ISENTRESS 400 mg film-coated tablets

Each film-coated tablet contains 400 mg of raltegravir (as potassium).

Excipient: Each tablet contains 26.06 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Pink, oval tablet, marked with "227" on one side.

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients (see sections 4.4 and 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1). The use of raltegravir in previously ART-naïve patients is based on a study in which it was co-administered with two NRTIs (see sections 4.4 and 5.1).

Posology

Adults

The recommended dosage of ISENTRESS is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2). It is not recommended to chew, crush or split the tablets.

Elderly

There is limited information regarding the use of ISENTRESS in the elderly (see section 5.2). Therefore ISENTRESS should be used with caution in this population.

Children and adolescents

Safety and efficacy have not been established in patients below 16 years of age (see sections 5.1 and 5.2).

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral

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

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance (see section 5.1).

In treatment naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be eva luated and treatment instituted when necessary.

Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.5).

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).

ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.

Effect of other agents on the pharmacokinetics of raltegravir

Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.

Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.

In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.

Table 1

Pharmacokinetic Interaction Data

Pregnancy

There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Lactation

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.

No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).

The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve patients; described below.

In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo.

In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 480 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 463 patient-years in the group receiving efavirenz 600 mg at bedtime.

In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9% in patients receiving ISENTRESS + OBT and 4.6% in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6% in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7% in patients receiving efavirenz + emtricitabine (+) tenofovir.

Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (^†). Adverse reactions identified from post-marketing experience are included in italics. Frequencies are defined as common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), and not known (cannot be estimated from the available data).

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