didanosine

[Shortening and alteration of DIDEOXYINOSINE.]

trade name: Videx; drug class: synthetic antiviral; action: converted by cellular enzymes that act as antimetabolites to inhibit HIV replication; uses: advanced HIV infections in adults and children who have been unable to use zidovudine or who have not responded to treatment with zidovudine.

Brand names: Videx®Videx® EC

Chemical formula:

Drug Forms:
• Didanosine, ddI powder for oral solution (below)
• Didanosine Oral capsule, gastro-resistant pellets
• Didanosine Chewable tablet
• Didanosine Oral solution

Español:
• Polvo para solución oral de didanosina, ddI
• Didanosina, Cápsula oral, bolitas gastrorresistentes
• Didanosina, Tableta masticable
• Didanosina, Solución oral

Didanosine, ddI powder for oral solution

What is didanosine, ddI, powder for oral solution?

DIDANOSINE, ddI (Videx®) is an antiviral drug called a nucleoside reverse transcriptase inhibitor or NRTI. Didanosine is used to treat human immunodeficiency virus (HIV) infection. Didanosine may reduce the amount of HIV in the blood and increase the number of CD4 cells (T-cells) in the blood. Didanosine is used in combination with other drugs to treat the HIV virus. Didanosine will not cure or prevent HIV infection or AIDS. You may still develop other infections or conditions associated with HIV. Generic didanosine buffered powder for oral solution is not yet available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• frequently drink alcoholic beverages
• gout
• heart or circulation problems
• high blood pressure
• high cholesterol
• kidney disease
• liver disease
• pancreatitis
• retain water
• tingling or numbness in the hands or feet
• an unusual or allergic reaction to didanosine, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take didanosine oral solution by mouth. Carefully open a packet of didanosine powder for oral solution and pour the contents of a packet into a glass with about 4 ounces (1/2 cup) of water. Stir for 2 to 3 minutes until the powder is completely dissolved. After the powder has been dissolved in water, the solution can be kept at room temperature, but must be used within 4 hours. Take didanosine on an empty stomach, at least 30 minutes before or 2 hours after food; do not take with food. Do not mix with fruit juice, carbonated drinks or other acid-containing liquid. Take your doses at regular intervals. Do not take your medicine more often than directed.

To help to make sure that your anti-HIV therapy works as well as possible, be very careful to take all of your medicine exactly as prescribed. Do not stop taking except on your prescriber's advice.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What drug(s) may interact with didanosine, ddI?

• alcohol
• allopurinol
• antacids that contain aluminum or magnesium
• atazanavir
• certain antibiotics (such as ciprofloxacin or tetracyclines)
• delavirdine
• ganciclovir
• hydroxyurea
• indinavir
• iron supplements or vitamin-mineral tablets with iron
• itraconazole
• ketoconazole
• methadone
• nelfinavir
• ribavirin
• ritonavir
• stavudine, d4T
• tenofovir
• thyroid hormones
• valganciclovir
• zalcitabine

Tell your prescriber or health care professional about all other medicines you are taking, including nonprescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking didanosine, ddI?

Visit your prescriber or health care professional for regular checks on your progress. Discuss any new symptoms with your prescriber or health care professional.

Alcohol can increase the risk of developing severe side effects when taken with didanosine. Avoid alcoholic drinks while you are taking didanosine. Do not treat yourself for nausea, vomiting or stomach pain. Call your prescriber or health care professional for advice.

Tell your prescriber or health care professional if you get tingling, pain or numbness in your hands or feet.

Didanosine powder contains large amounts of sodium. Be sure your prescriber or health care professional knows if you are on a low-sodium diet.

Didanosine will not cure HIV and you can still get other illnesses or complications associated with your disease. Taking didanosine does not reduce the risk of passing HIV infection to others through sexual or blood contact. It is best to avoid sexual contact so that you do not spread the disease to others. For any sexual contact, use a condom. Be careful about cuts, abrasions and other possible sources of blood contact. Never share a needle or syringe with anyone.

What side effects may I notice from taking didanosine, ddI?

Other drugs you are taking with didanosine may affect the severity and occurrence of side effects you experience. Not all the side effects listed occur in everyone. If you notice an unusual side effect, contact your health care provider.
Side effects that you should report to your prescriber or health care professional as soon as possible:
• changes in body appearance (such as weight gain or loss around the waist and/or face)
• changes in your eye sight
• fever or chills, sore throat
• nausea and vomiting
• stomach pain
• tingling, pain or numbness in the hands or feet
• rash, itching
• unusual bleeding or bruising
• unusual tiredness or weakness

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• diarrhea
• dry mouth or eyes
• gas
• headache
• heartburn
• muscle and joint pain
• stomach upset

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15—30 degrees C (59—86 degrees F). Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Didanosine
Systematic (IUPAC) name
9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3H-purin-6-one
Identifiers
CAS number	69655-05-6
ATC code	J05AF02
PubChem	50599
DrugBank	APRD00240
ChemSpider	45864
Chemical data
Formula	C10H12N4O3
Mol. mass	236.227 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	30 to 54%
Protein binding	Less than 5%
Metabolism	?
Half life	1.5 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B2(AU) B(US)
Legal status	POM(UK) ℞-only(US)
Routes	Oral
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Didanosine (2',3'-dideoxyinosine, ddI, DDI) is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy (HAART).

Contents 1 History 2 Mechanism of action 3 Pharmacokinetics 4 Drug interactions 5 Adverse effects 6 Resistance 7 Sources 8 Further reading

History

The related pro-drug of didanosine, 2'3'-dideoxyadenosine (ddA), was initially synthesized by M.J. Robins and R.K. Robins in 1964. Subsequently, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan in the National Cancer Institute (NCI) found that ddA and ddI could inhibit HIV replication in the test tube and conducted initial clinical trials showing that didanosine had activity in patients infected with HIV. On behalf of the NCI, they were awarded patents on these activities. Since the NCI does not market products directly, the National Institutes of Health (NIH) awarded a ten-year exclusive licensed to Bristol-Myers Squibb Co. (BMS) to market and sell ddI as Videx tablets.

Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the Food and Drug Administration (FDA) on Oct 9, 1991. Its FDA approval helped bring down the price of zidovudine (AZT), the initial anti-HIV drug.

Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.

At the end of its ten-year license, BMS re-formulated Videx as Videx EC and patented that, which reformulation the FDA approved in 2000. The new formulation is a smaller capsule containing coated microspheres instead of using a buffering compound. It is approved by the FDA for once-a-day dosing. Also at the end of that ten-year period, the NIH licensed didanosine to Barr Laboratories under a non-exclusive license, and didanosine became the first generic anti-HIV drug marketed in the United States.

One of the patents for ddI expired in the United States on 2006-08-29, but other patents extend beyond that time.

Mechanism of action

Didanosine (ddI) is a nucleoside analogue of adenosine. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has hypoxanthine attached to the sugar ring. Within the cell, ddI is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes. Like other anti-HIV nucleoside analogs, it acts as a chain terminator by incorporation and inhibits viral reverse transcriptase by competing with natural dATP.

Pharmacokinetics

Oral absorption of didanosine is fairly low (42%)^[1] but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach.^[1] The half-life in plasma is only 1.5 hours,^[1] but in the intracellular environment more than 12 hours. An enteric-coated formulation is now marketed as well. Elimination is predominantly renal; the kidneys actively secrete didanosine, the amount being 20% of the oral dose.

Drug interactions

• A significant interaction has also been recorded with allopurinol, and administration of these drugs together should be avoided.^[1]
• Indinavir and delavirdine show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times.^[1]
• Ketoconazole, itraconazole, ciprofloxacin should be administered at a different time from didanosine due to interactions with the buffering agent.^[1]
• Administration with drugs with overlapping toxicity, such as zalcitabine and stavudine, is not recommended.^[2]
• Alcohol can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.^[1]

Adverse effects

The most common adverse events with didanosine are diarrhea, nausea, vomiting, abdominal pain, fever, headache and rash. Peripheral neuropathy occurred in 21-26% of participants in key didanosine trials.^[1]

Pancreatitis is rarely observed but has caused occasional fatalities, and has black box warning status. Other reported serious adverse events are retinal changes, optic neuritis and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.

Resistance

Drug resistance to didanosine does develop, though slower than to zidovudine (AZT). The most common mutation observed in vivo is L74V in the viral pol gene, which confers cross-resistance to zalcitabine; other mutations observed include K65R and M184V .^[1][3]

Sources

1. ^ ^{a b c d e f g h i} VIDEX (didanosine): chewable/dispersible buffered tablets; buffered powder for oral solution; pediatric powder for oral solution. Product information (July 2000)
2. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)
3. ^ Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996;52:168-185

Further reading

• Robins MJ, McCarthy JR Jr., Robins RJ. Biochenistry 1966; 5(1): 224-31.

• Yarchoan R, Mitsuya H, Broder S. AIDS therapies. Sci Am 1988;259(4):110-9

• Männistö P.T., Tuominen R.K. in Farmakologia ja Toksikologia, 5^th edition: (ed. Koulu, Tuomisto, Paasonen) Medicina, 1996

• Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3^rd edition. Pearson Professional Ltd, 1995

• Watson et al.: Molecular Biology of the Gene 4^th edition. The Benjamin/Cummings Publishing Company, 1987

• Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249(4976):1533-44

• Yarchoan R, Mitsuya H, Thomas RV, et al. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 1989;245(4916):412-5
• NIH Oral History of Samuel Broder describing development of AIDS drugs
• NIH Oral History of Robert Yarchoan describing development of AIDS drugs
• NIH Office of Technology Transfer Report on Development and Licensing of ddI
• FDA reviews safety of two HIV drugs

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