What Is Histamine Intolerance?

Efavirenz, a prescription drug, was developed and produced by Merck (known as Merck in the United States and Canada).

Efavirenz is the first-line anti-HIV drug ^[1] , a selective non-nucleoside reverse transcriptase inhibitor (NNRTIS) of human immunodeficiency virus type 1 (HIV-1), through non-competitive binding It also inhibits HIV-1 reverse transcriptase (RT) activity, acts on templates, primers or nucleoside triphosphates, and has a small number of competitive inhibitory effects, thereby preventing virus transcription and replication.

It is suitable for adults, adolescents and children with HIV-1 infection in combination with other antiviral drugs.

Chinese name: Efavirenz
Foreign name: Efavirenz Tablets

Product name: STOCRIN®
Main ingredients: Efavirenz

Efavirenz Drug Information

Efavirenz Basic Information

[Chinese Phonetic Name] Yifeiweilun Pian

[Specifications] 600mg

[Packing] HDPE plastic bottle.

30 tablets per bottle.

[Storage] Store at 15-30 ° C.

[Validity] 24 months

[Approval number] National Medicine Standard H20133265 ^[2]

[Executive Standard] YBH03302013 ^[2]

[Main Ingredients] The main ingredient of this product is efavirenz

Chemical name: (S) -6-chloro-4- (cyclopropylethynyl) -1.4-hydro-4- (trifluoromethyl) -2H-3,1-oxazepine-2-one.

Chemical Structure:

[Molecular formula] C ₁₄ H ₉ ClF ₃ NO ₂

[Molecular weight] 315.68

[Properties] Yellow capsule-shaped film-coated tablets, white or off-white after removing the coating.

Efavirenz tablets indications

This product is suitable for the treatment of HIV-1 infection in adults, adolescents and children in combination with other antiviral drugs.

Efavirenz Tablets dosage

Adults: The recommended dose of this product in combination with protease inhibitors and / or nucleoside reverse transcriptase inhibitors (NRTIs) is 600 mg orally once daily. This product can be taken with or without food.

To improve tolerance to adverse reactions in the nervous system, it is recommended to take medications before going to bed two to four weeks after the start of treatment and in patients with persistent symptoms (see [Adverse Reactions]).

Antiretroviral drug combination therapy: This product must be used in combination with other antiretroviral drugs (see [Drug Interactions]).

Adolescents and children ( 17 years old and younger): The recommended dosage of this product in combination with protease inhibitors and / or nucleoside reverse transcriptase inhibitors (NRTIs) for patients 17 years old and younger is shown in Table 1. This product should only be used by children who are confident that they can swallow tablets. This product is recommended for fasting and before bedtime. Studies have not been conducted on children under 3 years of age or children weighing less than 13 kg.

Table 1: Pediatric patient doses once a day
Weight kg	Dosage of this product (mg)
13 <15	200
15 <20	250
20 <25	300
25 <32.5	350
32.5 to <40	400
40	600

Adverse effects of efavirenz tablets

Efavirenz is generally well tolerated in clinical studies. Efavirenz has been validated in more than 9,000 patients.

In a clinical controlled study in combination with protease inhibitors and / or nucleoside reverse transcriptase inhibitors, 1008 patients took 600 mg of this product daily, with an incidence rate of more than 5% and the most common adverse symptoms associated with treatment. The events were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%), and fatigue (5.5%). The incidence of nausea was higher in the control group. The most notable adverse events associated with this product were rashes, neurological symptoms, and mental symptoms. Taking this product with food at the same time will increase the exposure of efavirenz and increase the incidence of adverse reactions (see [ Precautions] ).

Other rare treatment-related adverse events in clinical studies include: allergic reactions, abnormal coordination, ataxia, confusion, coma, dizziness, vomiting, diarrhea, hepatitis, inattention, insomnia, anxiety, heterosexuality Dreams, sleepiness, depression, abnormal thinking, excitement, forgetfulness, insanity, emotional instability, euphoria, hallucinations, and mental symptoms.

In addition, some adverse events reported after post-market surveillance include: neurasthenia, paranoia, cerebellar coordination and balance disorders, convulsions, pruritus, abdominal pain, blurred vision, flushing, male breast development, liver failure, photosensitive dermatitis, pancreatitis Redistribution or accumulation of body fat in the back of the neck, breasts, abdomen and retroperitoneal cavity, tinnitus and tremors.

There are several post-marketing reports of liver failure, including patients with no previous history of liver disease or at risk for other diseases, with characteristics that may cause an outbreak, and some cases may progress to the level of liver transplantation or death.

Except for the higher incidence and severity of rash, the types and incidence of other adverse reactions in children are basically similar to those in adults.

Rash: In clinical trials, 26% of patients receiving 600mg of this product developed a rash (18% of which were considered to be treatment-related), compared with 17% of patients in the control group. Patients receiving this product experienced no more than 1% of severe rashes, and 1.7% of patients discontinued treatment due to the rash. The incidence of polymorphic erythema or Stevens-Johnson syndrome was 0.14%.

In three clinical trials with a median of 123 weeks, 58 (32%) of the 187 children treated with efavirenz developed a rash. Six of these children developed a severe rash. Before children begin receiving efavirenz, consider the appropriate use of preventive antihistamines.

The rash is usually a mild to moderate maculopapular rash that occurs during the first two weeks of treatment with this product. In most patients, the rash will resolve within one month as the product continues to be treated. Patients who discontinue treatment due to a rash can resume taking this product. When taking this product again, it is recommended to use appropriate antihistamines and / or corticosteroids (see [ Precautions ]).

This product has limited clinical experience in patients who have interrupted treatment with other antiretrovirals of the NNRTI class. Ninerapine has been discontinued in 19 patients due to a rash. Nine of these patients developed mild to moderate rash while taking this product, and two discontinued the drug due to the rash.

Psychiatric symptoms: Serious adverse events have been reported in patients receiving efavirenz. In a controlled study, 1,008 patients received an average of 1.6 years of treatment with efavirenz, and 635 patients in the control group received an average of 1.3 years of control. The incidences of special serious mental events in the efavirenz group and the control group were: severe depression (1.6%, 0.6%), suicidal tendency (0.6%, 0.3%), non-fatal suicide attempts (0.4%, 0%) ), Aggressive behavior (0.4%, 0.3%), paranoia (0.4%, 0.3%) and mania (0.1%, 0%). Patients with previous mental disorders appear to be at higher risk for the above-mentioned mental symptoms, with the incidence of mania rising to 0.3%, and the incidence of major depression and suicidal tendencies to 2.0%. Some post-market reports have reported suicides, illusions, and neurotic behavior, but these reports are not yet relevant to efavirenz.

Nervous System Symptoms: In clinical studies, patients who take 600 mg of this product per day often report neurological symptoms including but not limited to: dizziness, insomnia, sleepiness, inattention, and different dreams. In a controlled clinical trial of 600 mg of this product in combination with other antiretroviral drugs, 19.4% of patients experienced moderate to severe neurological symptoms (2.0% of which were severe symptoms), compared with patients taking the control drug Nervous symptoms occur in 9% (of which 1.3% are severe symptoms).

In clinical trials, 2.1% of patients treated with 600mg of this product discontinued treatment due to neurological symptoms.

Neurological symptoms usually begin on the first or second day of treatment and resolve after the first 2-4 weeks. In a clinical study, the monthly onset of at least moderate or more neurological symptoms is usually 4 to 48 weeks, occurring in 5% to 9% of patients receiving efavirenz and 3% to 5% of controls. Group of patients. In a study of uninfected volunteers, the median duration of onset of representative neurological symptoms was 1 hour after medication and the median duration was 3 hours. Taking medications at bedtime can improve the tolerance of these symptoms, and it is recommended to take the medications during the first week of treatment and in patients with persistent symptoms (see [ Dosage and Administration ]). It is not recommended to reduce the dose or to take the daily dose in divided doses.

Laboratory test abnormal

Liver enzymes: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased by more than 5 times the normal upper limit in 3% of 1,008 patients treated with 600 mg efavirenz. Similar elevations of liver enzymes were also observed in the control group. Among 156 patients receiving 600 mg efavirenz, 156 patients had hepatitis B and / or hepatitis C seropositivity, AST in 7% of patients, and ALT in 8% of patients increased more than five times the upper limit of normal. Among the patients in the control group, 91 patients had hepatitis B and / or hepatitis C seropositive, AST in 5% of patients, and ALT in 4% of patients. In all patients receiving 600 mg efavirenz, 4% of glutamyl transpeptidase (GGT) increased to more than five times the upper limit of normal, with an incidence of 10% in patients with hepatitis B and C. Patients in the control group, with or without infection with hepatitis B or C, had a similar incidence of GGT elevations of 1.5 to 2%. Increased GGT alone in efavirenz-treated patients reflects enzyme induction rather than liver toxicity (see [ Cautions ]).

Blood lipids: Some non-HIV-infected volunteers taking efavirenz may increase their total cholesterol by 10-20%. Non-fasting total cholesterol and high-density lipoprotein (HDL) in patients treated with efavirenz + zidovudine + lamivudine regimen can increase by approximately 20% and 25%, respectively, with efavirenz + indinavir Patients treated with the regimen increased by approximately 40% and 35%. The effects of efavirenz on triglycerides and low-density lipoproteins (LDL) have not been reported in detail. In another study, patients treated with efavirenz + zidovudine + lamivudine for 48 weeks showed a 21% increase in total cholesterol, HDL-cholesterol, fasting LDL-cholesterol, and fasting triglyceride. , 24%, 18% and 23%. The clinical significance of these changes in lipids is unknown.

Efavirenz Taboo

This product is contraindicated in patients who are clinically allergic to any component of this product.

This product should not be used in combination with the standard dose of voriconazole. Because efavirenz can significantly reduce the plasma concentration of voriconazole, while voriconazole also significantly increases the plasma concentration of efavirenz (see [Drug Interactions]). Dose adjustment when the two are combined (see [Drug Interactions]).

Little Forsythia (Hypericum): Patients taking efavirenz should avoid taking medicines containing Forsythia (Hypericum) as it can cause blood concentrations of efavirenz decline. This effect is due to the induction of CYP3A4 and can lead to a loss of efficacy and resistance.

Precautions for efavirenz tablets

This product should not be used alone for HIV treatment or as a single drug addition to ineffective treatment options.

When prescribing drugs for use with this product, physicians should refer to the product manufacturer's instructions for use.

If any antiretroviral drug is discontinued in a combination regimen due to suspected intolerance, careful consideration should be given to discontinuing all antiretroviral drugs. Anti-retroviral therapy should be restarted at the same time as the intolerance is resolved. Intermittent monotherapy and sequential re-administration of antiretroviral drugs is not advisable, as this increases the possibility of generating selective resistance mutant viruses.

It is not recommended to include efavirenz (for example: ATRIPIA) in compound products in combination with this product unless dose adjustment is required (such as in combination with rifampicin).

Malformed fetuses were observed in animals given efavirenz. Therefore, women taking this product should avoid pregnancy. Condom contraception and other methods of contraception (eg, oral contraceptives or other hormonal contraceptives) 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 the plasma concentration of drugs metabolized by CYP3A4 or CYP2B6. The significant role of efavirenz in steady state is to induce CYP3A4 and CYP2B6. However, efavirenz has shown an inhibitory effect of CYP3A4 in vitro. Therefore, for drugs metabolized by CYP3A4, there may theoretically be a temporary increase in drug levels. Patients taking CYP3A4 substrate should pay attention to narrower treatment indicators and possible serious and / or life-threatening adverse reactions (such as arrhythmia, long-term sedation or respiratory depression) in the first few days of treatment with this product. For ergot derivatives (dihydroergotamine, ergometrine, ergotamine, methylergometrine), midazolam, triazolam, benproperil, cisapride, pimozide should be used with caution This product.

Rash: In clinical trials of this product, mild to moderate rashes have been reported and usually resolve with continued treatment. Appropriate antihistamines and / or corticosteroids can improve tolerance and accelerate rash resolution. Less than 1% of patients treated with this product reported severe rashes with blistering, wet scaling, or ulcers. The incidence of polymorphic erythema or Stevens-Johnson syndrome was 0.14%. This product should be discontinued in patients with severe rashes with blistering, desquamation, mucosa involvement or fever. This product is not recommended for patients with life-threatening skin reactions (such as Stevens-Johnson syndrome). If this product is discontinued, other antiretroviral drugs should also be discontinued to avoid the generation of drug-resistant viruses (see [Adverse Reactions]).

In three clinical trials with a median of 123 weeks, 58 skin rashes (32%) were reported in 182 children treated with this product. Six children had severe rash. The median time to onset of rash in pediatric patients was 27 days (range 3 to 1504 days). Patients may consider appropriate antihistamine prevention before starting treatment with this product.

Psychiatric symptoms: Adverse events in the psychiatric system have been reported in patients treated with this product. Patients with previous mental disorders appear to be at greater risk for developing mental symptoms. Post-marketing adverse events have reported individual suicides, illusions, and behavioral abnormalities, but it cannot be concluded from these reports whether these conditions are related to this product. Patients are advised to contact the doctor as soon as the above symptoms occur to determine whether these symptoms are related to this product. If they are related, then further evaluate whether the risk of continued medication exceeds the benefits obtained (see [Adverse Reactions]).

Nervous System Symptoms: Patients treated with 600 mg orally of this product daily in clinical studies have experienced relatively uncomfortable neurological symptoms, including dizziness, insomnia, drowsiness, inattention and dreams, but not limited to this (see [Adverse Reaction ).

Neurological symptoms usually appear one to two days before treatment and usually resolve two to four weeks later. Patients should be informed that if these symptoms occur, continued treatment usually improves these symptoms and does not indicate any rare mental symptoms.

Convulsions: Convulsions are rare in patients taking efavirenz, usually with a known history of seizures. Patients also take anticonvulsants that are mainly metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital, and their plasma concentrations need to be monitored regularly. In a drug-drug interaction study, carbamazepine and efavirenz were taken simultaneously, and the plasma concentration of carbamazepine was reduced (see [Drug Interactions]). Patients with a history of convulsions should be used with caution.

Potential Reproductive Risk: Pregnancy is classified as D. Taking efavirenz in the first trimester of pregnancy can be harmful to the fetus. Pregnant women should avoid taking efavirenz. Condoms should be combined with other methods of contraception (such as oral contraceptives or other hormonal contraceptives). Due to the long half-life of efavirenz, it is recommended that appropriate contraceptive measures should still be taken 12 weeks after discontinuation of stonatine. Breastfeeding women should be tested for pregnancy before taking efavirenz, and efavirenz should be discontinued during pregnancy, unless the possible benefits to the mother outweigh the possible risks to the fetus and there is no other appropriate treatment. If a pregnant woman takes efavirenz during the first three months of pregnancy or is pregnant while taking efavirenz, she must be informed of the potential harm to the fetus.

There are currently no adequate and well-controlled studies in pregnant women. According to a post-marketing experience of antiretrovirals in pregnant women, in more than 700 reports of pregnant women taking efavirenz and antiretroviral drugs in the first three months of pregnancy, no There have been significant reports of teratogenicity. Very few neural tube defects have been reported, including myelomeningocele. Most of these reports are retrospective, but their relevance is unclear. Use efavirenz only if the potential benefit assessment of the fetus outweighs the potential risks. For example, pregnant women have no other treatment options.

Hepatotoxicity: For patients with a known or suspected history of hepatitis B or C, and for patients treated with other drugs with liver toxicity, monitoring of liver enzymes is recommended. For patients whose serum aminotransferases continue to rise more than 5 times the upper limit of the normal range, the benefits of continuous treatment with this product need to be weighed against the unknown risk of severe liver toxicity (see [Adverse Reactions]).

Elevated blood lipids: The use of this product can cause elevated blood cholesterol and triglyceride levels. A total cholesterol and triglyceride test should be performed before starting this product and during treatment.

Immune Reconstructed Inflammatory Syndrome: Immune reconstituted inflammatory syndrome has been reported in those patients who have combined antiretroviral therapy including this product (CART). In the early stages of treatment, patients whose immune system responds to CART may increase the inflammatory response to asymptomatic or residual opportunistic infections, which requires further evaluation and treatment. Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstruction. However, the reported onset time varies widely, and these events can occur months after starting treatment.

Fat redistribution: body fat redistribution / accumulation can be observed in patients receiving antiretroviral therapy, including centripetal obesity, neck and back fat accumulation (buffalo back), limb atrophy, facial wasting, breast hypertrophy, and "Cushing Face ". Its mechanism and long-term impact are unknown, and causality has not yet been established.

Medicine for special populations:

For patients with moderate or severe hepatic impairment, there are insufficient data to determine whether a dose adjustment is necessary, so efavirenz is not recommended. Because efavirenz metabolism is mediated by cytochrome P450, and patients with chronic liver disease have limited clinical experience with this product, this product should be used with caution in patients with liver damage. Patients with underlying liver disease (including chronic hepatitis B or C) have a significantly increased risk of severe and fatal liver adverse events when combined with antiretroviral drugs. Several post-marketing reports of liver failure have occurred in patients with no previous history of liver disease or at risk for other diseases. Consideration should be given to monitoring liver enzymes in patients with no previous history of liver disease or at risk for other diseases.

The pharmacokinetics of efavirenz have not been studied 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 the clearance of efavirenz. There is no experience in the use of patients with severe renal failure, and it is recommended that these patients be closely monitored for safety.

The small number of elderly patients evaluated in clinical studies is insufficient to determine whether the response to this product is different from younger patients.

This product has not been evaluated in children under 3 years of age or weighing less than 13 kg. There is evidence that efavirenz may alter the pharmacokinetics of young children. Therefore, efavirenz should not be used in children under 3 years of age.

Food effects : Taking efavirenz with food at the same time increases its exposure and increases the incidence of adverse reactions. The incidence of such adverse reactions will be higher when taking this product than in taking this product's hard capsules. Therefore, it is recommended to take this product before going to bed.

[Medication for pregnant and lactating women]

Women taking efavirenz should avoid pregnancy. Condoms should be combined with other methods of contraception (such as oral contraceptives or other hormonal contraceptives). Due to the long half-life of efavirenz, it is recommended that appropriate contraceptive measures should still be taken 12 weeks after discontinuation of stonatine. Breastfeeding women should be tested for pregnancy before taking efavirenz, and efavirenz should be discontinued during pregnancy, unless its possible benefits to the mother outweigh the risks to the fetus and there is no other appropriate treatment. If a pregnant woman takes efavirenz during the first three months of pregnancy or is pregnant when taking efavirenz, she must be informed of the potential harm to the fetus.

There are currently no adequate and well-controlled studies in pregnant women. According to a post-marketing experience of antiretrovirals in pregnant women, in more than 700 reports of pregnant women taking efavirenz and antiretroviral drugs in the first three months of pregnancy, no There have been significant reports of teratogenicity. There are very few reports on neural tube defects, including myelomeningocele, and most of these reports are retrospective, but their relevance is not clear.

Registration of pregnant women for antiretroviral treatment: Physicians are encouraged to register antiretroviral treatment for pregnant women by calling 910-256-0238 (1-800-258-4263 in the United States and Canada) so that Monitor the effects on the mother and fetus.

Efavirenz is secreted into the milk of lactating rats, and efavirenz has also been shown to enter human milk. It is therefore recommended that women taking efavirenz stop breastfeeding. To avoid transmission of HIV, it is recommended that women infected with HIV refrain from breastfeeding under any circumstances.

[Child medication]

Clinical studies of this product have not been performed in pediatric patients under 3 years of age or weighing less than 13 kg.

[Medication for elderly patients]

The clinical trial of this product did not include enough elderly subjects aged 65 and over to determine whether their response was different from that of young people.

Efavirenz drug interactions

Efavirenz is an inducer of CYP3A4 and CYP2B6. When combined with this product, it may reduce the plasma concentration of other compounds of CYP3A4 or CYP2B6 substrate. (See [Precautions]-Drug Interactions).

Combination with antiretroviral drugs

Fosanavir calcium: As a guide for the combination of this product with fosanavir and ritonavir, you should check for prescribing information for fosanavir calcium.

Atazanavir: Efavirenz reduces exposure to atazanavir. Refer to Atazanavir's Prescribing Information Guide when used with efavirenz.

Indinavir: Compared with the standard dose of indinavir alone (800mg / 8 hours), the uninfected volunteers increased the dose of indinavir (1000mg / 8 hours) with this product (600mg once daily) When taken at the same time, the AUC and Ctrough of indinavir were reduced by about 33 to 46% and 39 to 57%, respectively. Compared with the standard dose of indinavir alone (800mg / 8 hours), the increased dose of indinavir (1000mg / 8 hours) of infected subjects was taken simultaneously with this product (600mg once daily). Similar changes were also observed for Wei's AUC and Cmax. The optimal dose of indinavir combined with efavirenz is unknown. Increasing the dose of indinavir to 1000 mg / 8 hours does not compensate for the increased metabolism of indinavir due to efavirenz.

Patients with HIV-1 infection (n = 6) take efavirenz 600 mg once daily and indinavir / ritonavir 800/100 mg twice daily, indinavir and efavirenz The pharmacokinetics are comparable to data from uninfected volunteers.

Lopinavir / ritonavir: Compared with lopinavir / ritonavir alone, lopinavir / ritonavir combined with efavirenz, ritonavir was observed Cmin was significantly reduced in Wei. When taking lopinavir / ritonavir with efavirenz, consider increasing the dose of lopinavir / ritonavir capsules or oral solution to 533/133 mg (4 capsules or 6.5 mL) (each Twice a day, eating at the same time).

Diranavir / ritonavir: Efavirenz (600mg, once daily) in combination with darunavir / ritonavir (800/100 mg, once daily) may cause darunavir Wei Cmin decreased. If efavirenz is used in combination with darunavir / ritonavir, darunavir / ritonavir 600 / 100mg should be used twice daily. Review the prescribing information for darunavir / ritonavir to guide use with efavirenz.

Maraviroc: When combined with Maravero (100mg twice daily) and this product (600mg once daily), the AUC12 and Cmax of Maravero are 45% lower than those of Maravero alone. 51%. Use Marveiro's prescribing information as a guide when using efavirenz.

Latiravir: Compared with Latiravir alone, AUC, Cmax, Cmin of Latiravir and Efavirenz (600mg once daily) when combined with Latiravir (400mg once) Decrease by 36%, 36%, and 21%. The interaction mechanism is the induction of UGT1A1 enzyme by efavirenz. There is no need to adjust the dose of lativavir.

Ritonavir (Ritonavir): A combination study of 600 mg of this product (once a day before bedtime) and 500 mg of ritonavir (on a 12-hour basis) was performed in uninfected volunteers, and the results showed this combination Is not well tolerated and has a high incidence of clinical adverse reactions (such as dizziness, nausea, paresthesia) and laboratory test values (elevated liver enzymes). When this product is used in combination with ritonavir, it is recommended to monitor liver enzymes.

Saquinavir: When saquinavir (a soft capsule dosage form, 1200mg taken 3 times a day) is combined with this product, the AUC and Cmax of saquinavir decrease by 62% and 45-50%, respectively. It is not recommended to use this product with saquinavir as a separate protease inhibitor.

HCV protease inhibitor

Boceprevir: Efavirenz (600mg, once daily) in combination with boceprevir (800mg, three times daily) reduces the plasma trough concentration of boceprevir. (Cmin 44%) The clinical outcome of this reduction was not directly evaluated.

Trapivir: The combined application of trapivir and efavirenz results in a decrease in steady-state exposure of telapivir and efavirenz. When combined with 1125 mg of telapivir every 8 hours and 600 mg of efavirenz once daily, the AUC, Cmax, and Cmin of telapivir were reduced by 18 compared with 750 mg of telapivir administered alone every 8 hours %, 14%, and 25%, efavirenz reduced AUC, Cmax, and Cmin by 18%, 24%, and 10%. Refer to the instructions for telaprevir to guide the combination with this product.

Shaquinavir / ritonavir: There is no data showing the possible interactions of this product with the combined use of saquinavir and ritonavir.

Nucleoside reverse transcriptase inhibitors: A study of the combined use of this product with zidovudine and lamivudine has been performed in HIV-infected patients. No clinically significant pharmacokinetic interactions were observed. No special drug interaction studies have been conducted in combination with this product and other nucleoside reverse transcriptase inhibitors. Because nucleoside reverse transcriptase inhibitors are metabolized by different routes with this product, and it is impossible to compete with this product for the same metabolic enzymes and elimination pathways, it is not considered to have clinically significant interactions.

Non-nucleoside reverse transcriptase inhibitors: No studies have been conducted on the combination of this product with other non-nucleoside reverse transcriptase inhibitors.

Antibacterial drugs

Rifamycins: Rifampicin reduced AUC 26% and Cmax 20% of efavirenz in 12 volunteers who were not infected with HIV.

For patients weighing 50 kg or more, when taking this product with rifampin, the dose of this product should be increased to 800 mg / day. The dose of rifampin does not need to be adjusted when taken with this product. A study in uninfected HIV volunteers showed that efavirenz reduced rifabutin's Cmax by 32% and AUC by 38%, respectively, and increased rifabutin clearance. Rifabutin has no significant effect on the pharmacokinetics of efavirenz. The above information indicates that the daily dose of rifabutin should be increased by 50% when taken in combination with efavirenz. If taking rifabutin 2 to 3 times a week, the dose of rifabutin should be doubled.

Macrolides

Azithromycin: A single dose of azithromycin and multiple doses of efavirenz in uninfected volunteers will not cause any clinically significant pharmacokinetic interactions. When azithromycin is used in combination with efavirenz, no dose adjustment is necessary.

Clarithromycin: 400 mg once daily with 500 mg clarithromycin every 12 hours for 7 days, efavirenz will have a significant effect on the pharmacokinetics of clarithromycin. When combined with this product, the AUC and Cmax of clarithromycin were reduced by approximately 39% and 26%, respectively, while the AUC and Cmax of clarithromycin hydroxyl metabolites were increased by approximately 34% and 49%, respectively. The clinical significance of these changes in clarithromycin plasma levels is unclear. When taking this product and clarithromycin, 46% of uninfected volunteers developed a rash. When combined with clarithromycin, it is not necessary to adjust the dose of this product. Instead, consider alternatives to clarithromycin.

Antifungal drugs

Voriconazole: The combination of 400 mg once daily with voriconazole 200 mg every 12 hours showed a two-way interaction in uninfected volunteers. The steady-state AUC and Cmax of voriconazole decreased by 77% and 61%, respectively, while the steady-state AUC and Cmax of efavirenz increased by 44% and 38%, respectively. Therefore, the standard dose of this product and voriconazole should be contraindicated. (See [ taboo ])

In uninfected volunteers, the combination of efavirenz (300 mg, orally once daily) and voriconazole (300 mg, twice daily) reduced the AUC and Cmax of voriconazole compared to voriconazole alone (200 mg, twice daily). 55% and 36%; the AUC of efavirenz is equivalent, but the Cmax is reduced by 14% compared to efavirenz 600mg once daily.

In uninfected volunteers, the combination of efavirenz (300 mg orally once daily) and voriconazole (400 mg twice daily) reduced the AUC of voriconazole by 7% compared to voriconazole alone (200 mg twice daily). And Cmax increased by 23%. These differences were not clinically significant. Compared to taking efavirenz 600mg once daily, the AUC of efavirenz increased by 17% and Cmax was equivalent.

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%, such as 300 mg once daily. When voriconazole treatment is stopped, efavirenz should return to the original dose.

Itraconazole: Efavirenz (600 mg orally once daily) and itraconazole (200 mg orally every 12 hours) were used in uninfected volunteers compared to itraconazole alone , Itraconazole's steady-state AUC, Cmax, and Cmin were reduced by 39%, 37%, and 44%, respectively, while hydroxyitraconazole was reduced by 37%, 35%, and 43%, respectively. The pharmacokinetics of efavirenz were not affected. Since the recommended dose of itraconazole for the combined use of these two drugs cannot be given, other antifungal drugs should be considered instead of itraconazole.

Posaconazole: Compared with posaconazole alone, efavirenz (400 mg, orally once a day) and posaconazole (400 mg, orally once a day) are combined. AUC and C of posaconazole max is reduced by 50% and 45%, respectively. The combined use of posaconazole and efavirenz should be avoided unless the benefits to the patient outweigh the risks.

Antimalarial

Atovaquone and proguanil hydrochloride: When efavirenz (600 mg, once daily) is used in combination with atovaquone and proguanil (250 mg / 100 mg, single dose), glucuronic acid-induced reduction Torvaquinone has an AUC of 75% and a C max of 44%, which reduces the AUC of proguanil by 43%. Avoid using atovaquone / proguanil with efavirenz whenever possible.

Artemether / benzanol: Efavirenz (600mg, once daily) and artemether 20mg / benzanol 120mg tablets (taken 6 times in 3 days, 4 tablets each) lead to artemether, dihydrogen Artemisinin (the active metabolite of artemether) and benzophenone exposure (AUC) were reduced by approximately 51%, 46%, and 21%, respectively. There was no significant effect of efavirenz exposure. Because the reduced concentration of artemether, dihydroartemisinin, or phenacetin may lead to reduced antimalarial efficacy, caution should be exercised when combining this product with artemether / benzyl alcohol tablets.

Lipid-lowering drugs

In uninfected volunteers, efavirenz combined with HMG-CoA reductase inhibitors, such as atorvastatin, pravastatin, or simvastatin, showed reduced plasma concentrations of statins. Cholesterol levels must be monitored regularly and doses of statins adjusted.

Atorvastatin: uninfected volunteers combined efavirenz (600 mg, orally once daily) with atorvastatin (10 mg, once daily orally), compared with atorvastatin alone, atorvastatin The steady-state AUC and Cmax of statins were reduced by 43% and 12%, 2-hydroxyatorvastatin was reduced by 35% and 13%, and 4-hydroxyatorvastatin was reduced by 4% and 47%, respectively. HMG-CoA reductase inhibitors were reduced by 34% and 20%, respectively.

Pravastatin: Uninfected volunteers take efavirenz (600 mg, orally once a day) and pravastatin (40 mg, orally once a day), and the homeostasis of pravastatin compared to pravastatin alone AUC and Cmax were reduced by 40% and 18%, respectively.

Simvastatin: Efavirenz (600 mg, orally once daily) and simvastatin (40 mg, orally once daily) in uninfected volunteers. Homeostasis of simvastatin compared to simvastatin alone AUC and Cmax decreased by 69% and 76%, simvastatin acid decreased by 58% and 51%, total active HMG-CoA reductase inhibitors decreased by 60% and 62%, and total HMG-CoA reductase inhibition The agent was reduced by 60% and 70%, respectively.

The combination of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect the AUC and Cmax values of efavirenz, and no need to adjust the dose of efavirenz.

Anticoagulant

Warfarin / acetocoumarol: efavirenz may increase or decrease its plasma concentration and effect.

Anticonvulsants:

Carbamazepine: The interaction between efavirenz (600 mg, orally once a day) and carbamazepine (400 mg, once a day) in uninfected volunteers is bidirectional. The steady-state AUC, Cmax, and Cmin of carbamazepine decreased by 27%, 20%, and 35%, respectively, while the steady-state AUC, Cmax, and Cmin of efavirenz decreased by 36%, 21%, and 47%, respectively. Steady-state AUC, Cmax, and Cmin of active carbamazepine epoxidized metabolites were not changed. Carbamazepine's plasma levels must be monitored regularly. There is no data on the higher doses of these two drugs, so there is no recommended dosage, and other anticonvulsant drugs can be considered for treatment.

Other anticonvulsants: There is no data to suggest potential drug interactions with efavirenz combined with phenytoin, phenobarbital, or other anticonvulsants (substrates of CYP450 isoenzymes). When efavirenz is used in combination with these drugs, the plasma concentration of a single drug decreases or increases, and therefore plasma levels must be monitored regularly. No studies of efavirenz combined with aminohexenoic acid and gabapentin have been conducted. No clinically significant drug interactions are expected because aminohexene acid and gabapentin are eliminated in their original form only by urine, and are consistent with the pathway of efavirenz's enzyme metabolism and elimination.

Interaction with other drugs

Antacids / Famotidine: Either taking aluminum hydroxide / magnesium or famotidine does not alter the absorption of efavirenz in uninfected volunteers. These data suggest that changes in gastric acid pH caused by other drugs do not affect the absorption of efavirenz.

Hormonal contraceptives

Oral: When oral contraceptives (ethinylestradiol 0.035mg / norgestimate 0.25mg once daily) are combined with efavirenz (600mg once daily) for 14 days, efavirenz has no effect on the concentration of ethinylestradiol, but methyl The plasma concentrations of progesterone and levonorgestrel, and the effective metabolites of norgestimate were significantly reduced in the presence of efavirenz (methyl progesterone AUC, Cmax, and Cmin were reduced by 64%, 46%, and 82%, respectively. Leucorgestrel AUC, Cmax, and Cmin were reduced by 83%, 80%, and 86%, respectively). The clinical significance of these effects is unknown. No effect of ethinyl estradiol / norgestimate on the plasma concentration of efavirenz was observed.

Injectables: Limited information is available on the combination of efavirenz and hormonal contraceptives for injection. In a study of a 3-month drug interaction between nor-progesterone acetate (DMPA) and efavirenz, plasma progesterone levels were maintained below 5 ng / ml in all patients, consistent with ovulation inhibition.

Implants: The interaction of etonogestrel and efavirenz has not been studied. It is foreseeable that exposure to etonogestrel is reduced (CYP3A4 induction), and occasional reports after marketing: Patients taking efavirenz fail contraceptives when combined with etonogestrel.

Immunosuppressants: When immunosuppressants metabolized by CYP3A4 (such as cyclosporine A, tacrolimus, or sirolimus) are taken at the same time as efavirenz, immunosuppressant exposure may occur due to a decrease in CYP3A4 cut back. Adjustment of the immunosuppressant dose may be required. When starting or stopping efavirenz, it is recommended that the concentration of immunosuppressive agents be closely monitored for at least two weeks (until a stable concentration is reached).

Methadone: A study in HIV-infected intravenous drug users found that simultaneous use of efavirenz and methadone reduced plasma drug concentrations of methadone and produced opioid withdrawal symptoms. Methadone doses need to be increased by an average of 22% to reduce withdrawal symptoms. The patient's withdrawal symptoms should be monitored, and methadone doses can be increased to reduce withdrawal symptoms if necessary.

Antidepressants: There is no clinically significant effect on pharmacokinetic parameters when paroxetine and efavirenz are taken in combination, so no dose adjustment is required when the two drugs are combined Sertraline did not significantly affect the pharmacokinetics of efavirenz, but efavirenz reduced sertraline Cmax, C24, and AUC by 28.6-46.3%, respectively. When taking sertraline and efavirenz in combination, the dose of sertraline should be increased to compensate for the metabolic abnormalities of sertraline induced by efavirenz. Sertraline dose adjustment should be carried out under the guidance of clinical efficacy. When bupropion (single dose of 150 mg, sustained release) was combined with efavirenz (600 mg, once daily), AUC and Cmax were reduced by 55% and 34%, respectively. AUC of hydroxybupropion was not changed by CYP2B6 induction, and Cmax increased by 50%. The increase in bupropion dose should be based on clinical efficacy, but should not exceed the maximum recommended dose. There is no need to adjust the dose of efavirenz.

Cetirizine: The effect of cetirizine on the pharmacokinetic parameters of efavirenz has no significant clinical significance. Efavirenz reduced cetirizine Cmax by 24% but did not change the AUC of cetirizine. These changes have no obvious clinical significance. Because of this, the combined dose of cetirizine and efavirenz does not need to be adjusted.

Lorazepam: Efavirenz can increase Cmax 16.3% and AUC 7.3%, respectively. The effect of efavirenz on the pharmacokinetics of chlorhexidine has no obvious clinical significance. Therefore, there is no need to adjust the respective doses when the two drugs are used in combination.

Calcium channel blockers: Efavirenz (600 mg, orally once daily) and diltiazem (240 mg, once daily) were used in uninfected volunteers, and the steady-state AUC of diltiazem was compared to that of diltiazem, Cmax and Cmin decreased by 69%, 60%, and 63%, respectively; deacetyl aldithiol decreased by 75%, 64%, and 62%; and N-monodemethyldiltiazem decreased by 37%, 28%, and 37%. The dose of diltiazem should be adjusted according to the clinical response (refer to the instructions for diltiazem).

Although the pharmacokinetic parameters of efavirenz have slightly increased (11% to 16%), these changes have no clinical significance, so it is not necessary to adjust the dose of this product when combined with diltiazem.

Efavirenz and other CYP3A4 enzyme substrate calcium channel blockers (such as verapamil, felodipine, nifedipine, nicardipine) may interact, there is no corresponding data available . When efavirenz is combined with one of these drugs, the plasma concentration of calcium channel blockers 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. During some screening tests, false positives of the urine cannabinoid test were reported in uninfected and HIV-infected volunteers taking this product. A more accurate method (such as gas chromatography / mass spectrometry) is recommended to confirm the positive screening results of cannabinoids.

[Drug overdose]

Increased neurological symptoms have been reported in patients who occasionally take 600 mg of this product twice daily. One patient experienced involuntary muscle contractions.

Treatment of overdose with this product requires general supportive measures, including monitoring vital signs and observing the patient's clinical condition. Activated carbon may be administered to help remove unabsorbed drugs. There is no specific antidote for overdose of this product. Because efavirenz is highly bound to proteins, dialysis is unlikely to effectively clear the drug from the blood.

Efavirenz pharmacological effects

Mechanism of action

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), which acts on templates, primers or nucleoside triphosphates, and has a small number of competitive inhibitory effects. Efavirenz far exceeds the clinical therapeutic dose and has no inhibitory effect on HIV-2RT and human cell DNA polymerases , , , and d.

Animal Toxicology

a. chronic toxicity

The rhesus monkey has been taking efavirenz for 2 years. The average dose of AUC in plasma is 2 or 9 times that of the 600 mg / day AUC taken by patients. Mild to moderate hepatic bile duct hyperplasia was observed. In addition to moderate bile duct hyperplasia, a macaque monkey has mild cholestasis. After stopping the medication, bile duct hyperplasia is reversible. At the end of the 2-year treatment period, 9/10 of the rhesus monkeys receiving the maximum dose of efavirenz had mild to moderate bile duct hyperplasia. During the recovery period following the 26-week discontinuation of treatment, 3/5 of bile duct hyperplasia disappeared in monkeys previously treated with the highest dose of efavirenz. The remaining 2 macaques had mild bile duct hyperplasia.

Rhesus monkeys have been taking efavirenz for 2 years at a dose that causes the average AUC in plasma to be 2 or 9 times greater than the 600 mg / day AUC taken by patients. Slight thyroid follicular cell hypertrophy was observed. This change is due to an increase in thyroxine clearance following secondary liver enzyme induction. This pathological change does not increase the patient's risk of taking efavirenz, as long-term treatment with other known enzyme inducers is not associated with clinical hypothyroidism, goiter, or thyroid tumor.

Non-persistent seizures have been observed in rhesus monkeys taking efavirenz for 1 year or more. The doses given gave efavirenz's plasma concentration 4 to 13 times greater than 600 mg / day in humans. However, the central nervous system of these macaques found no microscopic changes associated with efavirenz.

b. Carcinogenicity

Carcinogenicity studies have shown an increase in the incidence of liver and lung tumors in female mice, but not in male mice. There was no increase in the incidence of any tumors in male mice, male or female rats taking efavirenz. Liver tumors may be due to the enzyme-induced effects of efavirenz; however, the reasons for the increased incidence of lung tumors and their corresponding effects in humans are unclear.

c. Mutagenicity

In vitro and in vivo genotoxicity analysis studies show that efavirenz is not mutagenic and genotoxic. Studies include bacterial mutation analysis in S. typhimurium and E. coli, and mammalian mutation analysis in Chinese hamster ovary cells , Analysis of chromosomal aberrations in human peripheral blood lymphocytes or Chinese hamster ovary cells, and micronucleus analysis of bone marrow in mice.

d. reproduction

Efavirenz does not reduce mating or fertility in female or male mice, and does not affect sperm and offspring of treated male mice. Efavirenz does not affect reproductive function in female rats. Due to the rapid clearance of efavirenz in rats, the systemic drug exposure of rats in these studies was equal to or lower than that of efavirenz given in humans.

e. Development Studies

An ongoing follow-up toxicity study found that rhesus monkeys treated with efavirenz had malformations in 3 of 20 fetuses / newborns. The dosage of efavirenz in pregnant macaques is 60 mg / kg per day, and the blood concentration of this dose is similar to the value of 600 mg / day in humans. In one fetus, anencephaly and unilateral malformations with secondary hypertrophy of the tongue, small eye deformities in the other fetus, and cleft palate in the third case (see [ Notes ])

Fetal malformations were not found in efavirenz-treated rats; however, increased fetal reabsorption was observed in the daily dose group of 200 mg / kg, and the peak plasma concentrations and AUC of pregnant rats at this dose were 600 mg / Day values are similar. Pregnant women taking efavirenz 75mg / kg daily did not find teratogenicity and embryo toxicity. The peak plasma concentration produced by this dose was similar to the value of 600mg / day in humans, and the AUC was approximately equivalent to 600mg / day in humans. half.

Efavirenz has been shown to pass the placental barrier in rats, rabbits and macaques. In these animals, the concentration of efavirenz in the fetal blood is similar to that in the mother.

Efavirenz pharmacokinetics

Absorption

Uninfected HIV volunteers received a single dose (100 mg to 1600 mg) of efavirenz at a peak plasma level (1.6 to 9.1 mM) 5 hours after oral administration. At doses up to 1600 mg, a dose-related increase in Cmax and AUC was observed; the increase in Cmax and AUC was not proportional to the dose, which supports that at higher doses, the absorption decreases with increasing dose. Multiple administrations did not change the time (3 to 5 hours) required to reach the peak drug concentration, and the plasma steady-state concentration was reached at 6 to 7 days.

The average Cmax, average Cmin, and average AUC of the HIV-infected patients at the steady-state plasma concentrations were linearly related to the daily oral doses of 200 mg, 400 mg, and 600 mg. Thirty-five patients who received 600 mg of this product once a day had a steady state C max of 12.9 mM, a steady state C min of 5.6 mM, and an AUC of 184 mM · h.

Effects of food on oral absorption

Among uninfected HIV volunteers, the bioavailability of 600 mg of this product in a single dose after high-fat or normal meals increased by 22% and 17%, respectively, when taken on an empty stomach. This product can be taken on an empty stomach or with food.

2. Distribution

Efavirenz is highly bound to human plasma proteins, mainly albumin (the binding rate is approximately 99.5-99.75%). People with HIV-1 infection (n = 9) take 200mg 600mg daily for at least 1 month. The drug concentration of cerebrospinal fluid is 0.26 1.19% (average 0.69%) corresponding to plasma concentration. This ratio is approximately three times higher than non-protein-bound (free) efavirenz in plasma.

3. Metabolism

Human studies and in vitro studies using human liver microsomes have shown that efavirenz is primarily metabolized by the cytochrome P450 system into hydroxyl-containing metabolites and their further glycosylated metabolites. These metabolites are essentially inactive against HIV-1. In vitro studies have confirmed that CYP3A4 and CYP2B6 are the major isoenzymes in efavirenz metabolism. At the same time, in vitro studies have shown that efavirenz inhibits the isozymes of P450 2C9, 2C19 and 3A4, and the Ki value is within the range of efavirenz's plasma concentration range of 8.5-17 mM. In vitro studies, efavirenz does not inhibit CYP2E1, and inhibits CYP2D6 and CYP1A2 only when the therapeutic dose is significantly exceeded (Ki value is 82-160 mM).

Efavirenz plasma exposure may increase in patients with a genetic variant of the homozygous G516T CYP2B6 isozyme.

P450 200400mg 10 2242%4055 (5276 )400mg 600mg 200mg AUC 400mg600mg CYP3A4

5276 4055 1434%1%

Child-Pugh A Child-Pugh B C

Child patient

3 13kg57(46%) 49600mg C max 14.2mMC min5.6mMAUC218mM·h 17 600mg C max11.8mMC min5.2mM AUC188mM ·h

Roche RT-PCRHIV-1 (AmplicorTM)HIV-RNA<400 /mL400 /mL400 /mLHIV-RNART-PCR 50 /mL

(NC=F)HIV-RNA >400 /mLHIV-RNA>400 /mL

006 (NRTI) + + + + +

006 (IDV)(ZDV)+(3TC)++(NNRTI)HIV-HIV-RNA 600mg+8 1000mg600mg+12 300mg+12 150mg8 800mg+12 300mg+12 150mg48 614 36.3 186458%86%CD4 342 /mmHIVRNA 4.76log ₁₀/mLHIV-RNA <400 /mL NC=F 11

020 NRTI +2 NRTIs /

020NRTINNRTI ++2 +2 NRTIs 24 600mg+8 1000mg+2 NRTIs 8800mg+2 NRTIs327 38.5 206952%83%69%NRTI CD4 328 /mmHIV-RNA 4.41log ₁₀/mL24 HIV-RNA <400 /mL NC=F 2

ACTG364 NRTI

ACTG364 NRTI 48 196 HIV 41 187674%88%NRTIs 600mg NFV750mg )STOCRIN600mg +NRTI NRTI 3

00332 75%NRTI10200mg22 2 200mgHIV-RNA 5.02Log ₁₀/mL98%1.67Log ₁₀/mL 5.21Log ₁₀/mL 1.52Log ₁₀/mL97%CD4 98+57.5 /mm59 (63%NRTI19%(200mg 600mg 800mg 1000mg 8 1000mg 8 +NC=F HIV-RNA<400 /mL 72 67.2%NRTI NRTI

Study 005: Study 005 is a double-blind, placebo-controlled, dose-ranging study to evaluate 137 HIV-1 infected patients who have not previously received antiretroviral therapy. The safety and effectiveness of combination of fududine and lamivudine. The average baseline for CD4 cell count was 367 cells / mm, and the average baseline for Log ₁₀ HIV-RNA plasma levels was 4.72 copies / mL. Patients were randomly given 200 mg, 400 mg or 600 mg of placebo or placebo, and given zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily) in combination. At 16 weeks, the observed response rate (percent <400 copies of HIV-RNA / mL) in the treatment group of this product was significantly higher than that of the placebo group (Zidovudine + Lamivudine). The response rate of the group was 88.9 to 93.5%, while that of the control group was 44.4%. The NC = F analysis of response rate was significantly higher than that of placebo. The response rate of the treatment group of this product ranged from 72.7 to 80.6%, while the control group was 36.4%. CD4 counts increased significantly in all treatment groups; no statistically significant differences were observed in the four treatment groups.

In an extended trial of ongoing study 005, all 11 patients who were originally randomized to 600 mg of this product were below detection levels at 16 weeks and plasma HIV-RNA levels remained below 400 copies / mL at 36 weeks.

ACTG382: ACTG382 is an ongoing open 48-week trial that validates the pharmacokinetics and antiviral activity of this product in combination with nelfinavir (20-30 mg / kg TID) and NRTIs in 57 children who have used NRTI And security. The mean age of patients was 8 years (range 3-16 years), and their mean baseline for HIV-RNA plasma levels was Log ₁₀ 4.09 (± 0.69) copies / mL. The initial dose of this product is 600 mg per day, which can be adjusted according to individual size to achieve AUC levels ranging from 190 to 380 mM · h. In patients who completed 48 weeks of treatment, the plasma HIV-RNA <400 copies was used as an index, and the response rate of plasma HIV-RNA <400 copies / mL was 60% (34/57). The average CD4 cell count increased by 63 cells / mm from baseline (see [Children's Medication]).