Non-nucleoside reverse transcriptase inhibitors - ATC code: J05AG03

Efavirenz

Each hard capsule contains 50 mg, 100 mg or 200 mg of efavirenz. Excipient: Each 50 mg hard capsule contains 28.5 mg of lactose monohydrate. Each 100 mg hard capsule contains 57.0 mg of lactose monohydrate. Each 200 mg hard capsule contains 114.0 mg of lactose monohydrate

Hard capsule 50 mg: Dark yellow and white, printed with "SUSTIVA" on the dark yellow cap and "50 mg" on the white body. 100 mg: White, printed with "SUSTIVA" on the body and "100 mg" on the cap. 200 mg: Dark yellow, printed with "SUSTIVA" on the body and "200 mg" on the cap.

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

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

Posology

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

Concomitant antiretroviral therapy: SUSTIVA must be given in combination with other antiretroviral medicines.

It is recommended that SUSTIVA be taken on an empty stomach. The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse reactions.

In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is recommended.

Adults: the recommended dose of SUSTIVA in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI is 600 mg orally, once daily.

Dose adjustment: If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg every 12 hours and the SUSTIVA 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.

If SUSTIVA is coadministered with rifampicin, an increase in the dose of SUSTIVA to 800 mg/day may be considered.

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.

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.

Paediatric population (3 to 17 years)

The recommended dose of SUSTIVA in combination with a PI and/or NRTIs for patients between 3 and 17 years of age is described in Table 1. SUSTIVA hard capsules must only be administered to children who are able to reliably swallow hard capsules. The safety and efficacy of SUSTIVA in children below the age of 3 years or weighing less than 13 kg have not yet been established.

Alternative method of administration: for children at least 3 years old and weighing at least 13 kg and adults who cannot reliably swallow hard capsules, SUSTIVA oral solution is the preferred formulation. Administration of the capsule contents with a small amount (1-2 teaspoons) of food may be considered for patients who cannot tolerate the oral solution. In a palatability study in healthy adults of efavirenz mixed with applesauce, grape jelly, yogurt, or infant formula, grape jelly received the highest rating of good overall taste. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. It is recommended to hold the capsule vertically with the cap facing up and to pull the cap away from the body of the capsule, and to mix the capsule contents with food in a small container. The mixture should be administered as soon as possible, but no more than 30 minutes after mixing. After administration of the efavirenz-food mixture, an additional small amount (approximately 2 teaspoons) of food must be added to the empty mixing container, stirred to disperse any remaining residue of the medicinal product, and administered to the patient. No additional food should be consumed for up to 2 hours after administration of efavirenz. There are limited safety and tolerability data for administration of the capsule contents in paediatric patients.

Table 1

Paediatric dose to be administered once daily

Hypersensitivity to the active substance or to any of the excipients.

Efavirenz must not be used in patients with severe hepatic impairment (Child Pugh Class C).

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].

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

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.

Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate is not recommended.

When prescribing medicinal products concomitantly with SUSTIVA, 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-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.

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.

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. 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. Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors.

Effect of food: the administration of SUSTIVA with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions. It is recommended that SUSTIVA 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.

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 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.

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.

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. 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.

Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP450 isoenzymes including CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz exposure may also be altered when given with medicinal products or food (for example, grapefruit juice) which affect CYP3A4 activity.

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.

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.

Other interactions

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

Table 2: Interactions between efavirenz and other medicinal products

Medicinal product by therapeutic areas (dose)	Effects on drug levels Mean percent change in AUC, Cmax, Cmin with confidence intervals if availablea (mechanism)	Recommendation concerning co-administration with efavirenz
ANTI-INFECTIVES
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) Cmin : 42%* (31 to 51)	Co-administration of efavirenz with atazanavir/ritonavir is not recommended. If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.
Atazanavir/ritonavir/Efavirenz (400 mg once daily/200 mg once daily/600 mg once daily, all administered with food)	Atazanavir (pm): AUC: ↔*/** (10 to ↑26) Cmax: ↔*/** (5 to ↑26) Cmin : ↑ 12%*/** (16 to ↑49) (CYP3A4 induction). * When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. ** based on historical comparison
Darunavir/ritonavir/Efavirenz (300 mg twice daily*/100 mg twice daily/600 mg once daily) *lower than recommended dose	Darunavir: AUC: 13% Cmin : 31% (CYP3A4 induction) Efavirenz: AUC: ↑ 21% Cmin : ↑ 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 dose adjustment is necessary for any of these medicinal products. See also ritonavir row below.
Fosamprenavir/Nelfinavir/ Efavirenz	Interaction not studied.	No dose adjustment is necessary for any of these medicinal products.
Fosamprenavir/Saquinavir/ Efavirenz	Interaction not studied.	Not recommended as the exposure to both PIs is expected to be significantly decreased.
Indinavir/Efavirenz (800 mg q8h/200 mg once daily)	Indinavir: AUC : 31% ( 8 to 47) Cmin : 40% A similar reduction in indinavir exposures was observed when indinavir 1000 mg q8h was given with efavirenz 600 mg daily. (CYP3A4 induction) Efavirenz: No clinically significant pharmacokinetic interaction	While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and indinavir.           No dose adjustment is necessary for efavirenz when given with indinavir or indinavir/ritonavir.         See also ritonavir row below.
Indinavir/ritonavir/Efavirenz (800 mg twice daily/100 mg twice daily/600 mg once daily)	Indinavir: AUC: 25% ( 16 to 32)b Cmax: 17% ( 6 to 26)b Cmin : 50% ( 40 to 59)b Efavirenz: No clinically significant pharmacokinetic interaction The geometric mean Cmin for indinavir (0.33 mg/l) when given with ritonavir and efavirenz was higher than the mean historical Cmin (0.15 mg/l) when indinavir was given alone at 800 mg q8h. In HIV-1 infected patients (n = 6), the pharmacokinetics of indinavir and efavirenz were generally comparable to these uninfected volunteer data.
Lopinavir/ritonavir soft capsules or oral solution/Efavirenz Lopinavir/ritonavir tablets/ Efavirenz (400/100 mg twice daily/600 mg once daily) (500/125 mg twice daily/600 mg once daily)	Substantial decrease in lopinavir exposure. Lopinavir concentrations: 30-40% Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz	With efavirenz, an increase of the lopinavir/ritonavir soft capsule or oral solution doses by 33% should be considered (4 capsules/~6.5 ml twice daily instead of 3 capsules/5 ml twice daily). Caution is warranted since this dose adjustment might be insufficient in some patients. The dose of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when co-administered with efavirenz 600 mg once daily. See also ritonavir row below.
Nelfinavir/Efavirenz (750 mg q8h/600 mg once daily)	Nelfinavir: AUC: ↑ 20% (↑ 8 to ↑ 34) Cmax: ↑ 21% (↑ 10 to ↑ 33) The combination was generally well tolerated.	No dose adjustment is necessary for either medicinal product.
Ritonavir/Efavirenz (500 mg twice daily/600 mg once daily)	Ritonavir: Morning AUC: ↑ 18% (↑ 6 to ↑ 33) Evening AUC: ↔ Morning Cmax: ↑ 24% (↑ 12 to ↑ 38) Evening Cmax: ↔ Morning Cmin : ↑ 42% (↑ 9 to ↑ 86) b Evening Cmin : ↑ 24% (↑ 3 to ↑ 50) b Efavirenz: AUC: ↑ 21% (↑ 10 to ↑ 34) Cmax: ↑ 14% (↑ 4 to ↑ 26) Cmin : ↑ 25% (↑ 7 to ↑ 46) b (inhibition of CYP-mediated oxidative metabolism) When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not available.	When using efavirenz with low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, due to possible pharmacodynamic interaction.
Saquinavir/ritonavir/Efavirenz	Interaction not studied.	No data are available to make a dose recommendation. See also ritonavir row above. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz (100 mg twice daily/600 mg once daily)	Maraviroc: AUC12 : 45% ( 38 to 51) Cmax: 51% ( 37 to 62) Efavirenz concentrations not measured, no effect is expected.	Refer to the Summary of Product Characteristics for the medicinal product containing maraviroc.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz (400 mg single dose/ -)	Raltegravir: AUC: 36% C12 : 21% Cmax: 36% (UGT1A1 induction)	No dose adjustment is necessary for raltegravir.
NRTIs and NNRTIs
NRTIs/Efavirenz	Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine, and tenofovir disoproxil 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.
Antibiotics
Azithromycin/Efavirenz (600 mg single dose/400 mg once daily)	No clinically significant pharmacokinetic interaction.	No dose adjustment is necessary for either medicinal product.
Clarithromycin/Efavirenz (500 mg q12h/400 mg once daily)	Clarithromycin: AUC: 39% ( 30 to 46) Cmax: 26% ( 15 to 35) Clarithromycin 14-hydroxymetabolite: AUC: ↑ 34% (↑ 18 to ↑ 53) Cmax: ↑ 49% (↑ 32 to ↑ 69) Efavirenz: AUC: ↔ Cmax: ↑ 11% (↑ 3 to ↑ 19) (CYP3A4 induction) Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.	The clinical significance of these changes in clarithromycin plasma levels is not known. Alternatives to clarithromycin (e.g. azithromycin) may be considered. No dose adjustment is necessary for efavirenz.
Other macrolide antibiotics (e.g.,erythromycin)/Efavirenz	Interaction not studied.	No data are available to make a dose recommendation.
Antimycobacterials
Rifabutin/Efavirenz (300 mg once daily/600 mg once daily)	Rifabutin: AUC: 38% ( 28 to 47) Cmax: 32% ( 15 to 46) Cmin : 45% ( 31 to 56) Efavirenz: AUC: ↔ Cmax: ↔ Cmin : 12% ( 24 to ↑ 1) (CYP3A4 induction)	The daily dose of rifabutin should be increased by 50% when administered with efavirenz. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week in combination with efavirenz.
Rifampicin/Efavirenz (600 mg once daily/600 mg once daily)	Efavirenz: AUC: 26% ( 15 to 36) Cmax: 20% ( 11 to 28) Cmin : 32% ( 15 to 46) (CYP3A4 and CYP2B6 induction)	When taken with rifampicin, 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. No dose 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) Cmin : 44% ( 27 to 58) (decrease in itraconazole concentrations: CYP3A4 induction) Hydroxyitraconazole: AUC: 37% ( 14 to 55) Cmax: 35% ( 12 to 52) Cmin : 43% ( 18 to 60) Efavirenz: No clinically significant pharmacokinetic change.	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Posaconazole/Efavirenz --/400 mg once daily	Posaconazole: AUC: 50% Cmax: 45% (UDP-G induction)	Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.
Voriconazole/Efavirenz (200 mg twice daily/400 mg once daily)         Voriconazole/Efavirenz (400 mg twice daily/300 mg once daily)	Voriconazole: AUC: 77% Cmax: 61% Efavirenz: AUC: ↑ 44% Cmax: ↑ 38% Voriconazole: AUC: 7% ( 23 to ↑ 13) * Cmax: ↑ 23% ( 1 to ↑ 53) * Efavirenz: AUC: ↑ 17% (↑ 6 to ↑ 29) ** Cmax: ↔** *compared to 200 mg twice daily alone ** compared to 600 mg once daily alone (competitive inhibition of oxidative metabolism)	When efavirenz is co-administered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg twice daily and the efavirenz dose must be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be restored.
Fluconazole/Efavirenz (200 mg once daily/400 mg once daily)	No clinically significant pharmacokinetic interaction	No dose adjustment is necessary for either medicinal product.
Ketoconazole and other imidazole antifungals	Interaction not studied	No data are available to make a dose recommendation.
ACID REDUCING AGENTS
Aluminium hydroxide-magnesium hydroxide-simethicone antacid/Efavirenz (30 ml single dose/400 mg single dose) Famotidine/Efavirenz (40 mg single dose/400 mg single dose)	Neither aluminium/magnesium hydroxide antacids nor famotidine altered the absorption of efavirenz.	Co-administration of efavirenz with medicinal products that alter gastric pH would not be expected to affect efavirenz absorption.
ANTIANXIETY AGENTS
Lorazepam/Efavirenz (2 mg single dose/600 mg once daily)	Lorazepam: AUC: ↑ 7% (↑ 1 to ↑ 14) Cmax: ↑ 16% (↑ 2 to ↑ 32) These changes are not considered clinically significant.	No dose adjustment is necessary for either medicinal product.
ANTICOAGULANTS
Warfarin/Efavirenz	Interaction not studied. Plasma concentrations and effects of warfarin are potentially increased or decreased by efavirenz.	Dose adjustment of warfarin may be required.
ANTICONVULSANTS
Carbamazepine/Efavirenz (400 mg once daily/600 mg once daily)	Carbamazepine: AUC: 27% ( 20 to 33) Cmax: 20% ( 15 to 24) Cmin : 35% ( 24 to 44) Efavirenz: AUC: 36% ( 32 to 40) Cmax: 21% ( 15 to 26) Cmin : 47% ( 41 to 53) (decrease in carbamazepine concentrations: CYP3A4 induction; decrease in efavirenz concentrations: CYP3A4 and CYP2B6 induction) The steady-state AUC, Cmax and Cmin of the active carbamazepine epoxide metabolite remained unchanged. Co-administration of higher doses of either efavirenz or carbamazepine has not been studied.	No dose recommendation can be made. An alternative anticonvulsant should be considered. Carbamazepine plasma levels should be monitored periodically.
Phenytoin, Phenobarbital, and other anticonvulsants that are substrates of CYP450 isoenzymes	Interaction not studied. There is a potential for reduction or increase in the plasma concentrations of phenytoin, phenobarbital and other anticonvulsants that are substrates of CYP450 isoenzymes when co-administered with efavirenz.	When efavirenz is co-administered with an anticonvulsant that is a substrate of CYP450 isoenzymes, periodic monitoring of anticonvulsant levels should be conducted.
Valproic acid/Efavirenz (250 mg twice daily/600 mg once daily)	No clinically significant effect on efavirenz pharmacokinetics. Limited data suggest there is no clinically significant effect on valproic acid pharmacokinetics.	No dose adjustment is necessary for efavirenz. Patients should be monitored for seizure control.
Vigabatrin/Efavirenz Gabapentin/Efavirenz	Interaction not studied. Clinically significant interactions are not expected since vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.	No dose adjustment is necessary for any of these medicinal products.
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz (50 mg once daily/600 mg once daily)	Sertraline: AUC: 39% ( 27 to 50) Cmax: 29% ( 15 to 40) Cmin : 46% ( 31 to 58) Efavirenz: AUC: ↔ Cmax: ↑ 11% (↑ 6 to ↑ 16) Cmin : ↔ (CYP3A4 induction)	Sertraline dose increases should be guided by clinical response. No dose adjustment is necessary for efavirenz.
Paroxetine/Efavirenz (20 mg once daily/600 mg once daily)	No clinically significant pharmacokinetic interaction	No dose adjustment is necessary for either medicinal product.
Fluoxetine/Efavirenz	Interaction not studied. Since fluoxetine shares a similar metabolic profile with paroxetine, i.e. a strong CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.	No dose adjustment is necessary for either medicinal product.
ANTIHISTAMINES
Cetirizine/Efavirenz (10 mg single dose/600 mg once daily)	Cetirizine: AUC: ↔ Cmax: 24% ( 18 to 30) These changes are not considered clinically significant. Efavirenz: No clinically significant pharmacokinetic interaction	No dose adjustment is necessary for either medicinal product.
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz (240 mg once daily/600 mg once daily)	Diltiazem: AUC: 69% ( 55 to 79) Cmax: 60% ( 50 to 68) Cmin : 63% ( 44 to 75) Desacetyl diltiazem: AUC: 75% ( 59 to 84) Cmax: 64% ( 57 to 69) Cmin : 62% ( 44 to 75) N-monodesmethyl diltiazem: AUC: 37% ( 17 to 52) Cmax: 28% ( 7 to 44) Cmin : 37% ( 17 to 52) Efavirenz: AUC: ↑ 11% (↑ 5 to ↑ 18) Cmax: ↑ 16% (↑ 6 to ↑ 26) Cmin : ↑ 13% (↑ 1 to ↑ 26) (CYP3A4 induction) The increase in efavirenz pharmacokinetic parameters is not considered clinically significant.	Dose adjustments of diltiazem should be guided by clinical response (refer to the Summary of Product Characteristics for diltiazem). No dose adjustment is necessary for efavirenz.
Verapamil, Felodipine, Nifedipine and Nicardipine	Interaction not studied. When efavirenz is co-administered with a calcium channel blocker that is a substrate of the CYP3A4 enzyme, there is a potential for reduction in the plasma concentrations of the calcium channel blocker.	Dose adjustments of calcium channel blockers should be guided by clinical response (refer to the Summary of Product Characteristics for the calcium channel blocker).
LIPID LOWERING MEDICINAL PRODUCTS
HMG Co-A Reductase Inhibitors
Atorvastatin/Efavirenz (10 mg once daily/600 mg once daily)	Atorvastatin: AUC: 43% ( 34 to 50) Cmax: 12% ( 1 to 26) 2-hydroxy atorvastatin: AUC: 35% ( 13 to 40) Cmax: 13% ( 0 to 23) 4-hydroxy atorvastatin: AUC: 4% ( 0 to 31) Cmax: 47% ( 9 to 51) Total active HMG Co-A reductase inhibitors: AUC: 34% ( 21 to 41) Cmax: 20% ( 2 to 26)	Cholesterol levels should be periodically monitored. Dose adjustment of atorvastatin may be required (refer to the Summary of Product Characteristics for atorvastatin). No dose adjustment is necessary for efavirenz.
Pravastatin/Efavirenz (40 mg once daily/600 mg once daily)	Pravastatin: AUC: 40% ( 26 to 57) Cmax: 18% ( 59 to ↑ 12)	Cholesterol levels should be periodically monitored. Dose adjustment of pravastatin may be required (refer to the Summary of Product Characteristics for pravastatin). No dose adjustment is necessary for efavirenz.
Simvastatin/Efavirenz (40 mg once daily/600 mg once daily)	Simvastatin: AUC: 69% ( 62 to 73) Cmax: 76% ( 63 to 79) Simvastatin acid: AUC: 58% ( 39 to 68) Cmax: 51% ( 32 to 58) Total active HMG Co-A reductase inhibitors: AUC: 60% ( 52 to 68) Cmax: 62% ( 55 to 78) (CYP3A4 induction) Co-administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or Cmax values.	Cholesterol levels should be periodically monitored. Dose adjustment of simvastatin may be required (refer to the Summary of Product Characteristics for simvastatin). No dose adjustment is necessary for efavirenz.
Rosuvastatin/Efavirenz	Interaction not studied. Rosuvastatin is largely excreted unchanged via the faeces, therefore interaction with efavirenz is not expected.	No dose adjustment is necessary for either medicinal product.
HORMONAL CONTRACEPTIVES
Oral: Ethinyloestradiol + Norgestimate/ Efavirenz (0.035 mg + 0.25 mg once daily/600 mg once daily)	Ethinyloestradiol: AUC: ↔ Cmax: ↔ Cmin : 8% (↑ 14 to 25) Norelgestromin (active metabolite): AUC: 64% ( 62 to 67) Cmax: 46% ( 39 to 52) Cmin : 82% ( 79 to 85) Levonorgestrel (active metabolite): AUC: 83% ( 79 to 87) Cmax: 80% ( 77 to Adverse Reactions : a. 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 SUSTIVA with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions. 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. b. 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 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 coordination and balance disturbances†, disturbance in attention (3.6%), dizziness (8.5%), headache (5.7%), somnolence (2.0%)* uncommon agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal,* tremor† Eye disorders uncommon vision blurred Ear and labyrinth disorders uncommon tinnitus†, vertigo Vascular disorders uncommon flushing† Gastrointestinal disorders common abdominal pain, diarrhoea, nausea, vomiting uncommon pancreatitis Hepatobiliary disorders 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. †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). c. 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. Psychiatric symptoms: serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In controlled trials, the frequency of specific serious psychiatric events were:   Efavirenz regimen (n=1,008) Control regimen (n=635) - severe depression 1.6% 0.6% - suicidal ideation 0.6% 0.3% - non-fatal suicide attempts 0.4% 0% - aggressive behaviour 0.4% 0.3% - paranoid reactions 0.4% 0.3% - manic reactions 0.1% 0% Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions with frequencies ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been post-marketing reports of death by suicide, delusions 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. 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. Dose reduction or splitting the daily dose has not been shown to provide benefit. Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the control arm. Hepatic failure: A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death. Immune Reactivation Syndrome: in HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. 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. 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. 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 Multi-Level 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. d. 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. e. 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 these co-infected patients in study 006, elevations in AST to greater than five times ULN developed in 13% of efavirenz-treated patients and in 7% of controls, and elevations in ALT to greater than five times ULN developed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with efavirenz and 2% in the control arm discontinued because of liverdisorders Manufacturer : Bristol-Myers Squibb Pharmaceutical Limited Drug Availability : (POM) Drug Updated : 17 February 2012 Related Drugs - AIDS AGENERASE COMBIVIR Film Coated Tablets (HIV) CRIXIVAN (HIV) Cymevene IV Emtriva 200 mg hard capsules EPIVIR (HIV) FORTOVASE (HIV) FOSCAVIR HIVID (HIV) Kaletra 200 mg/50 mg film-coated tablets Kaletra 80mg/20mg Oral Solution NEUTREXIN NORVIR (HIV) RETROVIR (HIV) Sporanox -Pulse Sustiva 50 mg, 100 mg and 200 mg Hard Capsules Trizivir film-coated tablets Truvada film-coated tablets VIDEX (HIV) VIDEX EC Viracept Film-coated Tablets VIRAMUNE (HIV) VITRAVENE WELLVONE ZERIT (HIV) ZIAGEN 300 mg Film Coated Tablets (HIV) Disease Knowledge – evidence based educational and clinical tools written for doctors and physicians Lysosomal Storage Disorders Men's Health Migraine Multiple Sclerosis Neuropathic Pain Niemann-pick Type C NSCLC Ophthalmics Opioids and Pain Parkinson's Disease Post-MI Heart Failure Prostate Cancer Renal Anaemia Renal Cell Carcinoma Soft Tissue Sarcoma Disease Knowledge Centres feed Alzheimer's Disease Arthritis Asthma Atopic Dermatitis Cholesterol Chronic Myeloid Leukemia (CML) Cystic Fibrosis Contraception Diabetes Gastrointestinal Stromal Tumours (GIST) Hepatitis Hereditary Angioedema Human Papillomavirus (HPV) & Cervical Cancer Insomnia New and updated Drugs UK Drugs Fostair 100/6 inhalation solution Epanutin capsules 25, 50 and 100mg Eprex 2000, 4000 and 10000 IU/ml solution for injection in pre-filled syringe FemSeven Conti Epanutin 300mg hard capsules Bedranol 80mg SR Capsules Bedranol 160mg SR Capsules Betim 10mg Tablets Carbo-Dome Cream Bisoprolol 2.5mg/5mg/10mg film coated tablet Phenergan Injection Rivotril 0.5 mg and 2 mgTablets Rivotril Ampoules RELPAX 20mg and 40mg Film-Coated Tablets Witch Doctor ® 81.5%w/w Gel Levetiracetam Actavis 1,000 mg film-coated tablets Levetiracetam Actavis 250 mg film-coated tablets Levetiracetam Actavis 500 mg film-coated tablets Levetiracetam Actavis 750 mg film-coated tablets Lidocaine Hydrochloride Injection BP 1% w/v plastic ampoules Spanish Drugs Benlysta 400 mg polvo para concentrado para solución para perfusión. Benlysta 120 mg polvo para concentrado para solución para perfusión. Qutenza 179 mg parche cutáneo MULTAQ 400 mg comprimidos recubiertos con película Onglyza 2,5 mg comprimidos recubiertos con película IRESSA 250 mg comprimidos recubiertos con película Mycamine 50 mg polvo para solución para perfusión Protopic 0,03% pomada Protopic 0,1% pomada Cayston 75 mg polvo y disolvente para solución para inhalación por nebulizador Altargo 1% pomada Xarelto 15 mg comprimidos recubiertos con película Xarelto 10 mg comprimidos recubiertos con película Xarelto 20 mg comprimidos recubiertos con película BRINAVESS 20 mg/ml, concentrado para solución para perfusión MEPACT 4 mg polvo para suspensión para perfusión. Fablyn Nebido 1000mg/4ml Testogel Nebido German Drugs Benlysta 120 mg Pulver zur Herstellung eines Infusionslösungskonzentrats. Benlysta 400 mg Pulver zur Herstellung eines Infusionslösungskonzentrats. MULTAQ® 400 mg Filmtabletten Qutenza 179 mg kutanes Pflaster Onglyza 2,5 mg Filmtabletten Protopic 0,1% Salbe IRESSA 250 mg Filmtabletten Mycamine 50 mg Pulver zur Herstellung einer Infusionslösung Vistide 75 mg/ml Konzentrat zur Herstellung einer Infusionslösung Cayston 75 mg Pulver und Lösungsmittel zur Herstellung einer Lösung für einen Vernebler Protopic 0,03% Salbe Xarelto 20 mg Filmtabletten Xarelto 15 mg Filmtabletten Xarelto 10 mg Filmtabletten Mycophenolatmofetil Teva 250 mg Hartkapseln Humira 40 mg MEPACT 4 mg Pulver zur Herstellung einer Infusionssuspension FABLYN Testogel Nebido 1000mg/4ml Norweigan Drugs Benlysta 120 mg pulver til konsentrat til infusjonsvæske, oppløsning. Benlysta 400 mg pulver til konsentrat til infusjonsvæske, oppløsning. Qutenza 179 mg hudplaster Onglyza 2,5 mg filmdrasjerte tabletter. 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