Retrovir IV for Infusion

/ GSK

The required dose of Retrovir IV for Infusion must be administered by slow intravenous infusion of the diluted product over a one-hour period.
Retrovir IV for Infusion must NOT be given intramuscularly.
Dilution: Retrovir IV for Infusion must be diluted prior to administration.
Adults: A dose for Retrovir IV for Infusion of 1 or 2 mg zidovudine/kg bodyweight every 4 hours provides similar exposure (AUC) to an oral dose of 1.5 or 3.0 mg zidovudine/kg every 4 hours (600 or 1200 mg/day for a 70 kg patient). The current recommended oral dose of Retrovir is 250 or 300 mg twice daily. This current dose is used as part of a multi-drug treatment regimen.
Patients should receive Retrovir IV for Infusion only until oral therapy can be administered.
Children: Limited data are available on the use of Retrovir IV for Infusion in children. A range of intravenous dosages between 80-160 mg/m² every 6 hours (320-640 mg/m²/day) have been used. Exposure following the 120 mg/m² dose every 6 hours approximately corresponds to an oral dose of 180 mg/m² every 6 hours. An oral dose of Retrovir of 360 to 480 mg/m² per day approximately corresponds to an intravenous dose of 240-320 mg/m²/day.
Dosage in the prevention of maternal-foetal transmission: Pregnant women (over 14 weeks of gestation) should be given 500 mg/day orally (100 mg five times per day) until the beginning of labour. During labour and delivery Retrovir should be administered intravenously at 2 mg/kg bodyweight given over one hour followed by a continuous intravenous infusion at 1 mg/kg/h until the umbilical cord is clamped.
The newborn infants should be given 2 mg/kg bodyweight orally every 6 hours starting within 12 hours after birth and continuing until 6 weeks-old (e.g. a 3 kg neonate would require a 0.6 ml dose of oral solution every 6 hours). Infants unable to receive oral dosing should be given Retrovir intravenously at 1.5 mg/kg bodyweight infused over 30 minutes every 6 hours.
In case of planned caesarean, the infusion should be started 4 hours before the operation. In the event of a false labour, the Retrovir infusion should be stopped and oral dosing restarted.
Dosage adjustments in patients with haematological adverse reactions: Substitution of zidovudine should be considered in patients whose haemoglobin level or neutrophil count fall to clinically significant levels. Other potential causes of anaemia or neutropenia should be excluded. Retrovir dose reduction or interruption should be considered in the absence of alternative treatments.
Elderly: Zidovudine pharmacokinetics have not been studied in patients over 65 years of age and no specific data are available. However, since special care is advised in this age group due to age-associated changes such as the decrease in renal function and alterations in haematological parameters, appropriate monitoring of patients before and during use of Retrovir is advised.
Renal impairment: In patients with severe renal impairment, the recommended IV dosage is 1 mg/kg 3-4 times daily. This is equivalent to the current recommended oral daily dosage for this patient group of 300 – 400 mg allowing for oral bioavailability of 60-70%.
Haematological parameters and clinical response may influence the need for subsequent dosage adjustment. For patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6-8 hrs (300 mg – 400 mg daily).
Hepatic impairment: Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage reductions may be necessary but, due to the large variability in zidovudine exposures in patients with moderate to severe liver disease, precise recommendations cannot be made. If monitoring of plasma zidovudine levels is not feasible, physicians will need to monitor for signs of intolerance, such as the development of haematological adverse reactions (anaemia, leucopenia, neutropenia) and reduce the dose and/or increase the interval between doses as appropriate.

Retrovir IV for Infusion is indicated for the short-term management of serious manifestations of Human Immunodeficiency Virus (HIV) infection in patients with Acquired Immune Deficiency Syndrome (AIDS) who are unable to take Retrovir oral formulations.
Retrovir chemoprophylaxis, is indicated for use in HIV-positive pregnant women (over 14 weeks of gestation) for prevention of maternal-foetal HIV transmission and for primary prophylaxis of HIV infection in newborn infants. Retrovir IV should only be used when oral treatment is not possible (except during labour and delivery).

Hypersensitivity to zidovudine, or to any of the excipients.
patients with abnormally low neutrophil counts (less than 0.75 x 10⁹/litre) or abnormally low haemoglobin levels (less than 7.5 g/decilitre or 4.65 mmol/litre).
Newborn infants with hyperbilirubinaemia requiring treatment other than phototherapy, or with increased transaminase levels of over five times the upper limit of normal.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Retrovir is not a cure for HIV infection or AIDS. Patients receiving Retrovir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection.
The concomitant use of rifampicin or stavudine with zidovudine should be avoided.
Haematological Adverse Reactions: Anaemia (usually not observed before six weeks of Retrovir therapy but occasionally occurring earlier), neutropenia (usually not observed before four weeks’ therapy but sometimes occurring earlier) and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving Retrovir; These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease.
Haematological parameters should be carefully monitored. For patients with advanced symptomatic HIV disease it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.
Depending on the overall condition of the patient, blood tests may be performed less often, for example every 1 to 3 months.
Lactic acidosis: lactic acidosis usually associated with hepatomegaly and hepatic steatosis has been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with zidovudine should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering zidovudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
See prescribing information for full details.

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia.
These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³. Dosage reduction or cessation of therapy may become necessary.
The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of Retrovir therapy.
See prescribing information for full details.

Limited data suggests that co-administration of zidovudine with rifampicin decreases the AUC (area under the plasma concentration curve) of zidovudine by 48% ± 34%. This may result in a partial loss or total loss of efficacy of zidovudine. The concomitant use of rifampicin with zidovudine should be avoided.
Zidovudine in combination with stavudine is antagonistic in vitro. The concomitant use of stavudine with zidovudine should be avoided.
Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be closely monitored for haematological toxicity.
A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin blood levels have been reported to be low in some patients receiving Retrovir, while in one patient a high level was noted. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both drugs.
Atovaquone: zidovudine does not appear to affect the pharmacokinetics of atovaquone.
However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%).
At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine.
Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy.
Valproic acid, fluconazole or methadone when co-administered with zidovudine have been shown to increase the AUC with a corresponding decrease in its clearance. As only limited data are available the clinical significance of these findings is unclear but if zidovudine is used concurrently with either valproic acid, fluconazole or methadone, patients should be monitored closely for potential toxicity of zidovudine.
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia. Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive drugs (eg. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant therapy with any of these drugs is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.
Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine with cotrimoxazole, aerosolised pentamidine, pyrimethamine and aciclovir at doses used in prophylaxis.

Pregnancy: As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV.
A large amount of data on pregnant women (more than 3000 outcomes from first trimester and more than 3000 outcomes from second and third trimester exposure) indicate no malformative toxicity. Retrovir can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on the mentioned large amount of data.
Breast-feeding: After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. It is recommended that mothers infected by HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Symptoms and signs: Dosages as high as 7.5 mg/kg by infusion every four hours for two weeks have been administered to five patients. One patient experienced an anxiety reaction while the other four had no untoward effects.
No specific symptoms or signs have been identified following acute oral overdose with zidovudine apart from those listed as undesirable effects such as fatigue, headache, vomiting, and occasional reports of haematological disturbances. Following a report where a patient took an unspecified quantity of zidovudine with serum levels consistent with an overdose of greater than 17 g there were no short term clinical, biochemical or haematological sequelae
identified.
Treatment: Patients should be observed closely for evidence of toxicity and given the necessary supportive therapy.
Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine but enhance the elimination of the glucuronide metabolite.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.