Triumeq (abacavir, dolutegravir, and lamivudine)

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.

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

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.

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

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

Abacavir

• Coadministration with Triumeq 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).

• Data from a birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, a component of Triumeq, is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens.
• As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.
• In addition, 2 of the 5 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester.
• Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to Triumeq should be considered at the time of conception through the first trimester of pregnancy.
• Initiation of Triumeq is not recommended in adolescents and adults actively trying to become pregnant unless there is no suitable alternative.
• 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. When administered to lactating rats, dolutegravir was present in milk.
• There is no information on the effects of Triumeq or its components 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 Triumeq.