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Lamivudine
Treatment Review
Lamivudine Demetrius James Porche, DNS, RN, CS, CCRN
Treatment Review is intended to inform and update nurses about treatments relevant to HIV/AIDS. Product information presented in this column does not imply endorsement by ANAC. Chemical Name: Lamivudine Brand Name: EpivirT M Tablets; EpivirTM Oral Solution Medication Classification: Antiviral; antiretroviral; synthetic nucleoside analogue Background
Recent research has demonstrated that the extent of viral activity in HIV-1 infected people has been underestimated. Research findings indicate that high levels of viral replication occur at all stages of HIV disease. Techniques used to measure HIV RNA indicate there is a high level of viral activity even in the clinical latency (asymptomatic) period of HIV disease. The half-life of HIV-1 in plasma is estimated to be two days. Approximately 50 million to 2 billion viral particles are turned over each day. There appears to be continual production and destruction of CD4 lymphocytes. Patients with HIV disease who are not treated with an antiretroviral medication experience a complete turn over every 15 days of their entire population of p e r i p h e r a l CD4 l y m p h o c y t e s (Burroughs Wellcome, 1995b). The role of lymph nodes in H1V pathogenesis is being delineated. The lymph nodes appear to be the major reservoir of infectious HIV-1. Cells of the lymph node filter, trap, and hold free H1V-1 and CD4 lymphocytes. The reservoir of HIV-1 in close contact with CD4 lymphocytes appears to facilitate continual infection of CD4 lymphocytes and/or syncytia formation. As HIV disease progresses, the lymph nodes lose their ability to filter and trap HIV-1 and permit more free HIV-1 to circulate in the blood. The lymph nodes appear to play an essential role in the propagation of H1V disease (Burroughs Wellcome, 1995b). Detailed background information on HIV-1 has been reviewed in a previous treatment review column. (Porche, 1995). JANAC VoL7, No. 3, May-June,1996
Indications
Lamivudine (formerly known as 3TC) in combination with zidovudine is indicated for the treatment of HIV infection in patients who experience disease progression as evidenced by clinical and/or immunological test. Contraindications
Contraindications include hypersensitivity to lamivudine or to any components of the formulation. Pharmacologic Action
Lamivudine is a synthetic nucleoside analog. It inhibits replication of HIV-1 in human cells by interfering with the enzyme reverse transcriptase. Pharmokinetics
Lamivudine is rapidly absorbed after oral consumption. Fasted and n o n - f a s t e d states do not interfere with lamivudine absorption; therefore, lamivudine can be administered with or without food. Binding of lamivudine to plasma proteins is <36%. The primary route of excretion is in the urine. The mean elimination half-life ranges from 5 to 7 hours. Decreased renal function increases the mean elimination half-life of lamivudine. Pharmokinetics effects of impaired renal function in pediatric patients are not known. Pharmokinetic properties of lamivudine have not been studied with respect to race, gender, or geriatrics (Burroughs Wellcome, 1995a). Efficacy Zidovudine naive patients (have never taken zidovudine) who received lamivudine 150 mg twice a day in combination with zidovudine 200 mg three times a day displayed increases in CD4 counts as compared to zidovudine monotherapy. In patients who received lamivudine in combination with zidovudine, CD4 cells increased by 42 cells/mm 3 above baseline at 24 weeks but patients who 51
Treatment Review
received zidovudine monotherapy had a CD4 cell increase of only 14 cells/mm3above baseline (Burroughs Wellcome, 1995a). Adult patients who had received zidovudine previously also had increases in CD4 cell counts with lamivudine and zidovudine combination therapy. At 24 weeks, these patients had CD4 cell increases of 31 cells/mm 3 above baseline with lamivudine plus zidovudine but patients who received z i d o v u d i n e plus ddC had a decrease of 16 ceUs/mm3(Burroughs Wellcome, 1995a). Development of drug resistance in HIV-1 infected patients is a significant concern in management of HIV infection. HIV-1 did develop resistance to lamivudine in vitro. HIV-1 strains resistant to both lamivudine and z i d o v u d i n e have been isolated in vitro (Burroughs Wellcome, 1995a). Dosage and Routes of Administration The r e c o m m e n d e d adult and adolescent dosage of lamivudine is 150 mg twice daily in combination with zidovudine. The adolescent age group for this recommendation is defined as 12 to 16 years of age. The recommended dosage of lamivudine for adults who weigh less than 50 kg (110 lbs) is 2 m g / k g twice daily in combination with zidovudine. There are no data to support a recommended dosage for adolescents who weigh less than 50 kg (Burroughs Wellcome, 1995a). Patients older than 16 years with impaired renal function should have the dosage of lamivudine modified based on creatinine clearance, as'follows: Creatinine Clearance
Dosage of Lamivudine .I
>50 30-49 15-29 5-14 <5
52
150 mg twice daily 150 mg once daily 150 mg first dose,then 100 mg once a day 150 mg first dose, then 50 mg once a day 50 mg first dose, then 25 mg once a day
The administration of lamivudine in combination with zidovudine in pediatric patients is based on limited pharmacokinetic and safety data with l a m i v u d i n e monotherapy. The recommended pediatric dosage of lamivudine in patients 3 months to 12 years of age is 4 mg/kg twice daily in combination with zidovudine. The maximum pediatric dosage of lamivudine is 150 mg twice a day (Burroughs Wellcome, 1995b). Adverse Reactions The most common adverse reactions of lamivudine therapy were headache (35%), nausea (33%), malaise and fatigue (27%), nasal symptoms (20%), peripheral neuropathy (12%), and neutropenia (7.2%). Pancreatitis was observed in <0.5% of the adult patients. Only 6% of the patients had to discontinue lamivudine therapy due to adverse reactions. Of the pediatric patients who received lamivudine monotherapy in clinical trials, 14% developed pancreatitis (Burroughs Wellcome, 1995a). Medication and Food Interactions Coadministrafion of trimethoprim/sulfamethoxazole (TMP 160 mg/SMX 800 rag) once a day and lamivudine increased the available amount of lamivudine. The amount of trimethoprim/sulfamethoxazole was not affectedby coadministrafion with lamivudine. No food interactions have been identified. Management of Overdosage Overdosage was reported in one adult who consumed 6 g of lamivudine. The adult did not experience any clinical signs or symptoms, nor hematologic abnormalities (Burroughs Wellcome, 1995a). There is no antidote for lamivudine overdosage. The elimination of lamivudine by peritoneal dialysis or hemodialysis is not known. Nursing Considerations Combination lamivudine and zidovudine therapy in pediatric patients who are at risk for pancreatifis or who JANAC Vol.7, No. 3, May-June,1996
have a history of pancreatitis should be used cautiously. The benefits of this combination therapy in these pediatric patients s h o u l d clearly o u t w e i g h the risk. Pediatric patients with clinical signs, symptoms, or abnormal laboratory tests suggestive of pancreatitis should have lamivudine therapy discontinued immediately. There is a lack of adequate studies of lamivudine administration in pregnant women. Pregnant women should receive lamivudine therapy only if the benefits clearly outweigh the risk. The extent to which lamivudine is excreted in human breast milk is not known. Mothers should be instructed to stop breastfeeding while receiving lamivudine therapy.
7. Lamivudine may be taken with or without food. 8. Parents or guardians should immediately report any signs or symptoms of pancreatitis in pediatric patients.
Nursing Evaluations Evaluate patient outcomes d u r i n g administration of lamivudine: 1. 2. 3. 4.
Medications are being taken as prescribed. Adverse reactions. Clinical progression of H1V disease. Laboratory results of CD4 test and creatinine clearance.
Nursing Assessment References Nursing assessment should include the following: 1. History of current medications, prescribed and over- the- counter 2. Ability to comply with prescribed medical regimen 3. Review of clinical symptoms 4. Review of laboratory test such as CD4 test and creatinine
Burroughs Wellcome. (1995a). Lamivudine TM (lamivudine) tables and oral solution (company package insert). Research Triangle Park, NC: Author. Burroughs Wellcome. (1995b). New perspectives on HIV pathogenesis: Viral replication is continuous throuxhout the course of disease. Research Triangle Park, NC: Author.. Porche, D. (1995). Treatment review: Zerit TM. ]ANAC, 6(5), 50-52.
Administration Instructions Nurses need to emphasize these points during patient education sessions: 1. Medication should be taken as prescribed9 2. Notify the physician/nurse when any of these potential adverse reactions occur such as headache, nausea, malaise and fatigue, and nasal signs and symptoms. 3. Mothers should not breastfeed while on lamivudine therapy. 4. Lamivudine is not a cure for HIV-1 infection, and illness assodated with HIV disease may occur while on lamivudine therapy. 5. Lamivudine has not been shown to decrease the risk of HIV-1 t r a n s m i s s i o n t h r o u g h sexual contact or blood/blood products. 6. Lamivudine should be used only in combination with zidovudine. JANAC Vol. 7, No. 3, May-June, 1996
This publication is available fl'om U N I in one or more
of the following formats: 9
In M i c r o f o r m - - t o m our collection of over 18000 penod~cais and 7,000 newspaper s
9
In Paper by the ar ticle or full issues through UMI Article Clearinghouse
9 Electronically, o n C D - R O M , online, a n d / o r magnetic tapeI-a br oad r ange of ProQuest databases avMable, including abstract and index ASCII lull-te• and innovative full image format Call toll-bee 800 521 0600, e x t 2888 lot more information or fill out the coupon b e l o w
COnlp,~rly/InSb[u[iOrl. . . . . . . . . . . . . . . . . . . . . . . . Address City/S[d[~/ZlU H,onc ( IIra interestedin the followmstltEeS) UNI A Bel~& Howell Company
800 52~-0600 toHIfree 3137611203hx
Box 78
300 North Zeeb Road Ann Arbor, M148106
53
Lamivudine Demetrius James Porche, DNS, RN, CS, CCRN
Treatment Review is intended to inform and update nurses about treatments relevant to HIV/AIDS. Product information presented in this column does not imply endorsement by ANAC. Chemical Name: Lamivudine Brand Name: EpivirT M Tablets; EpivirTM Oral Solution Medication Classification: Antiviral; antiretroviral; synthetic nucleoside analogue Background
Recent research has demonstrated that the extent of viral activity in HIV-1 infected people has been underestimated. Research findings indicate that high levels of viral replication occur at all stages of HIV disease. Techniques used to measure HIV RNA indicate there is a high level of viral activity even in the clinical latency (asymptomatic) period of HIV disease. The half-life of HIV-1 in plasma is estimated to be two days. Approximately 50 million to 2 billion viral particles are turned over each day. There appears to be continual production and destruction of CD4 lymphocytes. Patients with HIV disease who are not treated with an antiretroviral medication experience a complete turn over every 15 days of their entire population of p e r i p h e r a l CD4 l y m p h o c y t e s (Burroughs Wellcome, 1995b). The role of lymph nodes in H1V pathogenesis is being delineated. The lymph nodes appear to be the major reservoir of infectious HIV-1. Cells of the lymph node filter, trap, and hold free H1V-1 and CD4 lymphocytes. The reservoir of HIV-1 in close contact with CD4 lymphocytes appears to facilitate continual infection of CD4 lymphocytes and/or syncytia formation. As HIV disease progresses, the lymph nodes lose their ability to filter and trap HIV-1 and permit more free HIV-1 to circulate in the blood. The lymph nodes appear to play an essential role in the propagation of H1V disease (Burroughs Wellcome, 1995b). Detailed background information on HIV-1 has been reviewed in a previous treatment review column. (Porche, 1995). JANAC VoL7, No. 3, May-June,1996
Indications
Lamivudine (formerly known as 3TC) in combination with zidovudine is indicated for the treatment of HIV infection in patients who experience disease progression as evidenced by clinical and/or immunological test. Contraindications
Contraindications include hypersensitivity to lamivudine or to any components of the formulation. Pharmacologic Action
Lamivudine is a synthetic nucleoside analog. It inhibits replication of HIV-1 in human cells by interfering with the enzyme reverse transcriptase. Pharmokinetics
Lamivudine is rapidly absorbed after oral consumption. Fasted and n o n - f a s t e d states do not interfere with lamivudine absorption; therefore, lamivudine can be administered with or without food. Binding of lamivudine to plasma proteins is <36%. The primary route of excretion is in the urine. The mean elimination half-life ranges from 5 to 7 hours. Decreased renal function increases the mean elimination half-life of lamivudine. Pharmokinetics effects of impaired renal function in pediatric patients are not known. Pharmokinetic properties of lamivudine have not been studied with respect to race, gender, or geriatrics (Burroughs Wellcome, 1995a). Efficacy Zidovudine naive patients (have never taken zidovudine) who received lamivudine 150 mg twice a day in combination with zidovudine 200 mg three times a day displayed increases in CD4 counts as compared to zidovudine monotherapy. In patients who received lamivudine in combination with zidovudine, CD4 cells increased by 42 cells/mm 3 above baseline at 24 weeks but patients who 51
Treatment Review
received zidovudine monotherapy had a CD4 cell increase of only 14 cells/mm3above baseline (Burroughs Wellcome, 1995a). Adult patients who had received zidovudine previously also had increases in CD4 cell counts with lamivudine and zidovudine combination therapy. At 24 weeks, these patients had CD4 cell increases of 31 cells/mm 3 above baseline with lamivudine plus zidovudine but patients who received z i d o v u d i n e plus ddC had a decrease of 16 ceUs/mm3(Burroughs Wellcome, 1995a). Development of drug resistance in HIV-1 infected patients is a significant concern in management of HIV infection. HIV-1 did develop resistance to lamivudine in vitro. HIV-1 strains resistant to both lamivudine and z i d o v u d i n e have been isolated in vitro (Burroughs Wellcome, 1995a). Dosage and Routes of Administration The r e c o m m e n d e d adult and adolescent dosage of lamivudine is 150 mg twice daily in combination with zidovudine. The adolescent age group for this recommendation is defined as 12 to 16 years of age. The recommended dosage of lamivudine for adults who weigh less than 50 kg (110 lbs) is 2 m g / k g twice daily in combination with zidovudine. There are no data to support a recommended dosage for adolescents who weigh less than 50 kg (Burroughs Wellcome, 1995a). Patients older than 16 years with impaired renal function should have the dosage of lamivudine modified based on creatinine clearance, as'follows: Creatinine Clearance
Dosage of Lamivudine .I
>50 30-49 15-29 5-14 <5
52
150 mg twice daily 150 mg once daily 150 mg first dose,then 100 mg once a day 150 mg first dose, then 50 mg once a day 50 mg first dose, then 25 mg once a day
The administration of lamivudine in combination with zidovudine in pediatric patients is based on limited pharmacokinetic and safety data with l a m i v u d i n e monotherapy. The recommended pediatric dosage of lamivudine in patients 3 months to 12 years of age is 4 mg/kg twice daily in combination with zidovudine. The maximum pediatric dosage of lamivudine is 150 mg twice a day (Burroughs Wellcome, 1995b). Adverse Reactions The most common adverse reactions of lamivudine therapy were headache (35%), nausea (33%), malaise and fatigue (27%), nasal symptoms (20%), peripheral neuropathy (12%), and neutropenia (7.2%). Pancreatitis was observed in <0.5% of the adult patients. Only 6% of the patients had to discontinue lamivudine therapy due to adverse reactions. Of the pediatric patients who received lamivudine monotherapy in clinical trials, 14% developed pancreatitis (Burroughs Wellcome, 1995a). Medication and Food Interactions Coadministrafion of trimethoprim/sulfamethoxazole (TMP 160 mg/SMX 800 rag) once a day and lamivudine increased the available amount of lamivudine. The amount of trimethoprim/sulfamethoxazole was not affectedby coadministrafion with lamivudine. No food interactions have been identified. Management of Overdosage Overdosage was reported in one adult who consumed 6 g of lamivudine. The adult did not experience any clinical signs or symptoms, nor hematologic abnormalities (Burroughs Wellcome, 1995a). There is no antidote for lamivudine overdosage. The elimination of lamivudine by peritoneal dialysis or hemodialysis is not known. Nursing Considerations Combination lamivudine and zidovudine therapy in pediatric patients who are at risk for pancreatifis or who JANAC Vol.7, No. 3, May-June,1996
have a history of pancreatitis should be used cautiously. The benefits of this combination therapy in these pediatric patients s h o u l d clearly o u t w e i g h the risk. Pediatric patients with clinical signs, symptoms, or abnormal laboratory tests suggestive of pancreatitis should have lamivudine therapy discontinued immediately. There is a lack of adequate studies of lamivudine administration in pregnant women. Pregnant women should receive lamivudine therapy only if the benefits clearly outweigh the risk. The extent to which lamivudine is excreted in human breast milk is not known. Mothers should be instructed to stop breastfeeding while receiving lamivudine therapy.
7. Lamivudine may be taken with or without food. 8. Parents or guardians should immediately report any signs or symptoms of pancreatitis in pediatric patients.
Nursing Evaluations Evaluate patient outcomes d u r i n g administration of lamivudine: 1. 2. 3. 4.
Medications are being taken as prescribed. Adverse reactions. Clinical progression of H1V disease. Laboratory results of CD4 test and creatinine clearance.
Nursing Assessment References Nursing assessment should include the following: 1. History of current medications, prescribed and over- the- counter 2. Ability to comply with prescribed medical regimen 3. Review of clinical symptoms 4. Review of laboratory test such as CD4 test and creatinine
Burroughs Wellcome. (1995a). Lamivudine TM (lamivudine) tables and oral solution (company package insert). Research Triangle Park, NC: Author. Burroughs Wellcome. (1995b). New perspectives on HIV pathogenesis: Viral replication is continuous throuxhout the course of disease. Research Triangle Park, NC: Author.. Porche, D. (1995). Treatment review: Zerit TM. ]ANAC, 6(5), 50-52.
Administration Instructions Nurses need to emphasize these points during patient education sessions: 1. Medication should be taken as prescribed9 2. Notify the physician/nurse when any of these potential adverse reactions occur such as headache, nausea, malaise and fatigue, and nasal signs and symptoms. 3. Mothers should not breastfeed while on lamivudine therapy. 4. Lamivudine is not a cure for HIV-1 infection, and illness assodated with HIV disease may occur while on lamivudine therapy. 5. Lamivudine has not been shown to decrease the risk of HIV-1 t r a n s m i s s i o n t h r o u g h sexual contact or blood/blood products. 6. Lamivudine should be used only in combination with zidovudine. JANAC Vol. 7, No. 3, May-June, 1996
This publication is available fl'om U N I in one or more
of the following formats: 9
In M i c r o f o r m - - t o m our collection of over 18000 penod~cais and 7,000 newspaper s
9
In Paper by the ar ticle or full issues through UMI Article Clearinghouse
9 Electronically, o n C D - R O M , online, a n d / o r magnetic tapeI-a br oad r ange of ProQuest databases avMable, including abstract and index ASCII lull-te• and innovative full image format Call toll-bee 800 521 0600, e x t 2888 lot more information or fill out the coupon b e l o w
COnlp,~rly/InSb[u[iOrl. . . . . . . . . . . . . . . . . . . . . . . . Address City/S[d[~/ZlU H,onc ( IIra interestedin the followmstltEeS) UNI A Bel~& Howell Company
800 52~-0600 toHIfree 3137611203hx
Box 78
300 North Zeeb Road Ann Arbor, M148106
53