TRADE AND GENERIC NAME: : ZIDOVIR (ZIDOVUDINE).

FORMULA AND PHARMACEUTICAL DOSAGE FORM:

Each capsule contains:
Zidovudine 100 mg and 250 mg
Excipient qs 1 capsule

Manufacturer: APOTEX PROTEIN S. A. DE C.V.

Int. Sales Agent:

Genesis
Medical Division

THERAPEUTIC INDICATIONS:

ZIDOVIR is indicated for the treatment of some patients in initial stages of infection by human immunodeficiency virus (HIV), and those with symptoms related to HIV and/or other indicators of progress to advanced stages. Evidence of efficacy has been observed in patients with counts of T4 cells (T helpers) less than 500/mm3.

ZIDOVIR is also indicated for the treatment of patients with advanced disease by HIV such as those with Acquired Immunodeficiency Syndrome (AIDS) or complex related to AIDS (ARC). The evaluation of the benefit risk relationship, based on present available data, generally supports the need of treatment before reaching the final stages of the disease.

PHARMACOKINETICS AND PHARMACODINAMICS:

PHARMACOKINETICS: At all the levels of dose studied, the zidovudine is well absorbed in the intestine; bioavailability is 60-70%; mean plasma concentrations at steady state, maxima (Ossmax) and minima (Ossmin), following the administration of zidovudine oral (in solution) at doses 5 mg per Kg of body weight every 4 hours, were 1.9 and 0.1 mg/mL respectively. Available data is limited but it suggest that Ossmax and Ossmin levels following a 200-mg dose every 4 hours, are approximately 1.0 and < 0.1 mg/ml respectively, corresponding levels after a 250-mg dose every 4 hours are 1.2 and 0.2 mg/ml respectively.

In studies with zidovudine, administered by intravenous route, the plasma half-life is approximately 1.1 hours. Clearance of zidovudine exceeds by far that of creatinine, thus indicating that there is tubular secretion.
The 5-glucuronide of zidovudine is the main plasma and urinary metabolite, and it accounts for 50 to 60% of the administered dose eliminated by renal excretion; no other metabolites have been observed.
There is limited data about pharmacokinetics of zidovudine in children and in patients with renal or hepatic damage (see Administration). There is no data about the pharmacokinetics of zidovudine in the elderly. Levels of zidovudine in cephalorachidian liquid correspond approximately to 50% of plasma levels following the chronic administration. The limited available data suggest that zidovudine crosses the placenta and appears in the amniotic liquid and fetal blood. Zidovudine has also been detected in semen.
The bond to plasma proteins is relatively low (from 36% to 38%), and thus no pharmacological interactions that involve any displacement from sites of binding are expected.

CONTRAINDICATIONS:

ZIDOVIR is contraindicated in patients with known hypersensitivity to zidovudine. ZIDOVIR should not be administered to patients having an abnormally low count of neutrophiles (less than 0.75 x 10-9 /ml) or abnormally low levels of hemoglobin (less than 7.5 g/dL).

PRECAUTIONS OR RESTRICTIONS OF USE DURING PREGNANCY AND LACTATION:

It is not known if zidovudine can affect human fecundity, or if it may cause damage if administered during pregnancy. Use of zidovudine during pregnancy should be considered only if it is perfectly indicated or when potential benefits of the treatment for the mother outweigh any possible risk for the developing fetus.

Lactation: There is limited data indicating that zidovudine is excreted in the animal milk (Ruprecht et al, 1988). It is unknown if zidovudine is excreted in human milk. Since the drug can appear in the human milk and may cause serious toxicity to breast-feeding newborn, it is recommended that mothers given ZIDOVIR do not feed their babies.

ADVERSE REACTIONS:

The most frequent and important adverse reactions include anemia (that often needs blood transfusion), neutropenia and leucopenia. These occur with higher frequency at high doses (1,200 to 1,500 mg/day) and in patients with advanced disease by HVI. In patients with < 100 T4 helpers / mm3 it may be necessary a reduction of the dose or discontinuation of treatment (see Dose and Administration Route); incidence of neutropenia also increased in patients with previous neutropenia or in patients with low levels of vitamin B12 and anemia, and in patients under concomitant paracetamol (see Drug interactions).
Other adverse reaction reported in controlled clinical trials with placebo include: nausea, vomit, anorexia, abdominal pain, cephalea, cutaneous eruption, fever, myalgia, paresthesia, insomnia, malaise, asthenia, and dyspepsia. Besides the nausea, the most common and significant adverse effect in all the studies with zidovudine, other reported adverse effects were not consistent compared with placebo. The most common adverse effects reported in patients with advanced disease by HIV were severe headache, myalgia, and insomnia, however vomit, anorexia, malaise and asthenia were most common in patients with early disease by HIV.
Other recorded adverse effects included drowsiness, diarrhea, dizziness, perspiration, dyspnea, flatulence, taste alteration, pain in the chest, loss of mental acuteness, depression, generalized pain, chills, cough, hives, pruritus, and pseudogrippal syndrome.
Incidence of these and other less common reactions were similar in both groups under study.
The following events have been reported in patients treated with ZIDOVIR. They also can occur as part of the underlying process of the disease. Thus, the relationship of these reactions with the use of ZIDOVIR is hard to evaluate, particularly in the complicated cases that characterize an advanced infection by HIV.

- Convulsions and other cerebral problems.
- Myopathy.
- Ungual pigmentation.
- Pancytopenia with medullar hypoplasia and isolated thrombocytopenia.
- Hepatic disorders with increase in transaminases and bilirubin levels.

DRUG INTERACTIONS:

Because of the limited experience with zidovudine and its interactions with other drugs, caution should be exercised when administering concomitantly ZIDOVIR and other drugs.
The interactions stated below should not be considered absolute but representatives of the medicaments for which caution should be exercised.
It has been reported low blood levels of phenytoin in some patients given zidovudine, although it was observed an increased level in one patient. These observations suggest that plasma levels of phenytoin should be carefully monitored in patients that receive both drugs.
The concomitant use of paracetamol during the treatment with ZIDOVIR increases the incidence of neutropenia, especially after a chronic treatment, presumably because of the reduction in zidovudine metabolism.
Other drugs (such as acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clorfibrate, dapsone, and isoprinosine) may also alter the metabolism of zidovudine by competitively inhibiting the glucuronidation or direct inhibition of the hepatic microsomal metabolism.
Before the use of these drugs the interactions should be evaluated carefully, particularly during the chronic therapy in combination with ZIDOVIR.
The concomitant use with potentially nephrotoxic or myelosuppressive drugs (such as systemic pentamidine, dapsone, pirimethamine, amphotericin, flucitocine, gancyclovir, interferon, vinchristine, vinblastine, and doxorubicine) may also increase the risk of toxicity with ZIDOVIR.
Some antiviral analogs of nucleosides (e.g. ribavirine) antagonize in vitro the antiviral activity of zidovudine and therefor the simultaneous use of such drugs should be avoided.
Since some patients given zidovudine may continue experiencing opportunistic infections, it should be considered the concomitant use of an antimicrobial therapy with co-trimoxazol, pentamidine in aerosol, pirimethamine, and acyclovir.
The available data do not indicate increase in the risk of toxicity with the use of these drugs.
There is little data suggesting that probenecid, by reducing glucuronidation, raises the half-life and the area under the curve for the plasma concentration of zidovudine. The renal excretion of glucuronide (and possibly zidovudine itself) is decreased in presence of probenecid.

ALTERATIONS OF LABORATORY TESTS:

There are no reports of alteration in laboratory tests.

PRECAUTIONS AND RELATION WITH CARCINOGENIC, MUTAGENIC, TERATOGENIC, AND FERTILITY EFFECTS:

Patients should be warned about the use of drugs not prescribed by their physicians (see Drug interactions). Zidovudine has not shown reduction in the risk of HIV transmission through sexual intercourse or contamination with blood and its derivatives.

CARCINOGENESIS:
Zidovudine was administered in three levels of dosage by oral route to rats and mice (60 females and 60 males per group), at initial single doses of 30, 60, and 120 mg/Kg/day and 80, 220 and 600 mg/Kg/day to mice and rats respectively. After day 90th, doses in mice group were reduced to 20, 30 and 40 mg/Kg/day because of anemia related to treatment, only the highest dose was reduced for rats (to 450 and then to 300 mg/Kg/day at days 91st and 279th respectively).
With the highest dose, mice showed 7 neoplasms of late appearance (after 19 months; 5 squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp). One squamous cell polyp of late appearance occurred in the vagina of one animal treated with the medium dose. With the lowest dose there were no presence of vaginal tumors.
With the highest dose, rats showed two squamous cell carcinomas of late appearance (after 20 months) in the vagina. With the medium and lowest dose there were no presence of vaginal tumors.
No other tumors related with the drug were observed in both species and for both sexes.
The value of carcinogenesis studies in rodents, to predict carcinogenesis in man, is uncertain and thus the clinical relevance of these findings is not clear.

MUTAGENESIS:
In the test of Ames there is no evidence of mutagenesis; however, zidovudine was slightly mutagenic in one assay with lymphoma cells of mouse, and it was positive in one assay of cell transformation in vitro. Clastic effects (damage to chromosomes) were observed in one in vitro study with human lymphocytes and in micronucleus studies in vivo with repeated oral doses given to mice and rats.
One cytogenic study in vivo with rats, failed to show chromosomal damage.
The clinical relevance of these findings is not significant.

TERATOGENESIS:
Studies with pregnant rats and does, which were given zidovudine by oral route in doses up to 450 and 500 mg/Kg/day respectively during the main period of organogenesis, have not revealed evidence of teratogenesis. However, in rats given 150 to 450 mg/Kg/day and in does with 500 mg/Kg/day dose, there was an statistically significant increase in the incidence of fetal resorptions.

FERTILITY:
Zidovudine did not alter the fertility of male or female rats that received oral doses up to 450 mg/Kg/day.

DOSE AND ADMINISTRATION ROUTE:

ADULTS:
For a mean patient with 70 Kg, it is recommended an initial oral dose of 200 mg of zidovudine every 4 hours (1,200 mg/day).
A great number of doses have been used, usually between 500 and 1,500 mg/day. Optimum dose has not been established yet, and it may vary from patient to patient. In the practice many patients can be maintained adequately with doses of 1,000 mg/day divided in 4 or 5 doses.
In particular cases a lower dose can be chosen, depending on the stage of the disease and other relevant factors (such as the functioning of the marrowbone or patient body weight).
It is unknown the efficacy of lower doses for the treatment or prevention of neural dysfunctions related to HIV and neoplasias.
For patients with hematological toxicity it may be necessary to adjust the posology. Especially in those with marrowbone dysfunction previous to treatment, particularly in patients with advanced disease by HIV. If hemoglobin level decreases to values between 7.5 and 9 g/dl or the count of neutrophils decreases to values between 0.75 x 10 /L and 1.0 x 10 /L, then the daily dose can be divided (example, the recommended total daily dose can be administered every 8 hours) until there is evidence of marrowbone recovery. Then the posology can be increased until the original dose is reached. Alternatively, marrowbone recovery can be improved by the brief interruption (2 to 4 weeks) of zidovudine therapy.
The treatment must be interrupted if hemoglobin value falls below 7.5 g/dl or the count of neutrophils is less than 0.75 x 10 /L. Recovery is usually observed within two weeks, after this period the treatment with zidovudine may be resumed at reduced doses (i.e. the recommended daily dose divided in 3 doses or every 8 hours). After 2 to 4 weeks the dose can be increased gradually depending on patient’s tolerance, until the original posology is reached.

CHILDREN:
There is limited data about the use of zidovudine in children. Even though they are not experimental, initial doses of 150 to 180 mg/m2 every 6 hours (four times a day) have been employed widely.

ELDER:
There is no data about the use of zidovudine in elder, but due to the diminished renal function related to age, it is advised especial attention in this kind of patients.

RENAL DAMAGE:
The limited available data for patients with diminished renal function do not suggest the particular need of adjusting initial dose, because zidovudine levels do not increase significantly.
In case of renal failure it can be expected an accumulation of the glucuronide metabolite, however, the effect of such an accumulation is unknown. The monitoring of plasma levels of zidovudine (and its glucuronide metabolite), together with hematological parameters, may indicate the need of limited adjustment for the elimination of the glucuronide metabolite.

HEPATIC DAMAGE:
The limited available data for patients with cirrhosis suggest that in case of hepatic failure, it can occur accumulation of zidovudine due to the reduced glucuronidation. It may be necessary to adjust the dose, at present it is not possible to make precise recommendations. If it is not possible the monitoring of plasma levels of zidovudine, then the physicians will need to look for intolerance signs and increase the period of time between doses as necessary.

OVERDOSAGE OR ACCIDENTAL INTAKE; SYMPTOMS AND HANDLING (ANTIDOTES):
Symptoms and signs: There is limited available information about the acute intake of overdoses and its consequences. No specific symptoms related to overdose have been identified.
Oral doses up to 1,250 mg of ZIDOVIR every four hours during four weeks have been administered to two patients with advanced disease, one did not show adverse effects.
Treatment: Patients should be closely monitored to detect any possible evidence of toxicity (see Adverse reactions) and should receive any necessary supporting therapy.
Hemodialysis has a limited effect on the elimination of zidovudine, but improves the elimination of the glucuronide metabolite.

HOW SUPPLIED:
Bottle with 100 capsules of 100 mg.
Bottle with 30 capsules of 250 mg.
Carton with 100 capsules of 100 mg.
Carton with 30 capsules of 250 mg.

STORAGE:
Store in a dry and cool place.

PROTECTIVE STATEMENTS:
Literature exclusive for physicians. Keep out of reach of children. This medicine is sold only with medical prescription. Do not administer this medicine during pregnancy, lactation or children under 12 years of age.

PRODUCT REGISTRATION NUMBER:
280M92 SSA
Prescribing Information Code
FEAR-12985/93MR Trade Mark

Doctor

Zidovudine was the first FDA-approved antiretroviral drug. The patent for Zidovudine expires in 2005. Despite the lack of a significant impact on morbidity and mortality, it was used at that time by many patients as a single agent because there were no other alternatives. Without other agents with which to combine it, doses were often pushed much higher than the current dosage of 300 mg twice daily, leading many taking Zidovudine to experience significant nausea and vomiting. At current doses, this occurs much less frequently, though another potential side effect of Zidovudine, suppression of blood cells (myelosuppression), remains. Resistance to Zidovudine often means resistance to other drugs in this class. Because it has a similar mechanism of action as Stavudine (d4T), these drugs should not be given together. For greater simplicity, Zidovudine is often taken as Combivir (Zidovudine and 3TC in one pill) or Trizivir (Zidovudine, 3TC, and abacavir in one pill).

-Jonathan Uy, MD

Activist

( Zidovudine) is the first drug approved for the treatment of AIDS. This drug has taught the manufacturer, scientist and activist the importance of finding the most effective dose to suppress the HIV virus with minimal side effects. Initially, Zidovudine was approved for treating HIV disease at a dose of 1200-1500 mg a day. Further studies have shown that a lower dose, ranging from 500-600 mg a day, was better tolerated and achieved similar suppression of the HIV virus than the approved higher and more toxic dosage. The majority of people taking this drug experience side effects that resolve over time. Zidovudine continues to serve as a cornerstone of HIV regimens mainly due to its synergistic effect with Epivir (3TC). Since Zidovudine is the grandfather of HIV drugs approved in the USA, patients who are beginning therapy should take a resistance test because approximately 10% of patients may have acquired a virus that is resistant to Zidovudine.

-Charles A. Nelson

TRADE AND GENERIC NAME: APOSTAVINA (Stavudine)

FORMULA AND PHARMACEUTICAL DOSAGE FORM:

Each capsule contains:
Stavudine 40 mg
Excipient Qs 1 capsule

Manufacturer: APOTEX PROTEIN S.A. DE C.V.

Int. Sales Agent:

Genesis Capital Management Group, Ltd.
Medical Division

THERAPEUTIC INDICATIONS:

This medicine is indicated for the treatment of patients with HVI in advanced stages: those patients who have experienced significantly clinic or immunologic deterioration, or when the treatment with zidovudine is contraindicated.

PHARMACOKINETICS AND PHARMACODINAMICS:

Mechanism of action: APOSTAVINA contains stavudine a synthetic analog of thiamine nucleoside that is active against the human immunodeficiency virus (HIV).

Inside the cell these compounds act as an alternative substrate for the kinases that transform them into triphosphate compounds. Then these synthetic triphosphates compete with the natural triphosphates for the reverse transcriptase bound of the HIV and for the DNA synthesis, and thus inhibit the rate of viral DNA synthesis. Summarizing, these non-natural nucleoside triphosphates can act as alternative substrates for the reverse transcriptase and thus they may be incorporated into the DNA chain instead of a natural compound.

In T cells and mononuclear cells of peripheral blood, stavudine triphosphate has an intracellular half-life of 3 _ hours.

In selective in vitro studies and in some pairs of pre-treatment and post-treatment of HIV-1 isolated from clinical trials, it has been observed a reduction in the sensitivity of some strains of HIV-1 for stavudine.

Absorption: Following an oral administration, stavudine is rapidly absorbed. Mean absolute bioavailability is 86.4%. Maximum plasma concentration (Cmax) is reached within an hour or less following its administration and it increase in a proportional fashion with the dose. No significant accumulation of stavudine was observed for the repeated administration of the drug every 6, 8 or 12 hours.

In one study with asymptomatic patients infected with HIV, it was shown that systemic exposure (area under the curve of time for the plasma concentration [AUC]) is similar either with the administration of stavudine in fasted state or following a standard meal rich in fat.

APOSTAVINA pharmacokinetics is normal in patients with hepatic failure. Therefor it is not necessary an initial adjustment of the dose.

Distribution: Following the administration of single oral doses, the mean distribution apparent volume is 661 and is not dose dependent. Bond with serum proteins is not significant. Stavudine is fairly distributed between blood and plasma. Following the administration of an oral single dose of 40 mg of stavudine to healthy subjects, mean concentration in cephalorachidian liquid was 63 ng/ml (range 44-71 ng/ml) 4-5 hours after the administration of the dose. Mean rate for CPL and plasma was of 40% (range 31% to 45%).

After an intravenous infusion the mean distribution volume is 0.74 L/Kg. Concentrations in cephalorachidian liquid represent 16% to 125% of the simultaneous plasma concentrations.
Metabolism: In human beings the metabolism of stavudine has not been clearly established yet. Following the incubation of stavudine [C14] with cuts of human liver for a 6-hour period, 87% or radioactivity was attributed to the parent compound, 2% was metabolized into thiamine and 7% was related to polar compounds not identified.

Excretion: Following the administration of single oral doses, the half-life of terminal elimination was 1.44 hours, and it was not dose dependent. Approximately 40% of the total elimination of the drug occurs through the kidneys. Mean renal clearance is approximately twice of that for the mean clearance of endogenous creatinine, this indicates an active tubular secretion besides glomerular filtration.

CONTRAINDICATIONS:

APOSTAVINA is contraindicated in patients with hypersensitivity to stavudine or any of the ingredients of this formulation.

PRECAUTIONS OR RESTRICTIONS OF USE DURING PREGNANCY AND LACTATION:

Safety of this drug during pregnancy has not been established. It is not known if stavudine is excreted in human milk. Lactating mothers should discontinue the treatment because of adverse reactions of stavudine in lactating children, unless the benefit outweighs the risk. In one study with rats it was shown that stavudine is transmitted to the fetus through placenta.

ADVERSE REACTIONS:

Many of the severe adverse reactions reported with patients under stavudine, are related with the course of the infection by HIV.
The main clinical toxicity of APOSTAVINA is related with peripheral neuropathy that is usually characterized by numbness of the fingers or pain in fingers and hands. Should these symptoms develop, treatment with APOSTAVINA should be discontinued.
Patients should be monitored for the development of neuropathy, which can be resolved by treatment discontinuation.
Symptoms may worsen temporarily if therapy is stopped. Resume of the treatment with a lower dose may be considered if symptoms improve satisfactorily. Patients with history of peripheral neuropathy are in risk of developing neuropathy.
Pancreatitis, sometimes fatal, was reported in up to 2% of the patients enlisted in clinical trials. Generally this condition was attributed to disease or to the therapy with drugs known to be related to pancreatitis. The rate of pancreatitis was not related to the administered dose of stavudine. Patients with a history of pancreatitis seemed to have an increase in the recurrence of the disease. Physicians should monitor those patients in high risk of pancreatitis or those under drugs known to be related to pancreatitis.
Other adverse effects reported without considering causes include:
General: infection, headache, chills/fever, asthenia, abdominal pain, pain, malaise, backache, cold, allergic reactions, neoplasm, neckache, swollen abdomen, abscess, dead, hernia, neck rigidity, pelvic pain, addiction, cyst, facial edema.
Cardiovascular: pectoral pain, vasodilatation, syncope, hypertension, peripheral vascular disorder, angina pectoris, bleeding, and tachycardia.
Gastrointestinal: Diarrhea, nausea and vomit, anorexia, dyspepsia, rectal disorder, dental disorder, flatulence, constipation, mouth dryness, ulcerative estomatitis, dysphagia, dental pain, gastrointestinal disorder, gingivitis, glossitis, melena, rectal bleeding, esophagitis, gastritis, hepatomegaly, increased appetite, pancreatitis, tongue decoloration, dental caries.
Hematologic/Lymphatic: Lymphadenopathy, ecchymosis, hepatosplenomegaly.
Metabolic/Nutritional: Loss or gain in corporal weight, peripheral edema, edema, dehydration.
Skeletal muscle: Myalgia, arthralgia, pain in the bones, arthrosis, generalized spasm, myasthenia.
Neurological: Peripheral neurological symptoms that do not require dose modification such as insomnia, depression, anxiety, and neuropathy that needs dose modification such as nervosism, amnesia, drowsiness, tremors, vertigo, neuralgia, abnormal dreams and thoughts, convulsions, migraine, nervous tic, decreased reflexes, hypoesthasia, and hypertonia.
Respiratory: Rhinitis, cough, pharyngitis, respiratory disorders, dyspnea, bronchitis, pneumonia, pulmonary disorder, sinusitis, epistaxis, asthma, laryngitis, voice alteration.
Skin: Pruritus, perspiration, fungal dermatitis, dryness and wounds in the skin, folliculitis, macopapular itching, skin benign neoplasm, seborrhea, nails disorder, skin noduli, alopecia, hives, eczema, furunculosis, herpes simplex, herpes zoster, skin decoloration, psoriasis, pustular itching.
Senses: earache, conjunctivitis, abnormal vision, eyeache, medium otitis, conjunctival otitis, deafness, dryness and infection in the eyes, lachrymal disorders, external otitis, tinnitus.
Urogenital: Dysuria, vaginitis, urogenital neoplasm, dysmenorrhea, urinary frequency, hematuria, impotence, penis disorders, urinary tract infections.

DRUG INTERACTIONS:

The concomitant use of stavudine and dapsone, didanosine, zalcitabine, metronidazole, ethambutol, or isoniazide, may increase the risk of peripheral neuropathy.

ALTERATIONS OF LABORATORY TESTS:

In clinical trials it was observed a slight to moderate increase in SGPT and SGOT levels, however it was not necessary to discontinue the treatment. In case of clinically significant increase of SGOT or SGPT levels, it may be necessary to adjust the dose.

PRECAUTIONS AND RELATION WITH CARCINOGENIC, MUTAGENIC, TERATOGENIC, AND FERTILITY EFFECTS:

It was observed an increase in the incidence of deossification and incomplete ossification of the sternebras, a common skeletal variation, in the fetuses of rats with an exposition to the drug 399 times higher than that for humans, but not with an exposition of 216 times higher than that for humans. Early mortality of newborn rats (from birth to 4 days of age) increased with an exposition of 399 times higher than that for humans, but it was not affected with an exposition of 135 times higher than that for humans.
No teratogenic evidence was observed in rats or mice that were exposed (based on Cmax) up to 399 and 183 times, respectively, higher than the recommended clinical dose.

DOSE AND ADMINISTRATION ROUTE:

APOSTAVINA may be administered with or without meals.
Adults:
The recommended initial dose based on body weight is as follows:
40 mg every 12 hours for patients Ž 60 Kg
30 mg every 12 hours for patients < 60 Kg

Dose adjustment:

a) Peripheral neuropathy: Patients must be monitored for the developing of peripheral neuropathy. Following the discontinuation of the therapy, some patients may experience a temporary worsening of symptoms. These symptoms improve satisfactorily when the treatment with stavudine is considered according to the following dosage schedule:

20 mg every 12 hours for patients Ž 60 Kg
15 mg every 12 hours for patients < 60 Kg

b) Hepatic failure: it is not necessary an initial adjustment. There are clinically significative increases of hepatic transaminases (SGPT/SGOT > 5 times the normal highest limit) that should be treated as peripheral neuropathy as well.

c) Renal failure: APOSTAVINA can be administered to patients with renal failure, the recommended doses are as follows:

* regular dose, adjustment is not necessary.

There is not enough data to recommend a dose for patients with a creatinine clearance < 10 ml/min or for patients under dialysis.

OVERDOSAGE OR ACCIDENTAL INTAKE; SYMPTOMS AND HANDLING (ANTIDOTES):

In one study with adults given 12 to 24 times the recommended daily dose, the patients did not show any sign of toxicity. Chronic overdosage may include peripheral neuropathy and hepatic toxicity. It is unknown if peritoneal dialysis or hemodialysis eliminate stavudine.

HOW SUPPLIED:

Bottle with 60 capsules.

STORAGE:

Store the bottle well closed in a dry and cool place. Protect bottle from light.

PRECAUTION STATEMENTS:

This medicine is sold only with medical prescription. Literature exclusive for physicians. Keep out of reach of children. It is recommended that this medicine be prescribed by physicians with experience in the use of antiviral drugs.

PRODUCT REGISTRATION NUMBER:

Trade Mark

Doctor

Stavudine was the fourth FDA-approved antiretroviral drug. While it has a similar mechanism of action and similar resistance profile to Zidovudine, some studies in the pre-HAART era showed good Stavudine activity in patients with Zidovudine experience. Advantages of Stavudine over Zidovudine include the lack of myelosuppression, making Stavudine a good choice in patients with anemia. Stavudine is also very well-tolerated without the gastrointestinal side effects associated with Zidovudine. However, Stavudine does have a greater association with lipodystrophy and peripheral neuropathy compared with other drugs in this class, but the exact causes of these complications remain unknown. A once-daily formulation of Stavudine has been submitted to the FDA for approval, which is expected to come soon. Resistance to Stavudine usually means resistance to other drugs in this class. Because it has a similar mechanism of action as Zidovudine, these drugs should not be given together.

-Jonathan Uy, MD

Activist

Stavudine rapid development was delayed because its sister nuke (ddI) was further along the FDA approval path despite the vocal objections from activists. For patients and physicians, Stavudine has been a popular choice as one leg of an antiviral regimen for many years. Early studies found that Stavudine was as effective as Zidovudine and was shown to be less toxic. There is a growing body of data linking Stavudine to loss of body fat (lipoatrophy) and liver toxicity with or without a potentially fatal build up of acid in the body, known as lactic acidosis. Patients using this drug should discuss signs and potential symptoms of pancreatitis and lactic acidosis with their provider before starting this drug. Be on the safe side and have your liver enzymes monitored frequently while taking the product. One comment from the 2002 reviewer of Stavudine bears repeating "It is important to choose the dosage of Stavudine according to body weight: less than 132 lbs: 30 mg, greater than 132 lbs: 40 mg."

-Charles A. Nelson