Triumeq: HIV Medication Side Effects & Warnings

Generic drug: abacavir, dolutegravir, and lamivudine

Brand name: Triumeq

What is Triumeq (abacavir, dolutegravir, and lamivudine), and how does it work?

Triumeq (abacavir, dolutegravir, and lamivudine) is a prescription medicine used to treat HIV-1 infection in adults and children who weigh at least 88 pounds (40 kg).

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

Triumeq contains the prescription medicines abacavir, dolutegravir, and lamivudine.

Triumeq is not for use by itself in people who have or have had resistance to abacavir, dolutegravir, or lamivudine.

It is not known if Triumeq is safe and effective in children who weigh less than 88 pounds (40 kg).

What are the side effects of Triumeq?

WARNING

HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ
involvement, have occurred with abacavir, a component of Triumeq (abacavir,
dolutegravir, 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.

Triumeq 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 Triumeq or
reinitiation of therapy with Triumeq, unless patients have a previously
documented HLA-B*5701 allele assessment. Discontinue Triumeq 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 Triumeq, NEVER restart Triumeq 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.

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 alone or in
combination, including abacavir, lamivudine, and other antiretrovirals.
Discontinue Triumeq if clinical or laboratory findings suggestive of lactic
acidosis or pronounced hepatotoxicity occur.

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 Triumeq. Hepatic
function should be monitored closely with both clinical and laboratory follow-up
for at least several months in patients who discontinue Triumeq and are
co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B
therapy may be warranted.

Triumeq can cause serious side effects including:

Liver problems. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver function tests during treatment with
Triumeq. Liver problems including liver failure have also happened with
Triumeq in people without a history of liver disease or other risk factors. Liver failure resulting in liver transplant has also been reported with
Triumeq. Your healthcare provider may do blood tests to check your liver.
Call your healthcare provider right away if you develop any of the signs or symptoms of liver problems listed below.
- your skin or the white part of your eyes turns yellow (jaundice)
- dark or “tea-colored” urine
- light colored stools (bowel movements)
- loss of appetite
- nausea or vomiting
- pain, aching, or tenderness on the right side of your stomach area
Too much lactic acid in your blood (lactic acidosis). Too much lactic acidosis is a serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:
- feel very weak or tired
- unusual (not normal) muscle pain
- trouble breathing
- stomach pain with nausea and vomiting
- feel cold, especially in your arms and legs
- feel dizzy or lightheaded
- have a fast or irregular heartbeat
Lactic acidosis can also lead to severe liver problems, which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under “Liver problems”.
You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).
Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking
Triumeq.
Heart attack. Some HIV-1 medicines including Triumeq may increase your risk of heart attack.
The most common side effects of Triumeq include:
- trouble sleeping
- tiredness
- headache

These are not all the possible side effects of Triumeq.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the dosage for Triumeq?

Screening For HLA-B*5701 Allele Prior To Starting Triumeq

Screen for the HLA-B*5701 allele prior to initiating therapy with
Triumeq.

Pregnancy Testing Before Initiation Of Triumeq

Perform pregnancy testing before initiation of Triumeq in adolescents
and adults of childbearing potential.

Recommended Dosage

Triumeq is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.
The recommended dosage regimen of Triumeq in adults and in pediatric patients weighing at least 40 kg is one tablet once daily orally with or without food.

Dosage Recommendation With Certain Concomitant Medications

The dolutegravir dose (50 mg) in Triumeq is insufficient when coadministered with medications listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.

Table 1: Dosing Recommendations for Triumeq with Coadministered Medications

Coadministered Drug
Dosing Recommendation

Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin
The recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from
Triumeq, should be taken.

Not Recommended Due To Lack Of Dosage Adjustment

Because Triumeq is a fixed-dose tablet and cannot be dose adjusted, Triumeq is not recommended in:

patients with creatinine clearance less than 30 mL per minute.
patients with mild hepatic impairment. Triumeq is contraindicated in
patients with moderate or severe hepatic impairment.

What drugs interact with Triumeq?

Effect Of Dolutegravir On The Pharmacokinetics Of Other Agents

In vitro, dolutegravir inhibited the renal organic cation transporters
(OCT)2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter
(MATE)1 (IC50 = 6.34 microM).
In vivo, dolutegravir inhibits tubular secretion of creatinine by
inhibiting OCT2 and potentially MATE1.
Dolutegravir may increase plasma concentrations of drugs eliminated via
OCT2 or MATE1 (dofetilide, dalfampridine, and metformin).
In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.
In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following:
- cytochrome P450 (CYP)1A2,
- CYP2A6,
- CYP2B6,
- CYP2C8,
- CYP2C9,
- CYP2C19,
- CYP2D6,
- CYP3A,
- uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1,
- UGT2B7,
- P-glycoprotein (P-gp),
- breast cancer resistance protein (BCRP),
- bile salt export pump (BSEP),
- organic anion transporter polypeptide (OATP)1B1,
- OATP1B3,
- OCT1, or multidrug resistance protein (MRP)2, or
- MRP4.
In vitro, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs:
- daclatasvir,
- tenofovir,
- methadone,
- midazolam,
- rilpivirine, and
- oral contraceptives containing norgestimate and ethinyl estradiol.
Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs:
- atazanavir,
- darunavir,
- efavirenz,
- etravirine,
- fosamprenavir,
- lopinavir,
- ritonavir, and
- boceprevir.

Effect Of Other Agents On The Pharmacokinetics Of Dolutegravir

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir.
Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.
Etravirine significantly reduced plasma concentrations of dolutegravir,
but the effect of etravirine was mitigated by coadministration of
lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated
by atazanavir/ritonavir (Table 5).
In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.
Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.

Established And Other Potentially Significant Drug Interactions

There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets.
Information regarding potential drug interactions with the individual
components of Triumeq are provided below. These recommendations are based on
either drug interaction trials or predicted interactions due to the expected
magnitude of interaction and potential for serious adverse events or loss of
efficacy.

Table 5: Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions

Concomitant Drug Class: Drug Name
Effect on Concentration
Clinical Comment

HIV-1 Antiviral Agents

Non-nucleoside reverse transcriptase inhibitor: Etravirine^a
↓Dolutegravir
Use of Triumeq with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a
↓Dolutegravir
Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from
Triumeq.

Non-nucleoside reverse transcriptase inhibitor: Nevirapine
↓Dolutegravir
Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations.

Protease inhibitor: Fosamprenavir/ritonavir^a Tipranavir/ritonavir^a
↓Dolutegravir
Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from
Triumeq.

Other Agents

Antiarrhythmic: Dofetilide
↑Dofetilide
Coadministration is contraindicated with Triumeq.

Potassium channel blocker: Dalfampridine
↑Dalfampridine
Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with
Triumeq should be considered against the risk of seizures in these patients.

Carbamazepine^a
↓Dolutegravir
Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from
Triumeq.

Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (Hypericum perforatum)
↓Dolutegravir
Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations.

Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids^a or laxatives
Sucralfate Buffered medications
↓Dolutegravir
Administer Triumeq 2 hours before or 6 hours after taking medications containing polyvalent cations.

Oral calcium and iron supplements, including multivitamins containing calcium or iron^a
↓Dolutegravir
When taken with food, Triumeq and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions,
Triumeq should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron.

Metformin^a
↑Metformin
Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of
Triumeq and metformin.

Rifampin^a
↓Dolutegravir
Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from
Triumeq.

^a See prescribing
information for magnitude of interaction.

Methadone

Abacavir

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance
therapy with 600 mg of abacavir 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.

Sorbitol

Lamivudine

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

Riociguat