Lamivudine-Zidovudine

Drug overview for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Generic name: LAMIVUDINE/ZIDOVUDINE (la-MIV-ue-deen/zye-DOE-vue-deen)
Drug class: Lamivudine
Therapeutic class: Anti-Infective Agents

Lamivudine, an antiretroviral agent, is a human immunodeficiency virus Zidovudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI) that is active (HIV) nucleoside reverse transcriptase inhibitor (NRTI). against HIV and hepatitis B virus (HBV).

No enhanced Uses information available for this drug.

DRUG IMAGES

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The following indications for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine) have been approved by the FDA:

Indications:
HIV infection

Professional Synonyms:
Human immunodeficiency virus disease
Human immunodeficiency virus infection

The following dosing information is available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Dosing
Administration
LAMIVUDINE-ZIDOVUDINE
LAMIVUDINE-ZIDOVUDINE

Dosage of zidovudine in pediatric patients usually is based on body weight or, alternatively, body surface area. To avoid medication errors, use extra care in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosage instructions. Use a graduated oral syringe with 0.1

mL measurement increments to ensure accurate dosing of zidovudine oral solution in neonates. Zidovudine dosage in pediatric patients should not exceed adult dosage.

The usual dosage of lamivudine for the treatment of HIV-1 infection in Dosage interruption of zidovudine may be required in patients that develop adults is 150 mg twice daily or 300 mg once daily. significant anemia (hemoglobin levels of less than 7.5 g/dL or a reduction

of over 25% from baseline) and/or neutropenia (granulocyte count less than 750 cells/mm3or a reduction of over 50% from baseline) until bone marrow recovery is evident. In patients who develop significant anemia, dosage interruption does not necessarily eliminate the need for blood transfusions.

If marrow recovery occurs following dosage interruption, reinitiation of zidovudine therapy may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices such as serum erythropoetin level and patient tolerance.

When lamivudine oral solution containing 10 mg/mL is used for the treatment of HIV-1 infection in pediatric patients 3 months of age or older, the recommended dosage is 5 mg/kg twice daily or 10 mg/kg once daily (up to 300 mg maximum daily dosage). Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution.

When lamivudine 150-mg scored tablets are used in pediatric patients 3 months of age or older who weigh 14 kg or more and are able to swallow tablets, the recommended dosage is based on weight (see Table 1and Table 2). Data regarding efficacy of the once-daily regimen of lamivudine given as 150-mg scored tablets in pediatric patients 3 months of age or older is limited to those who transitioned from a twice-daily regimen to a once-daily regimen after 36 weeks of treatment.

Table 1. Twice-daily Lamivudine for Treatment of HIV-1 Infection in Pediatric Patients Weighing at least 14 kg (150-mg Tablets)

Weight (kg) AM Dose PM Dose 14 to <20 75 mg (half of 150-mg 75 mg (half of 150-mg tablet) tablet) 20 to <25 75 mg (half of 150-mg 150 mg (one 150-mg tablet) tablet) >=25 150 mg (one 150-mg 150 mg (one 150-mg tablet) tablet)

Table 2. Once-daily Lamivudine for Treatment of HIV-1 Infection in Pediatric Patients Weighing at least 14 kg (150-mg Tablets)

Weight (kg) Once-daily Dose 14 to <20 150 mg (one 150-mg tablet) 20 to <25 225 mg (one and one-half 150-mg tablets) >=25 300 mg (two 150-mg tablets or one 300-mg tablet)

Although safety and efficacy of lamivudine in infants younger than 3 months of age have not been established, some experts suggest that neonates younger than 4 weeks of age+ can receive lamivudine in a dosage of 2 mg/kg twice daily and infants 4 weeks of age or older+ can receive a dosage of 4 mg/kg (up to 150 mg) twice daily.

When empiric HIV therapy+ is used for prevention of perinatal HIV transmission + in neonates at highest risk of HIV acquisition, a 3-drug antiretroviral regimen of zidovudine, lamivudine, and nevirapine is recommended and should be initiated as soon as possible after birth (within 6-12 hours).

For empiric HIV therapy+ in HIV-exposed neonates, experts recommend that lamivudine be given in a dosage of 2 mg/kg twice daily from birth to 4 weeks of age followed by 4 mg/kg twice daily from 4-6 weeks of age.

The optimal duration of empiric HIV therapy+ in HIV-exposed neonates at highest risk of HIV acquisition is unknown. Many experts recommend that the 3-drug regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if the result of the neonate's HIV nucleic acid amplification test (NAAT) is negative, but recommend continuing zidovudine for 6 weeks.

Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding selection of antiretrovirals, including dosage considerations, for the prevention of perinatal HIV transmission.

When lamivudine (100-mg tablets or oral solution containing 5 mg/mL) is used for the treatment of chronic HBV infection in adults, the recommended dosage is 100 mg once daily.

The recommended oral dosage of lamivudine for the treatment of chronic HBV infection in pediatric patients 2-17 years of age is 3 mg/kg once daily up to a maximum daily dosage of 100 mg. The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or unable to swallow tablets.

Lamivudine is administered orally once or twice daily without regard to meals. For the treatment of HIV-1 infection, lamivudine is commercially available as an oral solution containing 10 mg/mL or tablets containing 150 or 300 mg of the drug (Epivir(R), generic). The 150-mg scored tablets are the preferred preparation in pediatric patients who weigh 14 kg or more and can swallow tablets.

The oral solution should be used in those unable to safely and reliably swallow tablets. Lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection. For the treatment of chronic HBV infection, lamivudine is commercially available as an oral solution containing 5 mg/mL or film-coated tablets containing 100 mg of the drug (Epivir-HBV(R), generic).

The 5-mg/mL oral solution should be used in patients requiring a dosage less than 100 mg and in children unable to reliably swallow tablets. Lamivudine preparations labeled by FDA for treatment of chronic HBV infection should not be used in HIV-infected patients because they contain a lower dosage of the drug than that required for treatment of HIV-1 infection. If such preparations are used for the management of chronic HBV infection in a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy for HIV-infected individuals.

Store lamivudine 100-mg, 150-mg, and 300-mg tablets at 25degreesC (excursions permitted between 15-30degreesC). Store lamivudine 5-mg/mL oral solution at 20-25degreesC and store lamivudine 10-mg/mL oral solution at 25degreesC.

Dosing information for LAMIVUDINE-ZIDOVUDINE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
LAMIVUDINE-ZIDOVUDINE TABLET	Maintenance	Adults take 1 tablet by oral route every 12 hours

Generic dosing information for LAMIVUDINE-ZIDOVUDINE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
LAMIVUDINE-ZIDOVUDINE TABLET	Maintenance	Adults take 1 tablet by oral route every 12 hours

The following drug interaction information is available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 12 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Zidovudine/Ganciclovir, Valganciclovir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The magnitude of the toxic effects of both drugs are increased. CLINICAL EFFECTS: Increased side effects, including hematologic and gastrointestinal toxicity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid this combination. Coadministration should be considered only if the potential benefits are judged to outweigh the risks. Dose reduction or interruption may be needed. Monitor with frequent complete blood counts with differential and platelet counts. DISCUSSION: Patients receiving zidovudine and ganciclovir concurrently developed hematologic toxicity, including neutropenia and anemia, and gastrointestinal toxicity. Both ganciclovir and zidovudine have box warnings regarding hematologic toxicity. Granulocytopenia (neutropenia), anemia, thrombocytopenia, and pancytopenia have been reported. In a study in 12 patients, an oral dose of ganciclovir (1000 mg every 8 hours) administered concurrently with zidovudine (100 mg every 4 hours) decreased the mean steady state area-under-the-curve (AUC) of ganciclovir 17% and increased the zidovudine AUC 19%.	GANCICLOVIR SODIUM, VALCYTE, VALGANCICLOVIR HCL
Stavudine; Zidovudine/Ribavirin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ribavirin is believed to inhibit the phosphorylation of zidovudine to its active form, zidovudine triphosphate, by reducing the activity of thymidine kinase.(1) Ribavirin is also believed to inhibit the phosphorylation of stavudine to its active form.(2) CLINICAL EFFECTS: Concurrent use of ribavirin with stavudine may result in decreased efficacy of stavudine(2,3) or hepatic failure.(4) Concurrent use of ribavirin and zidovudine may result in decreased efficacy of zidovudine,(3,5,6) hepatic failure,(4) neutropenia,(4) or anemia.(4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of zidovudine states that concurrent use with ribavirin should be avoided.(3,5) The manufacturer of Rebetol (ribavirin) states that the combination should be used with caution.(6) Patients receiving concurrent therapy with zidovudine and ribavirin should be closely monitored for hepatic failure, neutropenia, and anemia. The manufacturer of stavudine states that concurrent use with ribavirin should be approached with caution.(7) The manufacturer of Rebetrol (ribavirin) states that the combination should be used with caution.(6) Patients receiving concurrent therapy with stavudine and ribavirin should be closely monitored for hepatic failure. DISCUSSION: Zidovudine is converted to its active form by a series of phosphorylations. Ribavirin reduces the activity of thymidine kinase, resulting in higher levels of the natural nucleoside thymidine triphosphate and decreased levels of zidovudine triphosphate. Zidovudine triphosphate competes with thymidine triphosphate for insertion in the viral DNA chain. (3) Several in-vitro studies have shown that the concurrent administration of ribavirin results in decreased phosphorylation of zidovudine(1,8-10), increased sensitivity to zidovudine toxicity,(8) and decreased sensitivity to zidovudine.(9,10) However, no pharmacokinetic or pharmacodynamic changes were seen in a study of 6 subjects receiving concurrent ribavirin and zidovudine.(4) In study NR15961, patients receiving concurrent ribavirin, interferon, and zidovudine developed severe neutropenia (ANC less than 500, 15% versus 9%) and severe anemia (hemoglobin less than 8 g/dL, 5% versus 1%) more frequently than patients not receiving zidovudine.(4) Stavudine is also converted to its active form by a series of phosphorylations.(7) In vitro studies have shown that ribavirin inhibits this process.(2,4,7) However, no pharmacokinetic or pharmacodynamic changes were seen in a study of 10 subjects receiving concurrent ribavirin and stavudine.(4) In study NR15961, 14 (11%) of 129 HIV-positive chronic hepatitis C patients receiving HAART developed hepatic decompensation. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine.(4)	RIBAVIRIN
Stavudine; Zidovudine/Doxorubicin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Doxorubicin may inhibit the phosphorylation of stavudine(1,2) and zidovudine(3) to their active forms. Prolonged use of zidovudine may result in the resistance of tumor cells to doxorubicin.(4) CLINICAL EFFECTS: The concurrent use of doxorubicin may result in decreased levels and effectiveness of stavudine(1) and zidovudine.(3) Prolonged use of zidovudine may result in decreased effectiveness of doxorubicin.(4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of stavudine states that concurrent use of doxorubicin should be approached with caution.(2) The US manufacturer of zidovudine states that the concomitant use of zidovudine and doxorubicin should be avoided.(5) DISCUSSION: An in vitro study showed that doxorubicin inhibits the intracellular phosphorylation of stavudine to its active form at clinically relevant concentrations.(1) An in vitro study showed that doxorubicin inhibits the intracellular phosphorylation of zidovudine to its active form.(3) Another in vitro study found that long-term exposure to zidovudine decreased cell sensitivity to doxorubicin.(4)	ADRIAMYCIN, CAELYX, DOXIL, DOXORUBICIN HCL, DOXORUBICIN HCL LIPOSOME
Deferiprone/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1) CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal. PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2) PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1) DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)	DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY)
Clozapine/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2) CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal. PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia. PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent ANC monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. Clozapine is only available through a restricted distribution system which requires documentation of the absolute neutrophil count (ANC) prior to dispensing.(1-2) For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2) DISCUSSION: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing.(1) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)	CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ
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.	MAVENCLAD
Sorbitol/Lamivudine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sorbitol increases the osmotic pressure in the intestine, resulting in accelerated small intestinal transit time and decreased absorption and bioavailability of lamivudine. CLINICAL EFFECTS: Concurrent administration of sorbitol and lamivudine may result in decreased clinical efficacy of lamivudine.(1) Reduction in lamivudine exposure is sorbitol dose-dependent. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and sorbitol should be avoided.(1) Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided. DISCUSSION: In an open label, randomized sequence, 4-period, crossover trial in 16 healthy adults, coadministration of a single dose of lamivudine (300 mg) with sorbitol (3.2 grams) resulted in a dose-dependent decrease of lamivudine's area-under-the-curve (AUC(0-24), AUC infinity) and maximum concentration (Cmax) of 20%, 28%, and 28%. A single dose of lamivudine with sorbitol (10.2 grams) resulted in a decrease of lamivudine's AUC and Cmax of 39%, 52%, and 52%. A single dose of lamivudine with sorbitol (13.4 grams) resulted in a decrease of lamivudine's AUC and Cmax of 36%, 55%, and 55%.(1)	KIONEX, SPS
Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)	HICON, SODIUM IODIDE I-131
Betibeglogene Autotemcel/Anti-Retrovirals; Hydroxyurea SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1) CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells. DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)	ZYNTEGLO
Elivaldogene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells. DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)	SKYSONA
Lovotibeglogene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1) DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)	LYFGENIA
Atidarsagene Autotemcel/Anti-Retrovirals SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells. DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)	LENMELDY

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

Drug Interaction	Drug Names
Zidovudine/Probenecid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibition of zidovudine metabolism by probenecid. CLINICAL EFFECTS: Increased serum zidovudine levels and cutaneous reactions with systemic symptoms (eg, fever, malaise, myalgia,) have been reported. PREDISPOSING FACTORS: There may be an increased tendency of patients with disorders of the immune system to develop adverse reaction to these drugs. PATIENT MANAGEMENT: Observe patient for unexpected cutaneous reactions. It may be necessary to reduce the dosing frequency of zidovudine if probenecid is administered concurrently. DISCUSSION: Concomitant administration of zidovudine and probenecid may be therapeutically beneficial in reducing the daily dose of zidovudine. However, because of the narrow therapeutic index of zidovudine, the frequent need to treat patients with immune system disorders with various additional drugs, and the known ability of probenecid to inhibit metabolism or renal excretion of many drugs, would make combined zidovudine/probenecid treatment difficult to manage in many of these type of patients. Cutaneous reactions have been reported in many patients receiving zidovudine and probenecid concurrently.	PROBENECID, PROBENECID-COLCHICINE

Drug Interaction

Drug Names

Zidovudine/Probenecid

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

MECHANISM OF ACTION: Inhibition of zidovudine metabolism by probenecid.

CLINICAL EFFECTS: Increased serum zidovudine levels and cutaneous reactions with systemic symptoms (eg, fever, malaise, myalgia,) have been reported.

PREDISPOSING FACTORS: There may be an increased tendency of patients with disorders of the immune system to develop adverse reaction to these drugs.

PATIENT MANAGEMENT: Observe patient for unexpected cutaneous reactions. It may be necessary to reduce the dosing frequency of zidovudine if probenecid is administered concurrently.

DISCUSSION: Concomitant administration of zidovudine and probenecid may be therapeutically beneficial in reducing the daily dose of zidovudine. However, because of the narrow therapeutic index of zidovudine, the frequent need to treat patients with immune system disorders with various additional drugs, and the known ability of probenecid to inhibit metabolism or renal excretion of many drugs, would make combined zidovudine/probenecid treatment difficult to manage in many of these type of patients. Cutaneous reactions have been reported in many patients receiving zidovudine and probenecid concurrently.

PROBENECID, PROBENECID-COLCHICINE

The following contraindication information is available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*History of potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation. * *Previous hypersensitivity to lamivudine.

There are 4 contraindications. Absolute contraindication.

Contraindication List
Acute pancreatitis
Chronic pancreatitis
Lactation
Lactic acidosis

There are 10 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Anemia
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
Hepatomegaly
Myopathy
Myositis
Neutropenic disorder
Severe hepatic disease

There are 3 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Disease of liver
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Toxic amblyopia

The following adverse reaction information is available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse reactions occurring in 15% or more of adult patients receiving zidovudine for HIV-1 in clinical trials include headache, malaise, nausea, vomiting, and anorexia. In pediatric patients receiving zidovudine for HIV-1 in clinical trials, fever and cough were the most commonly reported adverse reactions, occurring in 15% or more of patients. In neonates who received zidovudine for the prevention of maternal-fetal transmission of HIV-1, the most common adverse reaction was anemia (incidence of 15% or greater).

Adverse systemic effects reported with IV zidovudine are similar to those reported with oral zidovudine. However, long-term IV zidovudine therapy (i.e., longer than 2-4 weeks) has not been evaluated in adults and may enhance adverse hematologic effects. In the treatment of HIV infection in adults, the most common reported adverse reactions (incidence >=15%) were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

In the treatment of HIV infection in pediatric patients, the most common reported adverse reactions (incidence >=15%) were fever and cough. In the treatment of HBV infection, the most common reported adverse reactions (incidence >=10% and reported at a rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea.

There are 28 severe adverse reactions.

More Frequent	Less Frequent
Leukopenia Paresthesia Peripheral neuropathy	None.

Rare/Very Rare
Acute pancreatitis Anaphylaxis Anemia Cardiomyopathy Dehydration Drug-induced hepatitis Erythema multiforme Heart failure Hyperglycemia Lactic acidosis Lymphadenopathy Myopathy Neutropenic disorder Pure red cell aplasia Rhabdomyolysis Seizure disorder Skin rash Splenomegaly Steatosis of liver Stevens-johnson syndrome Stomatitis Thrombocytopenic disorder Urticaria Vasculitis Wheezing

There are 25 less severe adverse reactions.

More Frequent	Less Frequent
Cough Diarrhea Fatigue Headache disorder Lipodystrophy associated with human immunodeficiency virus infection Malaise Musculoskeletal pain Nasal congestion Nausea	Abdominal pain with cramps Anorexia Arthralgia Chills Disorder of the digestive system Dizziness Dyspepsia Fever General weakness Insomnia Myalgia Vomiting

Rare/Very Rare
Alopecia Gynecomastia Hyperpigmentation of oral mucosa Muscle weakness

The following precautions are available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

Pediatric
Pregnant
Lactation
Geriatric

Pharmacokinetics of zidovudine in pediatric patients older than 3 months of age are similar to those reported in adults. Zidovudine pharmacokinetics in neonates 2 weeks of age and younger are substantially different from neonates over 2 weeks of age The safety and efficacy of lamivudine for the treatment of HIV-1 (Epivir(R)) have been established in pediatric patients 3 months of age and older. The scored tablet is the preferred formulation for HIV-1-infected pediatric patients weighing at least 14 kg for whom a solid dosage form is appropriate; in the ARROW trial, pediatric patients who received the oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently. The safety and efficacy of lamivudine for the treatment of chronic HBV (Epivir-HBV(R)) in pediatric patients younger than 2 years of age have not been established.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Zidovudine crosses the human placenta and concentrations in neonatal plasma at birth were equivalent to maternal plasma concentrations. In neonates and infants exposed to zidovudine in utero, cases of mild and transient serum lactate elevations, possibly due to mitochondrial dysfunction, have been reported; the clinical significance of these elevations is unknown. There have also been few reports of seizures, developmental delays, and other neurological disorders; however, a causal relationship of zidovudine exposure in utero or during the peri-partum phase with these events has not been established.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including zidovudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.APRegistry.com

to enroll such women. Data from the Antiretroviral Pregnancy Registry show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data include over 13,000 prospective reports of zidovudine exposures during pregnancy resulting in live births, including over 4000 first trimester exposures to the drug.

Lamivudine crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including lamivudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.apregistry.com/

to report cases of prenatal exposure to antiretroviral agents. Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Reproduction studies in rats or rabbits using oral lamivudine dosages that resulted in plasma concentrations up to approximately 35 times higher than plasma concentrations attained with the recommended human dosage used for the treatment of HIV infection in adults have not revealed evidence of teratogenicity. Although there was evidence of early embryolethality in rabbits at exposure levels similar to those observed in humans, this effect was not seen in rats at exposure levels up to 35 times higher than those in humans.

Zidovudine is distributed into human milk. The effects of zidovudine on milk production, or on the breast-fed infant are not known. The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.

The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.

Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery. Lamivudine is distributed into milk in humans. It is not known whether the drug affects human milk production or affects 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 lamivudine is being used for treatment of chronic HBV infection, the benefits of breast-feeding and the importance of lamivudine to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

While clinical experience to date has not revealed age-related differences in response to zidovudine, clinical studies evaluating zidovudine have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Zidovudine should be used with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Clinical trials of lamivudine (Epivir(R) and Epivir-HBV(R)) did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently from younger subjects. Use caution when administering lamivudine to geriatric patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The following prioritized warning is available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine):

WARNING: Zidovudine, one of the medications in this product, can decrease bone marrow function, which may lead to low numbers of red and white blood cells. A low number of red blood cells can lead to anemia. A low number of white blood cells can decrease your body's ability to fight serious, life-threatening infections.

These serious side effects occur more often in people with advanced HIV disease (AIDS). Tell your doctor right away if you develop any signs of anemia (such as unusual tiredness, fast breathing, pale skin, fast heartbeat) or signs of infection (such as sore throat that doesn't go away, fever, chills). Your doctor will check your blood cell counts while you are taking this medication to decrease the risk of these side effects.

Zidovudine may also cause muscle problems. Tell your doctor right away if you develop signs of muscle problems (such as wasting or decrease in muscle size, weight loss, muscle weakness/pain/tenderness). Rarely, lamivudine and zidovudine have caused severe (sometimes fatal) liver problems and a certain metabolic problem (lactic acidosis).

Get medical help right away if you develop symptoms of liver problems (such as nausea that doesn't stop, vomiting, stomach/abdominal pain, pale stools, dark urine, yellowing eyes/skin, unusual tiredness), or of lactic acidosis (such as stomach discomfort, nausea, vomiting, fast/difficult breathing, drowsiness, muscle pain, weakness, cold skin). These serious side effects may occur more often in women and obese patients. If you have hepatitis B infection and HIV, you may have a serious worsening of hepatitis symptoms if you stop taking lamivudine.

Talk with your doctor before stopping this medication. Your doctor will monitor liver tests for several months after you stop lamivudine. Tell your doctor right away if you develop symptoms of worsening liver problems.

The following icd codes are available for LAMIVUDINE-ZIDOVUDINE (lamivudine/zidovudine)'s list of indications:

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