Toremifene

Black Box Warnings

Prolongs QTc interval in a dose- and concentration-related manner

QT prolongation can result in Torsade de pointes, which may result in syncope, seizure, and/or death

Should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia

Drugs known to prolong QT interval and strong CYP3A4 inhibitors should be avoided

Contraindications

Hypersensitivity

Estrogen receptor-negative tumors

Thromboembolic history

Should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia

Cautions

May increase risk of ovarian CA, osteosarcoma

Risk of hypercalcemia & tumor flare

Long-term treatment discouraged in preexisting endometrial hyperplasia

Prolongs QTc interval; avoid in patients with congenital/acquired QT prolongation or uncorrected hypokalemia/hypomagnesemia

Avoid concomitant use of drugs known to prolong QT interval

Hepatotoxicity, both increases in serum concentration for grade 3 and 4 transaminitis; hyperbilirubinemia, including jaundice, hepatitis, and non-alcoholic fatty liver disease, have also been reported in clinical trials and postmarketing; liver function tests should be performed periodically

Endometrial cancer, endometrial hypertrophy, hyperplasia, and uterine polyps reported; endometrial hyperplasia of uterus observed in animals treated with toremifene; long-term use has not been established in patients with pre-existing endometrial hyperplasia; all patients should have baseline and annual gynecological examinations; patients at high risk of endometrial cancer should be closely monitored

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.

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

Toremifene is used to slow the growth of metastatic breast cancer (cancer that has spread from the original tumor). Unlike chemotherapy, toremifene does not actually destroy cancer cells.

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

• Breast Cancer

WARNING: QT PROLONGATION

Toremifene 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. Toremifene 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.

Usual Adult Dose for Breast Cancer:

60 mg orally once daily
Duration of therapy: Treatment is generally continued until disease progression is observed.

Use: Treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For toremifene, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to toremifene or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Toremifene is not indicated for use in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of toremifene in the elderly. However, elderly patients are more likely to have age-related liver problems, which may require caution and an adjustment in the dose for patients receiving toremifene.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking toremifene, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using toremifene with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Fluconazole
• Ketoconazole
• Mesoridazine
• Nelfinavir
• Pimozide
• Piperaquine
• Posaconazole
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Ziprasidone

Using toremifene with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin
• Amiodarone
• Amitriptyline
• Amoxapine
• Anagrelide
• Apomorphine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Asenapine
• Astemizole
• Atazanavir
• Azithromycin
• Buserelin
• Ceritinib
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Cobicistat
• Crizotinib
• Dabrafenib
• Dasatinib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Deutetrabenazine
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Droperidol
• Efavirenz
• Erythromycin
• Escitalopram
• Fingolimod
• Flecainide
• Fluoxetine
• Foscarnet
• Gatifloxacin
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Histrelin
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Idelalisib
• Iloperidone
• Imipramine
• Indinavir
• Itraconazole
• Ivabradine
• Lapatinib
• Leuprolide
• Levofloxacin
• Lopinavir
• Lumefantrine
• Mefloquine
• Methadone
• Metronidazole
• Mifepristone
• Moxifloxacin
• Nafarelin
• Nefazodone
• Nilotinib
• Norfloxacin
• Nortriptyline
• Octreotide
• Ofloxacin
• Ondansetron
• Paliperidone
• Panobinostat
• Pasireotide
• Pazopanib
• Pimavanserin
• Pitolisant
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Ranolazine
• Ribociclib
• Ritonavir
• Salmeterol
• Sevoflurane
• Sodium Phosphate
• Sorafenib
• Sotalol
• Sugammadex
• Sulpiride
• Sunitinib
• Tacrolimus
• Telavancin
• Telithromycin
• Tetrabenazine
• Trazodone
• Trifluoperazine
• Trimipramine
• Triptorelin
• Vandetanib
• Vardenafil
• Vemurafenib
• Venlafaxine
• Vinflunine
• Voriconazole
• Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using toremifene with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use toremifene, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of toremifene. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clots, or history of—Use is usually not recommended in patients with this condition.

• Bone problems (eg, bone cancer) or
• Congestive heart failure or
• Heart rhythm problems (eg, QT prolongation) or
• Leukopenia (low white blood cells in the blood) or
• Thrombocytopenia (low platelets in the blood)—Use with caution. May make these conditions worse.

• Heart rhythm problems (eg, congenital or acquired long QT syndrome) or
• Hypokalemia (low potassium in the blood), uncorrected or
• Hypomagnesemia (low magnesium in the blood), uncorrected—Should not be used in patients with these conditions.

• Liver disease (eg, cirrhosis, fibrosis)—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Unusual growth of the lining of the uterus (womb)—Long-term use of toremifene is usually not recommended.

Along with its needed effects, a medicine 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:

• 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 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

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use toremifene as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

(tore EM i feen)