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RETROVIR 100MG/10ML ORAL SOLUTION

Active substance(s): ZIDOVUDINE / ZIDOVUDINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Retrovir 100 mg/10 ml oral solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
10 ml of solution contains 100 mg zidovudine.
10 ml of solution contains 6.4 g of maltitol
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Retrovir 100 mg/10ml oral solution/syrup
A clear, pale yellow, strawberry-flavoured, sugar-free oral solution.
The pack contains an oral-dosing syringe which should be fitted to the bottle before
use.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Retrovir oral formulations are indicated in anti-retroviral combination therapy for
Human Immunodeficiency Virus (HIV) infected adults and children.
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.

4.2

Posology and method of administration
Retrovir should be prescribed by physicians who are experienced in the treatment of
HIV infection.
Dosage in adults and adolecents weighing at least 30 kg: The usual recommended
dose of Retrovir in combination with other anti-retroviral agents is 250 or 300 mg
twice daily.
Dosage in children: Retrovir 100 mg capsules are also available for use in children.
Children weighing at least 9 kg and less than 30 kg: The recommended dose of
Retrovir is 9 mg/kg twice daily in combination with other antiretroviral agents. The
maximum dosage should not exceed 300 mg twice daily.
Children weighing at least 4 kg and less than 9 kg: The recommended dose of
Retrovir is 12 mg/kg twice daily in combination with other antiretroviral agents.
Available data are insufficient to propose specific dosage recommendations for
children weighing less than 4 kg (See below -maternal foetal transmission and section
5.2).
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.
Due to the small volumes of oral solution required, care should be taken when
calculating neonate doses. To facilitate dosing precision a 1 ml syringe is included in
the neonate pack.
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: The recommended dose for patients with severe renal
impairment (creatinine clearance < 10 ml/min) and patients with end-stage renal
disease maintained on haemodialysis or peritoneal dialysis is 100 mg every 6 to 8 hrs
(300-400 mg daily). Haematological parameters and clinical response may influence
the need for subsequent dosage adjustment (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 Oral Formulations are contra-indicated in patients known to be
hypersensitive to zidovudine, or to any of the excipients listed in section 6.1.
Retrovir Oral Formulations 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 new born 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

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
(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; 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 (see section 4.8).
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.
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. 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 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.
Mitochondrial dysfunction following exposure in utero: Nucleoside and nucleotide
analogues may impact mitochondrial function to a variable degree, which is most
pronounced with stavudine, didanosine and zidovudine. There have been reports of
mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with
regimens containing zidovudine. The main adverse reactions reported are
haematological disorders (anaemia, neutropenia) and metabolic disorders
(hyperlactatemia, hyperlipasaemia). These events have often been transitory. Lateonset neurological disorders have been reported rarely (hypertonia, convulsion,
abnormal behaviour). Whether such neurological disorders are transient or permanent
is currently unknown. These findings should be considered for any child exposed in
utero to nucleoside and nucleotide analogues, who presents with severe clinical
findings of unknown etiology, particularly neurologic findings. These findings do not

affect current recommendations to use antiretroviral therapy in pregnant women to
prevent vertical transmission of HIV.
Lipoatrophy: Treatment with zidovudine has been associated with loss of
subcutaneous fat, which has been linked to mitochondrial toxicity. The incidence and
severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most
evident in the face, limbs and buttocks, may not be reversible when switching to a
zidovudine-free regimen. Patients should be regularly assessed for signs of
lipoatrophy during therapy with zidovudine and zidovudine-containing products
(Combivir and Trizivir). Therapy should be switched to an alternative regimen if there
is suspicion of lipoatrophy development.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids
and glucose may occur during antiretroviral therapy. Such changes may in part be
linked to disease control and life style. For lipids, there is in some cases evidence for a
treatment effect, while for weight gain there is no strong evidence relating this to any
particular treatment. For monitoring of blood lipids and glucose reference is made to
established HIV treatment guidelines. Lipid disorders should be managed as clinically
appropriate.
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. Autoimmune
disorders (such as Graves’ disease) have also been reported to occur in the setting of
immune reactivation; however, the reported time to onset is more variable and can
occur many months after initiation of treatment.

Patients should be cautioned about the concomitant use of self-administered
medications (see section 4.5).
Patients with rare hereditary problems of fructose intolerance should not take this
medicine.
Use in Elderly and in Patients with Renal or Hepatic Impairment: see section 4.2.
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 (eg. 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.
Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by
separating the administration of zidovudine and clarithromycin by at least two hours.
4.6

Fertility, pregnancy and lactation

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 (see section 5.3) 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.
Zidovudine has been associated with reproductive toxicity findings in animal studies
(see section 5.3). The active ingredients of Retrovir may inhibit cellular DNA
replication and zidovudine has been shown to be a transplacental carcinogen in one

animal study. The clinical relevance of these findings is unknown. Placental transfer
of zidovudine has been shown to occur in humans.
Mitochondrial dysfunction: 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 (see section 4.4).
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.
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.

4.7

Effects on ability to drive and use machines
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 (≥1/10 ), Common (≥1/100 to <1/10),

Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000) and Very rare
(<1/10,000).
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: Pancreatitis. Oral mucosa pigmentation, taste disturbance and dyspepsia.
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
The available data from both placebo-controlled and open-label studies indicate that
the incidence of nausea and other frequently reported clinical adverse reactions
consistently decreases 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.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly
and hepatic steatosis, have been reported with the use of zidovudine (see section 4.4).
Treatment with zidovudine has been associated with loss of subcutaneous fat which is
most evident in the face, limbs and buttocks. Patients receiving Retrovir should be
frequently examined and questioned for signs of lipoatrophy. When such development
is found, treatment with Retrovir should not be continued (see section 4.4).
Weight and levels of blood lipids and glucose may increase during antiretroviral
therapy (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).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms and signs:
No specific symptoms or signs have been identified following acute 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.
No antagonistic effects in vitro were seen with zidovudine and other antiretrovirals
(tested agents: abacavir, didanosine, lamivudine and interferon-alpha).
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:
Zidovudine is well absorbed from the gut and, at all dose levels studied, the
bioavailability was 60-70%. From a bioequivalence study, steady-state mean (CV%)
C[ss]max, C[ss]min, and AUC[ss] values in 16 patients receiving zidovudine 300 mg
tablets twice daily were 8.57 (54%) microM (2.29 μg/ml), 0.08 (96%) microM
(0.02 μg/ml), and 8.39 (40%) h*microM (2.24 h*μg/ml), respectively.
Distribution:
From studies with intravenous Retrovir, 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 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.
Biotransformation:
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.
Elimination:
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. Zidovudine is well absorbed from the gut and, at all dose
levels studied, its bioavailability was 60-74% with a mean of 65%. Cssmax levels
were 4.45µM (1.19 µg/ml) following a dose of 120 mg Retrovir (in solution)/m2 body
surface area and 7.7 µM (2.06 µg/ml) at 180 mg/m2 body surface area. Dosages of
180 mg/m2 four times daily in children produced similar systemic exposure (24 hour
AUC 40.0 hr µM or 10.7 hr µg/ml) as doses of 200 mg six times daily in adults (40.7
hr µM or 10.9 hr µg/ml).
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.
Biotransformation:
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.
Elimination:
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:
In patients with severe renal impairment, apparent zidovudine clearance after oral
zidovudine administration was approximately 50% of that reported in healthy subjects
with normal renal function. 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 on the pharmacokinetics of zidovudine in patients with hepatic
impairment (see section 4.2).
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 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 postnatally, 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.
Reproductive Toxicity:
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).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Maltitol solution
Glycerol
Citric Acid
E211 Sodium Benzoate
Saccharin Sodium
Flavour Strawberry
Flavour White Sugar
Purified Water.

6.2

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

6.3

Shelf life
2 years.
Discard oral solution 1 month after first opening bottle.

6.4

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

6.5

Nature and contents of container
Retrovir Oral Solution/Syrup:
200 ml amber glass bottle with a plastic or metal cap and polyethylene wad. A 10 ml
oral-dosing syringe is included in the pack, with an adaptor, which should be fitted to
the bottle before use.
Retrovir Oral Solution/Syrup (Neonate Pack):
200 ml amber glass bottle with a plastic or metal cap and polyethylene wad. A 1 ml
oral-dosing syringe is included in the pack, with an adaptor, which should be fitted to
the bottle before use.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7

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

8

MARKETING AUTHORISATION NUMBER(S)
PL 35728/0004

9

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

10

DATE OF REVISION OF THE TEXT

21/04/2017

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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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