Ke Ai Si

Ke Ai Si 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 Ke Ai Si oral formulations.).

Ke Ai Si is indicated in anti-retroviral combination therapy for Human Immunodeficiency Virus (HIV) infected adults and children.

Ke Ai Si 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.

Ke Ai Si should be prescribed by physicians who are experienced in the treatment of HIV infection.

The required dose of Ke Ai Si IV for Infusion must be administered by slow intravenous infusion of the diluted product over a one-hour period.

Ke Ai Si IV for Infusion must NOT be given intramuscularly.

Dilution: Ke Ai Si IV for Infusion must be diluted prior to administration.

Dosage in adults: A dose for Ke Ai Si 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 Ke Ai Si is 250 or 300 mg twice daily. This current dose is used as part of a multi-drug treatment regimen.

Patients should receive Ke Ai Si IV for Infusion only until oral therapy can be administered.

Dosage in children: Limited data are available on the use of Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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. Ke Ai Si dose reduction or interruption should be considered in the absence of alternative treatments.

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 Ke Ai Si 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).

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.

Ke Ai Si should be prescribed by physicians who are experienced in the treatment of HIV infection.

Posology

Dosage in adults and adolecents weighing at least 30 kg: The usual recommended dose of Ke Ai Si in combination with other anti-retroviral agents is 250 or 300 mg twice daily.

Paediatric populationChildren weighing more than 21 kg and less than 30 kg: The recommended dose of Ke Ai Si is two 100 mg capsules twice daily in combination with other antiretroviral agents.

Children weighing at least 14 kg and less than or equal to 21 kg: The recommended dose of Ke Ai Si is one 100 mg capsule taken in the morning and two 100 mg capsules taken in the evening.

Children weighing at least 8 kg and less than 14 kg: The recommended dose of zidovudone is one 100 mg capsule twice daily.

“Other pharmaceutical formulations containing Ke Ai Si is available for dosing children less than 8kg and for those children above 8kg unable to swallow capsules”.

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 Ke Ai Si 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 Ke Ai Si 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, then the Ke Ai Si infusion should be stopped and oral dosing restarted.

Dosage adjustments in patients with haematological adverse reactions:

Substitution of Ke Ai Si 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. Dose reduction or interruption of Ke Ai Si should be considered in the absence of alternative treatments.

Dosage in the Elderly:

Ke Ai Si 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 Ke Ai Si is advised.

Dosage in renal impairment:

The recommended dose for patients with severe renal impairment (creatinine clearance < 10ml/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.

Dosage in hepatic impairment:

Data in patients with cirrhosis suggest that accumulation of Ke Ai Si may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage reductions may be necessary but, due to the large variability in Ke Ai Si exposures in patients with moderate to severe liver disease, precise recommendations cannot be made. If monitoring of plasma Ke Ai Si 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.

Method of administration

Oral use.

Ke Ai Si 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).

Ke Ai Si 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.

Ke Ai Si 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).

Ke Ai Si 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.

While effective viral suppression with antiKe Ai Sial 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.

Ke Ai Si is not a cure for HIV infection or AIDS. Patients receiving Ke Ai Si or any other antiKe Ai Sial therapy may continue to develop opportunistic infections and other complications of HIV infection.

The concomitant use of rifampicin or stavudine with zidovudine should be avoided.

Haematological Adverse Reactions: Anaemia (usually not observed before six weeks of Ke Ai Si 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 Ke Ai Si IV for Infusion; These occurred more frequently at high dosages (1200-1500 mg/day orally) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease.

Haematological parameters should be carefully monitored. It is recommended that blood tests are performed at least weekly in patients receiving Ke Ai Si 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 Ke Ai Si therapy. Marrow recovery is usually observed within 2 weeks after which time Ke Ai Si therapy at a reduced dosage may be reinstituted. Data on the use of Ke Ai Si for periods in excess of 2 weeks are limited. In patients with significant anaemia, dosage adjustments do not necessarily eliminate the need for transfusions.

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 post-natally 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. Late-onset 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 antiKe Ai Sial 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 antiKe Ai Sial 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 antiKe Ai Sial 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 antiKe Ai Sial 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.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiKe Ai Sial 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..

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 antiKe Ai Sial 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.

Latex allergy: The rubber stopper of the Ke Ai Si IV for Infusion vials contains dry natural latex rubber that has the potential to cause allergic reactions in latex sensitive individuals.

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.

Ke Ai Si is not a cure for HIV infection or AIDS. Patients receiving Ke Ai Si 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 Ke Ai Si should be avoided.

Haematological Adverse Reactions: Anaemia (usually not observed before six weeks of Ke Ai Si 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 Ke Ai Si. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease.

Haematological parameters should be carefully monitored. For patients with advanced symptomatic HIV disease it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. Depending on the overall condition of the patient, blood tests may be performed less often, for example every 1 to 3 months.

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 Ke Ai Si therapy. Marrow recovery is usually observed within 2 weeks after which time Ke Ai Si therapy at a reduced dosage may be reinstituted. In patients with significant anaemia, dosage adjustments do not necessarily eliminate the need for transfusions.

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 Ke Ai Si There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing Ke Ai Si. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Late-onset 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 Ke Ai Si 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 Ke Ai Si-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with Ke Ai Si and Ke Ai Si 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: Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si exposure observed, therefore Ke Ai Si 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.

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.

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 Ke Ai Si is not recommended due to an increased risk of anaemia.

Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si should be borne in mind when considering the patient's ability to drive or operate machinery.

There have been no studies to investigate the effect of Ke Ai Si 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 Ke Ai Si should be borne in mind when considering the patient's ability to drive or operate machinery.

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³. Dosage reduction or cessation of therapy may become necessary.

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B₁₂ levels were low at the start of Ke Ai Si therapy.

The following events have been reported in patients treated with Ke Ai Si.

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: 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si.

Adverse reactions with Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si therapy. Other clinical adverse reactions and laboratory test abnormalities were similar in the Ke Ai Si and placebo groups. It is unknown whether there are any long-term consequences of in utero and infant exposure to Ke Ai Si.

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 zidovudine.

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Ke Ai Si should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Ke Ai Si should not be continued.

Weight and levels of blood lipids and glucose may increase during antiKe Ai Sial therapy

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiKe Ai Sial therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiKe Ai Sial therapy (CART). The frequency of this is unknown.

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.

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³. Dosage reduction or cessation of therapy may become necessary.

The incidence of neutropenia was also increased in those patients whose neutrophil counts haemoglobin levels and serum vitamin B₁₂ levels were low at the start of Ke Ai Si therapy.

The following events have been reported in patients treated with Ke Ai Si.

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),

Very rare (<1/10,000)

The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse reactionsconsistently decreases over time during the first few weeks of therapy with Ke Ai Si.

Adverse reactions with Ke Ai Si 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 Ke Ai Si and placebo groups. However, there was a trend for mild and moderate anaemia to be seen more commonly prior to delivery in the Ke Ai Si treated women.

In the same trial, haemoglobin concentrations in infants exposed to Ke Ai Si 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 Ke Ai Si therapy. Other clinical adverse reactions and laboratory test abnormalities were similar in the Ke Ai Si and placebo groups. It is unknown whether there are any long-term consequences of in utero and infant exposure to Ke Ai Si.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues.

Treatment with Ke Ai Si has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Ke Ai Si should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Ke Ai Si should not be continued.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy

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.

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.

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.

Symptoms and signs:

Dosages as high as 7.5 mg/kg by infusion every four hours for two weeks have been administered to five patients. One patient experienced an anxiety reaction while the other four had no untoward effects.

No specific symptoms or signs have been identified following acute oral overdose with zidovudine apart from those listed as undesirable effects such as fatigue, headache, vomiting, and occasional reports of haematological disturbances. Following a report where a patient took an unspecified quantity of zidovudine with serum levels consistent with an overdose of greater than 17 g there were no short term clinical, biochemical or haematological sequelae identified.

Treatment:

Patients should be observed closely for evidence of toxicity and given the necessary supportive therapy.

Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine but enhance the elimination of the glucuronide metabolite.

Symptoms and signs:

No specific symptoms or signs have been identified following acute overdose with Ke Ai Si 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 Ke Ai Si with serum levels consistent with an overdose of greater than 17 g there were no short term clinical, biochemical or haematological sequelae identified.

Treatment:

Patients should be observed closely for evidence of toxicity and given the necessary supportive therapy.

Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of Ke Ai Si but enhance the elimination of the glucuronide metabolite.

Pharmacotherapeutic group: nucleoside analogue , ATC code: J05A F01

Mode of action:

Zidovudine is an antiviral agent which is highly active in vitro against Ke Ai Siuses 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 Ke Ai Si 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 end-point 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-Ke Ai Sial 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-Ke Ai Sial naive patients.

No antagonistic effects in vitro were seen with zidovudine and other antiKe Ai Sials (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, Ke Ai Si 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 Ke Ai Si 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.

Pharmacotherapeutic group: Nucleoside analogue.

ATC code: J05A F01

Mechanism of action:

Ke Ai Si is an antiviral agent, which is highly active in vitro against retroviruses including the Human Immunodeficiency Virus (HIV).

Ke Ai Si is phosphorylated in both infected and uninfected cells to the monophosphate (MP) derivative by cellular thymidine kinase. Subsequent phosphorylation of Ke Ai Si-MP to the diphosphate (DP), and then the triphosphate (TP) derivative is catalysed by cellular thymidylate kinase and non-specific kinases respectively. Ke Ai Si-TP acts as an inhibitor of and substrate for the viral reverse transcriptase. The formation of further proviral DNA is blocked by incorporation of Ke Ai Si-MP into the chain and subsequent chain termination. Competition by Ke Ai Si-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 Ke Ai Si 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 Ke Ai Si has been reported for HIV isolates from patients who have received prolonged courses of Ke Ai Si 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 Ke Ai Si resistant strains limits the usefulness of Ke Ai Si monotherapy clinically. In clinical studies, clinical end-point data indicate that Ke Ai Si, 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 Ke Ai Si 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 Ke Ai Si in combination with lamivudine indicate that Ke Ai Si-resistant virus isolates can become Ke Ai Si sensitive when they simultaneously acquire resistance to lamivudine. Furthermore there is clinical evidence that Ke Ai Si plus lamivudine delays the emergence of Ke Ai Si resistance in anti-retroviral naive patients.

No antagonistic effects in vitro were seen with Ke Ai Si and other antiretrovirals (tested agents: abacavir, didanosine,lamivudine and interferon-alpha).

Resistance to thymidine analogues (of which Ke Ai Si 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 ACTG076 trial, Ke Ai Si was shown to be effective in reducing the rate of maternal-foetal transmission of HIV-1 (23% infection rate for placebo versus 8% for Ke Ai Si) 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 Ke Ai Si 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 Ke Ai Si). These data, and data from a published study comparing Ke Ai Si 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.

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 (C^ssmax) and trough (C^ssmin) 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.

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. C^ssmax 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.

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:

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..

Hepatic impairment:

There are limited data concerning the pharmacokinetics of zidovudine in patients with hepatic impairment. No specific data are available on the pharmacokinetics of zidovudine in the elderly.

Adults

Absorption:

Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si, 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 Ke Ai Si concentration ratio 2 to 4 hours after dosing was found to be approximately 0.5. Data indicate that Ke Ai Si crosses the placenta and is found in amniotic fluid and foetal blood. Ke Ai Si 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:

Ke Ai Si is primarily eliminated by hepatic conjugation to an inactive glucoronidated metabolite. The 5'-glucuronide of Ke Ai Si 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 Ke Ai Si following intravenous dosing.

Elimination:

Renal clearance of Ke Ai Si 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 Ke Ai Si is similar to that in adults. Ke Ai Si is well absorbed from the gut and, at all dose levels studied; its bioavailability was 60-74% with a mean of 65%. C^ssmax levels were 4.45µM (1.19µg/ml) following a dose of 120 mg Ke Ai Si (in solution)/m² body surface area and 7.7µM (2.06µg/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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si was similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, Ke Ai Si 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 Ke Ai Si in the elderly.

Renal impairment:

In patients with severe renal impairment, apparent Ke Ai Si clearance after oral Ke Ai Si administration was approximately 50% of that reported in healthy subjects with normal renal function. Haemodialysis and peritoneal dialysis have no significant effect on Ke Ai Si elimination whereas elimination of the inactive glucuronide metabolite is increased.

Hepatic impairment:

There are limited data on the pharmacokinetics of Ke Ai Si in patients with hepatic impairment.

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 Ke Ai Si 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.

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).

Mutagenicity:

No evidence of mutagenicity was observed in the Ames test. However, Ke Ai Si 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 Ke Ai Si than in those who had not.

A pilot study has demonstrated that Ke Ai Si is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking Ke Ai Si as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Ke Ai Si was also incorporated into DNA from cord blood leukocytes of infants from Ke Ai Si-treated mothers. A transplacental genotoxicity study conducted in monkeys compared Ke Ai Si alone with the combination of Ke Ai Si 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 Ke Ai Si alone. The clinical significance of these findings is unknown.

Carcinogenicity:

In oral carcinogenicity studies with Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si 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 Ke Ai Si in pregnancy has been well proven.

Reproductive Toxicity:

Studies in pregnant rats and rabbits given Ke Ai Si 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).

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

Not applicable.

Ke Ai Si 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 medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements.