Raltegravir (RAL)

DOSAGE

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.

Pediatric dosage (≥ 2 years and more than 7 kg and < 12 years)

Isentress^® : Chewable tablets (weight-dependent dose up to a maximum of 300 mg BID)

Isentress^® HD : Safety and efficacy have not been established in pediatric population (< 40 kg).

Adjustment in renal impairment

No dose adjustment is necessary in patients with renal impairment and in patients on hemodialysis.

Adjustment in hepatic impairment

Child-Pugh A or B : No adjustment required

Child-Pugh C : Administration not studied in this population

COMPARATIVE EFFICIENCY

Isentress^® has been studied in treatment-naive patients as well as in patients undergoing treatment with virological suppression.

Studies in patients who have never received antiretrovirals

Studies in patients with virological suppression

*OBT : Optimized background treatment

RESISTANCE

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.

ADVERSE REACTIONS

In short

• Raltegravir is a drug known to be usually very well tolerated.

Adverse reactions in adults who have already been treated

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.

OBT : Optimised background treatment

Discontinuation of treatment due to adverse effects: RAL (3.6%) vs Placebo (4.2%)

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.

ONCEMRK Study

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.

MECHANISM OF ACTION

Raltegravir

Integrase inhibitor

PHARMACOKINETICS

Bioavailability

Absolute bioavailability of raltegravir has not been established

Tmax

3 hours (on an empty stomach or after a meal low in fat)
4 hours (after meal moderately rich or high in fat)

Elimination T½ (plasma)

Diphasic; Phase 1: 1 hour; Phase 2: 9 hours

Metabolism

UGT1A1

Elimination

Urinary excretion 32% (9% unchanged) and in faeces (51% unchanged)

Binding to plasma proteins

83 %

PREGNANCY AND BREAST FEEDING

Pregnancy

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.

Breast feeding

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.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

• Hypersensitivity to the active or inactive molecules contained in the tablet (see product monograph for more details).

Precautions

600 mg tablets and 400 mg tablets

• As the presentations have different pharmacokinetic profiles, the 600 mg tablets should not be replaced by the 400 mg tablets to obtain the 1200 mg DIE dose, nor should the chewable tablets be used in place of the 400 mg or 600 mg tablets.

Chewable tablets

• Raltegravir chewable tablets contain phenylalanine, a component of aspartame. Phenylalanine may be harmful in patients with phenylketonuria.

Severe skin reactions

• Rare but severe skin reactions such as Stevens-Johnson syndrome and erythroderma bullosa with epidermolysis have been reported. Hypersensitivity reactions have also been reported and were characterized by a rash, constitutional manifestations and sometimes damage to various organs including liver failure. Stop raltegravir and other suspicious agents immediately if signs or symptoms of severe skin reactions or hypersensitivity occur.

Drugs interactions

• It is not recommended to administer antacids containing aluminum or magnesium in combination with Isentress^® 400 mg BID and Isentress^® HD 1200 mg DIE. Antacids containing calcium carbonate are not recommended with Isentress^® HD 1200 mg DIE.

• Co-administration with potent inducers of UGT 1A1 such as rifampin may decrease the concentration of raltegravir and compromise its effectiveness.
  WITH Isentress^® HD 1200 mg DIE
  Co-administration of strong enzyme inducers (e.g. rifampin) and Isentress^® HD at the dose of 1200 mg (two 600 mg tablets) once daily was not studied. A significant decrease in the concentration of raltegravir is suspected with this formulation. Therefore, co-administration of Isentress^® HD and potent enzyme inducers is not recommended.
  WITH Isentress^® 400 mg BID
  Due to the potential decrease in plasma concentrations of raltegravir with potent enzyme inducers, dose adjustment of Isentress^® is suggested.

For a safer use of these drugs used in combination with Isentress^® and Isentress^® HD, consult the product monograph or the drug interactions section.

FURTHER INFORMATION

Administration for patients with swallowing difficulties

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).

Storage

Store the tablets at a maximum temperature of 30° C.

REFERENCES

• Raltegravir (Isentress – Isentress HD), Merck, Quebec, Canada, Sept 19 2018.

• Steigbigel RT, Cooper DA, Kumar PN et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359: 339–354.

• Steigbigel RT, Cooper DA, Hedy Teppler H et al. Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials. Clin Infect Dis. 2010 February 15; 50(4): 605–612.

• M. Foisy, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., AAHIVP, Northern Alberta Program, KEC Site, Edmonton, Alberta, Sarah Lamb, PharmD Student (2017 updates), and A. Tseng, Pharm.D, AAHIVP, Toronto General Hospital. Oral antitetroviral administration: Information on crushing and liquid drug formulations.

• Sandkovsky U, Swindells S, Moore R, Acosta EP, Fletcher CV. Acceptable plasma concentrations of raltegravir and etravirine when administered by gastrostomy tube in a patient with advanced multidrug-resistant human immunodeficiency virus infection. Pharmacotherapy. 2012 Feb; 32(2): 142-7.

• Teppler H , Brown DD, Leavitt RY. Long-Term Safety from the Raltegravir Clinical Development Program. Current HIV Research, 2011, 9, 40-53.

• Teppler H, Thompson K, Chain A, Mathe M, Nachman S, Clarke D. Crushing of Raltegravir (RAL) chewable tablets for administration in infants and young children. 9th Int Workshop on HIV Pediatrics, Paris, France, July 23-26, 2017, [abstract 37].

• Cattaneo D, Baldelli S, Cerea M, Landonio S, Meraviglia P et al. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing. Antimicrob Agents Chemother. 2012 Dec; 56(12): 6132-6.

• Nachman S, Zheng N, Acosta EP et al. Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1–Infected Children Aged 2 Through 18 Years. Clin Infect Dis. 2014 Feb 1; 58(3): 413–422.

• Cattaneo D, Cossu MV, Fucile S, Riva A, Baldelli S et al. Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study. Ther Drug Monit. 2015 Feb; 37(1): 119-25.

• Croxtall JD, Scott LJ. Raltegravir: in treatment-naive patients with HIV-1 infection.Drugs. 2010 Mar 26; 70(5): 631-42.

• Nguyen BY, Isaacs RD, Teppler H, et al. Raltegravir: the first HIV-1 integrase strand transfer inhibitor in the HIV armamentarium. Ann NY Acad Sci. 2011 Mar; 1222: 83-9.

• Clarke DF, Acosta EP, Cababasay M et al. Raltegravir (RAL) in Neonates: Dosing, Pharmacokinetics (PK), and Safety in HIV-1-Exposed Neonates at Risk of Infection (IMPAACT P1110). J Acquir Immune Defic Syndr. 2020 May 1; 84(1): 70-77.

• Zembower TR, Gerzenshtein L, Coleman K et al. Severe Rhabdomyolysis Associated With Raltegravir Use. AIDS 2008 Jul 11; 22(11): 1382-4.

• Croce F, Vitello P, Dalla Pria A et al. Severe raltegravir-associated rhabdomyolysis: a case report and review of the literature. Int J STD AIDS. 2010 Nov; 21(11): 783-5.

• Dori L, Buonomini AR, Viscione M et al. A case of rhabdomiolysis associated with raltegravir use. AIDS. 2010 Jan 28; 24(3): 473-5.

• Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. DHHS DEC 2019.

ABBREVIATIONS

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.