Lamivudine-Zidovudine (lamivudine/zidovudine)

Dosage interruption of zidovudine may be required in patients that develop 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.

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.

The following drug interactions are based on studies using single-entity zidovudine. When a fixed combination containing zidovudine is used, interactions associated with each drug in the fixed combination should be considered.

The following drug interactions are based on studies using lamivudine. Additional drug interactions may exist for fixed-dose combination products containing lamivudine/zidovudine (Combivir(R), generic) , abacavir/lamivudine (Epzicom(R), generic) , abacavir/lamivudine/zidovudine (Trizivir(R), generic) , lamivudine/tenofovir disoproxil fumarate (Cimduo(R)) , doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo(R)) , dolutegravir/lamivudine (Dovato(R)) , efavirenz/lamivudine/tenofovir disoproxil fumarate (Symfi(R); Symfi(R) Lo) , and abacavir/dolutegravir/lamivudine (Triumeq(R); Triumeq PD(R)). See the full prescribing information for information on each of these combination products.

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

Anti-Retrovirals/Atidarsagene Autotemcel

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Anti-Retrovirals/Elivaldogene Autotemcel

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Anti-Retrovirals/Etuvetidigene Autotemcel

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Anti-Retrovirals/Lovotibeglogene Autotemcel

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

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.

Lamivudine/Zalcitabine

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: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of each other.(1-6)

CLINICAL EFFECTS: Concurrent administration of lamivudine and zalcitabine may result in decreased clinical efficacy of one or both agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and zalcitabine is not recommended.(1-3)

DISCUSSION: Both lamivudine(1-3) and zalcitabine(7) undergo a series of phosphorylations to their active metabolites. In an in vitro study, the presence of lamivudine significantly decreased the phosphorylation of zalcitabine, resulting in a 50% decrease in zalcitabine triphosphate levels.(4) In an in vitro study in peripheral blood mononuclear cells (PBMCs) and U937 cells, zalcitabine significantly inhibited the phosphorylation of lamivudine. No lamivudine triphosphate was found in the PBMCs and the amount of lamivudine triphosphate was decreased 33% when compared to control values in the U937 cell line.(5) In another in vitro study, lamivudine decreased total zalcitabine phosphates by 57%. There was no effect on lamivudine phosphorylation.(6)

Stavudine; Zidovudine/Doxorubicin

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: 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)

Zidovudine/Stavudine

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: Zidovudine may inhibit the phosphorylation of stavudine to its active form by competing for thymidine kinase.(1,2)

CLINICAL EFFECTS: The concurrent use of zidovudine and stavudine may result in decreased antiretroviral effectiveness.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of stavudine(4) and zidovudine(3) state than concurrent use of these agents should be avoided.

DISCUSSION: Both zidovudine and stavudine undergo a series of phosphorylations to their active forms. During this process, they compete for thymidine kinase. An in vitro study showed that the presence of zidovudine decreased intracellular phosphate metabolites of stavudine by 41-83%, depending on the concentration of zidovudine. There was no effect on zidovudine phosphorylation.(1) In a study in 145 HIV-positive subjects, subjects were randomized to one of four treatment arms: zidovudine with stavudine, zidovudine with didanosine, didanosine alone, or stavudine alone. Patients in the stavudine plus zidovudine arm had progressive declines in CD4 counts. Patients in all other arms had stable or increased CD4 counts. Mean levels of stavudine triphosphate were 10fmol/10x6 cells in patients receiving concurrent zidovudine. Mean levels of stavudine triphosphate were 65fmol/10x6 in patients receiving stavudine alone. There was no difference in zidovudine monophosphate or zidovudine triphosphate levels in patients receiving zidovudine alone or with stavudine.(2)

Zidovudine/Trimetrexate

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: Both trimetrexate and zidovudine can result in hepatotoxicity and hematologic toxicity.(1)

CLINICAL EFFECTS: Concurrent use may result in hepatotoxicity or hematologic toxicity, which may limit the dose of trimetrexate than can be safely administered.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of trimetrexate states that to allow for full therapeutic doses of trimetrexate, zidovudine therapy should be discontinued during trimetrexate therapy.(1)

DISCUSSION: Patients receiving trimetrexate may experience severe hepatic, hematologic, renal, and gastrointestinal toxicities. Caution should be used in treating patients with impaired hematologic, renal, or hepatic function. To allow for full therapeutic doses of trimetrexate, treatment with zidovudine should be discontinued during trimetrexate therapy.(1)

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

Agents That Increase Cpk/Aumolertinib

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

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. 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, and advanced age.(1,2) 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: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

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.

Lamivudine/Sorbitol

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)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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)

Selected Myelosuppressive Agents/Clozapine

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 absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. 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: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

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)

Selected Myelosuppressive Agents/Dipyrone

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

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, 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. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

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)

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%.

Moderate Interaction: Assess the risk to the patient and take action as needed.

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.

*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.

• Acute pancreatitis
• Chronic pancreatitis
• Lactation
• Lactic acidosis

• 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

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

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.

More Frequent

• Leukopenia
• Paresthesia
• Peripheral neuropathy

Rare or 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

More Frequent

• Cough
• Diarrhea
• Fatigue
• Headache disorder
• Lipodystrophy associated with human immunodeficiency virus infection
• Malaise
• Musculoskeletal pain
• Nasal congestion
• Nausea

Less Frequent

• Abdominal pain with cramps
• Anorexia
• Arthralgia
• Chills
• Disorder of the digestive system
• Dizziness
• Dyspepsia
• Fever
• General weakness
• Insomnia
• Myalgia
• Vomiting

Rare or Very Rare

• Alopecia
• Gynecomastia
• Hyperpigmentation of oral mucosa
• Muscle weakness

No enhanced messaging available.

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.

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.

The manufacturer provides no specific dosage recommendations in geriatric patients. The manufacturer states that in general, the dosage of zidovudine should be selected with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Use with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

While clinical experience to date has not revealed age-related differences in response to 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.