Brand name: Isentress

Generic name: raltegravir, or RAL

Class: Integrase inhibitor (integrase strand transfer inhibitor, or INSTI)

Manufacturer: Merck and Co.,, (800) 622-4477

AWP: $1,171.31/month

Standard Dose: One 400 mg film-coated tablet twice a day, with or without food, with no dietary restrictions. Can be taken by children two years or older. Dosing is based on weight for children 2-11 years old. A new pediatric formulation was also approved in the form of 25 mg and 100 mg scored chewable tablets (which can also be swallowed), taken with or without food. The dose of chewable tablets are not bioequivalent to the film-coated tablets; therefore, do not substitute chewable tablets for film-coated tablets. Take missed dose as soon as possible, unless it is closer to the time of your next dose. Do not double up on your next dose.

Potential side effects and toxicity: Very tolerable, but most common are diarrhea, nausea, headache, and fever. The side effect profile in children is comparable to adults. Less common are abdominal pain, vomiting, fatigue, weakness, dizziness, and lipodystrophy. May cause elevated levels of a muscle enzyme (creatine kinase) on blood tests. Contact your health care provider if you experience unexplained muscle pain, tenderness, or weakness. May cause anemia, neutropenia, and gastritis. Increases in ALT, AST, and total bilirubin, all signs of liver toxicity, seen in around 8% of people taking Isentress, especially those co-infected with hepatitis B or C. Although rarely seen, side effects can include severe and potentially fatal skin and hypersensitivity (allergic) reactions and cerebellar ataxia (sudden, uncoordinated movement due to disease or injury of the brain). Seek medical attention and immediately stop taking Isentress and your other HIV medications if you develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, general ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, swelling of the eyes, lips, mouth, or face, difficulty breathing, and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below the ribs). Chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria. See chart for potential drug class side effects.

Potential drug interactions: Tell your provider or pharmacist about all medications, herbs, and supplements you are taking or thinking of taking, prescribed or not. Reyataz and Reyataz/Norvir increase blood levels of Isentress, but no dose adjustment is recommended. Use caution with rifampin, which reduces plasma concentrations of Isentress; increase dose of Isentress to 800 mg twice a day. Remember to decrease the Isentress dose back to 400 mg twice a day when you finish taking rifampin. If rifabutin is used in place of rifampin, there is no need to increase the Isentress dose. There are no data to guide dosing of the new chewable tablets if combined with rifampin. Prilosec (omeprazole) can increase concentrations of Isentress, but no dose adjustment is recommended. There is no interaction with methadone.

More information: U.S. HIV guidelines list Isentress along with a Truvada backbone as a preferred regimen for first-time therapy. Isentress is the first drug in a class of HIV drugs called integrase inhibitors, with more on the way (see elvitegravir and dolutegravir). The data are in accord with the advocate view that advanced patients are having dramatic results and almost no side effects. The 96-week data in ART-naïve and ART-experienced patients show that Isentress continues to be effective with almost no side effects. The guidelines note drawbacks: twice-a-day dosing and a lower barrier to drug resistance than seen with boosted PIs. Greater tolerability, which results in greater adherence however, may help overcome those issues. Also, it's only one tablet per dose, and does not have to be taken with the dreaded Norvir, the way PIs are. The guidelines state that switching people from a boosted PI to Isentress should be done with caution, and avoided altogether in people who have HIV resistance to NRTI drugs unless they have fully active medications (to which their HIV is not resistant) to use. Moreover, the guidelines state that before prescribing Isentress, providers may want to order a resistance test that can measure INSTI resistance (standard tests cannot). See package insert for more complete information on potential side effects and interactions.

Doctor's Comments

Isentress made a stunning entrance when it was first approved for use in treatment-experienced patients. Perhaps more than any other drug, it revolutionized so-called "salvage therapy." In combination with other new or second-generation agents, it made it possible for just about anyone willing to swallow pills to have an undetectable viral load. The fact that it was virtually free of side effects or significant toxicity didn't hurt, either. The combination of Isentress and Truvada was subsequently shown to be as effective as Atripla for initial therapy, but with fewer side effects and lipid elevations, and a recent long-term look at the STARTMRK study results showed that it was superior to Atripla after 192 weeks, the first time that any regimen had bested Sustiva or Atripla. Isentress/Truvada is now a preferred regimen for initial therapy in the guidelines, though it is the only one that requires twice-daily dosing. Hopes that it could be dosed once a day were dashed by a clinical trial that clearly showed better results with twice-daily dosing, especially in people with high baseline viral loads. This combination also has no clear advantage over Atripla from a resistance standpoint: integrase mutations can occur when viral suppression isn't maintained, and Isentress resistance is likely to result in cross-resistance to other integrase inhibitors in development.

-- Joel Gallant, M.D., M.P.H.

Activist's Comments

The ultimate game changer, Isentress made undetectable viral load a reality for so many people! My personal favorite drug of them all; small, no side effects (I've never heard anyone report a bad thing about it), and it gets along with almost all of the other drugs possible in a regimen. Merck programs for PAPs and co-pay cards are a breeze. The icing on the cake? Merck quickly negotiated price freezes for ADAPs and worked well with the community on getting PAPs up and running, especially in Florida. The downside? Twice-a-day dosing can be a barrier for some, but for the overwhelming majority, this is a godsend. Salvage therapy clients rejoiced at the introduction of Isentress and a few other drugs a few years back, and are enjoying a span of good clinical labs now. I'm one happy camper over this drug! Hopes that it could be a once-a-day pill proved unattainable; results showed once-daily dosing was not as effective as twice-daily. There are no challengers in its class (yet), so for now, it is unrivaled!

-- Joey Wynn

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