Kadcyla

Kadcyla is a prescription medication used to treat a certain type of breast cancer. It used when the cancer has spread to other parts of the body and has not improved or has worsened after treatment with other medications. Kadcyla belongs to a group of drugs called antibody-drug conjugates. It works by killing cancer cells.

Kadcyla injection comes as a powder to be mixed with liquid and injected slowly into a vein by a healthcare professional.

Common side effects include constipation, nausea, headache, and fatigue. Do not drive or operate heavy machinery until you know how this medication will affect you.

Kadcyla is a prescription medication used to treat a certain type of breast cancer. It used when the cancer has spread to other parts of the body and has not improved or has worsened after treatment with other medications.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.
 

Kadcyla is part of the drug class:

• OTHER ANTINEOPLASTIC AGENTS

Kadcyla should be taken with caution with certain other medications that can change the way it is metabolized. Let your doctor know about other medications including supplements you may be taking before starting Kadcyla. Medications that interact with Kadcyla include:

• Ketoconazole
• Itraconazole
• Telithromycin
• Clarithromycin
• Ritonavir
• Indinavir
• Nelfinavir
• Salquinavir
• Nefazdone
• Chloramphenicol
• Clozapine

This is not a complete list of interactions with Kadcyla. 

Serious side effects have been reported with Kadcyla including the following:

• Kadcyla injection may cause serious infusion-related reactions, which may occur during the infusion of the medication. If you experience any of the following symptoms, tell your doctor immediately: flushing; fever; chills; dizziness; lightheadedness; fainting; shortness of breath; difficulty breathing; or fast, irregular, or pounding heartbeat.
• Kadcyla may cause serious or life-threatening liver problems. Tell your doctor if you have or have ever had liver disease, including hepatitis. Your doctor will order laboratory tests regularly before and during your treatment to see if Kadcyla is affecting your liver. Your doctor may tell you that you should not receive this medication if the tests show that you have liver problems. Tell your doctor and pharmacist about all the medications you are taking so they can check whether any of your medications may increase the risk that you will develop liver damage during your treatment with Kadcyla. Call your doctor immediately if you experience any of the following symptoms: nausea, vomiting, extreme tiredness, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, dark-colored urine, or flu-like symptoms.
• Kadcyla also may cause serious or life-threatening heart problems. Tell your doctor if you have or have ever had heart disease, a heart attack, chest pain, or irregular heartbeats. Your doctor will order tests before and during your treatment to see if your heart is working well enough for you to safely receive Kadcyla. Your doctor may tell you that you should not receive this medication if the tests show your heart's ability to pump blood has decreased. If you experience any of the following symptoms, call your doctor immediately: cough; shortness of breath; swelling of the arms, hands, feet, ankles or lower legs; weight gain (more than 5 pounds [about 2.3 kilograms] in 24 hours); dizziness; loss of consciousness; or fast, irregular, or pounding heartbeat.
• Tell your doctor if you are pregnant or plan to become pregnant. Kadcyla may harm your unborn baby. You should use birth control to prevent pregnancy during your treatment and for 6 months after your treatment. Talk to your doctor about birth control methods that will work for you. If you become pregnant during your treatment with Kadcyla, call your doctor immediately.

Do not drive or operate heavy machinery until you know how this medication will affect you.

Grapefruit and grapefruit juice may interact with this medication and can lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Keep all appointments with your doctor and the laboratory.

Some side effects may occur during the injection. Tell your caregiver right away if you feel cold, light-headed, feverish or sweaty, or have chest tightness, rapid heartbeats, or trouble breathing.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Ado-trastuzumab emtansine can harm your liver. Call your doctor at once if you have signs of liver problems--upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Also call your doctor at once if you have:

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• sudden severe headache, confusion, severe drowsiness, sudden numbness or weakness on one side of the body;

• problems with walking, breathing, speech, swallowing, or eye movement;

• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;

• swelling, rapid weight gain, severe dizziness;

• numbness or tingling in your hands or feet;

• pounding heartbeats or fluttering in your chest; or

• low white blood cell counts--fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing.

Common side effects may include:

• easy bruising or bleeding;

• nausea, constipation;

• joint or muscle pain;

• headache, tired feeling; or

• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In the U.S.

• Kadcyla

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antibody Drug Conjugate

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant may cause very serious birth defects. Use an effective form of birth control to keep from getting pregnant during treatment and for 7 months after the last dose. There is also a potential for this medicine to cause birth defects if the father is using it when his sexual partner becomes pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

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

This medicine may cause heart failure. Your doctor may test your heart before and during treatment. Contact your doctor right away if you have chest pain, increased coughing, trouble breathing, rapid weight gain, or swelling in your ankles or legs. These could be symptoms of heart failure.

Tell your doctor right away if you are having shortness of breath, chest tightness, or any type of breathing problem while receiving this medicine. These could be symptoms of a serious lung problem.

Ado-trastuzumab emtansine may cause a serious infusion reaction. This can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you have a fever, chills, chest pain, fast or uneven heartbeat, lightheadedness, dizziness, fainting, headache, rash, trouble breathing, or weakness while you receive the medicine or after the infusion.

This medicine 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.

Check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

Talk with your doctor before using this medicine if you plan to have children. Some men and women who use this medicine have become infertile (unable to have children).

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 or vitamin supplements.

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 or nurse immediately if any of the following side effects occur:

• Black, tarry stools
• bladder pain
• bleeding gums
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• burning, numbness, tingling, or painful sensations
• chills
• convulsions
• cough
• decreased urine
• difficult or labored breathing
• difficult, burning, or painful urination
• dizziness
• dry mouth
• fever
• frequent urge to urinate
• headache
• increased thirst
• irregular heartbeat
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea or vomiting
• nervousness
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• rapid weight gain
• slow or fast heartbeat
• sore throat
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• weakness in the arms, hands, legs, or feet

• Chest pain
• dilated neck veins
• extreme fatigue
• general feeling of discomfort or illness
• irregular breathing
• irregular heartbeat
• skin rash
• thickening of bronchial secretions

• Dark-colored urine
• general feeling of tiredness or weakness
• light-colored stools
• stomach bloating or pain
• vomiting blood
• yellow eyes or skin

• Abdominal or stomach tenderness
• itching

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:

• Acid or sour stomach
• belching
• change in taste
• constipation
• diarrhea
• difficulty with moving
• heartburn
• indigestion
• lack or loss of strength
• loss of taste
• muscle pain or stiffness
• pain in the joints
• stomach discomfort or upset
• swelling or inflammation of the mouth
• trouble sleeping

• Burning, dry, or itching eyes
• discharge or excessive tearing
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

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.

Hepatotoxicity

Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with Kadcyla [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with Kadcyla. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.

Monitor serum transaminases and bilirubin prior to initiation of Kadcyla treatment and prior to each Kadcyla dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue Kadcyla as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue Kadcyla treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. Kadcyla has not been studied in patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × ULN prior to the initiation of treatment.

In clinical trials of Kadcyla, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients, one of which was fatal). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, Kadcyla treatment must be permanently discontinued.

Left Ventricular Dysfunction

Patients treated with Kadcyla are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with Kadcyla. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the Kadcyla-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)].

Assess LVEF prior to initiation of Kadcyla and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. Treatment with Kadcyla has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold Kadcyla and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue Kadcyla if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

Embryo-Fetal Toxicity

Kadcyla can cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios, and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed in the postmarketing setting in patients treated with trastuzumab, the antibody component of Kadcyla. DM1, the cytotoxic component of Kadcyla, can cause embryo-fetal toxicity based on its mechanism of action.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Kadcyla. Advise pregnant women and females of reproductive potential that exposure to Kadcyla during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Kadcyla [see Use in Specific Populations (8.1, 8.3)].

Pulmonary Toxicity

Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with Kadcyla. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) has been reported, with one case of grade 3 pneumonitis. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may not occur as sequelae of infusion reactions. In the randomized trial (Study 1), the overall frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)].

Permanently discontinue treatment with Kadcyla in patients diagnosed with ILD or pneumonitis.

Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary toxicity.

Infusion-Related Reactions, Hypersensitivity Reactions

Treatment with Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity; treatment with Kadcyla is not recommended for these patients.

Infusion-related reactions, characterized by one or more of the following symptoms − flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of Kadcyla. In the randomized trial (Study 1), the overall frequency of IRRs in patients treated with Kadcyla was 1.4% [see Adverse Reactions (6.1)]. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. Kadcyla treatment should be interrupted in patients with severe IRR. Kadcyla treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent Kadcyla. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

Hemorrhage

Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been reported in clinical trials with Kadcyla. Some of these bleeding events resulted in fatal outcomes. In the randomized trial (Study 1), the overall frequency of hemorrhage was 32.2% in the Kadcyla-treated group and 16.4% in the lapatinib plus capecitabine-treated group. The incidence of ≥ Grade 3 hemorrhage was 1.8% in the Kadcyla-treated group and 0.8% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Although, in some of the observed cases the patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.

Thrombocytopenia

Thrombocytopenia, or decreased platelet count, was reported in clinical trials of Kadcyla (103 of 884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any Grade). The majority of these patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of Kadcyla, the incidence and severity of thrombocytopenia were higher in Asian patients.

In the randomized trial (Study 1), the overall frequency of thrombocytopenia was 31.2% in the Kadcyla-treated group and 3.3% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the Kadcyla-treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the incidence of > Grade 3 thrombocytopenia was 45.1% in the Kadcyla-treated group and 1.3% in the lapatinib plus capecitabine-treated group.

Monitor platelet counts prior to initiation of Kadcyla and prior to each Kadcyla dose [see Dosage and Administration (2.2)]. Kadcyla has not been studied in patients with platelet counts <100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer Kadcyla until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with Kadcyla.

Neurotoxicity

Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of Kadcyla (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any Grade). In the randomized trial (Study 1), the overall frequency of peripheral neuropathy was 21.2% in the Kadcyla-treated group and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the Kadcyla-treated group and 0.2% in the lapatinib plus capecitabine-treated group.

Kadcyla should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)].

HER2 Testing

Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for Kadcyla therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC.

Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub- optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Extravasation

In Kadcyla clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for Kadcyla extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

No formal drug-drug interaction studies with Kadcyla have been conducted. In vitro studies indicate that DM1, the cytotoxic component of Kadcyla, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with Kadcyla should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying Kadcyla treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and Kadcyla treatment cannot be delayed, patients should be closely monitored for adverse reactions.

NDC 50242-088-01

Kadcyla®
(ado-trastuzumab
emtansine)
For Injection

100 mg per vial

For Intravenous Infusion Only
Reconstitute and Dilute prior
to administration
Single-Dose Vial –
Discard Unused Portion

KEEP REFRIGERATED

Rx only

1 vial

Genentech

10165748

Usual Adult Dose for Breast Cancer:

Usual dose: 3.6 mg/kg IV every 3 weeks

Maximum dose: 3.6 mg/kg IV every 3 weeks

Duration of therapy: Until disease progression or unacceptable toxicity

Comments: Administer the first infusion over 90 minutes. Subsequent infusions may be administered over 30 minutes as tolerated.

Do not substitute ado-trastuzumab emtansine for or with trastuzumab.

Applies to ado-trastuzumab emtansine: intravenous powder for solution

Along with its needed effects, ado-trastuzumab emtansine (the active ingredient contained in Kadcyla) 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 or nurse immediately if any of the following side effects occur while taking ado-trastuzumab emtansine:

• Black, tarry stools
• bladder pain
• bleeding gums
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• burning, numbness, tingling, or painful sensations
• chills
• convulsions
• cough
• decreased urine
• difficult or labored breathing
• difficult, burning, or painful urination
• dizziness
• dry mouth
• fever
• frequent urge to urinate
• headache
• increased thirst
• irregular heartbeat
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea or vomiting
• nervousness
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• rapid weight gain
• slow or fast heartbeat
• sore throat
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• weakness in the arms, hands, legs, or feet

• Chest pain
• dilated neck veins
• extreme fatigue
• general feeling of discomfort or illness
• irregular breathing
• irregular heartbeat
• skin rash
• thickening of bronchial secretions

• Dark-colored urine
• general feeling of tiredness or weakness
• light-colored stools
• stomach bloating or pain
• vomiting blood
• yellow eyes or skin

• Abdominal or stomach tenderness
• itching

Some side effects of ado-trastuzumab emtansine 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:

• Acid or sour stomach
• belching
• change in taste
• constipation
• diarrhea
• difficulty with moving
• heartburn
• indigestion
• lack or loss of strength
• loss of taste
• muscle pain or stiffness
• pain in the joints
• stomach discomfort or upset
• swelling or inflammation of the mouth
• trouble sleeping

• Burning, dry, or itching eyes
• discharge or excessive tearing
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid