Dosage adjustments of ASPEN ZIDOVUDINE SYRUP in combination with other antiretroviral medicines
Dosage adjustments for each medicine should follow the dosing guidelines for the individual medicine.
For severe adverse events, where the causative agent is unclear, or those persisting after dose interruption or reduction of one medicine, the other medicine should also be interrupted or dose reduced.
The medical practitioner should refer to the package insert of the other antiretroviral medicines for a description of known adverse reactions.
Dosage in the elderly
Zidovudine pharmacokinetics have not been studied in patients over 65 years of age and no specific data are available. Due to age-associated changes such as the decrease in renal function and alterations in haematological parameters in this age group, special care is advised with the use of ASPEN ZIDOVUDINE SYRUP.
Appropriate monitoring of these patients before and during ASPEN ZIDOVUDINE SYRUP therapy is advised.
Dosage in renal impairment
Patients with advanced renal failure have a 50% higher maximum plasma concentration of zidovudine compared to healthy individuals. Systemic exposure to zidovudine (measured as the area under the time-concentration curve) is increased 100%; the half-life is not significantly altered. There is substantial accumulation of the major glucuronide metabolite in renal failure, but this does not appear to cause toxicity.
In patients with severe renal impairment on peritoneal or haemodialysis daily dosages of 300 mg to 400 mg in 3 to 4 divided dosages should be appropriate.
Haematological parameters and clinical response may influence the need for subsequent dosage adjustment. Haemodialysis and peritoneal dialysis have no significant effect on the elimination of zidovudine but enhance the elimination of the glucuronide metabolite. Dosage in hepatic impairment
There are only limited data available therefore precise dosage recommendations cannot be made, but dosage adjustments may be necessary. Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Medical practitioners will need to monitor for signs of intolerance and adjust the dose and/or increase the interval between doses as appropriate.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The adverse event profile appears to be similar for adults and children.
The most serious adverse reactions include anaemia, usually occurring after six weeks of therapy but occasionally earlier and often requiring transfusions; neutropenia, usually occurring at any time after 4 weeks of therapy but sometimes earlier; and leucopenia, which is usually secondary to neutropenia. Thrombocytopenia, pancytopenia with marrow hypoplasia have also been reported.
Anaemia, neutropenia, and leucopenia occur more frequently at higher dosages of 1 200 to 1 500 mg/day, and in patients with advanced HIV disease, especially where there is poor bone marrow reserve prior to treatment, and particularly in patients with low T4 (T-helper) cell counts (less than 100/mm3). Dosage reduction or cessation of therapy may become necessary (see DOSAGE AND DIRECTIONS FOR USE). The incidence of neutropenia was also increased in patients with pre-existing neutropenia or anaemia, those with low vitamin 612 levels and those taking paracetamol concomitantly (see Interactions).
The following events have also been reported in patients treated with ASPEN ZIDOVUDINE SYRUP. The relationship between these events and the use of ASPEN ZIDOVUDINE SYRUP may be difficult to evaluate, particularly in medically complicated situations that characterise advanced HIV disease.
A reduction in dose of ASPEN ZIDOVUDINE SYRUP therapy may be warranted in the management of these conditions.
Nausea, vomiting, pigmentation of the oral mucosa, abdominal pain, dyspepsia, anorexia, diarrhoea, flatulence
Liver disorders such as severe hepatomegaly with steatosis, raised blood levels of liver enzymes and bilirubin, pancreatitis
Lactic acidosis in the absence of hypoxia (see Special Precautions)
Muskuloskeletal system disorders:
Myalgia, myopathy, asthenia
Skin and appendages:
Nail and skin pigmentation, rash, urticaria, pruritis, sweating
Respiratory system disorders:
Dyspnoea, cough, chest pain
Central and Peripheral Nervous system disorders:
Headache, dizziness, insomnia, paraesthesia, somnolence, loss of mental acuity, convulsions
Genito-urinary system disorders:
Urinary frequency, gynaecomastia Special senses disorders:
Body as whole:
Fever, malaise, generalised pain, chills, influenza-like syndrome
Haematological parameters should be carefully monitored. It is recommended that blood tests be performed at least every two weeks for the first three months of therapy and at least once a month thereafter for patients with advanced symptomatic HIV disease. Haematological toxicity is less frequent in patients with early HIV disease, where bone marrow reserve is generally good. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months. If the haemoglobin level falls to between 7,5 g/dL (4,65 mmol/L) and 9 g/dL (5,59 mmol/L) or whose neutrophil count falls to between 0,75 x 109/L and 1,0 x 109/L, the daily dosage may be reduced until there is evidence of marrow recovery. Alternatively, recovery may be enhanced by a brief 2 to 4 weeks interruption of ASPEN ZIDOVUDINE SYRUP therapy. Marrow recovery is usually observed within 2 weeks after which time ASPEN ZIDOVUDINE SYRUP therapy may be restarted at a reduced dose. Dosage adjustments do not necessarily eliminate the need for transfusions in patients with significant anaemia (see Side-effects).
Lactic acidosis/severe hepatomegaly with steatosis:
Long-term use of ASPEN ZIDOVUDINE SYRUP can result in potentially fatal lactic acidosis. Symptomatic hyperlactataemia and lactic acidosis are uncommon. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase.
In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal <2 mmol/L), and respond as follows:
|–||Lactate 2 – 5 mmol/L : monitor regularly, and be alert for clinical signs.|
|–||Lactate 5 – 10 mmol/L without symptoms : monitor closely.|
|–||Lactate 5 – 10 mmol/L with symptoms : STOP all therapy. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma).|
|–||Lactate 5 – 10 mmol/L : STOP all therapy (80% mortality in case studies).|
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level.
Blood for lactate assays should be heparinised and stored on ice.
After recovery, NRTI’s should be avoided. Seek expert advice on medicine selection. The above lactate values may not be applicable to paediatric patients.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of ASPEN ZIDOVUDINE SYRUP alone or in combination for the treatment of HIV infection. Most cases were women. Caution should be exercised when administering ASPEN ZIDOVUDINE SYRUP to patients with known risk factors to liver disease. Treatment with ASPEN ZIDOVUDINE SYRUP should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Prevention of mother-to-foetus transmission
The long-term consequences of in utero and infant exposure to ASPEN ZIDOVUDINE SYRUP are unknown.
Low haemoglobin concentrations have been reported in infants exposed to zidovudine for this indication, but transfusion was not required. Anaemia resolved within 6 weeks after completion of zidovudine therapy.
To avoid the transmission of HIV to their infants women infected with HIV should not breast-feed.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Symptoms or signs such as fatigue, headache, vomiting, and reports of haematological disturbances, have been identified following acute over-dosage with zidovudine. Reported blood levels of zidovudine over 16 times the normal therapeutic level did not present with any short-term clinical, biochemical, or haematological sequelae in the patient.
Haemodialysis appears to have a limited effect on elimination of zidovudine but enhances the elimination of the inactive glucuronide metabolite.
TREATMENT IS SYMPTOMATIC AND SUPPORTIVE.
200 mL glass amber medical round bottles closed with a white tamper evident 28 mm duet cap or 250 mL white HDPE bottle closed with a white screwcap type polypropylene closure.
Store below 25°C in tightly closed containers. Protect from moisture and light.
KEEP OUT OF REACH OF CHILDREN.