Interacting drugs- summary

 + Zidovudine-

 Acetoaminophen
Acetoaminophen decrease the AUC of zidovudine

Bone marrow suppres/cytotoxic agents/Adriamycin,dapsone/Flucytosine, vincristine/vinblastine. 

Coadministration of zidovudine with drugs that are  nephrotoxic, cytotoxic or interfere  with RBC/WBC number  or function  increase the risk of hematologic toxicity
                 
 Fluconazole
Concurrent use  increase the zidovudine AUC and half life

 Ganciclovir
Concurrent use increases the risk of hematologic toxicities in  some patients
with advanced HIV disease. If combination is    necessary,
dose reduction or interruption of one or both agents
 may be necesary. Monitor hematologic parameters frequently.

 Interferon alfa
Hematologic toxicities have been seen with concurrent use.
If combination  use is necessary , dose reduction or interrruption
of one or both agents  necessary.
Monitor hematologic  parameters frequently.

 Interferon beta-1b
Zidovudine serum levels elevated
 
 Nucleoside analogs
Avoid concomittant use-  increase the potential for                    
 hematologic toxicites of zidovudine

 Probenecid
Increased zidovudine bioavailabilty ; cutaneous eruptions
 accompanied by systemic symptoms including malaise,
myalgia or fever,  and maculopapular rash, have occurred

 Rifamycin
AUC of zidovudine decreased

 Trimethoprin
Serum levels of zidovudine and its metabolites  increased
                
Zidovudine +

 Acyclovir
  Severe drowsiness and lethargy may occur with cuncurrent  use

 Zidovudine +Phenytoin 
Phenytoin levels have been reported to increase , decrease or not
change with concurrent use.  
                              
Phenytoin +   Zidovudine    
clearance was  decreased by phenytoin                              

Body as a whole-

Asthenia 19% diaphoresis 5% fever 16% headache 42% malaise 8%

CNS -

Dizziness 6% Insomnia 5% Paresthesia 6% Somnolence 8%

GI - 

Anorexia 11% Diarrhea 12% Dyspepsia 5% GI pain 20%

Nausea 46% Vomiting 6%

Other-

Dyspnea 5% Myalgia 8% Rash 17% Taste pervertion 5%

Low neutrophil counts (less than 0.75*10 to the power of 9/litre) or low haemoglobin levels (less than 7.5/decilitre). Lactation.

Special precautions:

Keep out of reach of children. Perform blood tests at least every 2 weeks for the 1st 3 months of therapy and atleast monthly thereafter. Adjust dose if anaemia or myelosupression occur or is present. Renal or hepatic impairment. Elderly.

Warnings

Safety/efficacy- the full safety and efficacy profile of zodovuldine is not complely defined, especially with prolonged use and in HIV individuals who have less advanced disease.

Hematologic effects- use with extreme caution in patients who have bone marrow compromise evidenced by granulocyte count.

Myopathy and myositis- with prolonged changes,similar to that produced by HIV disease, have been associated with prolonged use of zodovudine.

Lactic acidosios/severe hepatomegaly with steatosis- rare occurences of lactic acidosis in the absence of hypoxemia and severe hepatomegaly have been reported with the use of antiviral nucleoside analogs including zidovudine and zilcitabine which are potentially fatal.

Combination therapy- No benefit from combination therapy with zalcitabine has been observed in a study of patients with extensive prior exposure to zudovudine. Combination therapy is not recommended.

Hypersenstivity- sensitization reactions including anaphyaxis in one patient have occured with zidovudine therapy.

Renal/Hepatic functionimpairment- Patients with severely impaired hepatic function may be at greater risk of toxicity.

Pregnancy-

Congenital abnormalities have been noticed to infants born to mothers who received zidovudine. Observe caution.

Lactation:

Not known whether zidovudine is excreted in breast milk or zidovudine reduces the potential for transmission of HIV in breast milk.

Children-

A positive test for HIV-antibody in children < 15 months of age represent passively acquired maternal antibodies, rather than an active antibody response to infection in the infant. Therefore the presence of HIV-antibody in a child < 15 months of age must be interpreted with caution.

Indications:

HIV infections

Dosage:

Initial - 200 mg (2 100 mg capsules) or 4 teaspoonful of Syrup (20 ml syrup) every 4 hours round the clock. After I month this dose may be reduced to 100 mg every 4 hours.. Monitor hemalogic indice every 2 weeks to detect serious anemia. Storage:: Protect from light

Overdosage-

Symptoms- Only consistent finding was spontaneous or induced nausea and vomiting. Hematologic changes were transcient and not severe. CNS symptoms such as headache, dizziness, drowsiness, lethargy, and confusion.

Treatment

1. All patients recovered without permanent sequalae.

2. Hemodialysis and peritonal dialysis appear to have a negligable effect on zidovudine while elimination. of its primarymetabolite, GAZT is enhanced.

Missed dose

1. If you miss a dose of this medicine, take it as soon as possible.

2. However, if it is almost time for next dose, skip the missed dose and go back to your regular dosing schedule.

3. Do not double doses.

               EVIDENCE- BASED MEDICINE (MIMS April 2003)

Genital Herpes Comparative effectiveness of various interventions

Beneficial

1. Oral antiviral therapy in first episodes

2. Oral antiviral treatment taken at start of a recurrence

3. Daily oral antiviral treatment in people with high rates of recurrence.

Likely to be beneficial

1. Daily oral antiviral treatment in late pregnancy. In women with a hostory of genital herpes.

Unknown effectivess

1. Psychotherapy to reduce recurrence

2. Interventions to prevent sexual transmision

3. Serological screening and counselling in late pregnancy.

Likely to be ineffective or harmful

1. Abdominal delivery in women with genital lesions at terms.

KEY POINTS

1. Clinical trials have found that oral antiviral treatment reduces the duration of symptoms, lesions, and viral shedding in first and recurrent episodes of general herpes, and that daily treatment reduces the rate of recurrence.

2. Trials have found no significant difference in effectivenes or adverse effects beween acyclovir, valacyclovir and famcyclovir.

3. There is insufficient evidence on the role of interventions to prevent sexual transmission.

4. The highest risk of mother-to-baby transmission is in women newly infected with genital herpes in late pregnancy. There is inadquate evaluation of intervention to prevent infection in late pregnancy (such as serological screening and counselling)

5. It has been found that the effect of abdominal delivery on mother-to-baby transmission had not been adequately evaluated. The procedure has the risk of increased maternal morbidity and mortality.

6. Limited evidence from trials suggests that antiviral treatment may reduce the number of pregnant women with genital lesions at term. Since women with genital lesions are usually offered abdominal deliveries, antiviral treatment may reduce the risk of abdomnal delivery

Pharmacology:

Zidovudine is a thymide analog and an inhibitor of the in vitro replication of some retinovirues including HIV. Zidovudine triphosphates interferes with the HIV viral RNA- dependenr DNA polymerases. and thus inhibits viral replication.

Phamacokinetics:

After an oral dose, zidovudine is rapidly absorbed from the G I tract with peak serum concetrations occuring in 0.5 to 1.5 hours. The rate of absorption is greater in syrup than in capsules. The mean zidovudine half-life was about 1 hour(range 0.61 to 1.73).

High fat diet reduces rate and extent of absorption.

Pregnancy:

Congenital abnormalities have been noticed to infants born to mothers who received zidovudine. Observe caution.

Lactation:

Not known whether zidovudine is excreted in breast milk or zidovudine reduces the potential for transmission of HIV in breast milk.

Children- A positive test for HIV-antibody in children < 15 months of age represent passively acquired maternal antibodies, rather than an active antibody response to infection in the infant. Therefore the presence of HIV-antibody in a child < 15 months of age must be interpreted with caution.