Isentress Hd

Drug overview for ISENTRESS HD (raltegravir potassium):

Generic name: RALTEGRAVIR POTASSIUM (ral-TEG-ra-vir)
Drug class: Antiviral-HIV-1 Integrase Strand Transfer Inhibitors
Therapeutic class: Anti-Infective Agents

Raltegravir potassium, an antiretroviral agent, is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI).

No enhanced Uses information available for this drug.

DRUG IMAGES

ISENTRESS HD 600 MG TABLET

The following indications for ISENTRESS HD (raltegravir potassium) have been approved by the FDA:

Indications:
HIV infection

Professional Synonyms:
Human immunodeficiency virus disease
Human immunodeficiency virus infection

Dosing information for ISENTRESS HD
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ISENTRESS HD 600 MG TABLET	Maintenance	Adults take 2 tablets (1,200 mg) by oral route once daily

The following drug interaction information is available for ISENTRESS HD (raltegravir potassium):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 9 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Raltegravir/Aluminum & Magnesium Antacids & Magnesium Supplements SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Aluminum and/or magnesium containing antacids may alter raltegravir absorption by altering gastric pH. Magnesium antacids and supplements may bind to raltegravir in the GI tract, preventing its absorption.(1) CLINICAL EFFECTS: Aluminum and/or magnesium containing antacids and magnesium supplements may reduce levels and clinical effectiveness of raltegravir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of any formulation of raltegravir and aluminum and/or magnesium antacids is not recommended. Instruct patients not to use aluminum and/or magnesium containing antacids or magnesium supplements. Calcium carbonate may be used in place of aluminum and/or magnesium containing antacids in patients receiving raltegravir chewable tablets, oral suspension, or 400 mg tablets. Calcium carbonate is not recommended for patients receiving one daily raltegravir (600 mg tablets).(1) DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) with raltegravir (400 mg BID) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 44%, 49%, and 63%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 51%, 51%, and 56%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 30%, and 57%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 19%, and 60%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 30%, 32%, and 62%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 13%, and 50%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 11%, and 49%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 12 hours after after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC, and Cmin by 14%, 14%, and 58%, respectively.(1,2) Data from in vitro(3) and in vivo simulations(4) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH.	ALUMINUM HYDROXIDE, MAGNESIUM CHLORIDE
Raltegravir/Rifapentine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rifapentine may induce the metabolism of raltegravir by UDP-glucuronosyltransferase 1A1 (UGT1A1).(1) CLINICAL EFFECTS: Concurrent use of once-daily rifapentine may reduce levels and clinical effectiveness of raltegravir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of once-daily rifapentine is not recommended. Once-weekly rifapentine may be used concurrently at standard doses.(2) DISCUSSION: Concurrent use of rifapentine 600 mg once daily decreased raltegravir minimum concentration (Cmin) by 41%.(2) Concurrent use of rifapentine 900 mg once weekly increased raltegravir area-under-curve (AUC) by 71% and decreased Cmin 12%.(2)	PRIFTIN
Raltegravir (600 mg HD)/Calcium Carbonate SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Calcium carbonate may alter raltegravir absorption by altering gastric pH and binding to raltegravir in the GI tract, preventing its absorption.(1) CLINICAL EFFECTS: Calcium carbonate may reduce levels and clinical effectiveness of raltegravir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Calcium carbonate is not recommended for patients receiving one daily raltegravir (600 mg HD tablets).(1) DISCUSSION: Simultaneous administration of calcium carbonate (3000 mg) with raltegravir (1200 mg singe dose given as two 600 mg HD tablets) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 74%, 72%, and 48%, respectively.(1,2) Administration of calcium carbonate (3000 mg) 12 hours after raltegravir (1200 mg singe dose given as two 600 mg HD tablets) decreased raltegravir Cmax, AUC, and Cmin by 2%, 10%, and 57%, respectively.(1,2) Data from in vitro(3) and in vivo simulations(4) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH. Calcium may have a similar effect.	DILUENT FOR ROTARIX
Raltegravir/Selected UGT1A1 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase 1A1 (UGT1A1) may induce the metabolism of raltegravir.(1) CLINICAL EFFECTS: Concurrent use of carbamazepine, fosphenytoin, phenobarbital, phenytoin, or primidone may result in decreased levels and effectiveness of raltegravir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of raltegravir(1) and Department of Health and Human Services HIV guidelines(2) state that the concurrent use of carbamazepine, fosphenytoin, phenobarbital, phenytoin, or primidone with raltegravir is not recommended. The European AIDS Clinical Society HIV guidelines state that additional monitoring or dose adjustment is likely to be required if these agents are used concurrently.(3) DISCUSSION: Concurrent rifampin (600 mg daily) with raltegravir (400 mg single dose) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and 61%, respectively. When raltegravir was given at a dosage of 800 mg twice daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir were increased 62% and 27%, respectively, and the Cmin was decreased 53% when compared to the administration of raltegravir (400 mg twice daily) alone.(1,4) Strong inducers of UGT1A1, such as carbamazepine, fosphenytoin, phenobarbital, phenytoin, and primidone are expected to produce similar results.(1,2)	CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, FOSPHENYTOIN SODIUM, MYSOLINE, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, SEZABY, TEGRETOL, TEGRETOL XR
Betibeglogene Autotemcel/Anti-Retrovirals; Hydroxyurea SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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)	ZYNTEGLO
Elivaldogene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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)	SKYSONA
Lovotibeglogene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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)	LYFGENIA
Atidarsagene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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)	LENMELDY
Raltegravir (600 mg HD)/Tipranavir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Raltegravir is a substrate of UDP-glucuronosyltransferase 1A1 (UGT1A1). Inducers of UGT1A1 such as tipranavir may induce the metabolism of raltegravir.(1,2) CLINICAL EFFECTS: Tipranavir may reduce the levels and clinical effectiveness of raltegravir.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of raltegravir states that the concurrent use of raltegravir HD (600 mg) is not recommended.(1) No dose adjustment is recommended when raltegravir is dosed at 400 mg twice daily.(1,2) DISCUSSION: No clinical studies have been conducted to evaluate the drug interaction between tipranavir/ritonavir with raltegravir 1,200 mg daily. In a drug interaction study of 15 subjects, tipranavir/ritonavir (500 mg/200 mg twice daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of raltegravir 400 mg twice daily by 24% and 18%, respectively. This effect was not considered to be clinically meaningful.(1)	APTIVUS

There are 1 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Raltegravir/Rifampin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rifampin may induce the metabolism of raltegravir by UDP-glucuronosyltransferase 1A1 (UGT-1A1).(1-4) CLINICAL EFFECTS: Concurrent use of rifampin may reduce levels and clinical effectiveness of raltegravir.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of rifampin and raltegravir should be approached with caution.(1,2) The US manufacturer of raltegravir recommends a dosage of 800 mg raltegravir twice daily with or without food in adult patients receiving concurrent rifampin.(2) The UK manufacturer recommends considering this dosage adjustment as well if concurrent use of rifampin is unavoidable.(4) No dosage adjustment recommendation is available for patients younger than 18 years of age.(1) DISCUSSION: Concurrent rifampin (600 mg daily) with raltegravir (400 mg single dose) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and 61%, respectively.(1-4) When raltegravir was given at a dosage of 800 mg twice daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir were increased 62% and 27%, respectively, and the Cmin was decreased 53% when compared to the administration of raltegravir (400 mg twice daily) alone.(2)	RIFADIN, RIFAMPIN

Drug Interaction

Drug Names

Raltegravir/Rifampin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifampin may induce the metabolism of raltegravir by UDP-glucuronosyltransferase 1A1 (UGT-1A1).(1-4)

CLINICAL EFFECTS: Concurrent use of rifampin may reduce levels and clinical effectiveness of raltegravir.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of rifampin and raltegravir should be approached with caution.(1,2) The US manufacturer of raltegravir recommends a dosage of 800 mg raltegravir twice daily with or without food in adult patients receiving concurrent rifampin.(2) The UK manufacturer recommends considering this dosage adjustment as well if concurrent use of rifampin is unavoidable.(4) No dosage adjustment recommendation is available for patients younger than 18 years of age.(1)

DISCUSSION: Concurrent rifampin (600 mg daily) with raltegravir (400 mg single dose) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and 61%, respectively.(1-4) When raltegravir was given at a dosage of 800 mg twice daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir were increased 62% and 27%, respectively, and the Cmin was decreased 53% when compared to the administration of raltegravir (400 mg twice daily) alone.(2)

RIFADIN, RIFAMPIN

Contraindication List
Lactation

Severe List
Rhabdomyolysis

Moderate List
Myopathy

The following adverse reaction information is available for ISENTRESS HD (raltegravir potassium):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects reported in 2% or more of patients receiving raltegravir in conjunction with other antiretrovirals include insomnia, headache, dizziness, nausea, and fatigue. Creatine kinase elevations, myopathy, and rhabdomyolysis have been reported.

There are 20 severe adverse reactions.

More Frequent	Less Frequent
None.	Herpes simplex infection Herpes zoster

Rare/Very Rare
Abnormal hepatic function tests Angioedema Eosinophilia Gastritis Graves' disease Guillain-barre syndrome Hepatic failure Hepatitis Hypersensitivity drug reaction Kidney stone Myopathy Polymyositis Renal failure Rhabdomyolysis Stevens-johnson syndrome Suicidal ideation Thrombocytopenic disorder Toxic epidermal necrolysis

There are 18 less severe adverse reactions.

More Frequent	Less Frequent
Dizziness Fatigue Headache disorder Insomnia Nausea	Acute abdominal pain Dyspepsia Fever General weakness Vomiting

Rare/Very Rare
Ataxia Conjunctivitis Depression Diarrhea Malaise Paranoid disorder Skin rash Symptoms of anxiety

The following precautions are available for ISENTRESS HD (raltegravir potassium):

Pediatric
Pregnant
Lactation
Geriatric

Raltegravir (Isentress(R); 400-mg film-coated tablets) is indicated for use in pediatric patients weighing 2 kg or more and is not recommended in preterm neonates or pediatric patients weighing less than 2 kg. Raltegravir (Isentress(R)HD; 600-mg film-coated tablets) is indicated for use in pediatric patients weighing 40 kg or more. Although this formulation has not been studied in pediatric patients, the manufacturer states that population pharmacokinetic modeling and simulation support the use of the once-daily regimen (two 600-mg film-coated tablets once daily) in those weighing 40 kg or more.

Safety and pharmacokinetics of raltegravir for oral suspension were evaluated in 42 full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a phase 1, open-label, multicenter, clinical trial (IMPAACT P1110). The safety profile of the drug in these neonates was comparable to that observed in adults receiving the drug. Safety, efficacy, and pharmacokinetics of twice-daily raltegravir were evaluated in HIV-1 infected pediatric patients 4 weeks to 18 years of age in an open-label, multicenter, clinical trial (IMPAACT P1066). The safety profile of the drug in these pediatric patients was comparable to that observed in adults receiving the drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in females. Healthcare providers should register patients at 800-258-4263. Available data from the APR show no difference in the rate of overall birth defects in infants of pregnant females receiving raltegravir compared with the background rate of major birth defects of 2.7%

in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Based on prospective reports from the APR of over 850 exposures to raltegravir during pregnancy resulting in live births (including over 450 exposures in the first trimester), the prevalence of defects in live births was 3.1% following first trimester exposure to raltegravir-containing regimens and 3.7%

following second and third trimester exposure to raltegravir-containing regimens. In animal reproduction studies (rats and rabbits), there was no evidence of adverse developmental outcomes when raltegravir was given orally during organogenesis at doses producing exposures approximately 4 times those reported with the maximum recommended human dose of 1.2 g.

In animal studies, raltegravir has been shown to cross the placenta with fetal plasma concentrations 1.5-2.5 times greater than in maternal plasma in rats and 2% of maternal plasma concentrations in rabbits on gestation day 20.

There are limited data on the use of raltegravir 1.2 g (two 600-mg film-coated tablets) once daily in pregnant females.

There are no data available regarding the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on milk production. The drug is distributed into milk in rats; milk concentrations approximately 3 times higher than maternal plasma concentrations were reported at 2 hours after a dose on lactation day 14 in rats receiving oral raltegravir from gestation day 6 to lactation day 14. 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 raltegravir in geriatric patients, but recommends careful dosage selection because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Experience in adults 65 years of age and older is insufficient to determine whether they respond differently to raltegravir than younger adults. Reported clinical experience has not identified differences in response between elderly and younger subjects. Raltegravir should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

The following icd codes are available for ISENTRESS HD (raltegravir potassium)'s list of indications:

HIV infection
B20	Human immunodeficiency virus [HIv] disease
B97.35	Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere
O98.7	Human immunodeficiency virus [HIv] disease complicating pregnancy, childbirth and the puerperium
O98.71	Human immunodeficiency virus [HIv] disease complicating pregnancy
O98.711	Human immunodeficiency virus [HIv] disease complicating pregnancy, first trimester
O98.712	Human immunodeficiency virus [HIv] disease complicating pregnancy, second trimester
O98.713	Human immunodeficiency virus [HIv] disease complicating pregnancy, third trimester
O98.719	Human immunodeficiency virus [HIv] disease complicating pregnancy, unspecified trimester
O98.72	Human immunodeficiency virus [HIv] disease complicating childbirth
O98.73	Human immunodeficiency virus [HIv] disease complicating the puerperium
Z21	Asymptomatic human immunodeficiency virus [HIv] infection status