Saizen

You should not use this medicine if you are allergic to somatropin or benzyl alcohol, or if you have:

• a serious illness due to lung failure or complications from recent surgery, injury, or medical trauma;

• cancer;

• eye problems caused by diabetes (diabetic retinopathy); or

• if you are being treated for Prader-Willi syndrome and you are overweight or have severe breathing problems (including sleep apnea).

To make sure somatropin is safe for you, tell your doctor if you have:

• diabetes;

• a pituitary gland disorder;

• abnormal curvature of the spine (scoliosis);

• underactive thyroid;

• history of head injury or brain tumor; or

• a history of childhood brain cancer and radiation treatment.

Some brands of somatropin are not expected to harm an unborn baby, including Genotropin, Omnitrope, Saizen, Serostim, and Zorbtive.

It is not known whether certain other brands of somatropin will harm an unborn baby, including Humatrope, Norditropin, Nutropin, and Tev-tropin.

Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether somatropin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

The following important adverse reactions are also described elsewhere in the labeling:

• Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]
• Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)]
• Neoplasms [see Warnings and Precautions (5.3)]
• Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]
• Intracranial hypertension [see Warnings and Precautions (5.5)]
• Severe hypersensitivity [see Warnings and Precautions (5.6)]
• Fluid retention [see Warnings and Precautions (5.7)]
• Hypoadrenalism [see Warnings and Precautions (5.8)
• Hypothyroidism [see Warnings and Precautions (5.9)]
• Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)]
• Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)]
• Lipoatrophy [see Warnings and Precautions (5.13)]
• Pancreatitis [see Warnings and Precautions (5.15)]
• Benzyl alcohol [see Warnings and Precautions (5.16)]

Clinical Trials Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.

Growth Hormone Deficient Pediatric Patients

In clinical studies in which Saizen was administered to growth hormone deficient children, the following reactions were infrequently seen: local reactions at the injection site (such as pain, numbness, redness and swelling), hypothyroidism, hypoglycemia, seizures, exacerbation of preexisting psoriasis and disturbances in fluid balance.

Growth Hormone Deficient Adult Patients

For a description of the clinical trials refer to section 14. During the 6-month placebo-controlled study, adverse reactions were reported in 56 patients (93.3%) in the somatropin-treated group and 42 patients (76.4%) in the placebo-treated group. Adverse reactions with an incidence of ≥5% in Saizen-treated patients which were more frequent in Saizen-treated patients compared with placebo-treated patients are listed in Table 1. Arthralgia, myalgia, peripheral edema, other types of edema, carpal tunnel syndrome, paraesthesia and hypoaesthesia were common in the somatropin-treated patients and reported more frequently than in the placebo group. These types of adverse reactions are thought to be related to the fluid accumulating effects of somatropin. During the placebo-controlled portion of the study, approximately 10% of patients without preexisting diabetes mellitus or impaired glucose tolerance treated with somatropin manifested mild, but persistent, abnormalities of glucose tolerance, compared with none in the placebo group. During the open label phase of the study, approximately 10% of patients treated with somatropin required a small upward adjustment of thyroid hormone replacement therapy for preexisting central hypothyroidism and 1 patient was newly diagnosed with central hypothyroidism. In addition, during the open label phase of the study, when all patients were being treated with somatropin, two patients with preexisting central hypoadrenalism required upward titration of hydrocortisone maintenance therapy which was considered to be suboptimal (unrelated to intercurrent stress, surgery or disease), and 1 patient was diagnosed de novo with central adrenal insufficiency after six months of somatropin treatment. Anti-GH antibodies were not detected.

The adverse reaction pattern observed during the open label phase of the study was similar to the one presented above.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Saizen with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Saizen. 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.

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [See Warnings and Precautions (5.6)].

Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data fail to confirm the hypothesis of a relationship between growth hormone therapy and leukemia.

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) (see Warnings and Precautions [5.14]).

Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)

The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1 [see Warnings and Precautions (5.8)].

Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment

Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.

Cytochrome P450-Metabolized Drugs

Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450) mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.

Oral Estrogen

Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.2)].

Insulin and/or Oral/Injectable Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].

Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 31 and 62 times, respectively, the human (child) weekly dose based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Saizen. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Saizen is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Saizen is administered to a nursing woman.

Geriatric Use

The safety and effectiveness of Saizen in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of Saizen, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.2)].

Hepatic Impairment

A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. However, no studies have been conducted for Saizen in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Renal Impairment

Subjects with chronic renal failure tend to have decreased clearance of somatropin compared to those with normal renal function. However, no studies have been conducted for Saizen in patients with renal impairment [see Clinical Pharmacology (12.3)].

Gender Effect

In adults, the clearance of somatropin in both men and women tends to be similar. No gender studies have been performed in children.

Mechanism of Action

Somatropin (as well as endogenous growth hormone) binds to dimeric growth hormone receptors located within the cell membranes of target tissue cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by IGF-1 produced in the liver and also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (e.g., lipolysis) [see Pharmacodynamics (12.2)].

Pharmacodynamics

Tissue Growth

Skeletal Growth: Saizen stimulates skeletal growth in prepubertal children with pituitary growth hormone deficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends of long bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by growth hormone and one of its mediators, insulin-like growth factor-1. Serum levels of insulin-like growth factor-1 (IGF-1) are low in children and adolescents who are growth hormone deficient, but increase during treatment with Saizen. Linear growth continues until the growth plates fuse at the end of puberty.

Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells.

Organ Growth: Somatropin influences the size and function of internal organs and increases red cell mass.

Protein Metabolism

Linear growth is facilitated in part by increased cellular protein synthesis. This is reflected by increased cellular uptake of amino acids and nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during somatropin therapy.

Carbohydrate Metabolism

Somatropin is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. Saizen therapy may decrease glucose tolerance. Administration of Saizen to normal adults and patients with growth hormone deficiency resulted in transient increases in mean serum fasting and postprandial insulin levels. However, glucose levels remained in the normal range.

Lipid Metabolism

Acute administration of somatropin to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within one hour of Saizen administration. In growth hormone deficient patients, long-term somatropin administration often decreases body fat. Mean cholesterol levels decreased in patients treated with Saizen. The clinical significance of this decrease in cholesterol level is unknown.

Mineral Metabolism

Somatropin administration results in the retention of total body potassium, phosphorus, and sodium. Serum calcium levels appear to be unaffected.

Connective Tissue/Bone Metabolism

Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

Pharmacokinetics

Absorption - The absolute bioavailability of somatropin after subcutaneous administration ranges between 70 to 90%.

Distribution - The steady-state volume of distribution (mean ±SD) of somatropin following intravenous administration in healthy volunteers was estimated to be 12.0 ± 1.08 L.

Metabolism - The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation. The mean half-life of intravenous somatropin in normal males is around 0.6 hours, whereas subcutaneously and intramuscularly administered somatropin has a half-life of around 2 hours. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.

Excretion - The clearance (mean ±SD) of intravenously administered somatropin in six normal male volunteers was 14.6 ± 2.8 L/hr.

Specific Populations

Pediatric - The pharmacokinetics of somatropin is similar in children and adults. However, no pharmacokinetic studies of Saizen have been conducted in pediatric patients.

Gender - No gender studies have been performed in children for somatropin. In adults, the clearance of somatropin in both men and women tends to be similar. However, no studies have been conducted to evaluate the effect of gender on pharmacokinetics of Saizen.

Race - No studies have been conducted to determine the effect of race on the pharmacokinetics of Saizen.

Renal Impairment- Children and adults with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of Saizen.

Hepatic Impairment - A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls.

How Supplied

Saizen can be administered using (1) a standard sterile disposable syringe and needle, (2) a compatible Saizen needle-free injection device or (3) a compatible Saizen needle injection device. For proper use, refer to the Instructions for Use provided with the administration device.

Saizen is a sterile, non pyrogenic, white, lyophilized powder supplied in packages containing:

1 vial of 5 mg Saizen and 1 vial of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) NDC 44087-1005-2

1 vial of 8.8 mg Saizen and 1 vial of Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) NDC 44087-1088-1

1 click.easy® cartridge of 8.8 mg Saizen and 1.51 mL Sterile Water for Injection 0.3% (w/v) metacresol as a antimicrobial preservative NDC 44087-1080-1

1 Saizenprep® cartridge of 8.8 mg Saizen and 1.51 mL Sterile Water for Injection 0.3% (w/v) metacresol as antimicrobial preservative NDC 44087-0016-1

Storage and Handling

Before Reconstitution - Saizen should be stored at room temperature (15°-30°C/59°-86°F). Expiration dates are stated on the labels.

After Reconstitution - Saizen 5 mg and 8.8 mg vials reconstituted with the Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) provided should be stored under refrigeration (2°–8°C/36°–46°F) for up to 14 days.

Saizen 8.8 mg click.easy® cartridge reconstituted with the Sterile Water for Injection, 0.3% (w/v) metacresol provided should be stored under refrigeration (2°–8°C/36°–46°F) for up to 21 days.

Saizen 8.8 mg Saizenprep® cartridge reconstituted with the Sterile Water for Injection, 0.3% (w/v) metacresol provided should be stored under refrigeration (2°-8°C/36°-46°F) for up to 21 days.

Avoid freezing reconstituted vials or cartridges of Saizen.

COMPOSITION

Each vial of Saizen 8.8 mg contained in the 5.83 mg/mL click.easy® device contains the following ingredients:

• Active substance: Somatropin (Recombinant Human Growth Hormone) 8.8 mg.
• Excipients: Sucrose, Phosphoric acid, Sodium Hydroxide; 1 mL of the reconstituted Saizen solution contains 5.83 mg of somatropin when reconstituted with the contents of the diluent cartridge.

COMPOSITION OF DILUENT

Each cartridge of diluent contained in the click.easy® reconstitution device contains the following ingredients:

5.83 mg/mL click.easy®

Active substance: Metacresol USP (4.52 mg),

Excipients: Phosphoric acid 85% to adjust pH, Water for Injection, USP (1.51 mL)

Patients with a known sensitivity to any of the above active substances or excipients should avoid using this product.

PHARMACEUTICAL FORM

Powder and diluent for solution for injection: Powder and diluent (0.3% (w/v) metacresol in water for injection) for parenteral use.

METHOD AND ROUTE OF ADMINISTRATION

The product (powder in vials) must be reconstituted with the enclosed diluent (0.3% (w/v) metacresol in water for injection) using the click.easy® reconstitution device.

The reconstituted solution is intended for subcutaneous administration (under the skin) and should be clear with no particles. If the solution contains particles, it must not be injected.

IMPORTANT INFORMATION

Patients should be thoroughly instructed in the reconstitution procedure.

For young children, the reconstitution process should be supervised by an adult.

For administration of Saizen 8.8 mg contained in the click.easy® device, please read the following instructions carefully. Please consult your doctor, nurse or pharmacist if you have any questions concerning the reconstitution process.

Check that the click.easy® reconstitution device contains an unused Saizen vial (a) and an unused diluent cartridge (c).

Do NOT use the device if the vial or cartridge appear empty or used and return it to your pharmacist or doctor.

Wash your hands with soap and water.

HOW TO PREPARE YOUR SOLUTION OF Saizen®

1. Place the click.easy® device vertically on a clean flat surface with the Saizen vial on the bottom and the diluent cartridge outer housing cap (g) on top facing upward.
2. Push on the top diluent cartridge outer housing cap (g) firmly until the Saizen vial outer housing (h) is completely inside the main body. This step breaks the tamper evident seal on the vial.
3. Turn the diluent cartridge outer housing cap (g) clockwise until the green square (f) is visible at the lower end of the narrow rectangular opening. Push the diluent cartridge outer housing cap down very slowly until it will go no further and the green colored square appears at the upper end of the narrow rectangular opening.
4. Check that all the diluent has been transferred into the vial. Dissolve the Saizen powder with the diluent by gently swirling the click.easy® device (Note: Do not transfer the diluent forcefully or shake the click.easy® device. A fast transfer of the diluent or shaking of the click.easy® device will create more foam). Let the solution stand for 2-5 minutes until the Saizen powder is completely dissolved.
5. Turn the click.easy® device upside down so the Saizen vial is now on top and pull the diluent cartridge outer housing cap slowly downwards until the solution is completely drawn back into the cartridge. Check that no more than one or two drops of solution remain in the vial.
6. If there are more than one or two drops of solution remaining in the vial, slowly push the diluent cartridge outer housing cap up until some of the solution is back in the vial and gently tap the click.easy® device. Then draw the solution slowly again back into the cartridge.
7. Remove any excess air that has been drawn into the cartridge by slowly pushing the cap up until no air bubble is visible in the cartridge. There should be no air bubble in the cartridge (Note: Avoid pulling the cap down too fast, as this will draw air into the cartridge).
8. Turn the click.easy® device so that the cap is again on the top. Unscrew the cap and remove it.
9. Remove the cartridge containing the reconstituted Saizen solution from the click.easy® device by grasping the end of the cartridge and pulling straight out of the outer housing.
10. Carefully peel off the outer white label on the cartridge using the tab provided by slowly pulling in the direction of the black arrow.
    
11. Write the reconstitution date on the transparent inner label on the cartridge. This cartridge now contains the reconstituted Saizen solution that will be used for your treatment.
    
12. The cartridge containing the reconstituted Saizen solution is now ready to be used (Note: Please read the instruction manual provided with the injection device for instruction on how to inject the reconstituted Saizen solution from the cartridge).
13. The Saizen reconstituted solution should be stored in a refrigerator (2°-8°C / 36°-46°F) and should be used within 21 days after reconstitution. Do not freeze.
14. Discard the click.easy® device containing the empty Saizen vial safely in accordance with your local requirements. It is not necessary to remove the empty Saizen vial from the click.easy® device prior to disposal.
15. Injections should be given in different parts of your body. Do not use any areas in which you feel lumps, firm knots, depressions, or pain; talk to your doctor or healthcare professional about anything you find. Clean the skin at the injection site with soap and water.

STABILITY AND STORAGE

Vials of Saizen 8.8 mg pre-assembled in the click.easy® reconstitution device should be stored in the original package at room temperature (15°-30°C / 59°-86°F).

Saizen 8.8 mg reconstituted solution should be stored in a refrigerator (2°-8°C / 36°-46°F) and should be used within 21 days after reconstitution.

Do not freeze.

HOW SUPPLIED

Saizen 8.8 mg contained in the click.easy® device is available in the following pack sizes:

1 vial of Saizen 8.8 mg product and 1 cartridge of 1.51 mL diluent pre-assembled in 1 reconstitution device (click.easy®) comprising 1 device housing and 1 sterile transfer cannula
NDC 44087-1080-1

Manufactured for:
EMD Serono Inc., Rockland, MA 02370

Saizen® 5 mg
(somatropin) for injection

NDC 44087-1005-2

5 mg
For subcutaneous injection
Rx Only

1 vial Saizen
1 vial Bacteriostatic Water for
Injection, USP (0.9% Benzyl Alcohol)

EMD Serono

Applies to somatropin: powder for solution

Other dosage forms:

• powder for solution, solution

Along with its needed effects, somatropin (the active ingredient contained in Saizen) 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 somatropin:

• Abnormal or decreased touch sensation
• bleeding after defecation
• bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• bloating or swelling of the face, arms, hands, lower legs, or feet
• blood in the urine
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• changes in skin color
• cold flu-like symptoms
• cold hands and feet
• confusion
• constipation
• cough or hoarseness
• darkened urine
• decreased urination
• diarrhea
• difficult urination
• dizziness
• dry mouth
• fainting or loss of consciousness
• fast heartbeat
• fast or irregular breathing
• feeling unusually cold
• fever or chills
• full or bloated feeling
• general feeling of discomfort or illness
• headache
• increase in heart rate
• itching or skin rash
• joint pain
• light-colored stools
• lightheadedness
• loss of appetite
• lower back or side pain
• muscle aching or cramping
• muscle pain or stiffness
• nausea
• pain
• pain, redness, or swelling in the arm or leg
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pressure in the stomach
• rapid, shallow breathing
• rapid weight gain
• rectal bleeding
• runny nose
• shivering
• sneezing
• sore mouth or tongue
• sore throat
• stomach bloating, burning, cramping, or pain
• sudden decrease in the amount of urine
• sweating
• swelling of the abdominal or stomach area
• swelling of the eyes or eyelids
• swelling or puffiness of the face
• swollen joints
• thirst
• tightness in the chest
• tingling of the hands or feet
• trouble breathing
• trouble sleeping
• uncomfortable swelling around the anus
• unpleasant breath odor
• unusual tiredness or weakness
• unusual weight gain or loss
• vomiting
• vomiting of blood
• white patches in the mouth, tongue, or throat
• wrinkled skin
• yellow eyes or skin

• Bone or skeletal pain
• burning, numbness, pain, or tingling in all fingers except smallest finger
• chest pain
• depressed mood
• dry skin and hair
• feeling cold
• hair loss
• hoarseness or husky voice
• slowed heartbeat
• swelling of the ankles

Get emergency help immediately if any of the following symptoms of overdose occur while taking somatropin:

• Anxiety
• blurred vision
• changes in vision
• cold sweats
• coma
• cool, pale skin
• decrease in the amount of urine
• depression
• excessive sweating
• extreme weakness
• flushed, dry skin
• frequent urination
• fruit-like breath odor
• increase in hands and feet size
• increased hunger
• increased thirst
• increased urination
• increased volume of pale, diluted urine
• nightmares
• noisy, rattling breathing
• pain in the arms or legs
• seizures
• shakiness
• slurred speech
• stop in menstruation
• swelling of the fingers or hands
• troubled breathing at rest

Some side effects of somatropin 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:

• Body aches or pain
• breast pain
• change in the color, amount, or odor of vaginal discharge
• congestion
• discoloration of the fingernails or toenails
• dryness or soreness of the throat
• excess air or gas in the stomach or intestines
• frequent urge to defecate
• increased sweating
• passing gas
• sneezing
• straining while passing stool
• stuffy nose
• tender, swollen glands in neck
• trouble with swallowing
• voice changes

• Discouragement
• feeling sad or empty
• irritability
• lack of appetite
• loss of interest or pleasure
• tiredness
• trouble concentrating