Date of approval: 23 December 2016
Date of revision: 10/03/2017
Efavirenz Tablets Instructions for Use
Please read the instructions carefully and use under the guidance of a physician.
Contraindicated in persons with hypersensitivity to efavirenz or any other ingredients in the preparation
Drug Name]
Generic name: Efavirenz Tablets
English name: Efavirenz Tablets
Hanyu Pinyin: Yifeiweilun Pian
Ingredients】The main ingredient of this product is Efavirenz.
Chemical name: (S)-6-chloro-4-(cyclopropylacetyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-oxazanonaphthalen-2-one.
Chemical structure formula.
Molecular formula: C14H9ClF3NO2
Molecular weight: 315.68
Properties]: This product is a film-coated tablet, which appears white to off-white after removing the coating.
Indications
This product is indicated for the treatment of HIV-1 infection in adults, adolescents and children in combination with other antiviral drugs.
Specification】0.6g
Dosage]
Adults: The recommended dose of this product in combination with protease inhibitors and/or nucleoside reverse transcriptase inhibitors (NRTIs) is 0.6g orally, once daily. This product may be taken with or in addition to food.
To improve tolerability of neurological adverse effects, it is recommended to be taken at bedtime during the first two to four weeks of treatment and in patients who continue to experience these symptoms (see [Adverse Reactions]).
ARV Combination Therapy: This product must be used in combination with other ARVs (see [Drug Interactions]).
Adolescents and children (17 years and younger): The recommended dose of this product in combination with protease inhibitors and/or nucleoside reverse transcriptase inhibitors (NRTIs) in patients 17 years of age and younger is shown in Table 1. This product should be used only in children who are confidently able to swallow the tablet. This product is recommended to be taken on an empty stomach and at bedtime. No studies have been conducted on the use of this product in children under 3 years of age or in children weighing less than 13 kg.
Table 1 Once-daily dosing for pediatric patients
Body weight (kg) Dose of this product (mg) 13 ~ <1520015 ~ <2025020 ~ <2530025 ~ <32.535032.5 ~ <40400≥40600 [Adverse effects
According to the literature, in a controlled clinical study in combination with protease inhibitors and/or nucleoside reverse transcriptase inhibitors, the most common adverse events of moderate to severe severity occurring in 1008 patients taking 0.6 g efavirenz per day and related to treatment were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%), and malaise (5.5%). The incidence of nausea was higher in the control group. The most notable adverse events associated with efavirenz were rash, neurologic symptoms, and psychiatric symptoms. Concomitant administration with food increases exposure to efavirenz and can increase the incidence of adverse reactions (see [Precautions]).
Some other treatment-related adverse events that occurred less frequently in clinical studies include: allergic reactions, abnormal coordination, ataxia, confusion, coma, dizziness, vomiting, diarrhea, hepatitis, inattention, insomnia, anxiety, heterodreams, sleepiness, depression, abnormal thinking, euphoria, amnesia, confusion, emotional instability, euphoria, hallucinations, and psychotic symptoms.
In addition, some adverse events reported in post-marketing surveillance include: neurosis, paranoia, cerebellar coordination and balance deficits, convulsions, pruritus, abdominal pain, blurred vision, flushing, gynecomastia, hepatic failure, photosensitivity dermatitis, pancreatitis and redistribution or accumulation of body fat at the back of the neck, breasts, abdomen and retroperitoneum, tinnitus and tremors.
There have been several post-marketing reports of liver failure, including patients with no prior history of liver disease or at risk for other diseases, with features that may lead to flare-ups, and in some cases may progress to liver transplantation or death.
The types and incidence of adverse reactions in children were essentially similar to those in adults, except for a higher incidence and more severe degree of rash.
Rash: Rash was reported to occur in 26% of patients treated with 0.6 g efavirenz in clinical trials (18% of which were considered treatment-related) compared to 17% of patients in the control group. Severe rash occurred in no more than 1% of patients treated with efavirenz, while 1.7% of patients discontinued treatment due to rash. The incidence of erythema multiforme or Stevens-Johnson syndrome was 0.14%.
In the three 123-week (median) clinical trials, 58 of 187 children (32%) treated with efavirenz developed a rash. Six of these children developed a severe rash. Prophylactic application of appropriate antihistamines may be considered prior to initiation of efavirenz treatment in children.
The rash was usually a mild to moderate maculopapular rash that occurred during the first two weeks of initiating efavirenz treatment. In most patients, the rash resolves within a month with continued efavirenz treatment. Efavirenz may be restarted for patients who have interrupted treatment due to rash. When restarting efavirenz, appropriate antihistamines and/or corticosteroids are recommended (see [Precautions]).
Clinical experience with efavirenz in patients who have interrupted treatment with other anti-retrovirals in the NNRTI class is limited. 19 patients who interrupted nevirapine treatment for rash have received efavirenz. Nine of these patients experienced mild to moderate rash while taking efavirenz, and two discontinued due to rash.
Psychiatric symptoms: Serious psychiatric adverse events have been reported in patients treated with efavirenz. In a controlled study, 1008 patients received a mean of 1.6 years of treatment containing the efavirenz regimen, while 635 in the control group received a mean of 1.3 years of treatment with the control agent. The rates of specific serious psychiatric events in the efavirenz and control groups were: major depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), nonfatal suicide attempts (0.4%, 0%), aggressive behavior (0.4%, 0.3%), paranoia (0.4%, 0.3%), and mania (0.1%, 0%), respectively. The risk of developing these psychiatric symptoms may be higher in patients with prior psychiatric disorders, with an increased incidence of mania to 0.3% and major depression and suicidal ideation to 2.0%. Suicidal death, delusional and neurotic behavior have been reported in individual post-marketing reports, but it is not certain that these reports are associated with efavirenz.
Neurologic symptoms: Neurologic symptoms commonly reported in clinical studies in patients taking 0.6 g efavirenz daily include, but are not limited to: dizziness, insomnia, sleepiness, inattention, and heterodreams. In controlled clinical trials of 0.6 g efavirenz in combination with other anti-retroviral agents, 19.4% of patients experienced moderate to severe neurologic symptoms (2.0% of which were severe), compared to 9% of patients taking the control drug (1.3% of which were severe). In clinical trials, 2.1% of patients treated with 0.6 g efavirenz discontinued treatment due to neurological symptoms.
Neurologic symptoms usually started on the first or second day of treatment and resolved after the first 2 to 4 weeks. In one clinical study, monthly onset of at least moderate neurologic symptoms generally occurred between 4 and 48 weeks in 5% to 9% of patients treated with efavirenz and 3% to 5% of control patients. In a study of uninfected volunteers, the median time to onset of representative neurologic symptoms was 1 hour after dosing and the median duration was 3 hours. Dosing at bedtime improved the tolerability of these symptoms and is recommended during the first week of treatment and at bedtime for patients with persistent symptoms (see [DOSAGE]). Lowering the dose or splitting the daily dose does not provide benefit and is therefore not recommended.
Laboratory test abnormalities
Liver enzymes: 3% of the 1008 patients treated with 0.6 g efavirenz had elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) above 5 times the upper limit of normal. Similar elevations of liver enzymes were seen in the control group. Serum markers for hepatitis B and/or C were positive in 156 patients treated with 0.6 g efavirenz, and AST was elevated more than five times the upper limit of normal in 7% of patients and ALT in 8% of patients. In the control group, 91 patients had positive serum markers for hepatitis B and/or C, 5% had AST and 4% had ALT elevated to these levels. Glutamyl transpeptidase (GGT) was elevated more than 5 times the upper limit of normal in 4% of all patients treated with 0.6 g efavirenz, with an incidence of 10% in patients with hepatitis B and C. The incidence of similarly elevated GGT in patients in the control group, with or without hepatitis B or C infection, was 1.5-2%. Separate GGT elevations in efavirenz-treated patients reflect enzyme induction rather than hepatotoxicity (see [Precautions]).
Lipids: Total cholesterol may be elevated by 10-20% in some HIV-uninfected volunteers taking efavirenz. Non-fasting total cholesterol and high-density lipoprotein (HDL) may be elevated by approximately 20% and 25%, respectively, in patients treated with efavirenz + zidovudine + lamivudine regimens and by approximately 40% and 35% in patients treated with efavirenz + indinavir regimens. The effects of efavirenz on triglycerides and low-density lipoproteins (LDL) were not reported in detail. In another study, total cholesterol, HDL-cholesterol, fasting LDL-cholesterol, and fasting triglycerides were increased by 21%, 24%, 18%, and 23%, respectively, in patients treated with efavirenz + zidovudine + lamivudine for 48 weeks. The clinical significance of these lipid changes is unclear.
Contraindications
Efavirenz is contraindicated in patients with clinically significant hypersensitivity to any of the components of this product.
Efavirenz should not be used in combination with standard doses of voriconazole. Because efavirenz significantly reduces plasma concentrations of voriconazole and voriconazole significantly increases plasma concentrations of efavirenz (see [Drug Interactions]). Dose adjustments when the two are combined (see [Drug Interactions]).
Ranunculus spp. (Hypericum spp.): Patients taking efavirenz should avoid concomitant administration of drugs containing Ranunculus spp. (Hypericum spp.) because it can cause a decrease in efavirenz blood concentrations. This effect is due to the induction of CYP3A4 and can lead to loss of efficacy and development of drug resistance.
Precautions]
This product should not be used alone in HIV treatment or added to an ineffective regimen as a single agent.
When prescribing drugs in combination with this product, physicians should refer to the appropriate drug use instructions.
If any ARV in the combination regimen is interrupted due to suspected intolerance, careful consideration should be given to discontinuing all ARVs. Combination antiretroviral therapy should be restarted while intolerance resolves. Intermittent monotherapy and sequential reintroduction of ARVs is undesirable because it increases the likelihood of the development of selectively resistant mutant viruses.
The inclusion of efavirenz (e.g., ATRIPIA) in combination products with this product is not recommended. Unless dose adjustment is required (e.g., in combination with rifampin).
Malformed fetuses have been observed in animals given efavirenz. Therefore, women taking this product should avoid pregnancy. Condoms and other methods of contraception should be used in combination (see [Drug Interactions]).
Drug Interactions: Substrates, inhibitors, and inducers of CYP3A4 may alter the plasma concentration of efavirenz. Similarly, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A4 or CYP2B6. The significant effect of efavirenz at steady state is the induction of CYP3A4 and CYP2B6. however, efavirenz has been shown to inhibit CYP3A4 in vitro. Thus, for drugs metabolized by CYP3A4, there could theoretically be a temporary increase in drug levels. Patients taking CYP3A4 substrates should be aware of narrower therapeutic indications and possible serious and/or life-threatening adverse effects (e.g., arrhythmias, prolonged sedation, or respiratory depression) during the first few days of treatment with this product. This product should be used with caution for ergot derivatives (dihydroergotamine, ergometrine, ergotamine, methyl ergometrine), midazolam, triazolam, bepridil, cisapride, pimozide.
Rash: Mild to moderate rash has been reported in clinical trials regarding efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve tolerability and accelerate the resolution of the rash. Severe rash with blistering, wet flaking, or ulceration has been reported in less than 1% of efavirenz-treated patients. The incidence of erythema multiforme or Stevens-Johnson syndrome was 0.14%. The product should be discontinued in patients who develop a severe rash with blistering, desquamation, involvement of mucous membranes, or fever. It is not recommended for patients with life-threatening skin reactions, such as Stevens-Johnson syndrome. Discontinuation of other anti-retroviral agents should also be considered if treatment with this product is interrupted to avoid the development of resistant viruses (see [Adverse Reactions]).
In three 123-week (median) clinical trials, 58 cases of rash (32%) were reported in 182 children treated with efavirenz. 6 children had severe rash. The median time to initiation of rash in pediatric patients was 27 days (3 to 1504 days). Children may be considered for appropriate antihistamine prophylaxis prior to initiation of treatment with this product.
Psychiatric symptoms: Psychiatric systemic adverse events have been reported in patients treated with efavirenz. Patients with preexisting psychiatric disorders appear to be at a higher risk of developing psychiatric symptoms. Post-marketing adverse events have been reported in isolated cases of suicide, delusions, and abnormal behavior, but no conclusions can be drawn from these reports as to whether these conditions are related to this product. Patients are advised to contact their physician immediately upon onset of these symptoms to determine if they are related to this product and, if so, to further evaluate whether the risk of continued use of the drug outweighs the benefit (see [ADVERSE REACTIONS]).
Neurologic symptoms: More uncomfortable neurologic symptoms, commonly dizziness, insomnia, sleepiness, inability to concentrate, and bizarre dreams, were seen in patients treated with 0.6 g of efavirenz orally daily in clinical studies, but were not limited to these symptoms (see [ADVERSE REACTIONS]). Neurologic symptoms usually occur within the first one to two days of treatment and generally resolve after two to four weeks. Patients should be advised that if these symptoms occur, continuation of treatment will usually improve these symptoms and does not predict any rare psychiatric symptoms.
Convulsions: Convulsive episodes are rarely seen in patients taking efavirenz and are usually accompanied by a known history of seizures. Patients taking concomitant anticonvulsants that are primarily metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital, require regular monitoring of their plasma concentrations. In a drug interaction study, concomitant administration of carbamazepine and efavirenz decreased plasma concentrations of carbamazepine (see [Drug Interactions]). Use caution in patients with a history of convulsions.
Potential Reproductive Risks: Pregnancy is classified as D. Efavirenz may be harmful to the fetus when taken during the first trimester of pregnancy. Efavirenz should be avoided in pregnant women. A combination of condoms and other methods of contraception (such as oral contraceptives or other hormonal contraceptives) should be used. Due to the long half-life of efavirenz, it is recommended that appropriate contraceptive measures remain in place 12 weeks after discontinuation of this product. Breastfeeding women should have a pregnancy test before taking efavirenz. Efavirenz should be discontinued during pregnancy unless the possible benefits to the mother outweigh the possible risks to the fetus and no other suitable treatment is available. If a pregnant woman takes efavirenz during the first trimester of pregnancy or is found to be pregnant while taking efavirenz, she must be informed of the potential risks to the fetus.
Adequate and well-controlled studies in pregnant women have not been conducted. In a post-marketing experience with ARVs in pregnant women, no significant teratogenicity was reported in more than 700 pregnant women taking efavirenz in combination with ARVs during the first trimester. Very few neural tube defects, including spinal cord spinal herniation, have been reported. Most of these reports were retrospective, but their relevance was not clearly determined. Efavirenz should be used only if the potential benefit to the fetus is assessed to outweigh the potential risk, e.g., if no other therapeutic agent is available to the pregnant woman.
Hepatotoxicity: Monitoring of liver enzymes is recommended in patients with a known or suspected history of hepatitis B or C, and in patients treated with other drugs with hepatotoxic potential. In patients with persistent elevations of serum aminotransferases greater than 5 times the upper limit of the normal range, the benefit of continuous therapy with this product needs to be weighed against the unknown risk of serious hepatotoxicity (see [ADVERSE REACTIONS]).
Elevated Lipids: Use of this product may result in elevated total blood cholesterol and triglyceride levels. Total cholesterol and triglycerides should be checked prior to initiation of this product and during treatment.
Immune reconstitution inflammatory syndrome: Immune reconstitution inflammatory syndrome has been reported in patients treated with combination anti-retroviral therapy including this product (CART). During the initial phase of treatment, patients whose immune system responds to CART may have an increased inflammatory response with asymptomatic or residual opportunistic infections, which requires further evaluation and treatment. Autoimmune dysregulation during immune reconstitution has also been reported (e.g. Graves’ disease). However, the reported timing of the onset of episodes is more variable, with these events occurring several months after initiation of treatment.
Fat redistribution: Redistribution/accumulation of trunk fat, including centripetal obesity, neck and back fat accumulation (buffalo back), limb atrophy, facial wasting, breast enlargement and “Cushing’s face” can be observed in patients on ARV therapy. The mechanisms and long-term effects are unknown and a causal relationship has not been established.
Medication for Special Populations.
Efavirenz is not recommended for patients with moderate or severe hepatic impairment for whom there are insufficient data to determine whether dose adjustment is necessary. This product should be used with caution in patients with hepatic impairment due to the cytochrome P450-mediated metabolism of efavirenz and the limited clinical experience with its use in patients with chronic liver disease. Patients with underlying liver disease (including chronic hepatitis B or C) are at significantly increased risk of serious and fatal hepatic adverse events when treated with anti-retroviral drug combinations. Several postmarketing reports of liver failure have occurred in patients with no prior history of liver disease or at risk for other diseases. Monitoring of liver enzymes in patients with no prior history of liver disease or at risk for other diseases should be considered.
Pharmacokinetic studies of efavirenz have not been performed in patients with renal insufficiency; because less than 1% of efavirenz is excreted in the urine in its original form, impaired renal function has minimal effect on clearance of efavirenz. There is no experience with patients with severe renal failure, and close safety monitoring of these patients is recommended.
The small number of elderly patients evaluated in clinical studies is insufficient to determine whether the response to this product differs from that of younger patients.
This product has not been evaluated in children younger than 3 years of age or weighing less than 13 kg. There is evidence that efavirenz may alter the pharmacokinetics in younger children. Therefore, efavirenz should not be used in children younger than 3 years of age.
Food Effects: Concomitant administration of efavirenz with food increases its exposure and increases the incidence of adverse reactions. The incidence of such adverse reactions is higher with the tablet than with the hard capsule. Therefore, it is recommended that this product be taken before bedtime.
For Pregnant and Lactating Women
Women taking efavirenz should avoid pregnancy. Condoms and other methods of contraception (such as oral contraceptives or other hormonal contraceptives) should be used in combination. Due to the long half-life of efavirenz, it is recommended that appropriate contraceptive measures remain in place 12 weeks after discontinuation of this product. Breastfeeding women should be screened for pregnancy before taking efavirenz. Efavirenz should be discontinued during pregnancy unless the possible benefit to the mother outweighs the possible risk to the fetus and no other suitable treatment is available. If a pregnant woman takes efavirenz during the first trimester of pregnancy or is found to be pregnant while taking efavirenz, she must be informed of the potential risks to the fetus.
Adequate and well-controlled studies in pregnant women have not been conducted. In a post-marketing experience with ARVs in pregnant women, no significant teratogenicity was reported in more than 700 pregnant women taking efavirenz in combination with ARVs during the first trimester. Very few reports of neural tube defects, including spinal cord herniation, have been reported, and most of these reports were retrospective, but their relevance was not clearly judged.
Efavirenz can be secreted into the milk of lactating rats and has also been shown to enter human milk. Therefore, women taking efavirenz are advised to stop breastfeeding. To avoid HIV transmission, women with HIV are advised not to breastfeed under any circumstances.
[Pediatric Dosage].
Clinical studies of this product have not been conducted in pediatric patients under 3 years of age or weighing less than 13 kg.
[Geriatric Use].
Clinical trials of this product have not included a sufficient number of elderly subjects aged 65 years and older to determine whether they respond differently than younger people.
Drug Interactions]
Efavirenz is an inducer of CYP3A4 and CYP2B6. When combined with this drug, it may decrease plasma concentrations of other compounds that are substrates of CYP3A4 or CYP2B6. (See [Precautions] – Drug Interactions)
Combination with anti-retroviral drugs
Dronasvir calcium: As a guide to combining this product with dronasvir and ritonavir, prescribing information for dronasvir calcium should be consulted.
Atazanavir: Efavirenz will reduce atazanavir exposure. Refer to the prescribing information guidelines for atazanavir when combining with efavirenz.
Indinavir: The AUC and Ctrough of indinavir were reduced by approximately 33-46% and 39-57%, respectively, when the increased dose of indinavir (1000 mg/8 hours) was given concurrently with efavirenz (0.6 g once daily) in uninfected volunteers compared to the standard dose of indinavir alone (800 mg/8 hours). Similar changes in AUC and Cmax were observed with increased doses of indinavir (1000 mg/8 hours) compared with standard doses of indinavir alone (800 mg/8 hours) and with efavirenz (0.6 g once daily) in infected subjects. The optimal dose of indinavir in combination with efavirenz is not known. Increasing the dose of indinavir to 1000 mg/8 hours did not compensate for the increased metabolism of indinavir due to efavirenz.
The pharmacokinetics of indinavir and efavirenz in HIV-1-infected patients (n=6) receiving 0.6 g of efavirenz once daily along with indinavir/ritonavir 800/100 mg twice daily were comparable to data from uninfected volunteers.
Lopinavir/ritonavir: A significant reduction in Cmin was observed with lopinavir/ritonavir combination compared to lopinavir/ritonavir combination alone with concomitant administration of efavirenz. When lopinavir/ritonavir is administered concomitantly with efavirenz, an increase in the dose of lopinavir/ritonavir capsules or oral solution to 533/133 mg (4 capsules or 6.5 mL) (twice daily with food) should be considered.
Dirinavir/Ritonavir: Efavirenz (0.6 g once daily) may cause a decrease in dirinavir Cmin when combined with dirinavir/ritonavir (800/100 mg, once daily). If efavirenz is used in combination with dirinavir/ritonavir, dirinavir/ritonavir 600/100 mg twice daily should be used. Consult the prescribing information for dirinavir/ritonavir to guide the combination with efavirenz.
Maraviroc: When maraviroc (100 mg twice daily) and efavirenz (0.6 g once daily) were combined, the AUC12 and Cmax of maraviroc decreased by 45% and 51%, respectively, compared to maraviroc alone. Refer to the prescribing information for maraviroc as a guide when combining with efavirenz.
Raltegravir: The AUC, Cmax, and Cmin of raltegravir (400 mg single dose) were reduced by 36%, 36%, and 21%, respectively, when raltegravir was combined with efavirenz (0.6 g once daily) compared to raltegravir alone. The mechanism of interaction was the induction of the UGT1A1 enzyme by efavirenz. No dose adjustment of raltegravir is required.
Ritonavir: A combination study of efavirenz 0.6 g (once daily at bedtime) and ritonavir 500 mg (every 12 hours) in uninfected volunteers showed that the combination was not well tolerated and had a high incidence of clinical adverse effects (e.g., dizziness, nausea, sensory abnormalities) and abnormal laboratory test values (elevated liver enzymes). A high incidence of Monitoring of liver enzymes is recommended when efavirenz is co-administered with ritonavir.
Saquinavir: The AUC and Cmax of saquinavir were reduced by 62% and 45-50%, respectively, when saquinavir (softgel form, 1200 mg total daily in 3 divided doses) was combined with efavirenz. It is not recommended to combine efavirenz with saquinavir as a stand-alone protease inhibitor.
HCV protease inhibitors
Boceprevir: When efavirenz (0.6 g once daily) was combined with boceprevir (800 mg three times daily), the plasma trough concentration of boceprevir was reduced. (Cmin ↓44%) The clinical outcome of this reduction was not directly assessed.
Telaprevir: The combination of telaprevir and efavirenz resulted in a reduction in steady-state exposure to telaprevir and efavirenz. The combination of 1125 mg every 8 hours with efavirenz at 0.6 g once daily resulted in an 18%, 14%, and 25% reduction in AUC, Cmax, and Cmin for trabectedin and 18%, 24%, and 10% reduction in AUC, Cmax, and Cmin for efavirenz when the combination was administered compared to trabectedin at 750 mg every 8 hours alone. Refer to the instructions for telaprevir to guide coadministration with efavirenz.
Saquinavir/ritonavir: There are no data on possible interactions of efavirenz in combination with saquinavir and ritonavir.
Nucleoside reverse transcriptase inhibitors: Studies of efavirenz in combination with zidovudine and lamivudine were conducted in HIV-infected patients. No clinically significant pharmacokinetic interactions were observed. No drug interaction studies have been conducted specifically with efavirenz in combination with other nucleoside reverse transcriptase inhibitors. Because nucleoside reverse transcriptase inhibitors are metabolized by different pathways than efavirenz and are unlikely to compete with efavirenz for the same metabolic enzymes and elimination pathways, no clinically significant interactions were considered.
Non-nucleoside reverse transcriptase inhibitors: No studies have been performed combining efavirenz with other non-nucleoside reverse transcriptase inhibitors.
Antibacterial drugs
Rifamycins: In 12 HIV-uninfected volunteers, rifampicin reduced the AUC of efavirenz by 26% and Cmax by 20%. in patients 50 kg or heavier, the dose of efavirenz should be increased to 800 mg/day when efavirenz is administered with rifampicin. The dose of rifampin does not need to be adjusted when taken with efavirenz. A study in HIV-uninfected volunteers showed that efavirenz reduced the Cmax and AUC of rifabutin by 32% and increased the clearance of rifabutin by 38%, respectively. Rifabutin had no significant effect on the pharmacokinetics of efavirenz. The above data suggest that the daily dose of rifabutin should be increased by 50% when coadministered with efavirenz, or doubled if rifabutin is taken 2 to 3 times per week.
Macrolide antibacterial drugs
Azithromycin: Combining a single dose of azithromycin and multiple doses of efavirenz in uninfected volunteers does not result in any clinically significant pharmacokinetic interactions. When azithromycin and efavirenz are combined, no dose adjustment is required.
Clarithromycin: Combining efavirenz 400 mg once daily with clarithromycin 500 mg every 12 hours for 7 days, efavirenz will have a significant effect on the pharmacokinetics of clarithromycin. When coadministered with efavirenz, the AUC and Cmax of clarithromycin were reduced by approximately 39% and 26%, respectively, while the AUC and Cmax of the hydroxyl metabolite of clarithromycin were increased by approximately 34% and 49%, respectively. The clinical significance of these alterations in clarithromycin plasma levels is unclear. A rash developed in 46% of uninfected volunteers while taking efavirenz and clarithromycin. When co-administered with clarithromycin, it is recommended that no dose adjustment of efavirenz is necessary. Instead, other drugs should be considered as alternatives to clarithromycin.
Antifungal drugs
Voriconazole: Combining efavirenz at 400 mg once daily with voriconazole at 200 mg every 12 hours resulted in a bidirectional interaction in uninfected volunteers. Steady-state AUC and Cmax for voriconazole were reduced by 77% and 61%, respectively, while steady-state AUC and Cmax for efavirenz were increased by 44% and 38%, respectively. Combination of efavirenz with standard doses of voriconazole should therefore be contraindicated (see [Contraindications]).
In uninfected volunteers, the combination of efavirenz (300 mg orally once daily) with voriconazole (300 mg twice daily) resulted in a 55% and 36% reduction in AUC and Cmax for voriconazole compared with voriconazole alone (200 mg twice daily); the AUC for efavirenz was equivalent compared with efavirenz alone at 0.6 g once daily, but the Cmax was reduced by 14%. but with a 14% reduction in Cmax.
In uninfected volunteers, the combination of efavirenz (300 mg orally once daily) with voriconazole (400 mg twice daily) resulted in a 7% decrease in AUC and a 23% increase in Cmax for voriconazole compared with voriconazole alone (200 mg twice daily). These differences were not clinically significant. The AUC of efavirenz increased by 17% and the Cmax was equivalent when compared to efavirenz 0.6 g once daily alone.
When efavirenz and voriconazole are combined, the maintenance dose of voriconazole should be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50%, e.g., 300 mg once daily. When voriconazole therapy is discontinued, efavirenz should be restored to the original dose.
Itraconazole: Combining efavirenz (0.6 g orally once daily) and itraconazole (200 mg orally every 12 hours) in uninfected volunteers resulted in a 39%, 37%, and 44% reduction in steady-state AUC, Cmax, and Cmin for itraconazole, and 37%, 35%, and 43% reduction for hydroxyitraconazole, respectively, compared with itraconazole alone. The pharmacokinetics of efavirenz were unaffected. Since no recommended dose of itraconazole can be given for the combination of these two drugs, itraconazole should be considered as an alternative to other antifungal drugs.
Posaconazole: The combination of efavirenz (400 mg orally once daily) and posaconazole (400 mg orally once daily) decreased the AUC and Cmax of posaconazole by 50% and 45%, respectively, compared with posaconazole alone. The combination of posaconazole and efavirenz should be avoided unless the benefits to the patient outweigh the risks.
Antimalarials
Atovaquone and clonidine hydrochloride: efavirenz (0.6 g once daily) in combination with atovaquone and clonidine (250 mg/ 100 mg, single dose) reduced the AUC of atovaquone by 75% and the Cmax by 44% and the AUC of clonidine by 43% via glucuronide-induced effects. The combination of atovaquone/chlorguanidine with efavirenz should be avoided whenever possible.
Artemether/Benflunol: Efavirenz (0.6 g once daily) in combination with artemether 20 mg/benflunol 120 mg tablets (6 doses of 4 tablets over 3 days) resulted in reductions in exposure (AUC) of artemether, dihydroartemisinin (the active metabolite of artemether), and benflunol by approximately 51%, 46%, and 21%, respectively. Exposure to efavirenz had no significant effect. Because reduced concentrations of artemether, dihydroartemisinin, or benfluorenol may lead to reduced antimalarial efficacy, efavirenz should be used with caution in combination with artemether/benfluorenol tablets.
Lipid-lowering drugs
In uninfected volunteers, efavirenz in combination with HMG-CoA reductase inhibitors, such as atorvastatin, pravastatin or simvastatin, showed reduced plasma concentrations of statins. Regular monitoring of cholesterol levels and adjustment of statin doses is necessary.
Atorvastatin: Combining efavirenz (600 mg orally once daily) with atorvastatin (10 mg orally once daily) in uninfected volunteers reduced steady-state AUC and Cmax by 43% and 12% for atorvastatin, 35% and 13% for 2-hydroxyatorvastatin, and 4% and 47% for 4-hydroxyatorvastatin, respectively, compared with atorvastatin alone and 47%, respectively, and 34% and 20% reductions in total active HMG-CoA reductase inhibitors, respectively.
Pravastatin: Combining efavirenz (600 mg orally once daily) with pravastatin (40 mg orally once daily) in uninfected volunteers resulted in a 40% and 18% reduction in steady-state AUC and Cmax, respectively, for pravastatin compared with pravastatin alone.
Simvastatin: Combining efavirenz (600 mg orally once daily) with simvastatin (40 mg orally once daily) in uninfected volunteers reduced steady-state AUC and Cmax by 69% and 76%, respectively, simvastatin by 58% and 51%, respectively, total active HMG-CoA reductase inhibitors compared with simvastatin alone, and total active HMG-CoA reductase inhibitors by by 60% and 62%, and total HMG-CoA reductase inhibitors by 60% and 70%, respectively.
The combination of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect the AUC and Cmax values of efavirenz. No dose adjustment of efavirenz is required.
Anticoagulants
Warfarin/vinblastine: Efavirenz may increase or decrease its plasma concentration and effect.
Anticonvulsants.
Carbamazepine: The interaction between efavirenz (600 mg orally once daily) and carbamazepine (400 mg orally once daily) in uninfected volunteers is bidirectional. Steady-state AUC, Cmax, and Cmin were reduced by 27%, 20%, and 35%, respectively, for carbamazepine, while steady-state AUC, Cmax, and Cmin were reduced by 36%, 21%, and 47%, respectively, for efavirenz. Steady-state AUC, Cmax, and Cmin of the active carbamazepine epoxide metabolite were unchanged. Plasma levels of carbamazepine are subject to periodic monitoring. There are no data on higher doses of these two drugs and thus no recommended doses, and other anticonvulsants may be considered for treatment.
Other anticonvulsants: There are no data on potential drug interactions between efavirenz and phenytoin, phenobarbital, or other anticonvulsants (substrates of CYP450 isoenzymes). When efavirenz is combined with these drugs, a decrease or increase in plasma concentrations of individual drugs is produced, necessitating regular monitoring of plasma levels. No studies have been conducted with efavirenz in combination with aminoglutethimide and gabapentin. No clinically significant drug interactions are expected because aminoglutethimide and gabapentin are only eliminated in their native form via urine and follow the same pathway of enzymatic metabolism and elimination as efavirenz.
Interactions with other drugs
Antacids/Famotidine: Neither aluminum hydroxide/magnesium nor famotidine altered the absorption of efavirenz in uninfected volunteers. These data suggest that changes in gastric acid pH caused by other drugs do not affect efavirenz absorption.
Hormonal contraceptives
Oral: When oral contraceptives (ethinylestradiol 0.035 mg/norgestrel 0.25 mg once daily) and efavirenz (0.6 g once daily) were combined for 14 days, efavirenz had no effect on ethinylestradiol concentrations, but plasma concentrations of methandrostenolone and levonorgestrel, the active metabolites of norgestrel, were significantly reduced in the presence of efavirenz (methandrostenol AUC, Cmax and Cmin decreased by 64%, 46% and 82%, respectively). by 64%, 46% and 82%, respectively, and levonorgestrel AUC, Cmax and Cmin by 83%, 80% and 86%, respectively). The clinical significance of these effects is unclear. No effect of ethinylestradiol/norgestrel on the plasma concentration of efavirenz was seen.
Injectables: Information on the combination of efavirenz and injectable hormonal contraceptives is limited. In a study of drug-drug interactions between desogestrel acetate (DMPA) and efavirenz in combination for 3 months, plasma progesterone levels were maintained below 5 ng/ml in all patients, consistent with ovulation suppression.
Implantation: The interaction between etogestrel and efavirenz has not been studied. A decrease in exposure to etonogestrel (CYP3A4 induction) can be expected. Occasional post-marketing reports: contraceptive failure in patients taking efavirenz in combination with etonogestrel.
Immunosuppressants.
When immunosuppressants metabolized by CYP3A4 (e.g., cyclosporine A, tacrolimus, or sirolimus) are administered concomitantly with efavirenz, a reduction in immunosuppressant exposure may occur due to a reduction in CYP3A4. Immunosuppressive dose adjustments may be required. Close monitoring of immunosuppressive concentrations for at least two weeks (until stable concentrations are achieved) is recommended when starting or stopping efavirenz.
Methadone: A study in HIV-infected intravenous drug users found that concomitant administration of efavirenz and methadone reduced plasma drug concentrations of methadone and could produce opiate withdrawal symptoms. The dose of methadone needs to be increased by an average of 22% to reduce withdrawal symptoms. Patients should be monitored for withdrawal symptoms and the dose of methadone can be increased if necessary to reduce withdrawal symptoms.
Antidepressants: The combination of paroxetine and efavirenz has no clinically meaningful effect on pharmacokinetic parameters, so neither drug requires dose adjustment when combined. Sertraline had no significant effect on the pharmacokinetics of efavirenz, but efavirenz reduced sertraline Cmax, C24 and AUC by 28.6 to 46.3%, respectively. When sertraline and efavirenz are administered in combination, the dose of sertraline should be increased to compensate for the abnormal metabolism of sertraline induced by efavirenz. Sertraline dose adjustment should be guided by clinical efficacy. When bupropion (150 mg single dose, extended release) was combined with efavirenz (0.6 g once daily), the AUC and Cmax were reduced by 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and Cmax increased by 50% by CYP2B6 induction. Bupropion dose increases should be made based on clinical efficacy but should not exceed the maximum recommended dose. No dose adjustment of efavirenz is required.
Cetirizine: The effect of cetirizine on the pharmacokinetic parameters of efavirenz was not clinically significant. Efavirenz reduced the Cmax of cetirizine by 24% but did not alter the AUC of cetirizine. these changes were not clinically significant. Therefore, no dose adjustment is required for the combination of cetirizine and efavirenz.
Lorazepam: Efavirenz increased the Cmax and AUC of Lorazepam by 16.3% and 7.3%, respectively. The effect of efavirenz on the pharmacokinetics of clofazimibe was not clinically significant. Therefore, there is no need to adjust the respective doses of the two drugs when used in combination.
Calcium channel blockers: Combining efavirenz (0.6 g orally once daily) with diltiazem (240 mg orally once daily) in uninfected volunteers reduced steady-state AUC, Cmax, and Cmin by 69%, 60%, and 63%, respectively, for diltiazem and 75%, 64%, and 62%, respectively, for deacetyl diltiazem compared with diltiazem alone. while N-monodemethyldiltiazem was reduced by 37%, 28% and 37%, respectively. The dose of diltiazem should be adjusted according to the clinical response (refer to diltiazem instructions).
Although there was a slight increase in the pharmacokinetic parameters of efavirenz (11% to 16%), these changes were not clinically significant and therefore no dose adjustment of efavirenz is necessary when co-administered with diltiazem.
There may be interactions between efavirenz and other calcium channel blockers of CYP3A4 enzyme substrates (e.g., verapamil, felodipine, nifedipine, nicardipine) when combined, and no corresponding data are available. When efavirenz is combined with one of these drugs, it is possible that the plasma concentration of the calcium channel blocker may decrease. The dose should be adjusted according to the clinical response (refer to the relevant instructions for calcium channel blockers).
Cannabinoid Test Interactions: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid tests have been reported in uninfected and HIV-infected volunteers taking efavirenz when some screening tests were performed. Confirmation of positive screening results for cannabinoids is recommended by more accurate methods (e.g., gas chromatography/mass spectrometry).
[Drug overdose].
An increase in neurological symptoms has been reported in patients who occasionally took efavirenz 0.6g twice daily. One patient developed involuntary muscle contractions.
Treatment of efavirenz overdose requires general supportive measures, including monitoring vital signs and observing the patient’s clinical status. Activated charcoal may be given to help remove unabsorbed drug. There is no specific antidote for efavirenz overdose. Because efavirenz is highly protein-bound, dialysis is unlikely to be effective in removing the drug from the blood.
[Pharmacology and Toxicology]
Pharmacological effects
Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus-1 (HIV-1). Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT), acting on templates, primers, or nucleoside triphosphates, with a minor competitive inhibitory effect. Well above clinical therapeutic doses, efavirenz does not inhibit HIV-2RT and human cellular DNA polymorphases a, b, g and d.
Toxicological studies
Genotoxicity.
In vivo and in vitro genotoxicity studies have shown that efavirenz is not mutagenic or genotoxic. Studies include the Ames test in S. typhimurium and Escherichia coli, the mammalian mutation test in Chinese hamster ovary cells, the chromosomal aberration test in human peripheral blood lymphocytes or Chinese hamster ovary cells, and the bone marrow micronucleus test in mice in vivo.
Reproductive toxicity:
Efavirenz did not reduce mating or fertility in female or male mice and did not affect sperm or offspring in male mice. Efavirenz does not affect reproductive function in female rats. Due to the rapid clearance of efavirenz in rats, systemic drug exposure in these studies was equal to or lower than that of efavirenz administered to humans.
In an ongoing follow-up toxicity study, 3 out of 20 fetuses/newborns were found to be malformed in macaques receiving efavirenz. Pregnant macaques received efavirenz at a dose of 60 mg/kg/day, a dose with blood levels similar to those in humans at 600 mg/day. Anencephaly and unilateral anophthalmos with secondary tongue hypertrophy were observed in one litter, microphthalmos in another, and cleft palate in a third (see [Precautions]).
No fetal malformations were observed in efavirenz-administered rats; however, increased resorption of fetuses was observed in the 200 mg/kg/day dose group, and peak plasma concentrations and AUCs in pregnant rats at this dose were similar to those in humans at 600 mg/day. No teratogenicity or embryotoxicity was observed in pregnant rabbits given 75 mg/kg/day of efavirenz, and this dose produced peak plasma concentrations similar to the human dose of 600 mg/day, with an AUC approximately half that of the human dose of 600 mg/day.
Efavirenz has been shown to cross the placental barrier in rats, rabbits and macaques. In these animals, efavirenz concentrations in the blood of fetuses approximated maternal blood concentrations.
Carcinogenicity.
Carcinogenicity studies have shown that an increased incidence of liver and lung tumors was observed in female mice, while no such findings were observed in males. There was no increase in the incidence of any tumors in male mice, male or female rats receiving efavirenz. Liver tumors may be due to the enzyme-inducing effects of efavirenz; however, the reason for the increased incidence of lung tumors and their corresponding effects in humans is unknown.
Repeat dosing toxicity.
Mild to moderate hepatic bile duct hyperplasia was observed in rhesus macaques administered efavirenz for 2 years at doses that exceeded the mean plasma AUC by a factor of 2 or 9 times the AUC of patients receiving 600 mg/day. One macaque had mild cholestasis in addition to moderate bile duct hyperplasia. Bile duct hyperplasia was reversible after discontinuation of the drug, and at the end of the 2-year treatment period, 9/10 macaques treated with the highest dose of efavirenz had mild to moderate bile duct hyperplasia. During the subsequent 26-week recovery period after cessation of treatment, 3/5 of the monkeys previously treated with the highest dose of efavirenz had disappeared bile duct hyperplasia. The remaining 2 macaques had mild bile duct hyperplasia.
Slight thyroid follicular cell hypertrophy was observed in macaques receiving efavirenz for 2 years at a dose such that the mean plasma AUC exceeded the AUC of patients receiving 600 mg/day by a factor of 2 or 9. This alteration is due to an increase in thyroxine clearance secondary to induction of liver enzymes. This pathological alteration does not increase the risk of patients taking efavirenz, as long-term treatment with other known enzyme-inducing agents is not associated with clinical hypothyroidism, goiter, or thyroid tumors.
Nonsustained convulsive episodes were observed in rhesus macaques taking efavirenz for 1 year or more, and the doses administered resulted in blood concentrations of efavirenz exceeding 4-13 times those of humans taking 600 mg/day. However, no microscopic alterations in the central nervous system associated with efavirenz were observed in these macaques.
Pharmacokinetics]
1. Absorption
Efavirenz plasma concentrations peaked (1.6-9.1 μM) after 5 hours of oral administration of a single dose (100 mg~1600 mg) in HIV uninfected volunteers. A dose-related increase in Cmax and AUC was observed with increasing dose to 1600 mg; the fact that the increase in Cmax and AUC was not proportional to dose supports the idea that efavirenz absorption decreases with increasing dose at higher doses. Multiple dosing did not alter the time required to reach peak drug concentrations (3-5 hours), and steady-state plasma concentrations were reached at 6-7 days.
In HIV-infected patients, mean Cmax, mean Cmin, and mean AUC at steady-state blood concentrations were linearly related to oral doses of 200 mg, 400 mg, and 600 mg daily. 35 patients receiving efavirenz 600 mg once daily had a steady-state Cmax of 12.9 μM, a steady-state Cmin
was 5.6 μM, and the AUC was 184 μM-h.
Effect of food on oral absorption
In HIV-uninfected volunteers, the bioavailability of efavirenz 600 mg as a single dose after a high-fat or normal meal was increased by 22% and 17%, respectively, compared to fasting doses. Efavirenz can be taken on an empty stomach or with food.
2. Distribution
Efavirenz is highly bound to human plasma proteins, mainly albumin (binding rate is approximately 99.5 to 99.75%). 200 mg to 600 mg of efavirenz daily for at least 1 month in HIV-1-infected patients (n=9) resulted in cerebrospinal fluid concentrations of 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentrations. This percentage is approximately more than 3 times higher than that of efavirenz bound to non-protein (free) in plasma.
3. Metabolism
Human studies and in vitro studies with human liver microsomes have shown that efavirenz is metabolized primarily by the cytochrome P450 system to hydroxyl-containing metabolites and their further glucosylated metabolites. These metabolites are intrinsically devoid of anti-HIV-1 activity. In vitro studies confirmed that CYP3A4 and CYP2B6 are the major isozymes in the metabolism of efavirenz. In vitro studies have also shown that efavirenz inhibits the P450 isozymes 2C9, 2C19 and 3A4, with Ki values ranging from 8.5 to 17 μM at the observed plasma concentrations of efavirenz. efavirenz did not inhibit CYP2E1 in in vitro studies, but only inhibited CYP2D6 and CYP1A2 at doses well above the clinical therapeutic dose (Ki values of 82 to 160 μM). .
Efavirenz plasma exposure may be increased in patients with the G516T genetic variant of the CYP2B6 isozyme purifier. The clinical significance associated with this variant is not known; however, the possibility of an increase in the frequency and severity of efavirenz-related adverse events cannot be excluded.
Efavirenz has been shown to induce P450 enzymes, leading to auto-metabolism. At doses of 200-400 mg daily for 10 days, cumulative drug concentrations were lower than expected (22-42% lower), with an endpoint half-life of 40-55 hours, which was also lower than that of single-dose dosing (52-76 hours). Pharmacokinetic interaction studies found that the combination of 400 mg or 600 mg efavirenz with indinavir did not cause a further decrease in indinavir AUC compared to the 200 mg dose of efavirenz. This finding suggests that the induction of CYP3A4 by 400 mg or 600 mg efavirenz is similar.
4. Clearance
The endpoint half-life of efavirenz administered as a single dose is relatively long, 52 to 76 hours, compared to 40 to 55 hours after multiple doses. Radiolabeled efavirenz is found in approximately 14-34% of urine, and less than 1% of efavirenz is excreted into the urine in its original form.
5. Special populations
Impaired liver function
A multi-dose study showed no significant change in the pharmacokinetics of efavirenz in patients with mild hepatic impairment (Child-Pugh class A) compared to controls. There are insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects the pharmacokinetics of efavirenz (see [Precautions]).
Impaired Renal Function
The pharmacokinetics of efavirenz in patients with renal insufficiency have not been studied; however, less than 1% of efavirenz is excreted into the urine in its native form, so the effect of impaired renal function on clearance of efavirenz should be minimal.
Gender and ethnic differences
The pharmacokinetics of efavirenz were similar between male and female patients and between races.
Elderly patients
The number of patients 65 years and older in clinical studies of efavirenz is small, so it is not possible to determine whether older patients respond differently than younger patients.
Pediatric Patients
Efavirenz has not been studied in pediatric patients younger than 3 years of age and weighing less than 13 kg. In the 57 pediatric patients treated with efavirenz, the type and incidence of adverse reactions were generally similar to those in adults, except for a higher incidence of new-onset rash in children (46%) (see [Adverse Reactions]). The pharmacokinetics of efavirenz in children were similar to those in adults. 49 children received an equivalent dose of 600 mg of efavirenz in hard capsules (adjusted for body surface area based on body weight) with a steady-state Cmax of 14.2 μM, a steady-state Cmin of 5.6 μM, and an AUC of 218 μM-h. 17 children received the study oral solution in the marketed dose of 0.6 g of efavirenz in hard capsules (see [Adverse Reactions]). Efavirenz in hard capsules (dose adjusted based on body surface area calculated from body weight) had a steady-state Cmax of 11.8 μM, a steady-state Cmin of 5.2 μM, and an AUC of 188 μM-h.
Storage】Sealed and stored.
Package】High density polyethylene bottle for oral solid medicine 0.6g: 30 tablets/bottle
Package
Expiration date】24 months.
Standard】 YBH02702016
Approval Number】 0.6g: State Drug Registration H20163464
【Manufacturing Company
Company Name: Shanghai Dicenor Biopharmaceutical Co.
Address
Address: No. 1479, Zhangheng Road, China (Shanghai) Pilot Free Trade Zone
Postal Code: 201203
Telephone number: 021-51323300
Fax number: 021-51323311
Web
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