Isentress® and Isentress® HD
Raltegravir 400 mg
Raltegravir 600 mg
Raltegravir 100 mg
Raltegravir 25 mg
Fabricant : Merck
Isentress® : 1 tablet at 400 mg BID with or without food
Isentress® HD : 2 tablets at 600 mg DIE (and ≥ 40 kg)
Isentress® 400 mg tablets are not interchangeable with Isentress® HD 600 mg tablets.
Isentress® : Chewable tablets (weight-dependent dose up to a maximum of 300 mg BID)
Weight (kg) | Dosage |
7 to < 10 | 50 mg BID – (½ x 100 mg or 2 x 25 mg) |
10 to < 14 | 75 mg BID – (3 x 25 mg) |
14 to < 20 | 100 mg BID – (1 x 100 mg) |
20 to < 28 | 150 mg BID – (1 ½ x 100 or 1 x 100 + 2 x 25 mg) |
28 to < 40 | 200 mg BID – (2 x 100 mg) |
≥ 40 | 300 mg BID – (3 x 100 mg) |
The 100 mg chewable tablet can be divided into two equal parts. The dose with chewable tablets should not exceed 300 mg BID |
Isentress® HD : Safety and efficacy have not been established in pediatric population (< 40 kg).
No dose adjustment is necessary in patients with renal impairment and in patients on hemodialysis.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Administration not studied in this population
Isentress® has been studied in treatment-naive patients as well as in patients undergoing treatment with virological suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load
|
STARTMRK | RAL 400 mg BID + FTC + TDF (N=281) vs EFV 600 mg DIE + FTC + TDF (N=282) |
96 weeks Noninferiority of RAL + FTC + TDF (81.1% vs 78.7%, 95% CI -4.3 to 9.0%) |
STARTMRK | RAL 400 mg BID + FTC + TDF (N=279) vs EFV 600 mg DIE + FTC + TDF (N=279) |
240 weeks Noninferiority of RAL + FTC + TDF (71.0% vs 61.3%, 95% CI 1.7 to 17.3%), |
ONCEMRK | RAL 1200 mg DIE + FTC + TDF (N=531) vs RAL 400 mg BID + FTC + TDF (N=266) |
48 weeks Noninferiority of RAL 1200 mg DIE (89.8% vs 90.2%, 95% CI -4.9 to 4.0%) |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) with intention of treatment |
Types of patients |
BENCHMRK1-2 |
RAL + TFO (N=460) vs Placebo + TFO (N=237) |
Week 96 |
HIV+ patients (more than 16 years old) who had documented resistance to at least one drug from each of the three classes of antiretrovirals (NRTI, NNRTI and PI) |
*OBT : Optimized background treatment
A reduction in the replicative capacity of the virus and in sensitivity to raltegravir is observed in recombinant viruses carrying a single primary mutation (Q148H, K or R, or N155H).
In the studies, the mutations observed at the integrase level which contributed to resistance to raltegravir (either in vitro or in vivo) generally included a substitution for Y143 (modification in C, H or R), for Q148 (modification in H, K or R) or for N155 (modification in H) and at least one other mutation (eg L74I/M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R and D232N).
In general, mutations that confer resistance to raltegravir also confer resistance to elvitegravir, an integrase strand transfer inhibitor. Viruses carrying an amino acid 148 mutation in addition to one or more other mutations conferring resistance to raltegravir may also exhibit clinically relevant resistance to dolutegravir.
STARTMRK (never treated patients)
In week 96 of the STARTMRK study, four out of 6 subjects who had virologic failure had genotypic data. In these subjects, two cases of substitution in Y143H/R and two cases in Q148H/R were identified.
BENCHMRK (previously treated patients)
At 96 weeks and for the combined BENCHMRK1-2 studies, virologic failure occurred in 150 (33%) of 462 patients with raltegravir and in 148 (62%) of 237 placebo recipients. The resistance test results were available for 112 of the raltegravir subjects. Virus isolates from 73 (65%) of these patients had integrase mutations in 1 of 3 residues (Y143C/H/R, Q148H/K/R or N155H), usually in combination with at least 1 other mutation. Most mutations (77%) were observed after 24 weeks of treatment. Other known mutations in resistance to raltegravir (E92E/Q and L74M + E92Q) were found in 2 of 39 patients who did not have a primary mutation in resistance to raltegravir. Available phenotypic data revealed no resistance to raltegravir in the viral isolates of the remaining 37 patients.
Raltegravir was well tolerated in these clinical trials despite a population with advanced HIV.
After 96 weeks of treatment, the adverse event profile and laboratory abnormalities were generally comparable for raltegravir and placebo.
Elevations of creatine kinase were slightly more frequent in the raltegravir group but were not associated with clinical myopathy, myositis or rhabdomyolysis and did not lead to treatment interruption.
BENCHMRK 1-2 Studies
|
||
RAL 400 mg BID + OBT (N=462) |
Placebo + OBT (N=237) |
|
Abdominal pain |
1.2% |
1.5% |
Diarrhea |
1.8% |
4.5% |
Nausea |
2.3% |
4.1% |
Vomiting |
0.8% |
1.9% |
Fatigue |
1.8% |
0.7% |
Pyrexia |
0.5% |
2.79% |
Headache |
2.7% |
4.5% |
OBT : Optimised background treatment
Discontinuation of treatment due to adverse effects: RAL (3.6%) vs Placebo (4.2%)
STARTMRK Study
|
||
RAL 400 mg BID + FTC + TDF (N=281) |
EFV 600 mg DIE + FTC +TDF (N=282) |
|
Headache |
26.0% |
28.4%% |
Fatigue |
9.3% |
13.5% |
Flu |
11.7% |
13.5% |
Rhinopharyngitis |
26.7% |
22.3% |
Respiratory tract infection |
21.4% |
20.2% |
Arthralgia |
8.5% |
11.7% |
Back pain |
12.1% |
9.9% |
Cough |
16.7% |
12.1% |
Pyrexia |
15.7% |
13.8% |
Diarrhea |
25.6% |
27.0% |
Nausea |
16.7% |
14.5% |
Vomiting |
8.2% |
10.6% |
Dizziness |
16.4% |
38.3% |
Abnormal dreams |
8.2% |
13.1% |
Anxiety |
8.9% |
11.0% |
Depression |
10.3% |
11.7% |
Insomnia |
15.7% |
14.9% |
Skin rash |
7.8% |
13.8% |
In STARTMRK (96 wk), dizziness, adverse reaction considered to be related to the drug, was the most common adverse reaction encountered in (34.0%) of subjects taking efavirenz compared to 6.0% for subjects taking raltegravir. Otherwise, the most common drug-related adverse reactions were diarrhea, nausea, fatigue, headache, drowsiness, abnormal dreams, insomnia, and rashes. All have been reported at higher frequencies with efavirenz.
The safety profile of ISENTRESS® at the dose of 1,200 mg (two 600 mg tablets) DIE was established from the data obtained at week 48 and at week 96 of a double-blind, randomized, controlled trial by active comparator study in 797 never-treated HIV-infected patients : 531 patients receiving ISENTRESS® 1,200 mg (two 600 mg tablets) once daily and 266 patients receiving ISENTRESS® 400 mg BID, both treatments in combination with emtricitabine (+) tenofovir disoproxil fumarate. The percentage of patients with clinical and biochemical adverse reactions related to the drug at week 48 was generally comparable in the two treatment groups (24.5% and 1.5% vs 25.6% and 1.5%).
For management of adverse effects associated with antiretrovirals, see section adverse effects management.
Severe skin rashes and hypersensitivity reactions
Severe, fatal or potentially fatal skin reactions, including Stevens-Johnson syndrome or erythroderma bullosa with epidermolysis, have been reported. Hypersensitivity reactions, characterized by a rash, general and systemic symptoms including liver failure, have also been reported.
In the presence of signs or symptoms of a severe skin rash +/- accompanied by fever, general malaise, fatigue, muscle or joint pain, skin vesicles, oral lesions, conjunctivitis, edema facial, hepatitis, eosinophilia or angioedema, it is recommended that the patient be instructed to immediately discontinue administration of raltegravir.
Myalgia and myopathy
There have been post-marketing reports of myopathy and rhabdomyolysis with raltegravir.
Depression and suicidal thoughts
The incidence of depression and suicidal ideation was rare and occurred at a similar frequency for raltegravir and efavirenz.
Immune reconstitution inflammatory syndrome (IRIS)
This effect can be seen with any antiretroviral therapy. An inflammatory response to poorly progressive or residual opportunistic infections (e.g. Mycobacterium avium complex, cytomegalovirus, Pneumocystis jerovinci pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.
Integrase inhibitor
Absolute bioavailability of raltegravir has not been established
3 hours (on an empty stomach or after a meal low in fat)
4 hours (after meal moderately rich or high in fat)
Diphasic; Phase 1: 1 hour; Phase 2: 9 hours
UGT1A1
Urinary excretion 32% (9% unchanged) and in faeces (51% unchanged)
83 %
The selection of antiretrovirals for pregnant women is based on several factors that vary for each patient (DHHS Guidelines, Dec 2019).
Factors related to pregnancy include :
Potential teratogenic and other short- and long-term adverse effects on the fetus or newborn, including premature birth, mutagenicity and carcinogenicity;
Data available on the safety and results of the use of the drug during pregnancy;
Pharmacokinetic changes during pregnancy;
Potential side effects for women, especially those that can be exacerbated during pregnancy.
Factors at the individual level include :
Potential drug interactions with other drugs;
Results of genotypic resistance tests and previous exposure to ARV drugs;
Comorbidities;
Ability of the patient to adhere to a treatment regimen;
Convenience.
Isentress® 400 mg BID is one of the preferred antiretrovirals for the treatment of pregnant women.
According to the product monograph, data from the antiretroviral exposure registry during pregnancy with more than 500 prospective reports of exposure to raltegavir (Isentress®) at a dose of 400 mg twice daily day during pregnancy included in the registry and leading to live births (including more than 250 cases of exposure during the first trimester) did not show any difference in the general risk of congenital anomalies following a exposure to raltegravir compared to the 2.7% baseline birth defects rate in the reference population in the United States (Metropolitan Atlanta Congenital Defects Program [MACDP]).
There are no data from the use of Isentress® HD at a dose of 1200 mg DIE in pregnant women.
Professionals are encouraged to report pregnancy cases with a view to adding them to the register :
www.apregistry.com/ Telephone : 1-800-258-4263 Fax : 1-800-800-1052.
It is not known if raltegravir is excreted in human breast milk, but it has been detected in the milk of rats. In fact, the average drug concentration in the milk of rats given the dose of 600 mg/kg/day was approximately 3 times higher than in maternal plasma.
Because of the risk of HIV-1 transmission and the potential for adverse reactions for infants, HIV-positive mothers on antiretroviral therapy should be advised not to breastfeed their child.
600 mg tablets and 400 mg tablets
Chewable tablets
Severe skin reactions
Drugs interactions
For a safer use of these drugs used in combination with Isentress® and Isentress® HD, consult the product monograph or the drug interactions section.
The manufacturer does not recommend cutting or crushing the 400 mg or 600 mg tablet. However, pharmacokinetic data suggest that absorption of raltegravir was not compromised when a 400 mg raltegravir tablet was crushed, dissolved in water, and administered by gastrostomy tube to a 52-year-old HIV-positive patient (Sandkovsky et al, 2012). Two studies also showed that patients receiving raltegravir by chewing the tablet experienced higher drug absorption and reduced pharmacokinetic variability compared to patients swallowing the tablet intact (Cattaneo et al, 2012 et 2015).
No data on whether the 600 mg tablet can be cut or crushed.
The 100 mg chewable tablet can be divided into two equal parts. In vitro data suggest that raltegravir chewable tablets may be crushed and dissolved in a liquid and that this will result in therapeutic plasma concentrations, however, there are no data on the efficacy and security to support this use (Teppler et al, 2017).
Store the tablets at a maximum temperature of 30° C.
RAL, raltegravir; BID, twice a day; DIE, once daily; OBT, optimised background treatment; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; EFV, efavirenz; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors.