Tegretol Tablets 100mg, 200mg, 400mg Ref.[2613] Active ingredients: Carbamazepine

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2012  Publisher: Novartis Pharmaceuticals UK Limited Trading as Geigy Pharmaceuticals Frimley Business Park Frimley Camberley Surrey GU16 7SR England

Contraindications

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.

Patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).

The use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Special warnings and precautions for use

Warnings

Agranulocytosis and aplastic anaemia have been associated with Tegretol; however, due to the very low incidence of these conditions, meaningful risk estimates for Tegretol are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.

Decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tegretol. Nonetheless, complete pre-treatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline, and periodically thereafter.

Patients and their relatives should be made aware of early toxic signs and symptoms indicative of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult his physician immediately.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored (see Section 4.8 Undesirable Effects). However, treatment with Tegretol should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Tegretol should also be discontinued if any evidence of significant bone marrow depression appears.

Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.

Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.

Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Tegretol suspended pending the outcome of the evaluation.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for carbamazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as Lyell’s syndrome) and Stevens Johnson syndrome (SJS) have been reported very rarely with Tegretol. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tegretol. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Tegretol should be withdrawn at once and alternative therapy should be considered.

Cutaneous reactions

Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.

There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions (see section 4.2).

HLA-B*1502 allele – in Han Chinese, Thai and other Asian populations

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine (see section 4.2). If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.

There are some data that suggest an increased risk of serious carbamazepine-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.

The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).

HLA-A*3101 allele – European descent and Japanese populations

There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash (see section 4.8) in people of European descent and the Japanese.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.

There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.

If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.

Mild skin reactions e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).

Tegretol may trigger hypersensitivity reactions, including multi-organ hypersensitivity reactions, which can affect the skin, liver (including intrahepatic bile ducts), haematopoietic organs and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8 Undesirable Effects).

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be withdrawn immediately.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

Tegretol should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, Tegretol may exacerbate seizures. In case of exacerbation of seizures, Tegretol should be discontinued.

An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.

Abrupt withdrawal of Tegretol may precipitate seizures

If treatment with Tegretol has to be withdrawn abruptly, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).

Tegretol and oestrogen and/or progestogen preparations

Due to hepatic enzyme induction, Tegretol may cause failure of the therapeutic effect of oestrogen and/or progestogen containing products. This may result in failure of contraception, recurrence of symptoms or breakthrough bleeding or spotting.

Patients taking Tegretol and requiring hormonal contraception should receive a preparation containing not less than 50µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.

Although correlations between dosages and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see 4.5 Interaction with other Medicaments and other forms of Interaction).

Precautions

Tegretol should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.

Baseline and periodic complete urinalysis and BUN determinations are recommended.

Tegretol has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be warned and advised regarding possible hazards.

The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

Interaction with other medicinal products and other forms of interaction

Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of inhibitors of CYP 3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration of CYP 3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and therapeutic effect.

Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by induction of their metabolism.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.

Agents that may raise carbamazepine plasma levels

Isoniazid, verapamil, diltiazem, ritonavir, dextropropoxyphene, fluoxetine, fluvoxamine, paroxetine, possibly cimetidine, omeprazole, acetazolamide, danazol, nicotinamide (in adults, only in high dosage), trazodone, vigabatrin, macrolide antibiotics (e.g. erythromycin, clarithromycin), azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole), loratadine, olanzapine, grapefruit juice, protease inhibitors for HIV treatment (e.g. ritonavir).

Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored.

Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels

Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:

Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Agents that may decrease carbamazepine plasma levels

Phenobarbitone, phenytoin and fosphenytoin, primidone or theophylline, aminophylline, rifampicin, cisplatin or doxorubicin and, although the data are partly contradictory, possibly also clonazepam or oxcarbazepine. Mefloquine may antagonise the antiepileptic effect of Tegretol. The dose of Tegretol may consequently have to be adjusted.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10, 11-epoxide; carbamazepine plasma concentrations should be monitored.

Serum levels of carbamazepine can be reduced by concomitant use of the herbal remedy St John’s wort (Hypericum perforatum).

Effect of Tegretol on plasma levels of concomitant agents

Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirement: levothyroxine, clobazam, clonazepam, ethosuximide, primidone, valproic acid, alprazolam, corticosteroids, (e.g. prednisolone, dexamethasone); ciclosporin, digoxin, doxycycline; dihydropyridine derivatives, e.g. felodipine and isradipine; indinavir, saquinavir, ritonavir, haloperidol, imipramine, buprenorphine, methadone, paracetamol, tramadol, products containing oestrogens and/or progestogens (alternative contraceptive methods should be considered) see Section 4.4 “Special Warnings and Precautions for Use”, gestrinone, tibolone, toremifene, theophylline, oral anticoagulants (warfarin and acenocoumarol), lamotrigine, tiagabine, topiramate, bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine), clozapine, oxcarbazapine, olanzapine, quetiapine, itraconazole, imatinib and risperidone.

Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine, and there have been rare reports of an increase in plasma mephenytoin.

Combinations that require specific consideration

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Combined use of carbamazepine with metoclopramide or major tranquillisers, e.g. haloperidol, thioridazine, may also result in an increase in neurological side-effects.

Because it (carbamazepine) is structurally related to tricyclic anti-depressants, the use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs); before administering Tegretol, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (e.g. pancuronium). Their dosage should be raised and patients monitored closely for a more rapid recovery from neuromuscular blockade than expected.

Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.

Pregnancy and lactation

Pregnancy

In animals (mice, rats and rabbits) oral administration of carbamazepine during organogenesis led to increased embryo mortality at a daily doses which caused maternal toxicity (above 200mg/kg b.w. daily i.e. 20 times the usual human dosage). In the rat there was also some evidence of abortion at 300mg/kg body weight daily. Near-term rat foetuses showed growth retardation, again at maternally toxic doses. There was no evidence of teratogenic potential in the three animal species tested but, in one study using mice, carbamazepine (40-240 mg/kg b.w. daily orally) caused defects (mainly dilatation of cerebral ventricles in 4.7% of exposed foetuses as compared with 1.3% in controls).

Pregnant women with epilepsy should be treated with special care.

In women of childbearing age Tegretol should, wherever possible, be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy.

If women receiving Tegretol become pregnant or plan to become pregnant, or if the problem of initiating treatment with Tegretol arises during pregnancy, the drug’s potential benefits must be carefully weighed against its possible hazards, particularly in the first three months of pregnancy. Minimum effective doses should be given and monitoring of plasma levels is recommended.

During pregnancy, an effective antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.

Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental disorders, including malformations. The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk has been reported, although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. However, there are reports on developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with Tegretol. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy.

In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1, be given to the mother during the last weeks of pregnancy as well as to the neonate.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Tegretol use. These reactions may represent a neonatal withdrawal syndrome.

Use during lactation

Carbamazepine passes into the breast milk (about 25-60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Tegretol may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).

Fertility

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Effects on ability to drive and use machines

The patient’s ability to react may be impaired by dizziness and drowsiness caused by Tegretol, especially at the start of treatment or in connection with dose adjustments; patients should therefore exercise due caution when driving a vehicle or operating machinery.

Undesirable effects

Particularly at the start of treatment with Tegretol, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions.

The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and divide the daily dosage into smaller (i.e. 3-4) fractional doses.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10) common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Blood and lymphatic system disorders

Very common: Leucopenia

Common: Thrombocytopenia, eosinophilia.

Rare: Leucocytosis, lymphadenopathy, folic acid deficiency.

Very rare: Agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda, reticulocytosis, and possibly haemolytic anaemia.

Immune system disorders

Rare: A delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon).

Very rare: Aseptic meningitis, with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic oedema.

Endocrine disorders

Common: Oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.

Very rare: Blood prolactin increased with or without clinical symptoms such as galactorrhoea, gynaecomastia, abnormal thyroid function tests; decreased l-thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol), leading to osteomalacia /osteoporosis, increased blood cholesterol, including HDL cholesterol and triglycerides.

Psychiatric disorders

Rare: Hallucinations (visual or auditory), depression, anorexia, restlessness, aggression, agitation, confusional state.

Very rare: Activation of psychosis.

Nervous system disorders

Very common: Dizziness, ataxia, drowsiness, fatigue.

Common: Headache, diplopia, accommodation disorders (e.g. blurred vision).

Uncommon: Abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus.

Rare: Orofacial dyskinesia, eye movement disturbances, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, muscle weakness, and paresis

Very rare: Taste disturbances, neuroleptic malignant syndrome

Eye disorders

Very rare: lenticular opacities, conjunctivitis, intraocular pressure increased

Ear and labyrinth disorders

Very rare: Hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

Cardiac disorders

Rare: Cardiac conduction disorders, hypertension or hypotension.

Very rare: Bradycardia, arrhythmia, atrioventricular block with syncope, circulatory collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thrombo-embolism (e.g. pulmonary embolism).

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia.

Gastro-intestinal disorders

Very common: Nausea, vomiting.

Common: Dry mouth, with suppositories rectal irritation may occur.

Uncommon: Diarrhoea, constipation.

Rare: Abdominal pain

Very rare: Glossitis, stomatitis, pancreatitis.

Hepatobiliary disorders

Very common: Increased-gamma-GT (due to hepatic enzyme induction), usually not clinically relevant.

Common: Increased blood alkaline phosphatase.

Uncommon: Increased transaminases.

Rare: Hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice.

Very rare: Granulomatous hepatitis. Hepatic failure.

Skin and subcutaneous tissue disorders

Very common: Dermatitus allergic, urticaria, which may be severe.

Uncommon: Exfoliative dermatitis and erythroderma.

Rare: Systemic lupus erythematosus, pruritus.

Very rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss, hirsutism.

Musculoskeletal, connective tissue and bone disorders

Very rare: Arthralgia, muscle pain, muscle spasms.

Renal and urinary disorders

Very rare: Interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/ azotaemia), urinary frequency, urinary retention, sexual disturbances/impotence.

Reproductive System

Very rare: Spermatogenesis abnormal (with decreased sperm count and/or motility).

Investigations

Very rare: Hypogammaglobulinaemia

* In some Asian countries also reported as rare. See also section 4.4 Special warnings and precautions for use.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.

There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients, these reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among individuals of Han Chinese, Thai and some other Asian ancestry (see sections 4.2 and 4.4 for further information).

Incompatibilities

None known.

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