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ZERIT 15 mg Capsule
ZERIT 20 mg Capsule
ZERIT 30 mg Capsule
ZERIT 40 mg Capsule
ZERIT 1 mg/mL Powder for oral solution

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ZERIT 15 mg Capsule
ZERIT 20 mg Capsule
ZERIT 30 mg Capsule
ZERIT 40 mg Capsule
ZERIT 1 mg/mL Powder for oral solution

WARNING Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of Zerit alone or in combination. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other anti-retroviral agents (See Contraindications, Side Effects and Special Precautions.) The combination of stavudine and didanosine should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk. Fatal and non-fatal pancreatitis have occurred during therapy when ZERIT was part of a combination regimen that included didanosine in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. The combination of ZERIT and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring. The new regimen should contain neither didanosine nor hydroxyurea.

COMPOSITION
Capsules containing stavudine (15 mg, 20 mg, 30 mg and 40 mg). Powder for oral solution containing stavudine (1 mg/mL of constituted solution). The reconstituted powder for oral solution contains methylparaben 0,15% m/v and propylparaben 0,015% m/v, as preservatives.

PHARMACOLOGICAL CLASSIFICATION
A 20.2.8 Antiviral agents.

PHARMACOLOGICAL ACTION
ZERIT contains stavudine, a synthetic thymidine nucleoside analogue active against the Human Immunodeficiency Virus (HIV).
Stavudine inhibits the replication of HIV in human cells in vitro. It is phosphorylated by cellular kinases to stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural substrate, deoxythymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain termination due to a lack of the 3'-hydroxyl group necessary for DNA elongation. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma markedly reducing synthesis of mitochondrial DNA. Its activity against cellular DNA polymerase alpha and beta is 100-fold less than against HIV reverse transcriptase.
Stavudine triphosphate has an intracellular half-life of 3½ hours in CEM T-cells and peripheral blood mononuclear cells.
Reductions in sensitivity to stavudine of some HIV-1 strains has been observed in in vitro selection studies and in some pairs of pretreatment and posttreatment HIV-1 isolates from clinical studies. A genetic marker for in vivo resistance has yet to be identified. Some stavudine posttreatment isolates were resistant to didanosine and/or zidovudine.
In vitro studies of cytopathic effects of HIV-1 on CEM T-cells demonstrated additive antiviral effect with the combination of stavudine with didanosine at various molar ratios and synergistic antiviral effects with combinations of stavudine and zalcitabine. Additive antiviral activity was observed with the combination of stavudine and zidovudine at molar ratios of 100 and 500 (stavudine to zidovudine); an antagonistic antiviral effect was seen at a molar ratio of 20. Zidovudine in combination with Zerit is not recommended (see Interactions.)

PHARMACOKINETICS
Adults: Stavudine is rapidly absorbed following oral administration. Mean absolute bioavailability is 86.4%. Peak plasma concentrations (Cmax) occur 1 hour after dosing and increase in a dose-related manner.
A study in asymptomatic HIV-infected patients demonstrated that systemic exposure (area under the plasma concentration time curve) is similar whether stavudine is administered under fasting conditions or after a standardized high fat meal.
Serum protein binding is negligible. Stavudine distributes equally between red blood cells and plasma. Following a single 40 mg oral dose of stavudine in healthy subjects, mean cerebrospinal fluid (CSF) concentration was 63 ng/mL (range 44 to 71 ng/mL) at 4 to 5 hours post dose. Mean CSF in plasma concentration ratio was 40%.
The metabolism of stavudine in humans has not been elucidated. After incubation of human liver slices with stavudine for 6 hours, 87% of the radioactivity was accounted for by the parent compound, 2% was metabolized to thymine, and 7% was associated with unidentified polar compounds.
The mean terminal elimination half-life is 1.44 hours following single oral doses and is independent of dose. Renal elimination accounts for approximately 40% of overall clearance. Mean renal clearance is approximately twice the mean endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.
Children: Studies in HIV infected paediatric patients demonstrated a mean absolute bioavailability of stavudine of 78.5% and 69.2% following oral administration of capsule and solution formulations, respectively. Pharmacokinetic profiles are similar after the first-dose and in steady state, with no accumulation of stavudine at the dosages employed (0.125 to 2 mg/kg every 12 hours). Mean volume of distribution is 0.68 litres/kg following intravenous infusions. Cerebrospinal fluid concentrations correspond to 16% to 97% of simultaneous plasma concentrations. Mean terminal elimination half-life after a single oral dose is 0.91 hours.
Renal Insufficiency: The clearance of stavudine decreases as creatinine clearance decreases; therefore, it is recommended that the dosage of ZERIT be adjusted in patients with reduced renal function. (see DOSAGE AND DIRECTIONS FOR USE).
Hepatic Insufficiency: The pharmacokinetics of stavudine in patients with hepatic impairment are similar to those in patients with normal hepatic function. Therefore no initial adjustment of dose is necessary (see DOSAGE AND DIRECTIONS FOR USE).

INDICATIONS
ZERIT is indicated in combination with other antiretroviral agents, for the treatment of adults and children 6 months and older with HIV infection.
Monotherapy is not recommended.

CONTRA-INDICATIONS
ZERIT is contra-indicated in patients with hypersensitivity to stavudine or to any components of the formulations.
Pregnancy and Lactation: Safe use in pregnancy has not been established. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents.
It is not known whether stavudine is excreted in human milk.
Mothers should therefore be instructed to discontinue nursing if they are receiving ZERIT, because of the potential for adverse reactions from stavudine in nursing infants.
Paediatric patients: Not recommended for use in children below 6 months of age.

WARNINGS
Neurologic symptoms:
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including ZERIT. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy.
An important toxicity of ZERIT is peripheral neuropathy, which is dose-related and occurs more frequently in patients with advanced HIV infection, a history of neuropathy, or concurrent neurotoxic medication, including didanosine (See side effects.)
Pancreatitis: See boxed warning
Lactic Acidosis:
Patients should be informed of the importance of early recognition of symptoms of lactic acidosis, which include abdominal discomfort, sudden unexplained weight loss, nausea, vomiting, fatigue, dyspnoea and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of ZERIT therapy may be required. (See boxed warning).
Lactic acidosis/severe hepatomegaly with steatosis/hepatic failure:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of Zerit alone or in combination. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other anti-retroviral agents. Particular caution should be exercised when administering ZERIT to any patient with known risk factors of liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain and sudden unexplained weight loss); respiratory symptoms (tachypnoea and dyspnoea); or neurologic symptoms (including motor weakness, see Neurologic Symptoms) might be indicative of symptomatic hyperlactatemia or lactic acidosis syndrome. Treatment with ZERIT should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.) An increased risk of hepatotoxicity may occur in patients treated with ZERIT in combination with didanosine and hydroxyurea compared to when ZERIT is used alone. Deaths attributed to hepatotoxicityhave occurred in patients receiving this combination. Patients treated with this combination should be closely monitored for signs of liver toxicity.
Zerit in combination with 3TC:
At present there are no results from controlled clinical trials evaluating the effect of therapy with Zerit plus 3TC on the clinical progression of HIV infection, such as the incidence of opportunistic infections or survival. Patients receiving this combination may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close observation of physicians experienced in the treatment of patients with HIV-associated diseases.

DOSAGE AND DIRECTIONS FOR USE
ZERIT may be taken without regard to meals.

Adults:	The recommended starting dosage based on body weight is as follows:
	40 mg every 12 hours for patients >60 kg
	30 mg every 12 hours for patients <60 kg
Paediatrics:	(older than 6 months)
	1 mg/kg every 12 hours for patients <30 kg
	30 mg every 12 hours for patients = 30 kg to <60 kg
	40 mg every 12 hours for patients = 60 kg.

Dosage Adjustment
a) Peripheral Neuropathy: Patients should be monitored for the development of peripheral neuropathy, which is usually characterized by numbness, tingling, or pain in the feet or hands. These symptoms may be difficult to detect in children (See WARNINGS.)
If these symptoms develop, ZERIT therapy should be interrupted. Symptoms may resolve if therapy is withdrawn promptly. Some patients may experience a temporary worsening of symptoms following discontinuation of therapy. If symptoms resolve satisfactorily, treatment with ZERIT may be considered using half the recommended dose. If peripheral neuropathy recurs after resumption of ZERIT, permanent discontinuation should be considered.
b) Hepatic Impairment: In patients with stable hepatic impairment, no initial adjustment is necessary. In the event of rapidly elevating aminotransferase levels, treatment with ZERIT should be suspended.
c) Renal Impairment:
Adults: ZERIT may be administered to adult patients with impaired renal function. The following dosages are recommended:

Creatinine Clearance (mL/min)	Recommended ZERIT Dosage by Patient Weight
	>60kg	<60kg
>50 *	40 mg every 12 hours*	30 mg every 12 hours*
26 - 50	20 mg every 12 hours	15 mg every 12 hours
<25 **	20 mg every 24 hours	15 mg every 24 hours

*	Normal dose, no adjustment necessary.
**	For patients undergoing haemodialysis, the daily dose of ZERIT should be administered after the completion of a scheduled haemodialysis session. On non dialysis days, ZERIT should be administered at the same time of day as it is on dialysis days.

There are insufficient data to recommend a dosage for patients with a creatinine clearance of <10ml/min or for patients undergoing dialysis.
Paediatrics:
Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, the clearance may be altered in paediatrics with renal impairment. Although there are insufficient data to recommend a specific dosage adjustment of ZERIT in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.
Constitution of Oral Solution: The powder for oral solution should be constituted with purified water to a 200 mL deliverable volume solution of 1 mg/mL stavudine. Add 202 mL of purified water to the original bottle. Shake well until powder is completely dissolved. The solution may remain slightly hazy. Instruct the patient to shake well prior to measuring each dose.
After constitution, store ZERIT solutions in tightly closed bottles under refrigeration (2°C to 8°C) for up to 30 days.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Lactic Acidosis:
Fatal lactic acidosis has occurred in patients treated with ZERIT in combination with other antiretroviral agents. Patients with suspected lactic acidosis shouldimmediately suspend therapy with ZERIT. Permanent discontinuation of ZERIT should be considered for patients with confirmed lactic acidosis. ZERIT therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, ZERIT should be discontinued.
Peripheral Neuropathy:
ZERIT therapy has also been associated with peripheral sensory neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with neurotoxic drug therapy, including didanosine, in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy.
Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the hands or feet. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy.
If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the dose (see Dosage and Directions for Use). If neuropathy recurs after resumption, permanent discontinuation of ZERIT should be considered.
Hepatic dysfunction:
Hepatitis or liver failure, which was fatal in some cases, have been reported (see Special Precautions and Warnings.)
Pancreatitis:
The occurrences were not dose-related and were ocassionally fatal. Patients with a history of pancreatitis appear to be at increased risk for recurrence (see Warnings).
When ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. Pancreatitis, peripheral neuropathy, and liver function abnormalities occur more frequently in patients treated with the combination of ZERIT and didanosine. Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with ZERIT in combination with didanosine (See warnings.)
Many of the serious adverse clinical events reported from patients receiving ZERIT in clinical trials are consistent with the course of HIV infection. Concurrent dosing with other medications was allowed in trials. Therefore, it is difficult to distinguish which effects are related to ZERIT, the disease itself, or to other therapies.
Fat Redistribution:
Redistribution/accumulation of body fat (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy (including stavudine). The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Selected clinical adverse events reported in monotherapy or combination trials are listed below:

Peripheral neurologic symptoms/neuropathy

Headache

Chills/fever

Diarrhoea

Rash

Nausea/vomiting

Abdominal pain

Myalgia

Insomnia

Anorexia

Allergic reaction

Pancreatitis

Other adverse events reported without regard to causality, include:
Body as a Whole: Infection, asthenia, pain, malaise, back pain, flu syndrome, accident injury, neoplasms, neck pain, enlarged abdomen, abscess, death, hernia, neck rigidity, pelvic pain, addiction, cyst, face edema, mucous membrane disorder.
Cardiovascular: Chest pain, vasodilation, syncope, hypertension, peripheral vascular disorder, angina pectoris, haemorrhage, tachycardia.
Gastrointestinal: Dyspepsia, rectal disorder, tooth disorder, flatulence, constipation, dry mouth, ulcerative stomatitis, dysphagia, tooth pain, aphthous stomatitis, gastrointestinal disorder, gingivitis, glossitis, melena, rectal hemorrhage, oesophagitis, gastritis, hepatomegaly, increased appetite, tongue discolouration, tooth caries.
Hematologic/Lymphatic: Lymphadenopathy, ecchymosis, hepatosplenomegaly, macrocytosis.
Metabolic/Nutritional: Weight loss, peripheral edema, edema, dehydration, thirst, weight gain, fat atrophy.
Musculoskeletal: Arthralgia, bone pain, arthrosis, bursitis, generalized spasm, myasthenia.
Neurologic: Peripheral neurological symptoms not requiring dosage modification, depression, anxiety, neuropathy requiring dosage modification, nervousness, dizziness, confusion, amnesia, somnolence, tremor, vertigo, neuralgia, abnormal dreams, convulsion, drug dependence, abnormal thinking, migraine, twitching, decreased reflexes, hypoesthesia, hypertonia.
Respiratory: Rhinitis, cough, pharyngitis, respiratory disorder, dyspnea, bronchitis, pneumonia, lung disorder, sinusitis, epistaxis, asthma, hemoptysis, laryngitis, increased sputum, voice alteration.
Skin and Appendages: Sweating, pruritus, fungal dermatitis, skin lesions, dry skin, folliculitis, maculopapular rash, benign neoplasm of the skin, seborrhoea, nail disorder, skin nodules, alopecia, contact dermatitis, skin disorder, skin ulcer, urticaria, eczema, furunculosis, herpes simplex, herpes zoster, skin discolouration, psoriasis, pustular rash, vesiculobullous rash.
Special Senses: Ear pain, conjunctivitis, abnormal vision, ear disorder, eye disorder, eye pain, otitis media, conjunctival oedema, deafness, dry eye, eye infection, lacrimation disorder, otitis externa, tinnitus.
Urogenital: Dysuria, vaginitis, urogenital neoplasm, genital pain, dysmenorrhea, urinary frequency, hematuria, impotence, penis disorder, urinary tract infection, urination impaired.
Laboratory Abnormalities: Selected laboratory abnormalities reported in patients receiving stavudine monotherapy and combination therapy in clinical trials are listed below. Laboratory abnormalities reported to occur in patients treated with ZERIT in combination therapy regimens in clinical trials were similar in type, but generally of lesser severity than those reported in patients with more advanced disease treated with monotherapy

AST (SGOT) > 5 x ULN*,

ALT (SGPT) > 5 x ULN,

alkaline phosphate > 5 x ULN,

bilirubin >2,5 x ULN,

neutropenia <750 neutrophilis/mm³,

thrombocytopenia <50 000 platelets/mm³,

anemia <8g/dL,

amylase >1.0 x ULN.

Also lipase and GGT. (*ULN = upper limit of normal).

Observed during clinical practise:
The following events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to ZERIT, or a combination of these factors:
Body as a whole: abdominal pain, allergic reaction, chills and fever.
Haematological disorders: thrombocytopenia, anaemia, leukopenia.
Liver: lactic acidosis and hepatic steatosis (see Warnings), hepatitis and liver failure.
Digestive: anorexia
Musculoskeletal: myalgia
Nervous system: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis, See Warnings).
Paediatric patients: Adverse events and clinical laboratory abnormalities were generally similar to those seen in adults and generally related to underlying disease.

Special Precautions
Lactic Acidosis:
Refer to Warnings section.
Hepatic Dysfunction:
Hepatitis or liver failure, which was fatal in some cases, has been reported with ZERIT. In patients with pre-existing liver dysfunction, discontinuation of all nucleoside analogues should be considered when worstening liver disease occurs.
Renal impairment:
The clearance of stavudine decreased as creatinine decreased; therefore, it is recommended that the dosage of ZERIT be adjusted in patients with reduced renal function (creatinine clearance <50 mL/min; see Dosage and Directions for Use.)
Laboratory Tests: Mild to moderate increases in AST (SGOT) and ALT (SGPT) occurred commonly in clinical trials but did not interfere with continued therapy. Clinically significant elevations of AST and ALT may require dosage modification (See Dosage and Directions for Use).
Geriatric use:
Clinical studies of ZERIT did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Greater sensitivity of some older individuals to the effects of ZERIT cannot be ruled out.
Diabetes Mellitus: The constituted powder for oral solution contains 50 mg sucrose per mL of constituted solution.
Lactose Intolerance: ZERIT capsules contain lactose; the amount however is probably insufficient to induce specific symptoms of intolerance.
Interactions:
It is postulated that zidovudine may competatively inhibit the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT is not recommended.
No pharmacokinetic interaction was observed between ZERIT and didanosine when co-administered in a clinical trial.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Experience with adults treated with 12 to 24 times the recommended daily dosage showed no acute toxicity. It is not known whether stavudine is eliminated by peritoneal dialysis. Haemodialysis: Stavudine can be removed by haemodialysis; clearance 120 +18 mL/min.

IDENTIFICATION

ZERIT 15 mg:	Opaque capsule, with a dark red cap and light yellow body, containing a white to light beige powder, "BMS" over "1964" in black ink on one end of the capsule and "15" on the other.
ZERIT 20 mg:	Opaque capsule, with a light brown cap and body, containing a white to light beige powder with “Zerit and the company logo”in black ink printed radially around the circumference of the cap, and “20”on the body.
ZERIT 30 mg:	Opaque capsule, with a dark orange cap and light orange body, containing a white to light beige powder, with" Zerit and the company logo” in black ink printed radially around the circumference of the cap, and "30" on the body.
ZERIT 40 mg:	Opaque capsule, dark orange cap and body containing a white to light beige powder with “Zerit and the company logo”in black ink printed radially around the circumference of the cap, and "40" on the body.

ZERIT 1 mg/mL Powder for oral Solution:
Powder: Off-white to pale pink gritty powder.
Constituted Solution: Colourless to slightly pink, hazy, colloidal solution.

PRESENTATION
ZERIT CAPSULES:
Blister packs of 56 capsules.
ZERIT POWDER FOR ORAL SOLUTION:
200 mL high density polyethylene (plastic) bottles with child-resistant screw cap.

STORAGE INSTRUCTIONS
ZERIT capsules and powder for oral solution should be stored at room temperature not exceeding 25°C in tightly closed containers. Protect from light.
After constitution, store ZERIT solutions in tightly closed bottles under refrigeration (2°C to 8°C) for up to 30 days.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS
ZERIT 15 mg Capsule: 32/20.2.8/0264
ZERIT 20 mg Capsule: 32/20.2.8/0265
ZERIT 30 mg Capsule: 32/20.2.8/0266
ZERIT 40 mg Capsule: 32/20.2.8/0267
ZERIT 1 mg/ml Powder for oral solution: 32/20.2.8/0268

pp Zimbabwe only:
Zerit 30 mg capsule: 2001/7.13/3934
Zerit 40 mg capsule: 2001/7.13/3935
Zerit 1 mg/mL powder for oral solution: 2001/7.13/3936

NAME AND ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd*
47 Van Buuren Road
Bedfordview
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
July 2002

Authorised user of the TM ZERIT

Updated on this site: June 2005
Source: Pharmaceutical Industry
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