Fareston

Toremifene comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take toremifene at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take toremifene exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Toremifene may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hot flashes
• sweating
• blurred or abnormal vision
• sensitivity to light or seeing halos around lights
• difficulty seeing at night
• fading or yellowing of colors
• dry eyes
• dizziness
• swelling of the hands, feet, ankles, or lower legs

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• vaginal bleeding
• pelvic pain or pressure
• irregular periods
• unusual vaginal discharge
• sleepiness
• confusion
• muscle pain or weakness
• joint pain
• abdominal pain
• constipation
• frequent urination
• excessive thirst
• loss of appetite
• nausea
• vomiting

Some people who took toremifene developed cancer of the lining of the uterus. There is not enough information to tell if toremifene caused these people to develop cancer. Talk to your doctor about the risks of taking this medication.

Toremifene may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat, and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is:

and the molecular formula is C26H28ClNO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37°C is 0.63 mg/mL and in 0.02N HCl at 37°C is 0.38 mg/mL.

FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

WARNING: QT PROLONGATION

Fareston has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Fareston should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience

Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

Post-marketing Experience

The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

Read the entire FDA prescribing information for Fareston (Toremifene)

Toremifene blocks estrogen from reaching cancer cells. Certain types of breast cancer require estrogen to grow.

Toremifene is used in postmenopausal women to treat metastatic breast cancer (cancer that has spread to other parts of the body).

Toremifene may also be used for purposes not listed in this medication guide.

You should not use toremifene if you have a history of long QT syndrome, or low levels of potassium or magnesium in your blood.

Toremifene can cause a life-threatening heart rhythm disorder. Stop using toremifene and call your doctor at once if you have: headache with chest pain and severe dizziness, fainting, and fast or pounding heartbeats.

Metabolized principally by CYP3A4.1

No formal drug interaction studies to date.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4-6: Potential pharmacokinetic interaction (increased toremifene concentrations).1 29 30 Clinical importance unknown.1

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased toremifene concentrations).1 10 24

Drugs Affecting Calcium

Drugs that decrease renal calcium excretion (e.g., thiazide diuretics): Potential pharmacologic interaction (increased risk of hypercalcemia).1

Specific Drugs

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentration usually attained within 3 hours.1

Steady-state concentrations are reached in about 4–6 weeks.1

Food

Food does not appear to affect absorption.1

Distribution

Extent

Crosses the placenta and accumulates in the fetus in rodents.1 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

>99.5% (mainly albumin).1

Special Populations

Increased toremifene volume of distribution in geriatric female patients; however, no change in AUC.1 9

Elimination

Metabolism

Extensively metabolized, principally via CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo.1

Elimination Route

Excreted as metabolites principally in feces, with about 10% excreted in urine over 1 week.1

Half-life

Toremifene: Approximately 5 days.1

N-demethyltoremifene: 6 days.1 Deaminohydroxy toremifene: 4 days.1

Elimination is slow due to enterohepatic circulation.1

Special Populations

Increased toremifene elimination half-life in patients with hepatic impairment (i.e., cirrhosis, fibrosis).1 10

Pharmacokinetics are not altered in patients with renal impairment.1 10

Increased toremifene elimination half-life in geriatric female patients; however, no change in clearance.1 9

Storage

Oral

25°C (may be exposed to 15–30°C); protect from heat and light.1

In the U.S.

• Fareston

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiestrogen

Toremifene is used to treat metastatic breast cancer (cancer that has spread) that is hormone-receptor positive in women who have already stopped menstruating (postmenopausal).

Many of the breast cancer tumors will grow when estrogen is available in the body. This medicine blocks the effects of the estrogen hormone. As a result, the amount of estrogen that the tumor is exposed to is reduced, which will limit the growth of the tumor.

This medicine is available only with your doctor's prescription.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects. It is important for women to have regular gynecologic check-ups while taking this medicine.

It is unlikely that a postmenopausal woman may become pregnant. But, using this medicine while you are pregnant could harm your unborn baby. If you are a woman who can bear children, your doctor may give you a pregnancy test before you start using this medicine to make sure you are not pregnant. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using this medicine, tell your doctor right away.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you had a heart rhythm problem, such as QT prolongation.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Hypercalcemia (high calcium in the blood) and tumor flare (increased size of a tumor) are more likely to occur in patients with bone problems who are taking this medicine. Check with your doctor right away if you have stomach pain, confusion, constipation, depression, dry mouth, increased urination, loss of appetite, metallic taste, muscle weakness, pain and swelling in the bones and muscles surrounding a tumor, thirst, unusual tiredness, or weight loss.

This medicine may increase your risk of having uterus problems, including endometrial cancer. Talk with your doctor if you have concerns about this.

Toremifene can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

This medicine may cause you to have bleeding from the vagina, especially when you first start using it. If the bleeding continues or is bothersome, check with your doctor right away.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.7).]

Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, Fareston can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using Fareston. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

Nursing Mothers

It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Fareston, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

There is no indication for use of Fareston in pediatric patients.

Geriatric Use

The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC.

The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Fareston effectiveness or safety were noted.

Renal Impairment

The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic Impairment

The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Race

The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Fareston effectiveness or safety were noted.

Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

Fareston (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

Fareston is an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is:

and the molecular formula is C26H28ClNO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37°C is 0.63 mg/mL and in 0.02N HCl at 37°C is 0.38 mg/mL.

Fareston is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

Mechanism of Action

Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Pharmacodynamics

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Effects on Cardiac Electrophysiology

The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions (7.2)].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions (5.1)].

Pharmacokinetics

Absorption - Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution - Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

Metabolism - Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto-induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination - The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Renal insufficiency - The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.

Hepatic insufficiency - The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients - The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Fareston effectiveness or safety were noted.

Food - The rate and extent of absorption of Fareston are not influenced by food; thus Fareston may be taken with or without food.

Race - The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Fareston effectiveness or safety were noted.

NDC 42747-327-30

Fareston®
(toremifene citrate)
Tablets

60 mg

30 TABLETS

Rx only

KYOWA KIRIN

Applies to toremifene: oral tablet

Along with its needed effects, toremifene (the active ingredient contained in Fareston) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking toremifene:

• Anxiety
• arm, back, or jaw pain
• blurred vision
• change in how much and how often you urinate
• change in vaginal discharge
• changes in skin color
• changes in vision
• changes in weight
• chest pain, discomfort, tightness, or heaviness
• confusion
• constipation
• cough
• depression
• dilated neck veins
• dizziness, lightheadedness
• dry mouth
• fainting
• fast, slow, or irregular heartbeat
• inability to speak, incoherent speech
• irregular breathing
• loss of appetite
• metallic taste in the tongue
• muscle weakness
• nausea
• pain or discomfort in the arms, jaw, back, or neck
• pain or feeling of pressure in the pelvis
• pain, tenderness, or swelling of the foot or leg
• seizures
• severe or sudden headache
• stomach pain
• sweating
• swelling of the face, fingers, feet, or lower legs
• temporary blindness
• tenderness, pain, swelling, warmth, skin discoloration, prominent superficial veins over the affected area
• thirst
• troubled breathing
• unusual tiredness or weakness
• vaginal bleeding
• vomiting
• weakness in the arm and or leg on one side of the body, sudden and severe

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chills
• clay-colored stools
• dark urine
• fever
• itching
• painful or difficult urination
• pinpoint red spots on the skin
• rash
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• unpleasant breath odor
• unusual bleeding or bruising
• vomiting of blood
• yellow eyes or skin

Some side effects of toremifene may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blindness
• decreased vision
• dry eyes
• feeling of warmth
• redness of the face, neck, arms, and occasionally, the upper chest
• sudden sweating
• sweating

• Bone pain
• changes in vision
• double vision
• eye pain
• tearing

• Blistering, crusting, irritation, itching, or reddening of the skin
• cracked, dry, or scaly skin
• depression
• difficulty having a bowel movement
• feeling of constant movement of self or surroundings
• feeling unusually cold
• hair loss
• lack or loss of strength
• partial or slight paralysis
• sensation of spinning
• shakiness in the legs, arms, hands, or feet
• thinning of the hair