INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ASPEN STAVUDINE
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ASPEN STAVUDINE

ASPEN STAVUDINE 15 mg (Capsules)
ASPEN STAVUDINE 20 mg (Capsules)
ASPEN STAVUDINE 30 mg (Capsules)
ASPEN STAVUDINE 40 mg (Capsules)

COMPOSITION:
ASPEN STAVUDINE 15 mg (Capsules): Each capsule contains stavudine 15 mg
ASPEN STAVUDINE 20 mg (Capsules): Each capsule contains stavudine 20 mg
ASPEN STAVUDINE 30 mg (Capsules): Each capsule contains stavudine 30 mg
ASPEN STAVUDINE 40 mg (Capsules): Each capsule contains stavudine 40 mg
Excipients include lactose, microcrystalline cellulose, sodium starch glycollate and magnesium stearate. Hard gelatin capsules contain preservatives (Methyl Hydroxybenzoate 0,8 % m/m and Propyl Hydroxybenzoate 0,2 % m/m), colourants, surfactant and gelatin.

PHARMACOLOGICAL CLASSIFICATION:
A - 20.2.8 : Antiviral agents

PHARMACOLOGICAL ACTION:
Mechanism of Action
Stavudine is a synthetic thymidine nucleoside analogue, active against the Human Immunodeficiency Virus (HIV). Stavudine inhibits the replication of HIV in human cells in-vitro. It enters cells by diffusion and is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV reverse transcriptase both by competing with the natural substrate, deoxythymidine triphosphate, and by its incorporation into viral DNA causing the termination of DNA chain because stavudine lacks the essential 3’-OH group necessary for DNA elongation. It further inhibits cellular DNA polymerase and gamma, and markedly reduces the synthesis of mitochondrial DNA.
Synergies and resistance
In-vitro studies have shown that stavudine had an additive and synergistic activity in combination with didanosine and zalcitabine respectively. When combined with zidovudine it showed additive and antagonistic activity depending on the molar ratios of agents tested. However combination therapy with zidovudine is not recommended due to the possible competitive inhibition of the intracellular phosphorylation of stavudine (SEE “INTERACTIONS”). Further in-vitro studies have demonstrated that there is a reduction in sensitivity to stavudine of some HIV-1 strains. The genetic basis and clinical relevance of changes in stavudine susceptibility has not been identified or established. It was further found, that some post stavudine-treatment isolates developed moderate resistance to zidovudine and to didanosine.
Absorption, Distribution, and Elimination
Stavudine is acid-stable and is well absorbed after oral administration. Peak plasma concentrations average 0,8 micrograms/mL after 1,0 mg/kg doses in fed persons and occur about 1 hour after dosing and increase in a dose-related manner. Stavudine absorption is not affected by the presence of food. Stavudine distributes into extravascular spaces.
Cerebrospinal fluid concentrations average 40% of those in plasma. The plasma t½ of elimination averages about 1 hour and is independent of dose. Approximately 40% of stavudine appears unchanged in the urine through tubular secretion and glomerular filtration. The clearance of stavudine decreases as creatinine decreases and thus it is recommended that the dosage of stavudine be adjusted in renal insufficiency (SEE “DOSAGE AND DIRECTIONS FOR USE”). Non-renal clearance mechanisms account for about 50% of elimination of a dose, but the metabolic fate of stavudine has not been defined. Stavudine may be converted to thymine, which may undergo degradation or be used to make thymidine.

INDICATIONS:
ASPEN STAVUDINE is indicated in combination with other antiretroviral agents for treating adults with HIV infections for whom other therapies, such as zidovudine, are not or no longer appropriate. These patients may have experienced significant clinical or immunologic deterioration while on other therapies or in some patients such therapies are contra-indicated.

CONTRA-INDICATIONS:
ASPEN STAVUDINE is contra-indicated in patients with hypersensitivity to stavudine or to any of the components in the formulation.
Pregnancy and Lactation
Safety in pregnancy has not been established. Studies in animals suggest that stavudine is excreted in milk. Because of both the potential for HIV transmission and the potential for side-effects in breast-feeding infants, Aspen Stavudine is not recommended for use by breast-feeding mothers.

WARNINGS:
Less frequent cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Aspen Stavudine and other antiretrovirals. Obesity and prolonged nucleoside exposure may be risk factors. The majority of cases reported have been in women and fatal lactic acidosis has been reported in pregnant women who received the combination of Aspen Stavudine and didanosine with other antiretrovirals. Caution should be exercised when prescribing Aspen Stavudine to patients with known risk factors for liver disease. Patients with risk factors and those being given a combination of Aspen Stavudine, didanosine and hydroxyurea should be closely monitored for liver toxicity.
Peripheral neuropathy is a dose-related clinical toxicity that is characterized by numbness, tingling or pain in the hands and feet. Therapy should be withdrawn immediately. Symptoms may temporarily worsen following discontinuation of Aspen Stavudine. Should symptoms resolve satisfactorily, then a lower dose therapy may be considered (see “DOSAGE AND DIRECTIONS FOR USE”). Patients with either a history of neuropathy, or in the advanced stages of HIV infection or those using combination therapy of Aspen Stavudine with didanosine, are at greater risk for peripheral neuropathy and should be monitored closely.
Pancreatitis, either fatal or non-fatal, has been reported in patients on combination therapy with didanosine (with or without hydroxyurea). Combination therapy should be suspended should pancreatitis be suspected and reinstitution of stavudine therapy alone, once diagnosis is confirmed, should be undertaken with particular caution and close patient monitoring.

DOSAGE AND DIRECTIONS FOR USE:
Aspen Stavudine may be taken with food or on an empty stomach.
RECOMMENDED DOSAGE (based on body weight)
  ADULTS
Body weight: < 60 kg > 60 kg
Starting dose: 30 mg 40 mg
Interval: 12 hourly 12 hourly

DOSAGE ADJUSTMENT
  Peripheral Neuropathy Hepatic impairment Renal impairment
Adjusted: Withdraw therapy immediately and if symptoms resolve satisfactorily treatment may be considered using half the normal dosage No initial adjustment is necessary, however, in the event of rapidly elevating aminotransferase levels, discontinue all nucleoside analogue therapy May be administered to adults with renal impairment (refer to following table for dosage). No data is available for patients with a creatinine clearance below 10 mL/min or for those on dialysis

DOSAGE ADJUSTMENT for renal impairment
  Creatinine Clearance Patient weight
    < 60 kg > 60 kg
Adjusted: > 50 mL/min 30 mg every 12 hours 40 mg every 12 hours
  26-50 mL/min 15 mg every 12 hours 20 mg every 12 hours
  10-25 mL/min 15 mg every 24 hours 20 mg every 24 hours

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects
• Many serious adverse events reported from patients taking stavudine are consistent with the course of HIV infection. Since Aspen Stavudine is taken in combination with other antiretrovirals, it is difficult to distinguish whether the side-effects are due to Aspen Stavudine, the disease itself, or to other therapies.
• Aspen Stavudine produces dose-related peripheral neuropathy (see “WARNINGS”). This is seen most frequently in patients receiving = 2 mg/kg/day and symptoms usually resolved when the dose was reduced or stopped.
• An asymptomatic rise in AST (SGOT) and ALT (SGPT) liver enzymes (less than 5 times the upper limit of normal) can occur in patients with less advanced HIV infection (median CD4 count, 250 cells/mm) receiving Aspen Stavudine together with zidovudine.
• Less frequent occurrences of lactic acidosis, which can be fatal in some instances have been reported, and in some cases associated with severe hepatic steatosis. (see “WARNINGS”).
• Hepatitis or liver failure, which can be fatal in some instances, has been reported (see “SPECIAL PRECAUTIONS”).
• Pancreatitis is usually an indication of an advanced disease state. It can also be associated when combination therapy is given. Patients who have a history of pancreatitis, have an increased risk of recurrence (see “WARNINGS”).
• Other adverse events reported without regard to casualty, include:
Body as a whole:
  o abdominal pain
  o pain
  o neck pain
  o pelvic pain
  o back pain
  o malaise
  o headache
  o infection
  o chills/fever
  o allergic reaction
  o neoplasms
  o enlarged abdomen
  o abscess/cyst
  o asthenia
  o hernia
  o neck rigidity
  o face oedema
  o mucous membrane disorders
Cardiovascular:
  o chest pain
  o vasodilation
  o syncope
  o hypertension
  o peripheral vascular disorder
  o angina pectoris
  o haemorrhage
  o tachycardia
Gastro-intestinal:
  o diarrhoea
  o nausea & vomiting
  o anorexia
  o dyspepsia
  o dysphagia
  o flatulence
  o constipation
  o rectal disorder and haemorrhage
  o tooth disorder and pain
  o dry mouth
  o ulcerative stomatitis
  o aphthous stomatitis
  o gingivitis
  o glossitis
  o malaena
  o oesophagitis
  o gastritis
  o hepatomegaly
  o increased appetite
  o pancreatitis
  o tooth caries
  o tongue discolouration
Haematologic/Lymphatic
  o lymphadenopathy
  o ecchymosis
  o hepatosplenomegaly
Metabolic/Nutritional
  o weight loss
  o oedema
  o dehydration
  o thirst
  o weight gain
Musculoskeletal
  o myalgia and arthralgia
  o bone pain
  o arthrosis
  o bursitis
  o generalised spasm
  o myasthaenia gravis
Neurologic:
  o peripheral neurological symptoms not requiring dose modification
  o insomnia
  o depression
  o anxiety
  o neuropathy requiring dose modification:
  o nervousness
  o dizziness
  o confusion
  o amnesia
  o somnolence
  o tremor
  o vertigo
  o neuralgia
  o abnormal dreams
  o convulsion
  o drug dependence
  o abnormal thinking
  o migraine
  o twitching
  o decreased reflexes
  o hypoaesthesia
  o hypertonia
Respiratory:
  o rhinitis
  o cough
  o pharyngitis
  o respiratory disorder
  o dyspnoea
  o pneumonia
  o bronchitis
  o sinusitis
  o epistaxis
  o lung disorder
  o asthma
  o haemoptysis
  o laryngitis
  o increased sputum
  o voice alteration
Skin and Appendages
  o pruritus and rashes
  o sweating
  o dry skin
  o fungal dermatitis
  o skin lesions
  o maculopapular rash
  o nail disorder
  o folliculitis
  o benign neoplasm of the skin
  o seborrhoea
  o alopecia
  o skin ulcer
  o skin nodules
  o contact dermatitis
  o urticaria
  o eczema
  o furunculosis
  o herpes simplex
  o herpes zoster
  o skin discolouration
  o psoriasis
  o vesiculobullous rash
  o pustular rash
Special Senses:
  o ear/eye disorder
  o ear/eye pain
  o conjunctivitis
  o abnormal vision
  o otitis media/externa
  o conjuctival oedema
  o deafness
  o dry eye
  o eye infection
  o tinnitus
  o lachrymation disorder
Urogenital:
  o dysuria
  o urinary tract infection
  o impaired urination
  o vaginitis
  o impotence
  o genital pain
  o urogenital neoplasm
  o dysmenorrhea
  o frequent urination
  o penis disorder
  o haematuria
Laboratory Abnormalities: (*ULN = upper limit of normal)
  o AST (SGOT) >5 x ULN
  o ALT (SGPT) >5 x ULN
  o Alkaline phosphate >5 x ULN
  o Bilirubin >2.5 x ULN
  o Neutropaenia <750 neutrophils/mm³
  o Thrombocytopaenia <50 000 platelets/mm³
  o Anaemia <8 g/dL
  o Amylase >1.0 x ULN
Special Precautions
PERIPHERAL NEUROPATHY: Stavudine should be used with caution in patients with a history of peripheral neuropathy. Treatment must be suspended if peripheral neuropathy develops; if symptoms resolve on withdrawal, stavudine may be resumed at half the previous dose (see “WARNINGS”and “DOSAGE AND DIRECTIONS FOR USE)
PANCREATITIS: Patients with a history of pancreatitis should also be observed carefully for signs of pancreatitis during treatment with stavudine (see “WARNINGS”and “DOSAGE AND DIRECTIONS FOR USE).
LACTIC ACIDOSIS: Rare occurrences of lactic acidosis, usually with severe hepatic steatosis have been reported and in some cases have been fatal with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. In the event of raised aminotransferase levels, raised blood bilirubin, hepatomegaly, or metabolic/lactic acidosis, discontinuation of all nucleoside analogues should be considered (see “WARNINGS”). Didanosine and stavudine are contra-indicated in pregnancy since their use has resulted in fatal lactic acidosis (see “CONTRA-INDICATIONS”)
HEPATIC DYSFUNCTION: In patients with pre-existing liver dysfunction where the condition is deteriorating, discontinuation of nucleoside analogues should be considered (see “DOSAGE AND DIRECTIONS FOR USE”).
LABORATORY TESTS: A mild to moderate increase in ALT (SGPT) and AST (SGOT) is noticed when using stavudine. If these rise significantly, dosage modification may be required (see “DOSAGE AND DIRECTIONS FOR USE”).
LACTOSE INTOLERANCE: Aspen Stavudine capsules contain lactose. The amount however is insignificant to produce symptoms of lactose intolerance.
Interactions
The intracellular activation of Aspen Stavudine and hence its antiviral effect may be inhibited by zidovudine and doxorubicin. Zidovudine should not be used in combination with stavudine since zidovudine competitively inhibits the intracellular phosphorylation of stavudine. No interaction was seen between stavudine and didanosine.
Concurrent administration of Aspen Stavudine with other drugs known to cause pancreatitis (eg. intravenous pentamidine) or peripheral neuropathy (eg. metronidazole, isoniazid, and vincristine) should be avoided if possible.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Medications that may cause peripheral neuropathy, such as:
Chloramphenicol, cisplatin, dapsone, didanosine, ethambutol, ethionamide, hydralazine, isoniazid, lithium, metronidazole, nitrofurantoin, phenytoin, vincristine, zalcitabine (since stavudine has been shown to cause peripheral neuropathy other medications associated with the development of neuropathy should be avoided during stavudine therapy or, if concurrent use is necessary, used with caution).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Treatment is supportive and symptomatic.

IDENTIFICATION:
ASPEN STAVUDINE 15 mg (Capsules):
A no. 3 capsule with a brown cap and yellow body containing a white to off white free flowing powder.
ASPEN STAVUDINE 20 mg (Capsules):        Stavudine 20 mg
A no. 3 capsule with a yellow cap and yellow body containing a white to off white free flowing powder.
ASPEN STAVUDINE 30 mg (Capsules):        Stavudine 30 mg
A no. 2 capsule with a brown cap and orange body containing a white to off white free flowing powder.
ASPEN STAVUDINE 40 mg (Capsules):        Stavudine 40 mg
A no. 2 capsule with a brown cap and brown body containing a white to off white free flowing powder.

PRESENTATION:
60 capsules packed into one of the following:
  White, round, rigid plastic container (150 mL TRaCeR® PACK) with a silica gel sachet and sealed with a white “child-proof” snap-on tamper evident plastic cap.
  White, opaque, plastic, round jar (securitainer) with a foam insert and sealed with a white plastic, tamper evident snap-on cap.
  Amber glass jar with a silica gel sachet and sealed with a white screw cap lined with an EXPE liner
  White metallised lay flat “bank bag” (Patient-ready pack), sealed with a perforated tear line.

STORAGE INSTRUCTIONS:
Store below 25°C in tightly closed containers.
Protect from moisture and light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
Aspen Stavudine 15 mg:         37/20.2.8/0110
Aspen Stavudine 20 mg:         37/20.2.8/0111
Aspen Stavudine 30 mg:         37/20.2.8/0112
Aspen Stavudine 40 mg:         37/20.2.8/0113

NAME AND BUSINESS ADDRESS OF APPLICANT:
PHARMACARE LIMITED
7 Fairclough Road
Korsten
Port Elizabeth
6020
South Africa

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
25 April 2003

New addition to this site: September 2005
Source: Pharmaceutical Industry

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