RETROVIR 10 MG/ML IV CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance: ZIDOVUDINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Retrovir 10 mg/ml IV Concentrate for Solution for Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Vials containing zidovudine 200 mg in 20ml solution (10 mg zidovudine/ml)
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion (Sterile concentrate)
Retrovir IV for Infusion is a clear, nearly colourless, sterile aqueous solution with a
pH of approximately 5.5.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
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. If at all possible Retrovir IV should not be used as monotherapy for this
indication (see section 5.1).
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 –
see section 4.2).

4.2

Posology and method of administration

Retrovir should be prescribed by physicians who are experienced in the treatment of
HIV infection.
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 (see section
6.6).
Dosage in 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.
Dosage in 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 (see sections 4.3 and 4.4).
Dosage in the 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.
Dosage in 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) (see section 5.2).
Dosage in 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 (see section 4.4).

4.3

Contraindications
Retrovir IV for Infusion is contra-indicated in patients known to be hypersensitive to
zidovudine, or to any of the excipients.
Retrovir IV for infusion should not be given to 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).
Retrovir is contra-indicated in newborn infants with hyperbilirubinaemia requiring
treatment other than phototherapy, or with increased transaminase levels of over five
times the upper limit of normal.

4.4

Special warnings and precautions for use
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 stavudine with zidovudine should be avoided (see
section 4.5).
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 IV for Infusion; These occurred more frequently at high dosages (12001500 mg/day orally) and in patients with poor bone marrow reserve prior to
treatment, particularly with advanced HIV disease (see section 4.8).
Haematological parameters should be carefully monitored. It is recommended that
blood tests are performed at least weekly in patients receiving Retrovir IV for
Infusion.

If the haemoglobin level falls to between 7.5 g/dl (4.65 mmol/l) and 9 g/dl
(5.59 mmol/l) or the 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 brief (2-4 weeks) interruption of Retrovir
therapy. Marrow recovery is usually observed within 2 weeks after which time
Retrovir therapy at a reduced dosage may be reinstituted. Data on the use of Retrovir
for periods in excess of 2 weeks are limited. In patients with significant anaemia,
dosage adjustments do not necessarily eliminate the need for transfusions (see section
4.3).
Lactic acidosis: lactic acidosis usually associated with hepatomegaly and hepatic
steatosis has been reported with the use of nucleoside analogues. 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 nucleoside analogues 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 nucleoside analogues 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.
Mitochondrial toxicity: Nucleoside and nucleotide analogues have been demonstrated
in vitro and in vivo to cause a variable degree of mitochondrial damage. There have
been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero
and/or post-natally to nucleoside analogues. The main adverse events reported are
haematological
disorders
(anaemia,
neutropenia),
metabolic
disorders
(hyperlactataemia, hyperlipasaemia). These events are often transitory. Some lateonset neurological disorders have been reported (hypertonia, convulsion, abnormal
behaviour). Whether the neurological disorders are transient or permanent is currently
unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even
HIV-negative children, should have clinical and laboratory follow-up and should be
fully investigated for possible mitochondrial dysfunction in case of relevant signs or
symptoms. These findings do not affect current recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.

Lipodystrophy: Combination antiretroviral therapy has been associated with the
redistribution of body fat (lipodystrophy) in HIV patients.
The long-term
consequences of these events are currently unknown. Knowledge about the
mechanism is incomplete. A connection between visceral lipomatosis and PIs and
lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has
been associated with individual factors such as older age, and with drug related
factors such as longer duration of antiretroviral treatment and associated metabolic
disturbances. Clinical examination should include evaluation for physical signs of fat
redistribution. Consideration should be given to the measurement of fasting serum
lipids and blood glucose. Lipid disorders should be managed as clinically appropriate
(see section 4.8).
Liver disease: Zidovudine clearance in patients with mild hepatic impairment without
cirrhosis [Child-Pugh scores of 5-6] is similar to that seen in healthy subjects,
therefore no zidovudine dose adjustment is required. In patients with moderate to
severe liver disease [Child-Pugh scores of 7-15], specific dosage recommendations
cannot be made due to the large variability in zidovudine exposure observed,
therefore zidovudine use in this group of patients is not recommended.
Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at an increased risk of severe and potentially fatal hepatic adverse events.
In case of concomitant antiviral therapy for hepatitis B or C, please also refer to the
relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have
an increased frequency of liver function abnormalities during combination
antiretroviral therapy and should be monitored according to standard practice. If there
is evidence of worsening liver disease in such patients, interruption or discontinuation
of treatment must be considered (see section 4.2).
Immune Reactivation Syndrome: In HIV-infected patients with severe immune
deficiency at the time of institution of combination antiretroviral therapy (CART), an
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise
and cause serious clinical conditions, or aggravation of symptoms. Typically, such
reactions have been observed within the first few weeks or months of initiation of
CART. Relevant examples are cytomegalovirus retinitis, generalized and/or focal
mycobacterial infections and Pneumocystis carinii pneumonia. Any inflammatory
symptoms should be evaluated and treatment instituted when necessary.
Patients should be cautioned about the concomitant use of self-administered
medications (see section 4.5).
Patients should be advised that Retrovir therapy has not been proven to prevent the
transmission of HIV to others through sexual contact or contamination with blood.
Osteonecrosis: Although the etiology is considered to be multifactorial (including
corticosteroid use, alcohol consumption, severe immunosuppression, higher body

mass index), cases of osteonecrosis have been reported particularly in patients with
advanced HIV-disease and/or long-term exposure to combination antiretroviral
therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Patients co-infected with hepatitis C virus: The concomitant use of ribavirin with
zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

4.5

Interaction with other medicinal products and other forms of interaction
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 (see section 4.4).
Zidovudine in combination with stavudine is antagonistic in vitro. The concomitant
use of stavudine with zidovudine should be avoided (see section 4.4).
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 (see section 4.4). 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 (e.g. systemic pentamidine, dapsone, pyrimethamine, cotrimoxazole, 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.

4.6

Pregnancy and lactation
Pregnancy:
The use of Retrovir in pregnant women over 14 weeks of gestation, with subsequent
treatment of their newborn infants, has been shown to significantly reduce the rate of
maternal-foetal transmission of HIV based on viral cultures in infants.
The results from the pivotal U.S. placebo-controlled study indicated that Retrovir
reduced maternal-foetal transmission by approximately 70%. In this study, pregnant
women had CD4 cell counts of 200 to 1818/mm3 (median in treated group 560/mm3)
and began treatment therapy between weeks 14 and 34 of gestation and had no
clinical indications for Retrovir therapy; their newborn infants received Retrovir until
6-weeks old.
A decision to reduce the risk of maternal transmission of HIV should be based on the
balance of potential benefits and potential risk. Pregnant women considering the use
of Retrovir during pregnancy for prevention of HIV transmission to their infants
should be advised that transmission may still occur in some cases despite therapy.
The efficacy of zidovudine to reduce the maternal-foetal transmission in women with
previously prolonged treatment with zidovudine or other antiretroviral agents or
women infected with HIV strains with reduced sensitivity to zidovudine is unknown.
It is unknown whether there are any long-term consequences of in utero and infant
exposure to Retrovir.

Based on the animal carcinogenicity/mutagenicity findings a carcinogenic risk to
humans cannot be excluded (see section 5.3). The relevance of these findings to both
infected and uninfected infants exposed to Retrovir is unknown. However, pregnant
women considering using Retrovir during pregnancy should be made aware of these
findings.
A large amount of data on pregnant women (more than 3000 exposed outcomes)
indicate no malformative nor feto/neonatal toxitcity. Retrovir can be used during
pregnancy if clinically needed. Retrovir should only be used prior to the 14th week
of gestation when the potential benefit to the mother and foetus outweigh the risks.
Studies in pregnant rats and rabbits given zidovudine orally at dosage levels up to 450
and 500 mg/kg/day respectively during the major period of organogenesis have
revealed no evidence of teratogenicity. There was, however, a statistically significant
increase in foetal resorptions in rats given 150 to 450 mg/kg/day and in rabbits given
500 mg/kg/day.
A separate study, reported subsequently, found that rats given a dosage of
3000 mg/kg/day, which is very near the oral median lethal dose (3683 mg/kg), caused
marked maternal toxicity and an increase in the incidence of foetal malformations.
No evidence of teratogenicity was observed in this study at the lower dosages tested
(600 mg/kg/day or less).
Fertility:
Zidovudine did not impair male or female fertility in rats given oral doses of up to
450 mg/kg/day. There are no data on the effect of Retrovir on human female fertility.
In men, Retrovir has not been shown to affect sperm count, morphology or motility.
Lactation:
Health experts recommend that women infected with HIV do not breast feed their
infants in order to avoid the transmission of HIV. 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. Therefore, since the drug and the
virus pass into breast milk it is recommended that mothers taking Retrovir do not
breast feed their infants.

4.7

Effects on ability to drive and use machines
Retrovir IV for Infusion is generally used in an in-patient hospital population and
information on ability to drive and use machinery is not usually relevant. There have
been no studies to investigate the effect of Retrovir on driving performance or the
ability to operate machinery. Furthermore, a detrimental effect on such activities
cannot be predicted from the pharmacology of the drug. Nevertheless, the clinical
status of the patient and the adverse reaction profile of Retrovir should be borne in
mind when considering the patient’s ability to drive or operate machinery.

4.8

Undesirable effects
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
(see section 4.4).
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.
The following events have been reported in patients treated with Retrovir.
The adverse events considered at least possibly related to the treatment (adverse drug
reactions, ADR) are listed below by body system, organ class and absolute frequency.
Frequencies are defined as Very common (greater than 10%), Common (1 - 10%),
Uncommon (0.1-1%), Rare (0.01-0.1%) and Very rare (less than 0.01%).
Blood and lymphatic system disorders
Common: Anaemia, neutropenia and leucopenia
Uncommon: Pancytopenia with bone marrow hypoplasia, thrombocytopenia
Rare: Pure red cell aplasia
Very rare: Aplastic anaemia
Metabolism and nutrition disorders
Rare: Lactic acidosis in the absence of hypoxaemia, anorexia
Psychiatric disorders
Rare: Anxiety and depression
Nervous system disorders
Very common: Headache
Common: Dizziness
Rare:Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence
Cardiac disorders
Rare: Cardiomyopathy
Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea
Rare: Cough
Gastrointestinal disorders
Very common: Nausea
Common: Vomiting, diarrhoea and abdominal pain
Uncommon: Flatulence
Rare: Oral mucosa pigmentation, taste disturbance and dyspepsia. Pancreatitis.
Hepatobiliary disorders
Common: Raised blood levels of liver enzymes and bilirubin
Rare: Liver disorders such as severe hepatomegaly with steatosis
Skin and subcutaneous tissue disorders
Uncommon: Rash and pruritis
Rare: Urticaria, nail and skin pigmentation, and sweating
Musculoskeletal and connective tissue disorders
Common: Myalgia
Uncommon: Myopathy
Renal and urinary disorders
Rare: Urinary frequency
Reproductive system and breast disorders
Rare: Gynaecomastia
General disorders and administration site disorders
Common: Malaise
Uncommon: Asthenia, fever, and generalised pain
Rare: Chest pain and influenza-like syndrome, chills
Experience with Retrovir IV for Infusion treatment for periods in excess of two
weeks is limited, although some patients have received treatment for up to 12 weeks.
The most frequent adverse reactions were anaemia, neutropenia and leucopenia.
Local reactions were infrequent.

The available data from studies of Retrovir Oral Formulations indicate that the
incidence of nausea and other frequently reported clinical adverse reactions
consistently decreased over time during the first few weeks of therapy with Retrovir.
Adverse reactions with Retrovir for the prevention of maternal-foetal transmission:
In a placebo-controlled trial, overall clinical adverse reactions and laboratory test
abnormalities were similar for women in the Retrovir and placebo groups. However,
there was a trend for mild and moderate anaemia to be seen more commonly prior to
delivery in the zidovudine treated women.
In the same trial, haemoglobin concentrations in infants exposed to Retrovir for this
indication were marginally lower than in infants in the placebo group, but transfusion
was not required. Anaemia resolved within 6 weeks after completion of Retrovir
therapy. Other clinical adverse reactions and laboratory test abnormalities were
similar in the Retrovir and placebo groups. It is unknown whether there are any longterm consequences of in utero and infant exposure to Retrovir.
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Cases of lactic acidosis, sometimes fatal, usually associated with severe
hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside
analogues (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat
(lipodystrophy) in HIV patients including the loss of peripheral and facial
subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and
dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities
such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance,
hyperglycaemia and hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of
combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally
acknowledged risk factors, advanced HIV disease or long-term exposure to
combination antiretroviral therapy (CART). The frequency of this is unknown (see
section 4.4).

4.9

Overdose
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 (see section 4.8) 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: nucleoside analogue , ATC code: J05A F01
Mode of action:
Zidovudine is an antiviral agent which is highly active in vitro against retroviruses
including the Human Immunodeficiency Virus (HIV).
Zidovudine is phosphorylated in both infected and uninfected cells to the
monophosphate (MP) derivative by cellular thymidine kinase. Subsequent
phosphorylation of zidovudine-MP to the diphosphate (DP), and then the triphosphate
(TP) derivative is catalysed by cellular thymidylate kinase and non-specific kinases
respectively. Zidovudine-TP acts as an inhibitor of and substrate for the viral reverse
transcriptase. The formation of further proviral DNA is blocked by incorporation of
zidovudine-MP into the chain and subsequent chain termination. Competition by
zidovudine-TP for HIV reverse transcriptase is approximately 100-fold greater than
for cellular DNA polymerase alpha.
Clinical virology:
The relationships between in vitro susceptibility of HIV to zidovudine and clinical
response to therapy remain under investigation. In vitro sensitivity testing has not

been standardised and results may therefore vary according to methodological factors.
Reduced in vitro sensitivity to zidovudine has been reported for HIV isolates from
patients who have received prolonged courses of Retrovir therapy. The available
information indicates that for early HIV disease, the frequency and degree of
reduction of in vitro sensitivity is notably less than for advanced disease.
The reduction of sensitivity with the emergence of zidovudine resistant strains limits
the usefulness of zidovudine monotherapy clinically. In clinical studies, clinical endpoint data indicate that zidovudine, particularly in combination with lamivudine, and
also with didanosine or zalcitabine results in a significant reduction in the risk of
disease progression and mortality. The use of a protease inhibitor in a combination of
zidovudine and lamivudine, has been shown to confer additional benefit in delaying
disease progression, and improving survival compared to the double combination on
its own.
The anti-viral effectiveness in vitro of combinations of anti-retroviral agents are being
investigated. Clinical and in vitro studies of zidovudine in combination with
lamivudine indicate that zidovudine-resistant virus isolates can become zidovudine
sensitive when they simultaneously acquire resistance to lamivudine. Furthermore
there is clinical evidence that zidovudine plus lamivudine delays the emergence of
zidovudine resistance in anti-retroviral naive patients.
In some in vitro studies zidovudine has been shown to act additively or
synergistically with a number of anti-HIV agents, such as lamivudine, didanosine,
and interferon-alpha, inhibiting the replication of HIV in cell culture. However, in
vitro studieswith triple combinations of nucleoside analogues or two nucleoside
analogues and a protease inhibitor have been shown to bemore effective in inhibiting
HIV-1 induced cytopathic effects than one or two drug combinations.
Resistance to thymidine analogues (of which zidovudine is one) is well characterised
and is conferred by the stepwise accumulation of up to six specific mutations in the
HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire
phenotypic resistance to thymidine analogues through the combination of mutations
at codons 41 and 215 or by the accumulation of at least four of the six mutations.
These thymidine analogue mutations alone do not cause high-level cross-resistance to
any of the other nucleosides, allowing for the subsequent use of any of the other
approved reverse transcriptase inhibitors.
Two patterns of multi-drug resistance mutations, the first characterised by mutations
in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second
involving a T69S mutation plus a 6-base pair insert at the same position, result in
phenotypic resistance to AZT as well as to the other approved nucleoside reverse
transcriptase inhibitors. Either of these two patterns of multinucleoside resistance
mutations severely limits future therapeutic options.
In the US ACTGO76 trial, Retrovir was shown to be effective in reducing the rate of
maternal-foetal transmission of HIV-1 (23% infection rate for placebo versus 8% for
zidovudine) when administered (100 mg five times a day) to HIV-positive pregnant
women (from week 14-34 of pregnancy) and their newborn infants (2 mg/kg every 6

hours) until 6 weeks of age. In the shorter duration 1998 Thailand CDC study, use of
oral Retrovir therapy only (300 mg twice daily), from week 36 of pregnancy until
delivery, also reduced the rate of maternal-foetal transmission of HIV (19% infection
rate for placebo versus 9% for zidovudine). These data, and data from a published
study comparing zidovudine regimens to prevent maternal-foetal HIV transmission
have shown that short maternal treatments (from week 36 of pregnancy) are less
efficacious than longer maternal treatments (from week 14-34 of pregnancy) in the
reduction of perinatal HIV transmission.

5.2

Pharmacokinetic properties
Adults:
Absorption:
Dose-independent kinetics were observed in patients receiving one-hour infusions of
1 to 5 mg/kg 3 to 6 times daily. Mean steady state peak (Cssmax) and trough (Cssmin)
plasma concentrations in adults following a one-hour infusion of 2.5 mg/kg every 4
hours were 4.0 and 0.4 µM, respectively (or 1.1 and 0.1 µg/ml).
Distribution:
The mean terminal plasma half-life was 1.1 hours, the mean total body clearance was
27.1 ml/min/kg and the apparent volume of distribution was 1.6 litres/kg.
In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio 2 to 4
hours after chronic intermittent oral dosing was found to be approximately 0.5. Data
indicate that zidovudine crosses the placenta and is found in amniotic fluid and foetal
blood. Zidovudine has also been detected in semen and milk.
Plasma protein binding is relatively low (34 to 38%) and drug interactions involving
binding site displacement are not anticipated.
Metabolism:
Zidovudine is primarily eliminated by hepatic conjugation to an inactive
glucoronidated metabolite. The 5’-glucuronide of zidovudine is the major metabolite
in both plasma and urine, accounting for approximately 50-80% of the administered
dose eliminated by renal excretion. 3’-amino-3’-deoxythymidine (AMT) has been
identified as a metabolite of zidovudine following intravenous dosing.
Excretion:
Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that
significant tubular secretion takes place.
Paediatrics:
Absorption:
In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is
similar to that in adults. Cssmax levels were 1.46 µg/ml following an intravenous dose
of 80 mg zidovudine/m2 body surface area, 2.26 µg/ml following 120 mg/m2 and
2.96 µg/ml following 160 mg/m2.
Distribution:
With intravenous dosing, the mean terminal plasma half-life and total body clearance
were 1.5 hours and 30.9 ml/min/kg respectively.

In children the mean cerebrospinal fluid/plasma zidovudine concentration ratio
ranged from 0.52-0.85, as determined during oral therapy 0.5 to 4 hours after dosing
and was 0.87 as determined during intravenous therapy 1-5 hours after a 1 hour
infusion.
During continuous intravenous infusion, the mean steady-state
cerebrospinal fluid/plasma concentration ratio was 0.24.
Metabolism:
The major metabolite is 5’-glucuronide. After intravenous dosing, 29% of the dose
was recovered unchanged in the urine and 45% excreted as the glucuronide.
Excretion:
Renal clearance of zidovudine greatly exceeds creatinine clearance indicating that
significant tubular secretion takes place.
The data available on the pharmacokinetics in neonates and young infants indicate
that glucuronidation of zidovudine is reduced with a consequent increase in
bioavailability, reduction in clearance and longer half-life in infants less than 14 days
old but thereafter the pharmacokinetics appear similar to those reported in adults.
Pregnancy:
The pharmacokinetics of zidovudine has been investigated in a study of eight women
during the third trimester of pregnancy. As pregnancy progressed, there was no
evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to
that of non-pregnant adults. Consistent with passive transmission of the drug across
the placenta, zidovudine concentrations in infant plasma at birth were essentially
equal to those in maternal plasma at delivery.
Elderly:
No specific data are available on the pharmacokinetics of zidovudine in the elderly.
Renal impairment:
Compared to healthy subjects, patients with advanced renal failure have a 50% higher
peak plasma concentration after oral administration. Systemic exposure (measured as
area under the zidovudine concentration time curve) is increased 100%; the half-life
is not significantly altered. In renal failure there is substantial accumulation of the
major glucuronide metabolite but this does not appear to cause toxicity.
Haemodialysis and peritoneal dialysis have no significant effect on zidovudine
elimination whereas elimination of the inactive glucuronide metabolite is increased.
(see section 4.2).
Hepatic impairment:
There are limited data concerning the pharmacokinetics of zidovudine in patients with
hepatic impairment (see section 4.2). No specific data are available on the
pharmacokinetics of zidovudine in the elderly.

5.3

Preclinical safety data
Mutagenicity:
No evidence of mutagenicity was observed in the Ames test. However, zidovudine
was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in
vitro cell transformation assay. Clastogenic effects (chromosome damage) were
observed in an in vitro study in human lymphocytes and in in vivo oral repeat dose
micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not

show chromosomal damage. A study of the peripheral blood lymphocytes of eleven
AIDS patients showed a higher chromosome breakage frequency in those who had
received Retrovir than in those who had not. A pilot study has demonstrated that
zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant
women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of
mother to child viral transmission. Zidovudine was also incorporated into DNA from
cord blood leukocytes of infants from zidovudine-treated mothers. A transplacental
genotoxicity study conducted in monkeys compared zidovudine alone with the
combination of zidovudine and lamivudine at human-equivalent exposures. The
study demonstrated that foetuses exposed in utero to the combination sustained a
higher level of nucleoside analogue-DNA incorporation into multiple foetal organs,
and showed evidence of more telomere shortening than in those exposed to
zidovudine alone. The clinical significance of these findings is unknown.
Carcinogenicity:
In oral carcinogenicity studies with zidovudine in mice and rats, late appearing
vaginal epithelial tumours were observed. A subsequent intravaginal carcinogenicity
study confirmed the hypothesis that the vaginal tumours were the result of long term
local exposure of the rodent vaginal epithelium to high concentrations of
unmetabolised zidovudine in urine. There were no other drug-related tumours
observed in either sex of either species.
In addition, two transplacental carcinogenicity studies have been conducted in mice.
One study, by the US National Cancer Institute, administered zidovudine at
maximum tolerated doses to pregnant mice from day 12 to 18 of gestation. One year
post-natally, there was an increase in the incidence of tumours in the lung, liver and
female reproductive tract of offspring exposed to the highest dose level (420 mg/kg
term body weight).
In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24
months, with exposure beginning prenatally on gestation day 10. Treatment related
findings were limited to late-occurring vaginal epithelial tumours, which were seen
with a similar incidence and time of onset as in the standard oral carcinogenicity
study. The second study thus provided no evidence that zidovudine acts as a
transplacental carcinogen.
It is concluded that the transplacental carcinogenicity data from the first study
represents a hypothetical risk, whereas the reduction in risk of maternal transfection
of HIV to the uninfected child by the use of zidovudine in pregnancy has been well
proven.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Hydrochloric acid (pH for adjustment)

Sodium hydroxide (pH for adjustment)
Water for injection

6.2

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

6.3

Shelf life
3 years. (Refer to Section 6.6 for shelf life after opening)

6.4

Special precautions for storage
Do not store above 30°C.
Keep the vial in the outer carton.

6.5

Nature and contents of container
Type I glass vial (amber, neutral glass) with rubber stopper containing 20ml sterile
concentrate, available in pack sizes of 5.

6.6

Special precautions for disposal
Retrovir I.V. for Infusion must be diluted prior to administration. Since no
antimicrobial preservative is included, dilution must be carried out under full aseptic
conditions, preferably immediately prior to administration, and any unused portion of
the vial should be discarded.
The required dose should be added to and mixed with Glucose Intravenous Infusion
5% w/v to give a final zidovudine concentration of either 2 mg/ml or 4 mg/ml. These
dilutions are chemically and physically stable for up to 48 hours at both 5°C and
25°C. Should any visible turbidity appear in the product either before or after dilution
or during infusion, the preparation should be discarded.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS

8

MARKETING AUTHORISATION NUMBER(S)
PL 35728/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/04/1993 / 20/03/2006

10

DATE OF REVISION OF THE TEXT
06/01/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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