Informations for option: Efavirenz 600 Mg Film-Coated Tablets, show other option

Select option:

1. Efavirenz 600 Mg Film-Coated Tablets
2. Efavirenz 600 Mg Film-Coated Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Efavirenz 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 128 mg of lactose monohydrate. For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Film-coated tablet

Yellow capsule shaped, biconvex, bevelled-edge film-coated tablet debossed with “M” on one side and “EV6” on the other.

4    CLINICAL PARTICULARS

4.1 Therapeutic 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.

4.2 Posology and method of administration

Posology

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

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

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).

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

Adults and adolescents over 40 kg: the recommended dose 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. Other efavirenz formulations are available in the market for these patients. Please refer to the accompanying SmPC of suitable formulations for the paediatric posology (3 to 17 years).

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 using other efavirenz formulations available in the market. 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, an increase in the dose of efavirenz to 800 mg/day may be considered using available efavirenz formulations (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).

4.3 Contraindications

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

Efavirenz must not be used in patients with severe hepatic impairment (Child Pugh Grade C) (see section 5.2).

Efavirenz must not be administered concurrently 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 undesirable effects (for example, cardiac arrhythmias, prolonged sedation or respiratory depression) (see section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking efavirenz due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).

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. As with all other non-nucleoside reverse transcriptase inhibitors (NNRTIs), 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.

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.

Patients should be advised that current antiretroviral therapy, including efavirenz, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

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-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 undesirable effects 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 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.

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: 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.

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Osteonecrosis: although the etiology 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: 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 years of age or who weigh less than 13 kg. Therefore, efavirenz should not be given to children less than 3 years of age.

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.

Lactose: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Individuals with these conditions may take efavirenz oral solution, which is free from lactose.

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. Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect is 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 such as Ginkgo biloba extracts which induce these enzymes may give rise to decreased plasma concentrations of efavirenz; concomitant use of Ginkgo 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 (Hypericumperforatum): 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 “l ”, 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.

doses.		This combination should
	Efavirenz: AUC: T 21% Cmin : t 17% Cmax : t 15% (CYP3A4 inhibition)	be used with caution. See ritonavir row below.
Fosamprenavir/ritonavir/	No clinically significant	No dose adjustment is
Efavirenz (700 mg twice daily/100 mg twice daily/600 mg once daily)	pharmacokinetic interaction	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	Indinavir:	While the clinical significance of decreased
(800 mg q8h/200 mg once daily)	AUC : 131% (1 8 to 147) Cmin : 140% 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	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/Efavirenz	Indinavir:	indinavir/ ritonavir.
(800 mg twice daily/100 mg	AUC: i 25% (1 16 to I32)b
twice daily/600 mg once daily)	Cmax : 117% (l 6 to 126)b
	Cmm : l 50% (1 40 to l 59)b
	Efavirenz:
	No clinically significant pharmacokinetic interaction
	The geometric mean Cmin for indinavir (0.33 mg/l) when given	See also ritonavir row
	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.	below.
Lopinavir/ritonavir soft	Substantial decrease in lopinavir	With efavirenz, an
capsules or oral	exposure.	increase of the
solution/Efavirenz		lopinavir/ritonavir soft capsule or oral solution doses by 33% should be considered (4
Lopinavir/ritonavir tablets/		capsules/~6.5 ml twice
Efavirenz	Lopinavir concentrations: 4 30“	daily instead of 3 capsules/5 ml twice
(400/100 mg twice daily/ 600 mg once daily)	40%	daily). Caution is warranted since this dose
(500/125 mg twice daily/ 600 mg once daily)	Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz	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	Nelfinavir:	No dose adjustment is necessary for either
(750 mg q8h/600 mg once daily)	AUC: T 20% (t 8 to | 34)	medicinal product.
	Cmax : ! 21% (T 10 to ! 33)
	The combination was generally well

	tolerated.
Ritonavir/Efavirenz (500 mg twice daily/600 mg once daily)	Ritonavir: Morning AUC: | 18% (| 6 to | 33) Evening AUC: Morning Cmca : f 24% (| 12 to | 38) Evening Cmax : Morning Cmin : t 42% (| 9 to | 86) b Evening Cmin : | 24% (| 3 to | 50) b Efavirenz: AUC: t 21% ^ 10 to t 34) Cmax : t 14% (f 4 to ! 26) Cmin : t 25% (T 7 to t 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	Maraviroc:	Refer to the Summary of Product Characteristics for
(100 mg twice daily/600 mg once daily)	AUC12: 145% (4 38 to 4 51)	the medicinal product containing maraviroc.

	Cmax : 451%(4 37to 462) Efavirenz concentrations not measured, no effect is expected.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz (400 mg single dose/ -)	Raltegravir: AUC: 4 36% Cu : 421% Cmax: 4 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 fumarate. 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% Cmm: 4 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	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.

	25%
Telaprevir/Efavirenz (1,125 mg q8h/600 mg once daily)	Telaprevir (relative to 750 mg q8h): AUC: 1 18% (i 8 to 127)	If efavirenz and telaprevir are co-administered, telaprevir 1,125 mg every 8 hours should be used.
	Cmax: 1 14% (13 to 124) Cmm: 125% (1 14 to 134) Efavirenz: AUC: 1 18% (1 10 to 126) Cmax: 1 24% (115 to 1 32) Cmm: 110% (11 to 119) (CYP3A induction by efavirenz)
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: 139% (1 30 to 146) Cmax: 126% (1 15 to 135) Clarithromycin 14 ~ hydroxymetabolite: AUC: T 34% (t 18 to | 53) Cmax : T 49% (f 32 to | 69) Efavirenz: AUC: ^ Cmax : t 11% (f 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.
Antimycobacterials

	Hydroxyitraconazole: AUC: 4 37% (4 14 to 155) Cmax : 435% (4 12 to 152) Cmm : 443% (4 18 to 4 60) Efavirenz: No clinically significant pharmacokinetic change.
Posaconazole/Efavirenz	Posaconazole:	Concomitant use of posaconazole and efavirenz
--/400 mg once daily	AUC: 4 50%	should be avoided unless the benefit to the patient
	Cmax: 4 45% (UDP-G induction)	outweighs the risk.
V oriconazole/Efavirenz	Voriconazole:	When efavirenz is coadministered with
(200 mg twice daily/400 mg	AUC: 177%	voriconazole, the
once daily)		voriconazole maintenance
	Cmax: 4 61%	dose must be increased to 400 mg twice daily and the
	Efavirenz:	efavirenz dose must be reduced by 50%, i.e., to
	AUC: T 44%	300 mg once daily. When treatment with
	Cmax : ! 38% Voriconazole: AUC: 4 7% (4 23 to | 13)*	voriconazole is stopped, the
V oriconazole/Efavirenz (400 mg twice daily/300 mg		initial dose of efavirenz should be restored
once daily)	Cmax : t 23% (4 ltot 53)* Efavirenz: AUC: t 17% (t 6 to | 29) ** C : -_v** '-'max • ' ' *compared to 200 mg twice daily alone ** compared to 600 mg once daily alone (competitive inhibition of oxidative metabolism)

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.
ANTIMALERIAL
Atovaquone and proguanil hydrochlorothiazide/Efavirenz (250/100 mg single dose/600 mg once daily)	Atovaquone: AUC: 1 75% (1 62 to 1 84)	Concomitant administration of atovaquone/proguanil with efavirenz should be avoided whenever possible.
	Cmax: 1 44% (1 20 to 1 61) Proguanil: AUC: 1 43% (1 7 to 1 65) Cmax:
ACID REDUCING AGENTS
Aluminium hydroxide-magnesium hydroxide-simethicone antacid/Efavirenz (30 ml single dose/400 mg single dose) F amotidine/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: t 7% (T 1 to T 14) Cmax : t 16% (f 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	Carbamazepine:	No dose recommendation can be made. An

(400 mg once daily/600 mg once daily)	AUC: 427% (4 20 to 133) Cmax : 4 20% (4 15 to 124) Cmm : 4 35% (4 24 to 4 44) Efavirenz: AUC: 4 36% (4 32 to 440) Cmax : 4 21% (4 15 to 426) Cmm : 4 47% (4 41 to 4 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.	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 coadministered 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.
V igabatrin/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: 439% (I 27 to 150) Cmax : i 29% (1 15 to 140) Cmm : 446% (4 31 to 4 58) Efavirenz: AUC: ^ Cmax : t 11% (T 6 to ! 16) C : <-> v-/mm • (CYP3A4 induction)	Sertraline dose increases should be guided by clinical response. No dose adjustment is necessary for efavirenz.
Paroxetine/Efavirenz	No clinically significant	No dose adjustment is
	pharmacokinetic interaction	necessary for either
(20 mg once daily/600 mg once		medicinal product.
daily)
Fluoxetine/Efavirenz	Interaction not studied. Since	No dose adjustment is
	fluoxetine shares a similar	necessary for either
	metabolic profile with paroxetine, i.e. a strong CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.	medicinal product.
NOREPINEPHRINE AND DOPAMINE REUPTAKE INHIBITOR
Bupropion/Efavirenz	Bupropion:	Increases in bupropion dosage should be guided by
[150 mg single dose (sustained	AUC: 4 55% (4 48 to 4 62)	clinical response, but the
release)/600 mg once daily]		maximum recommended
	Cmax: 4 34% (4 21 to 447)	dose of bupropion should not be exceeded. No dose
	Hydroxybupropion: AUC: ^ Cmax: t 50% (T 20 to ! 80) (CYP2B6 induction)	adjustment is necessary for efavirenz.
ANTIHISTAMINES
Cetirizine/Efavirenz	Cetirizine:	No dose adjustment is necessary for either
(10 mg single dose/600 mg	AUC: ^	medicinal product.
once daily)
	Cmax : 4 24% (4 18 to 4 30) These changes are not considered clinically significant.

Efavirenz:

	No clinically significant pharmacokinetic interaction
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz (240 mg once daily/600 mg once daily)	Diltiazem: AUC: 4 69% (4 55 to 179) C„M, : 4 60% (1 50 to 168) Cmm : 4 63% (4 44 to 4 75) Desacetyl diltiazem: AUC: 475% (4 59 to 184) Cmax '■ 4 64% (4 57 to 4 69) Cmm : 4 62% (4 44 to 4 75) N “ monodesmethyl diltiazem: AUC: 4 37% (4 17 to 452) Cmax '■ 4 28% (4 7 to 4 44) Cmm : 4 37% (4 17 to 4 52) Efavirenz: AUC: T 11% (f 5 to t 18) Cmax : T 16% (f 6 to T 26) Cmin : t 13% (f 1 to t 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

	Cmax : 4 62% (I 55 to 178) (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 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: ^ C : <-> '-/max • ' ' Cmm : 4 8% (t 14 to 425) Norelgestromin (active metabolite): AUC: 464% (4 62 to 167) Cmax : 446% (4 39 to 4 52) Cmm : 4 82% (4 79 to 4 85) Levonorgestrel (active metabolite): AUC: 4 83% (4 79 to 4 87) Cmax : 4 80% (4 77 to 4 83) Cmm : 4 86% (4 80 to 4 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	In a 3-month drug interaction study, no significant differences in MPA pharmacokinetic parameters were found between	Because of the limited information available, a reliable method of barrier contraception must be used

(150 mg IM single dose DMPA)	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.	in addition to hormonal contraceptives (see section 4.6).
Implant: Etonogestrel/Efavirenz	Interaction not studied. 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).
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: 152% (l 33 to 166) Cmax : 145% (l 25 to 159) (CYP3A4 induction)	Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
	In a study of HIV infected intravenous drug users, coadministration 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/Efavir	Buprenorphine:	Despite the decrease in
enz		buprenorphine exposure,
	AUC: 150%	no patients exhibited withdrawal symptoms.
	Norbuprenorphine:	Dose adjustment of buprenorphine or efavirenz
	AUC: 171% Efavirenz: No clinically significant pharmacokinetic interaction.	may not be necessary when co-administered.

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

Paediatric population

Interaction studies have only been performed in adults.

4.6 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: as of July 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 718 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 604 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. All together there have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens in the first trimester. 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.

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

Breastfeeding: it is unknown whether efavirenz is excreted in human milk. Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. Risk to the infant can not be excluded. Breastfeeding should be

discontinued during treatment with Efavirenz Mylan. 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 Mylan 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 < /1,000); very rare (< 1/10,000) or not known (cannot be estimated form the available data).

Immune system disorders
Uncommon	hypersensitivity
Metabolism and nutrition disorders
Common	hypertriglyceridaemia1
Uncommon	hypercholesterolaemia1
Psychiatric disorders
Common	abnormal dreams, anxiety, depression, insomnia1
Uncommon	affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia, psychosis2, suicide attempt, suicide ideation1
Rare	delusion3, neurosis3, completed suicide1’3
Nervous system disorders
Common	cerebellar coordination and balance disturbances2, disturbance in attention (3.6%), dizziness (8.5%), headache (5.7%), somnolence (2.0%)1
Uncommon	agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal1, tremor2
Eye disorders
Uncommon	vision blurred
Ear and labyrinth disorders
Uncommon	2 tinnitus , vertigo
Vascular disorders
Uncommon	flushing
Gastrointestinal disorders
Common	abdominal pain, diarrhoea, nausea, vomiting
Uncommon	pancreatitis
Hepatobiliary disorders
Common	aspartate amino transferase (AST) increased1, alanine aminotransferase (ALT) increased1, gamma-glutamyltransferase (GGT) increased1
Uncommon	hepatitis acute
Rare	hepatic failure1,3
Skin and subcutaneous tissue disorders

Very common	rash (H.6%)1
Common	pruritus
Uncommon	erythema multiforme, Stevens-Johnson syndrome1
Rare	photoallergic dermatitis2
Reproductive system and breast disorders
Uncommon	gynaecomastia

General disorders and administration site conditions

1.    See section below. Description of selected adverse reactions for more details.

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

3.    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).

Description of selected adverse reactions

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.

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:

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 also occur many months after initiation of treatment (see section 4.4).

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 aspartate aminotransferase (AST) and alanine aminotransferase (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 gamma-glutamyltransferase (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.

Lipids: increases in total cholesterol of 10 - 20% have been observed in some uninfected volunteers receiving efavirenz. In clinical trials of various efavirenz-containing regimens in treatment naive patients, total cholesterol, HDL-cholesterol, and triglycerides increased over 48 weeks of treatment (21 - 31%, 23 - 34%, and 23 - 49%, respectively). The proportion of patients with a total cholesterol/HDL-cholesterol ratio greater than 5 was unchanged. The magnitude of changes in lipid levels may be influenced by factors such as duration of therapy and other components of the antiretroviral regimen.

Cannabinoid test interaction: efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received efavirenz. False positive test results have only been observed with the CEDIA DAU MultiLevel THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested including tests used for confirmation of positive results.

Paediatric population

Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (in a clinical study including 57 children who received efavirenz during a 48-week period, rash was reported in 46%) and was more often of higher grade than in adults (severe rash was reported in 5.3% of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered. Although nervous system symptoms are difficult for young children to report, they appear to be less frequent in children and were generally mild. In the study of 57 children, 3.5% of patients experienced nervous system symptoms of moderate intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of nervous system symptoms.

Other special populations

Liver enzymes in hepatitis B or C co-infectedpatients: in the long term data 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 a 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).

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: 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 (a, P, y or 8).

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 22fold 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 medications 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-naive 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.

	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%	62%	187
		(60%, 73%)	(55%, 69%)	(11.8)
EFV +	206	54%	48%	177
IDV		(47%, 61%)	(41%, 55%)	(11.3)
IDV + ZDV + 3TC	206	45%	40%	153
		(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.

		Responder rates (NC = Fa) Plasma HIV-RNA					Mean change from baseline-CD4 cell count
Study Number/ Treatment Regimensb	n	0/ %	(95% C.I.c)		0/ %	(95% C.I.)	3 cells/mm	(S.E.M.d)
Study ACTG 364 48 weeks		< 500 copies/ml			< 50 copies/ml
EFV + NFV + RTIs	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 : ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced paediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safety of efavirenz in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more NRTIs. The starting dose of efavirenz was the equivalent of a 600 mg dose (adjusted from calculated body size based on weight). The response rate, based on the NC = F analysis of the percentage of patients with plasma HIV-RNA < 400 copies/ml at 48 weeks was 60% (95%, C.I. 47, 72), and 53% (C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/ml. The mean CD4 cell counts were increased by 63 ± 34.5 cells/mm³ from baseline. The durability of the response was similar to that seen in adult patients.

5.2 Pharmacokinetic properties

Absorption: peak efavirenz plasma concentrations of 1.6 - 9.1 pM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in C_max 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 C_max , mean C_min, 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 C_max was 12.9 ± 3.7 pM (29%) [mean ± S.D. (% C.V.)], steady state C_min was 5.6 ± 3.2 pM (57%), and AUC was 184 ± 73 pMh (40%).

Effect of food: the AUC and C_max 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 C_max was 14.1 pM, steady state C_min was 5.6 pM, and AUC was 216 pMh. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.

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.

Exposure to efavirenz inhibits creatinine kinase activity at the central nervous system which may lead to neuronal death and degeneration involving multiple complexities of diseases leading to spatial learning and seizure provocation.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Efavirenz 600 mg film-coated tablets contain:

Core

Cellulose microcrystalline Croscarmellose sodium Hydroxypropyl cellulose Lactose monohydrate Silica, colloidal anhydrous Magnesium stearate

Film-coating Hypromellose Macrogol 400 Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life 3 years

The in-use shelf life of the product when stored in HDPE bottles is 100 days.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

PVC / PVDC-Aluminium blister pack of 30, 60, 90 and 100 film-coated tablets.

PVC / PVDC-Aluminium perforated unit dose blister pack of 30 x 1 film-coated tablets. HDPE bottles with pp screw cap of 30 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Any unused product or waste should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd. Station Close, Potters Bar, Hertfordshire EN6 1TL United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1303

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/10/2012

10    DATE OF REVISION OF THE TEXT

14/03/2014