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Efavirenz Teva (efavirenz) – Summary of product characteristics - J05AG03

Updated on site: 06-Oct-2017

Medication nameEfavirenz Teva
ATC CodeJ05AG03
Substanceefavirenz
ManufacturerTeva B.V.

1.NAME OF THE MEDICINAL PRODUCT

Efavirenz Teva 600 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 600 mg efavirenz.

Excipients with known effect

Each film-coated tablet contains 9.98 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

Yellow, capsule-shaped, film-coated tablet debossed with “Teva” on one side and “7541” on the other

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Efavirenz is indicated in antiviral combination treatment of human immunodeficiency virus-1 (HIV-1) infected adults, adolescents and children 3 years of age and older.

Efavirenz 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 efavirenz.

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

4.2Posology 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.

Dose adjustment

If efavirenz is co-administered 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 co-administered 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).

Method of administration

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

4.3Contraindications

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-administration 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).

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).

4.4Special 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 fumarate is not recommended, unless needed for dose adjustment (for example, with rifampicin).

Concomitant use of Ginko biloba extract 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 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 and psychosis-like behaviour. 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 post-marketing 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.

Effect of food

The administration of Efavirenz Teva 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 Teva be taken on an empty stomach, preferably at bedtime.

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) 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 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 4.2). There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.

Elderly patients

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

Paediatric population

Rash was reported in 26 of 57 children (46%) treated with efavirenz during a 48-week period and was severe in three patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.

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..

4.5Interaction 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 Ginko 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 Ginko biloba extracts is not recommended (see section 4.4).

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

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

ANTI-INFECTIVES

 

 

 

HIV antivirals

 

 

 

Protease inhibitors (PI)

 

 

 

Atazanavir/ritonavir/efavirenz

 

Atazanavir (pm):

Co-administration of efavirenz

(400 mg once daily/100 mg once

 

AUC: ↔* (↓ 9 to ↑ 10)

with atazanavir/ritonavir is not

daily/600 mg once daily, all

 

Cmax: ↑ 17%* (↑ 8 to ↑ 27)

recommended. If the

administered with food)

 

Cmin: ↓ 42%* (↓ 31 to ↓ 51)

co-administration of atazanavir

 

 

 

with an NNRTI is required, an

Atazanavir/ritonavir/efavirenz

 

Atazanavir (pm):

increase in the dose of both

(400 mg once daily/200 mg once

 

AUC: ↔*/** (↓ 10 to ↑ 26)

atazanavir and ritonavir to 400 mg

daily/600 mg once daily, all

 

Cmax: ↔*/** (↓ 5 to ↑ 26)

and 200 mg, respectively, in

administered with food)

 

Cmin: ↑ 12%*/** (↓ 16 to ↑ 49)

combination with efavirenz could

 

 

(CYP3A4 induction)

be considered with close clinical

 

 

* When compared to atazanavir

monitoring.

 

 

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

 

Darunavir/ritonavir/efavirenz

 

Darunavir:

Efavirenz in combination with

(300 mg twice daily*/100 mg

 

AUC: ↓ 13%

darunavir/ritonavir 800/100 mg

twice daily/600 mg once daily)

 

Cmin: ↓ 31%

once daily may result in

*lower than recommended doses,

 

Cmax: ↓ 15%

suboptimal darunavir Cmin. If

similar findings are expected with

 

(CYP3A4 induction)

efavirenz is to be used in

recommended doses

 

Efavirenz:

combination with

 

 

AUC: ↑ 21%

darunavir/ritonavir, the

 

 

Cmin: ↑ 17%

darunavir/ritonavir 600/100 mg

 

 

Cmax: ↑ 15%

twice daily regimen should be

Medicinal product by

 

Effects on drug levels

Recommendation concerning

therapeutic areas

 

Mean percent change in AUC,

co-administration with

(dose)

 

Cmax, Cmin with confidence

efavirenz

 

 

intervals if availablea

 

 

 

(mechanism)

 

 

 

 

(CYP3A4 inhibition)

used. This combination should be

 

 

 

 

used with caution. See also

 

 

 

 

ritonavir row below.

Fosamprenavir/ritonavir/ efavirenz

 

No clinically significant

No dose adjustment is necessary

(700 mg twice daily/100 mg twice

 

pharmacokinetic interaction

for any of these medicinal

daily/600 mg once daily)

 

 

products. See also ritonavir row

 

 

 

 

below.

Fosamprenavir/nelfinavir/ efavirenz

 

Interaction not studied

No dose adjustment is necessary

 

 

 

 

for any of these medicinal

Fosamprenavir/saquinavir/

 

Interaction not studied

products.

efavirenz

 

 

Not recommended as the

 

 

 

 

exposure to both PIs is expected

 

 

 

 

to be significantly decreased.

Indinavir/efavirenz

 

Indinavir:

While the clinical significance of

(800 mg q8h/200 mg once daily)

 

AUC: ↓ 31% (↓ 8 to ↓47)

decreased indinavir

 

 

 

Cmin: ↓ 40%

concentrations has not been

 

 

 

A similar reduction in indinavir

established, the magnitude of the

 

 

 

exposures was observed when

observed pharmacokinetic

 

 

 

indinavir 1000 mg q8h was given

interaction should be taken into

 

 

 

with efavirenz 600 mg daily.

consideration when choosing a

 

 

 

(CYP3A4 induction)

regimen containing both efavirenz

 

 

 

Efavirenz:

and indinavir.

 

 

 

 

 

 

 

No clinically significant

No dose adjustment is necessary

 

 

 

pharmacokinetic interaction

for efavirenz when given with

Indinavir/ritonavir/efavirenz

 

Indinavir:

indinavir or indinavir/ritonavir.

(800 mg twice daily/100 mg twice

 

AUC: ↓ 25% (↓ 16 to ↓32) b

 

daily/600 mg once daily)

 

Cmax: ↓ 17% (↓ 6 to ↓ 26) b

See also ritonavir row below.

 

 

 

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.

 

Lopinavir/ritonavir soft capsules or

 

Substantial decrease in lopinavir

With efavirenz, an increase of the

oral solution/ efavirenz

 

exposure.

lopinavir/ritonavir soft capsule or

Lopinavir/ritonavir tablets/

 

 

oral solution doses by 33% should

 

 

be considered (4 capsules/

efavirenz

 

 

~6.5 ml twice daily instead of 3

(400/100 mg twice daily/ 600 mg

 

Lopinavir concentrations: ↓ 30-40%

capsules/5 ml twice daily).

once daily)

 

 

Caution is warranted since this

(500/125 mg twice daily/ 600 mg

 

Lopinavir concentrations: similar to

dose adjustment might be

once daily)

 

lopinavir/ritonavir 400/100 mg

insufficient in some patients. The

 

 

 

twice daily without efavirenz

dose of lopinavir/ritonavir tablets

 

 

 

 

should be increased to

 

 

 

 

500/125 mg twice daily when

 

 

 

 

co-administered with efavirenz

 

 

 

 

600 mg once daily.

Medicinal product by

 

Effects on drug levels

Recommendation concerning

therapeutic areas

 

Mean percent change in AUC,

co-administration with

(dose)

 

Cmax, Cmin with confidence

efavirenz

 

 

intervals if availablea

 

 

 

(mechanism)

 

 

 

 

 

See also ritonavir row below.

Nelfinavir/efavirenz

 

Nelfinavir:

No dose adjustment is necessary

(750 mg q8h/600 mg once daily)

 

AUC: ↑ 20% (↑ 8 to ↑ 34)

for either medicinal product.

 

 

 

Cmax: ↑ 21% (↑ 10 to ↑ 33)

 

 

 

 

The combination was generally

 

 

 

 

well tolerated.

 

Ritonavir/efavirenz

 

Ritonavir:

When using efavirenz with

(500 mg twice daily/600 mg once

 

Morning AUC: ↑ 18% (↑ 6 to ↑ 33)

low-dose ritonavir, the possibility

daily)

 

Evening AUC: ↔

of an increase in the incidence of

 

 

 

Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)

efavirenz-associated adverse

 

 

 

Evening Cmax: ↔

events should be considered, due

 

 

 

Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) b

to possible pharmacodynamic

 

 

 

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) b

interaction.

 

 

 

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.

 

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

 

Maraviroc:

Refer to the Summary of Product

(100 mg twice daily/600 mg once

 

AUC12: ↓ 45% (↓ 38 to ↓ 51)

Characteristics for the medicinal

daily)

 

Cmax: ↓ 51% (↓ 37 to ↓ 62)

product containing maraviroc.

 

 

Efavirenz concentrations not

 

 

 

measured, no effect is expected.

 

Integrase strand transfer inhibitor

 

 

 

 

Raltegravir/efavirenz

 

Raltegravir:

No dose adjustment is necessary

(400 mg single dose/ -)

 

AUC: ↓ 36%

for raltegravir.

 

 

C12: ↓ 21%

 

 

 

Cmax: ↓ 36%

 

 

 

(UGT1A1 induction)

 

NRTIs and NNRTIs

 

 

 

 

NRTIs/efavirenz

 

Specific interaction studies have not

No dose adjustment is necessary

 

 

been performed with efavirenz and

for either medicinal product.

 

 

NRTIs other than lamivudine,

 

 

 

zidovudine and tenofovir disoproxil

 

 

 

fumarate. Clinically significant

 

 

 

interactions are not expected since the

 

 

 

NRTIs are metabolised via a different

 

 

 

route than efavirenz and would be

 

Medicinal product by

 

Effects on drug levels

 

Recommendation concerning

therapeutic areas

 

 

Mean percent change in AUC,

co-administration with

(dose)

 

 

Cmax, Cmin with confidence

 

efavirenz

 

 

 

intervals if availablea

 

 

 

 

 

(mechanism)

 

 

 

 

 

unlikely to compete for the same

 

 

 

 

metabolic enzymes and elimination

 

 

 

 

pathways.

 

 

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

Boceprevir:

 

Plasma trough concentrations of

(800 mg

times

AUC: ↔ 19%*

 

boceprevir were decreased when

daily/600 mg once daily)

Cmax: ↔ 8%

 

administered with efavirenz. The

 

clinical outcome of this observed

 

 

 

Cmin: ↓ 44%

 

 

 

 

 

reduction of boceprevir trough

 

 

 

Efavirenz:

 

 

 

 

 

concentrations has not been

 

 

 

AUC: ↔ 20%

 

 

 

 

 

directly assessed.

 

 

 

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%

 

 

Telaprevir/Efavirenz

Telaprevir (relative

to

If efavirenz and telaprevir are co-

(1,125 mg

q8h/600 mg

750 mg q8h):

 

administered, telaprevir 1,125 mg

once daily)

 

 

AUC: ↓ 18% (↓ 8 to ↓ 27)

every 8 hours should be used.

 

 

 

 

 

 

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)

 

Simeprevir/Efavirenz

 

 

Simeprevir:

 

Concomitant administration of

(150 mg once daily /600 mg once

AUC: ↓71% (↓67 to ↓74)

 

simeprevir with efavirenz resulted

daily)

 

 

Cmax: ↓51% (↓46 to ↓56)

 

in significantly decreased plasma

 

 

 

concentrations of simeprevir due

 

 

 

Cmin: ↓91% (↓88 to ↓92)

 

 

 

 

 

to CYP3A induction by efavirenz,

 

 

 

Efavirenz:

 

 

 

 

 

which may result in loss of

 

 

 

AUC: ↔

 

 

 

 

 

therapeutic effect of simeprevir.

 

 

 

Cmax: ↔

 

Co-administration of simeprevir

 

 

 

Cmin: ↔

 

with efavirenz is not

 

 

 

No effect (↔) equals a decrease in

recommended.

 

 

 

mean ratio estimate of ≤20% or

 

 

 

 

 

increase in mean ratio estimate of

 

 

 

 

≤25%

 

 

 

 

 

(CYP3A4 enzyme induction)

 

 

Antibiotics

 

 

 

 

 

Azithromycin/efavirenz

 

No clinically significant

 

No dose adjustment is necessary

(600 mg single dose/400 mg once

pharmacokinetic interaction

 

for either medicinal product.

daily)

 

 

 

 

 

Clarithromycin/efavirenz

 

Clarithromycin:

 

The clinical significance of these

(500 mg q12h/400 mg once daily)

AUC: ↓ 39% (↓ 30 to ↓ 46)

 

changes in clarithromycin plasma

 

 

 

Cmax: ↓ 26% (↓ 15 to ↓ 35)

 

levels is not known. Alternatives

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

 

Clarithromycin

to clarithromycin (e.g.

 

azithromycin) may be considered.

 

14-hydroxymetabolite:

No dose adjustment is necessary

 

AUC: ↑ 34% (↑ 18 to ↑ 53)

for efavirenz.

 

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.

 

Other macrolide antibiotics (e.g.

Interaction not studied

No data are available to make a

erythromycin)/efavirenz

 

dose recommendation.

Antimycobacterials

 

 

Rifabutin/efavirenz

Rifabutin:

The daily dose of rifabutin should

(300 mg once daily/600 mg once

AUC: ↓ 38% (↓ 28 to ↓ 47)

be increased by 50% when

daily)

Cmax: ↓ 32% (↓ 15 to ↓ 46)

administered with efavirenz.

 

Cmin: ↓ 45% (↓ 31 to ↓ 56)

Consider doubling the rifabutin

 

Efavirenz:

dose in regimens where rifabutin

 

is given 2 or 3 times a week in

 

AUC: ↔

combination with efavirenz. The

 

Cmax: ↔

clinical effect of this dose

 

Cmin: ↓ 12% (↓ 24% to ↑ 1%)

adjustment has not been

 

(CYP3A4 induction)

adequately evaluated. Individual

 

 

tolerability and virological

 

 

response should be considered

 

 

when making the dose adjustment

 

 

(see section 5.2).

Rifampicin/efavirenz

Efavirenz:

When taken with rifampicin in

(600 mg once daily/600 mg once

AUC: ↓ 26% (↓ 15 to ↓ 36)

patients weighing 50 kg or

daily)

Cmax: ↓ 20% (↓ 11 to ↓ 28)

greater, increasing efavirenz daily

 

Cmin: ↓ 32% (↓ 15 to ↓ 46)

dose to 800 mg may provide

 

(CYP3A4 and CYP2B6 induction)

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.

Antifungals

 

 

Itraconazole/efavirenz

Itraconazole:

Since no dose recommendation

(200 mg q12h/600 mg once daily)

AUC: ↓ 39% (↓ 21 to ↓ 53)

for itraconazole can be made,

 

Cmax: ↓ 37% (↓ 20 to ↓ 51)

alternative antifungal treatment

 

Cmin: ↓ 44% (↓ 27 to ↓ 58)

should be considered.

 

(Decrease in itraconazole

 

 

concentrations: CYP3A4 induction)

 

 

Hydroxyitraconazole:

 

 

AUC: ↓ 37% (↓ 14 to ↓ 55)

 

 

Cmax: ↓ 35% (↓ 12 to ↓ 52)

 

 

Cmin: ↓ 43% (↓ 18 to ↓ 60)

 

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

 

Efavirenz:

 

 

No clinically significant

 

 

pharmacokinetic change.

 

Posaconazole/efavirenz

Posaconazole:

Concomitant use of posaconazole

(--/400 mg once daily)

AUC: ↓ 50%

and efavirenz should be avoided

 

Cmax: ↓ 45%

unless the benefit to the patient

 

(UDP-G induction)

outweighs the risk.

Voriconazole/efavirenz

Voriconazole:

When efavirenz is

(200 mg twice daily/400 mg once

AUC: ↓ 77%

co-administered with

daily)

Cmax: ↓ 61%

voriconazole, the voriconazole

 

Efavirenz:

maintenance dose must be

 

increased to 400 mg twice daily

 

AUC: ↑ 44%

and the efavirenz dose must be

 

Cmax: ↑ 38%

reduced by 50%, i.e. to 300 mg

 

 

once daily. When treatment with

Voriconazole/efavirenz

Voriconazole:

voriconazole is stopped, the initial

(400 mg twice daily/300 mg once

AUC: ↓ 7% (↓ 23 to ↑ 13) *

dosage of efavirenz should be

daily)

Cmax: ↑ 23% (↓ 1 to ↑ 53) *

restored.

 

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)

 

Fluconazole/efavirenz

No clinically significant

No dose adjustment is necessary

(200 mg once daily/400 mg once

pharmacokinetic interaction

for either medicinal product.

daily)

 

 

Ketoconazole and other imidazole

Interaction not studied

No data are available to make a

antifungals

 

dose recommendation.

Antimalarials

 

 

Artemether/lumefantrine/

Artemether:

Since decreased concentrations of

Efavirenz

AUC: ↓ 51%

artemether, dihydroartemisinin, or

(20/120 mg tablet, 6 doses of 4

Cmax: ↓ 21%

lumefantrine may result in a

decrease of antimalarial efficacy,

tablets each over 3 days/600mg

Dihydroartemisinin:

caution is recommended when

once daily)

AUC: ↓ 46%

efavirenz and

 

Cmax: ↓ 38%

 

artemether/lumefantrine tablets

 

Lumefantrine:

are coadministered.

 

AUC: ↓ 21%

 

 

Cmax: ↔

 

 

Efavirenz:

 

 

AUC: ↓ 17%

 

 

Cmax: ↔

 

 

(CYP3A4 induction)

 

Atovaquone and proguanil

Atovaquone:

Concomitant administration of

hydrochloride/Efavirenz

AUC: ↓ 75% (↓ 62 to ↓ 84)

atovaquone/proguanil with

(250/100 mg single dose/600 mg

Cmax: ↓ 44% (↓ 20 to ↓ 61)

efavirenz should be avoided

once daily)

 

whenever possible.

 

Proguanil:

 

 

AUC: ↓ 43% (↓ 7 to ↓ 65)

 

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

 

Cmax: ↔

 

 

 

 

ACID-REDUCING AGENTS

 

 

Aluminium hydroxide-

Neither aluminium/magnesium

Co-administration of efavirenz

magnesium hydroxide-

hydroxide antacids nor famotidine

with medicinal products that alter

simethicone antacid/efavirenz

altered the absorption of efavirenz.

gastric pH would not be expected

(30 ml single dose/400 mg single

 

to affect efavirenz absorption.

dose)

 

 

Famotidine/efavirenz

 

 

(40 mg single dose/400 mg single

 

 

dose)

 

 

ANTIANXIETY AGENTS

 

 

Lorazepam/efavirenz

Lorazepam:

No dose adjustment is necessary

(2 mg single dose/600 mg once

AUC: ↑ 7% (↑ 1 to ↑ 14)

for either medicinal product.

daily)

Cmax: ↑ 16% (↑ 2 to ↑ 32)

 

 

These changes are not considered

 

 

clinically significant.

 

ANTICOAGULANTS

 

 

Warfarin/efavirenz

Interaction not studied. Plasma

Dose adjustment of warfarin or

Acenocoumarol/Efavirenz

concentrations and effects of warfarin

acenocoumarol may be required.

 

or acenocoumarol are potentially

 

 

increased or decreased by efavirenz.

 

ANTICONVULSANTS

 

 

Carbamazepine/efavirenz

Carbamazepine:

No dose recommendation can be

(400 mg once daily/600 mg once

AUC: ↓ 27% (↓ 20 to ↓ 33)

made. An alternative

daily)

Cmax: ↓ 20% (↓ 15 to ↓ 24)

anticonvulsant should be

 

Cmin: ↓ 35% (↓ 24 to ↓ 44)

considered. Carbamazepine

 

Efavirenz:

plasma levels should be

 

monitored periodically.

 

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.

 

Phenytoin, phenobarbital, and

Interaction not studied. There is a

When efavirenz is

other anticonvulsants that are

potential for reduction or increase in

co-administered with an

substrates of CYP450 isoenzymes

the plasma concentrations of

anticonvulsant that is a substrate

 

phenytoin, phenobarbital and other

of CYP450 isoenzymes, periodic

 

anticonvulsants that are substrates of

monitoring of anticonvulsant

 

CYP450 isoenzymes when

levels should be conducted.

 

co-administered with efavirenz.

 

Valproic acid/efavirenz

No clinically significant effect on

No dose adjustment is necessary

(250 mg twice daily/600 mg once

efavirenz pharmacokinetics. Limited

for efavirenz. Patients should be

daily)

data suggest there is no clinically

monitored for seizure control.

 

significant effect on valproic acid

 

 

pharmacokinetics.

 

Vigabatrin/efavirenz

Interaction not studied. Clinically

No dose adjustment is necessary

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

Gabapentin/efavirenz

significant interactions are not

for any of these medicinal

 

expected since vigabatrin and

products.

 

gabapentin are exclusively eliminated

 

 

unchanged in the urine and are

 

 

unlikely to compete for the same

 

 

metabolic enzymes and elimination

 

 

pathways as efavirenz.

 

ANTIDEPRESSANTS

 

 

Selective Serotonin Re-uptake Inhibitors (SSRIs)

 

Sertraline/efavirenz

Sertraline:

Sertraline dose increases should

(50 mg once daily/600 mg once

AUC: ↓ 39% (↓ 27 to ↓ 50)

be guided by clinical response.

daily)

Cmax: ↓ 29% (↓ 15 to ↓ 40)

No dose adjustment is necessary

 

Cmin: ↓ 46% (↓ 31 to ↓ 58)

for efavirenz.

 

Efavirenz:

 

 

AUC: ↔

 

 

Cmax: ↑ 11% (↑ 6 to ↑ 16)

 

 

Cmin: ↔

 

 

(CYP3A4 induction)

 

Paroxetine/efavirenz

No clinically significant

No dose adjustment is necessary

(20 mg once daily/600 mg once

pharmacokinetic interaction

for either medicinal product.

daily)

 

 

Fluoxetine/efavirenz

Interaction not studied. Since

No dose adjustment is necessary

 

fluoxetine shares a similar metabolic

for either medicinal product.

 

profile with paroxetine, i.e. a strong

 

 

CYP2D6 inhibitory effect, a similar

 

 

lack of interaction would be expected

 

 

for fluoxetine.

 

Norepinephrine and dopamine

reuptake inhibitor

 

Bupropion/Efavirenz

Bupropion:

Increases in bupropion dosage

[150 mg single dose (sustained

AUC: ↓ 55% (↓ 48 to ↓ 62)

should be guided by clinical

release)/600 mg once daily]

Cmax: ↓ 34% (↓ 21 to ↓ 47)

response, but the maximum

 

Hydroxybupropion:

recommended dose of bupropion

 

should not be exceeded. No dose

 

AUC: ↔

 

adjustment is necessary for

 

Cmax: ↑ 50% (↑ 20 to ↑ 80)

 

efavirenz.

 

(CYP2B6 induction)

 

ANTIHISTAMINES

 

 

Cetirizine/efavirenz

Cetirizine:

No dose adjustment is necessary

(10 mg single dose/600 mg once

AUC: ↔

for either medicinal product.

daily)

Cmax: ↓ 24% (↓ 18 to ↓ 30)

 

 

These changes are not considered

 

 

clinically significant.

 

 

Efavirenz:

 

 

No clinically significant

 

 

pharmacokinetic interaction

 

CARDIOVASCULAR AGENTS

 

 

Calcium Channel Blockers

 

 

Diltiazem/efavirenz

Diltiazem:

Dose adjustments of diltiazem

(240 mg once daily/600 mg once

AUC: ↓ 69% (↓ 55 to ↓ 79)

should be guided by clinical

daily)

Cmax: ↓ 60% (↓ 50 to ↓ 68)

response (refer to the Summary of

 

Cmin: ↓ 63% (↓ 44 to ↓ 75)

Product Characteristics for

 

Desacetyl diltiazem:

diltiazem). No dose adjustment is

 

necessary for efavirenz.

 

AUC: ↓ 75% (↓ 59 to ↓ 84)

 

 

Cmax: ↓ 64% (↓ 57 to ↓ 69)

 

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

 

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.

 

Verapamil, felodipine, nifedipine

Interaction not studied. When

Dose adjustments of calcium

and nicardipine

efavirenz is co-administered with a

channel blockers should be

 

calcium channel blocker that is a

guided by clinical response (refer

 

substrate of the CYP3A4 enzyme,

to the Summary of Product

 

there is a potential for reduction in

Characteristics for the calcium

 

the plasma concentrations of the

channel blocker).

 

calcium channel blocker.

 

LIPID-LOWERING MEDICINAL

PRODUCTS

 

HMG CoA Reductase Inhibitors

 

 

Atorvastatin/efavirenz

Atorvastatin:

Cholesterol levels should be

(10 mg once daily/600 mg once

AUC: ↓ 43% (↓ 34 to ↓ 50)

periodically monitored. Dose

daily)

Cmax: ↓ 12% (↓ 1 to ↓ 26)

adjustment of atorvastatin may be

 

2-hydroxy atorvastatin:

required (refer to the Summary of

 

Product Characteristics for

 

AUC: ↓ 35% (↓ 13 to ↓ 40)

atorvastatin). No dose adjustment

 

Cmax: ↓ 13% (↓ 0 to ↓ 23)

is necessary for efavirenz.

 

4-hydroxy atorvastatin:

 

 

AUC: ↓ 4% (↓ 0 to ↓ 31)

 

 

Cmax: ↓ 47% (↓ 9 to ↓ 51)

 

 

Total active HMG CoA reductase

 

 

inhibitors:

 

 

AUC: ↓ 34% (↓ 21 to ↓ 41)

 

 

Cmax: ↓ 20% (↓ 2 to ↓ 26)

 

Pravastatin/efavirenz

Pravastatin:

Cholesterol levels should be

(40 mg once daily/600 mg once

AUC: ↓ 40% (↓ 26 to ↓ 57)

periodically monitored. Dose

daily)

Cmax: ↓ 18% (↓ 59 to ↑ 12)

adjustment of pravastatin may be

 

 

required (refer to the Summary of

 

 

Product Characteristics for

 

 

pravastatin). No dose adjustment

 

 

is necessary for efavirenz.

Simvastatin/efavirenz

Simvastatin:

Cholesterol levels should be

(40 mg once daily/600 mg once

AUC: ↓ 69% (↓ 62 to ↓ 73)

periodically monitored. Dose

daily)

Cmax: ↓ 76% (↓ 63 to ↓ 79)

adjustment of simvastatin may be

 

Simvastatin acid:

required (refer to the Summary of

 

Product Characteristics for

 

AUC: ↓ 58% (↓ 39 to ↓ 68)

simvastatin). No dose adjustment

 

Cmax: ↓ 51% (↓ 32 to ↓ 58)

is necessary for efavirenz.

 

Total active HMG Co-A reductase

 

 

inhibitors:

 

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

 

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.

 

Rosuvastatin/efavirenz

Interaction not studied. Rosuvastatin

No dose adjustment is necessary

 

is largely excreted unchanged via the

for either medicinal product.

 

faeces, therefore interaction with

 

 

efavirenz is not expected.

 

HORMONAL CONTRACEPTIVES

 

 

Oral:

Ethinyloestradiol:

A reliable method of barrier

Ethinyloestradiol + norgestimate /

AUC: ↔

contraception must be used in

efavirenz

Cmax: ↔

addition to hormonal

(0.035 mg + 0.25 mg once

Cmin: ↓ 8% (↑ 14 to ↓ 25)

contraceptives (see section 4.6).

daily/600 mg once daily)

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.

 

Injection:

In a 3-month drug interaction study,

Because of the limited

Depomedroxyprogesterone

no significant differences in MPA

information available, a reliable

acetate (DMPA)/efavirenz

pharmacokinetic parameters were

method of barrier contraception

(150 mg IM single dose DMPA)

found between subjects receiving

must be used in addition to

 

efavirenz-containing antiretroviral

hormonal contraceptives (see

 

therapy and subjects receiving no

section 4.6).

 

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.

 

Implant: Etonogestrel/efavirenz

Interaction not studied. Decreased

A reliable method of barrier

 

exposure of etonogestrel may be

contraception must be used in

 

expected (CYP3A4 induction). There

addition to hormonal

 

have been occasional post-marketing

contraceptives (see section 4.6).

 

reports of contraceptive failure with

 

 

etonogestrel in efavirenz-exposed

 

 

patients.

 

IMMUNOSUPPRESSANTS

 

 

Immunosuppressants metabolized

Interaction not studied. Decreased

Dose adjustments of the

by CYP3A4 (e.g. ciclosporin,

exposure of the immunosuppressant

immunosuppressant may be

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

(dose)

Cmax, Cmin with confidence

efavirenz

 

intervals if availablea

 

 

(mechanism)

 

tacrolimus, sirolimus)/efavirenz

may be expected (CYP3A4

required. Close monitoring of

 

induction). These

immunosuppressant

 

immunosuppressants are not

concentrations for at least 2 weeks

 

anticipated to affect exposure of

(until stable concentrations are

 

efavirenz.

reached) is recommended when

 

 

starting or stopping treatment

 

 

with efavirenz.

OPIOIDS

 

 

Methadone/efavirenz

Methadone:

Patients should be monitored for

(stable maintenance, 35-100 mg

AUC: ↓ 52% (↓ 33 to ↓ 66)

signs of withdrawal and their

once daily/600 mg once daily)

Cmax: ↓ 45% (↓ 25 to ↓ 59)

methadone dose increased as

 

(CYP3A4 induction)

required to alleviate withdrawal

 

In a study of HIV infected

symptoms.

 

 

 

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.

 

Buprenorphine/naloxone/

Buprenorphine:

Despite the decrease in

efavirenz

AUC: ↓ 50%

buprenorphine exposure, no

 

Norbuprenorphine:

patients exhibited withdrawal

 

symptoms. Dose adjustment of

 

AUC: ↓ 71%

buprenorphine or efavirenz may

 

Efavirenz:

not be necessary when

 

co-administered.

 

No clinically significant

 

 

pharmacokinetic interaction

 

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.

4.6Fertility, 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

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 cannot be excluded. Breast-feeding should be discontinued during treatment with efavirenz. 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.

4.7Effects 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.

4.8Undesirable 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).

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*

Rare

Delusion , neurosis , completed suicide‡,*

Nervous system

disorders

Common

Cerebellar co-ordination and balance disturbances, disturbance in attention

 

(3.6%), dizziness (8.5%), headache (5.7%), somnolence (2.0%)*

Uncommon

Agitation, amnesia, ataxia, co-ordination 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

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 c. 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 re-initiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted.

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

Control regimen

 

 

(n=1,008)

(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 and psychosis-like behaviour.

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 post-marketing 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. 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) have 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

4.9Overdose

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

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, Non-nucleoside reverse transcriptase inhibitors 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).

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 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.

Table 2: Efficacy results for study 006

 

 

Treatment

n

Responder rates (NC = F a)

Mean change from

regimen d

 

Plasma HIV-RNA

baseline-CD4 cell count

 

 

< 400 copies/ml

<50 copies/ml

Cells/mm3 (S.E.M. c)

 

 

(95% C.I.b)

(95% C.I.b)

 

 

 

48 weeks

48 weeks

48 weeks

EFV +

67%

62%

ZDV + 3TC

 

(60%, 73%)

(55%, 69%)

(11.8)

EFV + IDV

54%

48%

 

 

(47%, 61%)

(41%, 55%)

(11.3)

IDV +

45%

40%

ZDV + 3TC

 

(38%, 52%)

(34%, 47%)

(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)

Mean change from

 

 

 

Plasma HIV-RNA

 

baseline-CD4 cell count

Study number/

n

%

(95% C.I.c)

%

(95% C.I.c)

cells/mm3

(S.E.M.d)

Treatment

 

 

 

 

 

 

 

regimensb

 

 

 

 

 

 

 

Study ACTG 364

 

< 500 copies/ml

< 50 copies/ml

 

 

48 weeks

 

 

 

 

 

 

 

EFV + NFV +

(59, 82)

---

---

(17.9)

NRTIs

 

 

 

 

 

 

 

EFV + NRTIs

(46, 70)

---

---

(21.0)

NFV + NRTIs

(19, 42)

---

---

(13.6)

Study 020

 

< 400 copies/ml

< 50 copies/ml

 

 

24 weeks

 

 

 

 

 

 

 

EFV + IDV +

(52, 68)

(41, 58)

(9.1)

NRTIs

 

 

 

 

 

 

 

IDV + NRTIs

(43, 59)

(30, 45)

(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

Study AI266922 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz 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 efavirenz. 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 efavirenz 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 efavirenz. At baseline, median plasma HIV-1 RNA was

4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, 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 efavirenz 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 efavirenz. 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%.

5.2Pharmacokinetic properties

Absorption

Peak efavirenz plasma concentrations of 1.6-9.1 microM 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 microM (29%) [mean ± S.D. (% C.V.)], steady-state Cmin was 5.6 ± 3.2 microM (57%), and AUC was 184 ± 73 microM·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

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

In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state Cmax was 14.1 microM, steady state Cmin was 5.6 microM, and AUC was 216 microM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.

5.3Preclinical 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, micro-ophthalmia 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

6.1List of excipients

Core

Cellulose, microcrystalline

Hydroxypropylcellulose

Sodium laurilsulfate

Sodium starch glycolate (Type A)

Poloxamer 407

Magnesium stearate

Film-coating

Hypromellose 6cP (HPMC 2910)

Lactose monohydrate

Titanium dioxide

Macrogol/PEG 3350

Triacetin 3

Iron oxide yellow

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

White opaque PVC/PVdC-aluminium or aluminium-aluminium blisters in a carton containing 30 or 90 film-coated tablets.

30 x 1 film-coated tablet in white opaque PVC/PVdC-aluminium or aluminium-aluminium perforated unit-dose blisters.

90 x 1 film-coated tablet in white opaque PVC/PVdC-aluminium perforated unit-dose blisters.

Multipack (bundle) containing 90 film-coated tablets (3 packs of 30 x 1 film-coated tablet) in white opaque PVC/PVdC-aluminium or aluminium-aluminium perforated unit-dose blisters.

Multipack (carton) containing 90 film-coated tablets (3 packs of 30 x 1 film-coated tablet) in white opaque PVC/PVdC-aluminium or aluminium-aluminium perforated unit-dose blisters.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements for disposal.

7.MARKETING AUTHORISATION HOLDER

Teva B.V., Swensweg 5, 2031GA Haarlem, The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/11/742/001-011

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 January 2012

Date of latest renewal:

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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