绥美凯的中文说明书

Chinese manual

Generic name: Doptabalamid tablets

Product name: Suimeikai

All names: Trimeq, Docetabalamid, TRIUMEQ, Inbec

Indications:

It is suitable for the treatment of adults and adolescents over 12 years old (with a weight of at least 40kg) infected with human immunodeficiency virus (HIV).

Usage and dosage:

dose

Adults and teenagers (weighing at least 40kg)

For adults and adolescents, the recommended dose of Trimax is one tablet, once daily.

Adults or adolescents whose body weight is less than 40 kg should not be given Trimax because Trimax is a fixed-dose tablet and the dose cannot be reduced.

Trimax is a fixed-dose tablet and should not be used in patients who require dose adjustments. If one of the active ingredients needs to be discontinued or a dose adjustment is required, separate formulations of dolutegravir, abacavir, or lamivudine may be used. In these cases, physicians should refer to the respective product information for these medicines.

  Miss a dose

If the patient misses a dose of Suimei Kai and there are more than 4 hours before the next dose, Sui Meikai should be taken as soon as possible. If the next dose is less than 4 hours away, patients should not take the missed dose and simply resume their usual dosing schedule.

elderly patients

There are limited data on the use of dolutegravir, abacavir, and lamivudine in patients aged ≥65 years, and there is no evidence that older patients require different doses than younger adults. Taking into account age-related changes, such as decreased renal function and changes in hematological parameters, special caution is recommended when administering the drug in this age group.

kidney damage

Patients whose creatinine clearance rate is less than 50mL/min are not recommended to take Suimeikai.

liver damage

Abacavir is primarily metabolized by the liver. There are no clinical data in patients with moderate or severe hepatic impairment, therefore, use of Trimax is not recommended unless deemed necessary. For patients with mild hepatic impairment, close monitoring is required, including monitoring of abacavir plasma levels if feasible

Adverse reactions:

Clinical data on Trimax are limited, and the most commonly reported adverse reactions that are possibly or probably related to dolutegravir and abacalongvir/lamivudine are nausea (12%), insomnia (7%), dizziness (6%), and headache (6%).

Adverse reactions (nausea, vomiting, diarrhea, pyrexia, drowsiness, rash) occur frequently in patients with abacavir hypersensitivity reactions. Therefore, patients who develop these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. Very rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been reported and abacavir hypersensitivity cannot be excluded. In such cases, abacavir-containing medicinal products should be discontinued.

In individual patients, the most serious adverse events that may be associated with dolutegravir and abacavir/lamivudine are hypersensitivity reactions, including rash and severe hepatic effects.

An analysis of pooled data from Phase IIb to IIIb clinical trials found that the adverse reactions observed with the combination of dolutegravir + abacavir/lamivudine were generally consistent with the adverse reaction profiles of the single ingredients dolutegravir, abacavir, and lamivudine.

There was no difference in the severity of adverse reactions observed between the combination and the single ingredients.

Taboo:

Contraindicated in patients with known hypersensitivity to dolutegravir, abacavir, and lamivudine or any excipients.

Concomitant use with dofetilide and pisicanide is prohibited.

Things to note:

Spread HIV

Although viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, residual risks cannot be excluded. Precautions should be taken to prevent transmission in accordance with national guidance.

hypersensitivity reaction

Both abacavir and dolutegravir carry the risk of triggering a hypersensitivity reaction (HSR) and share some common characteristics, such as fever and/or rash and other symptoms indicating involvement of multiple organs. It is clinically impossible to determine whether abacavir or dolutegravir is responsible for a hypersensitivity reaction that occurs with Trimeq. Hypersensitivity reactions have been observed to occur more commonly with abacavir, some of which can be life-threatening and, in rare cases, fatal if not managed appropriately. Patients who test positive for the HLA-B*5701 allele are at higher risk of developing abacavir hypersensitivity reactions. However, abacavir hypersensitivity reactions are reported less frequently in patients who do not carry this allele.

Therefore, the following measures should be followed:

Before starting treatment, HLA-B*5701 status must be confirmed.

Patients with a positive HLA-B5701 status, or patients with a negative HLA-B5701 status who had a suspected abacavir hypersensitivity reaction when previously receiving an abacavir-containing treatment regimen, should not be treated with Trimax.

If a hypersensitivity reaction is suspected, Trimax should be discontinued without delay, even if the HLA-B*5701 allele is not present. If a hypersensitivity reaction occurs and treatment with Trimax is not discontinued immediately, a life-threatening reaction may result. Clinical status, including hepatic aminotransferases and bilirubin, should be monitored.

After discontinuing Trimax due to suspected hypersensitivity reaction, Trimax or any other medicine containing abacavir or dolutegravir should never be restarted.

After a suspected hypersensitivity reaction to abacavir, symptoms may return within hours if abacavir-containing medicines are restarted. Relapses are generally more severe than the initial episode and may include life-threatening hypotension and death.

To avoid re-dosing abacavir and dolutegravir, patients with suspected hypersensitivity reactions should be instructed to discard remaining Trimax tablets.

Clinical description of hypersensitivity reactions

In clinical studies, <1% of patients treated with dolutegravir reported hypersensitivity reactions, manifesting as rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatic reactions.

Hypersensitivity reactions to abacavir have been well characterized during clinical studies and post-marketing surveillance. Symptoms generally occur within the first six weeks after starting abacavir treatment (median time to onset is 11 days), but these reactions may occur at any time during treatment.

Nearly all hypersensitivity reactions to abacavir include fever and/or rash. Other signs and symptoms observed as part of abacavir hypersensitivity reactions include respiratory and gastrointestinal symptoms. Importantly, these symptoms may lead to misdiagnosis of a hypersensitivity reaction as a respiratory illness (pneumonia, bronchitis, pharyngitis) or gastroenteritis. Continuing treatment can worsen symptoms associated with hypersensitivity reactions and may be life-threatening. These symptoms generally resolve after discontinuation of abacavir.

Rarely, life-threatening reactions may occur within hours of restarting abacavir in patients who have discontinued abacavir for reasons other than symptoms of a hypersensitivity reaction. In such patients, abacavir therapy must be restarted in an environment where immediate medical attention is available.

Body weight and metabolic parameters (lipids and blood glucose)

During antiretroviral therapy, weight gain and elevated blood lipid and blood glucose levels may occur. These changes may be related in part to disease control and lifestyle. In some cases, there is evidence of treatment effects on lipids, but there is no clear evidence that weight gain is associated with any particular treatment. Monitoring of lipids and blood glucose should refer to established HIV treatment guidelines. Dyslipidemia should be treated appropriately based on the clinical situation.

Liver disease

The safety and effectiveness of Trimax have not been established in patients with pre-existing severe liver disease. Suimeikan is not recommended for patients with moderate to severe liver damage.

Patients with pre-existing hepatic dysfunction, including those with chronic active hepatitis, develop hepatic dysfunction with increased frequency during combined antiretroviral therapy and should be monitored according to standard protocols. If in these patients there is evidence of worsening liver disease, withholding or discontinuing treatment should be considered.

Patients with chronic hepatitis B or hepatitis C

Patients with chronic hepatitis B or hepatitis C who receive combination antiretroviral therapy are at increased risk for serious and potentially fatal hepatic adverse effects. If you are also taking antiviral treatment for hepatitis B or hepatitis C, please refer to the relevant product information for these medicines.

Suimeikai contains lamivudine, which is effective against hepatitis B. Abacavir and dolutegravir lack such effects. It is generally believed that lamivudine monotherapy is not an adequate treatment for hepatitis B because of the high risk of developing hepatitis B virus resistance. Therefore, if Trimax is used to treat patients co-infected with hepatitis B, another antiviral drug is generally required. Treatment guidelines should be consulted.

If Trimax is discontinued in patients co-infected with hepatitis B virus, regular monitoring of liver function and HBV replication markers is recommended, as discontinuation of lamivudine may lead to an acute exacerbation of hepatitis.

immune reconstitution inflammatory syndrome

In severely immunodeficient HIV-infected patients when initiating combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to severe clinical illness or symptom exacerbation. Such reactions are usually observed in the weeks or months before starting CART therapy. Relevant examples include cytomegalovirus retinitis, systemic and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Symptoms of inflammation should be evaluated and treated if necessary. Autoimmune disorders (e.g., Graves' disease) have also been reported during immune reconstitution; however, the reported timing of onset is inconsistent and these events may occur many months after initiation of therapy.

In patients with co-infection with hepatitis B or hepatitis C virus, elevated liver chemistries consistent with immune reconstitution inflammatory syndrome have been observed upon initiation of dolutegravir therapy. In patients with hepatitis B and/or hepatitis C virus infection, monitoring of liver chemistry test values ​​is recommended.

Mitochondrial dysfunction following in utero exposure

Nucleosides and nucleoside analogs may affect mitochondrial function to varying degrees, with the effects being most significant when combined with stavudine, didanosine, and zidovudine. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally, primarily in association with zidovudine-containing treatment regimens. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactemia, hyperlipidemia). These reactions are often temporary or permanent. Some late-onset neurological disorders (hypertonia, convulsions, behavioral abnormalities) are rarely reported. It is unclear whether the neurological condition is temporary. These results should be considered in children exposed to nucleosides and nucleoside analogues in utero who have severe clinical symptoms of unknown etiology, especially neurological symptoms. These results do not affect current national guidelines for the use of antiretrovirals in pregnant women to prevent vertical transmission of HIV.

myocardial infarction

Observational studies have demonstrated an association between myocardial infarction and abacavir use. The patients participating in the study were mainly those who had received antiretroviral therapy. Clinical trial data show a limited number of myocardial infarctions and a small increase in risk cannot be ruled out. Overall, there are some inconsistencies between observational cohort data and randomized trial data, so a causal relationship between abacavir treatment and the risk of myocardial infarction cannot be confirmed or denied. To date, there is no precise biological mechanism to explain the possible increased risk. While using Trimax, steps should be taken to minimize all modifiable risk factors (such as smoking, hypertension, and hyperlipidemia).

osteonecrosis

Although the etiology is thought to be multifactorial (including use of corticosteroids, bisphosphonates, alcohol consumption, severe immunosuppression, and high body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical attention if they experience joint pain, joint stiffness, or difficulty moving.

Opportunistic infections

Patients should be informed that HIV infection cannot be cured by Trimax or any other antiretroviral treatment and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under close clinical observation by physicians experienced in treating HIV-related diseases.

Resistant

Because the recommended dose of dolutegravir in patients who are resistant to integrase inhibitors is 50 mg twice daily, Trimeq is not recommended for use in patients who are resistant to integrase inhibitors.

Drug interactions:

When administered concomitantly with etravirine (without potentiating protease inhibitors), efavirenz, nevirapine, rifampicin, tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital, and St. John's wort, the recommended dose of dolutegravir is 50 mg twice daily, so TRIUMEQ is not recommended in patients taking these medications.

TRIUMEQ should not be administered concurrently with antacids containing polyvalent cations. It is recommended to take TRIUMEQ 2 hours before or 6 hours after these medications.

It is recommended to take TRIUMEQ 2 hours before or 6 hours after dosing calcium or iron supplements.

Dolutegravir may increase metformin concentrations. If dolutegravir is administered concurrently with metformin, the metformin dose may require adjustment when therapy is initiated and discontinued to maintain glycemic control (see Drug Interactions). Metformin is eliminated by the kidneys, so renal function must be monitored when coadministered with dolutegravir. Concurrent administration may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45-59 mL/min), and a conservative approach is recommended. Metformin dose reduction is strongly recommended.

Coadministration of lamivudine with cladribine is not recommended.

TRIUMEQ should not be taken with other medicines containing dolutegravir, abacavir, lamivudine, or emtricitabine.

Effects on ability to drive and operate machinery

Patients should be informed that dizziness has been reported during treatment with dolutegravir. The patient's clinical status and TRIUMEQ's adverse effect profile should be kept in mind when considering a patient's ability to drive or operate machinery.

Mechanism of action:

Dolutegravir: Can inhibit HIV integrase by binding to the active site of integrase and blocking the strand transfer step of reverse transcription deoxyribonucleic acid (DNA) integration (a key step in the HIV replication cycle).

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analog. Abacavir is converted into the active metabolite carbavir triphosphate (CBV-TP) under the action of intracellular enzymes, which is a deoxyguanosine-5'-triphosphate (dGTP) analog. CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate dGTP and inserting into viral DNA.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Lamivudine is phosphorylated in cells to generate the active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The main mode of action of 3T-CTP is to terminate DNA chain synthesis by inserting nucleotide analogs, thereby inhibiting RT activity.

Efficacy and safety:

The effectiveness of Trimax in treating treatment-naïve HIV-infected subjects was based on an analysis of data from two randomized, international, double-blind, active-controlled trials, SINGLE (ING114467) and SPRING-2 (ING13086), and an international, open-label, active-controlled trial, FLAMINGO (ING114915).

In SINGLE, 833 patients received dolutegravir 50 mg once daily plus fixed-dose abacavir-lamivudine (DTG-ABC/3TC) or fixed-dose efavirenz-tenofodoxine-emtricitabine (EFV/TDF/FTC). At baseline, the median age of patients was 35 years, 16% were female, 32% were nonwhite, 7% were co-infected with hepatitis C virus, and 4% were CDCC category. These characteristics were similar between the two treatment groups.

In the 48-week primary analysis, the proportion of patients achieving virological suppression was better in the dolutegravir XxXABC/3TC group than in the FTC/TDF/ETC group, p=0.003. The same treatment difference was observed among subjects defined by baseline HIV RNA levels (or 100,000 copies/ml). Median time to virological suppression was shorter in the ABC/3TCXxXDTG group (28 days vs. 84 days, p<0.0001). Relative to baseline, the adjusted mean changes in CD4 cell counts were 267 cells vs. 208 cells/mm (p<0.001). Analyzes of time to attainment of virological suppression and change from baseline were prespecified and adjusted for multiplicity. At week 96, responses were 80% and -72%, respectively. The end point difference is still statistically significant (p=0.006). The statistically higher response in the DTGXxXABC/3TC group was primarily due to a higher proportion of withdrawals due to adverse events in the FTC/TDF/FTC group, independent of viral load stratification. Overall treatment differences at week 96 applied to patients with higher and lower baseline viral loads. Patients could maintain virological suppression during the 1440 weeks of the SINGLE open period, and the DTGXxXABC/3TC group (71%) was better than the EFV/TDF/FTC group (63%), with a treatment difference of 8.3% (2.0, 14.6).

In SPRING-2, 822 patients received dolutegravir 50 mg once daily or raltegravir 400 mg twice daily (blinded), both administered in an open-label manner in combination with fixed-dose ABC/3TC (approximately 40%) or TDF/FTC (approximately 60%). Dolutegravir was noninferior to raltegravir, including in the subset of patients treated with a nibicavir/lamivudine-based regimen.

In FLANINGO, 485 patients received dolutegravir 50 mg once daily or darunavir/ritonavir (DRX/rD 800 mg/100 mg once daily) in combination with ABC/3TC (approximately 33%) or TDF/FTC (approximately 67%). All treatments were administered in an open-label manner.

Virologic suppression was better in the dolutegravir group (80%) than in the DRY/r group (68%) at Week 96. Adjusted treatment difference [DTG-(DRVXxXRTV)]: 12.4%; 95% CI: [4.7, 20.2])2 Response rates at Week 96 were 82% (DTGXxXABC/3TC) and 75% (DRV/rXxXABC/3TC).

Emerging drug resistance in patients who failed treatment in the SINGLE, SPRING-2 and PLAMINGO studies

No emerging resistance to integrases or NRTIs was detected in patients treated with dolutegravir, abacavir/lamidoglutide, or lamivudine in any of the three studies.

Regarding the control drugs, typical resistance was detected in the TDF/FTC/EFV group (SINGLE; 6 cases with NNRTI-related resistance and one case with severe NRTI resistance) and 2NRTIXxX raltegravir (SPRING-2; 4 cases with severe NRTI resistance and one case with raltegravir resistance), while no de novo resistance was detected in patients treated with 2NRTIXxXDRV/RTV (FLAMINGO).

Children’s population:

In a phase I/II 48-week multicenter, open-label study (P1093/ING112578), the pharmacokinetic parameters and tolerability of dolutegravir were evaluated in HIV-I-infected infants, children, and adolescents receiving the combination dosing regimen.

At week 24, 16 of 23 adolescents (aged 12 to 17 years) who received once-daily dolutegravir (35mgn=4; 50mgn=19) plus OBR achieved viral loads <50 copies/mL.

Twenty of 23 children and adolescents (87%>) had a decrease in HIV-1 RNA from baseline of greater than 1 log10 copies/mL or HIV-1 RNA <400 copies/mL at week 24. Four subjects had virological failure, but none were INI resistant at the time of virological failure.

Storage:

Seal and store below 30℃.

Tablets should be stored in their original packaging to avoid moisture absorption. Seal the vial tightly and do not remove the desiccant.