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Tamoxifen citrate

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Tamoxifen
     1.2 Group
       Anti-oestrogen, non-steroidal derivative of triphenyl ethylene 
       ATC: L02B A01
     1.3 Synonyms
       (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethylamine citrate
       ICI 46 474
       [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene]
     1.4 Identification numbers
       1.4.1 CAS number
             10540
       1.4.2 Other numbers
             Tamoxifen citrate: 54965-24-1
     1.5 Brand names, Trade names
       Emblon (Berk)
       Noltam (Lederle)
       Nolvadex (ICI)
       Nolvadex-D (ICI)
       Nolvadex forte(ICI)
       Tamofen (Tillotts)
     1.6 Manufacturers, Importers
       Berk Pharmaceuticals Ltd., ICI Pharmaceuticals (UK).,
       Lederle Laboratories., Tillotts Laboratories.
    2. SUMMARY
     2.1 Main risks and target organs
       There is no record of serious effects from tamoxifen after 
       acute overdosage.
       
       Adverse effects in therapeutic use are usually mild. They 
       include effects caused by antagonism of endogenous oestrogens: 
       hot flushes, non-specific gastrointestinal effects (nausea and 
       vomiting), central nervous system effects, and rare ocular 
       effects. Adverse haematological effects have been reported, 
       also isolated cases of death from peliosis hepatis and from 
       hyperlipidaemia.
       
       In the treatment of breast cancer, hypercalcaemia and tumour 
       flare can occur.
     2.2 Summary of clinical effects
       Anti-oestrogenic effects in women treated with tamoxifen 
       include vasomotor symptoms (hot flushes), vaginal bleeding and 
       (in premenopausal women) irregular menses, and pruritus 
       vulvae.  Nausea and vomiting can occur.
       
       Dizziness, lethargy, depression, irritability and cerebellar 
       dysfunction have been described.
       
       Reversible retinopathy with macular oedema has been reported 
       after high cumulative doses (>7g), and corneal changes can 
       occur.

       
       Thrombocytopenia or leukopenia have been associated with 
       tamoxifen treatment.  Thromboembolism, which may be due to the 
       disease rather than the treatment, has been recorded in women 
       given tamoxifen for breast cancer.
     2.3 Diagnosis
       Based on history of exposure and occurrence of adverse effects 
       such as hot flushes, nausea, vomiting, ocular disorders, 
       tumour flare, hypercalcemia, vaginal bleeding and CNS signs 
       and symptoms.
     2.4 First aid measures and management principles
       General measures such as inducing emesis or gastric lavage may 
       be indicated in massive overdosage.
       
       Treatment is symptomatic.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Synthetic.
     3.2 Chemical structure
       (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-
       dimethylethylamine citrate
       
       C26H29NO, C6H8O7
       
       [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1, 2-diphenylbut-1-ene]
       
       Molecular weight = 563.6
       
       pKa = 8.85
     3.3 Physical properties
       3.3.1 Properties of the substance
             Solubility in water at 37 C = 0.05 g/100 ml.
       3.3.2 Properties of the locally available formulation
             No data available.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Assumed to be at least 5 years.
       3.4.2 Shelf-life of the locally available formulation
             Assumed to be at least 5 years.
       3.4.3 Storage conditions
             Store between 15 and 30 C
             Protect from light
       3.4.4 Bioavailability
             (to be added)
       3.4.5 Specific properties and composition
             (to be added by centre).
    4. USES
     4.1 Indications
        Treatment of advanced breast cancer and adjuvant 
        treatment of early breast cancer.
        Treatment of anovulatory infertility.
     4.2 Therapeutic dosage
       4.2.1 Adults
             Breast cancer: initial dose 10 mg twice daily;
             if no response after 1 month, 20 mg twice daily.
             

             Infertility: regular menstruation, 10 mg twice daily on 
             days 2,3,4 and 5 of cycle, increasing to 20 mg twice 
             daily and 40 mg twice daily in successive cycles if 
             ovulation does not occur.
             
             Amenorrhoea: 10 mg twice daily on 4 successive days, 
             increasing to 20 mg twice  daily and 40 mg twice daily 
             after intervals of 45 and 90 days if ovulation does not 
             occur.
       4.2.2 Children
             No data available.
     4.3 Contraindications
       Pregnancy is an absolute contraindication because of the anti-
       oestrogenic effects.
    5. ROUTES OF ENTRY
     5.1 Oral
       Usual route of entry
     5.2 Inhalation
       Not relevant.
     5.3 Dermal
       Not relevant.
     5.4 Eye
       Not relevant.
     5.5 Parenteral
       Not relevant.
     5.6 Other
       Not relevant.
    6. KINETICS
     6.1 Absorption by route of exposure
       Peak concentrations occur 4-7 h after oral dosing. Peak 
       concentrations after single oral doses of 20 mg are about 40 
       /l. There is no information on absolute bioavailability.
       (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989)
     6.2 Distribution by route of exposure
       Tamoxifen is more than 99% protein-bound in serum, 
       predominantly to albumin. In patients with breast cancer, 
       concentrations of tamoxifen and its metabolites in pleural, 
       pericardial and peritoneal effusion fluid are between 20 and 
       100% of those in serum, but only trace amounts enter the 
       cerebrospinal fluid. Concentrations in breast cancer tissue 
       exceed those in serum.
       
       The volume of distribution is 50-60 l/kg (Martindale, 1989; 
       Buckley & Goa, 1989; Lien et al., 1989)
     6.3 Biological half-life by route of exposure
       The elimination is biphasic, with an initial half-life of 
       around 7 h and a terminal half-life of 7-11 days. (Martindale, 
       1989; Buckley & Goa, 1989; Lien et al., 1989)
     6.4 Metabolism
       Tamoxifen citrate undergoes extensive hepatic metabolism to:
       
       1-(4-ethanolyloxyphenyl)-1,2-diphenylbut-1-ene (the primary 
       alcohol)
       N-desmethyl tamoxifen
       4-hydroxy tamoxifen
       4-hydroxy-N-desmethyl tamoxifen

       N-desdimethyl tamoxifen
       
       (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989)
     6.5 Elimination by route of exposure
       The major excretory route is via the bile as metabolites and 
       enterohepatic recirculation occurs. Less than 1% is excreted 
       in the urine. (Martindale, 1989; Buckley & Goa, 1989; Lien et 
       al., 1989).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             The adverse effects observed are due mainly to its anti-
             oestrogen effect, as Tamoxifen and certain of its 
             metabolites antagonise the effects of oestrogens in 
             oestrogen-sensitive tissues.
       7.1.2 Pharmacodynamics
             Tamoxifen and several of its metabolites (particularly 4-
             hydroxytamoxifen) bind to nuclear oestrogen receptors in 
             oestrogen-sensitive tissues, and also to a microsomal 
             protein termed the 'anti-oestrogen binding site'. 
             Tamoxifen interferes with the physiological sequence by 
             which oestrogen binds to its receptor,  is translocated 
             in the nucleus and then activates messenger RNA  
             synthesis. Although the tamoxifen-receptor complex is 
             transported  in the nucleus in the same way as oestrogen-
             receptor complex, it  fails to activate synthesis of 
             mRNA. (Buckley & Goa, 1990)
             
             A meta-analysis of published trials in breast cancer 
             (Early Breast Cancer Trialists, 1988) demonstrates a 
             reduction in odds of death of about 20% over the first 5 
             years from diagnosis in women aged over 50 years.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     There is no information on the acute toxicity of 
                     tamoxifen in overdosage.
                     
                     The lowest cumulative dose of tamoxifen known to 
                     have induced retinopathy, an adverse effect 
                     which is recognised to be dose-dependent, is 7.7 
                     g  (Griffiths, 1987)
             7.2.1.2 Children
                     No data available.
       7.2.2 Relevant animal data
             In some animal species, oestrogenic agonist effects 
             become manifest at dosages equivalent to 10-100 times 
             the human therapeutic dose (ABPI, 1989).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       A case-control study (Hardell, 1988) showed a significantly 
       increased relative risk of carcinoma of the uterus in women 
       previously treated with tamoxifen AND who had previously had 
       radiotherapy involving the uterus. The study showed an 
       increase in relative risk with tamoxifen treatment alone which 

       was NOT statistically significant (see also Section 7.4).
     7.4 Teratogenicity
       Studies in neonatal male (Taguchi, 1987) and female (Taguchi & 
       Nishizuka, 1985) mice at relative doses 10 times higher than 
       those used in humans have shown genital tract abnormalities 
       similar to those caused by diethylstilboestrol, a known 
       transplacental carcinogen (diethylstilboestrol causes vaginal 
       adenosis, which predisposes to clear cell carcinoma).
     7.5 Mutagenicity
       Tamoxifen is believed not to be mutagenic (Martindale, 1989).
     7.6 Interactions
       Tamoxifen POTENTIATES the anticoagulant effect of warfarin, 
       and this interaction can be life-threatening (Tenni et al, 
       1989; Ritchie & Grant, 1989).
     7.7 Main adverse effects
       Adverse effects are usually mild.  Thrombocytopenia, 
       leukopenia, thromboembolism, peliosis hepatis and 
       hyperlipidaemia have been mentioned in case reports.
       
       Severe hypercalcaemia can occur rarely when treatment is 
       started in patients with metastases to bone.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis

             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             No data available.
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Retinal damage and keratitis have been reported in 
             patients after large cumulative doses of tamoxifen, 
             generally over 180 mg per day for more than 1 year 
             (Buckley & Goa, 1989), though sometimes with smaller 
             doses (Griffiths, 1987).  There seems to be correlation 
             between long-term tamoxifen administration and 
             endometrical proliferation (Uziely et al, 1993).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       No data available.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             No data available.
       9.4.2 Respiratory
             No data available.
       9.4.3 Neurological
             9.4.3.1 CNS
                     A case of depression, syncope, and 
                     incoordination has been described during therapy 
                     with 10 mg twice daily (Pluss et al., 1984). The 

                     symptoms resolved when tamoxifen was 
                     discontinued and reappeared when treatment was 
                     restarted.
             9.4.3.2 Peripheral nervous system
                     No data available.
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     No data available.
       9.4.4 Gastrointestinal
             Nausea and vomiting occur with therapeutic doses in some 
             patients, and are anticipated in overdosage (ABPI, 1989)
       9.4.5 Hepatic
             A fatal case of peliosis hepatis has been reported in a 
             woman treated with tamoxifen for 2 years after 
             mastectomy for carcinoma (Loomus et al., 1983).
       9.4.6 Urinary
             9.4.6.1 Renal
                     No data available.
             9.4.6.2 Other
                     A case of persistent nocturnal priapism has been 
                     reported (Fernando & Tobias, 1989).
       9.4.7 Endocrine and reproductive systems
             The anti-oestrogenic effects of tamoxifen in 
             premenopausal women receiving therapeutic doses can 
             cause irregular menses.
             
             Anti-oestrogenic adverse effects in women treated with 
             tamoxifen include vasomotor symptoms (hot flushes), 
             vaginal bleeding and pruritus vulvae (Buckley & Goa, 
             1989).
       9.4.8 Dermatological
             No data available.
       9.4.9 Eye, ear, nose, throat: local effects
             Treatment has been associated with retinal and corneal 
             changes: see para 9.2.
       9.4.10 Haematological
              Thromboembolism may be more common in patients treated 
              with tamoxifen, though this is not certain, as patients 
              with cancer are at increased risk anyway.
              A small reduction in antithrombin III concentration was 
              noted in a study of 11 postmenopausal women treated 
              with tamoxifen, but it was clinically insignificant, 
              and no significant reduction was seen in a group of 
              premenopausal women (Jordan et al., 1987).
              
              Thrombocytopenia and leukopenia can occur during 
              therapy, but are not usually severe (ABPI, 1989). One 
              case of severe myelosuppression has been reported 
              (International Adjuvant Therapy Organisation, 1985).
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances

                       Severe hypercalcaemia, associated with 
                       increased bone resorption, has been noted when 
                       patients with bony metastases commenced 
                       therapy (Martindale, 1989).
              9.4.12.3 Others
                       Severe hyperlipidaemia is occasionally seen, 
                       and has been ascribed to an oestrogenic effect 
                       (Noguchi et al.,  1987)
       9.4.13 Allergic reactions
              No data available.
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              Pregnancy, breast feeding, enzyme deficiencies: no data 
              available (see sections 7.3 and 7.4)
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         It is unlikely that serious acute toxicity would occur, and 
         management is supportive.  The stomach should be emptied 
         after massive overdosage.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                No data available.
         10.2.2 Biomedical analysis
                Urea, creatinine and electrolytes may be helpful in 
                the assessment of patients who are vomiting.
         10.2.3 Toxicological analysis
                Not relevant.
         10.2.4 Other investigations
                Not relevant.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Nausea and vomiting may make intravenous fluid replacement 
         necessary.
      10.4 Decontamination
         Gastric lavage may be of value in massive overdosage, but 
         there are no data on this subject.
      10.5 Elimination
         Therapy to enhance elimination is not likely to be effective,
          given the large volume of distribution.
      10.6 Antidote treatment
         10.6.1 Adults
                Not relevant.
         10.6.2 Children
                Not relevant.
      10.7 Management discussion
         No data available.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         No data available.
      11.2 Internally extracted data on cases
         One manufacturer (ICI) is aware of the case of a woman aged 
         51 years who claimed to have swallowed 100 x 10 mg tablets 

         of tamoxifen, and who suffered no ill effects (JI Landles, 
         personal communication).
      11.3 Internal cases
         No data available.
    12. Additional information
      12.1 Availability of antidotes
         Not relevant.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         No data available.
    13. REFERENCES
    ABPI (Association of the British Pharmaceutical Industry) (1989) 
    Data Sheet Compendium. London.
    
    Buckley M M-T, Goa KL (1989).  Tamoxifen: a reappraisal of its 
    pharmacodynamic and pharmacokinetic properties and therapeutic 
    use. Drugs, 37: 451-490.
    
    Early Breast Cancer Trialists Collaborative Group (1988).  
    Effects of adjuvant tamoxifen and of cytotoxic therapy on 
    mortality in early breast cancer. New Eng. J. Med., 319: 1681-
    1692.
    
    Fernando IN, Tobias JS (1989).  Priapism in patient on tamoxifen. 
     Lancet; i:436
    
    Griffiths MFP (1987).  Tamoxifen retinopathy at low dosage. Am. 
    J. Ophthalmol., 104: 185-6.
    
    Hardell L (1988).  Pelvic irradiation and tamoxifen as risk 
    factors for carcinoma of cervix uteri. Lancet, ii: 1432.
    
    International Adjuvant Therapy Group (1985). Myelosuppression 
    occurring after receiving tamoxifen for breast cancer. Br, J. 
    Radiol., 58: 1220.
    
    Jordan VC, Fritz NF, Tormey DC (9187).  Long-term adjuvant 
    therapy with tamoxifen: effect on sex hormone binding globulin 
    and antithrombin III. Cancer Res., 47: 4517-4519.
    
    Lien EA, Solheim E, Lea OA et al (1989).  Distribution of 4-
    hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in 
    human biological fluids during tamoxifen treatment. Cancer Res., 
    49: 2175-2183.
    
    Lipton A, Harvey HA, Hamilton RW (1984).  Venous thrombosis as a 
    side effect of tamoxifen treatment. Cancer Treatment Reports, 68: 
    887-889.
    
    Loomus GN, Aneja P, Bota RA (1983).  A case of peliosis hepatis 
    in association with tamoxifen therapy. Am. J. Clin. Path., 80: 
    881-882.
    
    Reynolds EF, Ed (1989). Martindale, The Extra Pharmacopoeia. 29th 
    edition. Pharmaceutical Press, London.

    
    Merck Index (1983).  10th edition. Merck & Co., Inc., Rahaway, 
    NJ.
    
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author:   Dr R.E. Ferner
              Northern Drug and Therapeutics Centre
              The Wolfson Unit
              Royal Victoria Infirmary
              Newcastle-upon-Tyne NE1 4LP
              United Kingdom
    
              Tel: 44-91-2328511
              Fax: 44-91-2323613
    
    Date:         15 April 1990
    
    Peer Review:  Strasbourg, France, April 1990
    
    Review:       IPCS, May 1994




    See Also:
       Toxicological Abbreviations