Nucleoside (NRTI) & Nucleotide (NtRTI) Reverse Transcriptase Inhibitors

Detailed Prescribing Information

October 2005

100 mg caps & 300 mg tabs
Syrup 10 mg/cc in bottles of 240 cc

(300 mg ZDV + 3TC 150 mg = Combivir)

(300 mg ZDV + 150 mg 3TC + 300 mg abacavir = one Trizivir tablet)

Actually relatively well tolerated in most patients

Bone marrow depression with leukopenia and anemia (not thrombocytopenia)

Macrocytic anemia (consider if zidovudine is essential rHuEPO) 

Leukopenia, granulocytopenia (consider GM-CSF or G-CSF if zidovudine is essential or important)

Mild GI upset is common (usually mild), nausea (sometimes severe)

Headache usually mild and improves with time.

Some liver toxicity, especially with heavy alcohol use.

Mitochondrial toxicity: zidovudine may contribute to fat redistribution / lipoatrophy; rare hepatic steatosis and lactic acidosis

Zidovudine intensifies other marrow suppressive agents:

    Ganciclovir

    Sulfadiazine

    Sulfamethoxazole/trimethoprim (esp treatment dosing)

    Dapsone

    Antineoplastic chemotherapy

    Interferon

Forms Available

Dosing

one 250 mg EC capsule daily on an empty stomach*  or
one 125 mg wafer chewed or dispersed twice a day (consider two 125 mg wafers chewed once daily)

Wt. > 60 kg:    

one 400 mg enteric-coated capsule once a day on an empty stomach* or

two 100 mg wafers chewed or dispersed twice a day on an empty stomach*  or

two 200 mg wafers chewed or dispersed daily on an empty stomach*

*An empty stomach is defined as at least one hour before food or at least two hours after food

Possible exception: when used with tenofovir, this medication (Videx-EC)  may be taken with or without food

Diarrhea and GI upset common with wafer form

5-10% incidence of subclinical to rare fatal pancreatitis

Peripheral neuropathy - less common than zalcitabine or stavudine

Bad taste in mouth from wafer form of didanosine

Rare lactic acidosis and hepatic steatosis especially in setting of hepatitis C, ribavirin therapy, and concomitant stavudine

Didanosine may contribute to fat redistribution

Wafer form of didanosine lowers absorption of indinavir (see indinavir dosing below)

Wafer form decreases absorption of delavirdine

Tenofovir increases ddI levels: observe for ddI-related toxicity & reduce ddI-EC to 250 mg daily

Tenofovir and didanosine may produce mitochondrial toxicity and increased nephrotoxicity

Contraindicated with prior history of pancreatitis or elevated lipase / p-amylase

Contraindicated in moderate to heavy alcohol users.
Pancreatitis may be fatal.  Consider pancreatitis first in the differential diagnosis in patients on didanosine with compatible symptoms.

Avoid use with d4T/stavudine if possible
Rare lactic acidosis especially in persons with underlying liver disease: nausea, malaise, anion gap acidosis, renal failure, hepatic steatosis

Wt. < 60 kg: 0.375 mg po three times a day

Wt. > 60 kg: 0.75 mg po three times a day

25% incidence of peripheral neuropathy, oral ulcers, skin rash

<1% incidence of pancreatitis.

Rare lactic acidosis and hepatic steatosis

Peripheral neuropathy - initially involves soles of feet, spreads cephlad, and may initially present as foreign body sensation.
Monitor level of discomfort frequently and stop with any progression from "minimal" or “mild.”

“Coasting effect” =  peripheral neuropathy may continue to worsen for several weeks after discontinuation and then decrease in some cases.

Avoid use with d4T, ddI due to increased neurotoxicity.

Complete prescribing information

Powder for oral solution (1 mg/ml after reconstitution)

Immediate-release form:

Wt. > 60 kg: 40 mg twice a day

Wt. < 60 kg, OR if restarting after mild peripheral neuropathy resolves: 30 mg twice a day

Extended-release form:

Wt>60 kg: 100 mg daily

Wt<60 kg: 75 mg daily

Peripheral neuropathy (10-20%) [consider baseline neuropathy exam]

Rare pancreatitis, lactic acidosis and hepatic steatosis

Increasingly associated with fat redistribution, hyperlipidemia, metabolic syndrome

In general (in the author's opinion) stavudine should not be used especially in older, more ill or more immunodeficient patients without compelling reasons due to the issues of lipoatrophy, dyslipidemia, and peripheral neuropathy that are associated increasingly with this drug.
Do not use with other mitochondrial toxins (ddC, ddI)
Do not use with zidovudine, Combivir, or Trizivir due to antagonism (with zidovudine.)

Complete prescribing information

Rarely associated with pancreatitis.

Suggested Usage

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Solution 20 mg/cc

300 mg AZT + 150 mg 3TC + 300 mg abacavir as Trizivir
300 mg 3TC + 600 mg abacavir as Epzicom

Rare lactic acidosis and hepatic steatosis

5-8% incidence of Abacavir Hypersensitivity Syndrome (usually occurs in first 6 weeks of therapy) which is characterized by the following:

          Worsens with each dose

          Fever

          Rash

          Progressive nausea, malaise

          Pulmonary symptoms
          Diarrhea

Treatment of hypersensitivity syndrome: Discontinue abacavir and supportive care.

DO NOT RECHALLENGE.

DO NOT attempt desensitization

See Ziagen administration protocol below.
There is a slightly higher incidence of abacavir hypersensitivity with single daily dosing (Epzicom).

Suggested

Administration

Protocol
including
Evaluation & Management
of
Suspected or Proven
Hypersensitivity Syndrome

1.  Educate patient about the abacavir hypersensitivity syndrome and provide a written summary of the syndrome as well as contact information for the provider [patient handout HERE]

2.  Patient should be instructed to avoid travel for the first 6 weeks of therapy with abacavir if possible

3.  Patient should be instructed to notify provider of any symptoms compatible with the syndrome promptly

4.  Patient should be instructed to NOT discontinue the abacavir until seen by the provider unless the syndrome is already severe

5.  Patient should be physically seen by the provider as soon as possible if symptoms compatible with abacavir hypersensitivity develop

a.  If a detailed evaluation reveals a high likelihood of the syndrome, the abacavir should be discontinued promptly and permanently.  The supply of the drug should be disposed of with a witness present preferably or returned to the healthcare provider

b.  If the detailed evaluation is equivocal, the patient should be monitored very frequently or at least daily.  If the symptomatology increases with each subsequent dose of abacavir, the diagnosis is then certain, and the drug should be stopped permanently.  Drug should be returned to the provider or disposed of with a witness present.

If the patient discontinues the abacavir prior to being seen by a provider experienced in abacavir hypersensitivity evaluation, it is important to regard the patient as having had definite abacavir hypersensitivity, and the drug should be permanently discontinued.  

Rechallenge with abacavir for diagnostic or therapeutic purposes is CONTRAINDICATED.

Suggested Usage

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Possible flare of hepatitis B if tenofovir is discontinued suddenly.

Suggested Usage

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Diarrhea, nausea, rash at incidence similar to other agents
Skin discoloration, usually mild and asymptomatic: palms and/or soles 3%

Flare of hepatitis B if stopped suddenly.

Low barrier to one-step mutational resistance
Possible flare of hepatitis B if emtricitabine is discontinued suddenly.

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Fixed Dose Combination NRTI Formulations

Suggested Usage

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Rare lactic acidosis and hepatic steatosis.
Possible flare of hepatitis B if Trizivir is discontinued suddenly.

Suggested administration protocol

Suggested Usage

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Rare lactic acidosis and hepatic steatosis.
Do not used fixed dose combination in persons with renal insufficiency.

Severe acute exacerbations of chronic hepatitis B may be observed with sudden discontinuation of Epzicom.

Suggested administration protocol

Suggested Usage

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Rare lactic acidosis and hepatic steatosis.
Do not used fixed dose combination in persons with renal insufficiency.
Severe acute exacerbations of chronic hepatitis B may be observed with sudden discontinuation of Truvada.

Suggested Usage

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NRTI Summary Information

Generic
Brand
Nomenclature

AZT, ZDV