What to Know About Viramune (Nevirapine)

Viramune (nevirapine) is an antiretroviral drug used in combination therapy to treat HIV. It was the first in a class of drugs called non-nucleoside transferase inhibitors (NNRTIs) that works by blocking the virus' ability to hijack the genetic code of an infected cell.

Approved by the U.S. Food and Drug Administration (FDA) in 1996 for the treatment of HIV-1 infection, Viramune can be used in children and adults and to prevent the transmission of HIV during pregnancy.

Although Viramune is included on the World Health Organization's List of Essential Medicines, it is rarely used today in the first-line therapy. Still, it remains a vital drug in the treatment of HIV when other antiretroviral medications fail. In addition to its brand name form, Viramune is available as a low-cost generic under its chemical name nevirapine.

Viramune is approved for the treatment of HIV-1 infection in adults and children. HIV-1 is the predominant form of HIV worldwide, while HIV-2 is confined mainly to West Africa. Viramune is unable to treat HIV-2 because the receptor it is meant to bind to has a different structural conformation.

Viramune is typically used in second-line or subsequent therapies when other treatments fail or a person is intolerant to other available antiretrovirals.

Viramune is used in combination therapy with at least two other antiretroviral drugs. Viramune is never used on its own as it can quickly develop resistance with but a few missed doses. Combination therapy greatly reduces this risk.

All antiretroviral drugs work by blocking a stage in the HIV life cycle. By doing so, HIV is unable to replicate and infect other cells.

One of the key features of HIV infection is the virus' ability to infiltrate the DNA of an infected cell and "re-program" it so that churns out multiple copies of itself, essentially becoming an HIV factory. It does so with an enzyme called reverse transcriptase that transposes the genetic code of HIV into the DNA of the infected host.

NNRTIs like Viramune interfere with this process by binding to the site where reverse transcriptase turns single-stranded viral RNA into double-stranded DNA. Thinks of it as placing a piece of grit in a zipper. Without the ability to create double-helix DNA, HIV cannot hijack the host cell and generate copies of itself.

NNRTIs differ from nucleoside reverse transcriptase inhibitors (NRTIs) like Viread (tenofovir) and Ziagen (abacavir), the latter or which block transcription by inserting itself in the completed double-helix DNA chain.

Viramune has long been used in the prevention of mother-to-child transmission (PMTCT), wherein a single dose can reduce of transmission by 50%. Viramune is no longer used in this way or recommended for PMTCT the United States.

With that being said, Viramine is not contraindicated for use in pregnancy in women who had already started the drug prior to conception.

Furthermore, Viramune is still used for PMTCT in the developing world, where it is given to newborns as prophylaxis (preventative) therapy for six weeks following birth.

Even though Viramune remains an essential tool in the treatment of HIV, it is a far more complicated drug to use compared to the newer-generation antiretrovirals.

In fact, many of the more serious side effects occur in people with stronger immune systems (as measured by the CD4 count). Side effects include potentially life-threatening liver toxicity and allergies that affect women three times more than men.

For this reason, Viramune is only approved for:

• Men with a CD4 count under 400 cells per microliter (cells/µl)
• Women with a CD4 count under 200 cells/µl

This is unlike any other antiretroviral drug which can be started at any CD4 level (but ideally above 500 cells/mL). These same concerns do not apply to children.

Viramune is metabolized by the liver and can cause toxicity if the liver function is impaired. People with moderate to severe impairment (as measured by a Child-Pugh score of B or C) should not use Viramune. This includes people with cirrhosis or advanced chronic hepatitis.

Viramune should also be avoided in people whose treatment was stopped as a result of a drug allergy. If Viramune is stopped for this reason, it should never be used again even if the reaction was mild. Doing so may trigger a potentially life-threatening, whole-body reaction known as anaphylaxis.

Although Viramune is safe to use during pregnancy, the Centers for Disease Control and Prevention (CDC) advises mothers with HIV to avoid breastfeeding to prevent the possible transmission of the virus through breast milk.

Viramune was the first FDA-approved NNRTI but was soon followed by other drugs of the same class:

• Sustiva (efavirenz), approved in 1998
• Intelence (etravirine), approved in 2008
• Edurant (rilpivirine), approved in 2011
• Pifeltro (doravirine), approved in 2018

In addition, Viramune XR, an extended-release version, was approved by the FDA in 2011, allowing once-daily dosing.

One of the concerns about NNRTIs in general is the risk of cross-resistance. All it takes, for example, to develop resistance to Viramune is one common gene mutation, called the G190E. If you develop the G190E mutation, you will invariably be resistant to Viramune, Sustiva and, to a lesser degree, Intelence and Edurant. 

(Pifeltro poses a lesser concern because it requires multiple, unique mutations.)

Viramune is available as an oral tablet or suspension, either in an immediate-release (Viramune) or extended-release (Viramune XR) formulation. Depending on your age and/or weight, you may be given:

• Viramune immediate-release tablet: 200 milligrams (mg)
• Viramune XR tablet: 100 mg and 400 mg
• Viramune immediate-release suspension: 10 milligrams per milliliters (10 mg/mL)

To reduce the risk of a skin rash, a lower dose of Viramune or Viramune suspension is given for 14 days. Known as an induction dose, it allows your body to adapt to the drug gradually and avoid an immune system overreaction. Thereafter, the dose would be increased using either Viramune or Viramune XR.

If a mild allergy occurs, you may be able to continue treatment at the lower dose for up to 28 days until the symptoms resolve. If they do not, your doctor may consider a change in treatment.

According to the National Institutes of Health (NIH), the recommended dose of Viramune in adults is one 200-mg tablet daily for 14 days, followed by either one 200-mg Viramune tablet taken twice daily or one 400-mg Viramune XR tablet taken once daily.

The recommended Viramune dose in children varies by the body surface area (BSA). The BSA is based on the child's height and weight and is expressed in values of meters squared (m²). The dosing formula is described in milligrams per meters squared (mg/m²).

As with adults, children are typically given an induction dose to avoid a skin allergy. This may be unnecessary for children under two.

According to the NIH guidelines, the recommended dose of Viramune for children is as follows:

Viramune XR can be used in children 6 and over if their BSA is over a certain threshold. In such cases, the Viramune XR dose would be prescribed as follows:

People on hemodialysis for kidney failure should be given an additional dose of Viramune at the end of every dialysis session. This is because dialysis causes a rapid drop in the concentration of Viramune in the blood, something that the additional dose can compensate for.

Viramune can be taken with or without food. To maintain the optimal blood concentration, try to take Viramune at the same time every day.

Among the other considerations:

• Viramune suspension should be shaken before use and measured with a 5-mL dosing spoon or oral syringe to ensure accuracy.
• Oral tablets should be swallowed whole and never crushed, chewed, or divided.
• Viramune XR should never be used in children under 6 years of age.

Viramune tablets and suspension can be stored at room temperature, between 59 to 86 F (15 to 30 C). Never use Viramune that has expired.

The most common side effect of Viramune is rash, typically occurring within the first six weeks of treatment. Most cases are mild to moderate and do not inherently require the termination of treatment.

The rash will manifest with flat or raised red bumps with or without itchiness. The outbreak is often widespread and generalized, involving the trunk, leg, arms, or face. According to premarket research, around 13% of users will experience mild to moderate (Grade 1/2) rash.

Other common side effects include:

• Nausea
• Headache
• Fatigue
• Diarrhea
• Stomach pain
• Muscle aches

Most of the side effects are tolerable and tend to resolve once your body adapts to treatment.

In 2000, the FDA issued a black box warning, advising consumers and doctors that Viramune could cause life-threatening liver toxicity and skin reactions. According to the FDA, as many as 4% of users will develop drug-induced hepatitis, while 1.5% will develop a severe Grade 3/4 rash as a result of Viramune use.

Viramune-induced hepatotoxicity (liver toxicity) generally occurs within six weeks of starting therapy. Women with a CD4 count over 250 cells/µl and men with a CD4 count over 400 cells/µl are at greatest risk. Hepatotoxicity can also occur in late weeks or months in people co-infected with hepatitis B or hepatitis C.

Symptoms may include:

• Stomach pain
• Nausea
• Persistent fatigue
• Dark-colored urine
• Chalky or clay-colored stools
• Jaundice (yellowing of the skin and eyes)
• Loss of appetite
• Fever

Rash is also a common feature. In rare cases, Viramune-induced hepatoxicity has been known to cause liver damage, liver failure, and death.

To avoid hepatotoxic reactions, liver enzymes should be routinely monitored during treatment, particularly in people with cirrhosis or reduced liver function.

While most Viramune-induced skin reactions are mild, some can become deadly if not recognized and treated early. Chief among these are Stevens-Johnson syndrome (SJS) and the imminently more severe toxic epidermal necrosis (TEN).

Both are drug hypersensitivity reactions that manifest with the rapid and severe delamination of the skin layers. SJS and TEN tend to develop in the first six weeks of treatment, often in a sequential pattern. Symptoms include (by order of appearance):

• Sudden high fever
• Flu-like symptoms
• Unexplained, widespread skin pain
• Fast-developing red or purple rash
• Formation of blisters on the skin and mucous membranes of the mouth, nose, eyes, and genitals
• Severe shedding of the skin within days

If left untreated, SJS and TEN can lead to massive dehydration, local and systemic infection, sepsis, shock, multiple organ failure, and death.

Viramune is metabolized by a liver enzyme known as cytochrome P450 (CYP450). This is the same enzyme that many other drugs use for metabolization. If taken together, the competition for CYP450 can cause a drug's concentration to drop (reducing its efficacy) or rise (increasing the risk of side effects).

In some cases, separating or adjusting the doses can compensate for this effect. In others, a drug substitution may be needed.

Among some of the more concerning drug interactions are:

• Anti-arrhythmia drugs, like amiodarone and lidocaine
• Antibiotics like clarithromycin
• Anticoagulants like warfarin
• Anticonvulsants like carbamazepine and clonazepam
• Antifungals like fluconazole, ketoconazole, and itraconazole
• Calcium channel blockers like nifedipine and verapamil 
• Chemotherapy drugs like cyclophosphamide
• Immunosuppressants like cyclosporine and tacrolimus
• Opioids like fentanyl and methadone
• Oral contraceptives like norethindrone and ethinyl estradiol
• Tuberculosis drugs like rifampin and rifabutin

To avoid interactions, advise your doctor about any and all drugs you take, whether they are prescription, over-the-counter, nutritional, herbal, or recreational.