1.NOLVADEX HISTORY
(How was Nolvadex discovered?)

Nolvadex is a product of Astra-Zeneca International.

The US FDA approved Astra-Zeneca on October 29, 1998.

Astra-Zeneca is one of the world's leading pharmaceutical companies with 60,000 people - 12,000 in the US alone - dedicated to the discovery, development, and marketing of new pharmaceutical solutions, to enrich the quality of people's lives all over the world.

The focused areas of research include:

• Cardiovascular
• Gastrointestinal
• Infection
• Neuroscience
• Oncology
• Respiratory

Astra-Zeneca discovers new medicines that are designed to improve the health and quality of life of patients around the world - medicines which are innovative, effective and which offer added benefits such as reduced side effects or better ways of taking the treatment. Astra-Zeneca also focuses on getting the best from every medicine they make by exploring all the ways it can be used or improved.

At Astra-Zeneca, innovation is about more than just research. 

Note: World-drugs.net sells generic version of Nolvadex

2. NOLVADEX FACTS

Nolvadex tablets contain the active ingredient tamoxifen citrate, which is a type of medicine known as an 'anti-oestrogen'. Tamoxifen is mainly used to treat women with breast cancers that respond to the female sex hormone, oestrogen.

Nolvadex works by blocking the oestrogen receptors, thereby blocking the effect of oestrogen on the cancer. This starves the breast cancer cells and stops them from growing.

Nolvadex helps prevent breast cancer from spreading to other areas of the body and also reduces risk of developing cancer in the other breast. 

3.ABOUT NOLVADEX MEDICATION

What is breast cancer?

Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast.

The breast is made up of lobes and ducts. Each breast has 15 to 20 sections called lobes, which have many smaller sections called lobules. Lobules end in dozens of tiny bulbs that can produce milk. The lobes, lobules, and bulbs are linked by thin tubes called ducts.

Each breast also has blood vessels and lymph vessels. The lymph vessels carry an almost colorless fluid called lymph. Lymph vessels lead to organs called lymph nodes. Lymph nodes are small bean-shaped structures that are found throughout the body. They filter substances in lymph and help fight infection and disease. Clusters of lymph nodes are found near the breast in the axilla (under the arm), above the collarbone, and in the chest.

The most common type of breast cancer is ductal carcinoma, which begins in the cells of the ducts. Cancer that begins in the lobes or lobules is called lobular carcinoma and is more often found in both breasts than are other types of breast cancer. Inflammatory breast cancer is an uncommon type of breast cancer in which the breast is warm, red, and swollen.

Risks in developing breast cancer

Age and health history can affect the risk of developing breast cancer.

Anything that increases your chance of getting a disease is called a risk factor. Risk factors for breast cancer include the following:

• Older age.
• Menstruating at an early age.
• Older age at first birth or never having given birth.
• A personal history of breast cancer or benign (noncancer) breast disease.
• A mother or sister with breast cancer.
• Treatment with radiation therapy to the breast/chest.
• Breast tissue that is dense on a mammogram.
• Taking hormones such as estrogen and progesterone.
• Drinking alcoholic beverages.
• Being white.
• Breast cancer is sometimes caused by inherited gene mutations (changes).

The genes in cells carry the hereditary information that is received from a person's parents. Hereditary Breast cancer makes up approximately 5% to 10% of all Breast cancer. Some altered genes related to Breast cancer are more common in certain ethnic groups.

Women who have an altered gene related to Breast cancer and who have had Breast cancer in one breast have an increased risk of developing Breast cancer in the other breast. These women also have an increased risk of developing ovarian cancer, and may have an increased risk of developing other cancers. Men who have an altered gene related to Breast cancer also have an increased risk of developing this disease.

Tests have been developed that can detect altered genes. These genetic tests are sometimes done for members of families with a high risk of cancer.

Tests that are used to examine the breasts and detect (find) and diagnose Breast cancer. A doctor should be seen if changes in the breast are noticed. The following tests and procedures may be used:

Mammogram : An x-ray of the breast.

Biopsy : The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. If a lump in the breast is found, the doctor may need to cut out a small piece of the lump. Four types of biopsies are as follows:

• Excisional biopsy: The removal of an entire lump or suspicious tissue.
• Incisional biopsy: The removal of part of a lump or suspicious tissue.
• Core biopsy: The removal of part of a lump or suspicious tissue using a wide needle.
• Needle biopsy or fine-needle aspiration biopsy: The removal of part of a lump, suspicious tissue, or fluid, using a thin needle.

Estrogen and progesterone receptor test : A test to measure the amount of estrogen and progesterone (hormones) receptors in cancer tissue. If cancer is found in the breast, tissue from the tumor is examined in the laboratory to find out whether estrogen and progesterone could affect the way cancer grows. The test results show whether hormone therapy may stop the cancer from growing.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

• The stage of the cancer (whether it is in the breast only or has spread to lymph nodes or other places in the body).
• The type of Breast cancer.
• Estrogen-receptor and progesterone-receptor levels in the tumor tissue.
• A woman's age, general health, and menopausal status (whether a woman is still having menstrual periods).
• Whether the cancer has just been diagnosed or has recurred.  

Stages of Breast Cancer

After Breast cancer has been diagnosed, tests are done to find out if cancer cells have spread within the breast or to other parts of the body.

The process used to find out whether the cancer has spread within the breast or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following stages are used for Breast cancer:

Stage 0 (carcinoma in situ)

There are 2 types of breast carcinoma in situ:

• Ductal carcinoma in situ (DCIS) is a noninvasive, precancerous condition in which abnormal cells are found in the lining of a breast duct. The abnormal cells have not spread outside the duct to other tissues in the breast. In some cases, DCIS may become invasive cancer and spread to other tissues, although it is not known at this time how to predict which lesions will become invasive.  

• Lobular carcinoma in situ (LCIS) is a condition in which abnormal cells are found in the lobules of the breast. This condition seldom becomes invasive cancer; however, having lobular carcinoma in situ in one breast increases the risk of developing Breast cancer in either breast.  

 

TUMOR SIZES

Stage I
In stage I, the tumor is 2 centimeters or smaller and has not spread outside the breast.

Stage IIA
In stage IIA:

• no tumor is found in the breast, but cancer is found in the axillary lymph nodes (the lymph nodes under the arm); or
• the tumor is 2 centimeters or smaller and has spread to the axillary lymph nodes; or
• the tumor is larger than 2 centimeters but not larger than 5 centimeters and has not spread to the axillary lymph nodes.

Stage IIB
In stage IIB, the tumor is either:

• larger than 2 centimeters but not larger than 5 centimeters and has spread to the axillary lymph nodes; or
• larger than 5 centimeters but has not spread to the axillary lymph nodes.

Stage IIIA
In stage IIIA:

• no tumor is found in the breast, but cancer is found in axillary lymph nodes that are attached to each other or to other structures; or
• the tumor is 5 centimeters or smaller and has spread to axillary lymph nodes that are attached to each other or to other structures; or
• the tumor is larger than 5 centimeters and has spread to axillary lymph nodes that may be attached to each other or to other structures.

Stage IIIB
In stage IIIB, the cancer may be any size and:

• has spread to tissues near the breast (the skin or chest wall, including the ribs and muscles in the chest); and
• may have spread to lymph nodes within the breast or under the arm.

Stage IIIC
In stage IIIC, the cancer:

• has spread to lymph nodes beneath the collarbone and near the neck; and
• may have spread to lymph nodes within the breast or under the arm and to tissues near the breast.

Stage IIIC Breast cancer is divided into operable and inoperable stage IIIC.

In operable stage IIIC, the cancer :

• is found in 10 or more of the lymph nodes under the arm; or
• is found in the lymph nodes beneath the collarbone and near the neck on the same side of the body as the breast with cancer; or
• is found in lymph nodes within the breast itself and in lymph nodes under the arm.
• In inoperable stage IIIC Breast cancer, the cancer has spread to the lymph nodes above the collarbone and near the neck on the same side of the body as the breast with cancer.

Stage IV
In stage IV, the cancer has spread to other organs of the body, most often the bones, lungs, liver, or brain. 

Treatment for Breast cancer
Different types of treatment are available for patients with Breast cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI Web site. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

Four types of standard treatment are used:

1.) Surgery
Most patients with Breast cancer have surgery to remove the cancer from the breast. Some of the lymph nodes under the arm are usually taken out and looked at under a microscope to see if they contain cancer cells.

Breast-conserving surgery, an operation to remove the cancer but not the breast itself, includes the following:

• Lumpectomy: A surgical procedure to remove a tumor (lump) and a small amount of normal tissue around it.
• Partial mastectomy: A surgical procedure to remove the part of the breast that contains cancer and some normal tissue around it. This procedure is also called a segmental mastectomy.

BREAST CONSERVING SURGERY
Dotted lines show area containing the tumor that is removed and some of the lymph nodes that may be removed.

Patients who are treated with breast-conserving surgery may also have some of the lymph nodes under the arm removed for biopsy. This procedure is called lymph node dissection. It may be done at the same time as the breast-conserving surgery or after. Lymph node dissection is done through a separate incision.

Other types of surgery include the following:

• Total mastectomy: A surgical procedure to remove the whole breast that contains cancer. This procedure is also called a simple mastectomy. Some of the lymph nodes under the arm may be removed for biopsy at the same time as the breast surgery or after. This is done through a separate incision.

TOTAL MASTECTOMY

Dotted line shows entire breast is removed. Some lymph nodes under the arm may also be removed.

•  Modified radical mastectomy: A surgical procedure to remove the whole breast that contains cancer, many of the lymph nodes under the arm, the lining over the chest muscles, and sometimes, part of the chest wall muscles.

MODIFIED RADICAL MASTECTOMY
Dotted line shows entire breast and some lymph nodes are removed. Part of the chest wall muscle may also be removed. 

Radical mastectomy: A surgical procedure to remove the breast that contains cancer, chest wall muscles under the breast, and all of the lymph nodes under the arm. This procedure is sometimes called a Halsted radical mastectomy.

Even if the doctor removes all of the cancer that can be seen at the time of surgery, the patient may be given radiation therapy, chemotherapy, or hormone therapy after surgery to try to kill any cancer cells that may be left. Treatment given after surgery to increase the chances of a cure is called adjuvant therapy.

If a patient is going to have a mastectomy, breast reconstruction (surgery to rebuild a breast's shape after a mastectomy) may be considered. Breast reconstruction may be done at the time of the mastectomy or at a future time. The reconstructed breast may be made with the patient's own (nonbreast) tissue or by using implants filled with saline or silicone gel. The Food and Drug Administration (FDA) has decided that breast implants filled with silicone gel may be used only in clinical trials. 

2.) Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

3.) Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

4.) Hormone therapy
Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Hormones are substances produced by glands in the body and circulated in the bloodstream. The presence of some hormones can cause certain cancers to grow. If tests show that the cancer cells have places where hormones can attach (receptors), drugs, surgery, or radiation therapy are used to reduce the production of hormones or block them from working.

Hormone therapy with Nolvadex is often given to patients with early stages of Breast cancer and those with metastatic Breast cancer (cancer that has spread to other parts of the body). Hormone therapy with Nolvadex or estrogens can act on cells all over the body and may increase the chance of developing endometrial cancer. Women taking Nolvadex should have a pelvic examination every year to look for any signs of cancer. Any vaginal bleeding, other than menstrual bleeding, should be reported to a doctor as soon as possible.

Latest therapies include:

1.) Sentinel lymph node biopsy followed by surgery
Sentinel lymph node biopsy is the removal of the sentinel lymph node (the first lymph node the cancer is likely to spread to from the tumor) during surgery. A radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through the lymph ducts to the lymph nodes. The first lymph node to receive the substance or dye is removed for biopsy. A pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are not found, it may not be necessary to remove more lymph nodes. After the sentinel lymph node biopsy, the surgeon removes the tumor (breast-conserving surgery or mastectomy).

 

SENTINEL LYMPH NODE BIOPSY. Radioactive substance and/or blue dye is injected near the tumor (first panel), the injected material is followed visually or with a probe (middle panel), and the first lymph nodes to take up the material are removed and checked for cancer cells (last panel).

2.) High-dose chemotherapy with stem cell transplant
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Studies have shown that high-dose chemotherapy followed by stem cell transplant does not work better than standard chemotherapy in the treatment of breast cancer. Doctors have decided that, for now, high-dose chemotherapy should be tested only in clinical trials. Before taking part in such a trial, women should talk with their doctors about the serious side effects, including death, that may be caused by high-dose chemotherapy.

3.) Monoclonal antibodies as adjuvant therapy
Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies are also used in combination with chemotherapy as adjuvant therapy.

Trastuzumab (Herceptin) is a monoclonal antibody that blocks the effects of the growth factor protein HER2, which transmits growth signals to breast cancer cells. About one-fourth of patients with breast cancer have tumors that may be treated with trastuzumab combined with chemotherapy.

4.NOLVADEX EFFECTIVENESS
(When is Nolvadex best taken?)

Following a single oral dose of 20 mg Nolvadex, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after Nolvadex dosing. The decline in plasma concentrations of Nolvadex is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of Nolvadex 10 mg dose given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 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 71-183 ng/mL) and 353 ng/mL (range 152-706 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 steady-state, crossover study of 10 mg Nolvadex tablets given twice a day vs. a 20 mg Nolvadex tablet given once daily, the 20 mg Nolvadex tablet was bioequivalent to the 10 mg Nolvadex tablets.

Metabolism:
Nolvadex is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of Nolvadex have been identified as minor metabolites in plasma.

Excretion:
Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose of Nolvadex was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. Nolvadex is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity. 

5.NOLVADEX EFFECTS ON SPECIAL POPULATION
(How do different people react to Nolvadex?)

The effects of age, gender and race on the pharmacokinetics of Nolvadex have not been determined.

Pediatric Patients:
The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of Nolvadex in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for Nolvadex. A one-compartment model provided the best fit to the data.

In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of Nolvadex for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Nolvadex therapy in girls have not been established. In adults treated with Nolvadex an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted.

Nursing Mothers:
Nolvadex has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that Nolvadex significantly inhibits early postpartum milk production. In both studies Nolvadex was administered within 24 hours of delivery for between 5 and 18 days. The effect of Nolvadex on established milk production is not known.

There are no data that address whether Nolvadex is excreted into human milk. If excreted, there are no data regarding the effects of Nolvadex in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of Nolvadex to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis.

It is not known if Nolvadex is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Nolvadex, women taking Nolvadex should not breast feed.

6.NOLVADEX EFFECTS ON MEDICAL CONDITIONS
(How does Nolvadex affect your existing condition/ailment?)

The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined. 

7.OTHER/ALTERNATE USES OF NOLVADEX
(What else does Nolvadex treat?)

Nolvadex is also used in the treatment of female infertility that is caused by problems with ovulation. Again, it acts by blocking oestrogen receptors, this time in a part of the brain called the hypothalamus. The effect of this is an increase in the levels of the hormones that control the development and release of an egg. These hormones are released from the pituitary gland and are known as follicle stimulating hormone (FSH) and luteinising hormone (LH). FSH stimulates the ovaries and LH causes the release of an egg from the ovaries (ovulation).

8.ADVERSE/SIDE EFFECTS of NOLVADEX
(What are the side effects of Nolvadex?)

Adverse reactions to Nolvadex 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 Nolvadex 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 Nolvadex and generally subside rapidly.

In patients treated with Nolvadex for metastatic breast cancer, the most frequent adverse reaction to Nolvadex 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.

Premenopausal Women:
The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials, which compared Nolvadex therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Adverse Reactions	Nolvadex All Effects % of Women n=104	Ovarian Ablation All Effects % of Women n=100
Flush	33	46
Amenorrhea	16	69
Altered Menses	13	5
Oligomenorrhea	9	1
Bone Pain	6	6
Menstrual Disorder	6	4
Nausea	5	4
Cough/Coughing	4	1
Edema	4	1
Fatigue	4	1
Muscoloskeletal Pain	3	0
Pain	3	4
Ovarian Cyst(s)	3	2
Depression	2	2
Abdominal Cramps	1	2
Anorexia	1	2

Male Breast Cancer:
Nolvadex is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of Nolvadex in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of Nolvadex 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.

Adjuvant Breast Cancer:
In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of Nolvadex 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on Nolvadex than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with Nolvadex compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in Nolvadex-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with Nolvadex who had thrombotic events died.

Adverse Effect	% of Women
NOLVADEX	Placebo (n=1437)	(n=1422)
Hot Flashes	64	48
Fluid Retention	32	30
Vaginal Discharge	30	15
Nausea	26	24
Irregular Menses	25	19
Weight Loss (>5%)	23	18
Skin Changes	19	15
Increased SGOT	5	3
Increased Bilirubin	2	1
Increased Creatinine	2	1
Thrombocytopenia	2	1
Thrombotic Events
Deep Vein Thrombosis	0.8	0.2
Pulmonary Embolism	0.5	0.2
Superficial Phlebitis	0.4	0

Postmarketing experience:

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with Nolvadex therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Nolvadex.