Retrovir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RETROVIR (RETROVIR)

Composition:

Active substance: zidovudine;

1 ml of solution contains 10 mg of zidovudine;

Excipients: hydrochloric acid concentrated, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for infusion.

Main physicochemical properties: clear, colorless or pale yellow solution, practically free from visible foreign particles.

Pharmacotherapeutic group. Direct-acting antiviral agents. ATC code J05A F01.

Pharmacological properties.

Pharmacodynamics.

Zidovudine is an antiviral agent active against retroviruses, including human immunodeficiency virus (HIV).

Once inside the cell, the drug undergoes a series of sequential transformations catalyzed by cellular enzymes. In the final step, zidovudine triphosphate is formed, which inhibits viral DNA synthesis by competitively interacting with HIV reverse transcriptase.

In vitro studies show that a triple combination of nucleoside analogues or two nucleoside analogues combined with a protease inhibitor is more effective in suppressing HIV-induced cytopathic effects than a single drug or a combination of two drugs.

Pharmacokinetics.

Following intravenous administration, the mean elimination half-life is 1.1 hours, mean total clearance is 27.1 mL/min/kg, and volume of distribution is 1.6 L/kg. Zidovudine clearance significantly exceeds creatinine clearance, indicating that tubular secretion is a significant elimination mechanism. Zidovudine crosses the placenta and is found in amniotic fluid and fetal blood. Plasma protein binding is relatively low (34–38%).

Clinical characteristics.

Indications.

Retrovir for intravenous infusion is indicated for short-term treatment of severe manifestations of HIV infection in AIDS patients who cannot take oral formulations of the drug. If possible, Retrovir should not be used as monotherapy for this indication.

Retrovir is also indicated for use in HIV-positive pregnant women (pregnancy beyond 14 weeks) and newborns for the prevention of transplacental transmission of HIV and primary prophylaxis of HIV in newborns.

Contraindications.

Hypersensitivity to zidovudine or to any other components of the drug.

Retrovir is contraindicated in patients with abnormally low neutrophil count (less than 0.75 × 10⁹/L) or abnormally low hemoglobin levels (less than 7.5 g/dL or 4.65 mmol/L).

Retrovir is contraindicated for treatment of newborns with hyperbilirubinemia requiring therapy other than phototherapy, or with transaminase levels elevated more than five times above the upper normal limit.

Interaction with other medicinal products and other forms of interaction.

Zidovudine is primarily eliminated by hepatic conjugation to an inactive glucuronide metabolite. Active substances that are also eliminated via hepatic metabolism, particularly through glucuronidation, may potentially inhibit zidovudine metabolism. The interactions described below are not exhaustive but represent classes of medicinal products requiring caution when co-administered.

Atovaquone. There is no information on the effect of zidovudine on atovaquone pharmacokinetics. However, according to pharmacokinetic data, atovaquone slows the metabolism of zidovudine to its glucuronide metabolite (AUC of zidovudine increases by 33%, and peak plasma concentration of the glucuronide metabolite decreases by 19%). When dosing at 500 or 600 mg/day for 3 weeks of atovaquone treatment for Pneumocystis carinii pneumonia, rare cases of increased frequency of adverse effects related to higher plasma levels of zidovudine may occur. Close monitoring is required during prolonged atovaquone therapy.

Clarithromycin. Clarithromycin tablets reduce the absorption of zidovudine; therefore, a two-hour interval should be maintained between administration of these agents.

Lamivudine. A moderate increase in Cmax (28%) of zidovudine is observed when administered concomitantly with lamivudine, although overall exposure (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin. Low blood levels of phenytoin have been reported in some patients receiving Retrovir, although one patient had elevated levels. These data suggest that phenytoin levels should be closely monitored when both drugs are used concomitantly.

Valproic acid, fluconazole, or methadone. It has been shown that co-administration with zidovudine increases its AUC and correspondingly decreases zidovudine clearance. As data are limited, the clinical significance is unknown. Patients should be closely monitored for signs of zidovudine toxicity.

Probenecid. With limited data, probenecid increases the mean elimination half-life and area under the concentration-time curve (AUC, increase by 106%, ranging from 100 to 170%) of zidovudine by reducing glucuronidation. Renal excretion of the glucuronide (and of zidovudine itself) is reduced in the presence of probenecid. Patients receiving both drugs should be carefully monitored for hematological toxicity.

Ribavirin. Worsening of anemia associated with ribavirin use has been observed in patients taking zidovudine as part of a combination HIV treatment regimen, although the exact mechanism remains unclear. Therefore, combining ribavirin with zidovudine is not recommended. The physician should replace zidovudine with an alternative agent in the combination antiretroviral therapy regimen if already prescribed. This is particularly important for patients with a history of zidovudine-induced anemia.

Rifampicin. With limited data, co-administration of zidovudine and rifampicin reduces zidovudine AUC by 48% ± 34%, although the clinical significance of this effect is unknown. Concomitant use of rifampicin with zidovudine should be avoided (see section "Special precautions for use").

Stavudine. Zidovudine may inhibit the intracellular phosphorylation of stavudine when both medicinal products are administered simultaneously. Therefore, combining stavudine with zidovudine is not recommended.

Other interactions. Other active substances, including acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, and isoprinosine (the list is not limited to these agents), may affect zidovudine metabolism through competitive inhibition of glucuronidation or direct inhibition of hepatic microsomal metabolism. Therefore, potential interactions should be considered when prescribing these medicinal products, especially for chronic treatment, in combination with Retrovir.

Concomitant use, mostly in acute situations, with potentially nephrotoxic or myelosuppressive agents (e.g., systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, and doxorubicin) may also increase the risk of adverse effects of Retrovir. When concomitant use of these medicinal products is necessary, renal function and hematological parameters should be closely monitored, and dosage reduction of one or more agents may be required if necessary.

Since opportunistic infections may develop in some patients receiving Retrovir, prophylactic administration of antimicrobial agents may be appropriate. Such prophylaxis may include co-trimoxazole, aerosolized pentamidine, pyrimethamine, and acyclovir. Limited clinical study data indicate that concomitant use with these agents does not increase the frequency of adverse reactions to Retrovir.

Special precautions for use.

Patients should be warned against the simultaneous self-administration of any other medications (see section "Interaction with other medicinal products and other forms of interaction").

Patients must be informed that treatment cannot prevent HIV transmission to other individuals through sexual contact or contact with infected blood. Therefore, appropriate safety measures should be taken.

Retrovir does not cure HIV infection, and patients remain at risk of developing illnesses associated with immunosuppression, including opportunistic infections and malignancies. Although a reduced risk of opportunistic infections has been established, data regarding the development of tumors, including lymphomas, are insufficient. In patients with advanced HIV infection treated with Retrovir, the risk of developing lymphoma is similar to that in patients not treated with the drug. For patients with early-stage HIV infection, the risk of developing lymphoma during long-term Retrovir treatment is unknown.

Pregnant women considering Retrovir treatment to prevent HIV transmission to the child should be aware that, in individual cases, HIV transmission may still occur despite treatment.

Concomitant use of rifampicin or stavudine with zidovudine should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Hematological adverse reactions

In patients with advanced HIV infection, treatment with Retrovir may lead to the development of anemia (usually not earlier than 6 weeks after initiation of therapy, although occasionally earlier), neutropenia (usually not earlier than 4 weeks after initiation of therapy, but sometimes earlier), and leukopenia (secondary to neutropenia). These effects occur more frequently when high doses (1200–1500 mg/day) are used and in patients with low bone marrow reserve prior to treatment, especially in advanced stages of HIV infection.

Hematological parameters should be closely monitored. When Retrovir is administered intravenously, blood tests should be performed at least once weekly.

If hemoglobin levels decrease to between 7.5 g/dL (4.65 mmol/L) and 9 g/dL (5.59 mmol/L), or neutrophil counts decrease to between 0.75 × 10⁹/L and 1.0 × 10⁹/L, dose reduction may be required until signs of bone marrow recovery appear; alternatively, a short (2–4 week) treatment interruption may accelerate recovery. Bone marrow recovery usually occurs within 2 weeks, after which therapy may be resumed at reduced doses. Data on intravenous Retrovir use beyond 2 weeks are limited. In cases of severe anemia, dose reduction of Retrovir does not eliminate the need for blood transfusions (see section "Contraindications").

Lactic acidosis

Cases of lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, have been reported with zidovudine use. Early symptoms (symptomatic hyperlactatemia) include benign gastrointestinal symptoms (nausea, vomiting, 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 rate and may be associated with pancreatitis, hepatic or renal failure.

Lactic acidosis typically develops after several months or more of treatment.

If symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur, zidovudine treatment should be discontinued.

Zidovudine should be used with caution in any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medications and alcohol). Patients co-infected with hepatitis C and receiving alpha-interferon and ribavirin are at particular risk.

Patients at increased risk require ongoing monitoring.

Mitochondrial function disorders

Nucleoside and nucleotide analogs may cause mitochondrial dysfunction of varying degrees, particularly when used concomitantly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors in utero and/or postnatally, primarily in treatment regimens including zidovudine. The main adverse reactions reported are hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Rarely, neurological disorders (hypertonia, seizures, behavioral disturbances) have been reported, occurring with delayed onset after drug exposure. Whether such neurological disorders are transient or permanent is currently unknown. These disorders should be considered in any child exposed to nucleoside and nucleotide analogs in utero who presents with severe clinical symptoms of unknown etiology, particularly neurological symptoms. These data do not affect current recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Lipoatrophy

Zidovudine treatment is associated with loss of subcutaneous fat, linked to mitochondrial toxicity. The frequency and severity of lipoatrophy are related to cumulative exposure. This loss of fat deposits, most evident in the face, limbs, and buttocks, may be irreversible even after switching to a zidovudine-free treatment regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing products (Combivir and Trizivir). If lipoatrophy is suspected, therapy should be switched to an alternative regimen.

Body weight and metabolic parameters

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Contributing factors may also include disease control and lifestyle changes. In some cases, there is evidence supporting a treatment effect on increased lipid levels, whereas increased body weight lacks such confirmation. Monitoring of serum lipid and blood glucose levels should be performed according to established HIV treatment protocols. Treatment of lipid disorders should be based on clinical indications.

Liver disease

Zidovudine clearance in patients with mild hepatic impairment without cirrhosis (Child-Pugh score 5–6) is similar to that observed in healthy volunteers; therefore, dose adjustment of zidovudine is not required. For patients with moderate to severe hepatic impairment (Child-Pugh score 7–15), specific dosing recommendations cannot be made due to the wide variability in zidovudine exposure observed; thus, zidovudine is not recommended in this patient group.

Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse effects. When used concomitantly with other antiviral agents for the treatment of hepatitis B and C, refer to the appropriate medical instructions for these drugs.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk of liver function deterioration during combination antiretroviral therapy and require medical supervision. If signs of worsening liver disease occur in such patients, consideration should be given to interrupting or discontinuing treatment (see section "Method of administration and dosage").

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start of antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur, potentially causing severe clinical conditions or symptom exacerbation. Such reactions typically arise within the first weeks or months of antiretroviral therapy. Appropriate examples include cytomegalovirus retinitis, generalized or focal mycobacterial infections, or Pneumocystis jirovecii pneumonia. Any inflammatory conditions should be promptly investigated and treated if necessary.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported during immune reconstitution, although their onset is more variable and may occur months after starting treatment and sometimes present atypically.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases have been reported primarily in patients with advanced disease and/or long-term combination antiretroviral therapy. Patients should be advised to seek medical attention if joint pain, stiffness, or movement disorders occur.

Patients co-infected with hepatitis C virus

Worsening anemia associated with ribavirin use has been observed in patients when zidovudine was part of combination HIV treatment, although the exact mechanism remains unclear. Therefore, concomitant use of ribavirin and zidovudine is not recommended, and a decision should be made to replace zidovudine in the combination antiretroviral regimen if already prescribed. This is particularly important for patients with a known history of zidovudine-induced anemia.

Latex allergy. The rubber stopper of the vial contains dry natural rubber latex, which may cause allergic reactions in latex-sensitive individuals.

Use during pregnancy or breastfeeding.

Pregnancy.

Generally, when deciding on the use of antiretroviral drugs for treating HIV infection in pregnant women and reducing the risk of vertical HIV transmission to the newborn, data from animal studies and clinical experience in pregnant women are considered.

In this case, the use of zidovudine by pregnant women, followed by treatment of newborns, reduces the rate of HIV transmission from mother to fetus.
A large amount of data from pregnant women (over 3000 outcomes from the first trimester and more than 3000 outcomes during the second and third trimesters) indicates no evidence of teratogenic toxicity. Retrovir may be used during pregnancy if clinically justified. The risk of congenital malformations in humans is considered unlikely based on the large volume of data mentioned.

Data from animal studies with zidovudine indicate reproductive toxicity. The active components of Retrovir may inhibit DNA cell replication, and zidovudine has shown transplacental carcinogenic properties in one animal study. The clinical significance of these findings is unknown. Transplacental penetration of zidovudine in humans has been established.

Mitochondrial dysfunction: nucleotide and nucleoside analogs cause mitochondrial damage in vitro and in vivo. Reports of mitochondrial dysfunction have been documented in HIV-negative infants whose mothers used nucleoside analogs during pregnancy and/or postnatally (see section "Special precautions for use").

Fertility

Zidovudine did not reduce male or female fertility in rats administered doses up to 450 mg/kg/day. There are no data on the effect of Retrovir on female fertility. In men, Retrovir does not affect sperm count, morphology, or motility.

Lactation

After a single 200 mg dose of zidovudine was administered to HIV-infected women, the average concentration of zidovudine in breast milk was similar to that in blood serum. HIV-infected women are advised to avoid breastfeeding under any circumstances to prevent transmission of HIV infection to infants.

Ability to influence reaction speed when driving or operating machinery.

Studies investigating the effect of Retrovir on reaction speed during driving or operating machinery have not been conducted. Pharmacological data on the active substance do not suggest any harmful effect on the ability to drive a car or operate machinery. Nevertheless, the patient's general condition and the drug's adverse effect profile should always be considered when determining the possibility of performing such activities.

Administration and Dosage

Zidovudine therapy should be initiated by a physician experienced in the management of HIV infection.

Retrovir for intravenous infusion should only be used until such time as Retrovir for oral administration (tablelets or oral solution) can be administered.

Retrovir for intravenous infusion must be administered by slow intravenous infusion of the diluted solution over no less than 1 hour.

Retrovir for intravenous infusion must not be administered by intramuscular injection.

Reconstitution: The solution must be diluted immediately before use.

Since the product does not contain antimicrobial preservatives, reconstitution must be performed under full aseptic conditions, preferably immediately before administration, and any unused portion remaining in the vial must be discarded.
The required dose should be added to and mixed with 5% intravenous glucose solution to obtain a final zidovudine concentration of 2 mg/ml or 4 mg/ml. These dilutions are chemically and physically stable for 48 hours at 5 °C and 25 °C. If turbidity is observed before or after dilution or during infusion, the solution must be discarded.

Adults and children aged 12 years and older

Dose: 1–2 mg zidovudine/kg body weight every 4 hours. The efficacy of lower doses for the treatment and prevention of HIV-related neurological disorders is unknown.

Children aged 3 months to 12 years

Data on the use of intravenous Retrovir in children are limited. Doses ranging from 80 to 160 mg/m² body surface area every 6 hours (320–640 mg/m²/day) have been used.

Children under 3 months of age

Limited available data do not allow specific dosage recommendations for patients in this age group (see below, “Prevention of Maternal-Fetal Transmission”).

Prevention of Maternal-Fetal Transmission

The recommended dose for pregnant women (pregnancy beyond 14 weeks) is 500 mg/day orally (100 mg 5 times daily) until the onset of labor. During labor, Retrovir should be administered intravenously at a dose of 2 mg/kg body weight over 1 hour, followed by continuous intravenous infusion at 1 mg/kg/hour until umbilical cord clamping.

Newborns should receive Retrovir at a dose of 2 mg/kg body weight as oral solution every 6 hours, starting within the first 12 hours after birth and continuing until the infant reaches 6 weeks of age (e.g., for a 3 kg infant, 0.6 ml of oral solution every 6 hours). For neonates unable to receive the drug orally, Retrovir should be administered by intravenous infusion at a dose of 1.5 mg/kg body weight over 30 minutes every 6 hours.

In cases of planned cesarean section, intravenous infusion should be initiated 4 hours before surgery. In cases of false labor, intravenous infusion should be discontinued and oral administration resumed.

Renal Impairment

For patients with severe renal impairment, the recommended dose is 1 mg/kg intravenously 3–4 times daily (equivalent to the recommended oral daily dose for this patient group, 300–400 mg). Further dose adjustments may be required based on hematological parameters or clinical response.

Hemodialysis and peritoneal dialysis do not significantly affect zidovudine elimination but increase the elimination of zidovudine glucuronide. For patients with end-stage renal disease undergoing hemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6 or 8 hours.

Hepatic Impairment

Zidovudine accumulation has been observed in patients with liver cirrhosis due to reduced glucuronidation. Dose adjustment may be necessary; however, due to insufficient data, no definitive recommendations can be made. In the absence of plasma zidovudine level monitoring, signs of intolerance should be closely observed, and the dose adjusted or the dosing interval extended accordingly.

Dose Adjustment in Patients with Hematological Adverse Reactions

Patients whose hemoglobin levels decrease to between 7.5 g/dL (4.65 mmol/L) and 9 g/dL (5.59 mmol/L), or whose neutrophil count decreases to between 0.75 × 10⁹/L and 1.0 × 10⁹/L, may require dose reduction or temporary interruption of Retrovir therapy.

Elderly Patients

The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied, and therefore specific data are lacking. However, this patient group requires special attention due to age-related decline in renal function and changes in hematological parameters. Appropriate monitoring before and during Retrovir administration is recommended.

Children. The intravenous formulation is not recommended for use in children under 3 months of age; however, for prevention of maternal-fetal transmission when the neonate cannot take the drug orally, intravenous administration should be used.

Overdose.

There is experience with high-dose intravenous Retrovir (7.5 mg/kg body weight every 4 hours) administered over 4 weeks in 5 patients. One patient experienced anxiety, while the other 4 experienced no adverse events.

There are no specific symptoms or signs of acute zidovudine overdose beyond those listed in the section on adverse effects (fatigue, headache, vomiting, occasional hematological changes). One case has been reported in which a patient ingested an unknown quantity of zidovudine, resulting in blood levels more than 16 times higher than normal therapeutic levels, but no short-term clinical, biochemical, or hematological consequences were observed.

In the event of overdose, the patient should be carefully evaluated for signs of toxicity and appropriate supportive therapy initiated.

Hemodialysis and peritoneal dialysis have limited effect on zidovudine elimination but accelerate the elimination of its glucuronide metabolite.

Adverse Reactions

The nature of adverse effects in children and adults is similar.

Adverse reactions are classified according to the following frequency categories: very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10000 and <1/1000, very rare <1/10000.

Blood and lymphatic system disorders

Common: anaemia (which may require blood transfusions), neutropenia, and leucopenia.

These occur more frequently with high-dose regimens (1200–1500 mg daily) and in patients with advanced HIV disease (particularly those with poor bone marrow reserve prior to treatment initiation), especially in patients with CD4+ cell counts below 100/mm³. Dose reduction or discontinuation of therapy may be required due to these adverse effects. The incidence of neutropenia is also increased in patients who had low neutrophil counts, haemoglobin levels, and serum vitamin B12 levels at the start of zidovudine therapy.

Uncommon: thrombocytopenia and pancytopenia with bone marrow hypoplasia.

Rare: pure red cell aplasia.

Very rare: aplastic anaemia.

Metabolism and nutrition disorders

Common: hyperlactataemia.

Rare: lactic acidosis (see section "Special precautions"), anorexia.

Redistribution/accumulation of body fat (see section "Special precautions"). The frequency of this occurrence depends on many factors, including the specific antiretroviral drug combination used.

Psychiatric disorders

Rare: anxiety and depression.

Nervous system reactions

Very common: headache.

Common: dizziness.

Rare: insomnia, paraesthesia, somnolence, impaired mental function, seizures.

Cardiovascular system disorders

Rare: cardiomyopathy.

Respiratory system disorders

Uncommon: dyspnoea.

Rare: cough.

Gastrointestinal disorders

Very common: nausea.

Common: vomiting, abdominal pain, and diarrhoea.

Uncommon: flatulence.

Rare: pigmentation of the oral mucosa, taste disturbances, dyspepsia, pancreatitis.

Hepatobiliary disorders

Common: elevated liver enzymes and bilirubin levels.

Rare: hepatic dysfunction, such as severe hepatomegaly with steatosis.

Skin and subcutaneous tissue disorders

Uncommon: rash and pruritus.

Rare: nail and skin pigmentation, urticaria, increased sweating.

Musculoskeletal and connective tissue disorders

Common: myalgia.

Uncommon: myopathies.

Renal and urinary disorders

Rare: frequent urination.

Reproductive system and breast disorders

Rare: gynaecomastia.

General disorders and administration site conditions

Common: malaise.

Uncommon: fever, generalised pain, and asthenia.

Rare: chills, chest pain, influenza-like syndrome.

Data on intravenous administration of Retrovir for more than 2 weeks are limited; however, some patients have received treatment for up to 12 weeks. The most common adverse effects were anaemia, neutropenia, and leucopenia. Local reactions occurred infrequently.

Clinical trial data indicate that the frequency of nausea and other commonly occurring adverse effects consistently decreases over time after the first few weeks of Retrovir treatment.

Adverse effects in prevention of maternal-embryonic transmission.

In a placebo-controlled study, Retrovir was well tolerated in pregnant women at the recommended doses. The incidence of adverse effects was similar to that in the placebo group.

According to the same study, haemoglobin levels in infants treated with Retrovir were slightly lower than in the placebo group, but blood transfusions were not required. Anaemia resolved within 6 weeks after completion of Retrovir treatment. Other adverse effects and laboratory test abnormalities were similar between the placebo and Retrovir-treated groups. Long-term effects of the drug on the foetus and infant are unknown.

Cases of lactic acidosis, sometimes fatal, associated with severe hepatomegaly and hepatic steatosis have been reported with zidovudine use (see section "Special precautions").

Zidovudine treatment has been associated with loss of subcutaneous fat, most prominently in the face, limbs, and buttocks. Patients receiving Retrovir should be regularly monitored for signs of lipoatrophy. If such changes occur, continuation of Retrovir therapy should not be pursued (see section "Special precautions").

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy (see section "Special precautions").

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, inflammatory reactions to asymptomatic or residual opportunistic infections may occur (see section "Special precautions").

Cases of osteonecrosis have been reported, primarily in patients with confirmed risk factors, advanced HIV disease, or prolonged antiretroviral therapy. The frequency of this adverse reaction is unknown (see section "Special precautions").

Shelf life

3 years.

Storage conditions

Store below 30°C in a light-protected place. Keep out of reach of children.

Incompatibilities

Compatibility studies have not been conducted; therefore, this medicinal product should not be mixed with other medicinal products.

Packaging

20 ml amber glass vials with a rubber stopper, aluminium cap, and plastic cap. Pack of 5 vials in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Glaxo Operations UK Limited, United Kingdom.

Manufacturer's address and place of business

Glaxo Operations UK Limited, Harmire Road, Barnard Castle, DL12 8DT, United Kingdom / Glaxo Operations UK Limited, Harmire Road, Barnard Castle, DL12 8DT, United Kingdom.