Drug Monographs

Nelfinavir

By Dr. Mairin Ryan

Introduction

Nelfinavir (NFV) is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment combination with the non-nucleoside of HIV 1 and HIV 2 infection.

Nelfinavir is part of a second line regimen in the Ugandan National Antiretroviral Guidelines.

Dosage /Administration[1]

Adults:

For adults > 13 years NFV 1250mg twice daily or 750mg three times daily. NFV should be taken with a meal or light snack as food increases the bio-availability. For patients who have difficulty swallowing, the tablets may be crushed and mixed with milk or food.

Once crushed and mixed with food, NFV should be consumed within six hours. Mixing with acidic food (e.g. apple juice, orange juice) should be avoided due to a bitter taste. Alternatively there is a powder formulation which may be added to water, milk, soy milk or milk / soy milk based foods. Once reconstituted, powdered nelfinavir must be consumed within 6 hours.

Paediatrics[1,2]:

In children 2 years and older 20-30mg/kg three times daily. Twice daily dosing at 50- 55mg/kg is currently under evaluation in children older than 6 years. Children may receive the powder formulation or tablets as appropriate.

Pregnant women[1,3,4]:

Nelfinavir is classed as Pregnancy Class B; no treatment related malformations were seen in animal studies. A recent study indicated that nelfinavir concentration ratios were significantly lower in pregnant women especially during the third trimester. The authors have suggested that dose adjustment to 1500mg NFV twice daily may be required in some circumstances. Nelfinavir is distributed into breast milk. Standard guide-lines recommend avoidance of breast-feeding however, due to the risk of transmission of HIV via the breast milk to the infant.

Post exposure prophylaxis[1]:

Nelfinavir may be used for post exposure prophylaxis as part of a three-drug-regimen commonly containing two nucleoside analogues e.g. zidovudine and lamivudine for a period of 4 weeks.

Dosing in renal /hepatic impairment[1]:

Renal clearance of NFV is negligible therefore no dose adjustment in renal impairment is recommended. NFV is principally metabolised in the liver and therefore should be used with caution in patients with impaired liver function.

Precautions and Contraindications

Nelfinavir is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.

Side Effects[1]

The most frequently report-ed side effect is mild to moderate diarrhoea (occurring in up to 20% of patients) which may be controlled with anti-motility agents e.g. loeramide, diphenoxylate.

Other gastrointestinal side effects include nausea, flatulence and abdominal pain.

Substantial increases in AST and ALT have occurred in 3% of adults receiving NFV in clinical studies. Hepatitis, increased alkaline phos-phatase and gamma-glutamyl transferase have been report-ed in < 2% of patients. Other side effects associated with nelfinavir and other members of the protease inhibitor class include hyperglycaemia, hyperlipidaemia and lipodystrophy (redistribution / accumulation of body fat). Spontaneous bleeding in haemophiliacs has been reported with other protease inhibitors.

Monitoring parameters[1]

Ideally liver enzymes should be monitored regularly and cholesterol and blood glucose should be monitored periodi-cally.

Interactions[1,2,5,6]

Metabolism of nelfinavir is mediated to some extent by several cytochrome P450 iso-enzymes including CYP3A and CYP2C19.

Concomitant use of medications, which induce these enzymes, may result in reduced NFV concentrations and consequently increase the risk of virologic failure and the development of resistance. Therefore concomitant administration of drugs such as rifampicin, St John\'sWort should be avoid-ed. Nelfinavir inhibits CYP3A and may result in increased blood levels of drugs metabolised by this pathway. Amiodarone, astemizole, cisapride, ergot alkaloids, halofantrine, lumefantrine, midazolam, pimozide, quinidine, terfenadine and triazolam should not be prescribed with nelfinavir as increased levels of these agents may have life threatening consequences.

Co-administration with sim-vastatin and lovastatin is not recommended and caution is advised if used with atorvas-tatin. Pravastatin and fluvas-tatin are not metabolised by cytochrome P450 and there-fore have a low propensity to interact with NFV.

Co-administration of silde-nafil with nelfinavir requires caution as increased sildenafil concentrations may result in enhanced toxicity. Recommendations on dose adjustments when nelfinavir is prescribed with other pro-tease inhibitors may be found in the first newsletter in this series Vol 1, Issue 1 (avail- able from ATIC on request). Dose adjustments of NFV are not required when used in combination with the non-nucleoside reverse transcrip-tase inhibitors efavirenz and nevirapine Concomitant administration of NFV and oral contracep-tives containing ethinyl oestradiol and norethindrone results in lowered levels of these agents. Therefore alter-native means of contraception are required.

Resistance[1,5]

Resistance to nelfinavir is associated with the develop-ment of one or more of sever-al resistance mutations, which may or may not confer or contribute to resistance against other protease inhibitors.

Generics

Not available in Uganda

Storage[1,2]

Nelfinavir tablets and pow-der should be stored at 15- 30°C.

Presentations

Nelfinavir film is available as Viracept coated tablets 250mg, 625mg and as Viracept powder: 1 level 5ml teaspoon gives 200mg NFV, 1 level scoop provided gives 50mg NFV.

References

  1. American Hospital Formulary Service: drug Information, 2004. American Health-System pharmacists; Bethesda. US.
  2. Viracept Summary of Product Characteristics. Roche Products Ireland Ltd, 2004.
  3. Drugs in pregnancy and Lactation. Ed: Briggs et al, 2002. Lippincott, Williams and Willcot.
  4. Nellen J, Schillevoort I, Wit F et al. nelfinavir plasma con-centrations are low during pregnancy Clin Infect Dis 2004; 39: 736-740.
  5. www.hivinsite.ucsf.edu
  6. www.hiv-druginteractiosn.org

Lopinavir

By Kimberly Scarsi

Introduction

Lopinavir/ritonavir (LPV/r) is a combination or \'boost\' protease inhibitor. Lopinavir is the active agent to prevent HIV replication, while a low dose of ritonavir inhibits lopinavir metabolism, and boosts the drug levels.

Indication

LPV/r is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.[1,2]

Dosage/Administration[1,3]

Adults:

LPV/r 400/100 mg (3 capsules or 5 mL of oral solution) twice daily taken with food.

When taken with efavirenz or nevirapine: LPV/r 533/133 mg (4 capsules or 6.5 mL) twice daily taken with food. Non-FDA approved dosing currently under investigation: LPV/r 800/200 mg (6 capsules or 10 mL of oral solution) once daily taken with food.[3,4]

Paediatrics:

Indicated for children 6 months to 12 years of age. For children between 7-15 kg the LPV/r dose is 12/3 mg/kg twice daily with food. For children between 15-40 kg the dose is 10/2.5 mg/kg. For children >40kg the dose should not exceed 400mg/100mg twice daily.

When taken with efavirenz or nevirapine: LPV/r 13/3.25 mg/kg for those 7-15 kg, 11/2.75 mg/kg for those 15-45 kg, up to a maximum of 533/133 mg for those >45 kg.

Pregnant Women:

No known dosage adjustments at this time, research is ongoing.[1,2]

Co-administration and Cost

LPV/r is usually prescribed with two NRTIs, most commonly AZT and 3TC. It should never be prescribed alone. The cost of a months supply in Uganda for an adult is approximately 110,000 shillings or about US$60.

Contraindications and Precautions[1,2]

Hypersensitivity to either lopinavir or ritonavir. LPV/r is an inhibitor of the cytochrome P450 (CYP3A and CYP2D6). Co-administration of LPV/r with drugs that are metabolised by CYP3A or CYP2D6 may result in significant elevations of these agents.

LPV/r should be used cautiously in patients who require a drug that may result in serious or life-threatening toxicities due to elevated plasma concentrations.

Hyperglycemia and new onset diabetes have been observed in patients after the initiation of protease inhibitors. Monitoring of patients glucose is recommended after initiation.

Side Effects[1,2]

The most common side effect associated with LPV/r therapy is diarrhoea. The diarrhoea is usually mild to moderate, and similar to other protease inhibitors.

Nausea and vomiting are other potential gastrointestinal side effects with LPV/r therapy. Hypercholesterolemia and hypertriglyceridemia, can occur with LPV/r therapy.

The hypertriglyceridemia may be more common with LPV/r than other protease inhibitors. Another side effect reported with LPV/r and protease inhibitors in general is redistribution/ accumulation of body fat.

Monitoring Parameters

Ideally liver enzymes during the first several months of therapy and cholesterol and glucose periodically.[1,2]

Interruption of Therapy

If a patient misses a dose of LPV/r, the dose should be taken as soon as it is remembered. If the dose is not remembered until the following dose due time, a double dose of LPV/r should not be taken to make up for the missed dose. Treatment should be interrupted if any serious or life-threatening adverse effects occur.

If therapy is interrupted for several days, monitor for dose changes required with concomitant medications due to the LPV/r CYP3A and CYP2D6 enzyme inhibition.[1,2]

Interactions[1,2]

Metabolism of lopinavir is almost entirely via CYP3A and concomitant use of medications that induce this enzyme may result in reduced plasma concentrations of LPV/r. This decrease in plasma concentrations may increase the risk of virologic failure and the development of viral resistance.

The use of some agents with LPV/r is contraindicated because of the risk of virologic failure and resistance: rifampicin and St. John\'s wort (hypericum perforatum).

LPV/r is also a potent inhibitor of CYP3A and CYP2D6 isoenzymes. This may result in increased blood levels of drugs metabolised by these isoenzymes when used concomitantly with LPV/r (Example: ketoconazole, other protease inhibitors).

The use of some agents with LPV/r is contraindicated due to dangerous side effects from increased blood concentrations of the concomitant medication: flecainide, propafenone, astemizole, terfenadine, ergot-amine, dihydroergotamine, cisapride, lovastatin, simvastatin, pimozide, midazolam, and tria-zolam.

Pregnancy, lactation, Post-Exposure Prophylaxis[1,2]

LPV/r is classified as a Pregnancy Category C, no treatment related malformations were seen in animal studies. It is not known if LPV/r is excreted in human breast milk. Because of this, it is not recommended for nursing mothers yet.

Storage[1,2]

LPV/r may be stored at 2-8°C until the expiration date on the bottle. LPV/r may be stored up to 25°C for up to two months.

Presentations[1,2]

Kaletra capsules provide 133.3 mg of lopinavir and 33.3 mg of ritonavir per capsule. Kaletra oral solution contains 400mg of lopinavir and 100 mg of ritonavir per 5 mL (80/20mg/mL).

References

  1. Kaletra product information. Abbott Laboratories,
    North Chicago, IL, USA.
  2. American Hospital Formulary Service: Drug Information. 2004. American Health-System Pharmacists; Bethesda, MD.
  3. Gathe J, Podzamczer D, Johnson M, Schwartz R, Yeh V, Travers N, Luff K, Tressler R, and Brun S. Once-daily vs twice daily lopinavir/rionavir in antiretroviral-naïve patients: 48-week results. 11th Conference on Retroviruses and Opportunistic Infections, Poster session. February 9, 2004.
  4. Eron JJ, Feinberg J, Kessler HA, Horowitz HW, Witt MD, Carpio FF, Wheeler DA, Ruane P, Mildvan D, Yangco BG, Bertz R, Bernstein B, King MS, Sun, E. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis. 189(2):265-72, 2004 Jan 15.

Zidovudine

Introduction

Zidovudine, also referred to as AZT or ZDV, belongs to the antiretroviral (ARV) class of nucleoside reverse transcriptase inhibitors (NRTI).

Historical Perspective[1,2]

In 1987 AZT became the first ARV to gain FDA approval in the US. At that time, it was found to provide short-term survival benefit as monotherapy in patients with advanced AIDS. AZT was later found to improve outcomes in patients with early symptomatic or asymptomatic HIV infection. Interestingly, when AZT was first approved it was dosed every four hours. This dosing strategy was based on its serum half-life, which is only 1-2 hours. However, it is now known that the intracellular half-life of AZT, which is 8-12 hours, is of importance, thus every 12 hour dosing is recommended. Despite the introduction of many new antiretroviral agents, AZT remains a useful component of combination therapies for treatment of HIV.

Indications and Use[1,3]

AZT is indicated for the treatment of HIV infection in adult and pediatric patients when used in conjunction with other antiretroviral agents. AZT is also used for prevention of mother-to-child transmission and post-exposure prophylaxis in individuals exposed to HIV. AZT may also provide some improvement of the neurologic dysfunction associated with advanced HIV disease.

Dosage and Administration[2,3,4]

Adults - AZT 600 mg daily, generally given as 300 mg every 12 hours. This agent may be taken with or without food. When using AZT either in Combivir® or Trizivir®, the dose is one tablet twice daily. (Refer to \"Preparations and Cost\")

The usual IV dose is 1 mg/kg given as a 1-hour infusion every 5 to 6 hours. IV therapy should only be administered when the patient is unable to take oral therapy.

Pregnant Women[5]: 

AZT is used for prevention of mother-to-child transmission of HIV. In pregnant women, a dose of 300 mg twice daily may be initiated after 14 weeks gestation until the start of labor. During intrapartum/postpartum am oral regimen of AZT 600 mg and lamivudine 150 mg at the onset of labor, followed by AZT 300 mg every 3 hours and lamivudine 150 mg every 12 hours until delivery. In one study to reduce transmission, patients initiated a 7-day regimen of AZT 300 mg and lamivudine 150 mg every 12 hours after delivery. A 42% reduction in 6-week HIV transmission was demonstrated in this study group (versus placebo).6

Pediatrics[7]:

AZT is recommended in pediatric patients less than 4 weeks of age at a dose of 4mg/kg/dose twice daily, and patients 4 weeks to 12 years of age at a dose of 180 mg/m2/dose twice daily to a maximum of 300 mg twice daily.

Renal and Hepatic Impairment[2,4]:

AZT clearance significantly decreases with severe renal dysfunction. Thus, in patients with severe renal impairment, including hemodialysis or peritoneal dialysis, AZT should be given as 100 mg orally every 6 to 8 hours.

No dosage adjustments need to be made in patients with mild to moderate hepatic impairment. A lower daily dose may be needed in patients with severe hepatic dysfunction; however, specific recommendations have not yet been made. These patients should be more closely monitored for AZT-associated hematologic toxicities.

Anemia[2]:

Patients with severe anemia (Hgb < 7.5 g/dL or > 25% decrease from baseline) or severe neutropenia (absolute granulocyte count of < 750 cells/mm3 or > 50% decrease from baseline), may require dose reduction or discontinuation.

Precautions and Contraindications[2,4]

AZT should not be used in any patients who have experienced prior hypersensitivity to the drug in any of its dosage forms.

Although rare, fatal reports of lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of NRTIs, including AZT. Treatment with these agents should be discontinued in patients with symptomatic lactic acidosis, which may present as persistent fatigue, abdominal pain and distention, nausea and vomiting, difficulty breathing or shortness of breath, or enlarged fatty liver.

Patients should also be made aware of other possible complications associated with AZT use, including bone marrow suppression, primarily anemia and neutropenia, as well as myopathy or myositis and fat redistribution. (Refer to \"Side Effects\").

Side Effects[2,3,4]

A significant number of patients treated with AZT experience various gastrointestinal and non-specific side effects, which may include headache, malaise, nausea, vomiting, and loss of appetite. The drug may be taken with food in order to help alleviate some of the gastrointestinal symptoms. Fortunately, these symptoms generally resolve within the first few weeks of starting therapy.

AZT is associated with bone marrow suppression, which most commonly presents as anemia or leukopenia. These findings are most common in patients receiving long-term AZT treatment with advanced HIV disease; however, all patients should be closely monitored for signs and symptoms of bone marrow suppression, including hemoglobin and neutrophil count. Persistent anemia may require blood transfusion and/or dosage adjustment of AZT if discontinuation of the drug is not an option. (Refer to \"Dosage and Administration\" and \"Monitoring Parameters\")

The thymidine analog-NRTIs, including AZT and stavudine, are associated with fat redistribution. One phenomenon is lipodystrophy, including central obesity or fat accumulation or dorsocervical fat enlargement, also known as a \"buffalo hump.\" A varied presentation is lipoatrophy, which often includes facial and extremity wasting. These manifestations do not necessarily improve upon therapy discontinuation.

Drug Interactions[2,4]

AZT should never be used concomitantly with stavudine due to in vitro data suggesting antagonism between these NRTI agents. Similarly, AZT has also been found to have an antagonistic relationship with ribavirin, a nucleoside analog used in hepatitis C treatment, as well as the chemotherapeutic agent, doxorubicin. Concomitant use of AZT with these agents should be avoided, if possible.

Various other drug interactions have been reported; however, specific dosage adjustments to account for these interactions have not been made. AZT concentrations increased when given with valproic acid, probenecid, fluconazole, methadone, and atovaquone. Cautious monitoring of efficacy and toxicity should be employed when using AZT with any of these agents. Similarly, AZT should be used cautiously with other drugs that cause bone marrow suppression.

Pregnancy and Lactation[2,3,5]

AZT is pregnancy category C. However, it has been studied in pregnant women to determine its efficacy for prevention of mother-to-child transmission, during which a similar frequency of congenital abnormalities was noted in both the AZT and placebo groups. AZT is FDA-approved for use in pregnant women > 14 weeks gestation.

AZT is excreted in the breast milk. Due to the risk of adverse effects as well as HIV transmission, infected mothers should be instructed not to breastfeed their infants.

Use of AZT as part of a 2 or 3-drug regimen is recommended for post-exposure prophylaxis in persons exposed to HIV either through occupational or non-occupational encounters. AZT is generally dosed orally as 300 mg twice daily, frequently in combination with lamivudine as Combivir®.

Monitoring Parameters[2,4]

Patients receiving AZT therapy should be monitored at least every 3 months for hematologic toxicities, including anemia and leukopenia. Those patients with severe anemia or significant neutropenia may require more frequent monitoring and/or dosage adjustments. (Refer to \"Dosage and Administration\")

Storage[2]

Oral presentations should be stored at 15° to 25° C (59° to 77° F).

Presentations[2,3]

Retrovir® oral formulations are tablet (300 mg), capsule (100 mg), and strawberry-flavored syrup (50 mg per 5 ml). Oral AZT is also marketed as a generic 250 mg tablet and in two combination tablets, including Combivir® (AZT 300mg/lamivudine 150mg) and Trizivir® (AZT 300mg/lamivudine 150mg/abacavir 300mg).

References

  1. Fischl MA et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317(4):185-91.
  2. Retrovir® product information. GlaxoSmithKline. Research Triangle Park, NC.
  3. American Hospital Formulary Service: Drug Information. 2005. American Health-System Pharmacists; Bethesda, MD.
  4. Panel on Clinical Practices for Treatment of HIV Infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Updated 29 Oct 2004).
  5. Perinatal HIV Guidelines Working Group of the Public Health Service Task Force. Recommendations for Use of ARV Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the US. (Updated 24 Feb 2005).
  6. Petra Study Team. Efficacy of three short-course regimens of ZDV and 3TC in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda. Lancet 2002; 359:1178-86.
  7. World Health Organization. Scaling up of antiretroviral agents in resource-limited settings: Treatment guidelines for a public health approach. 2003 Revision.

Stavudine

Stavudine, also known as d4T or Zerit®, is a nucleoside reverse tran-scriptase inhibitor (NRTI) that is used in combination with other ARVs to treat the Human Immunodeficiency Virus type 1.

Dosage/Administration[1-4]

Stavudine can be taken with or without food.

Adults and adolescents:

> 60 kg: 40 mg (1 capsule or 40 mL of oral solution) by mouth every 12 hours

< 60 kg: 30 mg (1 capsule or 30 mL of oral solution) by mouth every 12 hours

Pregnant Women:

No change in dosage recommended. Renal Impairment Dosing Elimination may be reduced in patients with renal impairment.

Adults:

Creatinine clearance 26-50 mL/minute: 20mg every 12 hours if weigh > 60 kg and 15mg every 12 hours if weigh < 60 kg

Creatinine clearance 10-25 mL/minute: 20mg every 24 hours if weigh > 60 kg and 15mg every 24 hours if weigh < 60 kg

Hemodialysis: 20mg every 24 hours in adults who weigh > 60 kg and 15mg every 24 hours in adults who weigh < 60 kg administered after each hemodialysis session, given at the same time of day as on the days when the patient does not undergo hemodialysis

Paediatrics:

There are no specific dosage recommendations for paediatrics but manufacturers state that since renal clearance is expected to be altered, the dosage should be decreased and/or the time interval between doses increased.

Contraindications/Precautions[1-3]

Hypersensitivity to d4T or any of the components contained in the formulation. Use with caution in patients with known risk factors for hepatic disease; d4T can cause lactic acidosis and severe hepatomegaly with steatosis which has been fatal.

Therapy should be suspended if the patient develops symptomatic hyperlactatemia or pronounced hepatotoxicity. If lactic acidosis is confirmed, discontinuation of d4T treatment permanently should be considered.

Side Effects[1-3]

Nausea, diarrhoea, vomiting,headache, and rash are commonly experienced side effects of d4T. Potentially severe peripheral neuropathy can occur with d4T and may be dose related. Numbness, tingling, or pain in the hands or feet has been reported mostly in patients with advanced HIV disease, patients with a history of peripheral neuropathy, or patients receiving other neuro toxic drugs such as didanosine. Patients experiencing peripheral neuropathy may tolerate d4T therapy at a lower dose (20-30 mg bid). However, if the symptoms return upon reinitiation of d4T, or worsen during treatment, consider alternative therapy.

Fatal lactic acidosis, severe hepatomegaly with steatosis, and pancreatitis have all occurred with the treatment of d4T and may occur more commonly when used in combination with ddI. Fat redistribution, specifically lipoatrophy of theface, has been reported with use of d4T.

Monitoring Parameters[1-3]

The manufacturers recommend monitoring serum creatinine, complete blood count with differential, liver enzymes, amylase, lipase and lactate levels during treatment with d4T. However, due to limited resources in some settings, patients may be clinically monitored for signs of peripheral neuropathy, liver toxicity (malaise, nausea, vomiting, right upper quadrant pain, and/or jaundice), lactic acidosis (nausea, vomiting, general abdominal pain, fatigue and weakness), acute pancreatitis.

Interruption of Therapy[1]

If a patient misses a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should skip the missed dose and continue the regular dosing schedule. Treatment should be interrupted for any serious adverse effects including lactic acidosis, pancreatitis, and peripheral neuropathy.

Significant Interactions[1-3]

Zidovudine should not be used in combination with d4T due to antagonism secondary to competition for cellular thymidine kinase which is needed for phosphorylation of both drugs. In addition, ribavirin and doxorubicin have also been shown to inhibit the phosphorylation of d4T in vitro and should be used with caution. Didanosine and/or hydroxyurea should be used with caution in patients taking d4T due to increased risk of pancreatitis, peripheral neuropathy, and liver function abnormalities.

Pregnancy and Lactation [1-3]

Stavudine should be used when the benefit outweighs the associated risk. Cases of lactic acidosis including some that were fatal have been reported when d4T was used in pregnant women in combination with ddI, therefore use of this combination should be avoided unless there are no alternatives. In addition, although it is unknown if d4T is excreted in human breast milk, it has been shown to be excreted in the milk of lactating rats. Due to potential risks of adverse effects and transmission of HIV, breast-feeding is not currently recommended in mothers taking d4T.

Storage[1,2]

Stavudine capsules and oral solution prior to constitution should be stored in tightly closed containers between 15°C and 30° C.

Stavudine oral solution should be protected from excessive moisture and after constitution, tightly closed containers should be stored in a refrigerator, at 2° C to 8° C, with any unused portion discarded after 30 days.

Presentations[1,2]

Stavudine capsules are available in 15mg, 20mg, 30mg, and 40mg strengths.

Stavudine oral solution provides 200 mL/50ml of a 1 mg/mL.. Shake well before measuring a dose.

Additionally, d4T is an active component in the generic drug Triomune® 30 (D4T 30mg, 3TC 150mg, and NVP 200mg) and Triomune® 40 (D4T 40mg, 3TC 150mg, and NVP 200mg).

References

  1. Bristol-Myers Squibb Company. Zerit® (stavudine) package insert. Princeton, NJ, USA; 2004.
  2. American Society of Health System Pharmacists. American Hospital Formulary Service Drug Information. Bethesda, MD: ASHP; 2004.
  3. Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services. Guidelines for the use of anti retroviral agents in HIV-1 infected adults and adolescents [Internet]. 2004 Oct 29 [cited 2004 Nov 18]. Available from: http://www.aidsinfo.nih.gov//guidelines/adult/AA_102904.pdf
  4. Perinatal HIV GuidelinesWorking Group: Public Health Service Task Force. Recommendations for use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States [Internet]. 2004 June 23 [cited 2004 Nov 18]. Available from: http://www.aidsinfo.nih.gov/guidelines/perinatal/PER_062304.pdf

Lamivudine

By Clinical Pharmacist Saul Kidde

Introduction

Lamivudine, (also known as epivir or 3TC), is an anti-retroviral medicine in the class Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Lamivudine treats Hepatitis B in lower doses than that for HIV. It is used to prevent mother-to-child transmission of HIV and in post expo-sure prophylaxis in combination with other antiretrovirals.[1]

Dosage/Administration[2]

Treatment of HIV:

Adult:

150mg twice daily or 300 mg once daily.

Paediatric:

Infant age <30 days; 2mg/kg twice daily, 1 month to 12 years; 4mg/kg twice daily to a maximum of 150mg twice a day, adolescents weighing < 50 kg; 2mg/ kg twice daily and adolescents weighing > 50 kg, adult dose.

Dosing in renal insufficiency and hepatic impairment:

Adults with creatinine clearance (ml/min) of >= 50; normal dose, 30 — 49; 150mg once daily, 15 – 29; 150 mg first dose then 100mg once daily, 5 — 14; 150 mg first dose then 50mg once daily, <5; insufficient data but consider150 mg first dose then 25mg once daily.

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in adults, it is recommend-ed that the dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults.

Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

Treatment of Hepatitis B:

Lamivudine is active against hepatitis B virus, but resistant HBV is observed to emerge over several months in the set-ting of treatment with lamivudine alone.

Individuals with HIV and hep-atitis B receiving HIV therapy including lamivudine may experience an exacerbation of chronic active hepatitis B if lamivudine is discontinued.

The dose of lamivudine avail-able specifically for the treatment of hepatitis B is 100mg once daily for adults and 3mg/kg for children aged 2 -17 years to a maximum of 100mg which is substantially lower dose that is not appropriate for treatment of HIV.

Prevention of Mother to Child Transmission of HIV

The PETRA study was a placebo controlled study con-ducted in Africa in which one arm used lamivudine in combination with zidovudine (AZT) in a regimen that included giving a mother 600mg of oral AZT and 150mg of 3TC at the onset of labour followed by 300mg of AZT every 3 hours and 150mg of 3TC every 12 hours until delivery. Thereafter a seven day regimen of zidovudine and lamivudine was given to the mother every 12 hours and the baby received 4mg/kg of AZT and 2mg/kg of 3TC every 12 hours for the baby.

At 6 weeks postpartum, the rate of transmission was 9% in those receiving 2 drugs versus 15% in the placebo arm.

Contraindications and Precautions[3]

Hypersensitivity to lamivudine or to any of the excipients. Lamivudine is not recommend-ed for use as a monotherapy. In patients with moderate to severe renal impairment (Crcl<=50ml/min) the dose should be adjusted (see dosage in renal impairment).

Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues.

Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rap-idly elevating aminotransferase levels.

Side Effects

Lamivudine is generally well tolerated. The common side effects are headache, insomnia, nausea, vomiting, abdominal pain or cramps, diarrhoea, cough, nasal symptoms, rash, alopecia, arthralgia, muscle disorders, fatigue, malaise and fever.

Rare side effects include peripheral neuropathy (or paraesthesiae) and rises in serum amylase. Cases of pancreatitis have been reported as well as transient rises in liver enzymes (AST, ALT), hepatitis, skin and subcutaneous tissue disorders, rhabdomyolysis.

Lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis has also been reported with the use of nucleoside analogues.

Monitoring Parameters

Toxicity: Limited data are available on the consequences of ingestion of acute overdoses in humans.

Interactions[4]

The likelihood of metabolic interactions is low due to limit-ed metabolism and plasma protein binding and almost complete renal clearance. Zidovudine has no effect on the pharmacokinetics of lamivudine. The possibility of interactions with other medicinal products administered con-currently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system, for example, trimethoprim.

Pregnancy and Lactation

The safety of lamivudine in human pregnancy has not been established.

Reproductive studies in animals have not shown evidence of teratogenicity, and showed no effect on male or female fertility.

Storage

It should not be stored above 30°C

Presentations

Lamivudine is available as a 150mg tablet, Epivir and in generic form as Lamivir and Okavir (lamivudine 150mg),or in combinations as Triomune 40 (3TC 150mg, D4T 40mg and NVP 200mg), Triomune 30 (3TC 150mg, D4T 30mg and NVP 200mg), Maxivir (Same as Triomune), Combivir (3TC 150mg and AZT 300mg)

References

  1. Martindale, The Complete Drug Reference, 33 rd edition
  2. American Society of Health System Pharmacists, 2004.
  3. IPHA Compendium, 2004.
  4. Stockley's Drug Interactions, 6th Edition.

Abacavir

Introduction

Abacavir, also known as ABC or Ziagen®, is used in combination with other antiretrovirals (ARVs) in the treatment of Human Immunodeficiency Virus. Abacavir belongs to the family of antiretroviral medicines known as the nucleoside reverse transcriptase inhibitors (NRTIs). These NRTIs act as competitive inhibitors with human nucleosides for incorporation into nascent HIV viral DNA strands.

Dosage/Administration[1-4]

Abacavir may be taken with or without food.

Adults and adolescents:

Either 600mg by mouth once daily[1,2] or 300mg by mouth every 12 hours[3]

Pediatrics:

8mg/kg by mouth every 12 hours, with a maximum 300mg every 12 hours `can be used in children aged 3 months to 16 years[1,2]

Pregnant Women:

No change in dosage recommended. Pharmacokinetics of abacavir during pregnancy are currently under study[1,4,5].

Renal Impairment:

No change in dosage recommended.

Hepatic Impairment:

For mild hepatic impairment (Child Hugh Score of 5-6) the manufacturer recommends a dose of 200mg by mouth every 12 hours. The oral solution should be used to obtain an accurate dose of 200mg. Abacavir is contraindicated in patients with moderate to severe hepatic impairment because it has not been studied in these populations.

Pregnancy and Lactation[4,5]

Pregnancy:In animal studies of rats and mice abacavir was found to cross the placenta. Carcinogenic and teratogenic effects were found in the fetuses of rats given 35 times the human dose of abacavir. Teratogenicity was not found in studies done on rabbits. Rates of hypersensitivity reaction in pregnant versus non-pregnant women is unknown. Abacavir should be used during pregnancy when the potential benefits outweigh risk of toxicity.

Lactation:

Abacavir is distributed into breast milk in rats. It is unknown whether it is distributed into breast milk in humans. However, due to the risk of transmission of HIV, breastfeeding is not generally recommended for HIV-positive mothers.

Contraindications/Precautions[1,4]

Abacavir is contraindicated for use in patients with a history of abacavir hypersensitivity syndrome and in patients with moderate to severe hepatic disease.

Side Effects[1,3,4]

Common side effects include headache, fatigue, malaise, nausea and diarrhea. A hypersensitivity syndrome may occur in approximately 5-8% of patients treated with abacavir. This hypersensitivity syndrome usually presents with symptoms from 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (4) constitutional and (5) respiratory. If hypersensitivity reaction is suspected, abacavir should be discontinued and never administered again. Readministration of abacavir may result in potentially serious or even fatal reactions within hours. As with other NRTI agents, lactic acidosis with hepatic steatosis may occur.

Monitoring Parameters

Although the manufacturer does not have any specific recommendations, liver function tests and signs of hypersensitivity should be monitored when using abacavir.

Interruption of Therapy[4]

If a patient misses a dose of abacavir, it should be taken as soon as remembered unless the next dose is pending shortly. If the next dose is to be taken soon, the missed dose should be skipped and the regular dosing schedule should be continued. The patient should not double-dose. Therapy should be interrupted in the case of serious adverse effects such as lactic acidosis, hypersensitivity, and if signs of hepatotoxicity are present. Interruption does not put the patient at a greater risk for hypersensitivity reaction if the patient has never had that reaction to begin with.

Significant Drug Interactions[1,4]

No clinically significant interactions are expected with abacavir.

Storage[1]: Tablets and oral solution should ideally be stored at room temperature, between 68° to 77°F (20° to 25°C). Oral solution may be refrigerated, but should not be frozen.

Presentations[1,4]

Abacavir tablets are available as 300mg tablets. Abacavir is available in a 20mg/mL strawberry-banana flavored oral solution. Additionally, abacavir is present in the combination NRTI medications Trizivir® (zidovudine 300mg, lamivudine 150mg, abacavir 300mg) and in a once-daily formulation named Epzicom® (abacavir 600mg, lamivudine 300mg).

References

  1. Glaxo Smith Kline. Ziagen Package Insert [Internet]. 2004 August [cited 2005 June 7]. Available at http://us.gsk.com/products/assets/us_ziagen_tablets.pdf
  2. Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination (ZODIAC) Study. J Acquir Immune Defic Syndr. 2005 Apr 1;38(4):417-25.
  3. Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents [Internet]. 2004 Oct 29 [cited 2005 June 7]. Available at: http://www.aidsinfo.nih.gov//guidelines/adult/AA_102904.pdf
  4. American Society of Health-System Pharmacists. American Hospital Formulary Service Drug Information. Bethesda, MD: ASHP; 2004.
  5. Perinatal HIV Guidelines Working Group: Public Health Service Task Force. Recommendations for use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States [Internet]. 2004 Dec 17 [cited 2005 June 7]. Available from http://http://www.aidsinfo.nih.gov/guidelines/perinatal/PER_062304.pdf