04-14-2004, 08:38 AM #1Respected Member
- Join Date
- Apr 2002
- Miller's Crossing
Tamoxifen citrate tablets, a nonsteroidal antiestrogen, are for oral administration. Nolvadex tablets are available as:
10 mg Tablets: Each 10 mg tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.
20 mg Tablets: Each 20 mg tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.
Inactive Ingredients: Carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1).
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/ml and in 0.02 N HCl at 37°C, it is 0.2 mg/ml.
Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.
Tamoxifen is extensively metabolized after oral administration. Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose is excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.
N-desmethyl tamoxifen was the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma.
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/ml (range 35 to 45 ng/ml) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life about 5 to 7 days. The average peak plasma concentration for N-desmethyl tamoxifen is 15 ng/ml (range 10 to 20 ng/ml). Chronic administration of 10 mg tamoxifen given twice daily for three months to patients results in average steady-state plasma concentrations of 120 ng/ml (range 67 to 183 ng/ml) for tamoxifen and 336 ng/ml (range 148 to 654 ng/ml) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/ml (range 71 to 183 ng/ml) and 353 ng/ml (range 152 to 706 ng/ml), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite.
In a 3-month crossover steady-state bioavailability study with tamoxifen citrate 10 mg twice a day versus tamoxifen citrate 20 mg given once daily, tamoxifen citrate 20 mg taken once daily has comparable bioavailability to tamoxifen citrate 10 mg taken twice a day.
Adverse reactions to tamoxifen citrate are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen citrate as compared to placebo.
Metastatic Breast Cancer
Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen citrate and generally subside rapidly.
In patients treated with tamoxifen citrate for metastatic breast cancer, the most frequent adverse reaction to tamoxifen citrate is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.
Male Breast Cancer
Tamoxifen citrate is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen citrate in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported
When tamoxifen citrate is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial.
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen citrate.
Tamoxifen, N-desmethyl tamoxifen and 4-hydroxytamoxifen have been found to be potent inhibitors of hepatic cytochrome p-450 mixed function oxidases. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known.
One patient receiving tamoxifen citrate with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/ml vs. mean value of 122 ng/ml). However, the clinical significance of this finding is not known.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.
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