+VE ISSUE 28 – +VE DRUG WATCH
 
ddI COMES IN ALL SHAPES & SIZES

But all forms of ddI inhibit the absorption of protease inhibitors, so dosing regimens, among other things, can be awkward, as Tracy Barnes explains.

HOW ddI WORKS:
Didanosine (or ddI) like AZT and d4T belongs to the group of drugs referred to as nucleoside reverse transcriptase inhibitors (NRTIs) or nucleoside analogues. This class of drugs combat viral replication by disrupting the essential transcription process of HIV genetic material (RNA) into DNA. ddI is usually taken in combination with at least two other anti-retroviral drugs.

HISTORY:
In 1996 ddI was approved in Europe for use in combination anti-retroviral therapy for HIV-positive adults and children. In 1999, European approval was granted for once-daily dosing of ddI capsules. In September 2000 enteric coated capsules (Videx(r) ec) were introduced. The Indian manufacturer CIPLA also produce a generic version of ddI.

COMBINATION THERAPY:
ddI is an established component of combination anti-retroviral therapy. Its effectiveness as a nucleoside analogue component of combination therapy has been proven. It is commonly used in combination with AZT or d4T.

ddI DOSING:
ddI is produced in a variety of forms. Chewable, or dissolving, buffered tablets, buffered powder for oral solution in adults and children and enteric coated capsules, referred to as Videx(r) ec. The term buffered refers an antacid component of the drug that prevents stomach acid from making it inactive.

ddI tablets should not be swallowed whole, they need to be chewed or dissolved in either water or clear apple juice (no other kind of juice). The enteric coating on ddI capsules, introduced in September 2000, has enabled once daily dosing and eliminated the need for an antacid buffer. This has resulted in a medication that is smaller in size and no longer needs to be chewed or dissolved.

Although European approval for once daily dosing was granted in 1999, twice daily dosing, 12 hours apart, remains the most frequently used regime for ddI.

ddI tablets are produced in 100mg and 200mg strengths, the enteric coated ddI capsules are produced in 125mg, 200mg, 250mg and 400mg strengths. Dosing of ddI is dependent on weight. Adults over 60kg are usually prescribed 200mg, twice daily or 400mg, once daily. Patients under 60kg are usually prescribed 125mg, twice daily or 250mg, once daily. Dosing restrictions are usually indicated for patients with kidney or liver impairment.

DOSING RESTRICTIONS:
ddI must be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. ddI tablets cannot be taken whole, they must be either chewed or dissolved in water or clear apple juice (no other kind of juice is suitable).

Because ddI tablets and oral solution may inhibit the absorption of most of the protease inhibitors it should be taken at different times of the day, even if they too have their own food restrictions.

The only exception to this is the enteric coated ddI capsule which can be taken at the same time as a protease inhibitor provided the PI does not require food to be taken whilst dosing.

SIDE EFFECTS OF ddI:
The most frequently reported side effects of ddI are stomach pain, diarrhoea, peripheral neuropathy, rash, chills or fever, headache, nausea and vomiting, confusion and insomnia.

Many of the above side effects are easily remedied with dietary changes and/or over the counter medications to alleviate symptoms. It is always wise to check with your physician before taking any other medications in case it interferes with the efficacy of your treatment.

Peripheral neuropathy is a common side effect of ddI, especially when ddI is used in combination with d4T. If peripheral neuropathy does develop it will usually indicate the need to discontinue the use of ddI. ddI may be re-introduced, often at a reduced dose, when symptoms disappear.

Less commonly reported side effects include liver damage, seizures, headaches, chills, and allergic reactions, pancreatitis, lactic acidosis and, in children, optical damage.

RARE SIDE EFFECTS:
Lactic acidosis is a potentially life-threatening condition, characterised by unexplained and often severe tiredness, sickness and nausea, abdominal and/or liver pain, unexplained weight loss, breathlessness, poor circulation and sudden onset of peripheral neuropathy. Combinations that include ddI/d4T have been associated with this condition, especially during pregnancy and in patients who are overweight.

Pancreatitis is a potentially fatal (though thankfully rare) side effect of ddI. Pancreatitis is characterised by abdominal or back pain together with vomiting. Diagnosis is confirmed by blood test. Discontinuation or changing anti-retrovirals can prevent or stop pancreatitis developing. As the risk of developing pancreatitis is increased with alcohol - it is recommended to cease or decrease alcohol consumption while taking ddI. Although still a rare side effect, the incidence of pancreatitis is more common in older patients and those with advanced HIV infection.

Retinal and optical nerve changes ihave been reported in children. It is recommended that eyes be tested by an ophthalmologist every four to six months whilst being treated with ddI.

PRE-EXISTING CONDITIONS:
If you have had pancreatitis while taking ddI in the past, you should never restart ddI treatment.

If you have existing kidney or liver conditions, these should be made known to your physician as they may indicate that ddI should not be included in your treatment regime or that dose restrictions are necessary.

PAEDIATRIC USE OF ddI:
An oral suspension is available for use in young children over the age of 3 months, which should be taken on an empty stomach or one hour prior to a meal.
ddI is licensed in the UK for paediatric use for children aged 3 months and upwards. Enteric coated ddI is not licensed for use in children below 6 years of age. The formulation is produced in cherry and mint flavoured powder suspension that is reconstituted with water to produce an oral solution. The recommended daily dose is 120mg/m2 twice daily. Paediatric doses should also be administered at least 30 minutes before a meal.
 
ddI TREATMENT DURING PREGNANCY:
ddI is not contraindicated in pregnancy but careful monitoring for lactic acidosis is recommended, especially where ddI is used in combination with d4T.

ddI RESISTANT HIV:
Within the whole nucleoside analogue class of drugs, studies have shown that ddI resistant strains of HIV are less common than AZT and 3TC resistant strains. Strains of HIV that are resistant to ddI are also resistant to ddC though strains that are resistant to ddC usually retain sensitivity to ddI. This is an important fact when considering treatment sequencing and future treatment options.

OTHER CONSIDERATIONS:
Absorption of ddI in tablet form may be reduced in the presence of methadone.