Complera (emtricitabine/rilpivirine HCl/tenofovir disoproxil fumarate)
Antiviral-HIV (Antiretroviral) Nonnucleoside RT Inhibitor Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Tenofovir disoproxil fumarate (tenofovir DF), an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor that is active against HIV and hepatitis B virus (HBV).
Emtricitabine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).
Rilpivirine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).
Tenofovir disoproxil fumarate (tenofovir DF), a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor. Tenofovir DF is a prodrug and is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite, tenofovir diphosphate. After conversion to the pharmacologically active metabolite, tenofovir inhibits replication of retroviruses, including HIV type 1 (HIV-1), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
In vitro and in vivo studies indicate that tenofovir is active against HIV-1 and hepatitis B virus (HBV); the drug also has some activity against HIV-2.
Like HIV nucleoside reverse transcriptase inhibitors (NRTIs), the antiviral activity of tenofovir depends on intracellular conversion to an active metabolite; however, tenofovir is a nucleotide containing a phosphonate group and the steps and enzymes involved in enzymatic conversion to the active metabolite differ from those involved in the conversion of NRTIs. Tenofovir is phosphorylated by cellular nucleotide kinases to tenofovir diphosphate; tenofovir diphosphate is a structural analog of deoxyadenosine-5'-triphosphate, the usual substrate for viral RNA-directed DNA polymerase. Although other mechanisms may be involved in the antiretroviral activities of the drug, tenofovir diphosphate appears to compete with deoxyadenosine-5'-triphosphate for viral RNA-directed DNA polymerase and for incorporation into viral DNA.
Following incorporation of tenofovir diphosphate into the viral DNA chain, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.
Tenofovir diphosphate is a weak inhibitor of mammalian DNA alpha- and beta-polymerases and mitochondrial DNA gamma-polymerase. In vitro studies using human hepatoblastoma cells, skeletal muscle cells, or renal proximal tubule epithelial cells indicate that tenofovir has only a low potential to induce mitochondrial toxicity.
HIV-1 strains with reduced susceptibility to tenofovir DF can be produced in vitro and strains with reduced susceptibility to tenofovir have emerged during therapy with the drug. Resistant strains have contained a K65R substitution in reverse transcriptase. HIV-1 with a K70E substitution that results in low-level reduced susceptibility to tenofovir also have been selected in vitro and identified in clinical isolates.
Cross-resistance occurs between tenofovir and some NRTIs. The K65R and K70E substitutions selected by tenofovir also are selected in some patients treated with abacavir or didanosine; isolates with such substitutions may show reduced susceptibility to emtricitabine and lamivudine. Therefore, presence of the K65R or K70E substitution may result in cross-resistance between tenofovir and NRTIs.
In vitro studies indicate that HIV isolates with multiple substitutions associated with zidovudine resistance have reduced susceptibility to tenofovir. Cross-resistance between tenofovir and HIV protease inhibitors (PIs) or HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) is unlikely.
Tenofovir inhibits HBV replication through competitive inhibition of viral reverse transcriptase. Although treatment-emergent amino acid substitutions have been reported in patients with HBV infection who received at least 24 weeks of tenofovir DF monotherapy and remained viremic, no specific substitutions occurred at a sufficient frequency to be associated with tenofovir resistance (genotypic and phenotypic analysis). Tenofovir may be active against some HBV strains that are resistant to adefovir and/or lamivudine.
However, cross-resistance occurs among the HBV nucleoside/nucleotide reverse transcriptase inhibitors and some adefovir-, entecavir-, lamivudine-, or telbivudine-resistant HBV may have reduced susceptibility to tenofovir.
When a 300-mg tenofovir DF tablet is administered with a high-fat meal, plasma tenofovir concentrations and AUC are increased; pharmacokinetics are not appreciably affected by administration with a light meal.
The pharmacokinetics of tenofovir DF in healthy individuals is similar to that in individuals with HIV-1 infection. Following oral administration of tenofovir DF in fasting HIV-infected individuals, oral bioavailability of tenofovir is approximately 25% and peak plasma concentrations are attained in about 1 hour. Pharmacokinetics are dose proportional over a tenofovir DF dosage range of 75-600 mg and are not affected by repeated dosing.
In a single-dose study in nonfasting individuals, mean peak plasma concentrations of tenofovir were 26% lower when tenofovir DF was administered as an oral powder compared with administration as tablets; however, the mean AUC of tenofovir was similar with both preparations. Food delays the time to peak plasma concentrations by approximately 1 hour. Administration of 300 mg of tenofovir DF (as tablets) following a high-fat meal (approximately 700-1000 kcal containing 40-50% fat) increases oral bioavailability resulting in a 14% increase in peak plasma concentrations and 40% increase in AUC.
Administration of tenofovir DF with a light meal does not have a clinically important effect on the pharmacokinetics of tenofovir compared to administration in the fasting state.
In vitro, tenofovir is less than 0.7 or 7.2% bound to plasma or serum proteins, respectively, over the concentration range of 0.01-25 mcg/mL. Following oral administration of tenofovir DF, there is some evidence that tenofovir is distributed into semen and vaginal tissue and cervicovaginal fluid in low concentrations. Very low concentrations may be distributed into saliva.
Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate. Tenofovir and its prodrug are not substrates of cytochrome P-450 (CYP) isoenzymes. Tenofovir is eliminated principally by the kidneys via glomerular filtration and active tubular secretion.
Following multiple oral doses, approximately 32% of a dose is eliminated in urine over 24 hours. Tenofovir is removed by hemodialysis; following a 300-mg dose of tenofovir DF, a 4-hour hemodialysis session removes approximately 10% of the dose. Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Clinical studies did not include sufficient numbers from racial and ethnic groups other than white patients to adequately determine potential pharmacokinetic differences among these populations. Pharmacokinetics of tenofovir DF are similar in male and female patients.
Emtricitabine, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI). Emtricitabine is inactive until converted intracellularly to an active 5'-triphosphate metabolite. Following conversion to the pharmacologically active metabolite, the drug inhibits replication of human retroviruses by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
The pharmacokinetics of emtricitabine in healthy individuals are similar to that in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Following oral administration, emtricitabine is rapidly and extensively absorbed; peak plasma concentrations of the drug are attained within 1-2 hours. The mean absolute oral bioavailability of emtricitabine capsules is 93%.
The mean absolute oral bioavailability of emtricitabine oral solution is 75%. Food does not appear to have a clinically important effect on emtricitabine absorption. Administration of emtricitabine capsules with food (approximately 1000 kcal high-fat meal) did not affect the area under the concentration-time curve (AUC) of emtricitabine, but resulted in a 29% decrease in peak plasma concentrations of the drug.
Administration of emtricitabine oral solution with a high-fat or low-fat meal did not affect the AUC or peak plasma concentrations of emtricitabine. Pharmacokinetics in pediatric patients 3 months to 17 years of age receiving recommended emtricitabine dosage (6 mg/kg daily (up to 240 mg daily) as the oral solution or 200-mg capsule once daily) is similar to that reported in adults receiving 200 mg daily. The AUC reported in neonates receiving emtricitabine 3 mg/kg daily for 4 days is similar to that reported in children 3 months to 17 years of age receiving the recommended dosage.
Emtricitabine is less than 4% bound to plasma proteins; binding is independent of drug concentrations over the range of 0.01-200 mcg/mL. Emtricitabine is distributed into human milk in low concentrations. Emtricitabine undergoes oxidation and conjugation with glucuronic acid.
Intracellularly, emtricitabine is phosphorylated and converted by cellular enzymes to the active metabolite, emtricitabine 5'-triphosphate. Emtricitabine is eliminated in urine (86%) and feces (14%). The drug is eliminated in urine by glomerular filtration and active tubular secretion; 13% of a dose is recovered in urine as 3 metabolites.
Emtricitabine is removed by hemodialysis; it is not known whether the drug is removed by peritoneal dialysis. The plasma elimination half-life of emtricitabine is approximately 10 hours. Peak plasma concentrations and AUC of emtricitabine are increased in adults with renal impairment (creatinine clearance less than 50 mL/minute or end-stage renal disease requiring dialysis) due to reduced renal clearance of the drug.
Dosage adjustments are needed. The pharmacokinetics of emtricitabine are not affected by race or gender.
Emtricitabine is active against HIV type 1 (HIV-1) and also has some in vitro activity against HIV type 2 (HIV-2). HIV-1 strains with reduced susceptibility to emtricitabine can be produced in vitro and strains with reduced susceptibility to the drug have emerged during emtricitabine therapy. These strains have contained a M184V/I mutation.
HIV-1 strains with the M184V/I mutation have been resistant to lamivudine but retained susceptibility to didanosine, tenofovir, zidovudine, delavirdine, efavirenz, and nevirapine.
Rilpivirine, a diarylpyrimidine human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of HIV type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Diarylpyrimidine NNRTIs (e.g., rilpivirine, etravirine) are capable of adapting to mutations in HIV-1 reverse transcriptase because of structural flexibility that allows for binding to the allosteric NNRTI binding pocket in a variety of conformations. Unlike other currently available NNRTIs, rilpivirine contains a cyanovinyl group that contributes to potency and maintains the drug's binding ability, despite the emergence of some resistance mutations.
In vitro, rilpivirine is highly active against wild-type HIV-1, but has limited activity against HIV type 2 (HIV-2). Rilpivirine has been active against some clinical HIV-1 isolates resistant to other commercially available NNRTIs (efavirenz, nevirapine). However rilpivirine-resistant strains have been selected in cell culture and have emerged during clinical use.
Cross-resistance can occur between rilpivirine and other commercially available NNRTIs, and is expected in patients who have virologic failure while receiving a regimen that contains rilpivirine. Considerable cross-resistance occurs between rilpivirine and etravirine; up to 90% of rilpivirine-resistant isolates that developed in patients receiving rilpivirine in phase 3 clinical studies also were resistant to etravirine. In addition, patients experiencing virologic failure while receiving a rilpivirine regimen in phase 3 clinical studies were more likely to have developed NNRTI-class resistance and treatment-emergent resistance to nucleoside and HIV nucleotide reverse transcriptase inhibitors (NRTIs) than patients experiencing virologic failure while receiving an efavirenz regimen.
After oral administration, peak rilpivirine plasma concentrations are generally attained within 4-5 hours. Rilpivirine is primarily metabolized in the liver by cytochrome (CYP) P-450 isoenzyme 3A. After a single oral dose, an average of 85% of the dose is eliminated in feces (75% as metabolites) and 6% is eliminated in urine (only trace amounts as unchanged rilpivirine).
The terminal elimination half-life of rilpivirine is approximately 50 hours. In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment receiving multiple doses of rilpivirine, exposure to the drug was 47 or 5% higher, respectively, compared to healthy individuals. Coinfection with HIV and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) does not appear to have a clinically important effect on exposure to the drug.
Mild renal impairment does not have a clinically important effect on rilpivirine pharmacokinetics. Only limited data are available regarding pharmacokinetics of the drug in patients with moderate or severe renal impairment or end-stage renal disease, but rilpivirine concentrations may be increased as a result of altered absorption, distribution, or elimination. In vitro studies indicate that rilpivirine is approximately 99.7% bound to plasma proteins, primarily albumin.
Because rilpivirine is highly bound to plasma proteins, peritoneal dialysis and hemodialysis are unlikely to result in clinically important removal of the drug. Total exposure to rilpivirine dosage of 25 mg once daily is 30-40% lower during pregnancy when compared to the postpartum period; however, based on the exposure-response relationship of rilpivirine, this is not considered clinically relevant in patients who are virologically suppressed (viral load <50 copies/mL). Protein binding of rilpivirine is approximately 99% during the second and third trimesters, and the postpartum period.
Clinically relevant differences in pharmacokinetics based on sex, race, or hepatitis B and/or C coinfection have not been observed. Pharmacokinetics in treatment-naive HIV-1-infected pediatric patients 2 to less than 18 years of age and weighing >=16 kg receiving the recommended weight-based dosing regimen of rilpivirine tablets and tablets for oral suspension are similar or slightly higher than those observed in treatment-naive adult patients. In clinical trials, body weight in pediatric patients (ranging from 33-93 kg) did not have a clinically important effect on rilpivirine pharmacokinetics.
USES: This product contains 3 different medications: emtricitabine, rilpivirine, and tenofovir. It is used to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better.
This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life. Emtricitabine and tenofovir belong to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). Rilpivirine belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Emtricitabine/rilpivirine/tenofovir is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor. Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor.
Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Generic name: emtricitabine/rilpivirine HCl/tenofovir disoproxil fumarate
Pronunciation: (EM-trye-SYE-ta-been/RIL-pi-VIR-een/ten-OF-oh-vir)
Drug class: Antiviral-HIV (Antiretroviral) Nonnucleoside RT Inhibitor
Therapeutic class: Anti-Infective Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Complera:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Although tenofovir DF is a prodrug that requires metabolism for activation, dosage of the drug is expressed in terms of the prodrug diester (i.e., tenofovir DF).
Dosage of tenofovir DF oral powder containing 40 mg/g is expressed as the number of scoops of powder.
Emtricitabine capsules and oral solution are not bioequivalent. Bioavailability of the oral solution is 80% relative to that of the capsule.
Rilpivirine is commercially available as rilpivirine hydrochloride; dosage is expressed in terms of rilpivirine.
Reduce dosage in patients with renal impairment; emtricitabine is principally eliminated by the kidney.
If rilpivirine (Edurant(R)) is coadministered with rifabutin, the rilpivirine dosage should be increased to 50 mg once daily. If rifabutin coadministration is halted, the rilpivirine dosage should be decreased to 25 mg once daily.
Single-entity tenofovir DF is commercially available as tablets or oral powder.
Tenofovir DF tablet is administered orally once daily without regard to meals.
Tenofovir DF oral powder is administered once daily. Measure the appropriate dosage of the oral powder using only the scoop provided by the manufacturer. One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF. Mix the required number of scoops of the powder with 2-4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt), and ingest the entire mixture immediately to avoid a bitter taste. Do not administer the oral powder in a liquid since the powder may float to the top of the liquid, even after stirring.
Store tenofovir DF oral power and tablets at 25oC (excursions permitted to 15-30oC). Dispense in the original container, and keep the container tightly closed.
Emtricitabine is administered orally once daily without regard to meals.
Single-entity emtricitabine is commercially available as 200-mg capsules or an oral solution containing 10 mg/mL.
Emtricitabine is also commercially available in the following fixed-combination tablets for oral use: emtricitabine/tenofovir DF (Truvada(R)), efavirenz/emtricitabine/tenofovir DF (Atripla(R)), emtricitabine/rilpivirine/tenofovir DF (Complera(R)), elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild(R)), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya(R)), emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey(R)), emtricitabine/tenofovir alafenamide (Descovy(R)), and bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy(R)). See the full prescribing information for administration of each of these combination products.
Emtricitabine is used in conjunction with other antiretrovirals. Single-entity emtricitabine should not be used concomitantly with any other emtricitabine-containing preparations.
Store capsules at 25degreesC (excursions permitted to 15-30degreesC).
Store oral solution at 2-8degreesC. For patient use, store at 25degreesC (excursions permitted to 15-30degreesC); use within 3 months.
Rilpivirine hydrochloride is available as oral tablets (Edurant(R)) and tablets for oral suspension (Edurant PED(R)); both formulations are administered once daily with a meal. Rilpivirine tablets should be administered to adults and pediatric patients weighing >=25 kg. Rilpivirine tablets for oral suspension should be administered only to pediatric patients weighing >=14 kg to <25 kg.
Rilpivirine oral tablets and tablets for oral suspension have differing pharmacokinetic profiles; therefore, the tablets and tablets for oral suspension should not be substituted on a milligram-per-milligram basis.
Rilpivirine tablets for oral suspension must be dispersed in drinking water and immediately consumed with a meal. If not consumed immediately, the suspension should be discarded and a new dose prepared. Rilpivirine tablets for oral suspension should not be crushed, chewed, or swallowed whole.
In order to properly prepare the tablets for oral suspension for administration, an appropriate number of tablets should be placed in a cup and 5 mL of room temperature drinking water should be added. The cup should be swirled carefully for 1--2 minutes; the oral suspension should begin to have a cloudy appearance. After swirling the cup for 1--2 minutes, the oral suspension may be consumed immediately or the suspension can be further diluted with 5 mL of drinking water, orange juice, or applesauce to assist in administration. All the medicine within the cup should be consumed immediately; a spoon may be used if needed. If medicine is still present in the cup, another 5 mL of drinking water (or alternative beverage or soft food) may be added to the cup, swirled, and consumed immediately.
Food enhances rilpivirine bioavailability. Systemic exposure is approximately 40 or 50% lower if rilpivirine tablets are administered under fasting conditions or with only a protein-rich nutritional drink, respectively, compared with following a standard meal (533 kcal) or high-caloric meal (928 kcal). Systemic exposure is 31 or 28% lower if rilpivirine tablets for oral suspension are dispersed in drinking water in fasted conditions or after yogurt consumption, respectively, compared with following a meal in adults containing 533 kcal.
If a dose of rilpivirine is missed within 12 hours of the time it is usually taken, take the missed dose as soon as possible with a meal. If a dose of rilpivirine is missed by more than 12 hours, then skip the missed dose and resume the normal dosing schedule.
Rilpivirine must be used in conjunction with other antiretrovirals. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir alafenamide or cabotegravir/rilpivirine injeciton. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir DF, unless needed for adjustment of rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).
Store rilpivirine tablets and tablets for oral suspension at 20--25oC; (excursions permitted between 15-30oC). Store tablets in original bottle to protect from light and tablets for oral suspension in original package to protect from moisture.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Complera Tablet | Maintenance | Take 1 tablet by oral route once daily with a meal. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Emtricit-Rilp-Tenof 200-25-300 | Maintenance | Take 1 tablet by oral route once daily with a meal. |
Drug interactions
Tenofovir disoproxil fumarate (tenofovir DF) is a substrate of the P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP). Tenofovir and its prodrug (tenofovir DF) are not substrates of cytochrome P-450 (CYP) isoenzymes; in vitro studies indicate tenofovir does not inhibit CYP isoenzymes 3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.
The following drug interactions are based on studies using tenofovir DF; refer to the full prescribing information for further details. Additional drug interactions may exist for fixed-combinations containing emtricitabine and tenofovir DF (Truvada(R)); doravirine, lamivudine, and tenofovir DF (Delstrigo(R)); efavirenz, emtricitabine, and tenofovir DF (Atripla(R)); emtricitabine, rilpivirine, and tenofovir DF (Complera(R)); elvitegravir, cobicistat, emtricitabine, and tenofovir DF (Stribild(R)); and efavirenz, lamivudine, and tenofovir (Symfi(R) and Symfi Lo(R)). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered. See the full prescribing information for drug interactions of each combination product.
In vitro studies indicate that emtricitabine does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4. Emtricitabine does not inhibit uridine-5'-disphosphoglucuronyl transferase. The following drug interactions are based on studies using emtricitabine. When a fixed combination containing emtricitabine is used, interactions associated with each drug in the fixed combination should be considered.
Most rilpivirine drug interaction studies reported to date used rilpivirine dosages of 75 or 150 mg once daily; these dosages are considerably higher than the usually recommended rilpivirine dosage (25 mg once daily). Rilpivirine is primarily metabolized by cytochrome P-450 isoenzyme 3A (CYP3A).
The following drug interactions are based on studies using single-entity rilpivirine. When rilpivirine fixed combinations are used, interactions associated with each drug in the fixed combination should be considered.
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)
Emtricitabine; Lamivudine/Islatravir
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: Emtricitabine and lamivudine may inhibit the intracellular phosphorylation of islatravir by deoxycytidine kinase (dCK).(1)
CLINICAL EFFECTS: Concurrent administration of emtricitabine or lamivudine with islatravir may result in decreased clinical efficacy of islatravir.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of the doravirine-islatravir fixed-dose combination states that co-administration with emtricitabine or lamivudine is contraindicated.(1)
DISCUSSION: Islatravir undergoes a series of phosphorylations to its active metabolites.(1) In a clinical study in healthy participants, co-administration of multiple daily doses of 300 mg lamivudine and a single dose of 2 mg islatravir (8 times the recommended dosage) decreased intracellular ISL-TP (islatravir active metabolite) area under the curve (AUC) level by 87% and maximum concentration (Cmax) by 76% relative to islatravir alone. A similar effect is anticipated when islatravir is co-administered with emtricitabine.(1,2) Compounds phosphorylated by dCK and linked to this monograph include: emtricitabine and lamivudine.
Nnrtis/Cobicistat-Elvitegravir
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: Cobicistat inhibits CYP2D6, CYP3A4, BCRP, OATP1B1 and OATP1B3. Elvitegravir induces CYP2C9. Efavirenz may induce the metabolism of cobicistat via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors (NNRTIs) may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir should not be used with non-nucleoside reverse transcriptase inhibitors.(1)
DISCUSSION: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)
Rilpivirine/Proton Pump Inhibitors
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: Rilpivirine requires an acidic medium for absorption. The proton pump inhibitor induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)
CLINICAL EFFECTS: Concurrent use of a proton pump inhibitor may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of proton pump inhibitors is contraindicated.(1) When substituting antacids for proton pump inhibitors in patients maintained on rilpivirine, administer the antacid at least 2 hours before or 4 hours after rilpivirine.(1) When substituting H2 antagonists for proton pump inhibitors in patients maintained on rilpivirine, administer the H2 antagonist at least 12 hours before or 4 hours after rilpivirine.(1)
DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)
Rilpivirine/Selected Strong Cyp3a4 Inducers
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: Apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, and St. John's wort may induce the metabolism of rilpivirine by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of CYP3A4 inducers such as apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)
DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort.
Selected Nephrotoxic Agents/Bacitracin
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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)
CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)
PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)
PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)
DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)
Selected Nephrotoxic Agents/Cidofovir
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: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)
CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.
DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)
Tenofovir/Adefovir
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: The mechanism involves competition for active tubular secretion sites in the kidney.(1-4)
CLINICAL EFFECTS: Concurrent use of adefovir and tenofovir in the treatment of hepatitis B may result in elevated levels of tenofovir or adefovir.
PREDISPOSING FACTORS: Renal impairment or use of concurrent renally excreted drugs.
PATIENT MANAGEMENT: The US manufacturer of adefovir(1) and the UK(2) and US(3) manufacturers of tenofovir state that adefovir and tenofovir should be not be administered together.
DISCUSSION: Tenofovir is eliminated principally by renal tubular secretion and any competitive inhibition of excretion of tenofovir by adefovir increases the likelihood of increased serum concentrations of tenofovir and resultant toxicity.(1-4)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
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)
Deoxycytidine Kinase Substrates/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine may inhibit the intracellular phosphorylation of cladribine by deoxycytidine kinase (dCK).
CLINICAL EFFECTS: Concurrent administration of clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine, or zalcitabine with cladribine may result in decreased clinical efficacy of cladribine.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and cladribine is not recommended.(1) The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation should be avoided.(2)
DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites. In a case report, a patient on lamivudine who received cladribine concurrently did not experience a decrease in his lymphocyte count. After discontinuation of lamivudine and readministration of cladribine, his lymphocytes dropped as expected.(3) It is expected that other compounds phosphorylated by dCK would also decrease cladribine's efficacy.(4) Compounds phosphorylated by dCK include: clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine.
Oral Rilpivirine/Rifabutin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Rifabutin may induce the metabolism of rilpivirine by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of oral rilpivirine states that concurrent use of CYP3A4 inducers such as rifabutin warrants dose adjustment. When administering rifabutin with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)
DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1)
Selected Antiretrovirals/Orlistat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown. Orlistat may reduce the absorption of lipophilic antiretroviral HIV drugs by retention in the gastrointestinal tract or reduced gastrointestinal tract transit time.
CLINICAL EFFECTS: The concurrent administration of orlistat and atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, or tenofovir may result in a decrease in the levels and clinical effects of the antiretroviral, including loss of virological control.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: HIV RNA levels should be frequently monitored in patients taking orlistat while being treated for HIV infection. If there is a confirmed increase in HIV viral load, orlistat should be discontinued.(1)
DISCUSSION: Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with lipophilic antiretroviral drugs.(1) There are three case reports of patients having an increased HIV viral load after taking orlistat concomitantly with their HIV therapy.(2-4) Antiretrovirals included in this monograph are atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, and tenofovir.
Selected Antiviral Agents/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Antiviral agents may inhibit the intracellular phosphorylation of cladribine by competitive inhibition of intracellular kinases.(1-4)
CLINICAL EFFECTS: Concurrent administration of antiviral agents with cladribine may result in decreased clinical efficacy of cladribine.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation is not recommended.(1)
DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites.(1) Compounds phosphorylated by kinases linked to this monograph include: acyclovir, entecavir, ganciclovir, tenofovir, valacyclovir, and valganciclovir.
Selected Nephrotoxic Agents/Colistimethate
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)
CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.
PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.
PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)
DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)
Selected Nephrotoxic Agents/Foscarnet
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)
CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)
DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1)
Selected Nephrotoxic Agents/Inotersen
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inotersen can cause glomerulonephritis and renal toxicity. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)
CLINICAL EFFECTS: Concurrent use of inotersen with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.
PREDISPOSING FACTORS: Patients with pre-existing renal impairment.
PATIENT MANAGEMENT: The US manufacturer of inotersen state that caution should be used when administered concurrently with potentially nephrotoxic agents or agents that impair renal function.(1) If concurrent therapy is warranted, monitor renal function closely.(1)
DISCUSSION: The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents. Inotersen is only available through a Tegsedi REMS program because of the risk of glomerulonephritis and severe thrombocytopenia.(1)
Selected Protease Inhibitors And Nnrtis/Garlic
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown. Garlic may induce the metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) by CYP3A4. P-glycoproteins may also be involved.(1,2)
CLINICAL EFFECTS: Concurrent use of garlic and a protease inhibitor or NNRTI may result in decreased levels and effectiveness of the protease inhibitor or NNRTI therapy.(2-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients taking a protease inhibitor or NNRTI should avoid taking garlic supplements. Garlic from food sources is not likely to cause a problem, although there may be some concern if patients are ingesting a large quantity of garlic on a regular basis.
DISCUSSION: A study in nine HIV-negative subjects examined the effects of the concurrent use of a garlic supplement (taken twice daily) on saquinavir (1200 mg twice daily). Concurrent use resulted in a decrease in saquinavir area-under-curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to the administration of saquinavir alone. Following a garlic washout period, saquinavir levels only returned to 60-70% of baseline.(2) In a study in 10 healthy subjects, the administration of garlic (10 mg twice daily) for four days had no significant effects on a single dose of ritonavir (400 mg). Ritonavir AUC and Cmax decreased by 17% and by 25%, respectively. However, the authors cautioned that their results should not be extrapolated to steady-state conditions.(4)
Tenofovir Disoproxil/Cobicistat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown.
CLINICAL EFFECTS: Coadministration of cobicistat with tenofovir disoproxil increases the risk of new onset or worsening renal impairment including acute renal failure and Fanconi syndrome.(1-10)
PREDISPOSING FACTORS: Patients with impaired baseline renal function or who are receiving concomitant nephrotoxic agents may have an increased risk of renal-related adverse events.(1-10)
PATIENT MANAGEMENT: The Canadian, UK, and US manufacturers of atazanavir/cobicistat, cobicistat and darunavir/cobicistat do not recommend coadministration with tenofovir disoproxil fumarate (DF) in patents with a creatinine clearance (CrCl) below 70 ml/min or with concomitant or recent use of an additional nephrotoxic agent.(2-10) In patients receiving concurrent therapy, check glucose and urine protein at baseline and routinely monitor CrCl, urine glucose, urine protein, and serum phosphorus. Discontinue concurrent therapy if CrCl decreases below 70 ml/min.(2-10)
DISCUSSION: Renal toxicity has been documented with coadministration of cobicistat with tenofovir disoproxil fumarate (DF) but not tenofovir alafenamide (AF). Monitoring of renal function is prudent and discontinuation is recommended when CrCl decreases below 70 ml/min to avoid renal impairment.(1-10)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Delavirdine; Rilpivirine/Didanosine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is unknown.
CLINICAL EFFECTS: The simultaneous administration of delavirdine or rilpivirine and didanosine may result in decreased levels and effectiveness of the NNRTI and didanosine.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturers of delavirdine(1) and didanosine(2) recommend that the administration of delavirdine and didanosine be separated by at least one hour. The manufacturer of rilpivirine recommends that didanosine be administered at least 2 hours before or 4 hours after rilpivirine.(3)
DISCUSSION: In a study in nine HIV-1 infected patients, the simultaneous administration of delavirdine (400 mg three times daily) with didanosine (either 125 mg or 250 mg twice daily) for 4 weeks decreased the maximum concentration (Cmax) and area-under-curve (AUC) of didanosine by 20% and 21%, respectively. The Cmax and AUC of delavirdine decreased by 32% and 19%, respectively.(1) In a study in 12 HIV-infected patients, the simultaneous administration of delavirdine (400 mg single dose) with didanosine (125 mg or 200 mg every 12 hours) decreased delavirdine Cmax and AUC by 53% and 32%, respectively. Administration of delavirdine (400 mg single dose) 1 hour before didanosine (125 mg or 200 mg every 12 hours) increased delavirdine Cmax and AUC by 18% and 20%, respectively.(2) In a study in 21 subjects, administration of didanosine (400 mg delayed-release capsule daily) 2 hours before rilpivirine (150 mg daily) had no effect on the Cmax, AUC, or minimum concentration (Cmin) of rilpivirine. There were no significant effects on the Cmax or AUC of didanosine.(3)
Rilpivirine/Antacids; H2 Antagonists
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)
CLINICAL EFFECTS: Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: In patients maintained on rilpivirine, administer antacids at least 2 hours before or 4 hours after rilpivirine.(1) In patients maintained on rilpivirine, administer H2 antagonists at least 12 hours before or 4 hours after rilpivirine.(1) Concurrent use of proton pump inhibitors with rilpivirine is contraindicated.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.
DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)
Rilpivirine/Ombitasvir-Paritaprevir-Ritonavir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ombitasvir-paritaprevir-ritonavir may inhibit the CYP3A4 mediated metabolism of rilpivirine leading to increased systemic exposure (area-under-curve, AUC).(1)
CLINICAL EFFECTS: Increased exposure to rilpivirine may result in toxicity, including potentially life-threatening cardiac arrhythmias, such as torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with additional inhibitors of CYP3A4.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose, or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of rilpivirine with ombitasvir-paritaprevir-ritonavir is not recommended due to the potential risk for QT prolongation.(1) Rilpivirine does not prolong the QT interval at the recommended dose of 25 mg daily. In interaction studies the combination of ombitasvir-paritaprevir-ritonavir and dasabuvir with rilpivirine (25 mg daily) increased rilpivirine exposure (AUC) approximately 3-fold (range: 2.80-3.77), similar to the exposure associated with a rilpivirine dose of 75 mg daily.(3) In rilpivirine QT studies, a 75 mg daily dose increased the QTc interval by 10.7 msec, just above the 10 msec threshold for regulatory concern.(3,4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a clinical trial in healthy adults, rilpivirine at recommended dosages (25 mg daily) had no significant effects on the QTc interval. However, supratherapeutic dosages (75 mg daily and 300 mg daily) increased the QTc interval by 10.7 msec and 23.3 msec, respectively. Rilpivirine dosages of 75 mg daily and 300 mg daily resulted in rilpivirine maximum concentration (Cmax) levels of 2.6-fold and 6.7-respectively.(4)
Rilpivirine/Selected Moderate Cyp3a4 Inducers
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral or intramuscular rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(2) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)
DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)
Rilpivirine/Tecovirimat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tecovirimat may induce the metabolism of rilpivirine by CYP3A4.(1-4)
CLINICAL EFFECTS: Concurrent or recent use of tecovirimat may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Coadministration of rilpivirine with tecovirimat should be approached with caution. Consider increasing rilpivirine to 50 mg daily during treatment with tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)
DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine.(1) In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of midazolam by 39% and 32%, respectively.(2-3)
Selected Nephrotoxic Agents/Immune Globulin Iv (IGIV)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4)
CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.
PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4)
PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose.
DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4)
Tenofovir Disoproxil/Atazanavir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tenofovir disoproxil may induce the metabolism of atazanavir.(1) It is unknown how atazanavir increases tenofovir disoproxil levels.(2)
CLINICAL EFFECTS: Concurrent use of atazanavir and tenofovir disoproxil without concurrent ritonavir or cobicistat may result in decreased levels and effectiveness of atazanavir.(1-3) Concurrent use of atazanavir may result in increased levels and toxicity from tenofovir disoproxil.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of atazanavir states that patients on concurrent tenofovir disoproxil 300 mg daily should receive atazanavir 300 mg and ritonavir 100 mg once daily all as a single daily dose with food. Treatment-experienced patients on both tenofovir disoproxil and a H-2 antagonist should have their atazanavir dose increased to 400 mg with ritonavir 100 mg daily. Treatment-experienced pregnant patients in the second or third trimester on concurrent tenofovir disoproxil should also have their atazanavir dose increased to 400 mg with ritonavir 100 mg daily.(1) Atazanavir should not be administered with tenofovir disoproxil without concurrent ritonavir in adults or pediatric patients of at least 13 years of age and weighing at least 40 kg.(1-3) There are no data to recommend a dose of atazanavir with tenofovir disoproxil in pediatric patients weighing less than 40 kg.(1) Patients receiving concurrent therapy should be monitored for tenofovir associated adverse events and tenofovir should be discontinued in patients who experience adverse events.(1-2) The combination product containing efavirenz/emtricitabine/tenofovir disoproxil is not recommended for use in patients receiving atazanavir.(4) No dosage adjustment is required with the use of tenofovir alafenamide.(5)
DISCUSSION: In a study in healthy subjects, concurrent atazanavir (400 mg daily) with tenofovir disoproxil fumarate (300 mg daily) decreased atazanavir area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) by 25%, 21%, and 40%, respectively. The AUC, Cmax, and Cmin of tenofovir increased by 24%, 14%, and 22%, respectively.(1,2) In another study, atazanavir AUC, Cmax, and Cmin decreased by 25%, 28%, and 23%, respectively, when atazanavir (300 mg daily), ritonavir (100 mg daily), and tenofovir disoproxil fumarate (300 mg daily) were coadministered, when compared to the administration of atazanavir and ritonavir alone. However, these decreased levels were approximately 2.3-fold and 4-fold higher that the respective values for atazanavir (400 mg daily) alone.(1,2) Interim data suggests that rate of moderate or severe adverse effects is similar between atazanavir-treated patients and unboosted atazanavir-treated patients.(1) In a study of 12 subjects, the AUC, Cmax and Cmin of tenofovir disoproxil fumarate (300 mg daily) increased 37%, 34% and 29% respectively, when given with atazanavir (300 mg daily) and ritonavir (100 mg daily).(1) Because both efavirenz and tenofovir disoproxil decrease atazanavir concentrations and the effect of taking both on atazanavir pharmacokinetics has not been studied, the use of atazanavir with the combination product efavirenz/emtricitabine/tenofovir disoproxil is not recommended.(4)
Tenofovir/Didanosine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is unknown.
CLINICAL EFFECTS: Concurrent use of tenofovir and didanosine may result in elevated levels of didanosine(1-5) and toxicities(4-7) such as pancreatitis, symptomatic hyperlactatemia/lactic acidosis, peripheral neuropathy,(3-5) and renal failure.(8) Suppression of CD4 cell counts has been observed in patient receiving concurrent therapy.(1) Concurrent use of tenofovir, didanosine, and a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz or nevirapine may result in virological failure and the development of resistance.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturers of tenofovir(1-3) and didanosine(4,5) state that these agents should be coadministered with caution and patients should be closely monitored for didanosine-related adverse events(1-5) and efficacy.(4) Caution should be used when coadministering reduced-dose didanosine, tenofovir, and an NNRTI in treatment-naive patients with high viral loads at baseline since such use has been associated with reports of a high rate of virologic failure and emergence of resistance at an early stage. All patients receiving tenofovir disoproxil fumarate and didanosine concomitantly should be closely monitored for didanosine-related adverse events and clinical response.(4) In patients weighing 60 kg or more(1-5) with creatinine clearance equal to or greater than 60 ml/min,(4,5) the daily dosage of didanosine should be decreased to 250 mg.(3,5) In patients weighing less than 60 kg with creatinine clearance equal to or greater than 60 ml/min who are receiving tenofovir or the combination product of tenofovir/emtricitabine, the daily dosage of didanosine should be decreased to 200 mg.(4,5) Data are not available to recommend a dosage adjustment in patients weighing less than 60 kg and receiving the combination product of tenofovir/emtricitabine/efavirenz.(3) When coadministered, tenofovir or tenofovir/emtricitabine with enteric coated didanosine may be taken under fasted conditions or with a light meal consisting of less than 400 kcal and 20% fat. When coadministered, tenofovir or tenofovir/emtricitabine and the buffered formulation of didanosine should be taken in the fasted state.(1,2) Didanosine should be discontinued in patients who develop didanosine related adverse effects.(1,4)
DISCUSSION: In a study in 26 subjects, the administration of tenofovir (300 mg daily) two hours after the administration of a single dose of didanosine (400 mg, enteric coated) on an empty stomach increased both the didanosine maximum concentration (Cmax) and area-under-curve (AUC) by 48%. In a study in 25 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (400 mg, enteric coated) with food increased the didanosine Cmax and AUC by 64% and 60%, respectively.(1,4) There were no effects on tenofovir pharmacokinetics.(1) In a study in 14 subjects, administration of didanosine (250 mg or 400 mg once daily for 7 days) with tenofovir (300 mg daily) had no effects on tenofovir pharmacokinetics. The Cmax and AUC of didanosine increased 28% and 44%, respectively.(1) In a study in 28 subjects, the administration of tenofovir (300 mg daily) with didanosine 250 mg enteric coated capsules, didanosine levels were similar to those seen with didanosine 400 mg enteric coated capsules alone under fasted conditions.(1) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (200 mg, enteric coated) with food increased the AUC of didanosine by 16% and decreased didanosine Cmax by 12% when compared to a single 250 mg dose of didanosine.(5) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (250 mg, enteric coated) with food had no effect on the AUC of didanosine and decreased didanosine Cmax by 20% when compared to a single 400 mg dose of didanosine.(5) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (325 mg, enteric coated) with food increased the AUC of didanosine by 13% and decreased didanosine Cmax by 11% when compared to a single 400 mg dose of didanosine.(5) Pancreatitis,(7) fatal lactic acidosis,(6,8) and acute renal failure(8) have been reported in patients receiving concurrent therapy with tenofovir and didanosine. Virologic failure appears to be limited to the use of tenofovir and didanosine with either efavirenz or nevirapine. Data exist that support the efficacy of tenofovir with efavirenz and didanosine and efavirenz.(3)
Tenofovir/Selected Nephrotoxic Agents
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1)
CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2)
PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1)
PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3)
DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1)
Tenofovir/Telaprevir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is unknown.
CLINICAL EFFECTS: Concurrent use of telaprevir may result in elevated levels of and toxicity from tenofovir.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with telaprevir and tenofovir without efavirenz for increased tenofovir effects. Discontinue tenofovir in patients who develop tenofovir-associated toxicities.(1)
DISCUSSION: In a study in 16 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of tenofovir (300 mg daily for 7 days) by 30%, 30%, and 41%, respectively. There were no significant effects on telaprevir pharmacokinetics.(1) In a study in 15 subjects, concurrent telaprevir (1125 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 22%, 10%, and 17%, respectively.(1) In a study in 16 subjects, concurrent telaprevir (1500 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 24%, 10%, and 6%, respectively.(1)
Contraindications
*None.
*Known hypersensitivity to the drug or any ingredient in the formulation.
*Concomitant use of rilpivirine with drugs that induce cytochrome P-450 isoenzyme 3A (CYP3A) or drugs that elevate gastric pH is contraindicated since substantially decreased plasma rilpivirine concentrations may occur and may result in loss of virologic response and development of resistance to rilpivirine and/or class resistance to HIV NNRTIs.
- Lactation
- Lactic acidosis
- Acute renal failure
- Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
- Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Chronic kidney disease stage 5 (failure) GFr<15 ml/min
- Depression
- Disease of liver
- Fanconi syndrome
- Hypophosphatemia
- Osteomalacia
- Pathological fracture
- Suicidal ideation
- Chronic hepatitis B
- Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Chronic kidney disease stage 5 (failure) GFr<15 ml/min
- Osteopenia
- Viral hepatitis
Adverse reactions
The most common adverse effects (incidence >=10%; grades 2-4) in HIV-infected patients receiving tenofovir DF are rash, diarrhea, headache, pain, depression, asthenia, and nausea.
The most common adverse effect (all grades) in HBV-infected patients with compensated liver disease was nausea (9%).
The most common adverse effects (incidence >=10%; all grades) in HBV-infected patients with decompensated liver disease were abdominal pain, nausea, vomiting, pruritus, insomnia, dizziness, and pyrexia.
Adverse reactions in pediatric patients were consistent with those observed in adults.
The most common adverse reactions experienced in at least 10% of adult patients with HIV-1 treated with emtricitabine include headache, GI effects (diarrhea, nausea), fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. Adverse effects reported in pediatric patients 3 months of age or older receiving emtricitabine in clinical studies have been similar to those in adults, with the exception of a higher frequency of hyperpigmentation.
Adverse effects of at least moderate to severe intensity reported in 2% or more of patients in clinical trials include depressive disorders, insomnia, headache, and rash.
More Frequent
- Depression
- Depression
- Gastroenteritis
- Vomiting
Less Frequent
- Anemia
- Bullous dermatitis
- Hypercholesterolemia
- Increased alanine transaminase
- Increased aspartate transaminase
- Maculopapular rash
- Osteopenia
- Peripheral neuropathy
- Pneumonia
- Urticaria
Rare or Very Rare
- Abnormal hepatic function tests
- Abnormal hepatic function tests
- Acute renal failure
- Angioedema
- Angioedema
- Autoimmune hepatitis
- Autoimmune hepatitis
- Biliary calculus
- Blistering skin
- Bronchospastic pulmonary disease
- Cholecystitis
- Conjunctivitis
- DRESS syndrome
- Dyspnea
- Dyspnea
- Eosinophilia
- Facial edema
- Fanconi syndrome
- Glomerulonephritis
- Graves' disease
- Graves' disease
- Graves' disease
- Guillain-barre syndrome
- Guillain-barre syndrome
- Guillain-barre syndrome
- Hepatitis
- Hypersensitivity drug reaction
- Hypokalemia
- Hypophosphatemia
- Interstitial nephritis
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Kidney stone
- Lactic acidosis
- Lactic acidosis
- Nephrogenic diabetes insipidus
- Nephrotic syndrome
- Osteomalacia
- Pancreatitis
- Peripheral neuropathy
- Pneumonia
- Polymyositis
- Polymyositis
- Polymyositis
- Renal tubular necrosis
- Rhabdomyolysis
- Steatosis of liver
- Steatosis of liver
- Suicidal
- Suicidal ideation
More Frequent
- Acute abdominal pain
- Acute abdominal pain
- Back pain
- Cough
- Cough
- Diarrhea
- Diarrhea
- Dizziness
- Dizziness
- Dream disorder
- Dyspepsia
- Fatigue
- Fatigue
- Fever
- General weakness
- General weakness
- Headache disorder
- Headache disorder
- Headache disorder
- Injection site sequelae
- Insomnia
- Insomnia
- Musculoskeletal pain
- Nausea
- Nausea
- Pain
- Pruritus of skin
- Pruritus of skin
- Rhinitis
- Skin rash
- Skin rash
Less Frequent
- Acute bacterial otitis media
- Anorexia
- Arthralgia
- Arthralgia
- Chest pain
- Diarrhea
- Dizziness
- Dream disorder
- Dyspepsia
- Elevated serum amylase
- Elevated serum lipase
- Fatigue
- Fever
- Flatulence
- Insomnia
- Myalgia
- Myalgia
- Nausea
- Paresthesia
- Pharyngitis
- Polyuria
- Proteinuria
- Sinusitis
- Skin rash
- Vomiting
- Vomiting
- Weight loss
Rare or Very Rare
- Acute abdominal pain
- Agitation
- Anorexia
- Depression
- Drowsy
- Drug fever
- Dyschromia
- Hyperhidrosis
- Hypertriglyceridemia
- Muscle weakness
- Myopathy
- Oral hypoesthesia
- Sleep disorder
- Stomatitis
- Symptoms of anxiety
- Urticaria
- Urticaria
- Weight gain
Precautions
No enhanced messaging available.
Safety and efficacy of tenofovir DF for treatment of HIV-1 infection in pediatric patients 2 to <18 years of age are supported by data from 2 randomized controlled trials. Peak plasma concentrations and AUC of tenofovir in HIV-1-infected pediatric patients 2 to <18 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as oral powder or receiving 300 mg once daily as tablets were similar to peak plasma concentrations and AUC reported in adults receiving 300 mg once daily. Safety and efficacy of tenofovir DF for treatment of HIV-1 infection have not been established in children <2 years of age weighing <10 kg.
In HBV-infected pediatric patients 12 to <18 years of age receiving tenofovir DF 300 mg once daily as tablets, and pediatric patients 2 to <12 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as tablets or oral powder, tenofovir exposures were similar to those reported in HIV-1-infected adults receiving identical doses.
Safety and efficacy of tenofovir DF for treatment of chronic HBV infection have not been established in children <2 years of age weighing <10 kg.
Safety and efficacy of emtricitabine have been established for treatment of HIV-1 infection in children 3 months of age and older.
The pharmacokinetics and safety of emtricitabine were evaluated in a dose-finding study in 20 neonates born to HIV-infected mothers. These neonates received zidovudine prophylaxis for 6 weeks. In addition, these neonates received 2 short courses of emtricitabine (3 mg/kg daily for 4 days per course) during the first 12 weeks of life. This dosage was not associated with any safety issues. Systemic exposure (AUC) in infants 0-3 months of age receiving emtricitabine 3 mg/kg daily was similar to that reported in children 3 months to 17 years of age receiving emtricitabine 6 mg/kg daily. All neonates were HIV-1 negative at the end of the study (6 months postpartum); the efficacy of emtricitabine for the prevention or treatment of HIV was not determined.
Safety and efficacy of rilpivirine tablets (Edurant(R)) and tablets for oral suspension (Edurant PED(R)) have been established for the treatment of HIV-1 infection in treatment-naive pediatric patients >=2 years of age and weighing >=14 kg.
The use of rilpivirine in this patient population is supported by the results of 3 trials (i.e., Trial TMC278-C213, Trial TMC278HTX2002, MOCHA trial). The single arm, open-label, phase 2, TMC278-C213 trial involved 2 cohorts of treatment-naive HIV-1 infected pediatric patients. Cohort 1 assessed the efficacy, safety, and pharmacokinetics of rilpivirine tablets in 36 pediatric patients (12 to <18 years of age and weighing >=32 kg). Cohort 2 assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 18 pediatric patients (6 to <12 years of age and weighing >=17 kg). The single-arm, open-label, phase 2, TMC278HTX2002 trial assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 26 pediatric patients (2 to <12 years of age and weighing >=16 kg). In the ongoing MOCHA trial, the safety, tolerability, and pharmacokinetics of oral/injectable cabotegravir and oral/injectable rilpivirine are being evaluated.
Rilpivirine tablets for oral suspension (Edurant PED(R)) are not recommended for use in pediatric patients <2 years of age or weighing <14 kg.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to tenofovir DF during pregnancy. Clinicians are encouraged to register patients in the APR by calling 1-800-258-4263 or visiting https://www.apregistry.com/.
Based on prospective data from the APR, the prevalence of birth defects in live births was 2.3% and 2.1% following first and second/third trimester exposure, respectively, to tenofovir DF-containing regimens. The overall risk of birth defects with first-trimester exposure for tenofovir DF was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (the MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage is not reported in the APR. Tenofovir crosses the human placenta.
In published studies that included HBV-infected pregnant women treated with tenofovir DF, an increased risk of adverse pregnancy-related outcomes was not observed with use of tenofovir DF during the third trimester. Two stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in infants exposed to tenofovir DF. No clinically relevant drug-related safety findings were found in infants exposed to tenofovir DF during late gestation.
Animal reproduction studies did not find any adverse developmental effects when tenofovir DF was administered at doses >=14 (tenofovir DF) and exposures 2.7 (tenofovir) times the recommended daily dose of tenofovir DF in humans.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to emtricitabine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.APRegistry.com.
Based on prospective reports to the APR, the overall risk of birth defects among live births with first-trimester exposure to emtricitabine was 2.4%, and 2.3% with second/third trimester exposure, compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (i.e., MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage for individual drugs is not reported in the APR.
Additional observational data have not shown an increase in major malformations with emtricitabine exposure in pregnancy.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to rilpivirine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.apregistry.com/.
The overall risk of birth defects with first-trimester exposure for rilpivirine was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage is not reported in the APR.
In a small study of 19 HIV-1 infected women on a rilpivirine-based regimen, protein binding was similar during the second and third trimesters and the postpartum period; however, total exposure of rilpivirine was approximately 30-40% lower during pregnancy when compared to the postpartum period. Of the 12 virologically suppressed patients at baseline (<50 copies/mL), virologic suppression with a rilpivirine-based regimen was maintained through the third trimester in 10 patients, and was well-tolerated. Among 10 infants born to HIV-1 infected women, all were HIV-1 negative at delivery and for 16 weeks post-partum. All infants received prophylactic zidovudine treatment at delivery.
Animal data have shown no increases in embryo-fetal toxicity at rilpivirine exposures 15-70 times the equivalent human exposure.
Monitor viral load closely in pregnant women; lower rilpivirine exposures have been observed in pregnant individuals.
Tenofovir is distributed into human milk in low concentrations. In a study of breast-feeding women (not infected with HIV) who were on a tenofovir-containing regimen started between 1-24 weeks postpartum, tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. No serious adverse events were reported in mothers or infants.
It is not known whether tenofovir DF affects human milk production or has effects on the breast-fed infant.
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.
If using tenofovir DF for the treatment of HBV infection, consider the developmental and health benefits of breast-feeding and the importance of tenofovir DF to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
Based on published data, emtricitabine is distributed into human milk. It is not known whether emtricitabine affects milk production or has effects on the breast-fed infant.
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.
Based on limited data, rilpivirine is present in human milk; however, there are no data on the effects of rilpivirine on the breast-fed infant or on milk production.
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 geriatric patients. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection due to the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease and drug therapy.
Clinical studies did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently to tenofovir DF than younger adults. Select dosage in geriatric patients with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy. Pharmacokinetic studies have not been conducted in patients >=65 years of age.
Experience in those 65 years of age or older is insufficient to determine whether they respond differently to emtricitabine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Consult the product labeling of commercially available fixed-combination products containing rilpivirine for specific dosage adjustments of each component in geriatric patients.
Experience in those 65 years of age and older is insufficient to determine whether they respond differently to rilpivirine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.
ICD codes
| Code | Type | Description |
|---|---|---|
| HIV infection | ||
| B20 | ICD10CM | Human immunodeficiency virus [HIv] disease |
| B97.35 | ICD10CM | Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere |
| O98.7 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, childbirth and the puerperium |
| O98.71 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy |
| O98.711 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, first trimester |
| O98.712 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, second trimester |
| O98.713 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, third trimester |
| O98.719 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, unspecified trimester |
| O98.72 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating childbirth |
| O98.73 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating the puerperium |
| Z21 | ICD10CM | Asymptomatic human immunodeficiency virus [HIv] infection status |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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