Cabenuva is a long-acting HIV treatment given monthly or every two months to help maintain undetectable HIV levels. Cabenuva contains antiviral medications, cabotegravir and rilpivirine, that work by suppressing the virus and preventing it from multiplying. Cabenuva is a complete HIV treatment, so daily pills are no longer required, and less frequent dosing makes it a preferred option for many individuals managing HIV.

Cabenuva’s FDA approval is for HIV-1 treatment in adults and children over the age of 12 who weigh at least 77 pounds (35 kg). It is used to replace a stable antiretroviral regimen in patients with HIV that is virologically suppressed and have no history of treatment failure or resistance to cabotegravir or rilpivirine.

Cabenuva contains two injections (cabotegravir and rilpivirine) that are administered as separate intramuscular injections in the buttocks.  Before you start injections, your doctor may prescribe daily starter pills for about a month to check your tolerance to this medicine.

HIV-1 is the virus that can cause acquired immunodeficiency syndrome (AIDS). Cabenuva is not a cure for HIV or AIDS.

How does Cabenuva work?

Cabenuva contains two antiretroviral medicines, cabotegravir and rilpivirine, that work together to stop HIV from multiplying and keep the virus at undetectable levels.

• Cabotegravir’s mechanism of action is an integrase strand transfer inhibitor (INSTI) that prevents HIV from integrating its genetic material into the host’s DNA, a crucial step in the viral replication cycle.
• Rilpivirine’s mechanism of action is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that inhibits the reverse transcriptase enzyme, thereby blocking the conversion of viral RNA into DNA, another essential process for HIV replication.

Cabenuva side effects

Common Cabenuva side effects are: 

• pain, redness, swelling, itching, bruising, warmth, or a hard lump where an injection was given;
• fever;
• nausea;
• pain in your bones, joints, or muscles;
• feeling tired, sleep problems;
• headache, dizziness, or
• rash.

Serious Cabenuva side effects

Get emergency medical help if you have signs of an allergic reaction with symptoms of hives, fever, tiredness, body aches, not feeling well, sores or blisters in your mouth, red or puffy eyes, difficulty breathing, swelling of your face and lips, tongue, or throat.

Seek medical treatment if you have a serious drug reaction that can affect many parts of your body. Symptoms may include skin rash, fever, swollen glands, muscle aches, severe weakness, unusual bruising, or yellowing of your skin or eyes.

Your Cabenuva injections may be permanently discontinued if you have an allergic reaction.

Some side effects may occur within a few minutes after an injection. Tell your caregiver if you feel anxious, warm, light-headed, sweaty, or have stomach pain or numbness in your mouth.

Cabenuva may cause other serious side effects. Call your doctor at once if you have:

• unusual changes in mood or behavior;
• suicidal thoughts or actions; or
• liver problems – loss of appetite, nausea, vomiting, stomach pain (upper right side), itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects.

Warnings

This should not be given to people with a history of hypersensitivity reactions to the active ingredients cabotegravir or rilpivirine or to any of the inactive ingredients in the injection kit.

Tell your doctor about all your current medicines and any you start or stop using. Many drugs can interact, and some drugs can decrease the effectiveness of Cabenuva and should not be used together.

Serious injection-related reactions have occurred with the rilpivirine component. Tell your doctor if you experience any severe pain, swelling, or redness at the injection site.

Adverse liver toxicity has been reported with cabotegravir and rilpivirine injections, and your doctor will need to monitor your liver function tests.

Depression has also been reported. Tell your doctor if you experience any changes in your mood.

Although residual concentrations of cabotegravir or rilpivirine can remain in your circulation for up to 12 months following your last injections, it is important that if you discontinue Cabenuva or if virological failure is suspected, then a new regimen is initiated no later than 1 month after the final injection.

Before taking this medicine

To make sure that the Cabenuva injection kit is safe for you, tell your doctor if you have ever had:

• a skin rash or an allergic reaction after taking medicine that contains cabotegravir or rilpivirine
• liver disease, including hepatitis B or C
• mental illness
• long QT syndrome (in you or a family member).

Tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding.

Children

Cabenuva is not approved for use by anyone younger than 12 years old or weighing less than 77 pounds (35 kilograms).

Pregnancy

There is a lack of information about using Cabenuva during pregnancy and cabotegravir and rilpivirine can be detected in systemic circulation for up to 12 months or longer after discontinuing the injections. Talk to your doctor if you intend to become pregnant to discuss the risks versus benefits taking into consideration that HIV can be passed to your baby if the virus is not controlled during pregnancy.

If you inadvertently become pregnant there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cabotegravir or rilpivirine during pregnancy. Your healthcare provider can register you by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Lactation

Women with HIV or AIDS should not breastfeed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

How is Cabenuva administered?

Cabenuva is administered as two injections into your buttock muscles monthly or every other month by your healthcare provider .
Before your doctor administers Cabenuva injections, they may need to determine that you can tolerate the active ingredients, which are cabotegravir and rilpivirine. At least 28 days before your first injection, you may take the tablet forms of cabotegravir and rilpivirine once per day with a meal. This “lead-in dose” will help determine that you can safely use these medicines together.

• Cabenuva is given on a monthly or 2-monthly dosing schedule
• On the last day you take the tablets, you will receive your first injectable dose of this medicine.
• Cabenuva injection site is the gluteal (buttock) muscle. A healthcare provider will give you this medicine as 2 separate injections in the same muscle, 2cm apart, or one injection in each buttock.
• You will be watched closely for about 10 minutes after each injection, to make sure you do not have a serious reaction.
• The timing of your injections is very important to the success of your HIV treatment. Your doctor may set a calendar day as your “target treatment date” to help keep you on schedule. If needed, you may receive an injection early or late, up to 7 days before or 7 days after your target date.
• You must remain under the care of a doctor while receiving your injections. Stay on schedule to get the most benefit. Missing doses can increase your risk of medication-resistant HIV.
• If you stop using Cabenuva, you will need to start using other HIV medicines within 1 month to prevent your condition from becoming resistant. Call your healthcare provider right away to discuss your treatment options.
• You will need frequent medical tests. Cabenuva can have long-lasting effects on your body (up to 12 months after your last dose). You may still need medical tests for a short time after you stop using this medicine.

Cabenuva dose information

Cabenuva is administered by intramuscular injections into the gluteal muscle by your healthcare provider 

Cabenuva monthly dosing schedule

Start injections of Cabenuva (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in.

Thereafter, continue with injections of Cabenuva (400 mg cabotegravir and 600 mg rilpivirine) every month.

Cabenuva 2-monthly dosing schedule

Initiate injections of Cabenuva (600 mg cabotegravir and 900 mg rilpivirine) on the last day of current antiretroviral therapy or oral lead-in, for 2 consecutive months.

Thereafter, continue with injections of Cabenuva (600 mg cabotegravir and 900 mg rilpivirine) every 2 months.

Cabenuva dosage forms and strengths

Cabenuva Kit of single-dose vials:

• 400 mg/2 mL of cabotegravir and 600 mg/2 mL of rilpivirine 
• 600 mg/3 mL of cabotegravir and 900 mg/3 mL of rilpivirine 

What happens if I miss a dose?

Call your doctor for instructions if you miss an appointment for your Cabenuva injection.

If you plan to miss an injection by more than 7 days, you may need to take cabotegravir and rilpivirine tablets each day until your next monthly injection is due. You should start taking the tablets about 1 month after your last injection was given. If needed, daily tablets can replace the injections for up to 2 months in a row.

If you miss an injection by more than 7 days and you have not started taking the medicine in tablet form, your doctor may need to decide whether or not Cabenuva is the best treatment for you.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

What should I avoid while using Cabenuva?

Cabenuva is a complete treatment for HIV. Do not use other HIV medications unless your doctor tells you to.

Cabenuva J code

Cabenuva J code is J0741 (2mg/3mg, injection)
J codes are used for medicines that are not taken orally and include injections, inhalations, and chemotherapies. J codes are important for accurate and consistent coding for billing and reimbursement purposes.

Your physician will need the Cabenuva J code when filling out forms for your treatment.

What other drugs will affect Cabenuva?

Do not use Cabenuva with other medicines that are used to treat HIV.

Other medications can affect how the injections work. Examples include:

• apalutamide
• certain antibiotics – azithromycin, clarithromycin, erythromycin, rifabutin, rifampin, rifapentine; or
• dexamethasone (in more than 1 dose);
• enzalutamide
• medications with a known risk of Torsade de Pointes, such as droperidol or disopyramide
• methadone
• seizure medicine – carbamazepine, oxcarbazepine, phenobarbital, phenytoin.
• St. John’s wort;
• Viekira Pak (dasabuvir, ombitasvir, paritaprevir, and ritonavir).

Medications that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may also decrease the plasma concentrations of cabotegravir and rilpivirine.

Cabenuva can stay in your system for 12 months or longer. If you stop using it, follow your doctor’s instructions about using any other medicines during the first year after your last dose.

This list is not complete. Many other drugs may interact with atorvastatin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Cabenuva Package Insert 

HCPs and patients often use the Cabenuva Package Insert (PI) for more detailed information about this medicine. The Cabenuva Package Insert contains more comprehensive information on Indications and Usage, Dosage and Administration, Clinical Pharmacology, Clinical Studies, Drug Interaction, and more. Discuss any medical questions you have with your HCP (health care professional). This is not all the information you need to know about this medicine for safe and effective use, and it does not take the place of talking to your doctor about your treatment.

The Package Insert is sometimes called Cabenuva Prescribing Information (PI) or FDA label.

Ingredients

The Cabenuva injection kit contains cabotegravir and rilpivirine as separate single-dose vials. There are two different kit strengths.

Each dosing kit also contains 2 syringes, 2 syringe labels, 2 vial adapters, and 2 needles for intramuscular injection (23-gauge, 1½ inch). The vial stoppers are not made with natural rubber latex.

Cabenuva 400/600mg kit

• One single-dose vial of cabotegravir extended-release injectable suspension 400 mg/2 mL (200 mg/mL)
• One single-dose vial of rilpivirine extended-release injectable suspension 600 mg/2 mL (300 mg/mL).

Cabenuva 600/900mg kit

• One single-dose vial of cabotegravir extended-release injectable suspension 600 mg/3 mL (200 mg/mL)
• One single-dose vial of rilpivirine extended-release injectable suspension 900 mg/3 mL (300 mg/mL).

Biktarvy is a complete HIV-1 treatment in a once-a-day single tablet that contains the three antiviral medicines bictegravir, emtricitabine, and tenofovir alafenamide.  Biktarvy works by preventing HIV from multiplying in your body, lowering HIV blood levels, and decreasing your chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses, such as cancer or severe infections. 

Biktarvy is a complete treatment and should not be used with any other HIV medicines. Human immunodeficiency virus type 1 (HIV-1) is the virus that can cause acquired immune deficiency syndrome (AIDS).

There is no Biktarvy generic available.

Who can take Biktarvy?

Biktarvy is used to treat HIV-1 infection in adults and pediatric patients who weigh at least 14 kg who:

• have not taken HIV-1 medicine in the past OR
• to replace their current HIV-1 medicine if they are virologically suppressed (HIV-1 RNA less than 50 copies per mL), on a stable antiretroviral regimen with no history of treatment failure and with no known substitutions associated with resistance to bictegravir or tenofovir.
• have taken antiretroviral treatment in the past and are not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir.

Biktarvy’s FDA approval was first received on February 7, 2018, by Gilead Sciences, Inc. The latest expansion of FDA approval on July 30, 2025, makes Biktarvy a treatment option for patients with HIV who need to restart treatment and are not virologically suppressed.

Biktarvy is also recommended by the CDC as one of the preferred agents for PEP (post-exposure prophylaxis of HIV-1), despite it not being FDA-approved for this purpose. 

How does Biktarvy work?

Biktarvy contains three antiviral active ingredients that prevent HIV replication, which decreases viral load. 

Biktarvy’s mechanism of action is as an integrase strand transfer inhibitor (INSTI) for the active ingredient bictegravir, and as nucleoside reverse transcriptase inhibitors (NRTIs) for the active ingredients emtricitabine and tenofovir alafenamide. 

Biktarvy Side Effects

Common Biktarvy side effects

The most common Biktarvy side effects include: 

• Diarrhea (6%)
• Nausea (6%) 
• Headache (5%) 
• Tiredness (3%) 
• Abnormal dreams (3%) 
• dizziness (2%) 
• Sleep problems (2%) 
• Bloating abdomen (2%) 

These common side effects occurred in 2% or more of Biktarvy patients in clinical trial 1489. 

Biktarvy’s other side effects, of abdominal pain, gas (flatulence), indigestion (dyspepsia), and vomiting, occurred in less than 2% of patients in clinical trials 1489 and 1490.

Biktarvy side effects may also include laboratory abnormalities.

Serious Biktarvy side effects

If you are allergic to Biktarvy, get emergency medical help if you have signs of an allergic reaction, including rash, hives, shortness of breath, or swelling of your face, lips, tongue, or throat.

Biktarvy may cause other serious side effects. Call your doctor at once if you have:

• Kidney problems – little or no urination, swelling in your feet or ankles, feeling tired or short of breath;
• Lactic acidosis – muscle pain or weakness, numbness or cold feeling, trouble breathing, stomach pain, vomiting, irregular heart rate, dizziness, or feeling very weak or tired; or
• Liver problems – swelling around your midsection, upper stomach pain, unusual tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Biktarvy affects your immune system, which may cause certain side effects (even weeks or months after you’ve taken this medicine). Tell your doctor if you have:

• Signs of a new infection – fever, night sweats, swollen glands, cold sores, cough, wheezing, diarrhea, weight loss;
• Trouble speaking or swallowing, problems with balance or eye movement, weakness or prickly feeling; or
• Swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence.

This is not a complete list of side effects, and others may occur. Talk to your doctor, pharmacist, or healthcare provider for medical advice about side effects.

Warnings

Biktarvy has a boxed warning for worsening of hepatitis B virus (HBV) infection after stopping treatment with Biktarvy.  If you’ve ever had hepatitis B, it may become active or get worse after you stop using this medicine. You should have liver function tests with both clinical and laboratory follow-up before treatment and for several months after treatment to determine if you need to be prescribed medicine to treat hepatitis B. Always tell your prescriber about any new or unusual symptoms you may have after you stop taking this medicine.

Biktarvy is not recommended in patients with severe renal impairment, patients with end-stage renal disease who are not receiving chronic hemodialysis, or patients with no antiretroviral treatment history and end-stage renal disease (ESRD) who are receiving chronic hemodialysis

Do not run out of these tablets. Before your tablets are finished, you should refill your prescription or talk to your healthcare provider.

You should not stop taking these tablets without first talking to your doctor.

Before taking this medicine

You should not use this medicine if you are allergic to antiviral medicines bictegravir, emtricitabine, or tenofovir contained in medicines such as Atripla, Complera, Emtriva, Descovy, Genvoya, Odefsey, Stribild, or Truvada.

Some medicines can cause unwanted or dangerous effects when used with Biktarvy, and your doctor may need to change your treatment plan. Do not take Biktarvy if you also take a medicine that contains: 

• dofetilide; or
• rifampin.

Tell your doctor if you have or ever had:

• liver disease (especially cirrhosis) 
• hepatitis B virus (HBV)
• kidney disease

Before starting treatment with this medicine, you will be tested for hepatitis B virus infection.

Before starting treatment and during treatment, your serum creatinine, estimated creatinine clearance, urine glucose, and urine protein will be monitored as clinically appropriate. In patients with chronic kidney disease, serum phosphorus will also be assessed. 

Pregnancy

Tell your healthcare provider if you are pregnant or plan to become pregnant during treatment with this medicine. There is a pregnancy registry for women who take this medicine during pregnancy. The purpose of this registry is to collect information about your and your baby’s health. Talk with your healthcare provider about how you can take part in this registry by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258- 4263.

Breastfeeding

Tell your healthcare provider if you are breastfeeding or planning to breastfeed. This medicine passes to your baby in your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with this medicine: 

• The HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection. 
• The HIV-1 virus may become harder to treat if your baby has HIV-1 infection. 
• Your baby may get side effects from these tablets. 

Talk with your healthcare provider about the best way to feed your baby.

How should I take Biktarvy?

• Take one tablet once a day; it can be taken with or without food.
• Children who have difficulty swallowing a whole tablet can have the tablet split in half and then swallow each part separately, as long as all parts are swallowed within about 10 minutes.
• You should not change your dose or stop taking this medicine without first talking with your healthcare provider. Stay under a healthcare provider’s care during treatment with this medicine.
• If you take other medicines, such as antacids or supplements, see the drug interaction section for specific advice.
• For patients who are on dialysis, you should take your tablet following dialysis.
• Do NOT let your tablets run out. When your medicine supply starts to run low, get more from your healthcare provider or pharmacy before you run out. If the medicine is stopped for even a short time, the amount of virus in your blood may increase, and the virus may develop resistance to this medicine and become harder to treat.
• You will need frequent medical tests.
• Do not miss a dose of Biktarvy.

Take Biktarvy exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

Biktarvy is a complete HIV-1 treatment regimen. You should not take it with other HIV-1 medicines.

Biktarvy Dosage Information

Usual Biktarvy dose in adults and pediatric patients weighing at least 25 kg, or virologically-suppressed adults with estimated creatinine clearance below 15 mL/min receiving chronic hemodialysis:

• Biktarvy (Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) one tablet once a day, with or without food.

Recommended Biktarvy dosage in pregnant individuals who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to the individual components of Biktarvy: 

• Biktarvy (Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) one tablet once a day, with or without food.

Usual Biktarvy dose pediatric (weighing 14 kg to less than 25 kg):

• Biktarvy (Bictegravir 30 mg/emtricitabine 120 mg/tenofovir alafenamide 15mg) one tablet once a day, with or without food.

Renal impairment: Biktarvy is not recommended in patients with an estimated creatinine clearance of 15 to below 30 mL/min, or below 15 mL/min who are not receiving chronic hemodialysis, or below 15 mL/min who have no antiretroviral treatment history. 

Hepatic impairment: This medicine is not recommended in patients with severe hepatic impairment. 

Comments:

For children who are at least 14 kg to less than 25 kg and are unable to swallow a whole tablet, the tablet can be split, and each part can be taken separately as long as all parts are ingested within about 10 minutes.

Biktarvy tablets are available in two different strengths:

• 30 mg bictegravir, 120 mg emtricitabine, 15 mg tenofovir alafenamide
• 50 mg bictegravir, 200 mg emtricitabine, 25 mg tenofovir alafenamide

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not use two doses at one time.

When your tablets supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to this medicine and become harder to treat.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

What other drugs will affect Biktarvy?

Sometimes, it is not safe to use certain medications at the same time as taking Biktarvy. Drugs can affect the blood levels of other drugs you take, which may increase side effects or make the medications less effective.

You should not take Biktarvy with

• dofetilide; or
• Rifampin.

It is not recommended to take Biktarvy with:

• Rifabutin
• Rifapentine
• St. John’s wort

When taking Biktarvy, alternative anticonvulsants should be considered instead of:

• carbamazepine
• oxcarbazepine
• phenobarbital
• phenytoin.

Avoid taking these tablets with other medications that may also harm the kidneys. Serious side effects, such as acute renal failure, have been reported in postmarketing studies.

Antacids containing aluminium/magnesium:

• Biktarvy can be taken at least 2 hours before or 6 hours after taking antacids containing aluminium/magnesium.

Supplements or Antacids containing Calcium or Iron:

• Biktarvy and supplements or antacids containing calcium or iron can be taken together with food.

In pregnant individuals:

Antacids containing Al/Mg:

• Biktarvy can be taken at least 2 hours before or 6 hours after antacids containing aluminium/magnesium regardless of food intake.

Supplements or Antacids containing Calcium or Iron:

• Biktarvy and supplements or antacids containing calcium or iron can be taken together with food.
• When Biktarvy is taken on an empty stomach it should be taken at least 2 hours before or 6 hours after supplements or antacids containing calcium or iron.

General interaction information

Many drugs can interact with Biktarvy. This includes prescription, over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any medicine you start or stop using. 

Biktarvy Package Insert 

HCPs and patients often use the Biktarvy Package Insert (PI) for more detailed information about this medicine. The Package Insert contains more comprehensive information on Indications and Usage, Dosage and Administration, Clinical Pharmacology, Clinical Studies, Drug Interaction, and more. Discuss any medical questions you have with your HCP (health care professional). This is not all the information you need to know about this medicine for safe and effective use, and it does not take the place of talking to your doctor about your treatment.

The Package Insert is sometimes called the Biktarvy Prescribing Information (PI) or FDA label.

Storage

• Store tablets in the original bottle below 86°F (30 °C).
• Keep the bottle tightly closed.
• This medicine contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not eat the desiccant packet.
• Store the tablets blister pack at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
• Keep tablets in their original bottle or blister pack.
• Biktarvy comes in a child-resistant package.

What is Harvoni?

Harvoni is used to treat hepatitis C virus (HCV) infections in adults and children aged 3 years and older.

Harvoni’s mechanism of action involves preventing HCV from replicating (making copies of itself) in the body. Harvoni contains 2 antivirals, ledipasavir and sofosbuvir. Each has a different mechanism of action. Ledipasvir blocks the effects of an HCV protein required for HCV replication. Sofosbuvir is converted in the body to its active metabolite which incorporates itself into the RNA of HCV, also preventing HCV replication.  from making copies of itself.

Harvoni gained FDA approval for HCV on October 10, 2014. A Harvoni generic is available as ledipasvir 90 mg and sofosbuvir 400 mg. There is no Harvoni generic for the other strength of Harvoni (ledipasvir 45 mg sofosbuvir 200 mg) or Harvoni oral pellets.

Harvoni uses

Harvoni is used for HCV genotypes 1, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis.

Harvoni also treats HCV genotype 1 infection with advanced cirrhosis (decompensated) in combination with ribavirin and people with HCV genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis who have had a liver transplant, in combination with ribavirin.

Your doctor will perform tests to find out which hepatitis genotype you have. The treatment duration of Harvoni is usually 12 weeks.

Harvoni cost

Most insurance companies and Medicare cover the cost of Harvoni; however, you may have to meet certain criteria and you should always check with your insurance company first before you and your doctor make it your preferred treatment. There may also be a co-pay.

Harvoni side effects

The most common side effects of Harvoni include:

• tiredness
• headache
• weakness.

Serious side effects and warnings

Harvoni carries a Boxed Warning for the risk of hepatitis B (HBV) reactivation in people coinfected with HCV and HBV. 

Hepatitis B virus (HBV) reactivation. Before starting treatment with Harvoni, your healthcare provider will do blood tests to check for HBV. If you have ever had HBV, the hepatitis B virus could become active again during or after treatment of HCV with Harvoni. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking Harvoni. Call your healthcare provider right away if you develop right-sided upper abdominal pain, vomiting, loss of appetite, or yellowing of your skin or eyes.

Slow heart rate (bradycardia). Harvoni may slow your heart rate and cause other symptoms when taken alongside other heart medications such as amiodarone (Cordarone, Nexterone, Pacerone). In some cases, this has led to death or the need for a heart pacemaker. Get medical help right away if you take amiodarone with Harvoni and develop any of the following symptoms fainting or near-fainting, weakness, chest pains, dizziness or lightheadedness, extreme tiredness, confusion, not feeling well, shortness of breath, or memory problems.

Harvoni is used in combination with ribavirin in people with decompensated cirrhosis. Ribavirin can cause birth defects or death in an unborn baby. Do not use ribavirin if you are pregnant, or if you are a man and your sexual partner is pregnant. Use effective birth control to prevent pregnancy while using these medicines together and for at least 6 months after treatment ends.

It is unknown if Harvoni is safe and effective in children under 3 years of age.

These are not all the possible side effects of Harvoni. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA .

Before taking

Before taking Harvoni, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had a hepatitis B virus infection
• have liver problems other than hepatitis C infection
• have had a liver transplant
• have kidney problems or you are on dialysis
• have HIV infection
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed.

Pregnancy

It is not known if Harvoni will harm your unborn baby. Males and females who take Harvoni in combination with ribavirin should also read the Ribavirin Medication Guide for important pregnancy, contraception, and infertility information.

Breastfeeding

It is not known if Harvoni passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Harvoni.

How do I take Harvoni?

Take Harvoni treatment exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. Do not stop taking Harvoni without first talking with your healthcare provider.

• Take Harvoni tablets or oral pellets by mouth, with or without food.
• You must not miss or skip doses during treatment.
• Harvoni is usually given for 12 weeks.

Harvoni treatment

The usual dosage of Harvoni to treat HCV in adults is Harvoni 90 mg/400 mg, 1 tablet each day.

The usual dosage of Harvoni to treat HCV in children 3 years of age and older is based on body weight.

• Tell your healthcare provider if your child has problems with swallowing tablets.
• If your healthcare provider prescribes Harvoni oral pellets for your child, see below.

How should I give Harvoni oral pellets to my child?

See the Instructions for Use in the Harvoni Package insert for detailed information about giving or taking Harvoni oral pellets if you or your child are prescribed Harvoni treatment. Administer the pellets exactly as instructed by your healthcare provider.

• Do not open the packet until ready to use.
• Hold the Harvoni pellets packet with the cut line on top.
• Shake the pellets packet gently to settle the pellets.
• Tear or cut the packet along the cut line.
• Harvoni oral pellets can be taken with or without food.
• If your healthcare provider has prescribed more than one packet of pellets, take the next packet in the same way.

Taking Harvoni pellets with food 

If Harvoni pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature.

• Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream.
• Take Harvoni pellets within 30 minutes of gently mixing them with food and swallow the entire contents without chewing to avoid a bitter taste.
• Do not store any leftover Harvoni mixture (oral pellets mixed with food) for use at a later time. Throw away any unused portion.

Taking Harvoni pellets without food

If Harvoni pellets are taken without food, sprinkle the entire contents of the packet directly into the mouth and swallow without chewing to avoid a bitter taste.

• Water may be taken after swallowing the pellets to avoid a bitter taste. Make sure no pellets remain in the packet.

What to avoid

Ask your doctor before using an antacid or stomach acid-reducing medicine with Harvoni. Use only the type and amount your doctor recommends.

Using Harvoni will not prevent your disease from spreading. Do not have unprotected sex or share razors or toothbrushes if you have HCV. Talk with your doctor about safe ways to prevent HCV transmission during sex. Sharing drugs or medicine needles is never safe, even for a healthy person.

What happens if I miss a dose?

Do not miss a dose of Harvoni. Missing a dose lowers the amount of medicine in your blood. Refill your Harvoni prescription before you run out of medicine.

If you miss a dose of Harvoni, take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

If you take too much Harvoni, call your healthcare provider, call the Poison Help line, or go to the nearest hospital emergency room right away.

What other drugs will affect Harvoni?

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:

• Amiodarone, because coadministration may result in a seriously slow heartbeat ( bradycardia). Amiodarone should not be used with Harvoni
• P-gp inducers and/or moderate to strong CYP inducers (such as rifampin, St. John’s wort, and carbamazepine). May decrease concentrations of Harvoni. Use together is not recommended
• Omeprazole (Prilosec) or an antacid. Do not take them for at least 4 hours after you have taken your dose of Harvoni because these may affect the absorption of Harvoni.

Clearance of HCV with direct-acting antivirals may lead to changes in liver function, which may impact the safe and effective use of other medications. Frequent laboratory monitoring (INR and blood glucose) and dose adjustments may be necessary.

This is not a full list of interactions. Ask your healthcare provider or pharmacist for a list of medicines that interact with Harvoni. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Harvoni with other medicines.

Storage

Store Harvoni tablets or pellets below 86°F (30°C). Keep them in their original container. Do not use:

• Harvoni tablets if the seal over the bottle opening is broken or missing
• Harvoni pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or damaged.

Keep out of the reach of children.

Harvoni ingredients

Active ingredients: ledipasvir and sofosbuvir

Inactive ingredients, Harvoni 90/400 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Tablet film-coating contains FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Inactive ingredients, Harvoni 45/200 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Tablet film-coat contains polyethylene glycol, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.

Inactive ingredients, Harvoni Oral Pellets: amino-methacrylate copolymer, colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

Who makes Harvoni?

Gilead Sciences, Inc., makes Harvoni.

• Harvoni tablets 90 mg/ 400 mg and 45 mg/ 200 mg
• Harvoni pellets 45 mg/ 200 mg, 33.75 mg/150 mg.

Asegua Therapeutics LLC., a subsidiary of Gilead Sciences Inc., makes generic Harvoni tablets under the name ledipasvir 90 mg/ sofosbuvir 400 mg.

What is Mavyret?

Mavyret is an oral combination medicine containing fixed doses of 2 antivirals, glecaprevir, and pibrentasvir, that may be used to treat adults and children 3 years of age and older with:

• chronic (lasting a long time) hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
• HCV genotype 1 infection who have been previously treated with a regimen that contained an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both.

The 2 ingredients in Mavyret, glecaprevir and pibrentasvir, work in different ways to prevent the replication of the HCV virus. Glecaprevir inhibits an enzyme called NS3/4A protease which is essential for cleavage of HCV into its mature forms. Pibrentasvir inhibits NS5A, a protein that also plays a key role in HCV RNA replication. Cure rates of 95% to 99% after 8 weeks of treatment have been reported in people with hep C who took Mavyret.

Mavyret was first FDA-approved on August 3, 2017.

Mavyret side effects

The most common side effects of Mavyret affecting 10% or more people who take it are headache and tiredness.

These are not all the possible side effects of Mavyret. Call your doctor for medical advice about side effects. You may report side effects to the FDA

Warnings

Do not use if you:

• have moderate to severe liver disease (Child-Pugh B or C) or with a history of liver decompensation
• take atazanavir or rifampin.

Mavyret can cause serious side effects, including:

Hepatitis B virus reactivation. If you have ever had a hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment for the hepatitis C virus with Mavyret. Hepatitis B virus that becomes active again (called reactivation) may cause serious liver problems including liver failure and death. Before starting treatment, your healthcare provider will do blood tests to check for hepatitis B virus infection and will monitor you if you are at risk for hepatitis B virus reactivation during and after treatment.

A rare risk of worsening liver problems, liver failure, and death in people who had or have advanced liver problems before starting treatment. Your healthcare provider will check you for signs and symptoms of worsening liver problems during treatment with Mavyret. Tell your healthcare provider right away if you have any of the following signs and symptoms:

• nausea
• tiredness
• yellowing of your skin or the white part of your eyes
• bleeding or bruising more easily than normal
• confusion
• dark, black, or bloody stools
• loss of appetite
• diarrhea
• dark or brown (tea-colored) urine
• swelling or pain on the upper right side of your stomach area (abdomen)
• sleepiness
• vomiting of blood
• lightheadedness.

It is unknown if Mavyret is safe and effective in children under 3 years of age.

Before taking

Do not take Mavyret if you:

• have certain liver problems
• also take atazanavir or rifampin

Before taking Mavyret, tell your healthcare provider about all of your medical conditions, including if you:

• have had hepatitis B virus infection
• have liver problems other than hepatitis C virus infection.
• have HIV-1 infection
• have had a liver or a kidney transplant
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed.

Pregnancy

It is not known if Mavyret will harm your unborn baby.

Breastfeeding

It is not known if Mavyret passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby.

How should I take Mavyret?

Take Mavyret exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking it unless your healthcare provider tells you to.

The dosage of Mavyret varies depending on age, HIV coinfection, kidney disease, and some other factors.

• Usual Mavyret dosage for adults and children aged 12 years and older or weighing at least 99 pounds (45 kg): 3 tablets (each tablet contains glecaprevir 100 mg and pibrentasvir 40 mg) once a day.
• Usual Mavyret dosage for children aged 3 to less than 12 years: dosing is based on weight. See the prescribing information.

The length of time Mavyret is taken depends on the HCV genotype and the presence or absence of Cirrhosis.

• The usual treatment duration in treatment naïve patients with HCV genotype 1,2,3,4,5, or 6 is 8 weeks.
• Treatment durations of 12 weeks or 16 weeks are recommended for others depending on previous treatments or the presence of compensated cirrhosis (Child-Pugh A).

Take Mavyret with food or a snack.

Try to take it at around the same time each day.

How should I give Mavyret oral pellets to my child?

Administer Mavyret oral pellets exactly as instructed by your healthcare provider.

Give them once a day just before or after a snack or meal.

• Do not open the packet until your child or the person you are looking after who has been prescribed Mavyret is ready to take their dose.

Mix the pellets with a small amount of recommended food, such as peanut or nut butter, strawberry jam, yogurt, or hazelnut spread, in a small bowl and swallow. Do not attempt to crush or dissolve the pellets in soft food because they will taste bitter.

• The Mavyret pellet/food mixture should be taken right away. Tell your child not to chew the pellets. Add more food to the bowl and mix until every pellet has been taken.

If you wait more than:

• 5 minutes before taking the pellet/food mixture, it will taste bitter.
• 15 minutes before taking the pellet/food mixture, it will be less effective.

Follow up the medication with a snack or a meal.

Do not store any leftover mixture for use at a later time. Throw away any unused portion.

What happens if I miss a dose?

If you miss a dose of Mavyret and:

• Less than 18 hours have passed from the time you usually take it, take the missed dose with food as soon as possible. Then take your next dose at your usual time
• It is less than 6 hours till your next dose, do not take the missed dose. Take your next dose as usual with food.

What happens if I overdose?

If you take too much Mavyret, call your healthcare provider or go to the nearest hospital emergency room right away.

What other drugs will affect Mavyret?

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Other medicines may reduce the effectiveness of Mavyret or may cause side effects. Keep a list of your medicines to show your healthcare provider and pharmacist. Especially tell your healthcare provider if you take:

• Carbamazepine
• Dabigatran
• Digoxin
• Ethinylestradiol-containing medications, such as combined oral contraceptives
• HIV antivirals such as atazanavir, darunavir, efavirenz, lopinavir, or ritonavir
• Immunosuppressives, such as cyclosporine
• Rifampin
• St. John’s wort
• Statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin
• Other medications which are metabolized through the liver, such as warfarin, because clearance of HCV infection with Mavyret may lead to changes in liver function. Your healthcare provider should monitor your medications for any change in effect.

What is Paxlovid?

Paxlovid is an antiviral treatment for COVID-19 used to lower the risk of severe COVID-19, including hospitalization or death. Paxlovid contains nirmatrelvir tablets and ritonavir packaged together. 

Paxlovid is an FDA-approved medicine for adults with mild-to-moderate COVID-19 patients who are at high risk of severe COVID-19, including hospitalization or death.

Paxlovid has Emergency Use Authorisation (EUA) to treat patients 12 to 18 years old for mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.

People who are at high risk of severe COVID-19 are patients with:

• heart disease, diabetes, lung disease, cancer, blood disorders, immune disorders, mental health conditions, disabilities or other conditions
• being overweight or obese
• 50 years or older
• lifestyle factors, such as smoking
• physical, mental, and developmental disabilities.

Paxlovid works as nirmatrelvir blocks an enzyme (SARS-CoV-2-3CL protease) that the coronavirus needs to replicate. By preventing the virus from reproducing itself, nirmatrelvir reduces the severity of symptoms and decreases the number of hospitalizations and deaths in high-risk patients. Ritonavir is a medication that helps nirmatrelvir stay in the body longer and at a higher concentration, making nirmatrelvir a more effective antiviral.

You should start taking Paxlovid as soon as possible after COVID diagnosis and within the first 5 days that you have had symptoms. The usual Paxlovid dose is two nirmatrelvir tablets and one ritonavir tablet taken together twice daily for 5 days. The dose needs to be changed if you have kidney problems, and if you are taking certain medicines, Paxlovid is not suitable for some patients.

Paxlovid is not approved for use as a pre-exposure or post-exposure prophylaxis to prevent COVID-19 or for the prevention of long COVID.

Paxlovid may be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants licensed or authorized under state law to prescribe drugs. It may also be prescribed for an individual patient by a state-licensed pharmacist under specific conditions.

Paxlovid side effects

Common Paxlovid side effects

Common Paxlovid side effects include a bad taste or change in taste (5%) and diarrhea (3%) in the EPIC-HR clinical trial. Other Paxlovid side effects, including abdominal pain, nausea, vomiting, high blood pressure, headache, generally feeling unwell (malaise), allergic reaction, and hypersensitivity reactions, occurred in Paxlovid Emergency Use Authorization Experience. 

The Paxlovid side effect of bad taste or change in taste (dysgeusia) is the most common side effect, it is often described as a metallic taste or bitter taste and usually goes when you have finished the course. If you get this side effect, you may want to try gum, mints, or mouthwash for temporary relief.

Serious Paxlovid side effects

Paxlovid may cause serious side effects, including allergic reactions, hypersensitivity reactions, and liver problems.

Allergic reactions: Get emergency medical help if you have signs of an allergic reaction (hives, difficulty breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Liver problems: Call your doctor at once if you have:

• liver problems symptoms include loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Ritonavir side effects

Ritonavir, one of the active ingredients in Paxlovid, affects your immune system, which may cause certain side effects (even weeks or months after you’ve taken nirmatrelvir and ritonavir). Tell your doctor if you have:

• signs of a new infection–fever, night sweats, swollen glands, cold sores, cough, wheezing, diarrhea, weight loss;
• trouble speaking or swallowing, problems with balance or eye movement, weakness or prickly feeling; or
• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects.

Warnings

Paxlovid Drug Interactions: Paxlovid can interact with other medicines, causing severe or life-threatening side effects or death. It is important to know the medicines that should not be taken with Paxlovid. See the Interactions section below and check the interactions checker.

Hypersensitivity Reactions: Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with this medicine. Do not take this medicine if you are allergic to nirmatrelvir, ritonavir, or any of the ingredients in Paxlovid. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately stop taking Paxlovid and start appropriate medications and/or supportive care. 

Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir, one of the active ingredients in Paxlovid.

HIV-1 Drug Resistance: Using Paxovid may lead to a risk of HIV-1 developing resistance to HIV protease inhibitors if you have uncontrolled or undiagnosed HIV-1 infection. 

Paxlovid rebound and COVID rebound

COVID rebound is when COVID symptoms return between 2 and 8 days after finishing treatment; symptoms are mild, transient, and usually clear up in 1 to 3 days. COVID rebound can happen in some people who are vaccinated, unvaccinated, Paxlovid treated, and people who have not been treated with Paxlovid. When COVID-19 symptoms return in Paxlovid-treated patients, some people have called it Paxlovid rebound.

The CDC states that “There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.”

Before taking this medicine

You should not use Paxlovid if you are allergic to the active ingredients nirmatrelvir and ritonavir or any of the inactive ingredients. A list of ingredients is at the bottom of this page.

Some drugs have drug interactions with Paxlovid, and they should not be used with Paxlovid, such as those listed below.

• alfuzosin, colchicine;
• sildenafil (Revatio) when used to treat pulmonary arterial hypertension (PAH);
• pain medicine – pethidine, piroxicam, propoxyphene;
• heart medicine – amiodarone, dronedarone, flecainide, propafenone, quinidine, ranolazine;
• antipsychotic medicine – lurasidone, pimozide, clozapine;
• ergot medicine – dihydroergotamine, ergotamine, methylergonovine;
• cholesterol-lowering medicine – lovastatin, simvastatin; or
• a sedative – riazolam, oral midazolam.

Paxlovid should not be started immediately after discontinuation of any of the following drugs:

• rifampin;
• St. John’s Wort;
• a cancer medicine – apalutamide; or
• seizure medicine – carbamazepine, phenobarbital, phenytoin.

Not all possible interactions are listed here. Also, see the Interactions section below and check the interactions checker.

Tell your doctor if:

• you have liver problems or a liver disease such as hepatitis;
• you have kidney problems;
• you have an HIV-1 infection;
• you are pregnant or breastfeeding, or
• you have any serious or chronic disease.

Pregnancy

Tell your healthcare provider right away if you are or if you become pregnant. It is not known if Paxlovid can harm your unborn baby. Ritonavir can make birth control pills or birth control skin patches less effective. Ask your doctor about other birth control options such as an injection, implant, vaginal ring, condom, diaphragm, cervical cap, or contraceptive sponge.

Breastfeeding

Tell your healthcare provider you are breastfeeding or plan to breastfeed. It is not known if Paxlovid can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with this medicine.

How should I take Paxlovid?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

Paxlovid Instructions

Take nirmatrelvir together with ritonavir (two tablets of nirmatrelvir and one tablet of ritonavir) twice a day for 5 consecutive days. If you have kidney disease, talk to your healthcare provider, as you may need to take a different dose.

Take Paxlovid as soon as possible after diagnosis of COVID-19 and within 5 days of when symptoms first appear.

You may take Paxlovid with or without food.

Swallow the tablets whole and do not crush, chew, or break them.

General Information

You may need frequent blood tests to check your liver function.

If you are taking a ritonavir- or cobicistat-containing medicine to treat hepatitis C or Human Immunodeficiency Virus (HIV), you should continue to take your medicine as prescribed by your healthcare provider.

Talk to your healthcare provider if you do not feel better or if you feel worse after 5 days.

If you have kidney disease, your prescriber may prescribe you a lower dose. Talk to your healthcare provider to make sure you receive the correct Dose Pack.

Paxlovid Dosage information

Usual Paxlovid Dosing for Adult COVID-19 (FDA-approved)

Nirmatrelvir: 300 mg orally twice a day for 5 days
Ritonavir: 100 mg orally twice a day for 5 days

Usual Paxlovid Dosing for 12 to 18 Year Old COVID-19 (EUA)

For investigational use only
Use: Patients 12 to 18 years old weighing at least 40 kg:
Nirmatrlvir 300 mg orally twice a day for 5 days
Ritonavir 100 mg orally twice a day for 5 days

Usual Paxlovid Dosing for Renal Impairment

Use: Patients with moderate renal impairment (eGFR ≥30 to <60 mL/min)
Nirmatrelvir 150 mg twice daily for 5 days
Ritonavir 100 mg twice daily for 5 days 
No dosage adjustment is recommended in patients with mild renal impairment (eGFR ≥60 to <90 mL/min)

General Paxlovid Dosing information:

• If you have kidney disease, your healthcare provider may prescribe a lower dose. Talk to your healthcare provider to make sure you receive the correct Dose Pack.
• Nirmatrelvir must be coadministered with ritonavir. Prescriptions should specify the numeric dose of each active component within this product.
• This product should be started as soon as possible after COVID-19 has been diagnosed and within 5 days of symptom onset.
• If hospitalization is required due to severe/critical COVID-19 after starting treatment with this product, the patient should complete the full 5-day treatment course per health care provider’s discretion.

What happens if I miss a dose?

If you miss a dose of Paxlovid within 8 hours of the time it is usually taken, take it as soon as you remember. If you miss a dose by more than 8 hours, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of Paxlovid at the same time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

What other drugs will affect Paxlovid?

Sometimes it is not safe to use certain medicines at the same time. Some drugs can affect your blood levels of other drugs you use, which may increase side effects or make the medicines less effective.

Many drugs can affect Paxlovid and some drugs should not be used at the same time. Paxlovid can interact with other medicines causing severe or life-threatening side effects or death. Tell your doctor about all other medicines you use. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here.

Paxlovid Drug Interactions

Do not take Paxlovid if you are taking any of the following medicines: alfuzosin, amiodarone, apalutamide, carbamazepine, colchicine, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, finerenone, flecainide, flibanserin, ivabradine, lomitapide, lovastatin, lumacaftor/ivacaftor, lurasidone, methylergonovine, midazolam (oral), naloxegol, phenobarbital, phenytoin, pimozide, primidone, propafenone, quinidine, ranolazine, rifampin, rifapentine, St. John’s Wort (hypericum perforatum), sildenafil (Revatio®, Liqrev®) for pulmonary arterial hypertension, silodosin, simvastatin, tolvaptan, triazolam, ubrogepant, voclosporin.

These are not the only medicines that may cause serious or life-threatening side effects if taken with Paxlovid. It is very important to tell your healthcare provider about all of the medicines you are taking because additional laboratory tests or changes in the dose of your other medicines may be necessary during treatment with this Paxlovid. Your healthcare provider may also tell you about specific symptoms to watch out for that may indicate that you need to stop or decrease the dose of some of your other medicines.

Not all possible interactions are listed in this medication guide. Use the Paxlovid interaction checker below to check for more interaction information.

Ingredients

Nirmatrelvir 150 mg tablets

Active ingredient: nirmatrelvir
Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The following are the ingredients in the film coating: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide.

Ritonavir 100 mg tablets

Active ingredient: ritonavir
Inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, and titanium dioxide.

What is abacavir, dolutegravir, and lamivudine?

Abacavir, dolutegravir, and lamivudine is a combination medicine used to treat human immunodeficiency virus (HIV), the virus that can cause acquired immunodeficiency syndrome (AIDS). abacavir, dolutegravir, and lamivudine is not a cure for HIV or AIDS.

Abacavir, dolutegravir, and lamivudine is for use in adults and children who weigh at least 22 pounds (10 kilograms).

Abacavir, dolutegravir, and lamivudine should not be used by itself in those who are resistant to certain types of medicine.

Abacavir, dolutegravir, and lamivudine may also be used for purposes not listed in this medication guide.

Abacavir, dolutegravir, and lamivudine side effects

Call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:

• Group 1 – fever;
• Group 2 – rash;
• Group 3 – nausea, vomiting, diarrhea, stomach pain;
• Group 4 – general ill feeling, extreme tiredness, body aches;
• Group 5 – shortness of breath, cough, sore throat.

Once you have had an allergic reaction to a medicine that contains abacavir or dolutegravir, you must never use it again. If you stop taking abacavir, dolutegravir, and lamivudine for any reason, talk to your doctor before you start taking it again.

Abacavir, dolutegravir, and lamivudine may cause serious side effects. Call your doctor at once if you have:

• other signs of allergic reaction–skin blisters or peeling, eye redness, swelling in your face or throat, trouble breathing;
• lactic acidosis–unusual muscle pain, trouble breathing, stomach pain, vomiting, irregular heart rate, dizziness, feeling cold, or feeling very weak or tired; or
• liver problems–swelling around your midsection, right-sided upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Abacavir, dolutegravir, and lamivudine affects your immune system, which may cause certain side effects (even weeks or months after you’ve taken this medicine). Tell your doctor if you have:

• signs of a new infection–fever, night sweats, swollen glands, cold sores, cough, wheezing, diarrhea, weight loss;
• trouble speaking or swallowing, problems with balance or eye movement, weakness or prickly feeling; or
• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence.

Common side effects of abacavir, dolutegravir, and lamivudine may include:

• headache;
• tiredness; or
• trouble sleeping.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Warnings

You should not take abacavir, dolutegravir, and lamivudine if you have ever had an allergic reaction to any medicine that contains abacavir, or if you have a gene variation called HLA-B*5701 allele. Also, you should not use this medicine if you have moderate or severe liver disease, or if you are also taking dofetilide (Tikosyn).

Stop using this medicine and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.

If you’ve had hepatitis B, it may come back or get worse after you stop using abacavir, dolutegravir, and lamivudine. You may need frequent liver function tests for several months.

Before taking this medicine

You should not use abacavir, dolutegravir, and lamivudine if you are allergic to abacavir, dolutegravir, or lamivudine, or if:

• you also take dofetilide (Tikosyn);
• you have moderate or severe liver disease;
• you have a gene variation called HLA-B*5701 allele (your doctor will test you for this); or
• you have a history of allergic reaction to Combivir, Dutrebis, Epivir, Epzicom, Tivicay, Trizivir, or Ziagen.

Tell your doctor if you have ever had:

• liver disease (especially hepatitis B or C);
• heart problems or risk factors such as diabetes, smoking, high blood pressure, high cholesterol; or
• kidney disease.

You may develop lactic acidosis, a dangerous build-up of lactic acid in your blood. This may be more likely if you have other medical conditions, if you are overweight, or if you are a woman. Ask your doctor about your risk.

You may need to have a negative pregnancy test before starting this treatment.

Abacavir, dolutegravir, and lamivudine may harm an unborn baby if you take the medicine at the time of conception or during the first 12 weeks of pregnancy. Use effective birth control to prevent pregnancy, and tell your doctor if you become pregnant.

If you are pregnant, use your medications properly to control your infection. HIV can be passed to your baby if the virus is not controlled during pregnancy. Your name may be listed on a registry to track any effects of antiviral medicine on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

How should I take abacavir, dolutegravir, and lamivudine?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

Triumeq tablets are not the same as Triumeq PD tablets for oral suspension and should not be substituted for each other. Make sure you receive the correct dosage form each time your prescription is filled to avoid using the wrong medicine.

Doses are based on weight in children and teenagers. Your child’s dose may change if the child gains or loses weight.

Do not swallow, cut, crush, or chew a dispersible tablet. Dissolve the tablet in a small amount of water. Stir and drink this mixture right away.

You may take abacavir, dolutegravir, and lamivudine with or without food.

Abacavir, dolutegravir, and lamivudine comes with a Medication Guide and a Warning Card listing symptoms of an allergic reaction. Read this information and learn what symptoms to watch for. Keep the Wallet Card with you at all times.

You may need to take an extra daily dose of dolutegravir (Tivicay) if you take abacavir, dolutegravir, and lamivudine with certain other medicines.

Use all HIV medications as directed and read all medication guides you receive. Do not change your dose or stop using a medicine without your doctor’s advice. Every person with HIV should remain under the care of a doctor.

Store at room temperature away from moisture and heat. Keep the tablets in their original container, along with the packet or canister of moisture-absorbing preservative.

If you’ve had hepatitis B, it may come back or get worse after you stop using abacavir, dolutegravir, and lamivudine. You may need frequent liver function tests for several months.

Abacavir, dolutegravir, and lamivudine dosing information

Usual Adult Dose for HIV Infection:

Tablets: 1 tablet orally once a day

Comments:
-The tablets for oral suspension must not be used in adults.

Usual Pediatric Dose for HIV Infection:

Tablets for Oral Suspension:
-Weight 10 to less than 14 kg: 4 tablets orally once a day
-Weight 14 to less than 20 kg: 5 tablets orally once a day
-Weight 20 to less than 25 kg: 6 tablets orally once a day

Tablets:
-At least 25 kg: 1 tablet orally once a day

Comments:
-The tablets are not recommended for patients weighing less than 25 kg.
-The tablets for oral suspension are not recommended for patients weighing at least 25 kg.

Use: For the treatment of HIV-1 infection

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

Get your prescription refilled before you run out of medicine completely. If you miss several doses, you may have a dangerous or even fatal allergic reaction once you start taking this medication again.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

What should I avoid while taking abacavir, dolutegravir, and lamivudine?

Using abacavir, dolutegravir, and lamivudine will not prevent your disease from spreading. Do not have unprotected sex or share razors or toothbrushes. Ask your doctor how to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe.

What other drugs will affect abacavir, dolutegravir, and lamivudine?

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Some medicines can make abacavir, dolutegravir, and lamivudine much less effective when taken at the same time. If you take any of the following medicines, take your abacavir, dolutegravir, and lamivudine dose 2 hours before or 6 hours after you take the other medicine.

• antacids or laxatives that contain aluminum or magnesium (Maalox, Milk of Magnesia, Mylanta, Pepcid Complete, Rolaids, and others);
• the ulcer medicine sucralfate (Carafate);
• buffered medicine; or
• vitamin or mineral supplements that contain calcium or iron (can be taken at the same time with abacavir, dolutegravir, and lamivudine if you take with food).

Many drugs can affect abacavir, dolutegravir, and lamivudine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any medicine you start or stop using.

Highlights of Prescribing Information

These highlights do not include all the information needed to use ABACAVIR AND LAMIVUDINE TABLETS safely and effectively. See full prescribing information for ABACAVIR AND LAMIVUDINE TABLETS.

ABACAVIR and LAMIVUDINE tablets, for oral use
Initial U.S. Approval: 2004

WARNING: HYPERSENSITIVITY REACTIONS and EXACERBATIONS OF HEPATITIS B

See full prescribing information for complete boxed warning.Hypersensitivity Reactions
● Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products.

● Hypersensitivity to abacavir is a multi-organ clinical syndrome.

● Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir.

● Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.

● Discontinue abacavir and lamivudine as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue abacavir and lamivudine if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

● Following a hypersensitivity reaction to abacavir and lamivudine, NEVER restart abacavir and lamivudine or any other abacavir-containing product.
Exacerbations of Hepatitis B
● Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of abacavir and lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.

Recent Major Changes

Dosage and Administration, Not Recommended Due to

Lack of Dosage Adjustment 12/2021

Indications and Usage for Abacavir and Lamivudine Tablets

Abacavir and lamivudine tablets, are combination of abacavir and lamivudine, both nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. 

Abacavir and Lamivudine Tablets Dosage and Administration

• Before initiating abacavir and lamivudine tablets, screen for the HLA-B*5701 allele because abacavir and lamivudine tablets contain abacavir. 
• Adults: One tablet orally once daily. 
• Pediatric patients weighing at least 25 kg: One tablet daily. 
• Because abacavir and lamivudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets are not recommended in patients with creatinine clearance less than 30 mL per minute or patients with hepatic impairment. 

Dosage Forms and Strengths

Tablets: 600 mg of abacavir and 300 mg of lamivudine.

Contraindications

• Presence of HLA-B*5701 allele. 
• Prior hypersensitivity reaction to abacavir or lamivudine.
• Moderate or severe hepatic impairment.

Warnings and Precautions

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.

Adverse Reactions/Side Effects

The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5%) in an adult HIV-1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea. 

To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions

• Methadone: An increased methadone dose may be required in a small number of patients. 
• Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. 
• Riociguat: The riociguat dose may need to be reduced.

Use In Specific Populations

• Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. 

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2024

Full Prescribing Information

WARNING: HYPERSENSITIVITY REACTIONS and EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of abacavir and lamivudine. Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele .

Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients . All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine or reinitiation of therapy with abacavir and lamivudine, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir and lamivudine immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible .

Following a hypersensitivity reaction to abacavir and lamivudine, NEVER restart abacavir and lamivudine or any other abacavir-containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity.

Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, which is a component of abacavir and lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue abacavir and lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

1. Indications and Usage for Abacavir and Lamivudine Tablets

Abacavir and lamivudine tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

2. Abacavir and Lamivudine Tablets Dosage and Administration

2.1 Screening for HLA-B*5701 Allele Prior to Starting Abacavir and Lamivudine Tablets

Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine tablets .

2.2 Recommended Dosage for Adult Patients

The recommended dosage of abacavir and lamivudine tablets for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.

2.3 Recommended Dosage for Pediatric Patients

The recommended oral dose of abacavir and lamivudine tablets for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents. Before prescribing abacavir and lamivudine tablets, pediatric patients should be assessed for the ability to swallow tablets.

2.4 Not Recommended Due to Lack of Dosage Adjustment

Because abacavir and lamivudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets are not recommended for:

• patients with creatinine clearance less than 30 mL per minute .
• patients with mild hepatic impairment. Abacavir and lamivudine tablets are contraindicated in patients with moderate or severe hepatic impairment .

Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.

3. Dosage Forms and Strengths

Abacavir and lamivudine tablets, USP contain 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP. The tablets are orange colored, capsule-shaped, biconvex film-coated tablets, debossed with “LT” on one side and plain on other side.

4. Contraindications

Abacavir and lamivudine tablets are contraindicated in patients:

• who have the HLA-B*5701 allele .
• with prior hypersensitivity reaction to abacavir or lamivudine.
• with moderate or severe hepatic impairment.

5. Warnings and Precautions

5.1 Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment . Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:

• All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine or reinitiation of therapy with abacavir and lamivudine, unless patients have a previously documented HLA-B*5701 allele assessment.
• Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
• Before starting abacavir and lamivudine, review medical history for prior exposure to any abacavir­ containing product. NEVER restart abacavir and lamivudine or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
• To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir and lamivudine immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
• If a hypersensitivity reaction cannot be ruled out, do not restart abacavir and lamivudine or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.
• If a hypersensitivity reaction is ruled out, patients may restart abacavir and lamivudine. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir and lamivudine or any other abacavir-containing product is recommended only if medical care can be readily accessed.
• A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

5.2 Patients with Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-Resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of abacavir and lamivudine). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with abacavir and lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir and lamivudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.5 Myocardial Infarction

Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain the potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.

As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

6. Adverse Reactions/Side Effects

The following adverse reactions are discussed in other sections of the labeling:

• Serious and sometimes fatal hypersensitivity reactions .
• Exacerbations of hepatitis B .
• Lactic acidosis and severe hepatomegaly with steatosis .
• Immune reconstitution syndrome .
• Myocardial infarction.

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6.1 Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious and Fatal Abacavir-Associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).

Additional Adverse Reactions with Use of Abacavir and Lamivudine

Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1.

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Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.

The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.

Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

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6.2 Clinical Trials Experience in Pediatric Subjects

The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as abacavir and lamivudine, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults .

6.3 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abacavir

Cardiovascular: Myocardial infarction.

Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use .

Abacavir and Lamivudine

Body as a Whole: Redistribution/accumulation of body fat.

Digestive: Stomatitis.

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic: Lactic acidosis and hepatic steatosis , posttreatment exacerbations of hepatitis B.

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Muscle weakness, creatinine phosphokinase (CPK) elevation, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy, seizures.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

7. Drug Interactions

7.1 Methadone

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

7.2 Sorbitol

Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines .

7.3 Riociguat

Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions . The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).

8. Use In Specific Populations

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose (see Data).

Data

Human Data: Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .

Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine­-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Animal Data: Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.

Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300 and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving abacavir and lamivudine.

8.4 Pediatric Use

The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or abacavir and lamivudine .

In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.

8.5 Geriatric Use

Clinical trials of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of abacavir and lamivudine in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

8.6 Patients with Impaired Renal Function

Abacavir and lamivudine is not recommended for patients with creatinine clearance less than 30 mL per min because abacavir and lamivudine is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of abacavir and lamivudine, is required for patients with creatinine clearance less than 30 mL per min, .

Patients with a creatinine clearance between 30 and 49 mL per min receiving abacavir and lamivudine may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL per min. There are no safety data from randomized, controlled trials comparing abacavir and lamivudine to the individual components in patients with a creatinine clearance between 30 and 49 mL per min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL per min who receive abacavir and lamivudine should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, abacavir and lamivudine should be discontinued and the individual components should be used to construct the treatment regimen.

8.7 Patients with Impaired Hepatic Function

Abacavir and lamivudine is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of abacavir and lamivudine, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used].

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, abacavir and lamivudine is contraindicated in these patients .

10. Overdosage

There is no known specific treatment for overdose with abacavir and lamivudine. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

11. Abacavir and Lamivudine Tablets Description

Abacavir and Lamivudine

Abacavir and lamivudine tablets, USP contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1.

Abacavir and lamivudine tablets, USP are for oral administration. Each orange colored, capsule-shaped, biconvex film coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY orange YS-1-13065-A) that is made of FD&C Yellow No.6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

Abacavir Sulfate, USP

The chemical name of abacavir sulfate, USP is (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9­yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2•H2SO4and a molecular weight of 670.74 g per mol. It has the following structural formula:

Abacavir sulfate, USP is a white to almost white powder and is soluble in water.

In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.

Lamivudine, USP

The chemical name of lamivudine, USP is (2(1H)-Pyrimidinone,4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-, (2R-cis)-. Lamivudine, USP is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.26 g per mol. It has the following structural formula:

Lamivudine, USP is a white to almost white solid and is soluble in water, sparingly soluble in methanol, slightly soluble to practically insoluble in 96% ethanol and practically insoluble in acetone.

FDA approved dissolution test specifications differ from USP.

12. Abacavir and Lamivudine Tablets – Clinical Pharmacology

12.1 Mechanism of Action

Abacavir and lamivudine is an antiretroviral agent with activity against HIV-1.

12.3 Pharmacokinetics

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 abacavir and lamivudine tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.

Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmaxwas 4.26±1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5’-carboxylic acid and glucuronyl transferase to form the 5’-glucuronide.

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax(Cmax,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.

Effect of Food on Absorption of Abacavir And Lamivudine

Abacavir and lamivudine may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUClast, AUC∞, and Cmaxfor lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.

Specific Populations

Patients with Renal Impairment: The pharmacokinetics for the individual lamivudine component of abacavir and lamivudine has been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual lamivudine component).

Patients with Hepatic Impairment: The pharmacokinetics for the individual components of abacavir and lamivudine have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir and lamivudine components).

Pregnant Women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration ofabacavir and lamivudine in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or abacavir and lamivudine. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients .

Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.

Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.

Racial Groups: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.

Drug Interaction Studies

The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with abacavir and lamivudine.

Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.

Riociguat: Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞)compared with riociguat AUC(∞)reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies .

Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: Abacavir and lamivudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein 2 (MRP2) or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.

Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

Abacavir: Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h).

Other Interactions

Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

Methadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.

Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0 to 24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.

The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.

Coadministered Drug and Dose	Drug and Dose	n	Concentrations of Abacavir or Lamivudine		Concentration of Coadministered Drug
			AUC	Variability
Ethanol 0.7 g/kg	Abacavir Single 600 mg	24	↑41%	90% CI: 35% to 48%	a
Nelfinavir 750 mg every 8 h x 7 to 10 days	Lamivudine Single 150 mg	11	↑10%	95% CI: 1% to 20%
Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days	Lamivudine Single 300 mg	14	↑43%	90% CI: 32% to 55%
↑= Increase; = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval. a The drug-drug interaction was only evaluated in males.

12.4 Microbiology

Mechanism of Action

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5’-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng per mL) and 70 to 1,000 nM against HIV-1IIIBand HIV-1BaL, respectively, and the mean EC50value was 260 ± 180 nM against 8 clinical isolates. The median EC50values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A to G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50values against HIV-2 isolates (n = 4) ranged from 24 to 490 nM.

Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng per mL). The median EC50values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A to G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

Cross-Resistance

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

13. Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.

Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Mutagenicity

Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Impairment of Fertility

Abacavir: Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.

Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.

13.2 Animal Toxicology and/or Pharmacology

Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.

14. Clinical Studies

14.1 Adults

One abacavir and lamivudine tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy.

The following trial was conducted with the individual components of abacavir and lamivudine.

Therapy-Naive Adults

CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm3 (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10copies per mL (range: 2.60 to 6.99 log10copies per mL).

The outcomes of randomized treatment are provided in Table 4.

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm3 in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.

14.2 Pediatric Subjects

ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.

Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as abacavir and lamivudine.

The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

16. How is Abacavir and Lamivudine Tablets supplied

Abacavir and lamivudine tablets, USP contain 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP. The tablets are orange colored, capsule-shaped, biconvex film coated tablets, debossed with “LT” on one side and plain on other side. They are packaged as follows:

Bottles of 30 tablets NDC 42385-962-30
Bottles of 90 tablets NDC 42385-962-90
Bottles of 180 tablets NDC 42385-962-18

Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature.]

17. Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hypersensitivity Reactions

Inform patients:

• that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of abacavir and lamivudine tablets and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir and lamivudine tablets. The complete text of the Medication Guide is reprinted at the end of this document.
• to carry the Warning Card with them.
• how to identify a hypersensitivity reaction .
• that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir and lamivudine tablets.
• that a hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir and lamivudine tablets are not immediately discontinued.
• to not restart abacavir and lamivudine tablets or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
• that if they have a hypersensitivity reaction, they should dispose of any unused abacavir and lamivudine tablets to avoid restarting abacavir.
• that a hypersensitivity reaction is usually reversible if it is detected promptly and abacavir and lamivudine tablets are stopped right away.
• that if they have interrupted abacavir and lamivudine tablets for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
• to not restart abacavir and lamivudine tablets or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

Patients with Hepatitis B or C Co-infection

Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician .

Lactic Acidosis/Hepatomegaly with Steatosis

Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking abacavir and lamivudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity .

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when abacavir and lamivudine tablets are started .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine tablets during pregnancy .

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

Missed Dose

Instruct patients that if they miss a dose of abacavir and lamivudine tablets, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

Availability of Medication Guide

Instruct patients to read the Medication Guide before starting abacavir and lamivudine tablets and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

EPIVIR, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.

The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to Laurus Labs Limited. The makers of these brands are not affiliated with and do not endorse Laurus Labs Limited or its products.

Manufactured for:
Laurus Generics Inc.
400 Connell Drive
Suite 5200
Berkeley Heights, NJ 07922

Manufactured by:
Laurus Labs Limited
Anakapalli-531011
India

(Front of card)

WARNING CARD

Abacavir and Lamivudine Tablets

Patients taking abacavir and lamivudine tablets may have a serious allergic reaction (hypersensitivity reaction) that can cause death. If you get a symptom from 2 or more of the following groups while taking abacavir and lamivudine tablets, call your healthcare provider right away to find out if you should stop taking this medicine.

Always carry this Warning Card with you to help recognize symptoms of this allergic reaction.

(Back of Card)

WARNING CARD

Abacavir and Lamivudine Tablets

If you must stop treatment with abacavir and lamivudine tablets because you have had an allergic reaction to abacavir, NEVER take abacavir and lamivudine tablets or another abacavir-containing medicine (ZIAGEN®, TRIUMEQ®, or TRIZIVIR®) again. If you have an allergic reaction, dispose of any unused abacavir, and lamivudine tablets. Ask your pharmacist how to properly dispose of medicines. If you take abacavir and lamivudine tablets or another abacavir-containing medicine again after you have had an allergic reaction, WITHIN HOURS you may get life-threatening symptoms that may include very low blood pressure or death.

Please read the Medication Guide for additional information on abacavir and lamivudine tablets.

The brands listed are trademarks of their respective owners and are not trademarks of Laurus Labs Limited.

Revised: 03/2022

PRINCIPAL DISPLAY PANEL – Container Label (30’s count)

NDC 42385-962-30
Abacavir and Lamivudine
Tablets, USP
600 mg/300 mg
Notice to Authorized Dispenser.

Each time Abacavir and Lamivudine
Tablets are dispensed. give the
patient a Medication Guide and
Warning Card.
30 Tablets RX Only
LAURUS Labs