Abacavir (abacavir sulfate)

Abacavir is commercially available as abacavir sulfate; dosage is expressed in terms of abacavir.

Abacavir sulfate is administered orally once or twice daily without regard to meals. If a dose of abacavir is missed, administer the dose as soon as possible. Do not double the next dose or take more than the prescribed dose.

Abacavir is commercially available as a single entity preparation and in the following fixed-combination tablets for oral use: abacavir and lamivudine (Epzicom(R)); abacavir, lamivudine, and zidovudine (Trizivir(R)); and abacavir, dolutegravir, and lamivudine (Triumeq(R) and Triumeq PD(R)). Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.

Single-entity abacavir sulfate is commercially available as an oral solution or tablets.

Abacavir oral solution is used in pediatric patients or when a solid oral dosage form is inappropriate.

The scored 300-mg abacavir tablets are used in adults and may be used in children weighing 14 kg or greater who have undergone assessment demonstrating ability to reliably swallow tablets.

Store abacavir tablets and oral solution between 20-25degreesC. The oral solution may also be refrigerated.

In vitro studies indicate that abacavir has the potential to inhibit cytochrome P-450 (CYP) isoenzyme 1A1, and has limited potential to inhibit CYP3A4. Abacavir does not induce nor inhibit CYP2C9 or CYP2D6. At therapeutic exposures, abacavir is not expected to affect substrates of organic anion transporter polypeptide (OATP)1B1 or OATP1B3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.

In vitro studies indicate that abacavir is a substrate of BCRP and P-gp; however, the concomitant use of modulators of these transporters is not expected to have clinically relevant effects on abacavir serum concentrations. In vitro studies indicate that abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, or multidrug resistance-associated protein (MRP)2, or MRP4; therefore, the concomitant use of agents that modulate these transporters is not expected to affect abacavir serum concentrations.

The following drug interactions are based on studies using abacavir. Additional drug interactions may exist for fixed-dose combinations containing abacavir and lamivudine (Epzicom(R)); abacavir, lamivudine, and zidovudine (Trizivir(R)); and abacavir, dolutegravir, and lamivudine (Triumeq(R) and Triumeq PD(R)). See the full prescribing information for drug interactions of each of these combination products.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anti-Retrovirals/Atidarsagene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)

Anti-Retrovirals/Elivaldogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)

Anti-Retrovirals/Etuvetidigene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Etuvetidigene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating HIV-based lentiviral vector. Antiretrovirals may interfere with the manufacturing of the apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of etuvetidigene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should not take antiretrovirals for at least one month prior to mobilization and until at least 7 days after etuvetidigene autotemcel infusion.(1) If a patient requires antiretroviral agents for HIV post-exposure prophylaxis, etuvetidigene autotemcel treatment should be delayed until HIV testing is negative at 6 months post-exposure.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of etuvetidigene autotemcel therapy.(1)

Anti-Retrovirals/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)

Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Abacavir/Riociguat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5 and CYP2J2.(1,2) Abacavir has been shown to inhibit CYP1A1 in vitro and may decrease the metabolism of riociguat.(2,3)

CLINICAL EFFECTS: Concurrent use of abacavir with riociguat may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(2,3)

PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure to riociguat and may increase interaction risk or severity.(1,4)

PATIENT MANAGEMENT: The US manufacturer of abacavir states that the dose of riociguat may need to be reduced when used concurrently.(3) Although the manufacturer of riociguat does not make any recommendations for dose adjustment when used with a CYP1A1 inhibitor, it has been suggested that the initial dose of riociguat be reduced to 0.5 mg 3 times daily. This is the same dose modification recommended during concurrent therapy with strong CYP and P-gp/BCRP inhibitors, based on a similar magnitude of interaction between riociguat and ketoconazole.(2) Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of abacavir.

DISCUSSION: In an interaction study of 8 HIV-positive patients without pulmonary hypertension, abacavir (given as a fixed-dose combination of abacavir 600 mg-dolutegravir 50 mg-lamivudine 300 mg once daily) increased the area-under-curve (AUC) of single-dose riociguat 0.5 mg by about 3-fold, compared to historical healthy volunteers administered single-dose riociguat 0.5 mg alone.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure (AUC) relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

Anti-Retrovirals/Marnetegragene Autotemcel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Marnetegragene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of transduced cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of marnetegragene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the antiretrovirals) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of marnetegragene autotemcel.(1)

There are no moderate interactions for this drug.

*Presence of the human leukocyte antigen (HLA)-B*5701 allele.

*Moderate or severe hepatic impairment.

*History of hypersensitivity reaction to abacavir.

• HLa-B *57:01 positive
• Lactation
• Lactic acidosis
• Pancreatitis

• Child-pugh class A hepatic impairment
• Disease of liver

• Coronary artery disease
• Hypertriglyceridemia

Adverse effects of at least moderate intensity reported in 10% or more of adult patients receiving abacavir for HIV-1 infection include nausea, headache, fatigue and malaise, nausea and vomiting, and dreams/sleep disorders.

Adverse effects of at least moderate intensity reported in 5% or more of pediatric patients receiving abacavir for HIV-1 infection include fever and/or chills, nausea and vomiting, skin rash, and ear, nose, and throat infections.

More Frequent

• Headache disorder

Less Frequent

• Acute abdominal pain
• Arthralgia
• Bronchitis
• Cough
• Drug fever
• Dyspnea
• Hypersensitivity drug reaction
• Myalgia
• Pharyngitis
• Skin rash

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Acute respiratory distress syndrome
• Anaphylaxis
• Anemia
• Anorexia
• Edema
• Erythema multiforme
• Graves' disease
• Guillain-barre syndrome
• Hepatitis
• Hepatomegaly
• Hypotension
• Increased alanine transaminase
• Increased aspartate transaminase
• Lactic acidosis
• Multiple organ failure
• Pancreatitis
• Paresthesia
• Pneumonia
• Polymyositis
• Renal failure
• Steatosis of liver
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Diarrhea
• Dream disorder
• Fatigue
• Lipodystrophy associated with human immunodeficiency virus infection
• Malaise
• Nausea
• Sleep disorder
• Vomiting

Less Frequent

• Chills
• Dizziness
• Hypertriglyceridemia
• Musculoskeletal pain
• Symptoms of anxiety
• Upper respiratory infection

Rare or Very Rare

• Depression

No enhanced messaging available.

Safety and efficacy of single-entity abacavir tablets or oral solution have been established in infants and children 3 months of age and older. Use of abacavir in children 3 months of age and older is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials in adult and pediatric patients. Safety and efficacy have not been established in neonates and infants less than 3 months of age.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including abacavir, the Antiretroviral Pregnancy Registry (APR) was established. Clinicians are encouraged to contact the registry at 800-258-4263 to report cases of prenatal exposure to antiretroviral drugs.

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 Metropolitan Atlanta Congenital Defects Program (MACDP). Use of the MACDP population as the comparator group has several limitations; the MACDP assesses populations from a limited geographic area and does not include outcomes for births that occurred at <20 weeks' gestation. The rate of miscarriage is not reported in the APR.

Abacavir crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations. Concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. In animal reproductive studies, abacavir administration during organogenesis resulted in developmental toxicities (i.e., depressed fetal body weight, reduced crown-rump length) and fetal malformations (i.e., fetal anasarca, skeletal malformations) based on abacavir exposure 35 times the usual human exposure (based on AUC). No developmental effects were observed at exposures 3.5-times the usual human exposure (based on AUC).

Abacavir is distributed into human milk. The effects of abacavir on the breastfed infant, or the effects of the drug on milk production are not known.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

The manufacturer makes no specific dosage recommendations for single-entity abacavir in geriatric patients. Select dosage with caution due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

While clinical experience to date has not revealed age-related differences in response to abacavir, clinical studies evaluating abacavir have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Dosage of abacavir for geriatric patients should be selected carefully because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.