co-administration with elbasvir (EBR) and grazoprevir (GZR) due to the potential for significant 
decreases in plasma concentrations of EBR and GZR (see section 4.5). 

Herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of decreased 
plasma concentrations and reduced clinical effects of efavirenz (see section 4.5). 

Patients with: 
- a family history of sudden death or of congenital prolongation of the QTc interval on 
electrocardiograms, or with any other clinical condition known to prolong the QTc interval. 



37

- a history of symptomatic cardiac arrythmias or with clinically relevant bradycardia or with 
congestive cardiac failure accompanied by reduced left ventricle ejection fraction. 
- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia. 

Patients taking drugs that are known to prolong the QTc interval (proarrythmic).  
These drugs include: 

- antiarrhythmics of classes IA and III, 
- neuroleptics, antidepressive agents, 
- certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, 

imidazole and triazole antifungal agents, 
- certain non-sedating antihistamines (terfenadine, astemizole), 
- cisapride, 
- flecainide, 
- certain antimalarials,   

- methadone. 

4.4 Special warnings and precautions for use 

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing 
regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice 
of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration 
the potential for viral cross-resistance (see section 5.1). 

Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, 
and tenofovir disoproxil is not recommended unless needed for dose adjustment (for example, with 
rifampicin). 

Coadministration of sofosbuvir/velpatasvir with efavirenz is not recommended (see section 4.5). 
Concomitant administration of velpatasvir/sofosbuvir/ voxilaprevir with efavirenz is not recommended 
(see section 4.5). 

Coadministration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma 
concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Coadministration 
of glecaprevir/pibrentasvir with efavirenz is not recommended (see section 4.5). 

Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5). 

When prescribing medicinal products concomitantly with efavirenz, physicians should refer to the 
corresponding Summary of Product Characteristics. 

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines.  

If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected 
intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral 
medicinal products. The antiretroviral medicinal products should be restarted at the same time upon 
resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of 
antiretroviral agents is not advisable because of the increased potential for selection of resistant virus. 

Rash

Mild -to-moderate rash has been reported in clinical studies with efavirenz and usually resolves with 
continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and 
hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration 
has been reported in less than 1% of patients treated with efavirenz. The incidence of erythema 



38

multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz must be discontinued in 
patients developing severe rash associated with blistering, desquamation, mucosal involvement or 
fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting 
therapy with other antiretroviral agents to avoid development of resistant virus (see section 4.8). 

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class 
is limited (see section 4.8). Efavirenz is not recommended for patients who have had a life-threatening 
cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI. 

Psychiatric symptoms 

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a 
prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse 
reactions. In particular, severe depression was more common in those with a history of depression. 
There have also been post-marketing reports of severe depression, death by suicide, delusions, 
psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptoms 
such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately 
to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to 
determine whether the risks of continued therapy outweigh the benefits (see section 4.8). 

Nervous system symptoms

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and 
abnormal dreaming are frequently reported adverse reactions in patients receiving efavirenz 600 mg 
daily in clinical studies (see section 4.8). Nervous system symptoms usually begin during the first one 
or two days of therapy and generally resolve after the first 2 - 4 weeks. Patients should be informed 
that if they do occur, these common symptoms are likely to improve with continued therapy and are 
not predictive of subsequent onset of any of the less frequent psychiatric symptoms. 

Seizures 

Convulsions have been observed in adult and paediatric patients receiving efavirenz, generally in the 
presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant 
medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and 
phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, 
carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with 
efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures. 

Hepatic events 

A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic 
disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be 
considered for patients without pre-existing hepatic dysfunction or other risk factors. 

QTc Prolongation 

QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1).  

Consider alternatives to efavirenz for coadministration with a drug with a known risk of Torsade de 
Pointes or when to be administered to patients at higher risk of Torsade de Pointes.  

Effect of food 

The administration of efavirenz with food may increase efavirenz exposure (see section 5.2) and may 
lead to an increase in the frequency of adverse reactions (see section 4.8). It is recommended that 
efavirenz be taken on an empty stomach, preferably at bedtime. 



39

Immune Reactivation Syndrome 

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

Weight and metabolic parameters 

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

Osteonecrosis 

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement. 

Special populations 

Liver disease

Efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2) and 
not recommended in patients with moderate hepatic impairment because of insufficient data to 
determine whether dose adjustment is necessary. Because of the extensive cytochrome P450-mediated 
metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution 
must be exercised in administering efavirenz to patients with mild hepatic impairment. Patients should 
be monitored carefully for dose-related adverse reactions, especially nervous system symptoms. 
Laboratory tests should be performed to evaluate their liver disease at periodic intervals (see 
section 4.2). 

The safety and efficacy of efavirenz has not been established in patients with significant underlying 
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral 
therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. Patients with 
pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver 
function abnormalities during combination antiretroviral therapy and should be monitored according to 
standard practice. If there is evidence of worsening liver disease or persistent elevations of serum 
transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued 
therapy with efavirenz needs to be weighed against the potential risks of significant liver toxicity. In 
such patients, interruption or discontinuation of treatment must be considered (see section 4.8).  

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver 
enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please 
refer also to the relevant product information for these medicinal products. 



40

Renal insufficiency 

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, 
less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal 
impairment on efavirenz elimination should be minimal (see section 4.2). There is no experience in 
patients with severe renal failure and close safety monitoring is recommended in this population. 

Elderly patients

Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether 
they respond differently than younger patients. 

Paediatric population 

Efavirenz has not been evaluated in children below 3 months of age or who weigh less than 3.5 kg. 
Therefore, efavirenz should not be given to children less than 3 months of age. Efavirenz film-coated 
tablets are not suitable for children weighing less than 40 kg. 

Rash was reported in 59 of 182 children (32%) treated with efavirenz and was severe in six patients. 
Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may 
be considered. 

Lactose 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.  

4.5 Interaction with other medicinal products and other forms of interaction 

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of 
these enzymes may have decreased plasma concentrations when co-administered with efavirenz. In 
vitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initially 
increase the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates with 
narrow therapeutic index (see section 4.3). Efavirenz may be an inducer of CYP2C19 and CYP2C9; 
however, inhibition has also been observed in vitro and the net effect of co-administration with 
substrates of these enzymes is not clear (see section 5.2). 

Efavirenz exposure may be increased when given with medicinal products (for example, ritonavir) or 
food (for example, grapefruit juice), which inhibit CYP3A4 or CYP2B6 activity. Compounds or 
herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these 
enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John’s 
wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not 
recommended (see section 4.4). 

QT Prolonging Drugs 

Efavirenz is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval 
and Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant 
agents, certain antibiotics including some agents of the following classes: macrolides,  
fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics 
(terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3). 

Paediatric population 

Interaction studies have only been performed in adults. 

Contraindications of concomitant use 



41

Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, 
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, 
ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-
threatening events (see section 4.3). 

Elbasvir/grazoprevir 

Concomitant administration of efavirenz with elbasvir/grazoprevir is contraindicated because it may 
lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in 
elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. (see section 4.3). 

St. John’s wort (Hypericum perforatum)

Co-administration of efavirenz and St. John’s wort or herbal preparations containing St. John’s wort is 
contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John’s wort due 
to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort. If a patient is 
already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible efavirenz levels. 
Efavirenz levels may increase on stopping St. John’s wort and the dose of efavirenz may need 
adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of 
treatment (see section 4.3). 

Other interactions 

Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease 
inhibitors and other non-antiretroviral medicinal products are listed in Table 1 below (increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or 
“q12h”). If available, 90% or 95% confidence intervals are shown in parentheses. Studies were 
conducted in healthy subjects unless otherwise noted.  

Table 1: Interactions between efavirenz and other medicinal products in adults 

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

ANTI-INFECTIVES
HIV antivirals 
Protease inhibitors (PI) 
Atazanavir/ ritonavir/Efavirenz 
(400 mg once daily/100 mg once 
daily/600 mg once daily, all 
administered with food) 

Atazanavir (pm): 
AUC: ↔* (↓9 to ↑10) 
Cmax: ↑17%* (↑8 to ↑27)
Cmin: ↓42%* (↓31 to ↓51) 

Co-administration of efavirenz 
with atazanavir/ritonavir is not 
recommended. If the co-
administration of atazanavir 
with an NNRTI is required, an 
increase in the dose of both 
atazanavir and ritonavir to 
400 mg and 200 mg, 
respectively, in combination 
with efavirenz could be 
considered with close clinical 
monitoring.

Atazanavir/ritonavir/Efavirenz 
(400 mg once daily/200 mg once 
daily/600 mg once daily, all 
administered with food) 

Atazanavir (pm): 
AUC: ↔*/** (↓10 to ↑26) 
Cmax: ↔*/** (↓5 to ↑26) 
Cmin: ↑ 12%*/** (↓16 to ↑49) 
(CYP3A4 induction). 
* When compared to atazanavir 
300 mg/ritonavir 100 mg once daily in 
the evening without efavirenz. This 
decrease in atazanavir Cmin might 
negatively impact the efficacy of 
atazanavir. 
** based on historical comparison 



42

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Darunavir/ritonavir/Efavirenz 
(300 mg twice daily*/100 mg 
twice daily/600 mg once daily) 

*lower than recommended doses; 
similar findings are expected with 
recommended doses. 

Darunavir: 
AUC: ↓ 13% 
Cmin: ↓ 31% 
Cmax: ↓ 15% 
(CYP3A4 induction) 
Efavirenz: 
AUC: ↑ 21% 
Cmin: ↑ 17% 
Cmax: ↑ 15% 
(CYP3A4 inhibition) 

Efavirenz in combination with 
darunavir/ritonavir 800/100 mg 
once daily may result in 
suboptimal darunavir Cmin. If 
efavirenz is to be used in 
combination with 
darunavir/ritonavir, the 
darunavir/ritonavir 600/100 mg 
twice daily regimen should be 
used. This combination should 
be used with caution.See also 
ritonavir row below.

Fosamprenavir/ritonavir/Efavirenz 
(700 mg twice daily/100 mg twice 
daily/600 mg once daily) 

No clinically significant 
pharmacokinetic interaction 

No dose adjustment is necessary 
for any of these medicinal 
products. See also ritonavir row 
below.

Fosamprenavir/Nelfinavir/ 
Efavirenz 

Interaction not studied. No dose adjustment is necessary 
for any of these medicinal 
products.

Fosamprenavir/Saquinavir/ 
Efavirenz 

Interaction not studied. Not recommended as the 
exposure to both PIs is expected 
to be significantly decreased.

Indinavir/Efavirenz 
(800 mg q8h/200 mg once daily) 

Indinavir: 
AUC : ↓ 31% (↓ 8 to ↓ 47) 
Cmin : ↓ 40%
A similar reduction in indinavir 
exposures was observed when indinavir 
1000 mg q8h was given with efavirenz 
600 mg daily. 
(CYP3A4 induction) 
Efavirenz: 
No clinically significant 
pharmacokinetic interaction 

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 and indinavir. 

No dose adjustment is necessary 
for efavirenz when given with 
indinavir or indinavir/ritonavir. 

See also ritonavir row below. 

Indinavir/ritonavir/Efavirenz 
(800 mg twice daily/100 mg twice 
daily/600 mg once daily) 

Indinavir: 
AUC: ↓ 25% (↓ 16 to ↓ 32)b

Cmax: ↓ 17% (↓ 6 to ↓ 26)b

Cmin: ↓ 50% (↓ 40 to ↓ 59)
b

Efavirenz: 
No clinically significant 
pharmacokinetic interaction 
The geometric mean Cmin for indinavir 
(0.33 mg/l) when given with ritonavir 
and efavirenz was higher than the mean 
historical Cmin (0.15 mg/l) when 
indinavir was given alone at 800 mg 
q8h. In HIV-1 infected patients (n = 6), 
the pharmacokinetics of indinavir and 
efavirenz were generally comparable to 
these uninfected volunteer data.



43

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Lopinavir/ritonavir soft capsules or 
oral solution/Efavirenz 

Lopinavir/ritonavir tablets/ 
Efavirenz 
(400/100 mg twice daily/600 mg 
once daily) 
(500/125 mg twice daily/600 mg 
once daily) 

Substantial decrease in lopinavir 
exposure.  

Lopinavir concentrations: ↓ 30-40% 

Lopinavir concentrations: similar to 
lopinavir/ritonavir 400/100 mg twice 
daily without efavirenz 

With efavirenz, an increase of 
the lopinavir/ritonavir soft 
capsule or oral solution doses 
by 33% should be considered 
(4 capsules/~6.5 ml twice daily 
instead of 3 capsules/5 ml twice 
daily). Caution is warranted 
since this dose adjustment 
might be insufficient in some 
patients. The dose of 
lopinavir/ritonavir tablets 
should be increased to 
500/125 mg twice daily when 
co-administered with efavirenz 
600 mg once daily. 
See also ritonavir row below.

Nelfinavir/Efavirenz 
(750 mg q8h/600 mg once daily) 

Nelfinavir: 
AUC: ↑ 20% (↑ 8 to ↑ 34) 
Cmax: ↑ 21% (↑ 10 to ↑ 33)
The combination was generally well 
tolerated.

No dose adjustment is necessary 
for either medicinal product. 

Ritonavir/Efavirenz 
(500 mg twice daily/600 mg once 
daily) 

Ritonavir: 
Morning AUC: ↑ 18% (↑ 6 to ↑ 33)
Evening AUC: ↔ 
Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)
Evening Cmax: ↔ 
Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) 

b

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) 
b

Efavirenz: 
AUC: ↑ 21% (↑ 10 to ↑ 34)  
Cmax: ↑ 14% (↑ 4 to ↑ 26)
Cmin: ↑ 25% (↑ 7 to ↑ 46) 

b

(inhibition of CYP-mediated oxidative 
metabolism) 
When efavirenz was given with 
ritonavir 500 mg or 600 mg twice 
daily, the combination was not well 
tolerated (for example, dizziness, 
nausea, paraesthesia and elevated liver 
enzymes occurred). Sufficient data on 
the tolerability of efavirenz with low-
dose ritonavir (100 mg, once or twice 
daily) are not available. 

When using efavirenz with low-
dose ritonavir, the possibility of 
an increase in the incidence of 
efavirenz-associated adverse 
events should be considered, 
due to possible 
pharmacodynamic interaction. 

Saquinavir/ritonavir/Efavirenz Interaction not studied. No data are available to make a 
dose recommendation. See also 
ritonavir row above. Use of 
efavirenz in combination with 
saquinavir as the sole protease 
inhibitor is not recommended.

CCR5 antagonist
Maraviroc/Efavirenz 
(100 mg twice daily/600 mg once 
daily) 

Maraviroc: 
AUC12: ↓ 45% (↓ 38 to ↓ 51)

Cmax: ↓ 51% (↓ 37 to ↓ 62)
Efavirenz concentrations not measured, 
no effect is expected.

Refer to the Summary of 
Product Characteristics for the 
medicinal product containing 
maraviroc. 

Integrase strand transfer inhibitor



44

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Raltegravir/Efavirenz 
(400 mg single dose/ -) 

Raltegravir: 
AUC: ↓ 36% 
C12: ↓ 21% 
Cmax: ↓ 36% 
(UGT1A1 induction)

No dose adjustment is necessary 
for raltegravir. 

NRTIs and NNRTIs
NRTIs/Efavirenz Specific interaction studies have not 

been performed with efavirenz and 
NRTIs other than lamivudine, 
zidovudine, and tenofovir disoproxil. 
Clinically significant interactions are 
not expected since the NRTIs are 
metabolised via a different route than 
efavirenz and would be unlikely to 
compete for the same metabolic 
enzymes and elimination pathways.

No dose adjustment is necessary 
for either medicinal product. 

NNRTIs/Efavirenz Interaction not studied.  Since use of two NNRTIs 
proved not beneficial in terms 
of efficacy and safety, co-
administration of efavirenz and 
another NNRTI is not 
recommended.

Hepatitis C antivirals 
Boceprevir/Efavirenz 
(800 mg 3 times daily/600 mg 
once daily) 

Boceprevir: 
AUC: ↔ 19%* 
Cmax: ↔ 8% 
Cmin: ↓ 44% 
Efavirenz: 
AUC: ↔ 20% 
Cmax: ↔ 11% 
(CYP3A induction - effect on 
boceprevir) 
*0-8 hours 
No effect (↔) equals a decrease in 
mean ratio estimate of ≤20% or 
increase in mean ratio estimate of 
≤25%

Plasma trough concentrations of 
boceprevir were decreased 
when administered with 
efavirenz. The clinical outcome 
of this observed reduction of 
boceprevir trough 
concentrations has not been 
directly assessed. 

Telaprevir/Efavirenz 
(1,125 mg q8h/600 mg once daily) 

Telaprevir (relative to 750 mg q8h): 
AUC: ↓ 18% (↓ 8 to ↓ 27) 
Cmax: ↓ 14% (↓ 3 to ↓ 24) 
Cmin: ↓ 25% (↓ 14 to ↓ 34)% 
Efavirenz: 
AUC: ↓ 18% (↓ 10 to ↓ 26) 
Cmax: ↓ 24% (↓ 15 to ↓ 32) 
Cmin: ↓ 10% (↑ 1 to ↓ 19)% 
(CYP3A induction by efavirenz)

If efavirenz and telaprevir are 
co-administered, telaprevir 
1,125 mg every 8 hours should 
be used. 



45

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Simeprevir/Efavirenz 
(150 mg once daily /600 mg once 
daily) 

Simeprevir:  
AUC: ↓71% (↓67 to ↓74)  
Cmax: ↓51% (↓46 to ↓56) 
Cmin: ↓91% (↓88 to ↓92) 
Efavirenz: 
AUC: ↔  
Cmax: ↔ 
Cmin: ↔ 
No effect (↔) equals a decrease in 
mean ratio estimate of ≤20% or 
increase in mean ratio estimate of 
≤25% 
(CYP3A4 enzyme induction)

Concomitant administration of 
simeprevir with efavirenz 
resulted in significantly 
decreased plasma 
concentrations of simeprevir 
due to CYP3A induction by 
efavirenz, which may result in 
loss of therapeutic effect of 
simeprevir. Co-administration 
of simeprevir with efavirenz is 
not recommended. 

Sofosbuvir/ velpatasvir ↔sofosbuvir 

↓velpatasvir 

↔efavirenz

Concomitant administration 
of sofosbuvir/velpatasvir 
with efavirenz resulted in a 
reduction (approximately 
50%) in the systemic 
exposure of velpatasvir. The 
mechanism of the effect on 
velpatasvir is induction of 
CYP3A and CYP2B6 by 
efavirenz. Coadministration 
of sofosbuvir/velpatasvir 
with efavirenz is not 
recommended.  Refer to the 
prescribing information for 
sofosbuvir/velpatasvir for 
more information.

Velpatasvir/ sofosbuvir/ 
voxilaprevir

↓velpatasvir 

↓voxilaprevir

Concomitant administration 
of velpatasvir/sofosbuvir/ 
voxilaprevir with efavirenz is 
not recommended, as it may 
decrease concentrations of 
velpatasvir and voxilaprevir. 
Refer to the prescribing 
information for 
velpatasvir/sofosbuvir/ 
voxilaprevir for more 
information.



46

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Protease inhibitor : 

Elbasvir/ grazoprevir 

↓elbasvir 

↓grazoprevir

↔efavirenz

Concomitant administration 
of efavirenz with 
elbasvir/grazoprevir is 
contraindicated because it 
may lead to loss of virologic 
response to 
elbasvir/grazoprevir. This 
loss is due to significant 
decreases in elbasvir and 
grazoprevir plasma 
concentrations caused by 
CYP3A4 induction. Refer to 
the prescribing information 
for elbasvir/grazoprevir for 
more information.

Glecaprevir/pibrentasvir ↓glecaprevir 

↓ pibrentasvir 

Concomitant administration 
of glecaprevir/pibrentasvir 
with efavirenz may 
significantly decrease plasma 
concentrations of glecaprevir 
and pibrentasvir, leading to 
reduced therapeutic effect. 
Coadministration of 
glecaprevir/pibrentasvir with 
efavirenz is not 
recommended. Refer to the 
prescribing information for 
glecaprevir/pibrentasvir for 
more information.

Antibiotics
Azithromycin/Efavirenz 
(600 mg single dose/400 mg once 
daily)

No clinically significant 
pharmacokinetic interaction. 

No dose adjustment is necessary 
for either medicinal product. 

Clarithromycin/Efavirenz 
(500 mg q12h/400 mg once daily)

Clarithromycin: 
AUC: ↓ 39% (↓ 30 to ↓ 46) 
Cmax: ↓ 26% (↓ 15 to ↓ 35) 
Clarithromycin 14-hydroxymetabolite: 
AUC: ↑ 34% (↑ 18 to ↑ 53) 
Cmax: ↑ 49% (↑ 32 to ↑ 69) 
Efavirenz: 
AUC: ↔ 
Cmax: ↑ 11% (↑ 3 to ↑ 19) 
(CYP3A4 induction) 
Rash developed in 46% of uninfected 
volunteers receiving efavirenz and 
clarithromycin.

The clinical significance of 
these changes in clarithromycin 
plasma levels is not known. 
Alternatives to clarithromycin 
(e.g. azithromycin) may be 
considered. No dose adjustment 
is necessary for efavirenz.  

Other macrolide antibiotics 
(e.g.,erythromycin)/Efavirenz

Interaction not studied. No data are available to make a 
dose recommendation.



47

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Antimycobacterials
Rifabutin/Efavirenz 
(300 mg once daily/600 mg once 
daily) 

Rifabutin: 
AUC: ↓ 38% (↓ 28 to ↓ 47) 
Cmax: ↓ 32% (↓ 15 to ↓ 46) 
Cmin: ↓ 45% (↓ 31 to ↓ 56)  
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 12% (↓ 24 to ↑ 1) 
(CYP3A4 induction) 

The daily dose of rifabutin 
should be increased by 50% 
when administered with 
efavirenz. Consider doubling 
the rifabutin dose in regimens 
where rifabutin is given 2 or 
3 times a week in combination 
with efavirenz. The clinical 
effect of this dose adjustment 
has not been adequately 
evaluated. Individual 
tolerability and virological 
response should be considered 
when making the dose 
adjustment (see section 5.2).

Rifampicin/Efavirenz 
(600 mg once daily/600 mg once 
daily) 

Efavirenz: 
AUC: ↓ 26% (↓ 15 to ↓ 36)

Cmax: ↓ 20% (↓ 11 to ↓ 28) 
Cmin: ↓ 32% (↓ 15 to ↓ 46) 
(CYP3A4 and CYP2B6 induction) 

When taken with rifampicin in 
patients weighing 50 kg or 
greater, increasing efavirenz 
daily dose to 800 mg may 
provide exposure similar to a 
daily dose of 600 mg when 
taken without rifampicin. The 
clinical effect of this dose 
adjustment has not been 
adequately evaluated. 
Individual tolerability and 
virological response should be 
considered when making the 
dose adjustment (see section 
5.2). No dose adjustment is 
necessary for rifampicin, 
including 600 mg.

Antifungals
Itraconazole/Efavirenz 
(200 mg q12h/600 mg once daily)

Itraconazole:  
AUC: ↓ 39% (↓ 21 to ↓ 53)

Cmax: ↓ 37% (↓ 20 to ↓ 51) 
Cmin: ↓ 44% (↓ 27 to ↓ 58) 
(decrease in itraconazole 
concentrations: CYP3A4 induction) 
Hydroxyitraconazole: 
AUC: ↓ 37% (↓ 14 to ↓ 55) 

Cmax: ↓ 35% (↓ 12 to ↓ 52) 
Cmin: ↓ 43% (↓ 18 to ↓ 60) 
Efavirenz:  
No clinically significant 
pharmacokinetic change. 

Since no dose recommendation 
for itraconazole can be made, 
alternative antifungal treatment 
should be considered. 



48

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Posaconazole/Efavirenz 
--/400 mg once daily 

Posaconazole: 
AUC: ↓ 50%  
Cmax: ↓ 45% 
(UDP-G induction) 

Concomitant use of 
posaconazole and efavirenz 
should be avoided unless the 
benefit to the patient outweighs 
the risk. 

Voriconazole/Efavirenz 
(200 mg twice daily/400 mg once 
daily) 

Voriconazole/Efavirenz 
(400 mg twice daily/300 mg once 
daily) 

Voriconazole: 
AUC: ↓ 77%

Cmax: ↓ 61% 
Efavirenz: 
AUC: ↑ 44% 
Cmax: ↑ 38% 
Voriconazole: 
AUC: ↓ 7% (↓ 23 to ↑ 13) * 
Cmax: ↑ 23% (↓ 1 to ↑ 53) * 
Efavirenz: 
AUC: ↑ 17% (↑ 6 to ↑ 29) ** 
Cmax: ↔** 
*compared to 200 mg twice daily alone 
** compared to 600 mg once daily 
alone 
(competitive inhibition of oxidative 
metabolism)

When efavirenz is co-
administered with voriconazole, 
the voriconazole maintenance 
dose must be increased to 
400 mg twice daily and the 
efavirenz dose must be reduced 
by 50%, i.e., to 300 mg once 
daily. When treatment with 
voriconazole is stopped, the 
initial dose of efavirenz should 
be restored.  

Fluconazole/Efavirenz 
(200 mg once daily/400 mg once 
daily)

No clinically significant 
pharmacokinetic interaction  

No dose adjustment is necessary 
for either medicinal product. 

Ketoconazole and other imidazole 
antifungals

Interaction not studied No data are available to make a 
dose recommendation.

Antimalarials 
Artemether/lumefantrine/ 
Efavirenz 
(20/120 mg tablet, 6 doses of 4 
tablets each over 3 days/600mg 
once daily) 

Artemether: 
AUC: ↓ 51%  
Cmax: ↓ 21%  
Dihydroartemisinin: 
AUC: ↓ 46% 
Cmax: ↓ 38%  
Lumefantrine: 
AUC: ↓ 21%  
Cmax: ↔ 
Efavirenz: 
AUC: ↓ 17% 
Cmax: ↔ 
(CYP3A4 induction)

Since decreased concentrations 
of artemether, 
dihydroartemisinin, or 
lumefantrine may result in a 
decrease of antimalarial 
efficacy, caution is 
recommended when efavirenz 
and artemether/lumefantrine 
tablets are coadministered. 

Atovaquone and proguanil 
hydrochloride/Efavirenz 
(250/100 mg single dose/600 mg 
once daily) 

Atovaquone: 
AUC: ↓ 75% (↓ 62 to ↓ 84) 
Cmax: ↓ 44% (↓ 20 to ↓ 61) 
Proguanil: 
AUC: ↓ 43% (↓ 7 to ↓ 65) 
Cmax: ↔ 

Concomitant administration of 
atovaquone/proguanil with 
efavirenz should be avoided. 



49

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

ACID REDUCING AGENTS
Aluminium hydroxide-magnesium 
hydroxide-simethicone 
antacid/Efavirenz 
(30 ml single dose/400 mg single 
dose) 
Famotidine/Efavirenz 
(40 mg single dose/400 mg single 
dose)

Neither aluminium/magnesium 
hydroxide antacids nor famotidine 
altered the absorption of efavirenz.  

Co-administration of efavirenz 
with medicinal products that 
alter gastric pH would not be 
expected to affect efavirenz 
absorption. 

ANTIANXIETY AGENTS
Lorazepam/Efavirenz 
(2 mg single dose/600 mg once 
daily)

Lorazepam:  
AUC: ↑ 7% (↑ 1 to ↑ 14) 
Cmax: ↑ 16% (↑ 2 to ↑ 32) 
These changes are not considered 
clinically significant.

No dose adjustment is necessary 
for either medicinal product. 

ANTICOAGULANTS
Warfarin/Efavirenz 
Acenocoumarol/Efavirenz 

Interaction not studied. Plasma 
concentrations and effects of warfarin 
or acenocoumarol are potentially 
increased or decreased by efavirenz.

Dose adjustment of warfarin or 
acenocoumarol may be 
required. 

ANTICONVULSANTS
Carbamazepine/Efavirenz 
(400 mg once daily/600 mg once 
daily)

Carbamazepine: 
AUC: ↓ 27% (↓ 20 to ↓ 33) 
Cmax: ↓ 20% (↓ 15 to ↓ 24) 
Cmin: ↓ 35% (↓ 24 to ↓ 44) 
Efavirenz: 
AUC: ↓ 36% (↓ 32 to ↓ 40)

Cmax: ↓ 21% (↓ 15 to ↓ 26)
Cmin: ↓ 47% (↓ 41 to ↓ 53)
(decrease in carbamazepine 
concentrations: CYP3A4 induction; 
decrease in efavirenz concentrations: 
CYP3A4 and CYP2B6 induction)  
The steady-state AUC, Cmax and Cmin
of the active carbamazepine epoxide 
metabolite remained unchanged. Co-
administration of higher doses of either 
efavirenz or carbamazepine has not 
been studied.

No dose recommendation can 
be made. An alternative 
anticonvulsant should be 
considered. Carbamazepine 
plasma levels should be 
monitored periodically. 

Phenytoin, Phenobarbital, and 
other anticonvulsants that are 
substrates of CYP450 isoenzymes 

Interaction not studied. There is a 
potential for reduction or increase in 
the plasma concentrations of 
phenytoin, phenobarbital and other 
anticonvulsants that are substrates of 
CYP450 isoenzymes when co-
administered with efavirenz.

When efavirenz is co-
administered with an 
anticonvulsant that is a substrate 
of CYP450 isoenzymes, 
periodic monitoring of 
anticonvulsant levels should be 
conducted.

Valproic acid/Efavirenz 
(250 mg twice daily/600 mg once 
daily) 

No clinically significant effect on 
efavirenz pharmacokinetics. Limited 
data suggest there is no clinically 
significant effect on valproic acid 
pharmacokinetics.

No dose adjustment is necessary 
for efavirenz. Patients should be 
monitored for seizure control. 



50

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Vigabatrin/Efavirenz 
Gabapentin/Efavirenz 

Interaction not studied. Clinically 
significant interactions are not expected 
since vigabatrin and gabapentin are 
exclusively eliminated unchanged in 
the urine and are unlikely to compete 
for the same metabolic enzymes and 
elimination pathways as efavirenz.

No dose adjustment is necessary 
for any of these medicinal 
products. 

ANTIDEPRESSANTS 
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz 
(50 mg once daily/600 mg once 
daily) 

Sertraline: 
AUC: ↓ 39% (↓ 27 to ↓ 50)  
Cmax: ↓ 29% (↓ 15 to ↓ 40) 
Cmin: ↓ 46% (↓ 31 to ↓ 58) 
Efavirenz:  
AUC: ↔ 
Cmax: ↑ 11% (↑ 6 to ↑ 16) 
Cmin: ↔  
(CYP3A4 induction)

Sertraline dose increases should 
be guided by clinical response. 
No dose adjustment is necessary 
for efavirenz. 

Paroxetine/Efavirenz 
(20 mg once daily/600 mg once 
daily)

No clinically significant 
pharmacokinetic interaction 

No dose adjustment is necessary 
for either medicinal product. 

Fluoxetine/Efavirenz Interaction not studied. Since 
fluoxetine shares a similar metabolic 
profile with paroxetine, i.e. a strong 
CYP2D6 inhibitory effect, a similar 
lack of interaction would be expected 
for fluoxetine.

No dose adjustment is necessary 
for either medicinal product. 

NOREPINEPHRINE AND DOPAMINE REUPTAKE INHIBITOR 
Bupropion/Efavirenz 
[150 mg single dose (sustained 
release)/600 mg once daily] 

Bupropion: 
AUC: ↓ 55% (↓ 48 to ↓ 62)  
Cmax: ↓ 34% (↓ 21 to ↓ 47)  
Hydroxybupropion:  
AUC: ↔ 
Cmax: ↑ 50% (↑ 20 to ↑ 80)
(CYP2B6 induction)

Increases in bupropion dosage 
should be guided by clinical 
response, but the maximum 
recommended dose of 
bupropion should not be 
exceeded.  No dose adjustment 
is necessary for efavirenz. 

ANTIHISTAMINES
Cetirizine/Efavirenz 
(10 mg single dose/600 mg once 
daily)

Cetirizine: 
AUC: ↔ 
Cmax: ↓ 24% (↓ 18 to ↓ 30)
These changes are not considered 
clinically significant. 
Efavirenz:  
No clinically significant 
pharmacokinetic interaction

No dose adjustment is necessary 
for either medicinal product. 



51

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

CARDIOVASCULAR AGENTS 
Calcium Channel Blockers 
Diltiazem/Efavirenz 
(240 mg once daily/600 mg once 
daily) 

Diltiazem: 
AUC: ↓ 69% (↓ 55 to ↓ 79)  
Cmax: ↓ 60% (↓ 50 to ↓ 68)  
Cmin: ↓ 63% (↓ 44 to ↓ 75) 
Desacetyl diltiazem: 
AUC: ↓ 75% (↓ 59 to ↓ 84)  
Cmax: ↓ 64% (↓ 57 to ↓ 69) 
Cmin: ↓ 62% (↓ 44 to ↓ 75) 
N-monodesmethyl diltiazem: 
AUC: ↓ 37% (↓ 17 to ↓ 52) 
Cmax: ↓ 28% (↓ 7 to ↓ 44) 
Cmin: ↓ 37% (↓ 17 to ↓ 52) 
Efavirenz: 
AUC: ↑ 11% (↑ 5 to ↑ 18)

Cmax: ↑ 16% (↑ 6 to ↑ 26) 
Cmin: ↑ 13% (↑ 1 to ↑ 26)
(CYP3A4 induction) 
The increase in efavirenz 
pharmacokinetic parameters is not 
considered clinically significant.

Dose adjustments of diltiazem 
should be guided by clinical 
response (refer to the Summary 
of Product Characteristics for 
diltiazem). No dose adjustment 
is necessary for efavirenz. 

Verapamil, Felodipine, Nifedipine 
and Nicardipine 

Interaction not studied. When efavirenz 
is co-administered with a calcium 
channel blocker that is a substrate of 
the CYP3A4 enzyme, there is a 
potential for reduction in the plasma 
concentrations of the calcium channel 
blocker.

Dose adjustments of calcium 
channel blockers should be 
guided by clinical response 
(refer to the Summary of 
Product Characteristics for the 
calcium channel blocker). 

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors
Atorvastatin/Efavirenz 
(10 mg once daily/600 mg once 
daily) 

Atorvastatin: 
AUC: ↓ 43% (↓ 34 to ↓ 50)

Cmax: ↓ 12% (↓ 1 to ↓ 26) 
2-hydroxy atorvastatin: 
AUC: ↓ 35% (↓ 13 to ↓ 40)

Cmax: ↓ 13% (↓ 0 to ↓ 23)
4-hydroxy atorvastatin: 
AUC: ↓ 4% (↓ 0 to ↓ 31) 
Cmax: ↓ 47% (↓ 9 to ↓ 51)
Total active HMG Co-A reductase  
inhibitors:  
AUC: ↓ 34% (↓ 21 to ↓ 41)
Cmax: ↓ 20% (↓ 2 to ↓ 26) 

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of atorvastatin may 
be required (refer to the 
Summary of Product 
Characteristics for atorvastatin). 
No dose adjustment is necessary 
for efavirenz. 

Pravastatin/Efavirenz 
(40 mg once daily/600 mg once 
daily) 

Pravastatin: 
AUC: ↓ 40% (↓ 26 to ↓ 57) 
Cmax: ↓ 18% (↓ 59 to ↑ 12) 

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of pravastatin may 
be required (refer to the 
Summary of Product 
Characteristics for pravastatin). 
No dose adjustment is necessary 
for efavirenz.



52

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

Simvastatin/Efavirenz 
(40 mg once daily/600 mg once 
daily) 

Simvastatin: 
AUC: ↓ 69% (↓ 62 to ↓ 73) 
Cmax: ↓ 76% (↓ 63 to ↓ 79) 
Simvastatin acid: 
AUC: ↓ 58% (↓ 39 to ↓ 68)
Cmax: ↓ 51% (↓ 32 to ↓ 58) 
Total active HMG Co-A reductase 
inhibitors: 
AUC: ↓ 60% (↓ 52 to ↓ 68) 
Cmax: ↓ 62% (↓ 55 to ↓ 78) 
 (CYP3A4 induction) 
Co-administration of efavirenz with 
atorvastatin, pravastatin, or 
simvastatin did not affect efavirenz 
AUC or Cmax values.

Cholesterol levels should be 
periodically monitored. Dose 
adjustment of simvastatin may 
be required (refer to the 
Summary of Product 
Characteristics for simvastatin). 
No dose adjustment is necessary 
for efavirenz. 

Rosuvastatin/Efavirenz Interaction not studied. Rosuvastatin is 
largely excreted unchanged via the 
faeces, therefore interaction with 
efavirenz is not expected.

No dose adjustment is necessary 
for either medicinal product. 

HORMONAL CONTRACEPTIVES
Oral: 
Ethinyloestradiol + Norgestimate/ 
Efavirenz 
(0.035 mg + 0.25 mg once 
daily/600 mg once daily) 

Ethinyloestradiol: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 8% (↑ 14 to ↓ 25) 
Norelgestromin (active metabolite): 
AUC: ↓ 64% (↓ 62 to ↓ 67) 
Cmax: ↓ 46% (↓ 39 to ↓ 52) 
Cmin: ↓ 82% (↓ 79 to ↓ 85) 
Levonorgestrel (active metabolite): 
AUC: ↓ 83% (↓ 79 to ↓ 87) 
Cmax: ↓ 80% (↓ 77 to ↓ 83) 
Cmin: ↓ 86% (↓ 80 to ↓ 90) 
(induction of metabolism) 
Efavirenz: no clinically significant 
interaction. 
The clinical significance of these 
effects is not known.

A reliable method of barrier 
contraception must be used in 
addition to hormonal 
contraceptives (see section 4.6). 

Injection: 
Depomedroxyprogesterone acetate 
(DMPA)/Efavirenz 
(150 mg IM single dose DMPA) 

In a 3-month drug interaction study, no 
significant differences in MPA 
pharmacokinetic parameters were 
found between subjects receiving 
efavirenz-containing antiretroviral 
therapy and subjects receiving no 
antiretroviral therapy. Similar results 
were found by other investigators, 
although the MPA plasma levels were 
more variable in the second study. In 
both studies, plasma progesterone 
levels for subjects receiving efavirenz 
and DMPA remained low consistent 
with suppression of ovulation.

Because of the limited 
information available, a reliable 
method of barrier contraception 
must be used in addition to 
hormonal contraceptives (see 
section 4.6). 

Implant: Etonogestrel/Efavirenz Decreased exposure of etonogestrel 
may be expected (CYP3A4 induction). 
There have been occasional 
postmarketing reports of contraceptive 
failure with etonogestrel in efavirenz-
exposed patients.

A reliable method of barrier 
contraception must be used in 
addition to hormonal 
contraceptives (see section 4.6).



53

Medicinal product by 
therapeutic areas 

(dose) 

Effects on drug levels 
Mean percent change in AUC, Cmax, 

Cmin with confidence intervals if 
availablea 

(mechanism) 

Recommendation concerning 
co-administration with 

efavirenz 

IMMUNOSUPPRESSANTS
Immunosuppressants metabolized 
by CYP3A4 (eg, cyclosporine, 
tacrolimus, sirolimus)/Efavirenz 

Interaction not studied. Decreased 
exposure of the immunosuppressant 
may be expected (CYP3A4 induction). 
These immunosuppressants are not 
anticipated to affect exposure of 
efavirenz. 

Dose adjustments of the 
immunosuppressant may be 
required. Close monitoring of 
immunosuppressant 
concentrations for at least 2 
weeks (until stable 
concentrations are reached) is 
recommended when starting or 
stopping treatment with 
efavirenz.

OPIOIDS
Methadone/Efavirenz 
(stable maintenance, 35-100 mg 
once daily/600 mg once daily) 

Methadone: 
AUC: ↓ 52% (↓ 33 to ↓ 66)
Cmax: ↓ 45% (↓ 25 to ↓ 59) 
(CYP3A4 induction) 
In a study of HIV infected intravenous 
drug users, co-administration of 
efavirenz with methadone resulted in 
decreased plasma levels of methadone 
and signs of opiate withdrawal. The 
methadone dose was increased by a 
mean of 22% to alleviate withdrawal 
symptoms. 

Concomitant administration 
with efavirenz should be 
avoided due to the risk for QTc 
prolongation (see section 4.3). 

Buprenorphine/naloxone/Efavirenz Buprenorphine: 
AUC: ↓ 50%
Norbuprenorphine: 
AUC: ↓ 71% 
Efavirenz: 
No clinically significant 
pharmacokinetic interaction 

Despite the decrease in 
buprenorphine exposure, no 
patients exhibited withdrawal 
symptoms. Dose adjustment of 
buprenorphine or efavirenz may 
not be necessary when co-
administered. 

a 90% confidence intervals unless otherwise noted. 
b 95% confidence intervals. 

Other interactions: efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid 
test results have been reported with some screening assays in uninfected and HIV-infected subjects 
receiving efavirenz. Confirmatory testing by a more specific method such as gas chromatography/mass 
spectrometry is recommended in such cases. 

4.6 Fertility, pregnancy and lactation 

Women of childbearing potential 

See below and section 5.3. Efavirenz should not be used during pregnancy, unless the patient’s clinical 
condition requires such treatment. Women of childbearing potential should undergo pregnancy testing 
before initiation of efavirenz.  

Contraception in males and females 

Barrier contraception should always be used in combination with other methods of contraception (for 
example, oral or other hormonal contraceptives, see section 4.5). Because of the long half-life of 
efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is 
recommended.  

Pregnancy 



54

There have been seven retrospective reports of findings consistent with neural tube defects, including 
meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-
containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective 
and 1 retrospective) including events consistent with neural tube defects have been reported with the 
fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate. 
A causal relationship of these events to the use of efavirenz has not been established, and the 
denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development 
(at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz 
during the first trimester of pregnancy. 

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 
pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births. 
One child was reported to have a neural tube defect, and the frequency and pattern of other birth 
defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as 
those in HIV negative controls. The incidence of neural tube defects in the general population ranges 
from 0.5-1 case per 1,000 live births. 

Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3). 

Breast-feeding 

Efavirenz has been shown to be excreted in human milk.  There is insufficient information on the 
effects of efavirenz in newborns/infants. Risk to the infant can not be excluded. Breast-feeding should 
be discontinued during treatment with SUSTIVA. It is recommended that HIV infected women do not 
breast-feed their infants under any circumstances in order to avoid transmission of HIV. 

Fertility 

The effect of efavirenz on male and female fertility in rats has only been evaluated at doses that 
achieved systemic drug exposures equivalent to or below those achieved in humans given 
recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of male 
or female rats (doses up to 100 mg/kg/bid), and did not affect sperm or offspring of treated male rats 
(doses up to 200 mg/bid). The reproductive performance of offspring born to female rats given 
efavirenz was not affected.  

4.7 Effects on ability to drive and use machines 

Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be 
instructed that if they experience these symptoms they should avoid potentially hazardous tasks such 
as driving or operating machinery.

4.8 Undesirable effects 

Summary of the safety profile 

Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 
600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most 
frequently reported adverse reactions of at least moderate severity reported in at least 5% of patients 
were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most 
notable adverse reactions associated with efavirenz are rash and nervous system symptoms. Nervous 
system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 
weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric 
adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and 
seizures have been reported in patients treated with efavirenz. The administration of efavirenz with 
food may increase efavirenz exposure and may lead to an increase in the frequency of adverse 
reactions (see section 4.4). 



55

The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006) 
in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration 
180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine + 
lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not 
associated with any new safety concerns. 

Tabulated list of adverse reactions 

Adverse reactions of moderate or greater severity with at least possible relationship to treatment 
regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended 
dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions 
observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens. 
Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to 
< 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); or very rare (< 1/10,000). 

Immune system disorders 
uncommon hypersensitivity 

Metabolism and nutrition disorders 
common hypertriglyceridaemia* 

uncommon hypercholesterolaemia* 

Psychiatric disorders
common abnormal dreams, anxiety, depression, 

insomnia* 

uncommon affect lability, aggression, confusional state, 
euphoric mood, hallucination, mania, 
paranoia, psychosis†, suicide attempt, suicide 
ideation, catatonia* 

rare delusion ‡, neurosis ‡, completed suicide‡,*
Nervous system disorders 
common  cerebellar coordination and balance 

disturbances†, disturbance in attention 
(3.6%), dizziness (8.5%), headache (5.7%), 
somnolence (2.0%)* 

uncommon agitation, amnesia, ataxia, coordination 
abnormal, convulsions, thinking abnormal,* 
tremor†

Eye disorders
uncommon vision blurred 

Ear and labyrinth disorders
uncommon tinnitus†, vertigo 

Vascular disorders
uncommon flushing†

Gastrointestinal disorders
common abdominal pain, diarrhoea, nausea, vomiting 

uncommon pancreatitis 



56

Hepatobiliary disorders
common aspartate aminotransferase (AST) 

increased*, alanine aminotransferase (ALT) 
increased*, gamma-glutamyltransferase 
(GGT) increased* 

uncommon hepatitis acute 

rare  hepatic failure‡,* 

Skin and subcutaneous tissue disorders
very common rash (11.6%)* 

common pruritus 

uncommon erythema multiforme, Stevens-Johnson 
syndrome* 

rare photoallergic dermatitis†

Reproductive system and breast disorders
uncommon gynaecomastia 

General disorders and administration site conditions
common Fatigue 

*,†,‡ See section Description of selected adverse reactions for more details. 

Description of selected adverse reactions 

Information regarding post-marketing surveillance 

†These adverse reactions were identified through post-marketing surveillance; however, the 
frequencies were determined using data from 16 clinical trials (n=3,969).  

‡These adverse reactions were identified through post-marketing surveillance but not reported as drug-
related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare" was 
defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) on the 
basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of 
patients treated with efavirenz in these clinical trials (n=3,969). 

Rash

In clinical studies, 26% of patients treated with 600 mg of efavirenz experienced skin rash compared 
with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of 
patients treated with efavirenz. Severe rash occurred in less than 1% of patients treated with efavirenz, 
and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-
Johnson syndrome was approximately 0.1%. 

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two 
weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with 
efavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because of 
rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is 
restarted. 



57

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class 
is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy, 
primarily based on retrospective cohort data from published literature, range from 13 to 18%, 
comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.) 

Psychiatric symptoms

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In 
controlled trials, the frequency of specific serious psychiatric events were: 

Efavirenz regimen 
(n=1,008)

Control regimen 
(n=635)

- severe depression 1.6% 0.6%
- suicidal ideation 0.6% 0.3%
- non-fatal suicide attempts 0.4% 0%
- aggressive behaviour 0.4% 0.3%
- paranoid reactions 0.4% 0.3%
- manic reactions 0.1% 0%

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric 
adverse reactions with frequencies ranging from 0.3% for manic reactions to 2.0% for both severe 
depression and suicidal ideation. There have also been post-marketing reports of death by suicide, 
delusions, psychosis-like behaviour and catatonia. 

Nervous system symptoms

In clinical controlled trials, frequently reported adverse reactions included, but were not limited to 
dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system 
symptoms of moderate-to-severe intensity were experienced by 19% (severe 2%) of patients compared 
to 9% (severe 1%) of patients receiving control regimens. In clinical studies 2% of patients treated 
with efavirenz discontinued therapy due to such symptoms. 

Nervous system symptoms usually begin during the first one or two days of therapy and generally 
resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system 
symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous 
system symptoms may occur more frequently when efavirenz is taken concomitantly with meals 
possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to 
improve the tolerability of these symptoms and can be recommended during the first weeks of therapy 
and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or 
splitting the daily dose has not been shown to provide benefit. 

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset 
nervous system symptoms among efavirenz-treated patients were generally similar to those in the 
control arm. 

Hepatic failure 

A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing 
hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing 
in some cases to transplantation or death.

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 



58

also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). 

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). 
The frequency of this is unknown (see section 4.4). 

Laboratory test abnormalities 

Liver enzymes: elevations of AST and ALT to greater than five times the upper limit of the normal 
range (ULN) were seen in 3% of 1,008 patients treated with 600 mg of efavirenz (5-8% after long-
term treatment in study 006). Similar elevations were seen in patients treated with control regimens 
(5% after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 
4% of all patients treated with 600 mg of efavirenz and 1.5-2% of patients treated with control 
regimens (7% of efavirenz-treated patients and 3% of control-treated patients after long-term 
treatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction. 
In the long-term study (006), 1% of patients in each treatment arm discontinued because of liver or 
biliary system disorders. 

Amylase: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels 
greater than 1.5 times the upper limit of normal were seen in 10% of patients treated with efavirenz 
and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases 
in serum amylase is unknown. 

Metabolic parameters 

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 

Paediatric population 

Undesirable effects in children were generally similar to those of adult patients. Rash was reported 
more frequently in children (59 of 182 (32%) treated with efavirenz) and was more often of higher 
grade than in adults (severe rash was reported in 6 of 182 (3.3%) of children). Prophylaxis with 
appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered. .  

Other special populations 

Liver enzymes in hepatitis B or C co-infected patients: in the long-term data set from study 006, 
137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 
84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for 
hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected 
patients in study 006, elevations in AST to greater than five times ULN developed in 13% of 
efavirenz-treated patients and in 7% of control, and elevations in ALT to greater than five times ULN 
developed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with 
efavirenz and 2% in the control arm discontinued because of liver disorders (see section 4.4). 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 



59

4.9 Overdose 

Some patients accidentally taking 600 mg twice daily have reported increased nervous system 
symptoms. One patient experienced involuntary muscle contractions. 

Treatment of overdose with efavirenz should consist of general supportive measures, including 
monitoring of vital signs and observation of the patient’s clinical status. Administration of activated 
charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for 
overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove 
significant quantities of it from blood. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase 
inhibitors. ATC code: J05AG03 

Mechanism of action 

Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse 
transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or 
δ). 

Cardiac Electrophysiology 

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo 
controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects 
enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 
genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax 
observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz 
concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the 
mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in 
subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days 
(see section 4.5).

Antiviral activity 

The free concentration of efavirenz required for 90 to 95% inhibition of wild type or zidovudine-
resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell 
lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures. 

Resistance 

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 
48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to 
that observed against wild type viral strains. The single substitutions which led to the highest 
resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100 
(L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold 
resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing 
K103N in addition to other amino acid substitutions in RT. 

K103N was the most frequently observed RT substitution in viral isolates from patients who 
experienced a significant rebound in viral load during clinical studies of efavirenz in combination with 
indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving 
efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 



60

225 were also observed, but at lower frequencies, and often only in combination with K103N. The 
pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of 
the other antiviral medicines used in combination with efavirenz. 

Cross resistance 

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the 
K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine-
resistant clinical isolates examined were cross-resistant to efavirenz and contained the K103N 
substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant 
to efavirenz. 

Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed 
evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen 
isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and 
delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-to-
isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates 
tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and 
delavirdine. 

The potential for cross resistance between efavirenz and PIs is low because of the different enzyme 
targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of the 
different binding sites on the target and mechanism of action. 

Clinical efficacy 

Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely 
with CD4 counts < 50 cells/mm3, or in PI or NNRTI experienced patients. Clinical experience in 
controlled studies with combinations including didanosine or zalcitabine is limited. 

Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in 
combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of 
quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and NRTI-
experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced patients 
over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 
1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used without 
efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of NRTIs 
given every 12 hours were used in each of these studies. 

Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or efavirenz 
+ indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to be 
efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 
341 cells/mm3 and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for study 
006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 2. In 
the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who 
terminated the study early for any reason, or who had a missing HIV-RNA measurement that was 
either preceded or followed by a measurement above the limit of assay quantification were considered 
to have HIV-RNA above 50 or above 400 copies/ml at the missing time points. 



61

Table 2: Efficacy results for study 006 

Responder rates (NC = Fa) 
Plasma HIV-RNA 

Mean change 
from 

baseline-CD4 
cell count

< 400 copies/ml  
(95% C.I.b)

< 50 copies/ml  
(95% C.I.b)

cells/mm3 

(S.E.M.c)
Treatment 
Regimend

n 48 weeks 48 weeks 48 weeks 

EFV + 
ZDV + 3TC

202 67% 
(60%, 73%)

62% 
(55%, 69%)

187 
(11.8)

EFV + IDV 206 54% 
(47%, 61%)

48% 
(41%, 55%)

177 
(11.3)

IDV + 
ZDV + 3TC

206 45% 
(38%, 52%)

40% 
(34%, 47%)

153 
(12.3)

a NC = F, noncompleter = failure. 
b C.I., confidence interval. 
c S.E.M., standard error of the mean. 
d EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir. 

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with 
EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), 
suggest durability of response in terms of proportions of patients with HIV RNA < 400 copies/ml, 
HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell count.  

Efficacy results for studies ACTG 364 and 020 are found in Table 3. Study ACTG 364 enrolled 
196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 
327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed 
to change their patient’s NRTI regimen upon entry into the study. Responder rates were highest in 
patients who switched NRTIs.

Table 3: Efficacy results for studies ACTG 364 and 020 

Responder rates (NC = Fa) 
Plasma HIV-RNA 

Mean change from 
baseline-CD4 cell 

count
Study Number/ 
Treatment Regimensb

n % (95% C.I.c) % (95% C.I.) cells/mm3 (S.E.M.d) 

Study ACTG 364 
48 weeks

< 500 copies/ml < 50 copies/ml 

EFV + NFV + NRTIs 65 70 (59, 82) --- --- 107 (17.9)
EFV + NRTIs 65 58 (46, 70) --- --- 114 (21.0)
NFV + NRTIs 66 30 (19, 42) --- --- 94 (13.6)

Study 020 
24 weeks

< 400 copies/ml < 50 copies/ml 

EFV + IDV + NRTIs 157 60 (52, 68) 49 (41, 58) 104 (9.1)
IDV + NRTIs 170 51 (43, 59) 38 (30, 45) 77 (9.9)

a 
NC = F, noncompleter = failure. 

b EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor; 
NFV, nelfinavir. 

c C.I., confidence interval for proportion of patients in response. 
d S.E.M., standard error of the mean. 
---, not performed. 

Paediatric population 



62

 Study AI266922 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive 
and -experienced paediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 
years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10
copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The 
median time on study therapy was 132 weeks; 27% of patients discontinued before Week 48. Using an 
ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at 
Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in 
CD4+ count at 48 weeks was 215 cells/mm3 and the median increase in CD4+ percentage was 6%. 

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in paediatric patients 
who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 
9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 
4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm

3, and median CD4+ percentage was 
18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 
48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and 
<50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase 
from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in 
CD4+ percentage was 13%. 

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and 
antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviral-naive and 
NRTI-experienced paediatric patients. One hundred two patients 3 months to 16 years of age (median 
5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior 

antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median 

CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on 
study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, 
the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 
were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count 

at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.

5.2 Pharmacokinetic properties 

Absorption 

Peak efavirenz plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following single oral 
doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in Cmax and 
AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting 
diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours) did not 
change following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days. 

In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 
200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady 
state Cmax was 12.9 ± 3.7 μM (29%) [mean ± S.D. (% C.V.)], steady state Cmin was 
5.6 ± 3.2 μM (57%), and AUC was 184 ± 73 μM·h (40%). 

Effect of food 

The AUC and Cmax of a single 600 mg dose of efavirenz film-coated tablets in uninfected volunteers 
was increased by 28% (90% CI: 22-33%) and 79% (90% CI: 58-102%), respectively, when given with 
a high fat meal, relative to when given under fasted conditions (see section 4.4). 

Distribution 



63

Efavirenz is highly bound (approximately 99.5 - 99.75%) to human plasma proteins, predominantly 
albumin. In HIV-1 infected patients (n = 9) who received efavirenz 200 to 600 mg once daily for at 
least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the 
corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-
protein-bound (free) fraction of efavirenz in plasma. 

Biotransformation 

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz 
is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with 
subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially 
inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major 
isozymes responsible for efavirenz metabolism and that it inhibited P450 isozymes 2C9, 2C19, and 
3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at 
concentrations well above those achieved clinically. 

Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant 
of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, 
the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be 
excluded. 

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own 
metabolism, which may be clinically relevant in some patients. In uninfected volunteers, multiple 
doses of 200 - 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation 
(22 - 42% lower) and a shorter terminal half-life compared with single dose administration (see 
below). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 
substrate) are reduced in the presence of efavirenz (see section 4.5, table 1). 
Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been 
contradictory reports of both increased and decreased exposures to substrates of these enzymes when 
coadministered with efavirenz in vivo. The net effect of coadministration is not clear. 

Elimination 

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and 40 -
 55 hours after multiple doses. Approximately 14 - 34% of a radiolabelled dose of efavirenz was 
recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz. 

Hepatic impairment 

In a single-dose study, half life was doubled in the single patient with severe hepatic impairment 
(Child Pugh Class C), indicating a potential for a much greater degree of accumulation.  A multiple-
dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic 
impairment (Child-Pugh Class A) compared with controls.  There were insufficient data to determine 
whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz 
pharmacokinetics. 

Gender, race, elderly 

Although limited data suggest that females as well as Asian and Pacific Island patients may have 
higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic 
studies have not been performed in the elderly. 

Paediatric population 

The pharmacokinetic parameters for efavirenz at steady state in paediatric patients were predicted by a 
population pharmacokinetic model and are summarized in Table 4 by weight ranges that correspond to 
the recommended doses. 



64

Table 4: Predicted steady-state pharmacokinetics of efavirenz (capsules/capsule sprinkles) in 
HIV-infected paediatric patients 

Body Weight Dose Mean AUC(0-24) 
µM·h

Mean Cmax 
µg/mL

Mean Cmin 
µg/mL

3.5-5 kg 100 mg 220.52 5.81 2.43
5-7.5 kg 150 mg 262.62 7.07 2.71
7.5-10 kg 200 mg 284.28 7.75 2.87
10-15 kg 200 mg 238.14 6.54 2.32
15-20 kg 250 mg 233.98 6.47 2.3
20-25 kg 300 mg 257.56 7.04 2.55

25-32.5 kg 350 mg 262.37 7.12 2.68
32.5-40 kg 400 mg 259.79 6.96 2.69

>40 kg 600 mg 254.78 6.57 2.82

5.3 Preclinical safety data 

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays. 

Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of 20 foetuses/ 
newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma efavirenz 
concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with 
secondary enlargement of the tongue were observed in one foetus, microophthalmia was observed in 
another foetus, and cleft palate was observed in a third foetus. No malformations were observed in 
foetuses from efavirenz-treated rats and rabbits. 

Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for ≥ 1 year at a dose 
resulting in mean AUC values approximately 2-fold greater than those in humans given the 
recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has 
been observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenz 
for ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the 
recommended dose (see sections 4.4 and 4.8). 

Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female 
mice, but not in male mice. The mechanism of tumour formation and the potential relevance for 
humans are not known. 

Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic 
potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the 
potential carcinogenic risk to humans. 

6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients 

Tablet core 
Croscarmellose sodium 
Microcrystalline cellulose 
Sodium laurilsulfate 
Hydroxypropylcellulose 
Lactose monohydrate 
Magnesium stearate 

Film coating 
Hypromellose (E464) 



65

Titanium dioxide (E171) 
Macrogol 400 
Yellow iron oxide (E172) 
Carnauba wax 

Printing ink 
Hypromellose (E464) 
Propylene glycol 
Cochineal carminic acid (E120) 
Indigo carmine (E132) 
Titanium dioxide (E171) 

6.2 Incompatibilities 

Not applicable.

6.3 Shelf life 

2 years. 

6.4 Special precautions for storage 

This medicinal product does not require any special storage conditions. 

6.5 Nature and content of container 

HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 30 film-
coated tablets. 
Packs of 30 x 1 or multipacks of 90 (3 packs of 30 x 1) film-coated tablets in aluminium/PVC 
perforated unit dose blisters. 
Not all pack sizes may be marketed. 

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 

Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/008 - bottle 
EU/1/99/110/009 - blister 
EU/1/99/110/010 - blister 



66

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

Date of first authorisation: 28 May 1999 
Date of latest renewal: 23 April 2014 

10. DATE OF REVISION OF THE TEXT 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



67

ANNEX II 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



68

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer responsible for batch release 

Bristol-Myers Squibb S.r.l. 
Contrada Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

Aesica Queenborough Limited 
North Road, Queenborough 
Kent, ME11 5EL 
United Kingdom 

Aesica Pharmaceuticals GmbH - Monheim,  
Alfred-Nobel-Straße 10,  
40789 Monheim,  
Germany 

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

• Periodic Safety Update Reports  

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk Management Plan (RMP) 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 



69

ANNEX III 

LABELLING AND PACKAGE LEAFLET 



70

A. LABELLING 



71

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 

OUTER CARTON AND LABEL TEXT FOR BOTTLE PACK 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 50 mg hard capsules 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each hard capsule contains: efavirenz 50 mg. 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

30 hard capsules 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



72

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/001 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 50 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:> 



73

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 

OUTER CARTON AND LABEL TEXT FOR BOTTLE PACK 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 100 mg hard capsules 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each hard capsule contains: efavirenz 100 mg. 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

30 hard capsules 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



74

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/002 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 100 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:> 



75

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 

OUTER CARTON AND LABEL TEXT FOR BOTTLE PACK 
OUTER CARTON TEXT FOR BLISTER PACK 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 200 mg hard capsules 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each hard capsule contains: efavirenz 200 mg 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

90 hard capsules: bottle 
42 x 1 hard capsules: blister 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 



76

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/003: bottle 
EU/1/99/110/004: blister 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 200 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:>  



77

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

BLISTER TEXT 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 200 mg hard capsules 
efavirenz 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 

3. EXPIRY DATE 

EXP 

4. BATCH NUMBER 

Lot 

5. OTHER 



78

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 

OUTER CARTON AND LABEL TEXT FOR BOTTLE PACK 
OUTER CARTON TEXT FOR BLISTER PACK 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 600 mg film-coated tablets 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each film-coated tablet contains: efavirenz 600 mg. 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

Bottle: 
30 film-coated tablets 

Blister: 
30 x 1  film-coated tablets 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 



79

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

Bottle: 
EU/1/99/110/008 

Blister: 
EU/1/99/110/009 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 600 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:>  



80

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

OUTER CARTON TEXT FOR BLISTER MULTIPACK (INCLUDING BLUE-BOX) 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 600 mg film-coated tablets 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each film-coated tablet contains: efavirenz 600 mg. 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

Multipack: 90 (3 packs of 30 x 1) film-coated tablets 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use. 
Oral use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



81

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/010 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 600 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:>  



82

PARTICULARS TO APPEAR ON OUTER PACKAGING  

CARTON TEXT FOR BLISTER INTERMEDIATE PACK, COMPONENT OF A 
MULTIPACK (WITHOUT BLUE BOX)  
30 x 1 TABLETS 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 600 mg film-coated tablets 
efavirenz 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each film-coated tablet contains: efavirenz 600 mg. 

3. LIST OF EXCIPIENTS 

It contains: lactose monohydrate. See package leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

30 x 1 film-coated tablets 
Component of a multipack, can't be sold separately. 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Oral use. 
Read the package leaflet before use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

EXP 

9. SPECIAL STORAGE CONDITIONS 



83

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/110/010 

13. BATCH NUMBER 

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY 

Medicinal product subject to medical prescription. 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

SUSTIVA 600 mg 

17. UNIQUE IDENTIFIED – 2D BARCODE 

Outer carton: 2D barcode carrying the unique identifier included. 

18. UNIQUE IDENTIFIED – HUMAN READABLE DATA 

Outer carton 
PC: 
SN: 
<NN:>  



84

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

BLISTER TEXT 

1. NAME OF THE MEDICINAL PRODUCT 

SUSTIVA 600 mg film-coated tablet 
efavirenz 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

Bristol-Myers Squibb Pharma EEIG 

3. EXPIRY DATE 

EXP 

4. BATCH NUMBER 

Lot 

5. OTHER 



85

B. PACKAGE LEAFLET 



86

Package leaflet: Information for the user

SUSTIVA 50 mg hard capsules  
efavirenz 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
 If you get any side effects, talk to your doctor,  pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

What is in this leaflet 

1. What SUSTIVA is and what it is used for 
2. What you need to know before you take SUSTIVA 
3. How to take SUSTIVA 
4. Possible side effects 
5. How to store SUSTIVA 
6. Contents of the pack and other information

1. What SUSTIVA is and what it is used for 

SUSTIVA, which contains the active substance efavirenz, belongs to a class of antiretroviral 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It is an antiretroviral 
medicine that fights human immunodeficiency virus (HIV-1) infection by reducing the amount of 
the virus in blood. It is used by adults, adolescents and children 3 months of age and older and 
weighing at least 3.5 kg.  
Your doctor has prescribed SUSTIVA for you because you have HIV infection. 
SUSTIVA taken in combination with other antiretroviral medicines reduces the amount of the virus in 
the blood. This will strengthen your immune system and reduce the risk of developing illnesses linked 
to HIV infection.  

2. What you need to know before you take SUSTIVA 

Do not take SUSTIVA 
 if you are allergic  to efavirenz or any of the other ingredients of this medicine (listed in section 

6). Contact your doctor or pharmacist for advice. 

 if you have severe liver disease. 

 if you have a heart condition, such as changes in the rhythm or rate of the heart beat, a slow 
heart beat, or severe heart disease.

 if any member of your family (parents, grandparents, brothers or sisters) has died suddenly due to 
a heart problem or was born with heart problems.  

 if your doctor has told you that you have high or low levels of electrolytes such as potassium or 
magnesium in your blood. 

 if you are currently taking any of the following medicines (see also “Other medicines and 
Sustiva”):  
- astemizole or terfenadine (used to treat allergy symptoms)  



87

- bepridil (used to treat heart disease) 
- cisapride (used to treat heartburn) 
- ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and 

methylergonovine) (used to treat migraine and cluster headaches) 
- midazolam or triazolam (used to help you sleep) 
- pimozide, imipramine, amitriptyline or clomipramine (used to treat certain mental 

conditions) 
-  elbasvir or grazoprevir (used to treat hepatitis C) 
- St. John's wort (Hypericum perforatum) (a herbal remedy used for depression and 
anxiety) 
-  flecainide, metoprolol (used to treat irregular heart beat) 
-  certain antibiotics (macrolides, fluoroquinolones, imidazole)  
- triazole antifungal agents 
- certain antimalarial treatments
-  methadone (used to treat opiate addiction) 

If you are taking any of these medicines, tell your doctor immediately. Taking these 
medicines with SUSTIVA could create the potential for serious and/or life-threatening side-
effects or stop SUSTIVA from working properly. 

Warnings and precautions  
Talk to your doctor before taking SUSTIVA 

 SUSTIVA must be taken with other medicines that act against the HIV virus. If SUSTIVA 
is started because your current treatment has not prevented the virus from multiplying, another 
medicine you have not taken before must be started at the same time. 

 You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other 
people. This medicine is not a cure for HIV infection and you may continue to develop 
infections or other illnesses associated with HIV disease.  

 You must remain under the care of your doctor while taking SUSTIVA. 
 
 Tell your doctor: 

- if you have a history of mental illness, including depression, or of substance or alcohol 
abuse. Tell your doctor immediately if you feel depressed, have suicidal thoughts or have 
strange thoughts (see section 4, Possible side effects). 

- if you have a history of convulsions (fits or seizures) or if you are being treated with 
anticonvulsant therapy such as carbamazepine, phenobarbital and phenytoin. If you are 
taking any of these medicines, your doctor may need to check the level of anticonvulsant 
medicine in your blood to ensure that it is not affected while taking SUSTIVA. Your 
doctor may give you a different anticonvulsant. 

- if you have a history of liver disease, including active chronic hepatitis. Patients with 
chronic hepatitis B or C and treated with combination antiretroviral agents have a higher 
risk for severe and potentially life-threatening liver problems. Your doctor may conduct 
blood tests in order to check how well your liver is working or may switch you to another 
medicine. If you have severe liver disease, do not take SUSTIVA (see section 2, Do not 
take SUSTIVA). 

- if you have a heart disorder, such as abnormal electrical signal called prolongation 
of the QT interval. 

 Once you start taking SUSTIVA, look out for: 



88

- signs of dizziness, difficulty sleeping, drowsiness, difficulty concentrating or 
abnormal dreaming. These side effects may start in the first 1 or 2 days of treatment and 
usually go away after the first 2 to 4 weeks. 

- any signs of skin rash. If you see any signs of a severe rash with blistering or fever, stop 
taking SUSTIVA and tell your doctor at once. If you had a rash while taking another 
NNRTI, you may be at a higher risk of getting a rash with SUSTIVA. 

- any signs of inflammation or infection. In some patients with advanced HIV infection 
(AIDS) and a history of opportunistic infection, signs and symptoms of inflammation 
from previous infections may occur soon after anti-HIV treatment is started. It is believed 
that these symptoms are due to an improvement in the body’s immune response, enabling 
the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection, please tell your doctor immediately.  
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs 
when the immune system attacks healthy body tissue) may also occur after you start 
taking medicines for the treatment of your HIV infection. Autoimmune disorders may 
occur many months after the start of treatment. If you notice any symptoms of infection or 
other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please 
inform your doctor immediately to seek necessary treatment. 

- bone problems. Some patients taking combination antiretroviral therapy may develop a 
bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to 
the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be 
some of the many risk factors for developing this disease. Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement. If you notice any of these symptoms please inform your doctor. 

Children and adolescents 
SUSTIVA is not recommeded for children under the age of 3 months or weighing less than 3.5 kg 
because it has not been adequately studied in these patients. 

Other medicines and SUSTIVA 
You must not take SUSTIVA with certain medicines. These are listed under Do not take 
SUSTIVA, at the start of Section 2. They include some common medicines and a herbal remedy (St. 
John’s wort) which can cause serious interactions. 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 

SUSTIVA may interact with other medicines, including herbal preparations such as Ginkgo biloba
extracts. As a result, the amounts of SUSTIVA or other medicines in your blood may be affected. This 
may stop the medicines from working properly, or may make any side effects worse. In some cases, 
your doctor may need to adjust your dose or check your blood levels. It is important to tell your 
doctor or pharmacist if you are taking any of the following: 

 Other medicines used for HIV infection: 
- protease inhibitors: darunavir, indinavir, lopinavir/ritonavir, ritonavir, ritonavir boosted 

atazanavir, saquinavir or fosamprenavir/saquinavir. Your doctor may consider giving you 
an alternative medicine or changing the dose of the protease inhibitors. 

- maraviroc 
- the combination tablet containing efavirenz, emtricitabine, and tenofovir should not be 

taken with SUSTIVA unless recommended by your doctor since it contains efavirenz, the 
active ingredient of SUSTIVA. 



89

 Medicines used to treat infection with the hepatitis C virus: boceprevir, telaprevir, 
elbasvir/grazoprevir, simeprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, 
glecaprevir/pibrentasvir.

 Medicines used to treat bacterial infections, including tuberculosis and AIDS-related 
mycobacterium avium complex: clarithromycin, rifabutin, rifampicin. Your doctor may consider 
changing your dose or giving you an alternative antibiotic. In addition, your doctor may 
prescribe a higher dose of SUSTIVA. 

 Medicines used to treat fungal infections (antifungals): 
- voriconazole. SUSTIVA may reduce the amount of voriconazole in your blood and 

voriconazole may increase the amount of SUSTIVA in your blood. If you take these two 
medicines together, the dose of voriconazole must be increased and the dose of efavirenz 
must be reduced. You must check with your doctor first. 

- itraconazole. SUSTIVA may reduce the amount of itraconazole in your blood. 
- posaconazole. SUSTIVA may reduce the amount of posaconazole in your blood. 

 Medicines used to treat malaria: 
- artemether/lumefantrine:  SUSTIVA may reduce the amount of artemether/lumefantrine 

in your blood. 
- atovaquone/proguanil:  SUSTIVA may reduce the amount of atovaquone/proguanil in 

your blood. 

 Medicines used to treat convulsions/seizures (anticonvulsants): carbamazepine, phenytoin, 
phenobarbital. SUSTIVA can reduce or increase the amount of anticonvulsant in your blood. 
Carbamazepine may make SUSTIVA less likely to work. Your doctor may need to consider 
giving you a different anticonvulsant. 

 Medicines used to lower blood fats (also called statins): atorvastatin, pravastatin, simvastatin. 
SUSTIVA can reduce the amount of statins in your blood. Your doctor will check your 
cholesterol levels and will consider changing the dose of your statin, if needed. 

  Methadone (a medicine used to treat opiate addiction): your doctor may recommend an 
alternative treatment. 

 Sertraline (a medicine used to treat depression): your doctor may need to change your dose of 
sertraline. 

 Bupropion (a medicine used to treat depression or to help you stop smoking): your doctor may 
need to change your dose of bupropion. 

  Diltiazem or similar medicines (called calcium channel blockers which are medicines 
typically used for high blood pressure or heart problems): when you start taking SUSTIVA, 
your doctor may need to adjust your dose of the calcium channel blocker. 

 Immunosuppressants such as cyclosporine, sirolimus, or tacrolimus (medicines used to 
prevent organ transplant rejection): when you start or stop taking SUSTIVA, your doctor will 
closely monitor your plasma levels of the immunosuppressant and may need to adjust its dose. 

 Hormonal contraceptive, such as birth control pills, an injected contraceptive (for 
example, Depo-Provera), or a contraceptive implant (for example, Implanon): you must 
also use a reliable barrier method of contraception (see Pregnancy,breast-feeding and fertility). 
SUSTIVA may make hormonal contraceptives less likely to work. Pregnancies have occurred in 
women taking SUSTIVA while using a contraceptive implant, although it has not been 
established that the SUSTIVA therapy caused the contraceptive to fail. 



90

 Warfarin or acenocoumarol (medicines used to reduce clotting of the blood): your doctor may 
need to adjust your dose of warfarin or acenocoumarol. 

 Ginkgo biloba extracts (a herbal preparation) 

 Medicines that impact heart rhythm:
–  Medicines used to treat heart rhythm problems: such as flecainide or metoprolol. 
– Medicines used to treat depression such as imipramine, amitriptyline or clomipramine 
– Antibiotics, including the following types: macrolides, fluoroquinolones or imidazole. 

SUSTIVA with food and drink 
Taking SUSTIVA on an empty stomach may reduce the undesirable effects. Grapefuit juice should be 
avoided when taking SUSTIVA. 

Pregnancy and breast-feeding 
Women should not get pregnant during treatment with SUSTIVA, and for 12 weeks thereafter. 
Your doctor may require you to take a pregnancy test to ensure you are not pregnant before starting 
treatment with SUSTIVA.  

If you could get pregnant while receiving SUSTIVA, you need to use a reliable form of barrier 
contraception (for example, a condom) with other methods of contraception including oral (pill) or 
other hormonal contraceptives (for example, implants, injection). Efavirenz may remain in your blood 
for a time after therapy is stopped. Therefore, you should continue to use contraceptive measures, as 
above, for 12 weeks after you stop taking SUSTIVA.  

Tell your doctor immediately if you are pregnant or intend to become pregnant. If you are 
pregnant, you should take SUSTIVA only if you and your doctor decide it is clearly needed. Ask your 
doctor or pharmacist for advice before taking any medicine. 

Serious birth defects have been seen in unborn animals and in the babies of women treated with 
efavirenz or a combination medicine containing efavirenz, emtricitabine and tenofovir during 
pregnancy. If you have taken SUSTIVA or the combination tablet containing efavirenz, emtricitabine, 
and tenofovir during your pregnancy, your doctor may request regular blood tests and other diagnostic 
tests to monitor the development of your child. 

You should not breast feed your baby if you are taking SUSTIVA. 

Driving and using machines 
SUSTIVA contains efavirenz and may cause dizziness, impaired concentration, and drowsiness.
If you are affected, do not drive and do not use any tools or machines.  

SUSTIVA contains lactose in each 600-mg daily dose. 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  

3. How to take SUSTIVA 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor will give you instructions for proper dosing.  

 The dose for adults is 600 mg once daily. 
 The dose for SUSTIVA may need to be increased or decreased if you are also taking certain 

medicines (see Other medicines and SUSTIVA).  



91

 SUSTIVA is for oral use. SUSTIVA is recommended to be taken on an empty stomach 
preferably at bedtime. This may make some side effects (for example, dizziness, drowsiness) 
less troublesome. An empty stomach is commonly defined as 1 hour before or 2 hours after a 
meal.  

 It is recommended that the capsule be swallowed whole with water. 
 SUSTIVA must be taken every day. 
 SUSTIVA should never be used alone to treat HIV. SUSTIVA must always be taken in 

combination with other anti-HIV medicines. 

Use in children and adolescents 
 SUSTIVA 50 mg hard capsules can be taken by children and adolescents 3 months of age and 

older and weighing at least 3.5 kg who are able to swallow the capsules. Opening the capsule 
and taking the contents with a small amount of food may be considered for children who cannot 
swallow the hard capsule. 

 The dose for children and adolescents is calculated by body weight and is taken once daily as 
shown below: 

Body Weight SUSTIVA Number of Capsules or 
Tablets and Strength to 

Administer
kg Dose (mg) 

3.5 to < 5 100 one 100 mg capsule

5 to < 7.5 150 one 100 mg capsule + one 
50 mg capsule 

7.5 to < 15 200 one 200 mg capsule 
15 to < 20 250 one 200 mg capsule + one 

50 mg capsule
20 to < 25 300 three 100 mg capsules

25 to < 32.5 350 three 100 mg capsules + 
one 50 mg capsule

32.5 to < 40 400 two 200 mg capsules
≥ 40 600 one 600 mg tablet OR 

three 200 mg capsules

For children who are not able to swallow the capsules, the doctor may recommend opening the hard 
capsule and mixing the contents with a small amount (1-2 teaspoons) of food (e.g., yogurt ). The 
capsules must be opened carefully so that the contents do not spill or escape into the air. Hold the 
capsule with the cap facing up and pull the cap away from the body of the capsule. Use a small 
container for mixing. Give the mixture to the child as soon as possible, but no more than 30 minutes 
after mixing. Make sure the child eats the full amount of the mixture of food and capsule contents. 
Add another small amount (approximately 2 teaspoons) of the food to the empty mixing container, 
stirring to make sure there is no drug residue remaining in the container, and have the child eat the full 
amount again. The child should not be given any additional food for 2 hours. The doctor may also 
recommend this method of taking SUSTIVA for adults who cannot swallow capsules. 

Instructions for capsule sprinkle method: 

1 Avoid giving the daily SUSTIVA dose within 1 hour after a feeding or meal.
2 Wash and dry your hands before and after preparing the capsule sprinkle.
3 Choose a soft food the child likes. Examples of soft foods are applesauce, grape jelly, yogurt, 

or infant formula. In a taste preference study in adults, SUSTIVA mixed with grape jelly 
received the best rating.



92

4 Place 1-2 teaspoons of the food in a small container (illustration a). 

5 SUSTIVA capsules must be opened carefully over the food container, as described in steps 
6-7, so that the contents do not spill.

6 With your hands over the container, hold the capsule with the cap 
facing up (see illustration b). 

7 Carefully pull the cap away from the body of the capsule 
(illustration c). 

8 Sprinkle the contents of the capsule on the food (illustration d). 

9 If the daily dose consists of more than one capsule, follow steps 5-8 for each capsule. Do not
add more food.

10 Mix the capsule contents and food together (illustration e). 

Steps 11-14 must be completed within 30 minutes of mixing:
11 Give the mixture of food and capsule contents to the child, making 

sure he or she eats the full amount (illustration f). 

12 Add another small amount (approximately 2 teaspoons) of the food to the empty mixing 
container (illustration a).

13 Stir to make sure there is no drug residue remaining in the container (illustration e).
14 Have the child eat the full amount again (illustration f).
15 Do not give the child any additional food for 2 hours.

If you take more SUSTIVA than you should 
If you take too much SUSTIVA contact your doctor or nearest emergency department for advice. 
Keep the medicine container with you so that you can easily describe what you have taken. 

If you forget to take SUSTIVA 
Try not to miss a dose. If you do miss a dose, take the next dose as soon as possible, but do not take a 
double dose to make up for a forgotten dose. If you need help in planning the best times to take your 
medicine, ask your doctor or pharmacist. 



93

If you stop taking SUSTIVA 
When your SUSTIVA supply starts to run low, get more from your doctor or pharmacist. This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time. The virus may then become harder to treat. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.  

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  
When treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by SUSTIVA or by other medicines that you are taking at the same time, or by the HIV disease 
itself. 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

The most notable unwanted effects reported with SUSTIVA in combination with other anti-HIV 
medicines are skin rash and nervous system symptoms. 

You should consult your doctor if you have a rash, since some rashes may be serious; however, most 
cases of rash disappear without any change to your treatment with SUSTIVA. Rash was more 
common in children than in adults treated with SUSTIVA. 

The nervous system symptoms tend to occur when treatment is first started, but generally decrease in 
the first few weeks. In one study, nervous system symptoms often occurred during the first 1-3 hours 
after taking a dose. If you are affected your doctor may suggest that you take SUSTIVA at bedtime 
and on an empty stomach. Some patients have more serious symptoms that may affect mood or the 
ability to think clearly. Some patients have actually committed suicide. These problems tend to occur 
more often in those who have a history of mental illness. Always notify your doctor immediately if 
you have these symptoms or any side effects while taking SUSTIVA. 

Tell your doctor if you notice any of the following side effects: 

Very common (affects more than 1 user in 10)
- skin rash 

Common (affects 1 to 10 users in 100)
- abnormal dreams, difficulty concentrating, dizziness, headache, difficulty sleeping, drowsiness, 

problems with coordination or balance 
- stomach pain, diarrhoea, feeling sick (nausea), vomiting 
- itching 
- tiredness 
- feeling anxious, feeling depressed 
Tests may show: 
- increased liver enzymes in the blood 
- increased trigycerides (fatty acids) in the blood 

Uncommon (affects 1 to 10 users in 1,000)
- nervousness, forgetfulness,  confusion, fitting (seizures), abnormal thoughts 
- blurred vision 
- a feeling of spinning or tilting (vertigo) 
- pain in the abdomen (stomach) caused by inflammation of the pancreas 



94

- allergic reaction (hypersensitivity) that may cause severe skin reactions (erythema multiforme, 
Stevens-Johnson syndrome) 

- yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the 
liver 

- breast enlargement in males 
- angry behaviour, mood being affected, seeing or hearing things that are not really there 

(hallucinations), mania (mental condition characterised by episodes of overactivity, elation or 
irritability), paranoia, suicidal thoughts, catatonia (condition in which the patient is rendered 
motionless and speechless for a period) 

- whistling, ringing or other persistent noise in the ears 
- tremor (shaking) 
- flushing 
Tests may show: 
- increased cholesterol in the blood 

Rare (affects 1 to 10 users in 10,000)
- itchy rash caused by a reaction to sunlight 
- liver failure, in some cases leading to death or liver transplant, has occurred with efavirenz. 

Most cases occurred in patients who already had liver disease, but there have been a few reports 
in patients without any existing liver disease. 

- unexplained feelings of distress not associated with hallucinations, but it may be difficult to 
think clearly or sensibly 

- suicide 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

5. How to store SUSTIVA 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the bottle and on the carton after 
EXP. The expiry date refers to the last day of that month.  

Do not throw away any medicines  via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  

6. Contents of the pack and other information 

What SUSTIVA contains 

 Each SUSTIVA hard capsule contains 50 mg of the active substance efavirenz. 
 The other ingredients of the powder contained in the hard capsule are: sodium laurilsulfate, 

lactose monohydrate, magnesium stearate and sodium starch glycolate. 
 The capsule shell contains: gelatine, sodium laurilsulfate, yellow iron oxide (E172), titanium 

dioxide (E171) and silicon dioxide.  
 The capsules are printed with inks containing cochineal carminic acid (E120), indigo carmine 

(E132), and titanium dioxide (E171). 

What SUSTIVA looks like and contents of the pack 
SUSTIVA 50 mg hard capsules are supplied in bottles of 30 capsules.  



95

Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

Manufacturer 
Bristol-Myers Squibb S.r.l. 
Contrada Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

Aesica Queenborough Limited 
North Road, Queenborough 
Kent, ME11 5EL 
United Kingdom 

Aesica Pharmaceuticals GmbH - Monheim,  
Alfred-Nobel-Straße 10,  
40789 Monheim,  
Germany 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32(0)27766211) 
dpoc_belux@merck.com 

Lietuva
UAB Merck Sharp & Dohme 
Tel.: +370 5 278 02 47
msd_lietuva@merck.com 

България
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel:  +32(0)27766211 
dpoc_belux@merck.com 

Česká republika
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
dpoc_czechslovak @merck.com 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +361 888 53 00 
hungary_msd@merck.com 

Danmark 
MSD Danmark ApS 
Tlf: +45 44 82 40 00 
dkmail@merck.com 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 

Deutschland 
Bristol-Myers Squibb GmbH & CO. KGaA 
Tel: +49 89 121 42-0 

Nederland  
Merck Sharp & Dohme BV 
Tel: 0800 9999000 (+31 23 5153153) 
medicalinfo.nl@merck.com 

Eesti 
Merck Sharp & Dohme OÜ 
Tel.: +372 6144 200 
msdeesti@merck.com

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 



96

Eλλάδα 
MSD Α.Φ.Β.Ε.Ε 
Τηλ: + 30-210 98 97 300 
dpoc_greece@merck.com 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com

España 
Bristol-Myers Squibb, S.A. 
Tel: +34 91 456 53 00 

Polska
MSD Polska Sp. z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 

France 
Bristol-Myers Squibb Sarl. 
Tél: +33 (0)1 58 83 84 96 

Portugal
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465700 
clic@merck.com

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 

România
Merck Sharp & Dohme Romania S.R.L. 
Tel: + 4021 529 29 00 
msdromania@merck.com

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: +353 (0)1 483 3625 

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201 
msd_slovenia@merck.com 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel.: +421 2 58282010
dpoc_czechslovak @merck.com 

Ιtalia 
Bristol-Myers Squibb S.r.l. 
Tel: +39 06 50 39 61 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: +358 (0) 9 804650 
info@msd.fi 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 80000 673 (+357 22866700) 
cyprus_info@merck.com 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 (0)77 5700488 
medicinskinfo@merck.com 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: +371 67364 224 
msd_lv@merck.com 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd. 
Tel: +44 (0800) 731 1736

This leaflet was last revised in  

Other sources of information 



97

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



98

Package leaflet: Information for the user

SUSTIVA 100 mg hard capsules  
efavirenz 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
 If you get any side effects, talk to your doctor,  pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

What is in this leaflet 

1. What SUSTIVA is and what it is used for 
2. What you need to know before you take SUSTIVA 
3. How to take SUSTIVA 
4. Possible side effects 
5. How to store SUSTIVA 
6. Contents of the pack and other information

1. What SUSTIVA is and what it is used for 

SUSTIVA, which contains the active substance efavirenz, belongs to a class of antiretroviral 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It is an antiretroviral 
medicine that fights human immunodeficiency virus (HIV-1) infection by reducing the amount of 
the virus in blood. It is used by adults, adolescents and children 3 months of age and older and 
weighing at least 3.5 kg.  
Your doctor has prescribed SUSTIVA for you because you have HIV infection. 
SUSTIVA taken in combination with other antiretroviral medicines reduces the amount of the virus in 
the blood. This will strengthen your immune system and reduce the risk of developing illnesses linked 
to HIV infection.  

2. What you need to know before you take SUSTIVA 

Do not take SUSTIVA 
 if you are allergic  to efavirenz or any of the other ingredients of this medicine (listed in section 

6). Contact your doctor or pharmacist for advice. 

  if you have severe liver disease. 

     if you have a heart condition, such as changes in the rhythm or rate of the heart beat, a 
slow heart beat, or severe heart disease.

     if any member of your family (parents, grandparents, brothers or sisters) has died suddenly due 

to a heart problem or was born with heart problems.  

     if your doctor has told you that you have high or low levels of electrolytes such as potassium or 

magnesium in your blood. 

 if you are currently taking any of the following medicines(see also “Other medicines and 
Sustiva”):  
- astemizole or terfenadine (used to treat allergy symptoms)  



99

- bepridil (used to treat heart disease) 
- cisapride (used to treat heartburn) 
- ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and 

methylergonovine) (used to treat migraine and cluster headaches) 
- midazolam or triazolam (used to help you sleep) 
- pimozide, imipramine, amitriptyline or clomipramine (used to treat certain mental 

conditions) 
- elbasvir or grazoprevir (used to treat hepatitis C) 
- St. John's wort (Hypericum perforatum) (a herbal remedy used for depression and 
anxiety) 
-  flecainide, metoprolol (used to treat irregular heart beat) 
-  certain antibiotics (macrolides, fluoroquinolones, imidazole)  
- triazole antifungal agents
- certain antimalarial treatments
-  methadone (used to treat opiate addiction) 

If you are taking any of these medicines, tell your doctor immediately. Taking these 
medicines with SUSTIVA could create the potential for serious and/or life-threatening side-
effects or stop SUSTIVA from working properly. 

Warnings and precautions  
Talk to your doctor before taking SUSTIVA 

 SUSTIVA must be taken with other medicines that act against the HIV virus. If SUSTIVA 
is started because your current treatment has not prevented the virus from multiplying, another 
medicine you have not taken before must be started at the same time. 

 You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other 
people. This medicine is not a cure for HIV infection and you may continue to develop 
infections or other illnesses associated with HIV disease.  

 You must remain under the care of your doctor while taking SUSTIVA. 
 
 Tell your doctor: 

- if you have a history of mental illness, including depression, or of substance or alcohol 
abuse. Tell your doctor immediately if you feel depressed, have suicidal thoughts or have 
strange thoughts (see section 4, Possible side effects). 

- if you have a history of convulsions (fits or seizures) or if you are being treated with 
anticonvulsant therapy such as carbamazepine, phenobarbital and phenytoin. If you are 
taking any of these medicines, your doctor may need to check the level of anticonvulsant 
medicine in your blood to ensure that it is not affected while taking SUSTIVA. Your 
doctor may give you a different anticonvulsant. 

- if you have a history of liver disease, including active chronic hepatitis. Patients with 
chronic hepatitis B or C and treated with combination antiretroviral agents have a higher 
risk for severe and potentially life-threatening liver problems. Your doctor may conduct 
blood tests in order to check how well your liver is working or may switch you to another 
medicine. If you have severe liver disease, do not take SUSTIVA (see section 2, Do not 
take SUSTIVA). 

- if you have a heart disorder, such as abnormal electrical signal called prolongation 
of the QT interval. 



100

 Once you start taking SUSTIVA, look out for: 

- signs of dizziness, difficulty sleeping, drowsiness, difficulty concentrating or 
abnormal dreaming. These side effects may start in the first 1 or 2 days of treatment and 
usually go away after the first 2 to 4 weeks. 

- any signs of skin rash. If you see any signs of a severe rash with blistering or fever, stop 
taking SUSTIVA and tell your doctor at once. If you had a rash while taking another 
NNRTI, you may be at a higher risk of getting a rash with SUSTIVA. 

- any signs of inflammation or infection. In some patients with advanced HIV infection 
(AIDS) and a history of opportunistic infection, signs and symptoms of inflammation 
from previous infections may occur soon after anti-HIV treatment is started. It is believed 
that these symptoms are due to an improvement in the body’s immune response, enabling 
the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection, please tell your doctor immediately.  
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs 
when the immune system attacks healthy body tissue) may also occur after you start 
taking medicines for the treatment of your HIV infection. Autoimmune disorders may 
occur many months after the start of treatment. If you notice any symptoms of infection or 
other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please 
inform your doctor immediately to seek necessary treatment. 

- bone problems. Some patients taking combination antiretroviral therapy may develop a 
bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to 
the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be 
some of the many risk factors for developing this disease. Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement. If you notice any of these symptoms please inform your doctor. 

Children and adolescents 
SUSTIVA is not recommeded for children under the age of 3 months or weighing less than 3.5 kg 
because it has not been adequately studied in these patients. 

Other medicines and SUSTIVA 
You must not take SUSTIVA with certain medicines. These are listed under Do not take 
SUSTIVA, at the start of Section 2. They include some common medicines and a herbal remedy (St. 
John’s wort) which can cause serious interactions. 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 

SUSTIVA may interact with other medicines, including herbal preparations such as Ginkgo biloba
extracts. As a result, the amounts of SUSTIVA or other medicines in your blood may be affected. This 
may stop the medicines from working properly, or may make any side effects worse. In some cases, 
your doctor may need to adjust your dose or check your blood levels. It is important to tell your 
doctor or pharmacist if you are taking any of the following: 

 Other medicines used for HIV infection: 
- protease inhibitors: darunavir, indinavir, lopinavir/ritonavir, ritonavir, ritonavir boosted 

atazanavir, saquinavir or fosamprenavir/saquinavir. Your doctor may consider giving you 
an alternative medicine or changing the dose of the protease inhibitors. 

- maraviroc 



101

- the combination tablet containing efavirenz, emtricitabine, and tenofovir should not be 
taken with SUSTIVA unless recommended by your doctor since it contains efavirenz, the 
active ingredient of SUSTIVA. 

 Medicines used to treat infection with the hepatitis C virus: boceprevir, telaprevir, 
elbasvir/grazoprevir, simeprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, 
glecaprevir/pibrentasvir.

 Medicines used to treat bacterial infections, including tuberculosis and AIDS-related 
mycobacterium avium complex: clarithromycin, rifabutin, rifampicin. Your doctor may consider 
changing your dose or giving you an alternative antibiotic. In addition, your doctor may 
prescribe a higher dose of SUSTIVA. 

 Medicines used to treat fungal infections (antifungals): 
- voriconazole. SUSTIVA may reduce the amount of voriconazole in your blood and 

voriconazole may increase the amount of SUSTIVA in your blood. If you take these two 
medicines together, the dose of voriconazole must be increased and the dose of efavirenz 
must be reduced. You must check with your doctor first. 

- itraconazole. SUSTIVA may reduce the amount of itraconazole in your blood. 
- posaconazole. SUSTIVA may reduce the amount of posaconazole in your blood. 

 Medicines used to treat malaria: 
- artemether/lumefantrine:  SUSTIVA may reduce the amount of artemether/lumefantrine 

in your blood. 
- atovaquone/proguanil:  SUSTIVA may reduce the amount of atovaquone/proguanil in 

your blood. 

 Medicines used to treat convulsions/seizures (anticonvulsants): carbamazepine, phenytoin, 
phenobarbital. SUSTIVA can reduce or increase the amount of anticonvulsant in your blood. 
Carbamazepine may make SUSTIVA less likely to work. Your doctor may need to consider 
giving you a different anticonvulsant. 

 Medicines used to lower blood fats (also called statins): atorvastatin, pravastatin, simvastatin. 
SUSTIVA can reduce the amount of statins in your blood. Your doctor will check your 
cholesterol levels and will consider changing the dose of your statin, if needed. 

  Methadone (a medicine used to treat opiate addiction): your doctor may recommend an 
alternative treatment. 

 Sertraline (a medicine used to treat depression): your doctor may need to change your dose of 
sertraline. 

 Bupropion (a medicine used to treat depression or to help you stop smoking): your doctor may 
need to change your dose of bupropion. 

  Diltiazem or similar medicines (called calcium channel blockers which are medicines 
typically used for high blood pressure or heart problems): when you start taking SUSTIVA, 
your doctor may need to adjust your dose of the calcium channel blocker. 

 Immunosuppressants such as cyclosporine, sirolimus, or tacrolimus (medicines used to 
prevent organ transplant rejection): when you start or stop taking SUSTIVA, your doctor will 
closely monitor your plasma levels of the immunosuppressant and may need to adjust its dose. 

 Hormonal contraceptive, such as birth control pills, an injected contraceptive (for 
example, Depo-Provera), or a contraceptive implant (for example, Implanon): you must 
also use a reliable barrier method of contraception (see Pregnancy,breast-feeding and fertility). 
SUSTIVA may make hormonal contraceptives less likely to work. Pregnancies have occurred in 



102

women taking SUSTIVA while using a contraceptive implant, although it has not been 
established that the SUSTIVA therapy caused the contraceptive to fail. 

 Warfarin or acenocoumarol (medicines used to reduce clotting of the blood): your doctor may 
need to adjust your dose of warfarin or acenocoumarol. 

 Ginkgo biloba extracts (a herbal preparation) 

    Medicines that impact heart rhythm:
-  Medicines used to treat heart rhythm problems such as flecainide or metoprolol. 

-     Medicines used to treat depression such as imipramine, amitriptyline or clomipramine. 

-    Antibiotics, including the following types: macrolides, fluoroquinolones or imidazole. 

SUSTIVA with food and drink 
Taking SUSTIVA on an empty stomach may reduce the undesirable effects. Grapefuit juice should be 
avoided when taking SUSTIVA. 

Pregnancy and breast-feeding 
Women should not get pregnant during treatment with SUSTIVA, and for 12 weeks thereafter. 
Your doctor may require you to take a pregnancy test to ensure you are not pregnant before starting 
treatment with SUSTIVA.  

If you could get pregnant while receiving SUSTIVA, you need to use a reliable form of barrier 
contraception (for example, a condom) with other methods of contraception including oral (pill) or 
other hormonal contraceptives (for example, implants, injection). Efavirenz may remain in your blood 
for a time after therapy is stopped. Therefore, you should continue to use contraceptive measures, as 
above, for 12 weeks after you stop taking SUSTIVA.  

Tell your doctor immediately if you are pregnant or intend to become pregnant. If you are 
pregnant, you should take SUSTIVA only if you and your doctor decide it is clearly needed. Ask your 
doctor or pharmacist for advice before taking any medicine. 

Serious birth defects have been seen in unborn animals and in the babies of women treated with 
efavirenz or a combination medicine containing efavirenz, emtricitabine and tenofovir during 
pregnancy. If you have taken SUSTIVA or the combination tablet containing efavirenz, emtricitabine, 
and tenofovir during your pregnancy, your doctor may request regular blood tests and other diagnostic 
tests to monitor the development of your child. 

You should not breast feed your baby if you are taking SUSTIVA. 

Driving and using machines 
SUSTIVA contains efavirenz and may cause dizziness, impaired concentration, and drowsiness.
If you are affected, do not drive and do not use any tools or machines.  

SUSTIVA contains lactose in each 600-mg daily dose. 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  

3. How to take SUSTIVA 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor will give you instructions for proper dosing.  



103

 The dose for adults is 600 mg once daily. 
 The dose for SUSTIVA may need to be increased or decreased if you are also taking certain 

medicines (see Other medicines and SUSTIVA).  
 SUSTIVA is for oral use. SUSTIVA is recommended to be taken on an empty stomach 

preferably at bedtime. This may make some side effects (for example, dizziness, drowsiness) 
less troublesome. An empty stomach is commonly defined as 1 hour before or 2 hours after a 
meal.  

 It is recommended that the capsule be swallowed whole with water. 
 SUSTIVA must be taken every day. 
 SUSTIVA should never be used alone to treat HIV. SUSTIVA must always be taken in 

combination with other anti-HIV medicines. 

Use in children and adolescents 
 SUSTIVA 100 mg hard capsules can be taken by children and adolescents 3 months of age and 

older and weighing at least 3.5 kg who are able to swallow the capsules. Opening the capsule 
and taking the contents with a small amount of food may be considered for children who cannot 
swallow the hard capsule. 

 The dose for children and adolescents is calculated by body weight and is taken once daily as 
shown below: 

Body Weight SUSTIVA Number of Capsules or 
Tablets and Strength to 

Administer
kg Dose (mg) 

3.5 to < 5 100 one 100 mg capsule

5 to < 7.5 150 one 100 mg capsule + one 
50 mg capsule 

7.5 to < 15 200 one 200 mg capsule 
15 to < 20 250 one 200 mg capsule + one 

50 mg capsule
20 to < 25 300 three 100 mg capsules

25 to < 32.5 350 three 100 mg capsules + 
one 50 mg capsule

32.5 to < 40 400 two 200 mg capsules
≥ 40 600 one 600 mg tablet OR 

three 200 mg capsules

For children who are not able to swallow the capsules, the doctor may recommend opening the hard 
capsule and mixing the contents with a small amount (1-2 teaspoons) of food (e.g., yogurt ). The 
capsules must be opened carefully so that the contents do not spill or escape into the air. Hold the 
capsule with the cap facing up and pull the cap away from the body of the capsule. Use a small 
container for mixing. Give the mixture to the child as soon as possible, but no more than 30 minutes 
after mixing. Make sure the child eats the full amount of the mixture of food and capsule contents. 
Add another small amount (approximately 2 teaspoons) of the food to the empty mixing container, 
stirring to make sure there is no drug residue remaining in the container, and have the child eat the full 
amount again. The child should not be given any additional food for 2 hours. The doctor may also 
recommend this method of taking SUSTIVA for adults who cannot swallow capsules. 

Instructions for capsule sprinkle method: 

1 Avoid giving the daily SUSTIVA dose within 1 hour after a feeding or meal.
2 Wash and dry your hands before and after preparing the capsule sprinkle.
3 Choose a soft food the child likes. Examples of soft foods are applesauce, grape jelly, yogurt, 

or infant formula. In a taste preference study in adults, SUSTIVA mixed with grape jelly 
received the best rating.



104

4 Place 1-2 teaspoons of the food in a small container (illustration a). 

5 SUSTIVA capsules must be opened carefully over the food container, as described in steps 
6-7, so that the contents do not spill.

6 With your hands over the container, hold the capsule with the cap 
facing up (see illustration b). 

7 Carefully pull the cap away from the body of the capsule 
(illustration c). 

8 Sprinkle the contents of the capsule on the food (illustration d). 

9 If the daily dose consists of more than one capsule, follow steps 5-8 for each capsule. Do not
add more food.

10 Mix the capsule contents and food together (illustration e). 

Steps 11-14 must be completed within 30 minutes of mixing:
11 Give the mixture of food and capsule contents to the child, making 

sure he or she eats the full amount (illustration f). 

12 Add another small amount (approximately 2 teaspoons) of the food to the empty mixing 
container (illustration a).

13 Stir to make sure there is no drug residue remaining in the container (illustration e).
14 Have the child eat the full amount again (illustration f).
15 Do not give the child any additional food for 2 hours.

If you take more SUSTIVA than you should 
If you take too much SUSTIVA contact your doctor or nearest emergency department for advice. 
Keep the medicine container with you so that you can easily describe what you have taken. 

If you forget to take SUSTIVA 
Try not to miss a dose. If you do miss a dose, take the next dose as soon as possible, but do not take a 
double dose to make up for a forgotten dose. If you need help in planning the best times to take your 
medicine, ask your doctor or pharmacist. 



105

If you stop taking SUSTIVA 
When your SUSTIVA supply starts to run low, get more from your doctor or pharmacist. This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time. The virus may then become harder to treat. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.  

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  
When treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by SUSTIVA or by other medicines that you are taking at the same time, or by the HIV disease 
itself. 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

The most notable unwanted effects reported with SUSTIVA in combination with other anti-HIV 
medicines are skin rash and nervous system symptoms. 

You should consult your doctor if you have a rash, since some rashes may be serious; however, most 
cases of rash disappear without any change to your treatment with SUSTIVA. Rash was more 
common in children than in adults treated with SUSTIVA. 

The nervous system symptoms tend to occur when treatment is first started, but generally decrease in 
the first few weeks. In one study, nervous system symptoms often occurred during the first 1-3 hours 
after taking a dose. If you are affected your doctor may suggest that you take SUSTIVA at bedtime 
and on an empty stomach. Some patients have more serious symptoms that may affect mood or the 
ability to think clearly. Some patients have actually committed suicide. These problems tend to occur 
more often in those who have a history of mental illness. Always notify your doctor immediately if 
you have these symptoms or any side effects while taking SUSTIVA. 

Tell your doctor if you notice any of the following side effects: 

Very common (affects more than 1 user in 10)
- skin rash 

Common (affects 1 to 10 users in 100)
- abnormal dreams, difficulty concentrating, dizziness, headache, difficulty sleeping, drowsiness, 

problems with coordination or balance 
- stomach pain, diarrhoea, feeling sick (nausea), vomiting 
- itching 
- tiredness 
- feeling anxious, feeling depressed 
Tests may show: 
- increased liver enzymes in the blood 
- increased trigycerides (fatty acids) in the blood 

Uncommon (affects 1 to 10 users in 1,000)
- nervousness, forgetfulness,  confusion, fitting (seizures), abnormal thoughts 
- blurred vision 
- a feeling of spinning or tilting (vertigo) 
- pain in the abdomen (stomach) caused by inflammation of the pancreas 



106

- allergic reaction (hypersensitivity) that may cause severe skin reactions (erythema multiforme, 
Stevens-Johnson syndrome) 

- yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the 
liver 

- breast enlargement in males 
- angry behaviour, mood being affected, seeing or hearing things that are not really there 

(hallucinations), mania (mental condition characterised by episodes of overactivity, elation or 
irritability), paranoia, suicidal thoughts, catatonia (condition in which the patient is rendered 
motionless and speechless for a period) 

- whistling, ringing or other persistent noise in the ears 
- tremor (shaking) 
- flushing 
Tests may show: 
- increased cholesterol in the blood 

Rare (affects 1 to 10 users in 10,000)
- itchy rash caused by a reaction to sunlight 
- liver failure, in some cases leading to death or liver transplant, has occurred with efavirenz. 

Most cases occurred in patients who already had liver disease, but there have been a few reports 
in patients without any existing liver disease. 

- unexplained feelings of distress not associated with hallucinations, but it may be difficult to 
think clearly or sensibly 

- suicide 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

5. How to store SUSTIVA 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the bottle and on the carton after 
EXP. The expiry date refers to the last day of that month.  

Do not throw away any medicines  via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  

6. Contents of the pack and other information 

What SUSTIVA contains 

 Each SUSTIVA hard capsule contains 100 mg of the active substance efavirenz. 
 The other ingredients of the powder contained in the hard capsule are: sodium laurilsulfate, 

lactose monohydrate, magnesium stearate and sodium starch glycolate. 
 The capsule shell contains: gelatine, sodium laurilsulfate, titanium dioxide (E171) and silicon 

dioxide.  
 The capsules are printed with inks containing cochineal carminic acid (E120), indigo carmine 

(E132), and titanium dioxide (E171). 

What SUSTIVA looks like and contents of the pack 
SUSTIVA 100 mg hard capsules are supplied in bottles of 30 capsules.  



107

Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

Manufacturer 
Bristol-Myers Squibb S.r.l. 
Contrada Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

Aesica Queenborough Limited 
North Road, Queenborough 
Kent, ME11 5EL 
United Kingdom 

Aesica Pharmaceuticals GmbH - Monheim,  
Alfred-Nobel-Straße 10,  
40789 Monheim,  
Germany 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32(0)27766211) 
dpoc_belux@merck.com 

Lietuva
UAB Merck Sharp & Dohme 
Tel.: +370 5 278 02 47
msd_lietuva@merck.com 

България
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel:  +32(0)27766211 
dpoc_belux@merck.com 

Česká republika
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
dpoc_czechslovak @merck.com 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +361 888 53 00 
hungary_msd@merck.com 

Danmark 
MSD Danmark ApS 
Tlf: +45 44 82 40 00 
dkmail@merck.com 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 

Deutschland 
Bristol-Myers Squibb GmbH & CO. KGaA 
Tel: +49 89 121 42-0 

Nederland  
Merck Sharp & Dohme BV 
Tel: 0800 9999000 (+31 23 5153153) 
medicalinfo.nl@merck.com 

Eesti 
Merck Sharp & Dohme OÜ 
Tel.: +372 6144 200 
msdeesti@merck.com

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 



108

Eλλάδα 
MSD Α.Φ.Β.Ε.Ε 
Τηλ: + 30-210 98 97 300 
dpoc_greece@merck.com 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com

España 
Bristol-Myers Squibb, S.A. 
Tel: +34 91 456 53 00 

Polska
MSD Polska Sp. z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 

France 
Bristol-Myers Squibb Sarl. 
Tél: +33 (0)1 58 83 84 96 

Portugal
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465700 
clic@merck.com

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 

România
Merck Sharp & Dohme Romania S.R.L. 
Tel: + 4021 529 29 00 
msdromania@merck.com

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: +353 (0)1 483 3625 

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201 
msd_slovenia@merck.com 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel.: +421 2 58282010
dpoc_czechslovak @merck.com 

Ιtalia 
Bristol-Myers Squibb S.r.l. 
Tel: +39 06 50 39 61 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: +358 (0) 9 804650 
info@msd.fi 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 80000 673 (+357 22866700) 
cyprus_info@merck.com 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 (0)77 5700488 
medicinskinfo@merck.com 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: +371 67364 224 
msd_lv@merck.com 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd. 
Tel: +44 (0800) 731 1736

This leaflet was last revised in  

Other sources of information 



109

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



110

Package leaflet: Information for the user

SUSTIVA 200 mg hard capsules  
efavirenz 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
 If you get any side effects, talk to your doctor,  pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

What is in this leaflet 

1. What SUSTIVA is and what it is used for 
2. What you need to know before you take SUSTIVA 
3. How to take SUSTIVA 
4. Possible side effects 
5. How to store SUSTIVA 
6. Contents of the pack and other information

1. What SUSTIVA is and what it is used for 

SUSTIVA, which contains the active substance efavirenz, belongs to a class of antiretroviral 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It is an antiretroviral 
medicine that fights human immunodeficiency virus (HIV-1) infection by reducing the amount of 
the virus in blood. It is used by adults, adolescents and children 3 months of age and older and 
weighing at least 3.5 kg.  
Your doctor has prescribed SUSTIVA for you because you have HIV infection. 
SUSTIVA taken in combination with other antiretroviral medicines reduces the amount of the virus in 
the blood. This will strengthen your immune system and reduce the risk of developing illnesses linked 
to HIV infection.  

2. What you need to know before you take SUSTIVA 

Do not take SUSTIVA 
 if you are allergic  to efavirenz or any of the other ingredients of this medicine (listed in section 

6). Contact your doctor or pharmacist for advice. 

  if you have severe liver disease. 

     if you have a heart condition, such as changes in the rhythm or rate of the heart beat, a 

slow heart beat, or severe heart disease.

    if any member of your family (parents, grandparents, brothers or sisters) has died suddenly due 

to a heart problem or was born with heart problems.  

    if your doctor has told you that you have high or low levels of electrolytes such as potassium or 

magnesium in your blood. 

 if you are currently taking any of the following medicines (see also “Other medicines and 
Sustiva”):  
- astemizole or terfenadine (used to treat allergy symptoms)  



111

- bepridil (used to treat heart disease) 
- cisapride (used to treat heartburn) 
- ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and 

methylergonovine) (used to treat migraine and cluster headaches) 
- midazolam or triazolam (used to help you sleep) 
- pimozide, imipramine, amitriptyline or clomipramine (used to treat certain mental 

conditions) 
- elbasvir or grazoprevir (used to treat hepatitis C) 
- St. John's wort (Hypericum perforatum) (a herbal remedy used for depression and 

anxiety)  
-  flecainide, metoprolol (used to treat irregular heart beat) 
-  certain antibiotics (macrolides, fluoroquinolones, imidazole)  
- triazole antifungal agents
- certain antimalarial treatments
-  methadone (used to treat opiate addiction) 

If you are taking any of these medicines, tell your doctor immediately. Taking these 
medicines with SUSTIVA could create the potential for serious and/or life-threatening side-
effects or stop SUSTIVA from working properly. 

Warnings and precautions  
Talk to your doctor before taking SUSTIVA 

 SUSTIVA must be taken with other medicines that act against the HIV virus. If SUSTIVA 
is started because your current treatment has not prevented the virus from multiplying, another 
medicine you have not taken before must be started at the same time. 

 You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other 
people. This medicine is not a cure for HIV infection and you may continue to develop 
infections or other illnesses associated with HIV disease.  

 You must remain under the care of your doctor while taking SUSTIVA. 
 
 Tell your doctor: 

- if you have a history of mental illness, including depression, or of substance or alcohol 
abuse. Tell your doctor immediately if you feel depressed, have suicidal thoughts or have 
strange thoughts (see section 4, Possible side effects). 

- if you have a history of convulsions (fits or seizures) or if you are being treated with 
anticonvulsant therapy such as carbamazepine, phenobarbital and phenytoin. If you are 
taking any of these medicines, your doctor may need to check the level of anticonvulsant 
medicine in your blood to ensure that it is not affected while taking SUSTIVA. Your 
doctor may give you a different anticonvulsant. 

- if you have a history of liver disease, including active chronic hepatitis. Patients with 
chronic hepatitis B or C and treated with combination antiretroviral agents have a higher 
risk for severe and potentially life-threatening liver problems. Your doctor may conduct 
blood tests in order to check how well your liver is working or may switch you to another 
medicine. If you have severe liver disease, do not take SUSTIVA (see section 2, Do not 
take SUSTIVA). 

- if you have a heart disorder, such as abnormal electrical signal called prolongation 
of the QT interval. 



112

 Once you start taking SUSTIVA, look out for: 

- signs of dizziness, difficulty sleeping, drowsiness, difficulty concentrating or 
abnormal dreaming. These side effects may start in the first 1 or 2 days of treatment and 
usually go away after the first 2 to 4 weeks. 

- any signs of skin rash. If you see any signs of a severe rash with blistering or fever, stop 
taking SUSTIVA and tell your doctor at once. If you had a rash while taking another 
NNRTI, you may be at a higher risk of getting a rash with SUSTIVA. 

- any signs of inflammation or infection. In some patients with advanced HIV infection 
(AIDS) and a history of opportunistic infection, signs and symptoms of inflammation 
from previous infections may occur soon after anti-HIV treatment is started. It is believed 
that these symptoms are due to an improvement in the body’s immune response, enabling 
the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection, please tell your doctor immediately.  
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs 
when the immune system attacks healthy body tissue) may also occur after you start 
taking medicines for the treatment of your HIV infection. Autoimmune disorders may 
occur many months after the start of treatment. If you notice any symptoms of infection or 
other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please 
inform your doctor immediately to seek necessary treatment. 

- bone problems. Some patients taking combination antiretroviral therapy may develop a 
bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to 
the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be 
some of the many risk factors for developing this disease. Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement. If you notice any of these symptoms please inform your doctor. 

Children and adolescents 
SUSTIVA is not recommeded for children under the age of 3 months or weighing less than 3.5 kg 
because it has not been adequately studied in these patients. 

Other medicines and SUSTIVA 
You must not take SUSTIVA with certain medicines. These are listed under Do not take 
SUSTIVA, at the start of Section 2. They include some common medicines and a herbal remedy (St. 
John’s wort) which can cause serious interactions. 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 

SUSTIVA may interact with other medicines, including herbal preparations such as Ginkgo biloba
extracts. As a result, the amounts of SUSTIVA or other medicines in your blood may be affected. This 
may stop the medicines from working properly, or may make any side effects worse. In some cases, 
your doctor may need to adjust your dose or check your blood levels. It is important to tell your 
doctor or pharmacist if you are taking any of the following: 

 Other medicines used for HIV infection: 
- protease inhibitors: darunavir, indinavir, lopinavir/ritonavir, ritonavir, ritonavir boosted 

atazanavir, saquinavir or fosamprenavir/saquinavir. Your doctor may consider giving you 
an alternative medicine or changing the dose of the protease inhibitors. 

- maraviroc 



113

- the combination tablet containing efavirenz, emtricitabine, and tenofovir should not be 
taken with SUSTIVA unless recommended by your doctor since it contains efavirenz, the 
active ingredient of SUSTIVA. 

 Medicines used to treat infection with the hepatitis C virus: boceprevir, telaprevir, 
elbasvir/grazoprevir, simeprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, 
glecaprevir/pibrentasvir.

 Medicines used to treat bacterial infections, including tuberculosis and AIDS-related 
mycobacterium avium complex: clarithromycin, rifabutin, rifampicin. Your doctor may consider 
changing your dose or giving you an alternative antibiotic. In addition, your doctor may 
prescribe a higher dose of SUSTIVA. 

 Medicines used to treat fungal infections (antifungals): 
- voriconazole. SUSTIVA may reduce the amount of voriconazole in your blood and 

voriconazole may increase the amount of SUSTIVA in your blood. If you take these two 
medicines together, the dose of voriconazole must be increased and the dose of efavirenz 
must be reduced. You must check with your doctor first. 

- itraconazole. SUSTIVA may reduce the amount of itraconazole in your blood. 
- posaconazole. SUSTIVA may reduce the amount of posaconazole in your blood. 

 Medicines used to treat malaria: 
- artemether/lumefantrine:  SUSTIVA may reduce the amount of artemether/lumefantrine 

in your blood. 
- atovaquone/proguanil:  SUSTIVA may reduce the amount of atovaquone/proguanil in 

your blood. 

 Medicines used to treat convulsions/seizures (anticonvulsants): carbamazepine, phenytoin, 
phenobarbital. SUSTIVA can reduce or increase the amount of anticonvulsant in your blood. 
Carbamazepine may make SUSTIVA less likely to work. Your doctor may need to consider 
giving you a different anticonvulsant. 

 Medicines used to lower blood fats (also called statins): atorvastatin, pravastatin, simvastatin. 
SUSTIVA can reduce the amount of statins in your blood. Your doctor will check your 
cholesterol levels and will consider changing the dose of your statin, if needed. 

  Methadone (a medicine used to treat opiate addiction): your doctor may recommend an 
alternative treatment. 

 Sertraline (a medicine used to treat depression): your doctor may need to change your dose of 
sertraline. 

 Bupropion (a medicine used to treat depression or to help you stop smoking): your doctor may 
need to change your dose of bupropion. 

  Diltiazem or similar medicines (called calcium channel blockers which are medicines 
typically used for high blood pressure or heart problems): when you start taking SUSTIVA, 
your doctor may need to adjust your dose of the calcium channel blocker. 

 Immunosuppressants such as cyclosporine, sirolimus, or tacrolimus (medicines used to 
prevent organ transplant rejection): when you start or stop taking SUSTIVA, your doctor will 
closely monitor your plasma levels of the immunosuppressant and may need to adjust its dose. 

 Hormonal contraceptive, such as birth control pills, an injected contraceptive (for 
example, Depo-Provera), or a contraceptive implant (for example, Implanon): you must 
also use a reliable barrier method of contraception (see Pregnancy,breast-feeding and fertility). 
SUSTIVA may make hormonal contraceptives less likely to work. Pregnancies have occurred in 



114

women taking SUSTIVA while using a contraceptive implant, although it has not been 
established that the SUSTIVA therapy caused the contraceptive to fail. 

 Warfarin or acenocoumarol (medicines used to reduce clotting of the blood): your doctor may 
need to adjust your dose of warfarin or acenocoumarol. 

 Ginkgo biloba extracts (a herbal preparation)

     Medicines that impact heart rhythm:
- Medicines used to treat heart rhythm problems such as flecainide or metoprolol. 

-     Medicines used to treat depression such as imipramine, amitriptyline or clomipramine. 

-    Antibiotics, including the following types: macrolides, fluoroquinolones or imidazole. 

SUSTIVA with food and drink 
Taking SUSTIVA on an empty stomach may reduce the undesirable effects. Grapefuit juice should be 
avoided when taking SUSTIVA. 

Pregnancy and breast-feeding 
Women should not get pregnant during treatment with SUSTIVA, and for 12 weeks thereafter. 
Your doctor may require you to take a pregnancy test to ensure you are not pregnant before starting 
treatment with SUSTIVA.  

If you could get pregnant while receiving SUSTIVA, you need to use a reliable form of barrier 
contraception (for example, a condom) with other methods of contraception including oral (pill) or 
other hormonal contraceptives (for example, implants, injection). Efavirenz may remain in your blood 
for a time after therapy is stopped. Therefore, you should continue to use contraceptive measures, as 
above, for 12 weeks after you stop taking SUSTIVA.  

Tell your doctor immediately if you are pregnant or intend to become pregnant. If you are 
pregnant, you should take SUSTIVA only if you and your doctor decide it is clearly needed. Ask your 
doctor or pharmacist for advice before taking any medicine. 

Serious birth defects have been seen in unborn animals and in the babies of women treated with 
efavirenz or a combination medicine containing efavirenz, emtricitabine and tenofovir during 
pregnancy. If you have taken SUSTIVA or the combination tablet containing efavirenz, emtricitabine, 
and tenofovir during your pregnancy, your doctor may request regular blood tests and other diagnostic 
tests to monitor the development of your child. 

You should not breast feed your baby if you are taking SUSTIVA. 

Driving and using machines 
SUSTIVA contains efavirenz and may cause dizziness, impaired concentration, and drowsiness.
If you are affected, do not drive and do not use any tools or machines.  

SUSTIVA contains lactose in each 600-mg daily dose. 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  

3. How to take SUSTIVA 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor will give you instructions for proper dosing.  



115

 The dose for adults is 600 mg once daily. 
 The dose for SUSTIVA may need to be increased or decreased if you are also taking certain 

medicines (see Other medicines and SUSTIVA).  
 SUSTIVA is for oral use. SUSTIVA is recommended to be taken on an empty stomach 

preferably at bedtime. This may make some side effects (for example, dizziness, drowsiness) 
less troublesome. An empty stomach is commonly defined as 1 hour before or 2 hours after a 
meal.  

 It is recommended that the capsule be swallowed whole with water. 
 SUSTIVA must be taken every day. 
 SUSTIVA should never be used alone to treat HIV. SUSTIVA must always be taken in 

combination with other anti-HIV medicines. 

Use in children and adolescents 
 SUSTIVA 200 mg hard capsules can be taken by children and adolescents 3 months of age and 

older and weighing at least 3.5 kg who are able to swallow the capsules. Opening the capsule 
and taking the contents with a small amount of food may be considered for children who cannot 
swallow the hard capsule. 

 The dose for children and adolescents is calculated by body weight and is taken once daily as 
shown below: 

Body Weight SUSTIVA Number of Capsules or 
Tablets and Strength to 

Administer
kg Dose (mg) 

3.5 to < 5 100 one 100 mg capsule

5 to < 7.5 150 one 100 mg capsule + one 
50 mg capsule 

7.5 to < 15 200 one 200 mg capsule 
15 to < 20 250 one 200 mg capsule + one 

50 mg capsule
20 to < 25 300 three 100 mg capsules

25 to < 32.5 350 three 100 mg capsules + 
one 50 mg capsule

32.5 to < 40 400 two 200 mg capsules
≥ 40 600 one 600 mg tablet OR 

three 200 mg capsules

For children who are not able to swallow the capsules, the doctor may recommend opening the hard 
capsule and mixing the contents with a small amount (1-2 teaspoons) of food (e.g., yogurt ). The 
capsules must be opened carefully so that the contents do not spill or escape into the air. Hold the 
capsule with the cap facing up and pull the cap away from the body of the capsule. Use a small 
container for mixing. Give the mixture to the child as soon as possible, but no more than 30 minutes 
after mixing. Make sure the child eats the full amount of the mixture of food and capsule contents. 
Add another small amount (approximately 2 teaspoons) of the food to the empty mixing container, 
stirring to make sure there is no drug residue remaining in the container, and have the child eat the full 
amount again. The child should not be given any additional food for 2 hours. The doctor may also 
recommend this method of taking SUSTIVA for adults who cannot swallow capsules. 

Instructions for capsule sprinkle method: 

1 Avoid giving the daily SUSTIVA dose within 1 hour after a feeding or meal.
2 Wash and dry your hands before and after preparing the capsule sprinkle.
3 Choose a soft food the child likes. Examples of soft foods are applesauce, grape jelly, yogurt, 

or infant formula. In a taste preference study in adults, SUSTIVA mixed with grape jelly 
received the best rating.



116

4 Place 1-2 teaspoons of the food in a small container (illustration a). 

5 SUSTIVA capsules must be opened carefully over the food container, as described in steps 
6-7, so that the contents do not spill.

6 With your hands over the container, hold the capsule with the cap 
facing up (see illustration b). 

7 Carefully pull the cap away from the body of the capsule 
(illustration c). 

8 Sprinkle the contents of the capsule on the food (illustration d). 

9 If the daily dose consists of more than one capsule, follow steps 5-8 for each capsule. Do not
add more food.

10 Mix the capsule contents and food together (illustration e). 

Steps 11-14 must be completed within 30 minutes of mixing:
11 Give the mixture of food and capsule contents to the child, making 

sure he or she eats the full amount (illustration f). 

12 Add another small amount (approximately 2 teaspoons) of the food to the empty mixing 
container (illustration a).

13 Stir to make sure there is no drug residue remaining in the container (illustration e).
14 Have the child eat the full amount again (illustration f).
15 Do not give the child any additional food for 2 hours.

If you take more SUSTIVA than you should 
If you take too much SUSTIVA contact your doctor or nearest emergency department for advice. 
Keep the medicine container with you so that you can easily describe what you have taken. 

If you forget to take SUSTIVA 
Try not to miss a dose. If you do miss a dose, take the next dose as soon as possible, but do not take a 
double dose to make up for a forgotten dose. If you need help in planning the best times to take your 
medicine, ask your doctor or pharmacist. 



117

If you stop taking SUSTIVA 
When your SUSTIVA supply starts to run low, get more from your doctor or pharmacist. This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time. The virus may then become harder to treat. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.  

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  
When treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by SUSTIVA or by other medicines that you are taking at the same time, or by the HIV disease 
itself. 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

The most notable unwanted effects reported with SUSTIVA in combination with other anti-HIV 
medicines are skin rash and nervous system symptoms. 

You should consult your doctor if you have a rash, since some rashes may be serious; however, most 
cases of rash disappear without any change to your treatment with SUSTIVA. Rash was more 
common in children than in adults treated with SUSTIVA. 

The nervous system symptoms tend to occur when treatment is first started, but generally decrease in 
the first few weeks. In one study, nervous system symptoms often occurred during the first 1-3 hours 
after taking a dose. If you are affected your doctor may suggest that you take SUSTIVA at bedtime 
and on an empty stomach. Some patients have more serious symptoms that may affect mood or the 
ability to think clearly. Some patients have actually committed suicide. These problems tend to occur 
more often in those who have a history of mental illness. Always notify your doctor immediately if 
you have these symptoms or any side effects while taking SUSTIVA. 

Tell your doctor if you notice any of the following side effects: 

Very common (affects more than 1 user in 10)
- skin rash 

Common (affects 1 to 10 users in 100)
- abnormal dreams, difficulty concentrating, dizziness, headache, difficulty sleeping, drowsiness, 

problems with coordination or balance 
- stomach pain, diarrhoea, feeling sick (nausea), vomiting 
- itching 
- tiredness 
- feeling anxious, feeling depressed 
Tests may show: 
- increased liver enzymes in the blood 
- increased trigycerides (fatty acids) in the blood 

Uncommon (affects 1 to 10 users in 1,000)
- nervousness, forgetfulness,  confusion, fitting (seizures), abnormal thoughts 
- blurred vision 
- a feeling of spinning or tilting (vertigo) 
- pain in the abdomen (stomach) caused by inflammation of the pancreas 



118

- allergic reaction (hypersensitivity) that may cause severe skin reactions (erythema multiforme, 
Stevens-Johnson syndrome) 

- yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the 
liver 

- breast enlargement in males 
- angry behaviour, mood being affected, seeing or hearing things that are not really there 

(hallucinations), mania (mental condition characterised by episodes of overactivity, elation or 
irritability), paranoia, suicidal thoughts, catatonia (condition in which the patient is rendered 
motionless and speechless for a period) 

- whistling, ringing or other persistent noise in the ears 
- tremor (shaking) 
- flushing 
Tests may show: 
- increased cholesterol in the blood 

Rare (affects 1 to 10 users in 10,000)
- itchy rash caused by a reaction to sunlight 
- liver failure, in some cases leading to death or liver transplant, has occurred with efavirenz. 

Most cases occurred in patients who already had liver disease, but there have been a few reports 
in patients without any existing liver disease. 

- unexplained feelings of distress not associated with hallucinations, but it may be difficult to 
think clearly or sensibly 

- suicide 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

5. How to store SUSTIVA 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the bottle or blister and on the carton 
after EXP. The expiry date refers to the last day of that month.  

Do not throw away any medicines  via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  

6. Contents of the pack and other information 

What SUSTIVA contains 

 Each SUSTIVA hard capsule contains 200 mg of the active substance efavirenz. 
 The other ingredients of the powder contained in the hard capsule are: sodium laurilsulfate, 

lactose monohydrate, magnesium stearate and sodium starch glycolate. 
 The capsule shell contains: gelatine, sodium laurilsulfate, yellow iron oxide (E172) and silicon 

dioxide.  
 The capsules are printed with inks containing cochineal carminic acid (E120), indigo carmine 

(E132), and titanium dioxide (E171). 

What SUSTIVA looks like and contents of the pack 
SUSTIVA 200 mg hard capsules are supplied in bottles of 90 capsules and in packs containing 
42 x 1 capsules in aluminium/PVC perforated unit dose blisters. Not all pack sizes may be marketed. 



119

Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15 
D15 T867 
Ireland 

Manufacturer 
Bristol-Myers Squibb S.r.l. 
Contrada Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

Aesica Queenborough Limited 
North Road, Queenborough 
Kent, ME11 5EL 
United Kingdom 

Aesica Pharmaceuticals GmbH - Monheim,  
Alfred-Nobel-Straße 10,  
40789 Monheim,  
Germany 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32(0)27766211) 
dpoc_belux@merck.com 

Lietuva
UAB Merck Sharp & Dohme 
Tel.: +370 5 278 02 47
msd_lietuva@merck.com 

България
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel:  +32(0)27766211 
dpoc_belux@merck.com 

Česká republika
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
dpoc_czechslovak @merck.com 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +361 888 53 00 
hungary_msd@merck.com 

Danmark 
MSD Danmark ApS 
Tlf: +45 44 82 40 00 
dkmail@merck.com 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 

Deutschland 
Bristol-Myers Squibb GmbH & CO. KGaA 
Tel: +49 89 121 42-0 

Nederland  
Merck Sharp & Dohme BV 
Tel: 0800 9999000 (+31 23 5153153) 
medicalinfo.nl@merck.com 



120

Eesti 
Merck Sharp & Dohme OÜ 
Tel.: +372 6144 200 
msdeesti@merck.com

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 

Eλλάδα 
MSD Α.Φ.Β.Ε.Ε 
Τηλ: + 30-210 98 97 300 
dpoc_greece@merck.com 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com

España 
Bristol-Myers Squibb, S.A. 
Tel: +34 91 456 53 00 

Polska
MSD Polska Sp. z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 

France 
Bristol-Myers Squibb Sarl. 
Tél: +33 (0)1 58 83 84 96 

Portugal
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465700 
clic@merck.com

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 

România
Merck Sharp & Dohme Romania S.R.L. 
Tel: + 4021 529 29 00 
msdromania@merck.com

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: +353 (0)1 483 3625 

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201 
msd_slovenia@merck.com 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel.: +421 2 58282010
dpoc_czechslovak @merck.com 

Ιtalia 
Bristol-Myers Squibb S.r.l. 
Tel: +39 06 50 39 61 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: +358 (0) 9 804650 
info@msd.fi 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 80000 673 (+357 22866700) 
cyprus_info@merck.com 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 (0)77 5700488 
medicinskinfo@merck.com 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: +371 67364 224 
msd_lv@merck.com 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd. 
Tel: +44 (0800) 731 1736



121

This leaflet was last revised in  

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



122

Package leaflet: Information for the user

SUSTIVA 600 mg film-coated tablets  
efavirenz 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor,  pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

What is in this leaflet 

1. What SUSTIVA is and what it is used for 
2. What you need to know before you take SUSTIVA 
3. How to take SUSTIVA 
4. Possible side effects 
5. How to store SUSTIVA 
6. Contents of the pack and other information

1. What SUSTIVA is and what it is used for 

SUSTIVA, which contains the active substance efavirenz, belongs to a class of antiretroviral 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It is an antiretroviral 
medicine that fights human immunodeficiency virus (HIV-1) infection by reducing the amount of 
the virus in blood. It is used by adults, adolescents and children 3 months of age and older and 
weighing at least 3.5 kg.  
Your doctor has prescribed SUSTIVA for you because you have HIV infection. 
SUSTIVA taken in combination with other antiretroviral medicines reduces the amount of the virus in 
the blood. This will strengthen your immune system and reduce the risk of developing illnesses linked 
to HIV infection.  

2. What you need to know before you take SUSTIVA 

Do not take SUSTIVA 
 if you are allergic  to efavirenz or any of the other ingredients of this medicine (listed in section 

6). Contact your doctor or pharmacist for advice. 

 if you have severe liver disease. 

     if you have a heart condition, such as changes in the rhythm or rate of the heart beat, a 
slow heart beat, or severe heart disease. 

 if any member of your family (parents, grandparents, brothers or sisters) has died suddenly due  
to a heart problem or was born with heart problems.  

     if your doctor has told you that you have high or low levels of electrolytes such as potassium or 

magnesium in your blood. 

 if you are currently taking any of the following medicines (see also “Other medicines and 
Sustiva”):  
- astemizole or terfenadine (used to treat allergy symptoms)  



123

- bepridil (used to treat heart disease) 
- cisapride (used to treat heartburn) 
- ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and 

methylergonovine) (used to treat migraine and cluster headaches) 
- midazolam or triazolam (used to help you sleep) 
- pimozide, imipramine, amitriptyline or clomipramine (used to treat certain mental 

conditions) 
- elbasvir or grazoprevir (used to treat hepatitis C) 
- St. John's wort (Hypericum perforatum) (a herbal remedy used for depression and 

anxiety) 
-  flecainide, metoprolol (used to treat irregular heart beat) 
-  certain antibiotics (macrolides, fluoroquinolones, imidazole)  
- triazole antifungal agents
- certain antimalarial treatments
-  methadone (used to treat opiate addiction) 

If you are taking any of these medicines, tell your doctor immediately. Taking these medicines 
with SUSTIVA could create the potential for serious and/or life-threatening side-effects or stop  
SUSTIVA from working properly. 

Warnings and precautions  
Talk to your doctor before taking SUSTIVA 

 SUSTIVA must be taken with other medicines that act against the HIV virus. If SUSTIVA 
is started because your current treatment has not prevented the virus from multiplying, another 
medicine you have not taken before must be started at the same time. 

 You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other 
people. This medicine is not a cure for HIV infection and you may continue to develop 
infections or other illnesses associated with HIV disease.  

 You must remain under the care of your doctor while taking SUSTIVA. 

 Tell your doctor: 

- if you have a history of mental illness, including depression, or of substance or alcohol 
abuse. Tell your doctor immediately if you feel depressed, have suicidal thoughts or have 
strange thoughts (see section 4, Possible side effects). 

- if you have a history of convulsions (fits or seizures) or if you are being treated with 
anticonvulsant therapy such as carbamazepine, phenobarbital and phenytoin. If you are 
taking any of these medicines, your doctor may need to check the level of anticonvulsant 
medicine in your blood to ensure that it is not affected while taking SUSTIVA. Your 
doctor may give you a different anticonvulsant. 

- if you have a history of liver disease, including active chronic hepatitis. Patients with 
chronic hepatitis B or C and treated with combination antiretroviral agents have a higher 
risk for severe and potentially life-threatening liver problems. Your doctor may conduct 
blood tests in order to check how well your liver is working or may switch you to another 
medicine. If you have severe liver disease, do not take SUSTIVA (see section 2, Do not 
take SUSTIVA). 

- if you have a heart disorder, such as abnormal electrical signal called prolongation 
of the QT interval. 

 Once you start taking SUSTIVA, look out for: 



124

- signs of dizziness, difficulty sleeping, drowsiness, difficulty concentrating or 
abnormal dreaming. These side effects may start in the first 1 or 2 days of treatment and 
usually go away after the first 2 to 4 weeks. 

- any signs of skin rash. If you see any signs of a severe rash with blistering or fever, stop 
taking SUSTIVA and tell your doctor at once. If you had a rash while taking another 
NNRTI, you may be at a higher risk of getting a rash with SUSTIVA. 

- any signs of inflammation or infection. In some patients with advanced HIV infection 
(AIDS) and a history of opportunistic infection, signs and symptoms of inflammation 
from previous infections may occur soon after anti-HIV treatment is started. It is believed 
that these symptoms are due to an improvement in the body’s immune response, enabling 
the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection, please tell your doctor immediately.  
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs 
when the immune system attacks healthy body tissue) may also occur after you start 
taking medicines for the treatment of your HIV infection. Autoimmune disorders may 
occur many months after the start of treatment. If you notice any symptoms of infection or 
other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please 
inform your doctor immediately to seek necessary treatment. 

- bone problems. Some patients taking combination antiretroviral therapy may develop a 
bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to 
the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be 
some of the many risk factors for developing this disease. Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement. If you notice any of these symptoms please inform your doctor. 

Children and adolescents 
SUSTIVA is not recommeded for children under the age of 3 months or weighing less than 3.5 kg 
because it has not been adequately studied in these patients 

Other medicines and SUSTIVA 
You must not take SUSTIVA with certain medicines. These are listed under Do not take 
SUSTIVA, at the start of Section 2. They include some common medicines and a herbal remedy (St. 
John’s wort) which can cause serious interactions. 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 

SUSTIVA may interact with other medicines, including herbal preparations such as Ginkgo biloba
extracts. As a result, the amounts of SUSTIVA or other medicines in your blood may be affected. This 
may stop the medicines from working properly, or may make any side effects worse. In some cases, 
your doctor may need to adjust your dose or check your blood levels. It is important to tell your 
doctor or pharmacist if you are taking any of the following: 

 Other medicines used for HIV infection: 
- protease inhibitors: darunavir, indinavir, lopinavir/ritonavir, ritonavir, ritonavir boosted 

atazanavir, saquinavir or fosamprenavir/saquinavir. Your doctor may consider giving you 
an alternative medicine or changing the dose of the protease inhibitors. 

- maraviroc 
- the combination tablet containing efavirenz, emtricitabine, and tenofovir should not be 

taken with SUSTIVA unless recommended by your doctor since it contains efavirenz, the 
active ingredient of SUSTIVA. 



125

 Medicines used to treat infection with the hepatitis C virus: boceprevir, telaprevir, 
elbasvir/grazoprevir, simeprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, 
glecaprevir/pibrentasvir.

 Medicines used to treat bacterial infections, including tuberculosis and AIDS-related 
mycobacterium avium complex: clarithromycin, rifabutin, rifampicin. Your doctor may consider 
changing your dose or giving you an alternative antibiotic. In addition, your doctor may 
prescribe a higher dose of SUSTIVA. 

 Medicines used to treat fungal infections (antifungals): 
- voriconazole. SUSTIVA may reduce the amount of voriconazole in your blood and 

voriconazole may increase the amount of SUSTIVA in your blood. If you take these two 
medicines together, the dose of voriconazole must be increased and the dose of efavirenz 
must be reduced. You must check with your doctor first. 

- itraconazole. SUSTIVA may reduce the amount of itraconazole in your blood. 
- posaconazole. SUSTIVA may reduce the amount of posaconazole in your blood. 

 Medicines used to treat malaria: 
- artemether/lumefantrine:  SUSTIVA may reduce the amount of artemether/lumefantrine 

in your blood. 
- atovaquone/proguanil:  SUSTIVA may reduce the amount of atovaquone/proguanil in 

your blood. 

 Medicines used to treat convulsions/seizures (anticonvulsants): carbamazepine, phenytoin, 
phenobarbital. SUSTIVA can reduce or increase the amount of anticonvulsant in your blood. 
Carbamazepine may make SUSTIVA less likely to work. Your doctor may need to consider 
giving you a different anticonvulsant. 

 Medicines used to lower blood fats (also called statins): atorvastatin, pravastatin, simvastatin. 
SUSTIVA can reduce the amount of statins in your blood. Your doctor will check your 
cholesterol levels and will consider changing the dose of your statin, if needed. 

 Methadone (a medicine used to treat opiate addiction): your doctor may recommend an 
alternative treatment. 

 Sertraline (a medicine used to treat depression): your doctor may need to change your dose of 
sertraline. 

 Bupropion (a medicine used to treat depression or to help you stop smoking): your doctor may 
need to change your dose of bupropion. 

 Diltiazem or similar medicines (called calcium channel blockers which are medicines 
typically used for high blood pressure or heart problems): when you start taking SUSTIVA, 
your doctor may need to adjust your dose of the calcium channel blocker. 

 Immunosuppressants such as cyclosporine, sirolimus, or tacrolimus (medicines used to 
prevent organ transplant rejection): when you start or stop taking SUSTIVA, your doctor will 
closely monitor your plasma levels of the immunosuppressant and may need to adjust its dose. 

 Hormonal contraceptive, such as birth control pills, an injected contraceptive (for 
example, Depo-Provera), or a contraceptive implant (for example, Implanon): you must 
also use a reliable barrier method of contraception (see Pregnancy,breast-feeding and fertility). 
SUSTIVA may make hormonal contraceptives less likely to work. Pregnancies have occurred in 
women taking SUSTIVA while using a contraceptive implant, although it has not been 
established that the SUSTIVA therapy caused the contraceptive to fail. 



126

 Warfarin or acenocoumarol (medicines used to reduce clotting of the blood): your doctor may 
need to adjust your dose of warfarin or acenocoumarol. 

 Ginkgo biloba extracts (a herbal preparation)

     Medicines that impact heart rhythm:
-     Medicines used to treat heart rhythm problems such as flecainide or metoprolol. 

-     Medicines used to treat depression such as imipramine, amitriptyline or clomipramine. 

-    Antibiotics, including the following types: macrolides, fluoroquinolones or imidazole. 

SUSTIVA with food and drink 
Taking SUSTIVA on an empty stomach may reduce the undesirable effects. Grapefuit juice should be 
avoided when taking SUSTIVA. 

Pregnancy and breast-feeding 
Women should not get pregnant during treatment with SUSTIVA and for 12 weeks thereafter. 
Your doctor may require you to take a pregnancy test to ensure you are not pregnant before starting 
treatment with SUSTIVA.  

If you could get pregnant while receiving SUSTIVA, you need to use a reliable form of barrier 
contraception (for example, a condom) with other methods of contraception including oral (pill) or 
other hormonal contraceptives (for example, implants, injection). Efavirenz may remain in your blood 
for a time after therapy is stopped. Therefore, you should continue to use contraceptive measures, as 
above, for 12 weeks after you stop taking SUSTIVA.  

Tell your doctor immediately if you are pregnant or intend to become pregnant. If you are 
pregnant, you should take SUSTIVA only if you and your doctor decide it is clearly needed. Ask your 
doctor or pharmacist for advice before taking any medicine. 

Serious birth defects have been seen in unborn animals and in the babies of women treated with 
efavirenz or a combination medicine containing efavirenz, emtricitabine and tenofovir during 
pregnancy. If you have taken SUSTIVA or the combination tablet containing efavirenz, emtricitabine, 
and tenofovir during your pregnancy, your doctor may request regular blood tests and other diagnostic 
tests to monitor the development of your child.  

You should not breast feed your baby if you are taking SUSTIVA. 

Driving and using machines 
SUSTIVA contains efavirenz and may cause dizziness, impaired concentration, and drowsiness.
If you are affected, do not drive and do not use any tools or machines.  

SUSTIVA contains lactose in each 600-mg daily dose.  

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  

3. How to take SUSTIVA 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor will give you instructions for proper dosing. 

 The dose for adults is 600 mg once daily.  
 The dose for SUSTIVA may need to be increased or decreased if you are also taking certain 

medicines (see Other medicines and SUSTIVA). 



127

 SUSTIVA is for oral use. SUSTIVA is recommended to be taken on an empty stomach 
preferably at bedtime. This may make some side effects (for example, dizziness, drowsiness) 
less troublesome. An empty stomach is commonly defined as 1 hour before or 2 hours after a 
meal. 

 It is recommended that the tablet be swallowed whole with water. 
 SUSTIVA must be taken every day. 
 SUSTIVA should never be used alone to treat HIV. SUSTIVA must always be taken in 

combination with other anti-HIV medicines. 

Use in children and adolescents 
 SUSTIVA film-coated tablets are not suitable for children weighing less than 40 kg. 
 The dose for children weighing 40 kg or more is 600 mg once daily. 

If you take more SUSTIVA than you should 
If you take too much SUSTIVA, contact your doctor or nearest emergency department for advice. 
Keep the medicine container with you so that you can easily describe what you have taken. 

If you forget to take SUSTIVA 
Try not to miss a dose. If you do miss a dose, take the next dose as soon as possible, but do not take a 
double dose to make up for a forgotten dose. If you need help in planning the best times to take your 
medicine, ask your doctor or pharmacist. 

If you stop taking SUSTIVA 
When your SUSTIVA supply starts to run low, get more from your doctor or pharmacist. This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time. The virus may then become harder to treat. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.  

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  
When treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by SUSTIVA or by other medicines that you are taking at the same time, or by the HIV disease 
itself. 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

The most notable unwanted effects reported with SUSTIVA in combination with other anti-HIV 
medicines are skin rash and nervous system symptoms.  

You should consult your doctor if you have a rash, since some rashes may be serious; however, most 
cases of rash disappear without any change to your treatment with SUSTIVA. Rash was more 
common in children than in adults treated with SUSTIVA. 

The nervous system symptoms tend to occur when treatment is first started, but generally decrease in 
the first few weeks. In one study, nervous system symptoms often occurred during the first 1-3 hours 
after taking a dose. If you are affected your doctor may suggest that you take SUSTIVA at bedtime 
and on an empty stomach. Some patients have more serious symptoms that may affect mood or the 
ability to think clearly. Some patients have actually committed suicide. These problems tend to occur 
more often in those who have a history of mental illness. Always notify your doctor immediately if 
you have these symptoms or any side effects while taking SUSTIVA. 

Tell your doctor if you notice any of the following side effects: 



128

Very common (affects more than 1 user in 10)
- skin rash 

Common (affects 1 to 10 users in 100)
- abnormal dreams, difficulty concentrating, dizziness, headache, difficulty sleeping, drowsiness, 

problems with coordination or balance 
- stomach pain, diarrhoea, feeling sick (nausea), vomiting 
- itching 
- tiredness 
- feeling anxious, feeling depressed 
Tests may show: 
- increased liver enzymes in the blood 
- increased trigycerides (fatty acids) in the blood 

Uncommon (affects 1 to 10 users in 1,000)
- nervousness, forgetfulness,  confusion, fitting (seizures), abnormal thoughts 
- blurred vision 
- a feeling of spinning or tilting (vertigo) 
- pain in the abdomen (stomach) caused by inflammation of the pancreas 
- allergic reaction (hypersensitivity) that may cause severe skin reactions (erythema multiforme, 

Stevens-Johnson syndrome) 
- yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the 

liver 
- breast enlargement in males 
- angry behaviour, mood being affected, seeing or hearing things that are not really there 

(hallucinations), mania (mental condition characterised by episodes of overactivity, elation or 
irritability), paranoia, suicidal thoughts, catatonia (condition in which the patient is rendered 
motionless and speechless for a period) 

 whistling, ringing or other persistent noise in the ears 
 tremor (shaking) 
- flushing 
Tests may show: 
- increased cholesterol in the blood 

Rare (affects 1 to 10 users in 10,000)
- itchy rash caused by a reaction to sunlight 
- liver failure, in some cases leading to death or liver transplant, has occurred with efavirenz. 

Most cases occurred in patients who already had liver disease, but there have been a few reports 
in patients without any existing liver disease. 

- unexplained feelings of distress not associated with hallucinations, but it may be difficult to 
think clearly or sensibly 

- suicide 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

5. How to store SUSTIVA 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the bottle or blister and on the carton 
after EXP. The expiry date refers to the last day of that month.  



129

Do not throw away any medicines  via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  

6. FURTHER INFORMATION 

What SUSTIVA contains 

 Each SUSTIVA film-coated tablet contains 600 mg of the active substance efavirenz. 
 The other ingredients of the tablet core are: croscarmellose sodium, microcrystalline cellulose, 

sodium laurilsulfate, hydroxypropylcellulose, lactose monohydrate, and magnesium stearate. 
 The film coating contains: hypromellose (E464), titanium dioxide (E171), macrogol 400, yellow 

iron oxide (E172) and carnauba wax.  
 The tablets are printed with inks containing hypromellose (E464), propylene glycol, cochineal 

carminic acid (E120), indigo carmine (E132) and titanium dioxide (E171). 

What SUSTIVA looks like and contents of the pack 
SUSTIVA 600 mg film-coated tablets are supplied in bottles of 30 tablets.  
SUSTIVA 600 mg film-coated tablets are also supplied in packs containing 30 x 1 or multipacks of 90 
(3 packs of 30 x 1) tablets in aluminium/PVC perforated unit dose blisters. Not all pack sizes may be 
marketed. 

Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15  
D15 T867 
Ireland 

Manufacturer 
Bristol-Myers Squibb S.r.l. 
Contrada Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

Aesica Queenborough Limited 
North Road, Queenborough 
Kent, ME11 5EL 
United Kingdom 

Aesica Pharmaceuticals GmbH - Monheim,  
Alfred-Nobel-Straße 10,  
40789 Monheim,  
Germany 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32(0)27766211) 
dpoc_belux@merck.com 

Lietuva
UAB Merck Sharp & Dohme 
Tel.: +370 5 278 02 47
msd_lietuva@merck.com 



130

България
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel:  +32(0)27766211 
dpoc_belux@merck.com 

Česká republika
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
dpoc_czechslovak @merck.com 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +361 888 53 00 
hungary_msd@merck.com 

Danmark 
MSD Danmark ApS 
Tlf: +45 44 82 40 00 
dkmail@merck.com 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 

Deutschland 
Bristol-Myers Squibb GmbH & CO. KGaA 
Tel: +49 89 121 42-0 

Nederland  
Merck Sharp & Dohme BV 
Tel: 0800 9999000 (+31 23 5153153) 
medicalinfo.nl@merck.com 

Eesti 
Merck Sharp & Dohme OÜ 
Tel.: +372 6144 200 
msdeesti@merck.com

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 

Eλλάδα 
MSD Α.Φ.Β.Ε.Ε 
Τηλ: + 30-210 98 97 300 
dpoc_greece@merck.com 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com

España 
Bristol-Myers Squibb, S.A. 
Tel: +34 91 456 53 00 

Polska
MSD Polska Sp. z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 

France 
Bristol-Myers Squibb Sarl. 
Tél: +33 (0)1 58 83 84 96 

Portugal
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465700 
clic@merck.com

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 

România
Merck Sharp & Dohme Romania S.R.L. 
Tel: + 4021 529 29 00 
msdromania@merck.com

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: +353 (0)1 483 3625 

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201 
msd_slovenia@merck.com 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel.: +421 2 58282010
dpoc_czechslovak @merck.com 



131

Ιtalia 
Bristol-Myers Squibb S.r.l. 
Tel: +39 06 50 39 61 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: +358 (0) 9 804650 
info@msd.fi 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 80000 673 (+357 22866700) 
cyprus_info@merck.com 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 (0)77 5700488 
medicinskinfo@merck.com 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: +371 67364 224 
msd_lv@merck.com 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd. 
Tel: +44 (0800) 731 1736

This leaflet was last revised in  

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



132

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing 
authorisation(s) 



133

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for efavirenz, the scientific 

conclusions of CHMP are as follows:  

For the drug-drug interaction with etonogestrel implant, the PRAC noted the available data from 16 

case reports and the published literature articles by Vieira et al., 2014 and Chappel et al., 2017. 

Based on this new data, the PRAC considers that the statement that the interaction between 

etonogestrel and efavirenz has not been studied is no longer valid and that this statement should be 

removed from the SmPC of all efavirenz-containing products.  

In view of the data presented in the reviewed PSUR, the overall risk-benefit balance of efavirenz is 

therefore considered unchanged in the approved indications provided that the terms of the 

marketing authorisation are varied as relevant. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for efavirenz the CHMP is of the opinion that the benefit-

risk balance of the medicinal product(s) containing efavirenz is unchanged subject to the proposed 

changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing
authorisation(s)