Summary Of Exposure |
A) USES: Selective estrogen modulators are a class of compounds that act on estrogen receptors for a variety of uses including anovulation, managing menopause symptoms, contraception, osteoporosis, breast cancer, and vaginal atrophy. These drugs include tamoxifen, toremifene, and raloxifene. Clomiphene is covered under a separate management.
B) PHARMACOLOGY: These compounds work on the estrogen receptors with effects ranging from full agonists, to mixed agonists/antagonists (agonistic in some tissues while antagonistic in others) to pure antagonists to all estrogen receptors. For example, tamoxifen acts as an estrogen receptor antagonist in the breast, but as an agonist in the uterus. In contrast, raloxifene behaves as an antagonist in both tissues.
C) TOXICOLOGY: Toxic effects are secondary to their effects on estrogen receptors.
D) EPIDEMIOLOGY: Overdoses of these compounds are extremely rare; however, as they are widely used, adverse effects are common.
E) WITH THERAPEUTIC USE
1) ADVERSE EFFECTS: The most commonly reported adverse effects at recommended doses include hot flashes, nausea, and vomiting. Though infrequent, thromboembolism can occur and may be life-threatening. Other reported effects include liver damage, usually following chronic use, hypercalcemia and local disease flare with associated bone and tumor pain. There have been reports of fetal harm and toxicity with drugs from this class. Other potential side effects include ocular lesions, QT prolongation, neurologic effects (tremor, hyperreflexia, unsteady gait, dizziness) depression and gynecologic malignancies (uterine and endometrial cancers).
F) WITH POISONING/EXPOSURE
1) OVERDOSE: There is very little information regarding overdose of these compounds in humans. At doses 6 times (400 mg/m(2) the recommended doses (20 to 40 mg daily), neurotoxicity (seizures, tremor, hyperreflexia, unsteady gait, and dizziness) and ECG changes (prolonged QT interval) were noted.
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Vital Signs |
3.3.1) SUMMARY
A) Decreased respirations may occur following acute overdose.
3.3.2) RESPIRATIONS
A) Although not reported in humans, respiratory difficulties (no further description provided) have been observed in animal studies at the highest dose levels (Prod Info tamoxifen citrate oral tablets, 2007).
3.3.5) PULSE
A) Because ECG changes have been observed at higher doses (250 mg/m(2)), hearth rhythm and pulse may change following an acute overdose (Prod Info tamoxifen citrate oral tablets, 2007).
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Heent |
3.4.3) EYES
A) Corneal changes, cataracts, glaucoma, abnormal vision/diplopia, and retinopathy have been observed in patients receiving therapeutic tamoxifen or toremifene (Prod Info FARESTON(R) oral tablets, 2011; Prod Info tamoxifen citrate oral tablets, 2011).
B) TAMOXIFEN/INCIDENCE: Based on a review of the literature, the incidence rate of ocular lesions has been estimated at 6.3% in one prospective study. The mechanism related to the occurrence of tamoxifen-induced ocular lesions remains unknown (Ah-Song & Sasco, 1997).
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Cardiovascular |
3.5.1) SUMMARY
A) Prolongation of the QT interval has been with some of these agents.
B) Myocardial infarction has been reported with chronic therapeutic use.
3.5.2) CLINICAL EFFECTS
A) PROLONGED QT INTERVAL 1) TAMOXIFEN: Prolonged QT interval has been observed in the ECG of patients treated with a loading dose of 250 mg/m(2) followed by a maintenance dose of 80 mg/m(2) twice daily (Prod Info tamoxifen citrate oral tablets, 2007). a) The minimal dose needed to induce the QT prolongation was approximately 6 times higher than the maximum recommended dose.
2) TOREMIFENE: It has been shown to prolong the QTc interval in a dose- and concentration-related manner (Prod Info FARESTON(R) oral tablets, 2011). B) MYOCARDIAL INFARCTION 1) TAMOXIFEN: A 54-year-old woman who suffered an acute myocardial infarction due to thrombi in 2 coronary arteries had been taking tamoxifen 30 mg and medroxyprogesterone 1200 mg daily for 2 years (Nakagawa et al, 1994). 2) TOREMIFENE: In three controlled studies, myocardial infarction was reported in approximately 1% of patients during therapeutic use. Cardiac failure has also been reported rarely with use (Prod Info FARESTON(R) oral tablets, 2011). a) In the randomized, active-controlled, North American clinical trial in postmenopausal women with metastatic breast cancer, myocardial infarction was reported in 1% of patients who received toremifene 60 mg (n=221) compared with 1.5% of patients who received tamoxifen 20 mg (n=215) (Prod Info FARESTON(R) oral tablets, 2011).
C) HEART FAILURE 1) WITH THERAPEUTIC USE a) TOREMIFENE: In the randomized, active-controlled, North American clinical trial in postmenopausal women with metastatic breast cancer, cardiac failure was reported in 1% of patients who received toremifene 60 mg (n=221) compared with less than 1% of patients who received tamoxifen 20 mg (n=215) (Prod Info FARESTON(R) oral tablets, 2011).
D) CEREBROVASCULAR ACCIDENT 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) In the National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP), there were 34 cases of stroke in tamoxifen users compared to 24 cases in those receiving placebo. Seven cases were fatal; 3 in the placebo group and 4 in the tamoxifen group. The rate per 1000 women per year for tamoxifen was 1.43 ; relative risk was 1.42 (95% confidence interval 0.82 to 2.51) (Prod Info tamoxifen citrate oral tablets, 2011). a) In an updated follow-up (median 8.1 years) of the National Surgical Adjuvant Breast and Bowel Project B-24 (NSABP B-24) trial, 9 stroke events were reported; 7 in the tamoxifen arm, and 2 in the placebo arm (Prod Info tamoxifen citrate oral tablets, 2011).
b) A meta-analysis of randomized, controlled breast cancer trials involving tamoxifen as adjuvant therapy or prophylaxis found a 0.32% absolute increased risk of ischemic stroke (number needed to harm (NNH), 313) and a 0.3% increased risk of any form of stroke (NNH, 334) over an average study period of 4.9 years. Nine studies published since 1980 involving 39,601 patients, with 19,954 randomized to tamoxifen were analyzed). The mean age of patients ranged from 47 to 67 years. Tamoxifen was dosed at 20 milligrams daily in all trials. The calculated odds ratio (OR) of all strokes was 1.29 (95% confidence interval (CI) 0.92 to 1.81). Within the 6 trials that differentiated ischemic stroke from other stroke events, the OR for ischemic stroke was 1.82 (95% CI 1.41 to 2.36) (Bushnell & Goldstein, 2004).
b) RALOXIFENE 1) In the Raloxifene Use for The Heart (RUTH) trial, a randomized, placebo-controlled, double-blind clinical trial (n=10101), postmenopausal women (age range, 55-92 years) with documented coronary heart disease or at increased risk for coronary events treated with raloxifene hydrochloride (HCl) (average length of follow-up, 5.6 yr; median raloxifene HCl or placebo exposure, 5.1 yr) experienced an increased risk of death due to stroke. Fifty-nine patients (1.2%) treated with raloxifene HCl died due to stroke compared to 39 patients (0.8%) treated with placebo (Hazard ratio (HR), 1.49; 95% confidence interval (CI), 1-2.24, p=0.0499); however, there was no statistically significant difference between the groups in the incidence of stroke (4.9% (n=249) versus (vs) 4.4% (n=224), respectively; HR, 1.1; 95% CI, 0.92-1.32, p=0.3) or in all-cause mortality (incidence per year, 2.07% vs 2.25%, respectively). In women at risk for stroke (eg, previous history of stroke or transient ischemic attack, atrial fibrillation, hypertension, cigarette smokers), the risk-benefit balance should be considered before initiating raloxifene HCl (Prod Info EVISTA(R) oral tablet, 2007).
E) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) TOREMIFENE: In three clinical studies, toremifene administration was associated with infrequent reports of angina and dysrhythmias (no further description provided) during therapeutic use (Prod Info FARESTON(R) oral tablets, 2011).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) INTERSTITIAL PNEUMONIA 1) WITH THERAPEUTIC USE a) Postmarketing reports of interstitial pneumonitis have occurred following administration of tamoxifen (Prod Info tamoxifen citrate oral tablets, 2011).
B) PULMONARY EMBOLISM 1) WITH THERAPEUTIC USE a) TAMOXIFEN: In the National Surgical Adjuvant Breast and Bowel Projects (NSABP) P-1 trial, 18 cases of pulmonary embolism (including 3 fatalities) were reported in patients receiving tamoxifen (n=6681), compared with 6 cases in patients receiving placebo (n=6707). The event rates were 0.75 and 0.25 per 1000 women per year, for tamoxifen and placebo, respectively (relative risk, 3.01; 95% confidence interval, 1.15 to 9.27). In subjects receiving tamoxifen, pulmonary embolus appeared an average of 27 duration on therapy. Overall, 87% of the cases occurred in subjects greater than 50 years of age at time of randomization (Prod Info tamoxifen citrate oral tablets, 2011).
b) RALOXIFENE: In clinical trials, women treated with raloxifene hydrochloride (HCl) had an increased risk of venous thromboembolism (VTE). Approximately 1 in 100 patients treated with raloxifene HCl in clinical trials (average length raloxifene HCl exposure, 2.6 years) experienced a VTE, including deep vein thrombosis (DVT), pulmonary embolism (PE), and retinal vein thrombosis. Twenty-six patients treated with raloxifene HCl had a VTE compared to 11 patients treated with placebo (Hazard ratio, 2.4; 95% confidence interval, 1.2-4.5). The greatest risk for DVT and PE occurs during the first 4 months of treatment; additionally, the risk of DVT and PE is similar to the risk with hormone therapy. Discontinue raloxifene HCl at least 72 hours prior to and during prolonged immobilization (eg, post surgical recovery, prolonged bed rest) and therapy should restarted only after the patient is fully ambulatory. Advise women on raloxifene HCl to move about periodically during prolonged travel. Do not use raloxifene HCl in patients with active or a history of VTE and the risk-benefit balance should be considered before initiating raloxifene HCl in women at risk for VTE (eg, congestive heart failure, superficial thrombophlebitis, active malignancy) (Prod Info EVISTA(R) oral tablet, 2007).
3.6.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) RESPIRATORY DISORDER a) Respiratory difficulties have been observed in animal studies at the highest dose levels (Prod Info tamoxifen citrate oral tablets, 2007).
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Neurologic |
3.7.1) SUMMARY
A) Tremor, hyperreflexia, abnormal gait, dizziness and possibly seizures may result from an acute overdose.
B) Depression has been associated with these therapeutic agents.
3.7.2) CLINICAL EFFECTS
A) PARESTHESIA 1) WITH THERAPEUTIC USE a) SUMMARY: Paraesthesia and hypesthesia have been observed with therapeutic use of these agents (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011).
B) DEPRESSIVE DISORDER 1) WITH THERAPEUTIC USE a) SUMMARY 1) Depression has been associated with these agents during therapeutic use (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011; Prod Info tamoxifen citrate oral tablets, 2011).
b) TAMOXIFEN 1) CASE REPORT: Depression and emotional lability occurred in a 69-year-old woman with breast cancer after 2 weeks of tamoxifen 10 mg 3 times daily. Continuation of treatment resulted in dizziness, syncope, and cerebellar dysfunction. Symptoms of cerebellar dysfunction resolved within 2 to 4 days following drug withdrawal (Pluss & DiBella, 1984).
C) SEIZURE 1) WITH THERAPEUTIC USE a) TAMOXIFEN: One patient experienced a seizure several days after tamoxifen therapy was discontinued; the causal relationship to tamoxifen is unknown (Prod Info tamoxifen citrate oral tablets, 2007). The potential for seizures exists in large acute overdoses.
3.7.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) SEIZURES a) Animals have developed seizures at high doses (Prod Info tamoxifen citrate oral tablets, 2007).
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Gastrointestinal |
3.8.1) SUMMARY
A) Nausea and vomiting are common and may be expected following overdose.
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) SUMMARY: Nausea and/or vomiting are frequently reported adverse events with these agents (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011; Prod Info tamoxifen citrate oral tablets, 2011).
B) PANCREATITIS 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Rare cases of acute pancreatitis, in association with hypertriglyceridemia, have been reported following administration of tamoxifen (Prod Info tamoxifen citrate oral tablets, 2011).
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Hepatic |
3.9.1) SUMMARY
A) Liver enzyme levels may be elevated following overdose. Other liver damage has been reported, usually following chronic use.
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, more severe liver damage including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included deaths. A causal relationship is unclear (Prod Info tamoxifen citrate oral tablets, 2011).
2) The reported cases of hepatotoxicity associated with tamoxifen therapy appeared to be related to chronic administration (Maruyama et al, 1995; Loomus et al, 1983; Ching et al, 1992).
b) TOREMIFENE 1) Elevated liver enzymes (i.e., SGOT, alkaline phosphatase, bilirubin) have been associated with toremifene therapy (Prod Info FARESTON(R) oral tablets, 2011).
B) INFLAMMATORY DISEASE OF LIVER 1) RALOXIFENE a) CASE REPORT: A 49-year-old woman developed hepatitis after 30 days of raloxifene (60 mg daily) treatment. Symptoms included progressive malaise, an upper-body rash, and jaundice. Liver enzymes slowly improved following drug cessation. The authors suggested an immune response to therapy, due to the presence of a rash and a slightly elevated eosinophil count (Vilches et al, 1998).
2) TAMOXIFEN a) CHRONIC TOXICITY: Steatohepatitis progressing to cirrhosis has been reported in some women with breast cancer following long-term (3 to 5 years) adjunctive therapy with tamoxifen (Oien et al, 1999).
b) A prospective, randomized, double-blind, placebo controlled trial reported that 20 mg of tamoxifen daily is associated with a higher risk of developing nonalcoholic steatohepatitis (characterized by necro-inflammation, fibrosis, and fatty liver) in healthy women with a history of having hysterectomies. This risk is low and is restricted to overweight and obese women (BMI equal to or greater than 25) with features of metabolic syndrome. In women receiving tamoxifen, unexplained multiple elevations of alanine aminotransferase equal to or greater than 1.5 times the upper normal limit, are associated with development of steatohepatitis, reducing the need for liver biopsy (Bruno et al, 2005).
C) TOXIC LIVER DISEASE 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) SUMMARY: Liver injury has been reported in patients following therapeutic use of tamoxifen. In most cases, toxicity resolved with the discontinuation of tamoxifen A 69-year-old woman developed multifocal hepatic fatty infiltration after taking tamoxifen 20 mg twice daily as adjuvant therapy for left breast cancer eight years prior. Findings on computed tomography improved and hepatic transaminases normalized 6 months after tamoxifen was discontinued (Cai et al, 2000; Maruyama et al, 1995a; Loomus et al, 1983a; Ching et al, 1992a; Pratt et al, 1995).
2) CASE SERIES: The development of fatty liver was reported in 36.4% of patients who were treated with tamoxifen for breast cancer. The patients received tamoxifen 40 mg daily for 3 to 5 years. The changes in the liver were observed 1 to 44 months after tamoxifen started. Liver changes disappeared 1 to 14 months after termination of treatment (Ogawa et al, 1998).
3) CASE REPORTS: Liver injury including, multifocal hepatic fatty infiltration, liver cirrhosis, peliosis hepatitis, fatal agranulocytosis with massive hepatocellular necrosis and nonalcoholic steatohepatitis occurred in women with breast cancer with no prior history of liver disease after receiving tamoxifen therapy. Most improved with discontinuation of therapy (Cai et al, 2000; Maruyama et al, 1995a; Loomus et al, 1983a; Ching et al, 1992a; Pratt et al, 1995).
4) CASE REPORT: A case of tamoxifen-induced hepatitis in a 59-year-old woman with breast cancer has been reported. The patient received adjuvant tamoxifen treatment 20 mg daily for 4 months when a mild asymptomatic increase in her transaminase levels were detected. Within weeks, the patient developed fatigue, jaundice, nausea and vomiting, lightening of her stools, and darkening of her urine. As symptoms and transaminase levels worsened, the tamoxifen was discontinued. The patient was not at risk for viral hepatitis, and had no history of alcohol use or work exposure to chemicals. Additionally, there was no personal or family history of liver disease. Tests for Hepatitis A, B, and C were negative, as were extensive evaluations for the cause of her liver failure. The woman subsequently developed peripheral edema, ascites, and worsening hepatic function and was placed on the liver transplant list. Over a period of several months, her liver function stabilized and a final clinical diagnosis of tamoxifen-induced submassive hepatic necrosis was made (Storen et al, 2000).
D) MALIGNANT NEOPLASM OF LIVER 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group using adjuvant tamoxifen 40 mg per day for 2 to 5 years, 3 cases of liver cancer were reported in the tamoxifen treated group, compared with 1 case in the observation group (Prod Info tamoxifen citrate oral tablets, 2011).
2) In the NSABP P-1 trial one case of liver cancer was reported in 1 participant randomized to tamoxifen (Prod Info tamoxifen citrate oral tablets, 2011).
3) There are 2 case reports in the literature of liver cancer associated with long-term tamoxifen use (Fornander et al, 1989; Rutqvist, 1993).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) MALIGNANT NEOPLASTIC DISEASE 1) WITH THERAPEUTIC USE a) TAMOXIFEN: A review of the literature by Seoud et al (1993), indicated that the incidence of gynecological malignancies associated with the use of tamoxifen is dependent on the dose and duration of use. 1) Tamoxifen doses which resulted in gynecological malignancies in some women: 20 mg/day (23% of the patients), 30 mg/day (17 % of the patients) and 40 mg/day or higher (59% of the patients); 57% were treated with tamoxifen for less than 2 years.
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Hematologic |
3.13.1) SUMMARY
A) Thromboembolic events, including pulmonary embolism, have been reported with chronic tamoxifen of toremifene therapy. Thrombocytopenia may occur following an overdose, and should be monitored.
3.13.2) CLINICAL EFFECTS
A) THROMBOEMBOLUS 1) WITH THERAPEUTIC USE a) SUMMARY 1) Thromboembolic events, including pulmonary embolism, deep vein thrombosis and thrombophlebitis, have been associated with tamoxifen and toremifene (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011; Prod Info tamoxifen citrate oral tablets, 2011).
b) TAMOXIFEN 1) Tamoxifen was associated with the occurrence of venous thrombosis or pulmonary embolism within 6 months of treatment in 7 patients (Lipton et al, 1984).
2) Arterial thrombosis was reported in 2 women receiving tamoxifen 30 mg daily for at least 7 months (Dahan et al, 1985).
3) A 54-year-old woman who suffered an acute myocardial infarction due to thrombi in 2 coronary arteries had been taking tamoxifen 30 mg and medroxyprogesterone 1200 mg daily for 2 years (Nakagawa et al, 1994).
B) ANEMIA 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) In a study of adjuvant treatment of early breast cancer, anemia was reported in 5% of women receiving tamoxifen 20 mg daily (159 of 3094) compared with 4% of women receiving anastrozole 1 mg daily (113 of 3092) (Prod Info tamoxifen citrate oral tablets, 2011).
b) TOREMIFENE 1) Reduction in serum hemoglobin levels has been observed during toremifene therapy (Kivinen & Maenpaa, 1990; Hamm, 1990; Kohler et al, 1990).
C) LEUKOPENIA 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) Leukopenia has been reported during tamoxifen therapy. However, no cases of leukopenia were considered life-threatening and white count returned to normal in a few weeks despite continued therapy (Lerner et al, 1976; Tormey et al, 1976).
b) TOREMIFENE 1) Leukopenia has been reported in patients receiving toremifene therapy in clinical trials (Prod Info FARESTON(R) oral tablets, 2011). a) Leukopenia has been reported in approximately 10% of patients treated with toremifene 60 mg daily in some studies (Valavaara et al, 1988; Valavaara et al, 1990a). However, in phase I trials (Kohler et al, 1990) and other studies, leukopenia has not been observed with toremifene.
D) PANCYTOPENIA 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Neutropenia and pancytopenia have been reported rarely following administration of tamoxifen, including some severe cases (Prod Info tamoxifen citrate oral tablets, 2011).
E) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) TAMOXIFEN 1) Transient thrombocytopenia (platelet count below 100,000 cm(3)) may occur during tamoxifen therapy (Prod Info tamoxifen citrate oral tablets, 2011). a) Decreased platelet count was reported in 0.7% of women receiving tamoxifen 20 mg daily (n=6520), compared with 0.3% of women receiving placebo (n=6535) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study. Most instances of thrombocytopenia were between 50,000/mm(3) to 100,000/mm(3), although 6 women in the tamoxifen arm and 2 in the placebo arm experienced grade 3 to 4 decrease in platelet count, to less than 50,000/mm(3). Hemorrhagic events have rarely occurred in patients with pronounced thrombocytopenia, however a causal relationship with tamoxifen has not been established (Prod Info tamoxifen citrate oral tablets, 2011).
b) In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study, platelet count less than 100,000/mm(3) was reported in 2% of women receiving tamoxifen 20 mg daily (n=1422) compared with 1% of women receiving placebo (n=1437) in a 5-year study for adjuvant treatment of axillary node-negative breast cancer following primary surgery (Prod Info tamoxifen citrate oral tablets, 2011).
b) TOREMIFENE 1) Thrombocytopenia has been reported in patients receiving toremifene therapy in clinical trials (Prod Info FARESTON(R) oral tablets, 2011).
F) AGRANULOCYTOSIS 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Fatal agranulocytosis with massive hepatocellular necrosis and jaundice was reported in one breast cancer patient treated with tamoxifen 20 mg twice daily for 5 months (no concurrent drug therapy, or history of cirrhosis or distant metastases) (Ching et al, 1992).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERYTHEMA MULTIFORME 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Postmarketing experience has included rare reports of erythema multiforme following tamoxifen administration. In some cases, time to onset was more than one year following tamoxifen use (Prod Info tamoxifen citrate oral tablets, 2011).
B) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Postmarketing experience has included rare reports of Stevens-Johnson syndrome following administration of tamoxifen. In some cases, time to onset was more than one year following tamoxifen use (Prod Info tamoxifen citrate oral tablets, 2011).
C) MENOPAUSAL FLUSHING 1) WITH THERAPEUTIC USE a) SUMMARY: Menopausal flushing (hot flashes) are likely to occur with therapeutic use of these agents (Prod Info tamoxifen citrate oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011).
b) TAMOXIFEN: In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-I study, a randomized, double-blind, placebo-controlled trial in women aged 35 years and older at high risk for developing breast cancer, hot flash was the most common adverse event, reported in 80% of women in the tamoxifen arm (n=6441) and 68% of subjects in the placebo arm (n=6469). Symptoms were severe in 45% and 28% of subjects in the tamoxifen and placebo arms, respectively (Prod Info tamoxifen citrate oral tablets, 2011).
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Musculoskeletal |
3.15.1) SUMMARY
A) Local disease flare, associated with bone and tumor pain, has been reported.
3.15.2) CLINICAL EFFECTS
A) PAIN 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Increased bone and tumor pain, sometimes associated with local disease flare, have occurred with tamoxifen. The disease flare is seen shortly after starting tamoxifen therapy and generally subsides rapidly (Prod Info tamoxifen citrate oral tablets, 2011). 1) Plotkin et al (1978) reported that tamoxifen flare occurs in up to 26% of patients.
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) HYPERSENSITIVITY REACTION 1) WITH THERAPEUTIC USE a) TAMOXIFEN: Hypersensitivity reactions including angioedema have been noted during postmarketing surveillance of tamoxifen (Prod Info tamoxifen citrate oral tablets, 2011).
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Reproductive |
3.20.1) SUMMARY
A) Ospemifene, raloxifene, and bazedoxifene/conjugated estrogens are classified as FDA pregnancy category X and are contraindicated for use during pregnancy. Tamoxifen and toremifene are classified as FDA pregnancy category D. Although there are no adequate and well-controlled trials in pregnant women, there was evidence of fetal harm and toxicity in some case reports and studies of drugs in this class. Animal studies have also demonstrated fetal harm and toxicity. Tamoxifen may cause developmental abnormalities of the genital tract in humans and an interval of many years between in utero exposure and clinical manifestation could exist. When toremifene is given to pregnant women, fetal harm may occur. Toremifene is embryotoxic and fetotoxic in rats. Additionally, the drug was shown to cross the placenta and accumulate in rodent fetuses. Raloxifene is also contraindicated for use in nursing mothers. Toremifene has also been shown to be excreted in the milk of lactating rats. In animal studies, all drugs in this class demonstrated fertility and conception impairment.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the teratogenic potential of drugs in this class (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011; Prod Info tamoxifen citrate oral tablets, 2007).
B) CONGENITAL ANOMALIES 1) TAMOXIFEN a) According to one report of outcomes of 50 pregnancies associated with tamoxifen exposure, there were 19 normal births, 8 terminated pregnancies, 10 with a documented fetal or neonatal disorder (2 congenital craniofacial defects), and 13 unknown outcomes (Cullins & Pridjian, 1994).
b) CASE REPORT: A case report described a 35-year-old woman, treated with tamoxifen 20 mg/day throughout a 27-week pregnancy, who delivered a karyotypically normal infant. The child presented with right-sided microtia and hemifacial microsomia consistent with Goldenhar's syndrome (Cullins & Pridjian, 1994).
c) One infant exposed to tamoxifen during the first twenty weeks of gestation and delivered at 29 weeks presented with ambiguous genitalia, including an enlarged, phallic-like clitoris, a single perineal opening for the urethra and vagina, and fusion of the posterior portion of the rugated labioscrotal folds without gonads. Ultrasound revealed a uterus and bilateral ovaries; no male structures were identified (Tewari et al, 1997).
C) LACK OF EFFECT 1) TAMOXIFEN a) Although the clinical relevance of reproductive tract development effects are not known, vaginal adenosis and other changes were similar to those reported in young women who were exposed to diethylstilbestrol in utero. These women have a 1 in 1000 risk of developing vaginal or cervical clear-cell adenocarcinoma. There have been no reports of vaginal adenosis or cervical or vaginal clear-cell adenocarcinoma in association with tamoxifen use in young women. However, tamoxifen exposure in utero has only occurred in a small number of young women. Among in utero tamoxifen-exposed young women, there has been just a small number of cases in which long-term follow-up (age 15 to 20 years) has occurred to assess causality of tamoxifen in vaginal or cervical neoplasia (Prod Info tamoxifen citrate oral tablets, 2007)
b) According to one report, no fetal abnormalities were noted when 85 women became pregnant while undergoing tamoxifen treatment (Clark, 1993).
2) CASE REPORT: A 36-year-old infertile woman with breast cancer delivered a healthy baby under adjuvant tamoxifen therapy. The patient had been infertile for 9 years and had been taking adjuvant tamoxifen therapy for 15 months before becoming pregnant. The patient stopped tamoxifen during pregnancy and lactation. Although the child was delivered without complications or visible deformities, it is recommended that the child undergo long-term follow-up (up to 20 years) to assess the risk of carcinogenicity (Oksuzoglu & Guler, 2002). D) ANIMAL STUDIES 1) BAZEDOXIFENE WITH CONJUGATED ESTROGENS a) RATS, RABBITS: During animal studies, administration of maternally toxic bazedoxifene doses greater than or equal to 1 mg/kg/day (greater than or equal to 0.3 times the human AUC at the 20 mg dose) in rats resulted in a reduction in live fetuses and/or a reduction in fetal body weight. There were no reports of fetal developmental anomalies. In a similar study, administration of maternally toxic bazedoxifene doses greater than or equal to 0.5 mg/kg/day (approximately 2 times the human AUC at the 20 mg dose) in pregnant rabbits resulted in abortion and increased heart and skeletal anomalies, including ventricular septal defects, ossification delays, and misaligned bones of the spine and skull (Prod Info DUAVEE(R) oral tablets, 2013).
2) OSPEMIFENE a) RATS, RABBITS: Administration of ospemifene up to 4 mg/kg/day in rats and up to 30 mg/kg/day (10 times the human exposure based on surface area mg/m(2)) in rabbits from implantation through organogenesis resulted in increased total resorptions in rabbits. There was no evidence of drug induced malformations in either the rats or the rabbits (Prod Info OSPHENA(TM) oral tablets, 2013).
3) RALOXIFENE a) RABBITS: A low rate of fetal heart anomalies (ventricular septal defects) was observed when rabbits were exposed to raloxifene doses of 0.1 mg/kg (0.04 times the human dose based on surface area, mg/m(2)) or greater; hydrocephaly was observed in fetuses at raloxifene doses of 10 mg/kg (4 times the human dose) or greater (Prod Info EVISTA(R) oral tablet, 2011).
b) RATS: Retardation and abnormalities of fetal development (ie, wavy ribs and kidney cavitation) were observed when rats were exposed to doses of 1 mg/kg (0.2 times the human dose) or greater. When pregnant rats were exposed to 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose) during gestation and lactation, altered physical development, sex- and age-specific growth reductions, changes in pituitary hormone content, and reduced lymphoid compartment size in offspring were observed (Prod Info EVISTA(R) oral tablet, 2011).
4) TAMOXIFEN a) MARMOSETS: No congenital defects were observed when several pregnant marmosets were exposed to tamoxifen at a dose of 10 mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m(2) basis) during organogenesis or the last half of pregnancy (Prod Info tamoxifen citrate oral tablets, 2007).
b) RODENTS: Fetal reproductive tract development was reported in rodents that were exposed to tamoxifen (at doses 0.002 to 2.4-fold the daily maximum recommended human dose on a mg/m(2) basis). These adverse effects were observed in both sexes and are similar to those caused by estradiol, ethinyl estradiol and diethylstilbestrol (Prod Info tamoxifen citrate oral tablets, 2007).
5) TOREMIFENE a) RATS, RABBITS: There was evidence of fetal anomalies (eg, limb malformation, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema) when pregnant rats were exposed to doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m(2) basis) during organogenesis. Because toremifene was shown to cross the placenta and accumulate in the rodent fetus, the maternal toxicity may have played a part in the embryofetal adverse effects. There were similar embryofetal effects (eg, fetal anomalies, including incomplete ossification, and anencephaly) when rabbits were exposed to toremifene at doses of approximately 40% the daily recommended human dose. In rats and rabbits, the animal doses which resulted in embryofetal toxicities were greater than or equal to 1 mg/kg/day and 1.25 mg/kg/day, respectively (Prod Info FARESTON(R) oral tablets, 2011).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturers have classified bazedoxifene/conjugated estrogens, ospemifene and raloxifene as FDA pregnancy category X (Prod Info DUAVEE(R) oral tablets, 2013; Prod Info OSPHENA(TM) oral tablets, 2013; Prod Info EVISTA(R) oral tablet, 2011).
2) The manufacturers have classified tamoxifen and toremifene as FDA pregnancy category D (Prod Info FARESTON(R) oral tablets, 2011; Prod Info tamoxifen citrate oral tablets, 2007).
B) RISK OF FETAL HARM 1) BAZEDOXIFENE/CONJUGATED ESTROGENS: Bazedoxifene acetate/conjugated estrogens combination is contraindicated during pregnancy and should not be used in women who are or may become pregnant. Use of bazedoxifene acetate/conjugated estrogens during pregnancy may result in fetal harm. Animal studies have not been conducted with the combination bazedoxifene acetate/conjugated estrogens. If pregnancy occurs, apprise patient of possible hazard to fetus (Prod Info DUAVEE(R) oral tablets, 2013).
2) OSPEMIFENE: Ospemifene use is contraindicated in women who are or may become pregnant. Based on animal data, ospemifene increased the risk of embryofetal harm and/or death and increased labor difficulties. Advise patient of the potential fetal risk should pregnancy occur during treatment (Prod Info OSPHENA(TM) oral tablets, 2013).
3) RALOXIFENE: Raloxifene is contraindicated in women who are or who may become pregnant. Raloxifene may cause fetal harm if administered during pregnancy. In animal studies, there was evidence of fetal harm, including parturition disruption which resulted in maternal and fetal morbidity and mortality. Therefore, if the drug is used during pregnancy or if a patient becomes pregnant during raloxifene therapy, the patient should be informed of the potential hazard to the fetus (Prod Info EVISTA(R) oral tablet, 2011).
4) TAMOXIFEN: Although there are no adequate and well-controlled studies of tamoxifen use in pregnant women, there have been a few reports of spontaneous abortions, birth defects, fetal deaths, and vaginal bleeding associated with tamoxifen use during pregnancy. Therefore, if tamoxifen is administered during pregnancy or if the patient becomes pregnant while receiving tamoxifen or within 2 months after therapy discontinuation, apprise her of the potential for fetal harm, including the possibility for long-term diethylstilbestrol-like effects. For women who are sexually active and of childbearing potential, initiate tamoxifen during menstruation. If menstruation is irregular, a negative pregnancy test (beta-hCG) immediately before starting tamoxifen treatment should be adequate (Prod Info tamoxifen citrate oral tablets, 2007).
5) TOREMIFENE: There are no adequate and well-controlled studies of toremifene use during pregnancy. In animal studies, there was evidence of embryofetal and maternal toxicity, fetal anomalies, and loss of pregnancy. Based on these data from animal studies and the drug's mechanism of action in humans, there is the potential for fetal harm with maternal toremifene use. Therefore, toremifene is administered during pregnancy or if the patient becomes pregnant while receiving toremifene, apprise her of the potential for fetal harm. Toremifene is not indicated for use in premenopausal women; however, if a woman of childbearing potential is prescribed the drug, she should be advised to use effective non-hormonal contraception during toremifene therapy (Prod Info FARESTON(R) oral tablets, 2011).
C) SPONTANEOUS ABORTION 1) TAMOXIFEN a) No birth defects were reported among the nine offspring of pregnant women whose ovulatory cycles were induced with tamoxifen. Five other pregnancies conceived after ovulation induction with tamoxifen in this series resulted in spontaneous abortion (Ruiz-Velasco et al, 1979).
D) ANIMAL STUDIES 1) BAZEDOXIFENE WITH CONJUGATED ESTROGENS a) RATS, RABBITS: During animal studies, administration of maternally toxic bazedoxifene doses greater than or equal to 1 mg/kg/day (greater than or equal to 0.3 times the human AUC at the 20 mg dose) in rats resulted in a reduction in live fetuses and/or a reduction in fetal body weight. There were no reports of fetal developmental anomalies. In a similar study, administration of maternally toxic bazedoxifene doses greater than or equal to 0.5 mg/kg/day (approximately 2 times the human AUC at the 20 mg dose) in pregnant rabbits resulted in abortion and increased heart and skeletal anomalies, including ventricular septal defects, ossification delays, and misaligned bones of the spine and skull (Prod Info DUAVEE(R) oral tablets, 2013).
2) OSPEMIFENE a) RATS, RABBITS: Administration of ospemifene 0.05 or 0.25 mg/kg/day (approximately 0.8% and 4% the recommended human exposure based on surface area mg/m(2), respectively) in pregnant rats resulted in a prolonged and difficult gestation, increased postimplantation loss, increased stillbirths, and increased postnatal loss. There was no adverse effects in the surviving offspring of pregnant rats following drug exposures up to 4% the human exposure (Prod Info OSPHENA(TM) oral tablets, 2013).
3) RALOXIFENE a) RABBITS: Abortion was observed when rabbits were exposed to raloxifene doses of 0.1 mg/kg (0.04 times the human dose based on surface area, mg/m(2)) or greater. In rat studies, retardation and abnormalities of fetal development (ie, wavy ribs and kidney cavitation) were observed when rats were exposed to doses of 1 mg/kg (0.2 times the human dose) or greater. When pregnant rats were exposed to 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose) during gestation and lactation, delayed and disrupted parturition, reduced neonatal survival, altered physical development, sex- and age-specific growth reductions, changes in pituitary hormone content, and reduced lymphoid compartment size in offspring. Parturition was disrupted which resulted in maternal and fetal mortality and morbidity at doses of 10 mg/kg. Uterine hypoplasia and reduced fertility were reported in adult offspring (4 months of age); however, there was no ovarian or vaginal pathology (Prod Info EVISTA(R) oral tablet, 2011).
b) RATS: When pregnant rats were exposed to 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose) during gestation and lactation, delayed and disrupted parturition and reduced neonatal survival were observed. Parturition was disrupted which resulted in maternal and fetal mortality and morbidity at doses of 10 mg/kg. Uterine hypoplasia and reduced fertility were reported in adult offspring (4 months of age); however, there was no ovarian or vaginal pathology (Prod Info EVISTA(R) oral tablet, 2011).
4) TAMOXIFEN a) RATS, RABBITS: Reversible nonteratogenic developmental skeletal changes were observed when rats were exposed to dose levels equal to or below the human dose. A lower incidence of embryo implantation and a higher incidence of fetal death or slowed in utero growth were observed when rats and rabbits were exposed to doses equal to or less than human doses. In this rat study, slower learning behavior was evident in offspring compared with historical control (Prod Info tamoxifen citrate oral tablets, 2007).
b) Results from animal studies using tamoxifen are similar to those using diethylstilbestrol under similar conditions. It is thought that tamoxifen, like diethylstilbestrol, could cause developmental abnormalities of the genital tract in humans and that an interval of many years between in-utero exposure and clinical manifestations would exist (Vancutsem & Williams, 1993).
5) TOREMIFENE a) RATS, RABBITS: There are no adequate and well-controlled studies of toremifene use during pregnancy. In animal studies, there was evidence of maternal toxicity and increased preimplantation loss, increased resorptions, and decreased fetal weight when pregnant rats were exposed to doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m(2) basis) during organogenesis. Because toremifene was shown to cross the placenta and accumulate in the rodent fetus, the maternal toxicity may have played a part in the embryofetal adverse effects. There were similar embryofetal effects (eg, increased preimplantation loss and increased resorptions) when rabbits were exposed to toremifene at doses of approximately 40% the daily recommended human dose. In rats and rabbits, the animal doses which resulted in embryofetal toxicities were greater than or equal to 1 mg/kg/day and 1.25 mg/kg/day, respectively (Prod Info FARESTON(R) oral tablets, 2011). b) INHIBITION OF UTERINE DEVELOPMENT 1) Although the clinical relevance is unknown, there was inhibition of uterine development in rodents which was similar to that demonstrated with diethylstilbestrol and tamoxifen exposure. There are no rodent studies to evaluate the potential for toremifene to cause other diethylstilbestrol-like effects in offspring (ie, vaginal adenosis). Vaginal adenosis was reported following exposure to other drugs of this class in animal studies; there was also evidence of vaginal adenosis in women exposed to diethylstilbestrol in utero (Prod Info FARESTON(R) oral tablets, 2011).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to drugs in this class during lactation in humans (Prod Info FARESTON(R) oral tablets, 2011; Prod Info EVISTA(R) oral tablet, 2011; Prod Info tamoxifen citrate oral tablets, 2007).
B) BREAST MILK 1) BAZEDOXIFENE WITH CONJUGATED ESTROGENS a) Bazedoxifene acetate/conjugated estrogens combination is contraindicated in nursing mothers. It is unknown whether bazedoxifene acetate/conjugated estrogens is excreted into human milk however, estrogens have been detected in the milk of women, and estrogen administration may decrease the quality and quantity of breast milk (Prod Info DUAVEE(R) oral tablets, 2013).
2) OSPEMIFENE a) Lactation studies with ospemifene have not yet been conducted, however, ospemifene has been detected in the milk of lactating rats at concentrations higher than those of maternal plasma. It is not known whether ospemifene is excreted into human breast milk; however, there is the potential for serious adverse effects in nursing infants from ospemifene (Prod Info OSPHENA(TM) oral tablets, 2013). Therefore, lactating women should consult a physician prior to breastfeeding.
3) RALOXIFENE a) Raloxifene use is contraindicated in nursing mothers (Prod Info EVISTA(R) oral tablet, 2011).
C) ANIMAL STUDIES 1) TOREMIFENE a) RATS: Toremifene has been shown to be excreted in the milk of lactating rats (Prod Info FARESTON(R) oral tablets, 2011).
3.20.5) FERTILITY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to drugs in this class (Prod Info FARESTON(R) oral tablets, 2011; Prod Info tamoxifen citrate oral tablets, 2007). 2) BAZEDOXIFENE WITH CONJUGATED ESTROGENS a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info DUAVEE(R) oral tablets, 2013).
B) ANIMAL STUDIES 1) RALOXIFENE a) RATS: No pregnancies occurred when rats were given raloxifene at doses of at least 5 mg/kg/day (corresponding to 0.8 times or more the human dose based on mg/m(2) of body surface area). In male rats, sperm production or quality or reproductive performance were not affected at raloxifene doses of up to 100 mg/kg/day for 2 weeks (16 times the human dose based on body surface area). In female rats, there was evidence of reversibly disrupted estrous cycles, inhibited ovulation, and delayed and disrupted embryo implantation, resulting in prolonged gestation and a small litter size at raloxifene doses of 0.1 to 10 mg/kg/day (0.02 to 1.5 times the human dose) (Prod Info EVISTA(R) oral tablet, 2011).
2) TAMOXIFEN a) RATS: Fertility and conception were impaired when female rats were exposed to tamoxifen at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose (MRHD) on a mg/m(2) basis) for 2 weeks prior to mating through day 7 of gestation. This dose also resulted in fertility and reproductive indices that were markedly reduced with total fetal mortality. Fetal mortality occurred at a greater frequency when female rats were exposed to doses of 0.16 mg/kg/day (about 0.03-fold the MRHD) from days 7 to 17 of gestation. No teratogenic changes occurred in rats (Prod Info tamoxifen citrate oral tablets, 2007).
b) RABBITS: There was evidence of abortion, premature delivery, and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the MRHD). No teratogenic changes occurred in rabbits (Prod Info tamoxifen citrate oral tablets, 2007).
3) TOREMIFENE a) RATS: Impairment of fertility and conception was reported when male and female rats were exposed to toremifene at doses of 25 and 0.14 mg/kg/day (about 3.5 times and 0.02 the daily maximum recommended human dose (MRHD) on a mg/m(2) basis) or higher, respectively. At these doses, atrophy of seminal vesicles and prostate were seen in males and sperm counts, fertility indices, and conception rates were reduced. In females, fertility and reproductive indices were reduced markedly with increased pre- and postimplantation loss. Reproductive indices were also depressed in offspring of treated rats (Prod Info FARESTON(R) oral tablets, 2011).
b) DOGS: Ovarian atrophy was reported when dogs were exposed to doses of 3 mg/kg/day (about 1.5 times the daily MRHD on a mg/m(2) basis) or higher for 16 weeks (Prod Info FARESTON(R) oral tablets, 2011).
c) MONKEYS: Cystic ovaries and reduction in endometrial stromal cellularity were reported in monkeys exposed to doses of 1 mg/kg/day (about one-fourth of the daily MRHD on a mg/m(2) basis) or higher for 52 weeks (Prod Info FARESTON(R) oral tablets, 2011).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) A large, randomized trial indicated an increased incidence of uterine cancer after 2 to 5 years of tamoxifen therapy. However, data from the NSABP B-14 study showed no increase in non-uterine cancers among patients receiving tamoxifen. Based on a review of the literature, data in rat studies suggests an increased risk of hepatocellular cancer. However, no conclusive evidence linked tamoxifen with an increased risk in humans. At the time of this review, the manufacturer does not report any carcinogenic potential of conjugated estrogens/bazedoxifene in humans. In animal studies, a drug-related increased incidence of benign, ovarian granulosa-cell tumors was observed in animals given bazedoxifene. Drug-related renal adenomas and carcinomas were also noted, in the presence of renal toxicity, in male rats.
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) CONJUGATED ESTROGENS/BAZEDOXIFENE: At the time of this review, the manufacturer does not report any carcinogenic potential (Prod Info DUAVEE(R) oral tablets, 2013).
B) CARCINOMA 1) A large, randomized trial indicated an increased incidence of uterine cancer after 2 to 5 years of tamoxifen therapy (40 mg daily) (Rutqvist, 1993a; Prod Info Nolvadex(R), tamoxifen, 2000).
2) Based on a literature review, the incidence of endometrial cancer is increased in women after receiving tamoxifen therapy. Although a small risk, data suggests it may act as a tumor promoter in human endometrium (Stearns & Gelmann, 1998). SCREENING - Barakat et al (2000) conducted office endometrial biopsies on postmenopausal women treated with tamoxifen to determine the frequency of developing abnormal pathologic changes in the endometrium. The authors concluded that there is limited utility in conducting routine EMB for screening purposes in tamoxifen-treated women, and further suggest that there is no evidence that an effective screening tool currently exists.
C) LACK OF EFFECT 1) Data from the NSABP B-14 study showed no increase in non-uterine cancers among patients receiving tamoxifen (Prod Info Nolvadex(R), tamoxifen, 1995).
2) Based on a review of the literature, data in rat studies suggests an increased risk of hepatocellular cancer. However, no conclusive evidence linked tamoxifen with an increased risk in humans (Stearns & Gelmann, 1998).
3.21.4) ANIMAL STUDIES
A) BAZEDOXIFENE 1) A drug-related increased incidence of benign, ovarian granulosa-cell tumors was observed in female, transgenic Tg.RasH2 mice given bazedoxifene 150 or 500 mg/kg/day in 6-month oral gavage carcinogenicity studies. A drug-related increased incidence of benign, ovarian granulosa-cell tumors was also observed in female rats administered bazedoxifene at concentrations of 0.03% and 0.1% (approximately 3 and 8 times, respectively, the exposure of that in humans at the 20 mg/day dose). Drug-related renal adenomas and carcinomas were noted, in the presence of renal toxicity, in male rats at all doses tested (approximately 0.06 to 5 times the exposure of human dose of 20 mg/day) (Prod Info DUAVEE(R) oral tablets, 2013).
B) OSPEMIFENE 1) During a carcinogenicity study of 2 years duration in mice, administration of ospemifene 100, 400, or 1500 mg/kg/day resulted in increased adrenal subcapsular cell adenomas at 4 and 5 times the human exposure and adrenal cortical tumors at 5 times the human exposure. Increases in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas were also observed following doses 2 to 5 times the human exposure. A similar study in rats resulted in increased thymomas and hepatocellular tumors in rats administered ospemifene 10, 50, or 300 mg/kg/day (Prod Info OSPHENA(TM) oral tablets, 2013)
C) TAMOXIFEN 1) A conventional carcinogenesis study in rats (doses of 5, 20, and 35 milligrams/kilogram/day for up to 2 years) revealed hepatocellular carcinoma at all doses, the incidence being dose dependent. Rats given 20 or 35 milligrams/kilogram/day had a 69% incidence of tumors compared to 14% in rats given 5 milligrams/kilogram/day. The incidence of these tumors in rats given 5 milligrams/kilogram/day (29.5 milligram/square meter) were significantly greater than controls (Prod Info Nolvadex(R), tamoxifen, 2000).
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Genotoxicity |
A) CONJUGATED ESTROGENS/BAZEDOXIFENE: At the time of this review, the manufacturer does not report any genotoxic or mutagenic potential (Prod Info DUAVEE(R) oral tablets, 2013).
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