Raltegravir (Isentress)

Summary

Raltegravir is a type of anti-HIV drug called an integrase inhibitor. Raltegravir is generally well tolerated. Common side effects include diarrhea, nausea and headache; these are usually temporary and mild. The adult dose of raltegravir used is 400 mg twice daily. Raltegravir can be taken with or without food.

What is raltegravir?

Raltegravir, sold under the brand name Isentress, belongs to a class of anti-HIV (or antiretroviral) drugs called integrase inhibitors. Raltegravir is used in combination with other anti-HIV drugs to treat, but not cure, HIV.

How does raltegravir work?

Raltegravir works by interfering with an enzyme needed by HIV called integrase. Using raltegravir as part of combination therapy reduces HIV’s ability to infect cells and make copies of itself.

How do people with HIV use raltegravir?

Raltegravir is used in combination with several other anti-HIV drugs, usually nukes (nucleoside analogues), non-nukes (NNRTIs) and drugs from other classes, such as protease inhibitors. These combinations are called antiretroviral therapy, or ART. For more information on ART, see CATIE's Your Guide to HIV Treatment.

For many people with HIV, the use of ART has increased their CD4 counts and decreased the amount of HIV in their blood (viral load). This reduces a person’s risk of developing life-threatening infections and allows them to stay healthy for longer. Neither raltegravir nor any other anti-HIV medication is a cure for HIV. It is therefore important that you see your doctor for checkups and lab tests on a regular basis.

Evidence shows that HIV-positive people who are on ART, engaged in care, and have an ongoing undetectable viral load are substantially less likely to transmit HIV to others, be it through sex, when sharing equipment to use drugs, or during pregnancy and birth. In fact, the evidence for sexual transmission shows that people on ART who maintain an undetectable viral load do not pass HIV to their sexual partners. For further information see the CATIE fact sheet HIV treatment and an undetectable viral load to prevent HIV transmission. However, it is still a good idea to use condoms because they can reduce your risk for getting and passing on other sexually transmitted infections.
 

Warnings

1. Severe rash and allergic reactions

Although very rare, severe, and, in even more rare cases life-threatening, rash have been reported. If any of the  symptoms listed below are accompanied by a rash, contact your doctor immediately. If your doctor is not available, go to the nearest hospital emergency department.

  • fever
  • feeling being generally unwell
  • extreme tiredness
  • muscle or joint aches
  • blisters or sores in your mouth
  • blistered or peeling skin
  • red or swollen eyes
  • swollen mouth or face
  • difficulty breathing

An allergic reaction to raltegravir can potentially lead to liver injury. Contact your doctor immediately if you have any of the following symptoms:

  • yellowing of the skin or eyes
  • dark or tea-coloured urine
  • pale-coloured stool
  • nausea or vomiting
  • loss of appetite
  • pain or tenderness on the right side below the ribs

2. Pregnancy

If you are pregnant or plan on trying to get pregnant, talk to your doctor so that you can find medicines that are safe for you and your baby.

3. Other medicines

The manufacturer recommends that raltegravir be used cautiously if you are also taking drugs such as the antibiotic rifampin (used to treat tuberculosis). Levels of raltegravir may fall considerably when it is taken by people who are also taking rifampin.

The manufacturer also recommends not taking antacids at the same time as raltegravir because these can reduce the absorption of raltegravir. If you have indigestion or suffer from heart burn, acid reflux or related issues, and need to take antacids, speak to your pharmacist.

Side effects

1. General

Raltegravir is generally well-tolerated. Here is a list of some, usually temporay and mild, symptoms reported by raltegravir users in clinical trials:

  • diarrhea
  • headache
  • nausea
  • tiredness/fatigue
  • upper respiratory tract infection
  • cough
  • fever
  • rash
  • muscle pain
  • stomach pain
  • dizziness
  • constipation
  • itching
  • difficulty sleeping

2. Liver health

Raltegravir has not been well studied in people co-infected with HIV and hepatitis B or C. In clinical trials, only about 16% of people taking raltegravir were co-infected with these viruses. Liver enzymes (AST and ALT) were somewhat higher in co-infected people with mild liver disease after taking raltegravir. In about 3% of HIV-positive people who are not co-infected with  hepatitis viruses, researchers have found that levels of liver enzymes in their blood can be elevated due to raltegravir use.

3. Emotional issues—anxiety and depression

Note that all integrase inhibitors, including raltegravir, have been associated with rare cases of anxiety and depression. Whether these drugs caused anxiety or depression is not clear. In some reports, the rare cases of anxiety and/or depression associated with the use of integrase inhibitors occurred mainly in people who had a history of these issues.

Anxiety and depression are relatively common in HIV-positive people (regardless of whether they are on treatment or the type of treatment that they take). If you are taking raltegravir and think that you may have developed anxiety or depression, speak to your doctor right away. Your doctor can help determine if you have anxiety or depression and if there is any relationship between them and the medicines that you are taking.

Symptoms of anxiety and depression can include the following:

  • become easily upset or angry
  • feel fearful
  • excessive worry
  • have unexpected feelings of sadness
  • have prolonged feelings of sadness, anger or depression
  • feel hopeless
  • have loss of pleasure in everyday activities
  • unexpectedly feel tired or experience a lack of energy
  • have difficulty falling asleep, staying asleep or waking up prematurely
  • have strange thoughts

If you have any of these feelings, contact your doctor or nurse.

If you have thoughts of harming yourself or others, dial 911 right away.

4. Muscle weakness

There have been rare reports of cases of raltegravir-associated rhabdomyolysis—the breakdown of muscle tissue leading to muscle weakness. This rare problem may occur with all integrase inhibitors.

Muscles are highly active tissues, which require a lot of oxygen. They contain a protein called myoglobin that captures oxygen from the blood and helps to bring this gas to parts of the muscle that burn fuel to release energy. When muscles are injured they release myoglobin into the blood. This protein and the products into which it is broken down can—in large amounts—cause kidney dysfunction.

Rhabdomyolysis can occur under the following circumstances:

  • alcoholism
  • serious accidents where tissues are compressed (crush injuries)
  • exposure to stimulants such as amphetamine and methamphetamine, cocaine, ecstasy and excessive caffeine
  • inherited muscle disorders
  • heat stroke
  • muscle injury arising from veins being blocked by blood clots
  • lower-than-normal levels of phosphorus in the body
  • seizures
  • very intensive and exhaustive exercise
  • chills
  • many medicines have been associated with rhabdomyolsis but one class stands out: statins (a group of drugs used to treat high cholesterol levels)

Rhabdomyolysis may not initially cause symptoms but the following signs may appear later:

  • dark-coloured urine
  • decreased production of urine
  • fatigue
  • stiff or aching muscles
  • tender muscles
  • painful joints
  • seizures

If fatigue is bothersome or persistent or any of the above listed side effects appear, speak to your doctor right away.

Blood tests may reveal abnormal levels of an enzyme called creatine kinase. Levels of the waste product creatinine may also be abnormal.

In some cases, nurses may provide intravenous saline solution to hydrate the body. This solution, in cases of rhabdomyolysis, may also be rich in bicarbonate to help increase the production of urine and accelerate the removal of myoglobin.

In very severe cases of rhabdomyolysis, dialysis (artificial filtration of the blood) may be necessary to remove myoglobin and other proteins temporarily.

Some people quickly regain their energy after being treated for rhabdomyolysis, while others can have fatigue and muscle aches for several months after treatment.

Drug interactions

Always consult your doctor and pharmacist about taking any prescription or non-prescription medication, including over-the-counter medicines, herbs, supplements and street drugs.

Some drugs can interact with raltegravir. An interaction may increase or decrease the amount of raltegravir you have in your body. Increased drug levels can cause you to experience more side effects or make pre-existing side effects worse. On the other hand, if drug levels become too low, HIV can develop resistance and your future treatment options may become more limited.

If you must take a drug that could potentially interact with raltegravir, your doctor can do the following:

  • adjust your dose of anti-HIV drugs or other medications; or
  • prescribe different anti-HIV drugs for you.

Drug interactions with raltegravir

In general, raltegravir does not have many interactions with other medicines. Below are some drugs with which raltegravir can interact. Note that this list is not exhaustive. There may also be other drugs with which raltegravir can interact. To find out more about drug interactions with raltegravir, speak to your pharmacist.

  • Rifampin/rifampicin – these antibiotics are used to treat tuberculosis (TB) and could reduce levels of raltegravir in your body. The manufacturer recommends that such antibiotics be used cautiously.
  • Antacids and calcium supplements – raltegravir should not be taken at the same time as antacids (such as Tums, Maalox, Gaviscon and so on) or with calcium supplements. These all significantly decrease the absorption of raltegravir. If you have been prescribed raltegravir and must take antacids and/or calcium supplements, speak to your pharmacist about how to safely do so.

Resistance, cross-resistance and treatment interruption

Over time, as new copies of HIV are made in the body, the virus changes its structure. These changes, called mutations, can cause HIV to resist the effects of anti-HIV drugs, which means those drugs will no longer work for you. Combining raltegravir with at least two other anti-HIV drugs delays the development of drug resistance.

To reduce the risk of developing drug resistance, all anti-HIV drugs should be taken every day exactly as prescribed and directed. If doses are delayed, missed or not taken as prescribed, the level of raltegravir in the blood may fall too low. If this happens, the HIV in your body can become resistant to the medication. If you find you are having problems taking your medications as directed, speak to your doctor, nurse or pharmacist about this. They can find ways to help you.

When HIV becomes resistant to one drug in a class, it sometimes becomes resistant to other drugs in that class. This is called cross-resistance. There are other integrase inhibitors in development, one of which is elvitegravir. If your HIV becomes resistant to raltegravir, it will also likely become resistant to elvitegravir.

Feel free to talk with your doctor about your current and future treatment options. To help you decide what these future options might be, at some point your doctor can have a small sample of your blood analyzed to test for resistance. Should the HIV in your body become resistant to raltegravir, your doctor can recommend a new treatment combination for you.

Dosage and formulations

Raltegravir (Isentress) is available in 400 mg tablets. The drug may be taken with or without food. The dose of raltegravir used in adults with HIV is 400 mg twice daily.

Formulations can change and dosages may need to be customized. All medications should always be taken as exactly as prescribed and directed.

Availability

Raltegravir is licensed in Canada for the treatment of HIV infection in adults in combination with other anti-HIV drugs. Your doctor can tell you more about the availability and coverage of raltegravir in your region. CATIE’s online module Federal, Provincial and Territorial Drug Access Programs also contains information about Canadian drug coverage.

References

Merck Canada Inc. Isentress (as raltegravir potassium). Product monograph. Date of revision: June 21, 2017.

Author(s): Hosein SR

Published: 2018