Complera

Summary

Complera is the name of a fixed-dose co-formulation of three anti-HIV drugs: tenofovir, FTC and rilpivirine (Edurant). Complera can be used by itself as combination therapy for people with HIV who have not taken anti-HIV drugs in the past. Common side effects of Complera include headache, nausea and sleep problems. Complera is taken once daily with a meal.

What is Complera?

Complera is the name of a pill that contains the following three anti-HIV drugs:

  • rilpivirine, which belongs to a class of drugs called non-nukes or NNRTIs
  • tenofovir (Viread), which belongs to a class of drugs called nucleotide analogues
  • FTC (emtricitabine, Emtriva), which belongs to a class of drugs called nucleoside analogues, or nukes

Because Complera contains these three medications, it can be used as a once-daily treatment for HIV infection.

How does Complera work?

When HIV infects a cell, it takes control of that cell. HIV then forces the cell to make many more copies of the virus. To make these copies, the cell uses proteins called enzymes. When the activity of these enzymes is reduced the production of HIV slows.

All three medicines in Complera interfere with an enzyme called reverse transcriptase, which is used by HIV-infected cells to make more HIV. Since Complera inhibits, or reduces, the activity of this enzyme, this drug causes HIV-infected cells to slow down or stop producing new viruses.

How do people with HIV use Complera?

Because it contains several anti-HIV drugs, Complera is considered a kind of 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+ cell counts and decreased the amount of HIV in their blood (viral load). These beneficial effects help to greatly reduce the risk of developing a life-threatening infection. Neither Complera nor any other anti-HIV medication is a cure for HIV. It is therefore important that you do the following:

  • See your doctor regularly so that he or she can monitor your health.
  • Continue to practise safer sex and take other precautions, to avoid passing HIV on to other people and protect yourself from different strains of HIV as well as other germs.

Warnings

Because Complera contains rilpivirine—a relatively new medication—the full range of its side effects may not be known for many years. The following potentially serious side effects are uncommon; you may not experience any of them. However, if you do, report them to your doctor right away. (The following is not a complete list of potential side effects.)

1. Cardiovascular health

The manufacturer advises that Complera should be used with caution in people who might have cardiovascular health conditions, including abnormal heart rhythms, heart failure, poor circulation of blood to the heart and so on. In clinical trials, researchers found that exposure to rilpivirine (one of the drugs in Complera) gradually affected the hearts of some volunteers so that they were more likely to develop abnormal heart rhythms.

Symptoms of abnormal heart rhythms can include the following:

  • dizziness
  • fainting
  • heart palpitations (a feeling that your heart is pumping very hard or fast when you are at rest)
  • seizures

If you develop any of these symptoms, talk to your doctor right away.

If you have cardiovascular disease, including abnormal heart rhythms, or have a parent, brother or sister with any type of heart problem, let your doctor(s) know.

2. Mental health

In clinical trials, problems related to depressive illness occurred. These included depression, anxiety and negative thoughts. In about 4% of participants, the severity of these symptoms ranged from moderate to life-threatening. However, only about 1% of Complera users in clinical trials needed to stop taking this drug because of symptoms of depressive illness.

If you experience any of the following symptoms while taking Complera, see your doctor right away:

  • you become easily upset or angry
  • you have unexpected feelings of sadness
  • you feel hopeless
  • you have strange thoughts
  • you have thoughts about harming yourself or others
  • you have thoughts about suicide

3. Hepatitis and liver health

Rilpivirine (one of the drugs in Complera) has been tested in only a small number of people with mild to moderate liver damage. Therefore, the manufacturer recommends that Complera not be used in people with severe liver damage and that it be used with caution in people with mild to moderate liver damage.

In clinical trials in which HIV-positive patients co-infected with hepatitis B or C received rilpivirine, increased levels of liver enzymes in the blood occurred. The increased levels of these enzymes were greater than in other clinical trial participants who were not co-infected with hepatitis viruses.

Increased levels of liver enzymes may suggest liver inflammation and dysfunction; talk to your doctor about your test results.

4. Pancreatitis

Painfully swollen pancreas glands have been reported by some people taking tenofovir (one of the drugs in Complera) as part of ART. Higher-than-normal levels in the blood of the enzyme amylase (made by the pancreas gland) have been detected in people taking tenofovir. This increase may suggest inflammation in the pancreas gland. Symptoms of pancreatitis can include the following:

  • abdominal pain, particularly when laying down
  • nausea
  • vomiting
  • unexpected sweating
  • fever
  • anxiety

If these symptoms occur, talk to your doctor right away.

5. High HIV viral load

In clinical trials of rilpivirine (one of the drugs in Complera), some volunteers had high viral loads (more than 100,000 copies/ml) before receiving this drug. These people were more likely to develop virologic failure when given rilpivirine-based ART than people whose pre-study viral loads were less than 100,000 copies/ml. Moreover, volunteers whose rilpivirine-based regimens failed developed HIV that was resistant not only to rilpivirine and other non-nukes (such as efavirenz (Sustiva and in Atripla), etravirine (Intelence) and nevirapine (Viramune)) but to nukes as well. Taking this information into account, the United States Department of Health and Human Services (DHHS), which writes comprehensive HIV treatment guidelines, has stated that “caution should be exercised when using rilpivirine in patients [whose viral load is greater than] 100,000 copies/ml.”

6. Pregnancy

As there is no information from large numbers of pregnant women on the safety of Complera for these women or their fetuses, the manufacturer recommends that Complera “should not be used during pregnancy unless the benefits outweigh the potential risks to the fetus.”

7. Age

The manufacturer recommends that Complera should be used with caution in patients 65 years and older since clinical trials did not enroll sufficient people in this age group to assess its safety.

Side effects

1. General

Rilpivirine (one of the drugs in Complera) is a relatively new drug so the full range of its side effects are not yet known. However, data from clinical trials suggest that rilpivirine is generally well-tolerated. Long-term monitoring of rilpivirine use is underway.

In clinical trials, rilpivirine was used as part of combination therapy so it is difficult to be certain which side effects are caused by this drug. Here is a list of some symptoms reported by rilpivirine users in clinical trials:

  • dizziness
  • feeling sleepy during the daytime
  • headache
  • rash
  • nausea
  • stomach pain

2. Depression (see Warnings)

Complera has the potential to cause depression and anxiety, although in clinical trials, less than 10% of people reported this problem. Before severe depression occurs, more subtle symptoms may appear, including:

  • difficulty concentrating
  • problems falling asleep
  • problems staying asleep
  • persistent irritability
  • difficulty remembering
  • fatigue
  • changes in appetite
  • persistent nightmares

If you notice these or changes to your mood, speak to your doctor right away.

3. Lactic acidosis

Some people who have used the medicines in Complera or related anti-HIV drugs have experienced a condition called lactic acidosis—higher-than-normal levels of lactic acid in the blood. Women who are overweight are at increased risk for lactic acidosis. Sometimes the liver of a person with lactic acidosis becomes swollen because of fatty deposits.

Signs and symptoms of lactic acidosis may include the following:

  • nausea
  • vomiting
  • abdominal pain
  • diarrhea
  • unexpected tiredness
  • unexpected muscle pain
  • feeling cold especially in the arms and legs
  • feeling dizzy or light-headed

If these symptoms persist, see your doctor right away.

4. Bone health

Complera contains tenofovir. In experiments on monkeys using tenofovir at doses 10 to 30 times greater than the dose that would be used in people, the animals’ bones became thinner over a period of one year. Before you start taking Complera, tell your doctor if you have bone problems, thinner-than-normal bones (osteopenia or osteoporosis), or if your parents, brothers or sisters have bone problems.

In clinical trials of regimens containing tenofovir, thinner bones in the spine and elsewhere, as well as bone pain have been reported. Thinner bones are generally weaker and are at increased risk for breaking (fractures) should accidents or trauma occur.

Researchers are not certain why bone thinning may occur in some people exposed to tenofovir. One theory is that bones became thinner because tenofovir may have caused the kidneys to malfunction. The kidneys filter blood, putting waste materials into the urine and returning nutrients back to the blood. In the cases of tenofovir-associated bone loss, damaged kidneys may not be able to restore bone-building nutrients to the blood.

Bear in mind that some people with HIV can develop thinner-than-normal bones without ever using tenofovir. This occurs in some people who use ART. The decrease in bone density tends to stabilize within one or two years after starting ART. It may be useful for you to discuss with your doctor the possibility of having bone density assessments done before you begin taking Complera or any other anti-HIV therapy. If your bones are thin, talk to your doctor about your intake of calcium and vitamin D3. Regular monitoring of bone density may also be useful.

For more information about vitamin D and bones, see CATIE’s A Practical Guide to Nutrition for People Living with HIV.

5. Kidney health

Complera contains tenofovir, which is broken down by the kidneys. There have been reports of kidney dysfunction in some people who used tenofovir. Complera users may wish to have regular blood and urine tests done so that their doctors can assess the health of their kidneys. These tests can include the following:

  • creatinine
  • e-GFR (estimated glomerular filtration rate)
  • calcium
  • phosphorus
  • bicarbonate

In addition to tenofovir, there are other medications processed by the kidneys that have the potential to damage these organs. Many of these medications are antibiotics, such as:

  • beta-lactams—penicillin and amoxicillin
  • quinolones—ciprofloxacin and related compounds
  • aminoglycosides—amikacin and gentamicin
  • macrolides—erythromycin
  • tetracyclines—minocycline
  • anti-tuberculosis agents—rifampin and ethambutol
  • other antibiotics—co-trimoxazole (Septra/Bactrim) and vancomycin (Vanocin)

Bear in mind that there are other medications that can potentially damage the kidneys, including:

  • antiviral agents—acyclovir (Zovirax), valacyclovir (Valtrex), cidofovir (Vistide), foscarnet (Foscavir), indinavir (Crixivan)
  • antifungal agents—amphotericin B (Fungizone), intravenous pentamidine
  • anti-seizure drugs—phenytoin, carbamazepine, valproic acid
  • NSAIDs (non-steroidal anti-inflammatory drugs)—acetaminophen (Tylenol), ibuprofen (Advil, Motrin), indomethacin (Indocid), naproxen (Naprosyn)
  • transplant drugs—cyclosporine (Neoral, Sandimmune)

(The above list is not exhaustive.)

6. Lipodystrophy syndrome

The HIV lipodystrophy syndrome is the name given to a range of symptoms that can develop over time when people use ART. Some features of the lipodystrophy syndrome include:

  • loss of fat just under the skin (subcutaneous fat) in the face, arms and legs
  • bulging veins in the arms and/or legs due to the loss of fat under the skin
  • increased waist and belly size
  • fat pads at the back of the neck (“buffalo hump”) or at the base of the neck (“horse collar”)
  • small lumps of fat in the abdomen
  • increased breast size (in women)

Together with these physical changes, blood tests may detect the following:

  • increased levels of fatty substances called triglycerides
  • increased levels of LDL-cholesterol (low-density lipoprotein), or “bad” cholesterol
  • decreased levels of HDL-cholesterol (high-density lipoprotein), or “good” cholesterol
  • increased levels of sugar (glucose)
  • increased levels of the hormone insulin
  • decreased sensitivity to insulin (insulin resistance)

The precise causes of HIV lipodystrophy syndrome are not clear and are difficult to understand because some people with HIV may experience one or more aspects of the syndrome. For instance, some people may experience fat wasting, others fat gain, and others may experience both fat gain and wasting. What is becoming increasingly clear is that unfavourable changes in levels of glucose, cholesterol and triglycerides over a period of several years increase a person’s risk of diabetes and cardiovascular disease. So far, however, the many benefits of ART far outweigh the increased risk of cardiovascular disease or other side effects.

Maintaining a normal weight, eating a healthy diet, exercising regularly and quitting smoking are all important in helping you to reduce your risk of diabetes, heart disease and other complications. Regular visits to your doctor for checkups and blood tests are a vital part of staying healthy. If necessary, your doctor can prescribe lipid-lowering therapy.

Researchers are studying lipodystrophy syndrome to try to discover ways of helping people with HIV avoid or reduce this problem. To find out more about options for managing aspects of lipodystrophy syndrome, see CATIE’s A Practical Guide to HIV Drug Side Effects.

Food interactions

Complera must always be taken with a meal so that it is absorbed.

Avoid eating grapefruit or drinking grapefruit juice as these will increase the concentration of rilpivirine in your body leading to side effects.

Drug and herb interactions

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

Some drugs can interact with Complera, increasing or decreasing its levels in your body. Increased drug levels can cause you to experience side effects or make pre-existing side effects worse. On the other hand, if drug levels become too low, HIV can become drug-resistant and your future treatment options may be reduced.

If you must take a drug that has the potential to interact with your other medications, your doctor can do the following:

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

The manufacturer warns that the following drugs and herbs should not be used with Complera because they can severely reduce the concentration of rilpivirine (one of the drugs in Complera) in the blood and cause HIV to become resistant to rilpivirine and other anti-HIV medications (note that the following list is not exhaustive):

Antibiotics for tuberculosis or MAC (mycobacterium avium complex)

  • rifabutin (Mycobutin), rifampin (Rifadin, Rofact and in Rifater), rifampicin and rifapentene

Antiseizure drugs

  • carbamazepine, oxcarbazepine, phenobarbital, phenytoin

Corticosteroids

  • Dexamethasone given as pills or by injection. High doses of corticosteroids can accumulate in the body and interact with rilpivirine

Herbs

  • St. John’s wort (hypericin, hyperforin)

Proton pump inhibitors

  • esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Losec), pantoprazole (Pantoloc), rabeprazole (Pariet)

The manufacturer warns that the following drugs should not be used with Complera because they can greatly increase levels of rilpivirine (one of the drugs in Complera) and can cause side effects:

Non-nukes

  • efavirenz (Sustiva, also in Atripla), etravirine (Intelence), nevirapine (Viramune) and delavirdine (Rescriptor)

The manufacturer warns that the following drugs can increase rilpivirine levels and suggests that physicians exercise caution when prescribing these drugs to patients who are taking Complera:

Antacids

  • containing aluminum, magnesium hydroxide or calcium carbonate. These drugs should be used with caution as they can affect the acidity of the stomach and greatly decrease absorption of rilpivirine and reduce its levels in the blood. The manufacturer recommends that antacids should only be used “either at least two hours before or at least four hours after Complera.”

Antifungal agents

  • fluconazole (Diflucan), itraconazole (Sporanox), posaconazole (Spirafil) and voriconazole (Vfend). These can all increase levels of rilpivirine in the blood and rilpivirine can reduce the concentration of these drugs, which can lead to new or recurring fungal infections

HIV protease inhibitors

  • Atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Telzir), lopinavir-ritonavir (Kaletra), ritonavir (Norvir), saquinavir (Fortovase), tipranvir (Aptivus). Rilpivirine should not increase levels of these other drugs

Macrolide antibiotics

  • Clarithromycin (Biaxin), erythromycin and troleandomycin can all increase rilpivirine levels and lead to side effects. The manufacturer suggests that where possible, physicians consider the use of an alternative macrolide, such as azithromycin (Zithromax)

The following drugs can decrease rilpivirine levels and must be used with caution:

Histamine2-receptor antagonists

  • cimetidine (Tagamet), famotidine (Pepcid), nizatidine , ranitidine (Zantac). These drugs reduce the acidity of the stomach and can therefore significantly reduce the absorption of rilpivirine. This can lead to HIV becoming resistant to rilpivirine and other anti-HIV drugs. The manufacturer suggests that these drugs should be used with caution and if they must be used, they should only be taken “at least 12 hours before or at least four hours after Complera.”

Other drugs

Medicines that cause people to urinate excessively (such as water pills or diuretics) or have diarrhea (laxatives or enemas), or other drugs such as amphotericin B (Fungizone, Abelcet) can upset the balance of minerals in your blood and could affect your heart’s rhythm. The manufacturer recommends that such drugs be used with caution in people taking Complera.

Interactions are not expected

The manufacturer does not expect Complera to interact with these drugs:

  • methadone
  • HIV and hepatitis drugs—receptor blockers (maraviroc (Celsentri) and nukes for hepatitis C treatment, such as ribavirin; integrase inhibitors, such as raltegravir (Isentress). The drug ddI (Videx) needs to be taken on an empty stomach at least two hours before or at least four hours after taking Complera
  • erectile dysfunction drugs, such as sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra)
  • lipid-lowering agents, called statins, including atorvastatin (Lipitor), rosuvastatin (Crestor) and similar drugs
  • oral contraceptives (“the pill”)

Complera contains tenofovir, which can interact with the following medications by raising or lowering their levels. Or these drugs may change tenofovir levels:

  • ddI (Videx, Videx EC)
  • lopinavir (in Kaletra)
  • atazanavir (Reyataz)

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 are called mutations and can cause HIV to resist the effects of anti-HIV drugs, which means those drugs will no longer work for you. Combining rilpivirine with at least two other anti-HIV drugs, as Complera does, 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. If doses are delayed, missed or not taken as prescribed, levels of rilpivirine in the blood may fall too low. If this happens, resistant virus can develop. If you are having problems taking your medications as directed, speak to your doctor and nurse 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. Feel free to talk with your doctor about your current and future treatment options. To help you decide what these options might be, your doctor can have a small sample of your blood analyzed using resistance testing. Should HIV in your body become resistant to rilpivirine, your doctor can recommend a new drug combination for you.

Dosage and formulations

Complera is available as purplish-pink tablets. Each tablet contains the following medications:

  • rilpivirine—25 mg
  • FTC—200 mg
  • tenofovir—300 mg

The adult dose is one tablet taken once daily with a meal.

Availability

Complera is licensed in Canada for the treatment of HIV infection in adults who have never used antiretroviral drugs. Your doctor can tell you more about the availability and coverage of Complera in your region. CATIE’s online module Federal, Provincial and Territorial Drug Access Programs also contains information about Canadian drug coverage.

 

References

Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011 Jul 16;378(9787):229-37.

Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Recommendations for NNRTI use in antiretroviral treatment-naïve patients with HIV-1 infection. 16 August, 2011.

Gilead Sciences. Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate tablets). Product monograph. 21 September, 2011.

Mocroft A, Kirk O, Reiss P et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS. 2010 Jul 17;24(11):1667-78.

Molina JM, Cahn P, Grinsztejn B et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011 Jul 16;378(9787):238-46.

Wilkin A, Pozniak A, Morales-Ramirez J et al. Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV Type-1-infected antiretroviral-naïve patients: Week 192 results from a phase IIb randomized trial. AIDS Research and Human Retroviruses. 2011 Sep 9. [Epub ahead of print].

Author(s): Hosein SR

Published: 2017