Pocket Drug Guide

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Zerit 20 mg hard capsules

Zerit 30 mg hard capsules

Zerit 40 mg hard capsules

Stavudine

1. WHAT ZERIT IS AND WHAT IT IS USED FOR

Zerit belongs to a group of antiviral medicines, also known as antiretrovirals, called nucleoside reverse transcriptase inhibitors (NRTIs).

These are used to treat Human Immunodeficiency Virus (HIV) infection.

This medicinal product, in combination with other antiretrovirals, reduces the HIV viral load and keeps it at a low level. It also increases CD4 cell counts. These CD4 cells play an important role in maintaining a healthy immune system to help fight infection. Response to treatment with Zerit varies between patients. Your doctor will therefore be monitoring the effectiveness of your treatment.

Zerit may improve your condition, but it is not a cure for your HIV infection. Treatment with Zerit has not been shown to reduce the risk of passing HIV infection on to others by sexual contact or by blood transfer. Therefore, you must continue to take appropriate precautions to avoid giving the virus to others.

During your treatment, other infections linked to your weakened immunity (opportunistic infections) may arise. These will require specific and sometimes preventive treatment.

2. BEFORE YOU TAKE ZERIT

Do not take Zerit:

If you are allergic (hypersensitive) to stavudine or any of the other ingredients of Zerit. Contact your doctor or pharmacist for advice.

Take special care with Zerit:

Before treatment with Zerit, you should have told your doctor:

■  if you suffer from kidney disease or liver disease (such as hepatitis),

■  if you have had peripheral neuropathy (persistent numbness, tingling, or pain in the feet and/or hands), or

■  if you have suffered from pancreatitis (inflammation of the pancreas).

The class of medicines to which Zerit belongs (NRTIs) can cause a sometimes fatal condition called lactic acidosis, together with an enlarged liver. This condition usually does not occur until a few months after onset of treatment. This rare, but very serious side effect occurs more often in women, particularly if very overweight. In addition, rare cases of liver failure/renal failure or fatal hepatitis have been reported.

Patients with chronic hepatitis B or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests for control of liver function.

If you develop one of the following, contact your doctor:

■  persistent numbness, tingling or pain in feet and/or hands (this may indicate the beginning of peripheral neuropathy, an adverse effect on the nerves), muscular weakness or

■  abdominal pain, nausea or vomiting, or

■  rapid deep breathing, drowsiness (which may indicate pancreatitis, liver disturbance such as hepatitis, or lactic acidosis).

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

Redistribution, accumulation, or loss of body fat may occur in patients receiving antiretroviral therapy. Some NRTIs, such as stavudine, have been associated with a loss of body fat (lipoatrophy). Contact your doctor if you notice changes in body fat.

Bone problems: some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Except for zidovudine, which interferes with the activity of stavudine, Zerit may be taken with many of the other medicines commonly used in patients with HIV infection. These include the protease inhibitors (such as nelfinavir) and NRTIs. Please tell your doctor if you are taking doxorubicin or ribavirin as undesirable interactions may occur.

Taking Zerit with food and drink:

For maximum effect, Zerit should be taken on an empty stomach, and preferably at least one hour before a meal. If this is not possible, the capsules may also be taken with a light meal.

Pregnancy and breast-feeding:

Pregnancy

If you become pregnant, or are planning to become pregnant, you must contact your doctor to discuss the potential adverse effects and the benefits and risks of your antiretroviral therapy to you and your child. Lactic acidosis (sometimes fatal) has been reported in pregnant women who received stavudine in combination with other antiretroviral treatment.

If you have taken Zerit during your pregnancy, your doctor may request regular visits to monitor the development of your child. Such visits may include blood tests and other diagnostic tests.

In children whose mother took nucleoside and nucleotide analogues during pregnancy, the benefit from the reduced chance of being infected with HIV is greater than the risk of suffering from side effects.

Breast-feeding

Tell your doctor if you are breast-feeding. It is recommended that HIV-infected women should not breast-feed under any circumstances in order to avoid transmission of HIV to the baby.

Driving and using machines:

It is unlikely that Zerit affects the ability to drive or operate machinery.

Important information about some of the ingredients of Zerit:

These capsules contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE ZERIT

Always take Zerit exactly as your doctor has told you. You should check with your doctor if you are not sure. Your doctor has defined your daily dose based on your weight and individual characteristics.

Please follow these recommendations closely as they will give you the best chance to delay development of a resistance to the medicinal product. Do not change the dose on your own. Continue to take this medicine until your doctor tells you otherwise.

For adults whose body weight is 30 kg or more, the usual starting dose is 30 or 40 mg given twice daily (with approximately 12 hours between each dose).

To obtain optimal absorption, the capsules should be swallowed with a glass of water, preferentially at least one hour before a meal and on an empty stomach. If this is not possible, Zerit may also be taken with a light meal.

If you have problems swallowing capsules you should ask your doctor about the possibility of changing to the solution form of this medicine or you could carefully open the capsule and mix its contents with some food.

Use in Children

For children whose body weight is 30 kg or more, the usual starting dose is 30 or 40 mg given twice daily (with approximately 12 hours between each dose).

Children older than 3 months, whose body weight is less than 30 kg, should receive 1 mg/kg twice daily.

If you take more Zerit than you should:

If you have taken too many capsules or if someone accidentally swallows some, there is no immediate danger. However, you should contact your doctor or the nearest hospital for advice.

If you forget to take Zerit:

If you accidentally miss a dose, then simply take your normal dose when the next one is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking Zerit:

The decision to stop using Zerit should be discussed with your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Zerit can cause side effects, although not everybody gets them.

When treating HIV infection, it is not always possible to differentiate between unwanted effects caused by Zerit, or those caused by any other medicines you may be taking at the same time, or by the complications of the infection. For this reason, it is important that you inform your doctor of any change in your health.

Therapy for HIV including stavudine often causes changes in body shape due to changes in fat distribution. These may include loss of fat from legs, arms and face (lipoatrophy), and development of fatty lumps on the back of the neck (“buffalo hump”). Loss of body fat has been shown to be not fully reversible after discontinuation of stavudine. It occurs more often with Zerit compared to other HIV medicines. Your doctor should monitor for clinical signs and symptoms of changes in your body shape. Tell your doctor if you notice any changes in your body shape or loss of fat from your legs, arms, and face. When these signs occur, consideration should be given to discontinuing ZERIT treatment.

The frequency of possible side effects listed below is defined using the following convention:

very common:	affects more than 1 user in 10
common:	affects 1 to less than 10 users in 100
uncommon:	affects 1 to less than 10 users in 1,000
rare:	affects 1 to less than 10 users in 10,000
very rare:	affects less than 1 user in 10,000
not known:	frequency cannot be estimated from the available data

Patients treated with Zerit have reported the following side effects: Common:

■  asymptomatic hyperlactatemia (build up of acid in your blood)

■  lipoatrophy or lipodystrophy syndrome (body changes due to fat redistribution, accumulation, or loss of body fat),

■  depression

■  peipheral neurologic symptoms including peripheral neuropathy, paresthesia, and peripheral neuritis (numbness, weakness, tingling or pain in the arms and legs)

■  dizziness, abnormal dreams, headache

■  insomnia (difficulty sleeping), somnolence (sleepiness), abnormal thinking,

■  diarrhoea, abdominal pain (stomach pain of discomfort),

■  nausea, dyspepsia (indigestion)

■  rash, pruritus (itching)

■  fatigue (extreme tiredness)

Uncommon:

■  lactic acidosis (build up of acid in your blood) in some cases involving motor weakness (weakness in your arms, legs or hands)

■  gynaecomastia (breast enlargement in men)

■  anorexia (loss of appetite), anxiety, emotional lability

■  pancreatitis (inflammation of the pancreas), vomiting

■  hepatitis, jaundice (yellow of the skin or eyes)

■  urticaria (itchy rash), arthralgia (joint pain)

■  myalgia (aching muscles), asthenia (unusual tiredness or weakness)

Frequency not known:

■  anemia, thrombocytopenia, neutropenia (blood disorders)

■  diabetes mellitis, hyperglycaemia (high sugar levels in the blood)

■  motor weakness (most often reported in the setting of symptomatic hyperlacetatemia or lactic acidosis syndrome

■  liver failure, hepatitis (infiamation of the liver) and hepatic steatosis (fat in the liver)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell you doctor or pharmacist.

5. HOW TO STORE ZERIT

Keep out of the reach and sight of children.

Store below 25 °C (aclar/alu blisters) Do not store above 30°C. (HDPE bottles) Store in the original package.

Do not use Zerit after the expiry date which is stated on the carton, the bottle label and/or the blister after EXP. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Zerit contains

The active substance is stavudine

The other ingredients of the powder contained in the hard capsule are: lactose (120 mg, 180mg, or 240mg), magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

The ingredients of the capsule shell are gelatine, iron oxide colorant (E172), silicon dioxide, sodium laurilsulphate and titanium dioxide colorant (El71).

The capsule shells are marked using edible black printing ink containing shellac, propylene glycol, purified water, potassium hydroxide and iron oxide (El72).

What Zerit looks like and content of the pack

Zerit 20 mg hard capsules are brown and marked with “BMS 1965″ on one side and “20″ on the other side.

Zerit 30 mg hard capsules are light and dark orange and marked with “BMS 1966″ on one side and “30″ on the other side.

Zerit 40 mg hard capsules are dark orange and marked with “BMS 1967″ on one side and “40″ on the other side.

Zerit 20 mg, 30 mg & 40 mg hard capsules are supplied in blister packs of 56 hard capsules or bottles of 60 hard capsules. To help protect the capsules from excessive moisture, the bottle includes a desiccant canister.

 

Overview

PTKs are enzymes that catalyze the phosphorylation of tyrosine residues. These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, antiapoptotic signaling, and neurite outgrowth. Unregulated activation of these enzymes, through mechanisms such as point mutations or overexpression, can lead to various forms of cancer as well as benign proliferative conditions. More than 70% of the known oncogenes and proto-oncogenes involved in cancer encode PTKs. Two protein tyrosine kinase inhibitors, Bristol-Myers Squibb’s BMS-354825 and Novartis’s AMN-107, are detailed in this section. Lack of published data precludes discussion of other protein tyrosine kinase inhibitors in development for chronic myelogenous leukemia. Ariad Pharmaceuticals’ AP-23464, and Wyeth’s SKI-606 are two such agents.

Mechanism Of Action

The rationale for developing tyrosine kinase inhibitors for the treatment of cancer is based on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. In chronic myelogenous leukemia, affected cells have a consistent cytogenetic abnormality — the Philadelphia (Ph) chromosome, which carries a BCR-ABL

fusion gene encoding a tyrosine kinase oncoprotein. Imatinib, the treatment of choice for chronic myelogenous leukemia, is a specific inhibitor of this oncoprotein.

The development of resistance to imatinib is a frequent setback in patients with advanced phases of the disease. This resistance is frequently the result of mutations in the BCR-ABL kinase domain and overexpression of tyrosine kinases that are not inhibited by imatinib. The majority of amino acid substitutions that cause resistance to imatinib impair the ability of the kinase to adopt the specific closed conformation to which imatinib binds, while a small fraction of these substitutions directly interfere with drug binding. This insight suggests that other small-molecule ABL kinase inhibitors with less stringent requirements for binding could be effectively deployed to combat resistance.

BMS-354825

Bristol-Myers Squibb’s BMS-354825 is an oral agent that inhibits five tyrosine kinase proteins. They include BCR-ABL, the protein that accounts for abnormal cell growth in chronic myelogenous leukemia, and steroid receptor coactivator (SRC) proteins that may play a role in imatinib resistance. The compound has completed Phase I trials at the M. D. Anderson Cancer Center in Houston, Texas, and the University of California at Los Angeles (UCLA) in patients with imatinib-resistant chronic myelogenous leukemia, and is now in Phase II.

The Phase I study involved patients with Ph chromosome-positive chronic, accelerated, and blastic-phase chronic myelogenous leukemia patients (36, 8, and 21, respectively) who were either resistant to or intolerant of imatinib. Of the chronic-phase patients, 86% demonstrated a complete hematologic response (CHR). In 29 patients for whom cytogenetic data were available, 8 (28%) demonstrated a major cytogenetic response (major cytogenetic response). In the accelerated-phase patient group, 75% demonstrated a hematologic response. At the time of presentation, no cytogenetic responses were seen in patients with accelerated disease. In the blastic-phase patient group, 79% demonstrated a hematologic response. Of 15 patients for whom cytogenetic data were available, 53% demonstrated a major cytogenetic response.

No patients discontinued the Phase I study because of toxicity, though several patients experienced serious side effects. In the chronic-phase population, 3 of 26 patients for whom data were available had grade 4 thrombocytopenia requiring treatment modification, and two patients were reported as having gastrointestinal bleeding possibly related to BMS-354825. Two patients in the blastic phase had evidence of tumor lysis syndrome (a serious complication of cancer therapy that causes metabolic abnormalities), and one patient with accelerated-phase chronic myelogenous leukemia had pneumonia possibly related to BMS-354825. Additional side effects reported in all phases during the study included arthralgia, pyrexia, fatigue, peripheral edema, headache, and diarrhea.

In vitro studies of BMS-354825 have demonstrated more than 500-fold increased potency relative to imatinib versus BCR-ABL; more importantly, BMS-354825 retained activity against 14 of 15 imatinib-resistant BCR-ABL mutants. The compound also proved equally effective against several preclinically and clinically derived tumor models of imatinib resistance.

BMS-354825 is not a P-glycoprotein (Pgp) substrate, a feature that may eliminate the blood-brain-barrier problems experienced with imatinib. Instead, imatinib is a substrate of Pgp, the gene product of MDR1. The generally accepted action of MDR1 (MDR stands for multidrug resistance) is to reduce intracellular drug accumulation through Pgp-mediated efflux, thereby hampering the achievement of effective drug levels at the target site.

One weakness of BMS-354825 is that, like imatinib (and AMN-107), it does not target the T315i mutation. This mutation has been identified in patients who present with or progress to the accelerated or blastic phase and accounts for 15-20% of imatinib-resistant chronic myelogenous leukemia cases.

If BMS-354825 progresses quickly through clinical trials, it could initially be approved for the treatment of chronic myelogenous leukemia in patients who have failed on imatinib therapy or who present in accelerated- or blastic-phase disease. Once the drug’s efficacy is proven in these subsets of patients, studies may be conducted to compare BMS-354825 with imatinib in first-line therapy and to investigate its potential in combination with imatinib. However, considering the very high cytogenetic response rates achieved by imatinib and the absence of data demonstrating that BMS-354825 confers a complete molecular response rate (i.e., cure rate) superior to that of imatinib, BMS-354825 is unlikely to usurp imatinib’s role in first-line therapy.

AMN-107

Novartis’s AMN-107 is an oral novel aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinase BCR-ABL and some mutant forms of this protein. The compound is in Phase I trials at the M.D. Anderson Cancer Center and the Johann Wolfgang Goethe University in Frankfurt, Germany. It is being studied in chronic myelogenous leukemia patients with accelerated- or blastic-phase disease that is imatinib-resistant. Once an effective dose has been determined, the study will expand to treat chronic-phase chronic myelogenous leukemia patients who have experienced imatinib failure.

Sixty-five imatinib-resistant patients were involved in the Phase I study; 36 had accelerated-phase chronic myelogenous leukemia, 15 had myeloid blast-phase chronic myelogenous leukemia, 7 had lymphoid blast-phase chronic myelogenous leukemia, and 7 had acute lymphocytic leukemia (acute lymphocytic leukemia). Each patient received escalating oral doses of AMN-107, starting at 50 mg/day up to 1,200 mg/day. Cytogenetic responses were observed in 20% of accelerated-phase patients, 8% of myeloid blastic-phase patients, and 17% of lymphoid blastic-phase patients.

Preclinical data reported at the 46th American Society for Hematology (ASH) meeting in 2004 showed that AMN-107 was 10- to 20-fold more potent than imatinib in vitro against wild-type BCR-ABL kinase and against BCR-ABL-dependent cell proliferation. AMN-107 was also effective against clinically relevant imatinib-resistant mutations G250E, E255K/V, E292K, F317L, and M351T. Additional data presented at ASH show that AMN-107 is more effective than imatinib at inhibiting both BCR-ABL-positive cell lines (e.g., K562, KCL-22, Lama-84) and primary cells derived from two BCR-ABL-positive chronic myelogenous leukemia patients who were resistant

to imatinib and one newly diagnosed chronic-phase chronic myelogenous leukemia patient. In a further study, AMN-107 was tested against BCR-ABL-positive cell lines (K562, Lama-84, AR230, BaF/BCR-ABL) and was found to inhibit these cells at nanomolar concentrations; these concentrations were 100-fold less than imatinib.

AMN-107 is unlikely to be used in combination with imatinib because both drugs have a similar mode of action. However, AMN-107, like imatinib and BMS-354825, does not inhibit the T315i mutation. This drawback presents a clinical problem because, as mentioned previously, this mutation is observed in 15-20% of patients who progress to the accelerated and blastic phases and become imatinib-resistant. Nonetheless, patients with chronic-phase chronic myelogenous leukemia who fail to achieve a cytogenetic response with imatinib (approximately 25% of patients), patients who present in the accelerated and blastic phases, and patients who relapse on imatinib (i.e., are no longer in cytogenetic remission) could benefit from AMN-107, especially if its toxicity profile is found superior.