Thymazide

Overdose

Symptoms and signs:

No specific symptoms or signs have been identified following acute overdose with Thymazide 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 Thymazide 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 Thymazide but enhance the elimination of the glucuronide metabolite.

Thymazide price

Contraindications

Thymazide 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).

Thymazide 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.

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

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

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 Thymazide therapy.

The following events have been reported in patients treated with Thymazide.

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 Thymazide.

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

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

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 Thymazide has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Thymazide should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Thymazide 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.

Preclinical safety data

Mutagenicity:

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

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

Carcinogenicity:

In oral carcinogenicity studies with Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide in pregnancy has been well proven.

Reproductive Toxicity:

Studies in pregnant rats and rabbits given Thymazide 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).

Therapeutic indications

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

Thymazide 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.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Nucleoside analogue.

ATC code: J05A F01

Mechanism of action:

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

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

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

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

Pharmacokinetic properties

Adults

Absorption:

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

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

Elimination:

Renal clearance of Thymazide 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 Thymazide is similar to that in adults. Thymazide is well absorbed from the gut and, at all dose levels studied; its bioavailability was 60-74% with a mean of 65%. Cssmax levels were 4.45µM (1.19µg/ml) following a dose of 120 mg Thymazide (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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide was similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, Thymazide 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 Thymazide in the elderly.

Renal impairment:

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

Hepatic impairment:

There are limited data on the pharmacokinetics of Thymazide in patients with hepatic impairment.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Thymazide is not a cure for HIV infection or AIDS. Patients receiving Thymazide 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 Thymazide should be avoided.

Haematological Adverse Reactions: Anaemia (usually not observed before six weeks of Thymazide 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 Thymazide. 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 Thymazide therapy. Marrow recovery is usually observed within 2 weeks after which time Thymazide 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 Thymazide 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 Thymazide. 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 Thymazide 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 Thymazide-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with Thymazide and Thymazide 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: Thymazide 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 Thymazide 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 Thymazide exposure observed, therefore Thymazide 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 Thymazide is not recommended due to an increased risk of anaemia.

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide 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 Thymazide infusion should be stopped and oral dosing restarted.

Dosage adjustments in patients with haematological adverse reactions:

Substitution of Thymazide 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 Thymazide should be considered in the absence of alternative treatments.

Dosage in the Elderly:

Thymazide 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 Thymazide 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 Thymazide may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage reductions may be necessary but, due to the large variability in Thymazide exposures in patients with moderate to severe liver disease, precise recommendations cannot be made. If monitoring of plasma Thymazide 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.

Special precautions for disposal and other handling

No special requirements.