Sustiva 600 mg Film-coated Tablets

ANTI-INFECTIVES

Antiretrovirals

Protease inhibitors (PI)

Atazanavir/ ritonavir/Efavirenz

(400 mg once daily/100 mg once daily/600 mg once daily, all administered with food)

Atazanavir (pm):

AUC: ↔* (↓9% to ↑10%)

Cmax: ↑17%* (↑8% to ↑27%)

C_min: ↓42%* (↓31% to ↓51%)

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

Atazanavir/ritonavir/Efavirenz

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

Atazanavir (pm):

AUC: ↔*/** (↓10% to ↑26%)

Cmax: ↔*/** (↓5% to ↑26%)

C_min: ↑ 12%*/** (↓16% to ↑49%)

(CYP3A4 induction).

* When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir.

** based on historical comparison

Darunavir/ritonavir/Efavirenz

(300 mg twice daily*/100 mg twice daily/600 mg once daily)

*lower than recommended dose

Darunavir:

AUC: ↓ 13%

C_min: ↓ 31%

(CYP3A4 induction)

Efavirenz:

AUC: ↑ 21%

C_min: ↑ 17%

(CYP3A4 inhibition)

The clinical significance of the changes has not been established. Similar findings are expected with the approved darunavir/ritonavir 600/100 mg twice daily dose. This combination should be used with caution. See ritonavir row below.

Fosamprenavir/ritonavir/Efavirenz

(700 mg twice daily/100 mg twice daily/600 mg once daily)

No clinically significant pharmacokinetic interaction

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

Fosamprenavir/Nelfinavir/ Efavirenz

Interaction not studied.

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

Fosamprenavir/Saquinavir/ Efavirenz

Interaction not studied.

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

Indinavir/Efavirenz

(800 mg q8h/200 mg once daily)

Indinavir:

AUC : ↓ 31% (↓ 8 to ↓ 47)

C_min : ↓ 40%

A similar reduction in indinavir exposures was observed when indinavir 1000 mg q8h was given with efavirenz 600 mg daily.

(CYP3A4 induction)

Efavirenz:

No clinically significant pharmacokinetic interaction

While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and indinavir.

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

See also ritonavir row below.

Indinavir/ritonavir/Efavirenz

(800 mg twice daily/100 mg twice daily/600 mg once daily)

Indinavir:

AUC: ↓ 25% (↓ 16 to ↓ 32) b

Cmax: ↓ 17% (↓ 6 to ↓ 26)b

C_min: ↓ 50% (↓ 40 to ↓ 59)b

Efavirenz:

No clinically significant pharmacokinetic interaction

The geometric mean C_min for

indinavir (0.33 mg/l) when given with ritonavir and efavirenz was higher than the mean historical C_min (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 oral solution/Efavirenz

Lopinavir/ritonavir tablets/ Efavirenz

(400/100 mg twice daily/600 mg once daily)

(500/125 mg twice daily/600 mg once daily)

Substantial decrease in lopinavir exposure.

Lopinavir concentrations: ↓ 30‑40%

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

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

See also ritonavir row below.

Nelfinavir/Efavirenz

(750 mg q8h/600 mg once daily)

Nelfinavir:

AUC: ↑ 20% (↑ 8 to ↑ 34)

Cmax: ↑ 21% (↑ 10 to ↑ 33)

The combination was generally well tolerated.

No dosage adjustment is necessary for either medicinal product.

Ritonavir/Efavirenz

(500 mg twice daily/600 mg once daily)

Ritonavir:

Morning AUC: ↑ 18% (↑ 6 to ↑ 33)

Evening AUC: ↔

Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)

Evening Cmax: ↔

Morning C_min: ↑ 42% (↑ 9 to ↑ 86) b

Evening C_min: ↑ 24% (↑ 3 to ↑ 50) b

Efavirenz:

AUC: ↑ 21% (↑ 10 to ↑ 34)

Cmax: ↑ 14% (↑ 4 to ↑ 26)

C_min: ↑ 25% (↑ 7 to ↑ 46) b

(inhibition of CYP-mediated oxidative metabolism)

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

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

Saquinavir/ritonavir/Efavirenz

Interaction not studied.

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

CCR5 antagonist

Maraviroc/Efavirenz

(100 mg twice daily/600 mg once daily)

Maraviroc:

AUC₁₂: ↓ 45% (↓ 38 to ↓ 51)

Cmax: ↓ 51% (↓ 37 to ↓ 62)

Efavirenz concentrations not measured, no effect is expected.

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

Integrase strand transfer inhibitor

Raltegravir/Efavirenz

(400 mg single dose/ -)

Raltegravir:

AUC: ↓ 36%

C₁₂: ↓ 21%

Cmax: ↓ 36%

(UGT1A1 induction)

No dosage 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 dosage 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.

Antibiotics

Azithromycin/Efavirenz

(600 mg single dose/400 mg once daily)

No clinically significant pharmacokinetic interaction.

No dosage adjustment is necessary for either medicinal product.

Clarithromycin/Efavirenz

(500 mg q12h/400 mg once daily)

Clarithromycin:

AUC: ↓ 39% (↓ 30 to ↓ 46)

Cmax_{: ↓ 26% (↓ 15 to ↓ 35)}

Clarithromycin 14‑hydroxymetabolite:

AUC: ↑ 34% (↑ 18 to ↑ 53)

Cmax: ↑ 49% (↑ 32 to ↑ 69)

Efavirenz:

AUC: ↔

Cmax: ↑ 11% (↑ 3 to ↑ 19)

(CYP3A4 induction)

Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.

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

Rifabutin/Efavirenz

(300 mg once daily/600 mg once daily)

Rifabutin:

AUC: ↓ 38% (↓ 28 to ↓ 47)

Cmax: ↓ 32% (↓ 15 to ↓ 46)

C_min: ↓ 45% (↓ 31 to ↓ 56)

Efavirenz:

AUC: ↔

Cmax: ↔

C_min: ↓ 12% (↓ 24 to ↑ 1)

(CYP3A4 induction)

The daily dose of rifabutin should be increased by 50% when administered with efavirenz. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week in combination with efavirenz.

Rifampicin/Efavirenz

(600 mg once daily/600 mg once daily)

Efavirenz:

AUC: ↓ 26% (↓ 15 to ↓ 36)

Cmax: ↓ 20% (↓ 11 to ↓ 28)

C_min: ↓ 32% (↓ 15 to ↓ 46)

(CYP3A4 and CYP2B6 induction)

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

Antifungals

Itraconazole/Efavirenz

(200 mg q12h/600 mg once daily)

Itraconazole:

AUC: ↓ 39% (↓ 21 to ↓ 53)

Cmax: ↓ 37% (↓ 20 to ↓ 51)

C_min: ↓ 44% (↓ 27 to ↓ 58)

(decrease in itraconazole concentrations: CYP3A4 induction)

Hydroxyitraconazole:

AUC: ↓ 37% (↓ 14 to ↓ 55)

Cmax: ↓ 35% (↓ 12 to ↓ 52)

C_min: ↓ 43% (↓ 18 to ↓ 60)

Efavirenz:

No clinically significant pharmacokinetic change.

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

Posaconazole/Efavirenz

--/400 mg once daily

Posaconazole:

AUC: ↓ 50%

Cmax: ↓ 45%

(UDP-G induction)

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

Voriconazole/Efavirenz

(200 mg twice daily/400 mg once daily)

Voriconazole/Efavirenz

(400 mg twice daily/300 mg once daily)

Voriconazole:

AUC: ↓ 77%

Cmax: ↓ 61%

Efavirenz:

AUC: ↑ 44%

Cmax: ↑ 38%

Voriconazole:

AUC: ↓ 7% (↓ 23 to ↑ 13) *

Cmax: ↑ 23% (↓ 1 to ↑ 53) *

Efavirenz:

AUC: ↑ 17% (↑ 6 to ↑ 29) **

Cmax: ↔**

*compared to 200 mg twice daily alone

** compared to 600 mg once daily alone

(competitive inhibition of oxidative metabolism)

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

Fluconazole/Efavirenz

(200 mg once daily/400 mg once daily)

No clinically significant pharmacokinetic interaction

No dosage adjustment is necessary for either medicinal product.

Ketoconazole and other imidazole antifungals

Interaction not studied

No data are available to make a dose recommendation.

ACID REDUCING AGENTS

Aluminium hydroxide-magnesium hydroxide-simethicone antacid/Efavirenz

(30 ml single dose/400 mg single dose)

Famotidine/Efavirenz

(40 mg single dose/400 mg single dose)

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

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

ANTIANXIETY AGENTS

Lorazepam/Efavirenz

(2 mg single dose/600 mg once daily)

Lorazepam:

AUC: ↑ 7% (↑ 1 to ↑ 14)

Cmax: ↑ 16% (↑ 2 to ↑ 32)

These changes are not considered clinically significant.

No dosage adjustment is necessary for either medicinal product.

ANTICONVULSANTS

Carbamazepine/Efavirenz

(400 mg once daily/600 mg once daily)

Carbamazepine:

AUC: ↓ 27% (↓ 20 to ↓ 33)

Cmax: ↓ 20% (↓ 15 to ↓ 24)

C_min: ↓ 35% (↓ 24 to ↓ 44)

Efavirenz:

AUC: ↓ 36% (↓ 32 to ↓ 40)

Cmax: ↓ 21% (↓ 15 to ↓ 26)

C_min: ↓ 47% (↓ 41 to ↓ 53)

(decrease in carbamazepine concentrations: CYP3A4 induction; decrease in efavirenz concentrations: CYP3A4 and CYP2B6 induction)

The steady-state AUC, Cmax and C_min of the active carbamazepine epoxide metabolite remained unchanged. Co‑administration of higher doses of either efavirenz or carbamazepine has not been studied.

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

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

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

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

Valproic acid/Efavirenz

(250 mg twice daily/600 mg once daily)

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

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

Vigabatrin/Efavirenz

Gabapentin/Efavirenz

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

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

ANTIDEPRESSANTS

Selective Serotonin Reuptake Inhibitors (SSRIs)

Sertraline/Efavirenz

(50 mg once daily/600 mg once daily)

Sertraline:

AUC: ↓ 39% (↓ 27 to ↓ 50)

Cmax: ↓ 29% (↓ 15 to ↓ 40)

C_min: ↓ 46% (↓ 31 to ↓ 58)

Efavirenz:

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

C_min: ↔

(CYP3A4 induction)

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

Paroxetine/Efavirenz

(20 mg once daily/600 mg once daily)

No clinically significant pharmacokinetic interaction

No dosage adjustment is necessary for either medicinal product.

Fluoxetine/Efavirenz

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

No dosage adjustment is necessary for either medicinal product.

ANTIHISTAMINES

Cetirizine/Efavirenz

(10 mg single dose/600 mg once daily)

Cetirizine:

AUC: ↔

Cmax: ↓ 24% (↓ 18 to ↓ 30)

These changes are not considered clinically significant.

Efavirenz:

No clinically significant pharmacokinetic interaction

No dosage adjustment is necessary for either medicinal product.

Cardiovascular Agents

Calcium Channel Blockers

Diltiazem/Efavirenz

(240 mg once daily/600 mg once daily)

Diltiazem:

AUC: ↓ 69% (↓ 55 to ↓ 79)

Cmax: ↓ 60% (↓ 50 to ↓ 68)

C_min: ↓ 63% (↓ 44 to ↓ 75)

Desacetyl diltiazem:

AUC: ↓ 75% (↓ 59 to ↓ 84)

Cmax: ↓ 64% (↓ 57 to ↓ 69)

C_min: ↓ 62% (↓ 44 to ↓ 75)

N‑monodesmethyl diltiazem:

AUC: ↓ 37% (↓ 17 to ↓ 52)

Cmax: ↓ 28% (↓ 7 to ↓ 44)

C_min: ↓ 37% (↓ 17 to ↓ 52)

Efavirenz:

AUC: ↑ 11% (↑ 5 to ↑ 18)

Cmax: ↑ 16% (↑ 6 to ↑ 26)

C_min: ↑ 13% (↑ 1 to ↑ 26)

(CYP3A4 induction)

The increase in efavirenz pharmacokinetic parameters is not considered clinically significant.

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

Verapamil, Felodipine, Nifedipine and Nicardipine

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

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

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co‑A Reductase Inhibitors

Atorvastatin/Efavirenz

(10 mg once daily/600 mg once daily)

Atorvastatin:

AUC: ↓ 43% (↓ 34 to ↓ 50)

Cmax: ↓ 12% (↓ 1 to ↓ 26)

2‑hydroxy atorvastatin:

AUC: ↓ 35% (↓ 13 to ↓ 40)

Cmax: ↓ 13% (↓ 0 to ↓ 23)

4‑hydroxy atorvastatin:

AUC: ↓ 4% (↓ 0 to ↓ 31)

Cmax: ↓ 47% (↓ 9 to ↓ 51)

Total active HMG Co‑A reductase inhibitors:

AUC: ↓ 34% (↓ 21 to ↓ 41)

Cmax: ↓ 20% (↓ 2 to ↓ 26)

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

Pravastatin/Efavirenz

(40 mg once daily/600 mg once daily)

Pravastatin:

AUC: ↓ 40% (↓ 26 to ↓ 57)

Cmax: ↓ 18% (↓ 59 to ↑ 12)

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

Simvastatin/Efavirenz

(40 mg once daily/600 mg once daily)

Simvastatin:

AUC: ↓ 69% (↓ 62 to ↓ 73)

Cmax: ↓ 76% (↓ 63 to ↓ 79)

Simvastatin acid:

AUC: ↓ 58% (↓ 39 to ↓ 68)

Cmax: ↓ 51% (↓ 32 to ↓ 58)

Total active HMG Co‑A reductase inhibitors:

AUC: ↓ 60% (↓ 52 to ↓ 68)

Cmax: ↓ 62% (↓ 55 to ↓ 78)

(CYP3A4 induction)

Co‑administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or Cmax values.

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

Rosuvastatin/Efavirenz

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

No dosage adjustment is necessary for either medicinal product.

HORMONAL CONTRACEPTIVES

Oral:

Ethinyloestradiol + Norgestimate/ Efavirenz

(0.035 mg + 0.25 mg once daily/600 mg once daily)

Ethinyloestradiol:

AUC: ↔

Cmax: ↔

C_min: ↓ 8% (↑ 14 to ↓ 25)

Norelgestromin (active metabolite):

AUC: ↓ 64% (↓ 62 to ↓ 67)

Cmax: ↓ 46% (↓ 39 to ↓ 52)

C_min: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (active metabolite):

AUC: ↓ 83% (↓ 79 to ↓ 87)

Cmax: ↓ 80% (↓ 77 to ↓ 83)

C_min: ↓ 86% (↓ 80 to ↓ 90)

(induction of metabolism)

Efavirenz: no clinically significant interaction.

The clinical significance of these effects is not known.

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

Injection: Depomedroxyprogesterone acetate (DMPA)/Efavirenz

(150 mg IM single dose DMPA)

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

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

Implant: Etonogestrel/Efavirenz

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: ↓ 52% (↓ 33 to ↓ 66)

Cmax: ↓ 45% (↓ 25 to ↓ 59)

(CYP3A4 induction)

In a study of HIV infected intravenous drug users, co‑administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.

Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Buprenorphine/naloxone/Efavirenz

Buprenorphine:

AUC: ↓ 50%

Norbuprenorphine:

AUC: ↓ 71%

Efavirenz:

No clinically significant pharmacokinetic interaction

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